FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Lau, EF Burns, S Gramfort, A Delaney-Busch, N Fields, E Fanucci, K Holcomb, P Kuperberg, G AF Lau, Ellen F. Burns, Scott Gramfort, Alexandre Delaney-Busch, Nate Fields, Eric Fanucci, Kristina Holcomb, Phillip Kuperberg, Gina TI USING MULTIMODAL IMAGING TO DISTINGUISH ACTIVE PREDICTION FROM PASSIVE PRIMING SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res DE semantic; language; MEG C1 [Lau, Ellen F.; Burns, Scott; Gramfort, Alexandre; Kuperberg, Gina] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lau, Ellen F.; Burns, Scott; Delaney-Busch, Nate; Fields, Eric; Fanucci, Kristina; Holcomb, Phillip; Kuperberg, Gina] Tufts Univ, Medford, MA 02155 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S104 EP S105 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200584 ER PT J AU Lee, DJ Rosebrock, LE Marino-Carper, T Arditte, KA Sloan, DM Kamholz, BW Liverant, GI AF Lee, Daniel J. Rosebrock, Laina E. Marino-Carper, Teresa Arditte, Kimberly A. Sloan, Denise M. Kamholz, Barbara W. Liverant, Gabrielle I. TI ASSOCIATION BETWEEN RESTING RESPIRATORY SINUS ARRHYTHMIA (RSA) AND USE OF THOUGHT SUPPRESSION AMONG VETERANS WITH UNIPOLAR DEPRESSION SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res DE respiratory sinus arrhythmia; emotion regulation; depression C1 [Rosebrock, Laina E.; Marino-Carper, Teresa; Kamholz, Barbara W.; Liverant, Gabrielle I.] VA Boston Healthcare Syst, Boston, MA USA. [Arditte, Kimberly A.] Univ Miami, Coral Gables, FL 33124 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S60 EP S61 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200337 ER PT J AU Liu, TS Zhao, ZX McCarley, RW Niznikiewicz, MA AF Liu, Taosheng Zhao, Zhongxin McCarley, Robert W. Niznikiewicz, Margaret A. TI THE INFLUENCE OF EMOTION ON AUDIOVISUAL INTEGRATION OF FACE AND VOICE SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res DE audiovisual integration; emotion C1 [Liu, Taosheng; McCarley, Robert W.; Niznikiewicz, Margaret A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Liu, Taosheng; Zhao, Zhongxin] Second Mil Med Univ, Shanghai, Peoples R China. [McCarley, Robert W.; Niznikiewicz, Margaret A.] VA Boston Healthcare Syst, Boston, MA 02132 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S100 EP S100 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200558 ER PT J AU Spencer, KM Mears, RP AF Spencer, Kevin M. Mears, Ryan P. TI ELECTROPHYSIOLOGICAL MEASURES OF AUDITORY NEUROPLASTICITY IN SCHIZOPHRENIA SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res C1 [Spencer, Kevin M.; Mears, Ryan P.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S10 EP S11 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200056 ER PT J AU Webb, AK Traviglia, DF Wendelken, SM Pollack, MH AF Webb, Andrea K. Traviglia, Daniel F. Wendelken, Suzanne M. Pollack, Mark H. TI SENSOR TECHNOLOGY IN THE ASSESSMENT OF POST TRAUMATIC STRESS DISORDER SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res DE PTSD; emotion C1 [Pollack, Mark H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S59 EP S59 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200328 ER PT J AU Wittenberg, E Paczynski, M Wiese, H Jackendoff, R Kuperberg, G AF Wittenberg, Eva Paczynski, Martin Wiese, Heike Jackendoff, Ray Kuperberg, Gina TI LIGHT VERBS MAKE HEAVY WORK SO PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 51st Annual Meeting of the Society-of-Psychophysiological-Research CY SEP 14-18, 2011 CL Boston, MA SP Soc Psychophysiol Res DE sustained negativity; argument structure; language erp C1 [Wittenberg, Eva] Univ Potsdam, Tufts Univ, Potsdam, Germany. [Wiese, Heike] Tufts Univ, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Medford, MA 02155 USA. [Wiese, Heike] Univ Potsdam, Potsdam, Germany. [Kuperberg, Gina] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2011 VL 48 SU 1 SI SI BP S105 EP S105 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 800TE UT WOS:000293389200585 ER PT J AU Nechuta, SJ Caan, BJ Chen, WY Flatt, SW Lu, W Patterson, RE Poole, EM Kwan, ML Chen, Z Weltzien, E Pierce, JP Shu, XO AF Nechuta, Sarah J. Caan, Bette J. Chen, Wendy Y. Flatt, Shirley W. Lu, Wei Patterson, Ruth E. Poole, Elizabeth M. Kwan, Marilyn L. Chen, Zhi Weltzien, Erin Pierce, John P. Shu, Xiao Ou TI The After Breast Cancer Pooling Project: rationale, methodology, and breast cancer survivor characteristics SO CANCER CAUSES & CONTROL LA English DT Article DE Breast neoplasm; Survival; Recurrence; Lifestyle ID FOOD FREQUENCY QUESTIONNAIRE; BODY-MASS INDEX; PHYSICAL-ACTIVITY; LIFE-STYLE; CLINICAL-TRIALS; HEALTH SURVEY; WOMEN; RECURRENCE; DIET; PROGNOSIS AB The After Breast Cancer Pooling Project was established to examine the role of physical activity, adiposity, dietary factors, supplement use, and quality of life (QOL) in breast cancer prognosis. This paper presents pooled and harmonized data on post-diagnosis lifestyle factors, clinical prognostic factors, and breast cancer outcomes from four prospective cohorts of breast cancer survivors (three US-based and one from Shanghai, China) for 18,314 invasive breast cancer cases diagnosed between 1976 and 2006. Most participants were diagnosed with stage I-II breast cancer (84.7%). About 60% of breast tumors were estrogen receptor (ER)+/progesterone receptor (PR)+; 21% were ER-/PR-. Among 8,118 participants with information on HER-2 tumor status, 74.8% were HER-2- and 18.5% were HER-2+. At 1-2 years post-diagnosis (on average), 17.9% of participants were obese (BMI a parts per thousand yen 30 kg/m(2)), 32.6% were overweight (BMI 25-29 kg/m(2)), and 59.9% met the 2008 Physical Activity Guidelines for Americans (a parts per thousand yen2.5 h per week of moderate activity). During follow-up (mean = 8.4 years), 3,736 deaths (2,614 from breast cancer) and 3,564 recurrences have been documented. After accounting for differences in year of diagnosis and timing of post-diagnosis enrollment, five-year overall survival estimates were similar across cohorts. This pooling project of 18,000 breast cancer survivors enables the evaluation of associations of post-diagnosis lifestyle factors, QOL, and breast cancer outcomes with an adequate sample size for investigation of heterogeneity by hormone receptor status and other clinical predictors. The project sets the stage for international collaborations for the investigation of modifiable predictors for breast cancer outcomes. C1 [Shu, Xiao Ou] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, IMPH, Nashville, TN 37203 USA. [Nechuta, Sarah J.; Chen, Wendy Y.; Shu, Xiao Ou] Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol, Nashville, TN 37203 USA. [Caan, Bette J.; Kwan, Marilyn L.; Weltzien, Erin] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Chen, Wendy Y.; Poole, Elizabeth M.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Chen, Wendy Y.; Poole, Elizabeth M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Flatt, Shirley W.; Patterson, Ruth E.; Pierce, John P.] Univ Calif San Diego, Canc Prevent & Control Program, Moores UCSD Canc Ctr, La Jolla, CA 92093 USA. [Lu, Wei] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai 200336, Peoples R China. RP Shu, XO (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, IMPH, 2525 W End Ave,Suite 600, Nashville, TN 37203 USA. EM Xiao-ou.shu@vanderbilt.edu FU National Cancer Institute [3R01CA118229-03S1, R01 CA118229]; SBCSS (Department of Defense, DAMD) [17-02-1-0607]; WHEL (Susan G. Komen Foundation) [KG100988]; LACE (National Cancer Institute) [R01 CA129059]; NHS [P01 CA87969] FX This study was supported by the National Cancer Institute (Grant number 3R01CA118229-03S1). The parent grants for each individual cohort included in the After Breast Cancer Pooling Project are as follows: SBCSS (Department of Defense, DAMD 17-02-1-0607 and National Cancer Institute, R01 CA118229), WHEL (Susan G. Komen Foundation, #KG100988), LACE (National Cancer Institute, R01 CA129059), and NHS (P01 CA87969). NR 51 TC 17 Z9 17 U1 2 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2011 VL 22 IS 9 BP 1319 EP 1331 DI 10.1007/s10552-011-9805-9 PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 799OO UT WOS:000293296200010 PM 21710192 ER PT J AU Brasky, TM Lampe, JW Slatore, CG White, E AF Brasky, Theodore M. Lampe, Johanna W. Slatore, Christopher G. White, Emily TI Use of glucosamine and chondroitin and lung cancer risk in the VITamins And Lifestyle (VITAL) cohort SO CANCER CAUSES & CONTROL LA English DT Article DE Adenocarcinoma; Chondroitin; Glucosamine; Non-small-cell lung cancer; Small-cell lung cancer; Supplement ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; LOW-DOSE ASPIRIN; KNEE OSTEOARTHRITIS; WOMENS HEALTH; SULFATE; CHEMOPREVENTION; RECOMMENDATIONS; INFLAMMATION; METAANALYSIS; SUPPLEMENTS AB Inflammation plays an important role in lung carcinogenesis. Epidemiologic studies have reported inverse associations of non-steroidal anti-inflammatory drug (NSAID) use and lung cancer risk. Previously, we found that ever use of glucosamine and chondroitin, which have anti-inflammatory properties, were inversely associated with lung cancer risk. After an additional year of follow-up, we further examined the association including frequency/duration of use, interaction with factors associated with inflammation, and lung cancer histology. Participants were members of the VITamins And Lifestyle cohort. Adults, aged 50-76 years, who were residents of western Washington State, completed a baseline questionnaire in 2000-2002 (n = 76,904). Participants were queried on their use of glucosamine and chondroitin, over the 10 years prior to baseline, and categorized as nonuser, low use < 4 days/week or < 3 years, or high use a parts per thousand yen4 days/week and a parts per thousand yen3 years. Lung cancer cases (n = 808) were ascertained through linkage to the Surveillance, Epidemiology, and End Results cancer registry. High 10-year use of glucosamine [hazard ratio (HR), 0.77; 95% CI: 0.56-1.07; p trend = 0.04] but not chondroitin was associated with a reduction in lung cancer risk. The association with glucosamine was limited to adenocarcinoma (HR, 0.49; 95% CI: 0.27-0.90; p trend < 0.01) and was not modified by NSAID use or smoking status. Our results for glucosamine use are similar to the prior human studies of NSAID use and lung cancer, both in magnitude and the limitation of the association to adenocarcinoma. Unlike NSAIDs, glucosamine has no known adverse effects. Although confirmatory studies are needed, glucosamine is an attractive candidate for lung cancer chemoprevention. C1 [Brasky, Theodore M.; Lampe, Johanna W.; White, Emily] Fred Hutchinson Canc Res Ctr, Canc Prevent Unit, Seattle, WA 98109 USA. [Brasky, Theodore M.; Lampe, Johanna W.; White, Emily] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Slatore, Christopher G.] Portland VA Med Ctr, Portland, OR USA. [Slatore, Christopher G.] Oregon Hlth & Sci Univ, Dept Pulm & Crit Care Med, Portland, OR 97201 USA. RP Brasky, TM (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Unit, 1100 Fairview Ave N,M4-B402, Seattle, WA 98109 USA. EM tbrasky@fhcrc.org OI Slatore, Christopher/0000-0003-0958-8122 FU National Institutes of Health, National Cancer Institute [R25-CA94880, R01-CA142545, K05-CA154337] FX This work is supported in part by grants R25-CA94880, R01-CA142545, and K05-CA154337 from the National Institutes of Health, National Cancer Institute. Dr. Slatore's work on this project was supported with resources and the use of facilities at the Portland VA Medical Center. NR 39 TC 8 Z9 9 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2011 VL 22 IS 9 BP 1333 EP 1342 DI 10.1007/s10552-011-9806-8 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 799OO UT WOS:000293296200011 PM 21706174 ER PT J AU Emmons, KM Cleghorn, D Tellez, T Greaney, ML Sprunck, KM Bastani, R Battaglia, T Michaelson, JS Puleo, E AF Emmons, Karen M. Cleghorn, Dean Tellez, Trinidad Greaney, Mary L. Sprunck, Kim M. Bastani, Roshan Battaglia, Tracy Michaelson, James S. Puleo, Elaine TI Prevalence and implications of multiple cancer screening needs among Hispanic community health center patients SO CANCER CAUSES & CONTROL LA English DT Article DE Cancer screening; Low income; Community health centers ID UNITED-STATES; INFORMATION-TECHNOLOGY; ETHNIC DISPARITIES; INTERVIEW SURVEY; WOMEN; CARE; INTERVENTIONS; MEN; LANGUAGE; PROGRESS AB To examine adherence rates for multiple cancer screening tests, which will inform prevention efforts in community health centers (CHCs). We report on the prevalence of screening for multiple cancers (cervical, breast and colorectal) among 43,000 patients who are predominantly Hispanic, in four CHC sites that share an integrated electronic medical record. Among the 20,057 patients eligible for at least one test, 43% of the population was current on all screening targets; 15,887 additional screening tests were needed among 11,526 individuals. Expanding use of health information technology in community health centers provides an opportunity to create an electronic infrastructure for addressing multiple screening needs from a patient-centered perspective. C1 [Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Cleghorn, Dean; Tellez, Trinidad] Greater Lawrence Family Hlth Ctr, Lawrence, MA USA. [Greaney, Mary L.; Sprunck, Kim M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bastani, Roshan] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. [Battaglia, Tracy] Boston Med Ctr, Evans Dept Med, Gen Internal Med Sect, Womens Hlth Unit, Boston, MA USA. [Battaglia, Tracy] Boston Univ, Sch Med, Womens Hlth Interdisciplinary Res Ctr, Boston, MA 02118 USA. [Battaglia, Tracy] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Michaelson, James S.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Michaelson, James S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Puleo, Elaine] Univ Massachusetts, Sch Publ Hlth, Dept Publ Hlth, Amherst, MA 01003 USA. RP Emmons, KM (reprint author), Harvard Univ, Sch Publ Hlth, 44 Binney St,LW703, Boston, MA 02115 USA. EM karen_m_emmons@dfci.harvard.edu OI Battaglia, Tracy/0000-0001-8475-1212 FU National Cancer Institute [5R01CA126596, 1K05 CA124415] FX This study was supported by grants from the National Cancer Institute, 5R01CA126596 and 1K05 CA124415. The authors would like to acknowledge Nancy Klockson for participation in the manuscript preparation, and the clinical staff at Greater Lawrence Community Health Center for their support of this project. NR 38 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2011 VL 22 IS 9 BP 1343 EP 1349 DI 10.1007/s10552-011-9807-7 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 799OO UT WOS:000293296200012 PM 21728056 ER PT J AU Waldinger, RJ Kensinger, EA Schulz, MS AF Waldinger, Robert J. Kensinger, Elizabeth A. Schulz, Marc S. TI Neural activity, neural connectivity, and the processing of emotionally valenced information in older adults: links with life satisfaction SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Aging; Well-being; Life satisfaction; Neural connectivity; Positivity effect ID EVENT-RELATED FMRI; YOUNGER ADULTS; HUMAN AMYGDALA; MEMORY; AGE; HIPPOCAMPUS; PERSPECTIVE; ACTIVATION; SCALE; METAANALYSIS AB This study examines whether differences in late-life well-being are linked to how older adults encode emotionally valenced information. Using fMRI with 39 older adults varying in life satisfaction, we examined how viewing positive and negative images would affect activation and connectivity of an emotion-processing network. Participants engaged most regions within this network more robustly for positive than for negative images, but within the PFC this effect was moderated by life satisfaction, with individuals higher in satisfaction showing lower levels of activity during the processing of positive images. Participants high in satisfaction showed stronger correlations among network regions-particularly between the amygdala and other emotion processing regions-when viewing positive, as compared with negative, images. Participants low in satisfaction showed no valence effect. Findings suggest that late-life satisfaction is linked with how emotion-processing regions are engaged and connected during processing of valenced information. This first demonstration of a link between neural recruitment and late-life well-being suggests that differences in neural network activation and connectivity may account for the preferential encoding of positive information seen in some older adults. C1 [Waldinger, Robert J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Waldinger, Robert J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kensinger, Elizabeth A.] Boston Coll, Dept Psychol, Chestnut Hill, MA 02167 USA. [Schulz, Marc S.] Bryn Mawr Coll, Dept Psychol, Bryn Mawr, PA 19010 USA. RP Waldinger, RJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM rwaldinger@partners.org FU National Institute on Aging [R01 AG 034554] FX The study was supported by a grant from the National Institute on Aging (R01 AG 034554). NR 57 TC 8 Z9 8 U1 3 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD SEP PY 2011 VL 11 IS 3 BP 426 EP 436 DI 10.3758/s13415-011-0039-9 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 798UW UT WOS:000293238700013 PM 21590504 ER PT J AU Nickerson, A Hinton, DE AF Nickerson, Angela Hinton, Devon E. TI Anger Regulation in Traumatized Cambodian Refugees: The Perspectives of Buddhist Monks SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE Buddhism; Anger regulation; Mindfulness; Traditional healing ID POSTTRAUMATIC-STRESS-DISORDER; GENERALIZED ANXIETY DISORDER; COGNITIVE-BEHAVIOR THERAPY; TREATMENT-RESISTANT PTSD; PANIC-ATTACKS; MINDFULNESS MEDITATION; MENTAL-HEALTH; COMMITMENT THERAPY; CANCER OUTPATIENTS; REDUCTION PROGRAM AB Recent research has highlighted the importance of traditional methods of healing in relation to the treatment of psychological distress in non-Western populations. This pilot study, conducted in Massachusetts, investigates what Buddhist Cambodian monks consider to be the causes, phenomenology and appropriate intervention strategies for anger among Cambodian refugees. Six monks were interviewed at four major temples in Massachusetts. Findings suggested that anger was common in the Cambodian community, was frequently triggered by marital discord, and commonly resulted in verbal and physical violence and, sometimes, suicidality. Buddhist-based anger management strategies identified as useful by the monks included education about Buddhist doctrines, mindfulness meditation practices, and the use of herbal medication and holy water. These anger regulation strategies and treatments are discussed in the context of Buddhist beliefs and Western psychological interventions. C1 [Nickerson, Angela; Hinton, Devon E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nickerson, Angela; Hinton, Devon E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nickerson, Angela] Univ New S Wales, Sch Psychol, Sydney, NSW 2052, Australia. [Hinton, Devon E.] Arbour Counseling Serv, Lowell, MA 01852 USA. RP Nickerson, A (reprint author), Massachusetts Gen Hosp, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM anickerson@psy.unsw.edu.au FU NIMH NIH HHS [5R01MH79032] NR 92 TC 15 Z9 15 U1 3 U2 18 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD SEP PY 2011 VL 35 IS 3 BP 396 EP 416 DI 10.1007/s11013-011-9218-y PG 21 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA 797NS UT WOS:000293135200004 PM 21630119 ER PT J AU Kowalczyk, KJ Huang, AC Hevelone, ND Lipsitz, SR Yu, HY Ulmer, WD Kaplan, JR Patel, S Nguyen, PL Hu, JC AF Kowalczyk, Keith J. Huang, Andy C. Hevelone, Nathanael D. Lipsitz, Stuart R. Yu, Hua-yin Ulmer, William D. Kaplan, Joshua R. Patel, Sunil Nguyen, Paul L. Hu, Jim C. TI Stepwise Approach for Nerve Sparing Without Countertraction During Robot-Assisted Radical Prostatectomy: Technique and Outcomes SO EUROPEAN UROLOGY LA English DT Article DE Robot-assisted surgery; Nerve-sparing radical prostatectomy; Outcomes; Prostate cancer ID LAPAROSCOPIC PROSTATECTOMY; VIDEO DOCUMENTATION; FUNCTIONAL OUTCOMES; ERECTILE FUNCTION; CANCER; PRESERVATION; RECOVERY; TENSION; SUTURE; LIFE AB Background: Although subtle technical variation affects potency preservation during robot-assisted laparoscopic radical prostatectomy (RARP), most prostatectomy studies focus on achieving the optimal anatomic nerve-sparing dissection plane. However, the impact of active assistant/surgeon neurovascular bundle (NVB) countertraction on sexual function outcomes has not been studied or quantified. Objective: To illustrate technique and compare sexual function outcomes for nerve sparing without (NS-0C) versus with (NS-C) assistant and/or surgeon NVB countertraction. Design, setting, and participants: This is a retrospective study of 342 NS-0C versus 268 NS-C RARP procedures performed between August 2008 and February 2011. Surgical procedure: RARP. Measurements: We used the Expanded Prostate Cancer Index Composite (EPIC) sexual function and potency scores, estimated bloodloss (EBL), operative time, and positive surgical margin (PSM). Results and limitations: In unadjusted analysis, men undergoing NS-0C versus NS-C were older, had worse baseline sexual function, higher biopsy and pathologic Gleason grade, and higher preoperative prostate-specific antigen (PSA) levels (all p <= 0.023). However, NS-0C versus NS-C was associated with higher 5-mo sexual function scores (20 vs 10; p < 0.001), and this difference was accentuated for bilateral intrafascial nerve sparing in preoperatively potent men (35.8 vs 16.6; p < 0.001). Similarly, 5-mo potency for preoperatively potent men was better with bilateral intrafascial NS-0C versus NS-C (45.0% vs 28.4%; p = 0.039). However, no difference in sexual function or potency was observed at 12 mo. In adjusted analyses, NS-0C versus NS-C was associated with improved 5-mo sexual function (parameter estimate: 10.90; standard error: 2.16; p < 0.001) and potency (odds ratio: 1.69; 95% confidence interval, 1.01-2.83; p = 0.046). NS-0C versus NS-WC was associated with shorter operative times (p = 0.001) and higher EBL (p = 0.001); however, there were no significant differences in PSM. Limitations include the retrospective, single-surgeon study design and smaller numbers for 12-mo comparison. Conclusions: Reliance on countertraction to facilitate dissecting NVB away from the prostate leads to neuropraxia and delayed recovery of sexual function and potency. Subtle technical modification to dissect the prostate away from the NVB without countertraction enables earlier return of sexual function and potency. (C) 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Kowalczyk, Keith J.; Huang, Andy C.; Yu, Hua-yin; Ulmer, William D.; Kaplan, Joshua R.; Patel, Sunil; Hu, Jim C.] Harvard Univ, Brigham & Womens Faulkner Hosp, Sch Med, Div Urol Surg, Boston, MA 02130 USA. [Hevelone, Nathanael D.; Lipsitz, Stuart R.] Harvard Univ, Brigham & Womens Faulkner Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02130 USA. [Nguyen, Paul L.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dept Radiat Oncol, Boston, MA 02115 USA. RP Hu, JC (reprint author), Harvard Univ, Brigham & Womens Faulkner Hosp, Sch Med, Div Urol Surg, 1153 Ctr St,Suite 4420, Boston, MA 02130 USA. EM jhu2@partners.org OI Hevelone, Nathanael/0000-0003-4740-2085 FU Robert and Kathy Salipante Minimally Invasive Urologic Oncology Fellowship; Taipei City Hospital; New York Academy of Medicine; American Urologic Association Foundation; US Department of Defense [W81XWH-08-1-0283] FX I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr Kowalczyk receives salary support from the Robert and Kathy Salipante Minimally Invasive Urologic Oncology Fellowship; Dr Huang receives salary support from a Taipei City Hospital Research Fellowship; Dr Ulmer receives salary support from the New York Academy of Medicine David E. Rogers Fellowship and the American Urologic Association Foundation Herbert Brendler Summer Medical Student Fellowship Awarded; Dr Yu receives salary support from an American Urological Association Foundation Research Fellowship Award; and Dr Hu receives salary support from US Department of Defense Physician Training Award W81XWH-08-1-0283. NR 31 TC 20 Z9 22 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD SEP PY 2011 VL 60 IS 3 BP 536 EP 547 DI 10.1016/j.eururo.2011.05.001 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 799JN UT WOS:000293283100032 PM 21620561 ER PT J AU Guthrie, CR Kraemer, BC AF Guthrie, Chris R. Kraemer, Brian C. TI Proteasome Inhibition Drives HDAC6-Dependent Recruitment of Tau to Aggresomes SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE HDAC6; Aggresome; Tau; Protein aggregation; Proteasome; Tauopathy ID HELICAL FILAMENT-TAU; ALZHEIMERS-DISEASE; AUTOPHAGIC DEGRADATION; PHOSPHORYLATED TAU; FTDP-17 MUTATIONS; AGGREGATION; PROTEIN; TAUOPATHY; CELLS; MODEL AB Lesions containing aggregated and hyperphosphorylated tau protein are characteristic of neurodegenerative tauopathies. We have developed a cellular model of pathological tau deposition and clearance by overexpressing wild type human tau in HEK293 cells. When proteasome activity is inhibited, HEK293/tau cells accumulate tau protein in structures that bear many of the hallmarks of aggresomes. These include recruitment of tau into large spherical inclusions, accumulation of the retrograde motor protein dynein at the centrosome, formation of an intermediate filament cage around inclusions, and clustering of mitochondria at the aggresome. Tau aggresomes form rapidly and can be cleared upon relief of proteasome inhibition. We observe recruitment of pathological misfolded phospho-tau species to aggresomes. Immunoblotting reveals accumulation of detergent insoluble aggregated tau species. Knockdown of histone deacetylase 6, a protein known to interact with tau, reveals a requirement for HDAC6 activity in tau aggresome formation. Direct observation of the accumulation and clearance of abnormal tau species will allow us to dissect the cellular and molecular mechanisms at work in clearing aggresomal tau and its similarity to disease relevant pathological tau clearance mechanisms. C1 [Kraemer, Brian C.] Seattle Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Guthrie, Chris R.; Kraemer, Brian C.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Kraemer, Brian C.] Univ Washington, Div Gerontol & Geriatr Med, Dept Med, Seattle, WA 98104 USA. RP Kraemer, BC (reprint author), Seattle Vet Affairs Puget Sound Hlth Care Syst, S182 1660 S Columbian Way, Seattle, WA 98108 USA. EM kraemerb@uw.edu FU Department of Veterans Affairs; National Institute of Neurological Disorders and Stroke [R01 NS064131] FX This work was supported by a Department of Veterans Affairs Merit Review Grant (B. C. K.) and by National Institute of Neurological Disorders and Stroke Grant R01 NS064131 (B. C. K.) We thank Pam McMillan for critical reading of the manuscript. We thank the anonymous reviewers for their critical reviews and advice which helped improve this manuscript. We thank Elaine Loomis and Susan Danner for outstanding technical assistance. We thank Peter Davies, Virginia Lee, and Peter Seubert for tau antibodies and the Developmental Studies Hybridoma Bank (NICHD) for the beta-tubulin antibody E7. NR 43 TC 17 Z9 19 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD SEP PY 2011 VL 45 IS 1 BP 32 EP 41 DI 10.1007/s12031-011-9502-x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 798GT UT WOS:000293191300005 PM 21340680 ER PT J AU Gros, DF AF Gros, Daniel F. TI Startle Inhibition to Positive-Activated Compared to Neutral Stimuli: Variations in Self-Reported Behavioral Approach SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Inhibition; Startle reflex; Behavioral approach system; Drive; Depression ID FEAR-POTENTIATED STARTLE; AFFECTIVE MODULATION; BIS/BAS SCALES; EMOTION; DEPRESSION; REFLEX; PUNISHMENT; RESPONSES; DISORDER; SYSTEMS AB In contrast to the research on potentiation of startle during negative emotional states, limited research has focused on the influence of individual differences in reward sensitivity on inhibition of startle during positive-activated emotional states. The present study attempted to replicate and extend previous research by investigating the influence of behavioral approach system (BAS) on the inhibition of startle. Based on a pre-screening of 3,000 participants, 76 undergraduates were recruited for low, moderate, and high BAS groups. Participants viewed a series of positive-activated, neutral, and negative-activated pictures, and bilateral startle eyeblink magnitude was recorded. Inhibition of startle was demonstrated across the entire sample; however, these findings appeared to be driven by participants in the high BAS group. Further, the Group x Affect interaction only was demonstrated in one BAS subscale (BAS-Drive) and the total BAS scale, suggesting differences among the subtypes of BAS in the processing of affective materials. C1 [Gros, Daniel F.] Ralph H Johnson VA Med Ctr, Mental Hlth Serv 116, Charleston, SC 29401 USA. [Gros, Daniel F.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. RP Gros, DF (reprint author), Ralph H Johnson VA Med Ctr, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. EM grosd@musc.edu NR 43 TC 2 Z9 2 U1 3 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD SEP PY 2011 VL 33 IS 3 BP 308 EP 314 DI 10.1007/s10862-011-9240-y PG 7 WC Psychology, Clinical SC Psychology GA 797PF UT WOS:000293139100002 ER PT J AU Wheaton, MG Braddock, AE Abramowitz, JS AF Wheaton, Michael G. Braddock, Autumn E. Abramowitz, Jonathan S. TI The Sweating Cognitions Inventory: A Measure of Cognitions in Hyperhidrosis SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Excessive sweating; Hyperhidrosis; Social anxiety; Anxiety sensitivity ID ILLNESS INTRUSIVENESS; RATING-SCALE; ANXIETY; INDIVIDUALS; VALIDATION; ACTIVATION; STABILITY; QUALITY; RETAIN; SAMPLE AB Primary hyperhidrosis is a dermatological condition involving excessive sweating. Little research has been conducted on the psychological processes associated with this condition. A cognitive-behavioral approach would suggest that negative beliefs about the nature and consequences of sweating paradoxically increase sweating, and therefore maintain hyperhidrosis. The present research reports on the development and psychometric evaluation of the Sweating Cognitions Inventory (SCI), a self-report measure that assesses dysfunctional beliefs in hyperhidrosis. The SCI was administered to a clinical sample of patients diagnosed with hyperhidrosis (N = 226) as well as a student comparison group (N = 482). The SCI demonstrated good internal consistency and a stable, unidimensional factor structure in both samples. Sweating cognitions differentiated between the two groups, indicating discriminant validity. Correlations with comparison measures indicated that sweating cognitions were strongly related to sweating severity, and also to social anxiety and anxiety sensitivity. These results are consistent with our conceptualization that dysfunctional sweating cognitions can maintain and exacerbate excessive sweating. A cognitive-behavioral conceptualization of hyperhidrosis could advance our understanding of the condition and could lead to novel treatment approaches. C1 [Wheaton, Michael G.; Abramowitz, Jonathan S.] Univ N Carolina, Dept Psychol, Chapel Hill, NC 27599 USA. [Braddock, Autumn E.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Abramowitz, JS (reprint author), Univ N Carolina, Dept Psychol, Campus Box 3270,Davie Hall, Chapel Hill, NC 27599 USA. EM mwheaton@email.unc.edu; autumn.braddock@va.gov; jabramowitz@unc.edu OI Wheaton, Michael/0000-0002-7465-7879 NR 38 TC 1 Z9 1 U1 3 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD SEP PY 2011 VL 33 IS 3 BP 393 EP 402 DI 10.1007/s10862-010-9211-8 PG 10 WC Psychology, Clinical SC Psychology GA 797PF UT WOS:000293139100011 ER PT J AU Pickett, BE Striker, R Lefkowitz, EJ AF Pickett, B. E. Striker, R. Lefkowitz, E. J. TI Evidence for separation of HCV subtype 1a into two distinct clades SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE bioinformatics; drug resistance; hepatitis C virus; phylogeny; selection pressure ID HEPATITIS-C VIRUS; OPEN-READING FRAME; MULTIPLE SEQUENCE ALIGNMENT; HYPERVARIABLE REGION 1; RIBOSOME ENTRY SITE; PHYLOGENETIC ANALYSIS; RESISTANCE MUTATIONS; POSITIVE SELECTION; HYPERIMMUNE SERUM; PLUS RIBAVIRIN AB The nucleotide sequence diversity present among hepatitis C virus (HCV) isolates allows rapid adjustment to exterior forces including host immunity and drug therapy. This viral response reflects a combination of a high rate of replication together with an error-prone RNA-dependent RNA polymerase, providing for the selection and proliferation of the viruses with the highest fitness. We examined HCV subtype 1a whole-genome sequences to identify positions contributing to genotypic and phenotypic diversity. Phylogenetic tree reconstructions showed two distinct clades existing within the 1a subtype with each clade having a starlike tree topology and lacking definite correlation between time or place of isolation and phylogeny. Identification of significant phylogenetically informative sites at the nucleotide level revealed positions not only contributing to clade differentiation, but which are located at or proximal to codons associated with resistance to protease inhibitors (NS3 Q41) or polymerase inhibitors (NS5B S368). Synonymous/nonsynonymous substitution mutation analyses revealed that the majority of nucleotide mutations yielded synonymous amino acids, indicating the presence of purifying selection pressure across the polyprotein with pockets of positive selection also being detected. Despite evidence for divergence at several loci, certain 1a characteristics were preserved including the length of the alternative reading frame/F protein (ARF/F) gene, and a subtype 1a-specific phosphorylation site in NS5A (S349). Our analysis suggests that there may be strain-specific differences in the development of antiviral resistance to viruses infecting patients who are dependent on the genetic variation separating these two clades. C1 [Pickett, B. E.; Lefkowitz, E. J.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Striker, R.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Striker, R.] Univ Wisconsin, Dept Med, Madison, WI USA. [Striker, R.] Univ Wisconsin, Dept Med Microbiol & Immunol, Madison, WI 53706 USA. RP Lefkowitz, EJ (reprint author), BBRB 276-11,1530 3rd Ave S, Birmingham, AL 35294 USA. EM elliotl@uab.edu OI Lefkowitz, Elliot/0000-0002-4748-4925 FU PHS [5 T32 AI007150-29]; NIH/NIAID [HHSN266200400036C]; American Cancer Society; Veteran's Administration [5I01CX000117-02]; University of Wisconsin Institute for Clinical and Translational Research; NIH [1UL1RR025011]; Public Health Service [5 T32 AI007150-29] FX We wish to thank Dr John Tavis and the Virahep-C study group for providing the drug resistance data and Dr. Cecile Ane for statistical help and critical reading of the manuscript. This work was supported by PHS Training grant 5 T32 AI007150-29 to BP and NIH/NIAID contract number HHSN266200400036C to EJL. RS is supported by the American Cancer Society, a Veteran's Administration Merit Award (5I01CX000117-02) and in part by the University of Wisconsin Institute for Clinical and Translational Research and funded through an NIH Clinical and Translational Science Award (CTSA), grant number 1UL1RR025011.; This study was funded (in part or in full) by: National Institutes of Health/National Institute for Allergies and Infectious Diseases, contract number HHSN266200400036C; Public Health Service, grant number 5 T32 AI007150-29; and National Institutes of Health, grant number 1UL1RR025011. NR 55 TC 37 Z9 37 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1352-0504 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD SEP PY 2011 VL 18 IS 9 BP 608 EP 618 DI 10.1111/j.1365-2893.2010.01342.x PG 11 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 798GV UT WOS:000293191500002 PM 20565573 ER PT J AU Cote, CJ Cravero, J AF Cote, Charles J. Cravero, Joseph TI Brave New World: do we need it, do we want it, can we afford it? SO PEDIATRIC ANESTHESIA LA English DT Editorial Material ID PEDIATRIC PROCEDURAL SEDATION; DEPARTMENT SAFETY PROFILE; HIGH-DOSE DEXMEDETOMIDINE; EMERGENCY-DEPARTMENT; ADVERSE EVENTS; THERAPEUTIC PROCEDURES; RESEARCH CONSORTIUM; KETAMINE SEDATION; OPERATING-ROOM; GUIDELINES C1 [Cote, Charles J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Management, MassGen Hosp Children, Div Pediat Anesthesia, Boston, MA 02114 USA. [Cote, Charles J.] Harvard Univ, Sch Med, Boston, MA USA. [Cravero, Joseph] Childrens Hosp Dartmouth, Dept Anesthesiol, Lebanon, NH USA. [Cravero, Joseph] Dartmouth Med Sch, Dartmouth Hitchcock Med Ctr, Lebanon, NH USA. RP Cote, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Management, MassGen Hosp Children, Div Pediat Anesthesia, Boston, MA 02114 USA. EM cjcote@partners.org NR 26 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1155-5645 EI 1460-9592 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD SEP PY 2011 VL 21 IS 9 BP 919 EP 923 DI 10.1111/j.1460-9592.2011.03647.x PG 5 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA 799JP UT WOS:000293283300002 PM 21793977 ER PT J AU Mrakotsky, CM Silverman, LB Dahlberg, SE Alyman, MCA Sands, SA Queally, JT Miller, TP Cranston, A Neuberg, DS Sallan, SE Waber, DP AF Mrakotsky, Christine M. Silverman, Lewis B. Dahlberg, Suzanne E. Alyman, M. Cheryl A. Sands, Stephen A. Queally, Jennifer T. Miller, Tamara P. Cranston, Amy Neuberg, Donna S. Sallan, Stephen E. Waber, Deborah P. TI Neurobehavioral Side Effects of Corticosteroids During Active Treatment for Acute Lymphoblastic Leukemia in Children Are Age-Dependent: Report From Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 SO PEDIATRIC BLOOD & CANCER LA English DT Article DE ALL; behavior; chemotherapy neurotoxicities; corticosteroids; pediatric hematology/oncology ID DEXAMETHASONE; BUDESONIDE; NEUROTOXICITY; CHEMOTHERAPY; PREDNISOLONE; HIPPOCAMPUS; TRIAL AB Background. Although corticosteroids remain a mainstay of treatment for acute lymphoblastic leukemia (ALL), they can cause troublesome neurobehavioral changes during active treatment, especially in young children. We evaluated acute neurobehavioral side effects of corticosteroid therapy in preschool versus school-age children by obtaining structured reports weekly for 1 month. Procedure. Parents of 62 children (2-17 years) treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 00-01 participated during the continuation phase of treatment. Patients received cyclical twice-daily 5-day courses of prednisone (PRED; 40 mg/m(2)/day) or dexamethasone (DEX; 6 mg/m(2)/day). Parents completed behavior rating scales about their child weekly during one steroid cycle [baseline (Day 0), active steroid (Day 7), post-steroid (Days 14 and 21)]. Results. Behavioral side effects increased significantly (P < 0.001) during the steroid week for preschool children (< 6 years) on measures of emotional control, mood, behavior regulation, and executive functions, returning to baseline during the two "off-steroid'' weeks. In contrast, school-age children (>= 6 years) did not demonstrate an increase in side effects during the steroid week. Steroid type (PRED vs. DEX) was not a significant predictor of neurobehavioral side effects. Conclusions. Preschool children are at greater risk for neurobehavioral side effects during active steroid treatment for ALL than school-age children and adolescents. DEX was not associated with more neurobehavioral side effects than PRED. Counseling of families about side-effects should be adapted according to age. The observed effects, moreover, were transient, reducing concerns about longer-term neurobehavioral toxicities. Pediatr Blood Cancer 2011; 57: 492-498. (C) 2011 Wiley-Liss, Inc. C1 [Mrakotsky, Christine M.; Queally, Jennifer T.; Waber, Deborah P.] Childrens Hosp, Dept Psychiat, Div Psychol, Boston, MA 02115 USA. [Mrakotsky, Christine M.; Silverman, Lewis B.; Queally, Jennifer T.; Sallan, Stephen E.; Waber, Deborah P.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Mrakotsky, Christine M.; Silverman, Lewis B.; Queally, Jennifer T.; Sallan, Stephen E.; Waber, Deborah P.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Silverman, Lewis B.; Sallan, Stephen E.] Childrens Hosp, Div Hematol, Dept Med, Boston, MA 02115 USA. [Silverman, Lewis B.; Sallan, Stephen E.] Childrens Hosp, Div Oncol, Dept Med, Boston, MA 02115 USA. [Silverman, Lewis B.; Sallan, Stephen E.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Dahlberg, Suzanne E.; Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Alyman, M. Cheryl A.; Cranston, Amy] McMaster Univ, Med Ctr, Div Pediat Hematol Oncol, Hamilton, ON, Canada. [Sands, Stephen A.] Columbia Univ Coll Phys & Surg, Dept Pediat, New York, NY 10032 USA. [Sands, Stephen A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Miller, Tamara P.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Mrakotsky, CM (reprint author), Childrens Hosp, Dept Psychiat, Div Psychol, 300 Longwood Ave, Boston, MA 02115 USA. EM christine.mrakotsky@childrens.harvard.edu FU Michael J. Garil Fund for Leukemia Research FX Grant sponsor: Michael J. Garil Fund for Leukemia Research. NR 25 TC 13 Z9 13 U1 1 U2 4 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2011 VL 57 IS 3 BP 492 EP 498 DI 10.1002/pbc.23060 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 799GD UT WOS:000293272800022 PM 21560226 ER PT J AU Teng, E Kepe, V Frautschy, SA Liu, J Satyamurthy, N Yang, FS Chen, PP Cole, GB Jones, MR Huang, SC Flood, DG Trusko, SP Small, GW Cole, GM Barrio, JR AF Teng, Edmond Kepe, Vladimir Frautschy, Sally A. Liu, Jie Satyamurthy, Nagichettiar Yang, Fusheng Chen, Ping-Ping Cole, Graham B. Jones, Mychica R. Huang, Sung-Cheng Flood, Dorothy G. Trusko, Stephen P. Small, Gary W. Cole, Gregory M. Barrio, Jorge R. TI [F-18]FDDNP microPET imaging correlates with brain A beta burden in a transgenic rat model of Alzheimer disease: Effects of aging, in vivo blockade, and anti-A beta antibody treatment SO NEUROBIOLOGY OF DISEASE LA English DT Article DE [F-18]FDDNP; Positron emission tomography; Amyloid; Transgenic rat; Naproxen; Immunotherapy ID POSITRON-EMISSION-TOMOGRAPHY; PITTSBURGH COMPOUND-B; MILD COGNITIVE IMPAIRMENT; AMYLOID-BETA; MOUSE MODEL; PET; PLAQUES; PATHOLOGY; DEPOSITION; CLEARANCE AB In vivo detection of Alzheimer's disease (AD) neuropathology in living patients using positron emission tomography (PET) in conjunction with high affinity molecular imaging probes for beta-amyloid (A beta) and tau has the potential to assist with early diagnosis, evaluation of disease progression, and assessment of therapeutic interventions. Animal models of AD are valuable for exploring the in vivo binding of these probes, particularly their selectivity for specific neuropathologies, but prior PET experiments in transgenic mice have yielded conflicting results. In this work, we utilized microPET imaging in a transgenic rat model of brain A beta deposition to assess [F-18]FDDNP binding profiles in relation to age-associated accumulation of neuropathology. Cross-sectional and longitudinal imaging demonstrated that [F-18[FDDNP binding in the hippocampus and frontal cortex progressively increases from 9 to 18 months of age and parallels age-associated A beta accumulation. Specificity of in vivo [F-18]FDDNP binding was assessed by naproxen pretreatment, which reversibly blocked [F-18]FDDNP binding to A beta aggregrates. Both [F-18]FDDNP microPET imaging and neuropathological analyses revealed decreased A beta burden after intracranial anti-A beta antibody administration. The combination of this non-invasive imaging method and robust animal model of brain A beta accumulation allows for future longitudinal in vivo assessments of potential therapeutics for AD that target A beta production, aggregation, and/or clearance. These results corroborate previous analyses of [F-18]FDDNP PET imaging in clinical populations. (C) 2011 Elsevier Inc. All rights reserved. C1 [Teng, Edmond; Frautschy, Sally A.; Cole, Gregory M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Kepe, Vladimir; Liu, Jie; Satyamurthy, Nagichettiar; Cole, Graham B.; Huang, Sung-Cheng; Barrio, Jorge R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Frautschy, Sally A.; Yang, Fusheng; Chen, Ping-Ping; Jones, Mychica R.; Cole, Gregory M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Small, Gary W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Teng, Edmond; Frautschy, Sally A.; Yang, Fusheng; Chen, Ping-Ping; Jones, Mychica R.; Cole, Gregory M.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Teng, E (reprint author), W Los Angeles VA Healthcare Ctr, Neurobehav Unit 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM eteng@ucla.edu; vkepe@mednet.ucla.edu FU National Institute on Aging [P50 AG 16570, RC1 AG 035878, K08 AG 34628]; National Institutes of Health [P01 AG025831]; VA Merit Review Award Program; John Douglas French Alzheimer's Foundation; Brotman Foundation FX This research was supported by grants from the National Institute on Aging (P50 AG 16570 [pilot grants to ET, VK], RC1 AG 035878 [to GMC, SAF], K08 AG 34628 [to ET; jointly sponsored by NIA, AFAR, the John A. Hartford Foundation, the Atlantic Philanthropies, the Starr Foundation and an anonymous donor]), National Institutes of Health (P01 AG025831), VA Merit Review Award Program (to GMC, SAF), the John Douglas French Alzheimer's Foundation, and the Brotman Foundation. The funding sources had no involvement in study design; collection, analysis and interpretation of data; writing of the report; or the decision to submit the report for publication. We would like to thank Gerald Timbol for his management of the animal breeding colony and Waldemar Ladno and Judy Edwards for their assistance NR 55 TC 22 Z9 22 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD SEP PY 2011 VL 43 IS 3 BP 565 EP 575 DI 10.1016/j.nbd.2011.05.003 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 796GX UT WOS:000293040900005 PM 21605674 ER PT J AU Pedamallu, CS Ozdamar, L AF Pedamallu, Chandra Sekhar Ozdamar, Linet TI Solving kinematics problems by efficient interval partitioning SO OPTIMIZATION AND ENGINEERING LA English DT Article DE Kinematics; Branch and bound technique; Interval partitioning approaches; Local search methods; Constraint satisfaction ID MANIPULATORS; OPTIMIZATION; CONTINUATION AB In this study, a generic solution methodology is presented for solving constraint satisfaction problems with smooth continuous constraint functions. We apply the proposed method in solving small scale kinematics problems with the goal of identifying all real solutions to a given problem. The developed approach assumes a collaborative methodology that integrates interval partitioning, a new interval inference method, and local search. The resulting methodology aims at reducing the search space and discarding infeasible sub-spaces effectively and reliably during the early stages of the search so that exact solutions can be identified faster by local methods. C1 [Ozdamar, Linet] Yeditepe Univ, Dept Syst Engn, TR-34755 Istanbul, Turkey. [Pedamallu, Chandra Sekhar] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Pedamallu, Chandra Sekhar] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Ozdamar, L (reprint author), Yeditepe Univ, Dept Syst Engn, TR-34755 Istanbul, Turkey. EM pcs.murali@gmail.com; linetozdamar@lycos.com NR 30 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-4420 EI 1573-2924 J9 OPTIM ENG JI Optim. Eng. PD SEP PY 2011 VL 12 IS 3 BP 459 EP 476 DI 10.1007/s11081-010-9121-3 PG 18 WC Engineering, Multidisciplinary; Operations Research & Management Science; Mathematics, Interdisciplinary Applications SC Engineering; Operations Research & Management Science; Mathematics GA 792LA UT WOS:000292744800009 ER PT J AU Toh, WS Lee, EH Cao, T AF Toh, Wei Seong Lee, Eng Hin Cao, Tong TI Potential of Human Embryonic Stem Cells in Cartilage Tissue Engineering and Regenerative Medicine SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE BMP-2; TGF-beta 1; Chondrogenic; Differentiation; Embryonic stem cells; Biomaterials; Cartilage; Tissue engineering; Repair; Regenerative medicine ID HUMAN ARTICULAR CHONDROCYTES; DIFFERENTIATION IN-VITRO; MESENCHYMAL PROGENITOR CELLS; BONE MORPHOGENETIC PROTEIN-2; CHONDROGENIC DIFFERENTIATION; GROWTH-FACTORS; PERMANENT CARTILAGE; CULTURE-CONDITIONS; HUMAN BLASTOCYSTS; SUBCHONDRAL BONE AB The current surgical intervention of using autologous chondrocyte implantation (ACI) for cartilage repair is associated with several problems such as donor site morbidity, de-differentiation upon expansion and fibrocartilage repair following transplantation. This has led to exploration of the use of stem cells as a model for chondrogenic differentiation as well as a potential source of chondrogenic cells for cartilage tissue engineering and repair. Embryonic stem cells (ESCs) are advantageous, due to their unlimited self-renewal and pluripotency, thus representing an immortal cell source that could potentially provide an unlimited supply of chondrogenic cells for both cell and tissue-based therapies and replacements. This review aims to present an overview of emerging trends of using ESCs in cartilage tissue engineering and regenerative medicine. In particular, we will be focusing on ESCs as a promising cell source for cartilage regeneration, the various strategies and approaches employed in chondrogenic differentiation and tissue engineering, the associated outcomes from animal studies, and the challenges that need to be overcome before clinical application is possible. C1 [Toh, Wei Seong; Cao, Tong] Natl Univ Singapore, Fac Dent, Singapore 119083, Singapore. [Lee, Eng Hin] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Orthopaed Surg, NUS Tissue Engn Program, Singapore 117510, Singapore. [Toh, Wei Seong] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 USA. RP Toh, WS (reprint author), VA Boston Healthcare Syst, Tissue Engn Labs, 150 S Huntington Ave,MS 151, Boston, MA 02130 USA. EM wtoh@partners.org; tong_cao@nuhs.edu.sg RI Toh, Wei Seong/K-7720-2013; CAO, Tong/B-1008-2008 OI Toh, Wei Seong/0000-0001-9147-6423; CAO, Tong/0000-0002-7994-9627 FU Ministry of Education of Singapore [R223000014112, R223000018112]; National University of Singapore (NUS); A*STAR; Agency for Science, Technology and Research (A*STAR) Singapore FX This work was partially supported by grants (R223000014112 and R223000018112) from the Ministry of Education of Singapore (to TC), National University of Singapore (NUS) Research Scholarship and President Graduate Fellowship (to WST). WST is presently supported by A*STAR International Fellowship, Agency for Science, Technology and Research (A*STAR) Singapore. The authors are grateful to Dr. Victor Nurcombe, Institute of Medical Biology, A*STAR, for his helpful encouragements in this review preparation. NR 136 TC 40 Z9 43 U1 0 U2 20 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD SEP PY 2011 VL 7 IS 3 BP 544 EP 559 DI 10.1007/s12015-010-9222-6 PG 16 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 793PG UT WOS:000292835000009 PM 21188652 ER PT J AU Marshall, AD Panuzio, J Makin-Byrd, KN Taft, CT Holtzworth-Munroe, A AF Marshall, Amy D. Panuzio, Jillian Makin-Byrd, Kerry N. Taft, Casey T. Holtzworth-Munroe, Amy TI A Multilevel Examination of Interpartner Intimate Partner Violence and Psychological Aggression Reporting Concordance SO BEHAVIOR THERAPY LA English DT Article ID CONFLICT-TACTICS-SCALES; MARITAL SATISFACTION; PHYSICAL AGGRESSION; RISK-FACTORS; AGREEMENT; RELIABILITY; COUPLES; VALIDITY; SPOUSES; ATTRIBUTIONS AB Low concordance of reports across partners has consistently been observed when partners report the frequency of intimate partner violence (IPV) and psychological aggression (PA) in their relationship. Researchers have been unsuccessful in the quest to discover systematic biases across reporters, perhaps due to examining constructs that are not the source of bias (e.g., gender, victim/perpetrator status) or examining potentially fruitful constructs using underpowered statistics or erroneous conceptualizations (e.g., examining variables at a dyadic, rather than an individual, level). We used multilevel modeling with two samples (Ns=88 and 164 couples) to examine husbands' and wives' relationship satisfaction as individual-level correlates of husband- and wife-perpetrated IPV and PA reporting concordance. Consistent with prior literature, low to moderate levels of agreement were observed, and gender and victim/perpetrator status were not consistently associated with reporting concordance. In contrast, for both husbands and wives, relationship satisfaction was associated with reporting concordance such that high relationship satisfaction was related to reporting less of one's partner's PA than the partner reported, whereas low relationship satisfaction was related to reporting more of one's partner's PA than the partner reported. A similar pattern of results emerged for the reporting of IPV, but results did not cross validate between samples. These findings suggest that relationship satisfaction may lead to either reluctance, or increased willingness, to attribute negative relationship events to partner behavior, potentially due to partner blame and relationship schemas. In addition, the influence of individual-level factors may be occluded when aggregated across partners to examine correlates of interpartner reporting concordance. C1 [Marshall, Amy D.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Panuzio, Jillian] Univ Nebraska, Lincoln, NE USA. [Taft, Casey T.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Taft, Casey T.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Holtzworth-Munroe, Amy] Indiana Univ, Bloomington, IN 47405 USA. RP Marshall, AD (reprint author), Penn State Univ, Dept Psychol, 415 Moore Bldg, University Pk, PA 16802 USA. EM AmyMarshall@psu.edu FU NICHD NIH HHS [K12 HD055882, 1 K12 HD055882] NR 43 TC 17 Z9 18 U1 2 U2 9 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 J9 BEHAV THER JI Behav. Therapy PD SEP PY 2011 VL 42 IS 3 BP 364 EP 377 DI 10.1016/j.beth.2010.09.003 PG 14 WC Psychology, Clinical SC Psychology GA 781SW UT WOS:000291957800002 PM 21658520 ER PT J AU Reese, HE McNally, RJ Wilhelm, S AF Reese, Hannah E. McNally, Richard J. Wilhelm, Sabine TI Reality Monitoring in Patients With Body Dysmorphic Disorder SO BEHAVIOR THERAPY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; POPULATION-BASED SURVEY; MEMORY CONFIDENCE; SCHIZOPHRENIA; SCALE; RELIABILITY; VALIDITY; INFORMATION; PREVALENCE; DELUSIONS AB Patients with body dysmorphic disorder (BDD) typically have very poor insight into their disorder. Their conviction in their ugliness is often of delusional intensity. Reality monitoring is the ability to distinguish in memory between things that one has imagined and things that one has perceived. Deficits in reality monitoring have been associated with the development of other delusional beliefs. Therefore, in the present study we investigated whether individuals with BDD (n=20) demonstrate impairments in reality monitoring relative to individuals with obsessive-compulsive disorder (OCD; n=20) and healthy controls (n=20). This hypothesized impairment might predispose people with BDD to confuse memories of how they imagine themselves to appear (i.e., ugly) with memories of how they actually appear (i.e., normal). All participants completed a memory task assessing reality-monitoring ability for verbal stimuli. The BDD patients did not exhibit a reality-monitoring deficit despite elevated levels of focal delusionality. The results suggest that impairments in reality monitoring do not contribute to the development or maintenance of appearance-related beliefs in BDD. C1 [Reese, Hannah E.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Reese, Hannah E.; Wilhelm, Sabine] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Reese, HE (reprint author), Harvard Univ, Massachusetts Gen Hosp, 185 Cambridge St,Suite 2000, Boston, MA 02114 USA. EM hreese@partners.org NR 47 TC 10 Z9 11 U1 2 U2 7 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 J9 BEHAV THER JI Behav. Therapy PD SEP PY 2011 VL 42 IS 3 BP 387 EP 398 DI 10.1016/j.beth.2010.10.001 PG 12 WC Psychology, Clinical SC Psychology GA 781SW UT WOS:000291957800004 PM 21658522 ER PT J AU Martin, N Li, Y AF Martin, Nirian Li, Yi TI A new class of minimum power divergence estimators with applications to cancer surveillance SO JOURNAL OF MULTIVARIATE ANALYSIS LA English DT Article DE Minimum power divergence estimators; Age-adjusted cancer rates; Annual percent change (APC); Trends; Poisson sampling ID OVERLAPPING REGIONS; COMPARING TRENDS; RATES AB The annual percent change (APC) has been adopted as a useful measure for analyzing the changing trends of cancer mortality and incidence rates by the NCI SEER program. Difficulties, however, arise when comparing the sample APCs between two overlapping regions because of induced dependence (e.g., comparing the cancer mortality change rate of California with that of the national level). This paper deals with a new perspective for understanding the sample distribution of the test-statistics for comparing the APCs between overlapping regions. Our proposal allows for computational readiness and easy interpretability. We further propose a more general family of estimators, namely, the so-called minimum Power divergence estimators, including the maximum likelihood estimators as a special case. Our simulation experiments support the superiority of the proposed estimator to the conventional maximum likelihood estimator. The proposed method is illustrated by the analysis of the SEER cancer mortality rates observed from 1991 to 2006, (C) 2011 Elsevier Inc. All rights reserved. C1 [Martin, Nirian] Univ Carlos III Madrid, Dept Stat, Madrid 28903, Spain. [Li, Yi] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Li, Yi] Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. RP Martin, N (reprint author), Univ Carlos III Madrid, Dept Stat, Madrid 28903, Spain. EM nirian.martin@uc3m.es RI Martin, Nirian/A-1603-2010 OI Martin, Nirian/0000-0003-4766-1909 FU Real Colegio Complutense; [MTM2009-10072]; [R01CA95747]; [1P01CA134294] FX The authors thank the associate editor and two referees for their valuable comments and suggestions. This work was carried out during the stay of the first author as Visiting Scientist at Harvard University and Dana Farber Cancer Institute, supported by the Real Colegio Complutense and grant MTM2009-10072. Li's work was partially supported by R01CA95747 and 1P01CA134294. NR 15 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0047-259X J9 J MULTIVARIATE ANAL JI J. Multivar. Anal. PD SEP PY 2011 VL 102 IS 8 BP 1175 EP 1193 DI 10.1016/j.jmva.2011.03.011 PG 19 WC Statistics & Probability SC Mathematics GA 779EI UT WOS:000291760500001 PM 22368308 ER PT J AU Reese, HE McNally, RJ Wilhelm, S AF Reese, Hannah E. McNally, Richard J. Wilhelm, Sabine TI Probabilistic reasoning in patients with body dysmorphic disorder SO JOURNAL OF BEHAVIOR THERAPY AND EXPERIMENTAL PSYCHIATRY LA English DT Article DE Body dysmorphic disorder; Insight; Delusionality; Reasoning; Obsessive compulsive disorder ID OBSESSIVE-COMPULSIVE DISORDER; SCALE; RELIABILITY; CONCLUSIONS; DELUSIONS; PSYCHOSIS; VALIDITY; INDIVIDUALS; INFORMATION; CONTINUUM AB Background and Objectives: Many patients with body dysmorphic disorder (BDD) have poor insight into their condition. Indeed, their conviction in their ugliness is often delusional. Perhaps the most robust information-processing abnormality associated with delusions is a jumping to conclusions (JTC) reasoning bias such that delusional individuals request significantly less information before making a decision relative to healthy controls. We investigated whether patients with BDD (n = 20) demonstrate a JTC reasoning style relative to patients with OCD (n = 20) and healthy controls (n = 20). Methods: Participants completed a clinician-rated measure of delusionality and two tests of probabilistic reasoning: the beads task and the survey task. Results: Patients with BDD did exhibit higher delusionality than the patients with OCD. They did not, however, exhibit a JTC reasoning bias relative to the patients with OCD or the healthy controls. Patients with poor insight BDD requested significantly less information before making a decision than did patients with fair insight BDD. Limitations: The clinical groups were characterized by multiple comorbidities and concomitant medications. The BDD group had relatively good insight as compared to other studies examining delusionality in BDD. Conclusions: Taken together, our results suggest that although a JTC reasoning bias was not present in all patients with BDD, a modest JTC reasoning bias may be present among patients with poor insight BDD. Future studies could provide additional information on this hypothesis. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Reese, Hannah E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Reese, Hannah E.; Wilhelm, Sabine] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Reese, Hannah E.; McNally, Richard J.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Reese, HE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 185 Cambridge St,Suite 2000, Boston, MA 02114 USA. EM hreese@partners.org; rjm@wjh.harvard.edu; sabinewilhelmwilhelm@earthlink.net NR 41 TC 12 Z9 12 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7916 J9 J BEHAV THER EXP PSY JI J. Behav. Ther. Exp. Psychiatry PD SEP PY 2011 VL 42 IS 3 BP 270 EP 276 DI 10.1016/j.jbtep.2010.11.005 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 763JR UT WOS:000290553100004 PM 21349243 ER PT J AU Fruhwirth, R Mani, DR Pyne, S AF Fruehwirth, Rudolf Mani, D. R. Pyne, Saumyadipta TI Clustering with position-specific constraints on variance: Applying redescending M-estimators to label-free LC-MS data analysis SO BMC BIOINFORMATICS LA English DT Article ID BIOMARKER DISCOVERY; MASS-SPECTROMETRY; OVARIAN-CANCER; SERUM; PATTERN; MIXTURES AB Background: Clustering is a widely applicable pattern recognition method for discovering groups of similar observations in data. While there are a large variety of clustering algorithms, very few of these can enforce constraints on the variation of attributes for data points included in a given cluster. In particular, a clustering algorithm that can limit variation within a cluster according to that cluster's position (centroid location) can produce effective and optimal results in many important applications ranging from clustering of silicon pixels or calorimeter cells in high-energy physics to label-free liquid chromatography based mass spectrometry (LC-MS) data analysis in proteomics and metabolomics. Results: We present MEDEA (M-Estimator with DEterministic Annealing), an M-estimator based, new unsupervised algorithm that is designed to enforce position-specific constraints on variance during the clustering process. The utility of MEDEA is demonstrated by applying it to the problem of "peak matching"-identifying the common LC-MS peaks across multiple samples-in proteomic biomarker discovery. Using real-life datasets, we show that MEDEA not only outperforms current state-of-the-art model-based clustering methods, but also results in an implementation that is significantly more efficient, and hence applicable to much larger LC-MS data sets. Conclusions: MEDEA is an effective and efficient solution to the problem of peak matching in label-free LC-MS data. The program implementing the MEDEA algorithm, including datasets, clustering results, and supplementary information is available from the author website at http://www.hephy.at/user/fru/medea/. C1 [Mani, D. R.; Pyne, Saumyadipta] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. [Fruehwirth, Rudolf] Austrian Acad Sci, Inst High Energy Phys, A-1010 Vienna, Austria. [Pyne, Saumyadipta] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Mani, DR (reprint author), Broad Inst MIT & Harvard Univ, Cambridge, MA USA. EM manidr@broadinstitute.org; Saumyadipta_Pyne@dfci.harvard.edu RI Fruhwirth, Rudolf/H-2529-2012 FU National Cancer Institute as part of the Clinical Proteomic Technologies Initiative [R01-CA126219]; Gates Grand Challenges in Global Health [GC-13] FX This work was supported in part by a grant R01-CA126219 to D. R. Mani from the National Cancer Institute as part of the Clinical Proteomic Technologies Initiative. The MitoMix data is publicly available as part of the PEPPeR publication [10]. The DarTB data was generated as part of the Gates Grand Challenges in Global Health (GC-13) grant to Steven A. Carr (Broad Institute, Cambridge, MA, USA). The sample collection and protocols were conceived by Michael A. Gillette and Rushdy Ahmad, and the samples were processed with help from Margaret Pyle (all from the Broad Institute, Cambridge, MA, USA). This data will be published as part of a separate manuscript under preparation. NR 32 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 31 PY 2011 VL 12 AR 358 DI 10.1186/1471-2105-12-358 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 823SI UT WOS:000295145100001 PM 21884583 ER PT J AU Hu, YH Flockhart, I Vinayagam, A Bergwitz, C Berger, B Perrimon, N Mohr, SE AF Hu, Yanhui Flockhart, Ian Vinayagam, Arunachalam Bergwitz, Clemens Berger, Bonnie Perrimon, Norbert Mohr, Stephanie E. TI An integrative approach to ortholog prediction for disease-focused and other functional studies SO BMC BIOINFORMATICS LA English DT Article ID ONLINE MENDELIAN INHERITANCE; DROSOPHILA-MELANOGASTER; PHYLOGENETIC TREES; EUKARYOTIC GENOMES; GLOBAL ALIGNMENT; PROTEIN NETWORKS; MAN OMIM; DATABASE; MODEL; GENES AB Background: Mapping of orthologous genes among species serves an important role in functional genomics by allowing researchers to develop hypotheses about gene function in one species based on what is known about the functions of orthologs in other species. Several tools for predicting orthologous gene relationships are available. However, these tools can give different results and identification of predicted orthologs is not always straightforward. Results: We report a simple but effective tool, the Drosophila RNAi Screening Center Integrative Ortholog Prediction Tool (DIOPT; http://www.flyrnai.org/diopt), for rapid identification of orthologs. DIOPT integrates existing approaches, facilitating rapid identification of orthologs among human, mouse, zebrafish, C. elegans, Drosophila, and S. cerevisiae. As compared to individual tools, DIOPT shows increased sensitivity with only a modest decrease in specificity. Moreover, the flexibility built into the DIOPT graphical user interface allows researchers with different goals to appropriately 'cast a wide net' or limit results to highest confidence predictions. DIOPT also displays protein and domain alignments, including percent amino acid identity, for predicted ortholog pairs. This helps users identify the most appropriate matches among multiple possible orthologs. To facilitate using model organisms for functional analysis of human disease-associated genes, we used DIOPT to predict high-confidence orthologs of disease genes in Online Mendelian Inheritance in Man (OMIM) and genes in genome-wide association study (GWAS) data sets. The results are accessible through the DIOPT diseases and traits query tool (DIOPT-DIST; http://www.flyrnai.org/diopt-dist). Conclusions: DIOPT and DIOPT-DIST are useful resources for researchers working with model organisms, especially those who are interested in exploiting model organisms such as Drosophila to study the functions of human disease genes. C1 [Hu, Yanhui; Flockhart, Ian; Vinayagam, Arunachalam; Perrimon, Norbert; Mohr, Stephanie E.] Harvard Univ, Dept Genet, Sch Med, Drosophila RNAi Screening Ctr, Boston, MA 02115 USA. [Bergwitz, Clemens] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Berger, Bonnie] MIT, Dept Math, Cambridge, MA 02139 USA. [Berger, Bonnie] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Perrimon, Norbert] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Mohr, SE (reprint author), Harvard Univ, Dept Genet, Sch Med, Drosophila RNAi Screening Ctr, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM Stephanie_Mohr@hms.harvard.edu RI Arunachalam, Vinayagam/J-7925-2012; OI Arunachalam, Vinayagam/0000-0003-0091-4497; Mohr, Stephanie/0000-0001-9639-7708 FU NIH [R01 GM067761]; Dana Farber/Harvard Cancer Center; NIDDK [5K08DK78361]; Harvard Catalyst FX The authors would like to thank members of the Perrimon lab and Lizabeth Perkins for helpful suggestions and discussions. We also thank Daniel Park and Rohit Singh for critical comments on the manuscript. This work was supported by NIH R01 GM067761 to N.P. In addition, N.P. is an Investigator of the Howard Hughes Medical Institute, S.E.M. is supported in part by the Dana Farber/Harvard Cancer Center and C.B. is supported by NIDDK 5K08DK78361 and Harvard Catalyst. NR 73 TC 64 Z9 64 U1 3 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD AUG 31 PY 2011 VL 12 AR 357 DI 10.1186/1471-2105-12-357 PG 16 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 824TP UT WOS:000295225400001 PM 21880147 ER PT J AU Dobrin, R Greenawalt, DM Hu, GH Kemp, DM Kaplan, LM Schadt, EE Emilsson, V AF Dobrin, Radu Greenawalt, Danielle M. Hu, Guanghui Kemp, Daniel M. Kaplan, Lee M. Schadt, Eric E. Emilsson, Valur TI Dissecting Cis Regulation of Gene Expression in Human Metabolic Tissues SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; DISEASE; VARIANTS; RISK; CANCER; LOCUS AB Complex diseases such as obesity and type II diabetes can result from a failure in multiple organ systems including the central nervous system and tissues involved in partitioning and disposal of nutrients. Studying the genetics of gene expression in tissues that are involved in the development of these diseases can provide insights into how these tissues interact within the context of disease. Expression quantitative trait locus (eQTL) studies identify mRNA expression changes linked to proximal genetic signals (cis eQTLs) that have been shown to affect disease. Given the high impact of recent eQTL studies, it is important to understand what role sample size and environment plays in identification of cis eQTLs. Here we show in a genotyped obese human population that the number of cis eQTLs obey precise scaling laws as a function of sample size in three profiled tissues, i.e. omental adipose, subcutaneous adipose and liver. Also, we show that genes (or transcripts) with cis eQTL associations detected in a small population are detected at approximately 90% rate in the largest population available for our study, indicating that genes with strong cis acting regulatory elements can be identified with relatively high confidence in smaller populations. However, by increasing the sample size we allow for better detection of weaker and more distantly located cis-regulatory elements. Yet, we determined that the number of tissue specific cis eQTLs saturates in a modestly sized cohort while the number of cis eQTLs common to all tissues fails to reach a maximum value. Understanding the power laws that govern the number and specificity of eQTLs detected in different tissues, will allow a better utilization of genetics of gene expression to inform the molecular mechanism underlying complex disease traits. C1 [Dobrin, Radu; Hu, Guanghui; Kemp, Daniel M.] Merck Res Labs, Rahway, NJ USA. [Greenawalt, Danielle M.] Merck Res Labs, Boston, MA USA. [Kaplan, Lee M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schadt, Eric E.] Pacific Biosci, Menlo Pk, CA USA. [Emilsson, Valur] Iceland Heart Assoc, Kopavogur, Iceland. RP Dobrin, R (reprint author), Johnson & Johnson Pharmaceut Res & Dev, Radnor, PA 19087 USA. EM r.dobrin@gmail.com OI Dobrin, Radu/0000-0002-3336-0091 FU Merck Co., Inc. FX This study was funded by Merck & Co., Inc. which employed several of the authors responsible for study design, data collection and analysis, decision to publish, and preparation of the manuscript. NR 24 TC 7 Z9 7 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 31 PY 2011 VL 6 IS 8 AR e23480 DI 10.1371/journal.pone.0023480 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817NM UT WOS:000294680800012 PM 21912597 ER PT J AU Hubbard, CS Labus, JS Bueller, J Stains, J Suyenobu, B Dukes, GE Kelleher, DL Tillisch, K Naliboff, BD Mayer, EA AF Hubbard, Catherine S. Labus, Jennifer S. Bueller, Joshua Stains, Jean Suyenobu, Brandall Dukes, George E. Kelleher, Dennis L. Tillisch, Kirsten Naliboff, Bruce D. Mayer, Emeran A. TI Corticotropin-Releasing Factor Receptor 1 Antagonist Alters Regional Activation and Effective Connectivity in an Emotional-Arousal Circuit during Expectation of Abdominal Pain SO JOURNAL OF NEUROSCIENCE LA English DT Article ID IRRITABLE-BOWEL-SYNDROME; LOCUS-COERULEUS NEURONS; IBS PATIENTS; NORADRENERGIC NEURONS; BEHAVIORAL-RESPONSES; ANTICIPATORY ANXIETY; SEX-DIFFERENCES; MOTOR FUNCTION; PRIMATE BRAIN; STRESS AB Alterations in corticotropin-releasing factor (CRF) signaling pathways have been implicated in irritable bowel syndrome (IBS) pathophysiology. We aimed to (1) determine the effect of the selective CRF receptor 1 antagonist (CRF(1)) GW876008 relative to placebo, on regional activation and effective connectivity of a stress-related emotional-arousal circuit during expectation of abdominal pain using functional magnetic resonance imaging in human subjects with a diagnosis of IBS and healthy controls (HCs), and (2) examine GW876008 effects on state-trait anxiety and hypothalamic-pituitary-adrenal (HPA) axis response. Although there were no drug-related effects on peripheral HPA activity, significant central effects were observed in brain regions associated with the stress response. Effective connectivity analysis showed drug-induced normalizations between key regions of the emotional-arousal circuit in patients. During pain expectation, orally administered GW876008 relative to placebo produced significant blood oxygen level-dependent (BOLD) signal reductions in the amygdala, hippocampus, insula, anterior cingulate, and orbitomedial prefrontal cortices across groups. Patients showed significantly greater BOLD responses in the left locus coeruleus and hypothalamus after placebo compared with HCs, and BOLD signal decreases in the left hypothalamus after drug. The inhibitory effects of GW876008 in the hypothalamus in patients were moderated by anxiety; patients having average and high levels of state anxiety showed drug-related BOLD decreases. GW876008 represents a novel tool for elucidating the neuronal mechanisms and circuitry underlying hyperactivation of CRF/CRF(1) signaling and its role in IBS pathophysiology. The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF(1) receptor antagonism for patients with stress-sensitive disorders. C1 [Mayer, Emeran A.] Univ Calif Los Angeles, Ctr Neurobiol Stress, Div Digest Dis, Los Angeles, CA 90095 USA. [Hubbard, Catherine S.; Bueller, Joshua; Stains, Jean; Suyenobu, Brandall; Tillisch, Kirsten; Mayer, Emeran A.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Mayer, Emeran A.] Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90095 USA. [Labus, Jennifer S.; Naliboff, Bruce D.; Mayer, Emeran A.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90095 USA. [Naliboff, Bruce D.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Dukes, George E.; Kelleher, Dennis L.] GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA. RP Mayer, EA (reprint author), Univ Calif Los Angeles, Ctr Neurobiol Stress, Div Digest Dis, CHS 47-122,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM emayer@ucla.edu OI Hubbard, Catherine/0000-0002-9139-2198 FU GlaxoSmithKline; NIH [R01 DK 48351, P50 DK 64539, R24 AT002681, K23 DK 073451-05, K08 DK 071626, T32-DK07180-34] FX This research was supported by GlaxoSmithKline, NIH Grants R01 DK 48351, P50 DK 64539, R24 AT002681, K23 DK 073451-05, and K08 DK 071626, and NIH GI Training Grant T32-DK07180-34. We thank Dr. Yvette Tache for valuable comments to this manuscript. NR 69 TC 43 Z9 45 U1 3 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 31 PY 2011 VL 31 IS 35 BP 12491 EP 12500 DI 10.1523/JNEUROSCI.1860-11.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 814KV UT WOS:000294451900013 PM 21880911 ER PT J AU Stetler, CB Damschroder, LJ Helfrich, CD Hagedorn, HJ AF Stetler, Cheryl B. Damschroder, Laura J. Helfrich, Christian D. Hagedorn, Hildi J. TI A Guide for applying a revised version of the PARIHS framework for implementation SO IMPLEMENTATION SCIENCE LA English DT Article ID QUERI SERIES; CONCEPTUAL-FRAMEWORK; PROMOTING ACTION; MODEL; CONTEXT; FACILITATION; EXPLORATION; INSTRUMENT; CARE AB Background: Based on a critical synthesis of literature on use of the Promoting Action on Research Implementation in Health Services (PARIHS) framework, revisions and a companion Guide were developed by a group of researchers independent of the original PARIHS team. The purpose of the Guide is to enhance and optimize efforts of researchers using PARIHS in implementation trials and evaluations. Methods: Authors used a planned, structured process to organize and synthesize critiques, discussions, and potential recommendations for refinements of the PARIHS framework arising from a systematic review. Using a templated form, each author independently recorded key components for each reviewed paper; that is, study definitions, perceived strengths/limitations of PARIHS, other observations regarding key issues and recommendations regarding needed refinements. After reaching consensus on these key components, the authors summarized the information and developed the Guide. Results: A number of revisions, perceived as consistent with the PARIHS framework's general nature and intent, are proposed. The related Guide is composed of a set of reference tools, provided in Additional files. Its core content is built upon the basic elements of PARIHS and current implementation science. Conclusions: We invite researchers using PARIHS for targeted evidence-based practice (EBP) implementations with a strong task-orientation to use this Guide as a companion and to apply the revised framework prospectively and comprehensively. Researchers also are encouraged to evaluate its use relative to perceived strengths and issues. Such evaluations and critical reflections regarding PARIHS and our Guide could thereby promote the framework's continued evolution. C1 [Stetler, Cheryl B.] Boston Univ, Sch Publ Hlth, Dept Hlth Serv, Boston, MA 02215 USA. [Damschroder, Laura J.] VA Ann Arbor Healthcare Syst, HSR&D Ctr Clin Management Res & Diabet QUERI, Ann Arbor, MI USA. [Helfrich, Christian D.] VA Puget Sound Healthcare Syst, NW HSR&D Ctr Excellence, Seattle, WA USA. [Helfrich, Christian D.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Hagedorn, Hildi J.] Minneapolis VA Med Ctr, VA Substance Use Disorders Qual Enhancement Res, Minneapolis, MN USA. [Hagedorn, Hildi J.] Univ Minnesota, Sch Med, Dept Psychiat, Minneapolis, MN 55455 USA. RP Stetler, CB (reprint author), Boston Univ, Sch Publ Hlth, Dept Hlth Serv, Boston, MA 02215 USA. EM cheryl.stetler@comcast.net RI Helfrich, Christian/D-2382-2016; OI Helfrich, Christian/0000-0002-9827-4768; Damschroder, Laura/0000-0002-3657-8459 FU U.S. Department of Veterans Affairs, Office of Research and Development Health Services FX This material is based upon work supported by the U.S. Department of Veterans Affairs, Office of Research and Development Health Services R&D Program. NR 37 TC 88 Z9 89 U1 4 U2 27 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD AUG 30 PY 2011 VL 6 AR 99 DI 10.1186/1748-5908-6-99 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 828AJ UT WOS:000295472200001 PM 21878092 ER PT J AU Oberaigner, W Daniaux, M Geiger-Gritsch, S Knapp, R Siebert, U Buchberger, W AF Oberaigner, Willi Daniaux, Martin Geiger-Gritsch, Sabine Knapp, Rudolf Siebert, Uwe Buchberger, Wolfgang TI Introduction of organised mammography screening in Tyrol: results following first year of complete rollout SO BMC PUBLIC HEALTH LA English DT Article ID BREAST-CANCER; PROGRAM AB Background: In Tyrol, Austria, the existing system of spontaneous mammography screening was switched in 2007 to an organised program by smoothly changing the established framework. This process followed most EU recommendations for organised mammography screening with the following exceptions: women aged 40-49 are part of the target population, screening is offered annually to the age group 40-59, breast ultrasound is available as an additional diagnostic tool, and double reading has not yet been implemented. After a pilot phase the program was rolled out to all of Tyrol in June 2008. The aim of this study was to analyse the performance of the organised screening system by comparing quality indices and recommended levels given in the well-established EU guidelines. Methods: Working from the results of the pilot phase, we extended the organised mammography system to all counties in Tyrol. All women living in Tyrol and covered by compulsory social insurance were invited for a mammography, in the age group 40-59 annually and in the age group 60-69 biennially. Screening mammography was offered mainly by radiologists in private practice, with further assessment performed at hospitals. Using the screening database, all well-established performance indicators were analysed and compared with accepted/desired levels as per the EU guidelines. Results: From June 2008 to May 2009, 120,440 women were invited. Per 1000 mammograms, 14 women were recalled for further assessment, nine underwent biopsy and four cancer cases were detected. Of invasive breast cancer cases, 32.3% and 68.4% were <= 10 mm and <= 15 mm in size, respectively, and 79.2% were node-negative. The positive predictive value for further assessment and for biopsy was 25.9% and 39.9%, respectively. Estimated two-year participation rate was 57.0%. In total, 14 interval cancer cases were detected during one year of follow-up; this is 18.4% of the background incidence rate. Conclusions: In Tyrol, Austria, an organised mammography screening program was implemented in a smooth transition from an existing spontaneous screening system and was completely rolled out within a short time. The high level of performance already seen in the pilot phase was maintained after rollout, and improvements resulting from the pilot phase were affirmed after one year of complete rollout. C1 [Oberaigner, Willi; Geiger-Gritsch, Sabine] Tyrolean State Hosp Ltd, Canc Registry Tyrol, Dept Clin Epidemiol, Innsbruck, Austria. [Oberaigner, Willi; Siebert, Uwe; Buchberger, Wolfgang] Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth & Hlth Technol Assessment, UMIT, Inst Publ Hlth Med Decis Making & Hlth Technol As, Hall In Tirol, Austria. [Oberaigner, Willi; Siebert, Uwe] Ctr Personalized Canc Med, ONCOTYROL, Innsbruck, Austria. [Daniaux, Martin] Innsbruck Med Univ, Dept Radiol, Innsbruck, Austria. [Knapp, Rudolf] Kufstein Cty Hosp, Dept Radiol, Kufstein, Austria. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Buchberger, Wolfgang] Tyrolean State Hosp Ltd, Dept Med, Innsbruck, Austria. RP Oberaigner, W (reprint author), Tyrolean State Hosp Ltd, Canc Registry Tyrol, Dept Clin Epidemiol, Innsbruck, Austria. EM willi.oberaigner@iet.at FU ONCOTYROL Center for Personal Cancer Medicine; Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT); Austrian Federal Ministry of Economics, Family and Youth (BMWFJ); Tyrolean Future Foundation (TZS); State of Styria; UMIT - University for Health Sciences, Medical Informatics and Technology; Innsbruck Medical University; Tyrolean Health Insurance Fund; Tyrolean Health Company FX This work was supported by the ONCOTYROL Center for Personal Cancer Medicine. ONCOTYROL is a COMET Center funded by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT) and the Austrian Federal Ministry of Economics, Family and Youth (BMWFJ), the Tyrolean Future Foundation (TZS) and the State of Styria represented by the Styrian Business Promotion Agency (SFG) and supported by UMIT - University for Health Sciences, Medical Informatics and Technology, Innsbruck Medical University, Tyrolean Health Insurance Fund and Tyrolean Health Company. NR 17 TC 8 Z9 8 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD AUG 30 PY 2011 VL 11 AR 673 DI 10.1186/1471-2458-11-673 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 826UM UT WOS:000295380700001 PM 21878122 ER PT J AU Fox, ER Musani, SK Bidulescu, A Nagarajarao, HS Samdarshi, TE Gebreab, SY Sung, JH Steffes, MW Wang, TJ Taylor, HA Vasan, RS AF Fox, Ervin R. Musani, Solomon K. Bidulescu, Aurelian Nagarajarao, Harsha S. Samdarshi, Tandaw E. Gebreab, Samson Y. Sung, Jung Hye Steffes, Michael W. Wang, Thomas J. Taylor, Herman A. Vasan, Ramachandran S. TI Relation of Obesity to Circulating B-Type Natriuretic Peptide Concentrations in Blacks The Jackson Heart Study SO CIRCULATION LA English DT Article DE diabetes mellitus; hypertension; natriuretic peptide; obesity ID VENTRICULAR HYPERTROPHY; DIASTOLIC DYSFUNCTION; ATHEROSCLEROTIC RISK; RECEPTOR EXPRESSION; BLOOD-PRESSURE; BODY-MASS; HYPERTENSION; ASSOCIATION; FAILURE; IMPACT AB Background-Lower plasma B-type natriuretic peptide (BNP) concentrations in obese individuals ("natriuretic handicap") may play a role in the pathogenesis of obesity-related hypertension. Whether this phenomenon may contribute to hypertension in blacks is unknown. We tested the hypothesis that body mass index is inversely related to BNP concentrations in blacks. Methods and Results-We examined the relation of plasma BNP to body mass index in 3742 Jackson Heart Study participants (mean age, 55 +/- 13; 62% women) without heart failure using multivariable linear and logistic regression, adjusting for clinical and echocardiographic covariates. The multivariable-adjusted mean BNP was higher for lean participants compared with obese participants in both normotensive (P < 0.0001) and hypertensive (P < 0.0012) groups. In sex-specific analyses, the adjusted mean BNP was higher in lean hypertensive individuals compared with obese hypertensive individuals for both men (20.5 versus 10.9 pg/mL, respectively; P=0.0009) and women (20.0 versus 13.8 pg/mL; P=0.011). The differences between lean and obese participants were more pronounced in normotensive participants (men, 9.0 versus 4.4 pg/mL; P < 0.0001; women, 12.8 versus 8.4 pg/mL; P=0.0005). For both hypertensive and normotensive individuals in the pooled sample, multivariable-adjusted BNP was significantly related to both continuous body mass index (P < 0.05 and P < 0.0001, respectively) and categorical body mass index (P for trend < 0.006 and < 0.0001, respectively). Conclusion-Our cross-sectional study of a large community-based sample of blacks demonstrates that higher body mass index is associated with lower circulating BNP concentrations, thereby extending the concept of a natriuretic handicap in obese individuals observed in non-Hispanic whites to this high-risk population. (Circulation. 2011; 124: 1021-1027.) C1 [Fox, Ervin R.] Univ Mississippi, Med Ctr, Div Cardiovasc Dis, Jackson, MS 39216 USA. [Bidulescu, Aurelian] Morehouse Sch Med, Atlanta, GA 30310 USA. [Gebreab, Samson Y.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Sung, Jung Hye; Taylor, Herman A.] Jackson State Univ, Jackson, MS USA. [Steffes, Michael W.] Univ Minnesota, Minneapolis, MN USA. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02118 USA. RP Fox, ER (reprint author), Univ Mississippi, Med Ctr, Div Cardiovasc Dis, 2500 N State St, Jackson, MS 39216 USA. EM efox@medicine.umsmed.edu RI Bidulescu, Aurelian/N-2617-2014; OI Bidulescu, Aurelian/0000-0001-8211-8309; Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health [N01-HC-95170, N01-HC-95171, N01-HC-95172]; National Heart, Lung, and Blood Institute [HL076784]; National Center for Minority Health and Health Disparities; National Institute of Aging [AG028321]; National Institutes of Health, National Center for Research Resources [UL1 RR025008] FX The JHS is supported by National Institutes of Health contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172; HL076784 from the National Heart, Lung, and Blood Institute and the National Center for Minority Health and Health Disparities; and AG028321 from the National Institute of Aging. This study was partially supported by PHS Award UL1 RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources, to Dr Bidulescu. NR 24 TC 16 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 30 PY 2011 VL 124 IS 9 BP 1021 EP U88 DI 10.1161/CIRCULATIONAHA.110.991943 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 813BF UT WOS:000294340400012 PM 21824924 ER PT J AU Egan, BM Zhao, YM Axon, RN Brzezinski, WA Ferdinand, KC AF Egan, Brent M. Zhao, Yumin Axon, R. Neal Brzezinski, Walter A. Ferdinand, Keith C. TI Uncontrolled and Apparent Treatment Resistant Hypertension in the United States, 1988 to 2008 SO CIRCULATION LA English DT Article DE epidemiology; hypertension; population; race/ethnicity ID HIGH-BLOOD-PRESSURE; NUTRITION EXAMINATION SURVEY; JOINT NATIONAL COMMITTEE; DIABETES-MELLITUS; US POPULATION; ADULTS; HEALTH; PREVALENCE; TRENDS; AWARENESS AB Background-Despite progress, many hypertensive patients remain uncontrolled. Defining characteristics of uncontrolled hypertensives may facilitate efforts to improve blood pressure control. Methods and Results-Subjects included 13 375 hypertensive adults from National Health and Nutrition Examination Surveys (NHANESs) subdivided into 1988 to 1994, 1999 to 2004, and 2005 to 2008. Uncontrolled hypertension was defined as blood pressure >= 140/>= 90 mm Hg and apparent treatment-resistant hypertension (aTRH) when subjects reported taking >= 3 antihypertensive medications. Framingham 10-year coronary risk was calculated. Multivariable logistic regression was used to identify clinical characteristics associated with untreated, treated uncontrolled on 1 to 2 blood pressure medications, and aTRH across all 3 survey periods. More than half of uncontrolled hypertensives were untreated across surveys, including 52.2% in 2005 to 2008. Clinical factors linked with untreated hypertension included male sex, infrequent healthcare visits (0 to 1 per year), body mass index < 25 kg/m(2), absence of chronic kidney disease, and Framingham 10-year coronary risk < 10% (P < 0.01). Most treated uncontrolled patients reported taking 1 to 2 blood pressure medications, a proxy for therapeutic inertia. This group was older, had higher Framingham 10-year coronary risk than patients controlled on 1 to 2 medications (P < 0.01), and comprised 34.4% of all uncontrolled and 72.0% of treated uncontrolled patients in 2005 to 2008. We found that aTRH increased from 15.9% (1998-2004) to 28.0% (2005-2008) of treated patients (P < 0.001). Clinical characteristics associated with aTRH included >= 4 visits per year, obesity, chronic kidney disease, and Framingham 10-year coronary risk > 20% (P < 0.01). Conclusion-Untreated, undertreated, and aTRH patients have consistent characteristics that could inform strategies to improve blood pressure control by decreasing untreated hypertension, reducing therapeutic inertia in undertreated patients, and enhancing therapeutic efficiency in aTRH. (Circulation. 2011; 124: 1046-1058.) C1 [Egan, Brent M.; Zhao, Yumin; Axon, R. Neal; Brzezinski, Walter A.] Med Univ S Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Axon, R. Neal] Ralph H Johnson Vet Affairs Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charlestown, MA USA. [Ferdinand, Keith C.] Emory Univ, Div Cardiol, Dept Med, Atlanta, GA 30322 USA. RP Egan, BM (reprint author), Med Univ S Carolina, Dept Med, Div Gen Internal Med & Geriatr, 135 Rutledge Ave,1230 RT, Charleston, SC 29425 USA. EM eganbm@musc.edu FU state of South Carolina (Hypertension Initiative), National Institutes of Health (NIH), National Heart, Lung and Blood Institute [HL07080684]; NIH, National Institute of Diabetes and Digestive and Kidney Diseases [DK067615]; NIH, National Institute of Neurological Disorders and Stroke [NS058728]; US Army [W81XWH-10-2-0057]; Daiichi-Sankyo; Novartis; Takeda FX This work was supported in part by the state of South Carolina (Hypertension Initiative), National Institutes of Health (NIH) R01 National Heart, Lung and Blood Institute HL07080684, NIH R01 National Institute of Diabetes and Digestive and Kidney Diseases DK067615, NIH R01 National Institute of Neurological Disorders and Stroke NS058728, and US Army W81XWH-10-2-0057. The funding agencies were not involved in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.; Dr Egan has received grant support from Daiichi-Sankyo, Novartis, and Takeda; has served as a lecturer with honoraria on CME-accredited programs for the American Society of Hypertension Carolinas-Georgia-Florida Chapter and International Society of Hypertension in Blacks; and has been a consultant to NicOx. Dr Ferdinand has served on the speakers' bureau at AstraZeneca, Novartis, Forest, and Daiichi-Sankyo; has received honoraria from AstraZeneca, Novartis, and Forest; and has served as a consultant/advisory board member for AstraZeneca, Novartis, and Forest. The other authors report no conflicts. NR 35 TC 245 Z9 253 U1 1 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 30 PY 2011 VL 124 IS 9 BP 1046 EP 1058 DI 10.1161/CIRCULATIONAHA.111.030189 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 813BF UT WOS:000294340400015 PM 21824920 ER PT J AU Clause, A Nguyen, T Kandler, K AF Clause, Amanda Tuan Nguyen Kandler, Karl TI An acoustic startle-based method of assessing frequency discrimination in mice SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Acoustic startle response; Prepulse inhibition; Frequency discrimination; Mice; Auditory system; Behavior ID SENSORINEURAL HEARING-LOSS; AUDITORY-CORTEX; PREPULSE INHIBITION; REFLEX MODIFICATION; GAP DETECTION; RATS; LISTENERS; DOMAIN AB The acoustic startle response (ASR) is a reflexive contraction of skeletal muscles in response to a loud, abrupt acoustic stimulus. ASR magnitude is reduced if the startle stimulus is preceded by a weaker acoustic or non-acoustic stimulus, a phenomenon known as prepulse inhibition (PPI). PPI has been used to test various aspects of sensory discrimination in both animals and humans. Here we show that PPI of the ASR is an advantageous method of assessing frequency discrimination. We describe the apparatus and its performance testing frequency discrimination in young CD1 mice. Compared to classical conditioning paradigms, PPI of the ASR is less time consuming, produces robust results, and can be used without training even in young animals. This approach can be used to investigate the neuronal mechanisms underlying frequency discrimination, its maturation during development, and its relationship to tonotopic organization. (C) 2011 Elsevier B.V. All rights reserved. C1 [Clause, Amanda; Tuan Nguyen; Kandler, Karl] Univ Pittsburgh, Sch Med, Dept Otolaryngol, Pittsburgh, PA 15261 USA. [Clause, Amanda; Tuan Nguyen; Kandler, Karl] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA 15261 USA. [Clause, Amanda; Kandler, Karl] Univ Pittsburgh, Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA. [Clause, Amanda; Kandler, Karl] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. RP Clause, A (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. EM amanda_clause@meei.harvard.edu; atn@pitt.edu; kkarl@pitt.edu OI Kandler, Karl/0000-0002-6053-6400 FU National Institute on Deafness and Other Communication Disorders [RO1 04199]; National Institutes of Health [T32 NS007433]; National Science Foundation [DGE 0549352] FX We thank Courtney Pedersen for help with ABRs. This work was supported by the National Institute on Deafness and Other Communication Disorders Grant RO1 04199 (K.K.), a National Institutes of Health Basic Neuroscience Predoctoral Training Grant T32 NS007433 (A.C.), and a National Science Foundation IGERT Training Grant DGE 0549352 (A.C.). NR 27 TC 10 Z9 11 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 30 PY 2011 VL 200 IS 1 BP 63 EP 67 DI 10.1016/j.jneumeth.2011.05.027 PG 5 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 815DZ UT WOS:000294507600009 PM 21672556 ER PT J AU Ko, M Bandukwala, HS An, J Lamperti, ED Thompson, EC Hastie, R Tsangaratou, A Rajewsky, K Koralov, SB Rao, A AF Ko, Myunggon Bandukwala, Hozefa S. An, Jungeun Lamperti, Edward D. Thompson, Elizabeth C. Hastie, Ryan Tsangaratou, Angeliki Rajewsky, Klaus Koralov, Sergei B. Rao, Anjana TI Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MYELOPROLIFERATIVE NEOPLASMS; MYELODYSPLASTIC SYNDROMES; DNA METHYLTRANSFERASE; SELF-RENEWAL; MYELOID MALIGNANCIES; SOMATIC MUTATIONS; DNMT3A MUTATIONS; MUTANT TET2; 5-HYDROXYMETHYLCYTOSINE; HYPOMETHYLATION AB The Ten-Eleven-Translocation 2 (TET2) gene encodes a member of TET family enzymes that alters the epigenetic status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies, including myelodysplastic syndromes, myeloproliferative neoplasms, and chronic myelomonocytic leukemia. By analyzing mice with targeted disruption of the Tet2 catalytic domain, we show here that Tet2 is a critical regulator of self-renewal and differentiation of hematopoietic stem cells (HSCs). Tet2 deficiency led to decreased genomic levels of 5hmC and augmented the size of the hematopoietic stem/progenitor cell pool in a cell-autonomous manner. In competitive transplantation assays, Tet2-deficient HSCs were capable of multi-lineage reconstitution and possessed a competitive advantage over wild-type HSCs, resulting in enhanced hematopoiesis into both lymphoid and myeloid lineages. In vitro, Tet2 deficiency delayed HSC differentiation and skewed development toward the monocyte/macrophage lineage. Our data indicate that Tet2 has a critical role in regulating the expansion and function of HSCs, presumably by controlling 5hmC levels at genes important for the self-renewal, proliferation, and differentiation of HSCs. C1 [Ko, Myunggon; An, Jungeun; Hastie, Ryan; Tsangaratou, Angeliki; Rao, Anjana] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA. [Bandukwala, Hozefa S.; Lamperti, Edward D.; Thompson, Elizabeth C.; Rajewsky, Klaus; Rao, Anjana] Harvard Univ, Sch Med, Immune Dis Inst, Dept Pathol, Boston, MA 02115 USA. [Bandukwala, Hozefa S.; Lamperti, Edward D.; Thompson, Elizabeth C.; Rajewsky, Klaus; Rao, Anjana] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA. [Koralov, Sergei B.] NYU, Langone Med Ctr, Dept Pathol, New York, NY 10016 USA. RP Rao, A (reprint author), La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA. EM arao@liai.org FU National Institutes of Health (NIH) [AI44432, RC1 DA028422, HD065812, R37 AI054636]; Leukemia and Lymphoma Society; Lady Tata Memorial Trust; GlaxoSmithKline-Immune Disease Institute Alliance FX We thank members of the A.R. laboratory for valuable discussions. This work was funded by National Institutes of Health (NIH) Grants AI44432, RC1 DA028422, and HD065812 (to A.R.) and R37 AI054636 (to K. R.), a Special Fellow award from the Leukemia and Lymphoma Society (to M.K.), and postdoctoral fellowships from the Lady Tata Memorial Trust and from the GlaxoSmithKline-Immune Disease Institute Alliance (to H.S.B.). NR 41 TC 190 Z9 196 U1 2 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2011 VL 108 IS 35 BP 14566 EP 14571 DI 10.1073/pnas.1112317108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 814DH UT WOS:000294425900043 PM 21873190 ER PT J AU Leavenworth, JW Wang, XY Wenander, CS Spee, P Cantor, H AF Leavenworth, Jianmei W. Wang, Xiaoyang Wenander, Carola Schellack Spee, Pieter Cantor, Harvey TI Mobilization of natural killer cells inhibits development of collagen-induced arthritis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antibody therapy; Qa-1; T helper subsets ID CD4(+) T-CELLS; RHEUMATOID-ARTHRITIS; ANIMAL-MODELS; NK CELLS; AUTOIMMUNITY AB Although natural killer (NK) cells have been implicated in regulating immune responses, their ability to modulate disease development in autoimmune arthritis has not been analyzed. Here we investigate the contribution of NK cells to regulating collagen-induced arthritis, a well-characterized preclinical model of human rheumatoid arthritis. We find that the disease is induced by the combined action of two CD4(+) T helper (T-H) subsets: follicular T-H cells and T(H)17 cells. Both CD4(+) T-H subsets are highly susceptible to lysis by NK cells after activation. Administration of antibody that activates NK cells through blockade of its inhibitory CD94/NKG2A receptor allows enhanced elimination of pathogenic follicular T-H and T(H)17 cells and arrest of disease progression. These results suggest that antibody-dependent enhancement of NK activity may yield effective, previously undescribed therapeutic approaches to this autoimmune disorder. C1 [Leavenworth, Jianmei W.; Wang, Xiaoyang; Cantor, Harvey] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Leavenworth, Jianmei W.; Wang, Xiaoyang; Cantor, Harvey] Harvard Univ, Sch Med, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Wang, Xiaoyang] Univ Gothenburg, Sahlgrenska Acad, Dept Neurosci & Physiol, Perinatal Ctr, S-40530 Gothenburg, Sweden. [Wang, Xiaoyang] Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou 450052, Peoples R China. [Wenander, Carola Schellack] Novo Nordisk AS, Dept Immunopharmacol, DK-2760 Malov, Denmark. [Spee, Pieter] Novo Nordisk AS, Dept Translat Immunol, DK-2760 Malov, Denmark. RP Cantor, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM harvey_cantor@dfci.harvard.edu FU National Institutes of Health [AI 037562]; Novo Nordisk; National Research Service [T32 CA070083]; Swedish Research Council; National Natural Science Foundation of China FX This work was supported in part by National Institutes of Health Research Grant AI 037562 (to H. C.), a Collaborative Sponsored Research Agreement with Novo Nordisk (H. C.), a gift from The Leroy Schecter Research Foundation (H. C.), a Swedish Research Council Award (X. W.), and a grant from the National Natural Science Foundation of China (to X. W.). J.W.L. is a National Research Service Award Fellow (T32 CA070083). NR 20 TC 22 Z9 24 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2011 VL 108 IS 35 BP 14584 EP 14589 DI 10.1073/pnas.1112188108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 814DH UT WOS:000294425900046 PM 21873193 ER PT J AU Moon, JJ Dash, P Oguin, TH McClaren, JL Chu, HH Thomas, PG Jenkins, MK AF Moon, James J. Dash, Pradyot Oguin, Thomas H., III McClaren, Jennifer L. Chu, H. Hamlet Thomas, Paul G. Jenkins, Marc K. TI Quantitative impact of thymic selection on Foxp3(+) and Foxp3(-) subsets of self-peptide/MHC class II-specific CD4(+) T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tetramer; Treg; tolerance; T-cell receptor; transgenic ID TRANSCRIPTION FACTOR FOXP3; NEGATIVE SELECTION; CLONAL DELETION; EPITHELIAL-CELLS; TCR-ALPHA; REG CELLS; ANTIGEN; RECEPTOR; TOLERANCE; REPERTOIRE AB It is currently thought that T cells with specificity for self-peptide/MHC (pMHC) ligands are deleted during thymic development, thereby preventing autoimmunity. In the case of CD4(+) T cells, what is unclear is the extent to which self-peptide/MHC class II (pMHCII)-specific T cells are deleted or become Foxp3(+) regulatory T cells. We addressed this issue by characterizing a natural polyclonal pMHCII-specific CD4(+) T-cell population in mice that either lacked or expressed the relevant antigen in a ubiquitous pattern. Mice expressing the antigen contained one-third the number of pMHCII-specific T cells as mice lacking the antigen, and the remaining cells exhibited low TCR avidity. In mice lacking the antigen, the pMHCII-specific T-cell population was dominated by phenotypically naive Foxp3(-) cells, but also contained a subset of Foxp3(+) regulatory cells. Both Foxp3(-) and Foxp3(+) pMHCII-specific T-cell numbers were reduced in mice expressing the antigen, but the Foxp3(+) subset was more resistant to changes in number and TCR repertoire. Therefore, thymic selection of self-pMHCII-specific CD4(+) T cells results in incomplete deletion within the normal polyclonal repertoire, especially among regulatory T cells. C1 [Moon, James J.; Chu, H. Hamlet; Jenkins, Marc K.] Univ Minnesota, Sch Med, Dept Microbiol, Minneapolis, MN 55455 USA. [Moon, James J.; Chu, H. Hamlet; Jenkins, Marc K.] Univ Minnesota, Sch Med, Ctr Immunol, Minneapolis, MN 55455 USA. [Dash, Pradyot; Oguin, Thomas H., III; McClaren, Jennifer L.; Thomas, Paul G.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. RP Moon, JJ (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, 149 13th St, Charlestown, MA 02129 USA. EM jjmoon@mgh.harvard.edu RI Jenkins, Marc/G-1063-2012; OI Jenkins, Marc/0000-0001-8009-7655; Dash, Pradyot/0000-0001-5467-0657; Thomas, Paul G./0000-0001-7955-0256 FU National Institutes of Health [F32 AI63793, R01 AI077714, R01 AI35296]; American Heart Association; Department of Health and Human Services [HHSN266200700005C]; American Syrian Lebanese Associated Charities FX We thank Drs. A. Rudensky for Foxp3GFP mice, S. Way for 2W-expressing L. monocytogenes, and T. Dileepan and P. Cleary for 2W-expressing S. pyogenes. We also thank Drs. J. Kappler, A. Liu, W. Kwok, and T. Cameron for technical expertise and materials related to tetramer construction and J. Walter, R. Speier, A. Schmidt, and M. Preiss for assistance with mice. This work was supported by the National Institutes of Health (F32 AI63793 to J. J. M., R01 AI077714 to P.G.T., R01 AI35296 to M. K. J.), the American Heart Association (fellowship to H. H. C.), the Department of Health and Human Services (HHSN266200700005C to P.G.T.), and the American Syrian Lebanese Associated Charities (P.G.T.). NR 46 TC 47 Z9 47 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2011 VL 108 IS 35 BP 14602 EP 14607 DI 10.1073/pnas.1109806108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 814DH UT WOS:000294425900049 PM 21873213 ER PT J AU Jing, EX Emanuelli, B Hirschey, MD Boucher, J Lee, KY Lombard, D Verdin, EM Kahn, CR AF Jing, Enxuan Emanuelli, Brice Hirschey, Matthew D. Boucher, Jeremie Lee, Kevin Y. Lombard, David Verdin, Eric M. Kahn, C. Ronald TI Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mitochondrial metabolism; protein acetylation ID LYSINE ACETYLATION; DIABETES-MELLITUS; GENE-EXPRESSION; POTENTIAL ROLE; RESISTANCE; STRESS; MICE; DEACETYLASE; HOMOLOG; HUMANS AB Sirt3 is a member of the sirtuin family of protein deacetylases that is localized in mitochondria and regulates mitochondrial function. Sirt3 expression in skeletal muscle is decreased in models of type 1 and type 2 diabetes and regulated by feeding, fasting, and caloric restriction. Sirt3 knockout mice exhibit decreased oxygen consumption and develop oxidative stress in skeletal muscle, leading to JNK activation and impaired insulin signaling. This effect is mimicked by knockdown of Sirt3 in cultured myoblasts, which exhibit reduced mitochondrial oxidation, increased reactive oxygen species, activation of JNK, increased serine and decreased tyrosine phosphorylation of IRS-1, and decreased insulin signaling. Thus, Sirt3 plays an important role in diabetes through regulation of mitochondrial oxidation, reactive oxygen species production, and insulin resistance in skeletal muscle. C1 [Jing, Enxuan; Emanuelli, Brice; Boucher, Jeremie; Lee, Kevin Y.; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Hirschey, Matthew D.; Verdin, Eric M.] Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. [Hirschey, Matthew D.; Verdin, Eric M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lombard, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu RI Emanuelli, Brice/M-2097-2016; OI Verdin, Eric/0000-0003-3703-3183; Hirschey, Matthew/0000-0003-4541-5376 FU Ellison Foundation; Mary K. Iacocca Professorship; Joslin Diabetes Endocrinology Research Center core laboratories; [R01DK33201]; [R24DK085610] FX We thank Dr. Marcelo Mori and Dr. Steven Russell for providing CR mice skeletal muscles. We also thank Dr. Stephane Gesta for active discussion and help with the Seahorse Bioscience analysis. The work was supported by research Grants R01DK33201 (to C. R. K) and R24DK085610 (to C. R. K and E. M. V.), a grant from the Ellison Foundation (to C. R. K.), and the Mary K. Iacocca Professorship. This study also received support from the Joslin Diabetes Endocrinology Research Center core laboratories. NR 41 TC 148 Z9 158 U1 2 U2 21 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2011 VL 108 IS 35 BP 14608 EP 14613 DI 10.1073/pnas.1111308108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 814DH UT WOS:000294425900050 PM 21873205 ER PT J AU Dewland, TA Pellegrini, CN Wang, YF Marcus, GM Keung, E Varosy, PD AF Dewland, Thomas A. Pellegrini, Cara N. Wang, Yongfei Marcus, Gregory M. Keung, Edmund Varosy, Paul D. TI Dual-Chamber Implantable Cardioverter-Defibrillator Selection Is Associated With Increased Complication Rates and Mortality Among Patients Enrolled in the NCDR Implantable Cardioverter-Defibrillator Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE complication; defibrillator; dual-chamber ICD ID DETECTION ENHANCEMENTS; INAPPROPRIATE THERAPY; TRIAL AB Objectives The aim of this study was to compare single-versus dual-chamber implantable cardioverter-defibrillator (ICD) implantation and complication rates in a large, real-world population. Background The majority of patients enrolled in ICD efficacy trials received single-chamber devices. Although dual-chamber ICDs offer theoretical advantages over single-chamber defibrillators, the clinical superiority of dual-chamber models has not been conclusively proven, and they may increase complications. Methods The National Cardiovascular Data Registry ICD Registry was used to examine the association between baseline characteristics and device selection in 104,049 patients receiving single-and dual-chamber ICDs between January 1, 2006, and December 31, 2007. A longitudinal cohort design was then used to determine in-hospital complication rates. Results Dual-chamber devices were implanted in 64,489 patients (62%). Adverse events were more frequent with dual-chamber than with single-chamber device implantation (3.17% vs. 2.11%, p < 0.001), as was the rate of inhospital mortality (0.40% vs. 0.23%, p < 0.001). After adjusting for demographics, medical comorbidities, diagnostic test data, and ICD indication, the odds of any complication (odds ratio: 1.40; 95% confidence interval: 1.28 to 1.52; p < 0.001) and in-hospital mortality (odds ratio: 1.45; 95% confidence interval: 1.20 to 1.74; p < 0.001) were increased with dual-chamber versus single-chamber ICD implantation. Conclusions In this large, multicenter cohort of patients, dual-chamber ICD use was common. Dual-chamber device implantation was associated with increases in periprocedural complications and in-hospital mortality compared with single-chamber defibrillator selection. (J Am Coll Cardiol 2011; 58: 1007-13) (C) 2011 by the American College of Cardiology Foundation C1 [Varosy, Paul D.] Univ Colorado, Denver Vet Affairs Med Ctr, VA Eastern Colorado Hlth Care Syst, Denver, CO 80220 USA. [Dewland, Thomas A.] Univ Calif San Francisco, Div Cardiol, San Francisco, CA USA. [Pellegrini, Cara N.; Marcus, Gregory M.; Keung, Edmund] Univ Calif San Francisco, Electrophysiol Sect, San Francisco, CA 94143 USA. [Wang, Yongfei] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Pellegrini, Cara N.; Keung, Edmund] VA Med Ctr San Francisco, Cardiol Sect, San Francisco, CA USA. [Varosy, Paul D.] Colorado Cardiovasc Outcomes Res Grp, Denver, CO USA. RP Varosy, PD (reprint author), Univ Colorado, Denver Vet Affairs Med Ctr, VA Eastern Colorado Hlth Care Syst, 1055 Clermont St, Denver, CO 80220 USA. EM paul.varosy@va.gov FU Veterans Administration Office of Health Services Research and Development [RCD 04-115-2]; St. Jude Medical; Biotronik FX Funding for this study was provided in part by a Research Career Development Award (RCD 04-115-2 to Dr. Varosy) from the Veterans Administration Office of Health Services Research and Development. Dr. Marcus has received research funding from St. Jude Medical and speaker's fees from Biotronik and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 15 TC 65 Z9 68 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 30 PY 2011 VL 58 IS 10 BP 1007 EP 1013 DI 10.1016/j.jacc.2011.04.039 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 811JR UT WOS:000294205900004 PM 21867834 ER PT J AU Melonakos, ED Shenton, ME Rathi, Y Terry, DP Bouix, S Kubicki, M AF Melonakos, Eric D. Shenton, Martha E. Rathi, Yogesh Terry, Douglas P. Bouix, Sylvain Kubicki, Marek TI Voxel-based morphometry (VBM) studies in schizophrenia-can white matter changes be reliably detected with VBM? SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Review DE Diffusion tensor imaging; Meta-analysis; Chronic schizophrenia; First-episode schizophrenia; Fractional anisotropy ID EARLY-ONSET SCHIZOPHRENIA; DIFFUSION TENSOR; 1ST-EPISODE SCHIZOPHRENIA; AUDITORY HALLUCINATIONS; UNCINATE FASCICULUS; CORPUS-CALLOSUM; WHOLE-BRAIN; EARLY-STAGE; ABNORMALITIES; INTEGRITY AB Voxel-based morphometry (VBM) is a hypothesis-free, whole-brain, voxel-by-voxel analytic method that attempts to compare imaging data between populations. Schizophrenia studies have utilized this method to localize differences in diffusion tensor imaging (DTI) derived fractional anisotropy (FA), a measure of white matter integrity, between patients and healthy controls. The number of publications has grown, although it is unclear how reliable and reproducible this method is, given the subtle white matter abnormalities expected in schizophrenia. Here we analyze and combine results from 23 studies published to date that use VBM to study schizophrenia in order to evaluate the reproducibility of this method in DTI analysis. Coordinates of each region reported in DTI VBM studies published thus far in schizophrenia were plotted onto a Montreal Neurological Institute atlas, and their anatomical locations were recorded. Results indicated that the reductions of FA in patients with schizophrenia were scattered across the brain. Moreover, even the most consistently reported regions were reported independently in less than 35% of the articles studied. Other instances of reduced FA were replicated at an even lower rate. Our findings demonstrate striking inconsistency, with none of the regions reported in much more than a third of the published articles. This poor replication rate suggests that the application of VBM to DTI data may not be the optimal way for finding the subtle microstructural abnormalities suggested in schizophrenia. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Melonakos, Eric D.; Shenton, Martha E.; Rathi, Yogesh; Terry, Douglas P.; Bouix, Sylvain; Kubicki, Marek] Harvard Univ, Sch Med, Brigham & Womens Hosp, Psychiat Neuroimaging Lab,Dept Psychiat, Boston, MA 02215 USA. [Shenton, Martha E.; Kubicki, Marek] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Dept Psychiat, Boston, MA 02215 USA. RP Kubicki, M (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Psychiat Neuroimaging Lab,Dept Psychiat, 1249 Boylston St, Boston, MA 02215 USA. EM kubicki@bwh.harvard.edu OI Bouix, Sylvain/0000-0003-1326-6054; Melonakos, Eric D./0000-0002-3643-9838 FU National Institute of Health [K05 MH070047, R01 MH 50740, R01 MH 082918, R01MH 074794, P50MH 080272]; Department of Veterans Affairs; VA Schizophrenia Center; National Institutes of Health through the NIH Roadmap for Medical Research [U54 EB005149] FX This work was supported by the National Institute of Health (K05 MH070047 and R01 MH 50740 to MES, R01 MH 082918 to SB and R01MH 074794 to MK, P50MH 080272 to MES), the Department of Veterans Affairs Merit Awards (MES), the VA Schizophrenia Center Grant (MES). This work is also part of the National Alliance for Medical Image Computing (NAMIC), funded by the National Institutes of Health through the NIH Roadmap for Medical Research, Grant U54 EB005149 (MK, MES). NR 63 TC 40 Z9 42 U1 1 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD AUG 30 PY 2011 VL 193 IS 2 BP 65 EP 70 DI 10.1016/j.pscychresns.2011.01.009 PG 6 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 799CA UT WOS:000293259900001 PM 21684124 ER PT J AU Cardenas, VA Samuelson, K Lenoci, M Studholme, C Neylan, TC Marmar, CR Schuff, N Weiner, MW AF Cardenas, Valerie A. Samuelson, Kristin Lenoci, Maryann Studholme, Colin Neylan, Thomas C. Marmar, Charles R. Schuff, Norbert Weiner, Michael W. TI Changes in brain anatomy during the course of posttraumatic stress disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Deformation morphometry; Longitudinal; MRI; Neuropsychological testing; PTSD; Vietnam veterans ID ADMINISTERED PTSD SCALE; HIPPOCAMPAL VOLUME; N-ACETYLASPARTATE; MEMORY; SURVIVORS; TRAUMA; ABUSE; MRI; CINGULATE; ANTERIOR AB The goal of this study was to determine whether posttraumatic stress disorder (PTSD) was associated with an increase in time-related decline in macrostructural brain volume and whether these changes were associated with accelerated cognitive decline. To quantify brain structure, three-dimensional T1 weighted MRI scans were performed at baseline and again after a minimum of 24 months in 25 patients with PTSD (PTSD+) and 22 controls (PTSD-). Longitudinal changes in brain volume were measured using deformation morphometry. For the group as a whole. PTSD+ patients did not show significant ongoing brain atrophy compared to PTSD-. PTSD+ patients were then subgrouped into those with decreasing or increasing symptoms. We found little evidence for brain markers of accelerated atrophy in PTSD+ veterans whose symptoms improved over time, with only a small left parietal region showing greater ongoing tissue loss than PTSD-. PTSD patients whose symptoms increased over time showed accelerated atrophy throughout the brain, particularly brainstem and frontal and temporal lobes. Lastly, for the sample as a whole, greater rates of brain atrophy were associated with greater rates of decline in verbal memory and delayed facial recognition. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Cardenas, Valerie A.] Univ Calif San Francisco, Dept Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Cardenas, Valerie A.; Samuelson, Kristin; Lenoci, Maryann; Neylan, Thomas C.; Marmar, Charles R.; Schuff, Norbert; Weiner, Michael W.] San Francisco VA Med Ctr, San Francisco, CA USA. [Samuelson, Kristin] Alliant Int Univ, San Francisco, CA USA. [Marmar, Charles R.] NYU, New York, NY USA. RP Cardenas, VA (reprint author), Univ Calif San Francisco, Dept Vet Affairs Med Ctr, 4150 Clement St,114M, San Francisco, CA 94121 USA. EM valerie.cardenas-nicolson@ucsf.edu RI Schueter, nicos/A-3625-2014 FU DOD Center of Excellence [W81XWH-05-2-0094 I (PI: Cardenas)]; NIBIB [R03EB8136]; Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center (MIRECC); Department of Veterans Affairs; NCRR [P41RR023953] FX We are grateful to the staff at the Center for Imaging of Neurodegenerative Diseases at the San Francisco VA Hospital for the MRI scanning, and to Linda Chao, Susanne Mueller, Brigitte Apfel, and Tim Durazzo for their helpful comments. This work was partially supported by a DOD Center of Excellence Grant W81XWH-05-2-0094 I (PI: Cardenas), NIBIB R03EB8136 (PI: Cardenas), the Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), a Department of Veterans Affairs Merit Award Grant (PI: Weiner), and NCRR P41RR023953. NR 47 TC 16 Z9 18 U1 2 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD AUG 30 PY 2011 VL 193 IS 2 BP 93 EP 100 DI 10.1016/j.pscychresns.2011.01.013 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 799CA UT WOS:000293259900005 PM 21683556 ER PT J AU O'Brien, LM Ziegler, DA Deutsch, CK Frazier, JA Herbert, MR Locascio, JJ AF O'Brien, Liam M. Ziegler, David A. Deutsch, Curtis K. Frazier, Jean A. Herbert, Martha R. Locascio, Joseph J. TI Statistical adjustments for brain size in volumetric neuroimaging studies: Some practical implications in methods SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE MRI; Statistics; Regression models; Morphometry ID WHITE-MATTER; CEREBRAL-CORTEX; GRAY-MATTER; HEAD SIZE; MORPHOMETRIC-ANALYSIS; HIPPOCAMPAL VOLUME; HUMAN NEOCORTEX; SEX-DIFFERENCES; AUTISM; MRI AB Volumetric magnetic resonance imaging (MRI) brain data provide a valuable tool for detecting structural differences associated with various neurological and psychiatric disorders. Analysis of such data, however, is not always straightforward, and complications can arise when trying to determine which brain structures are "smaller" or "larger" in light of the high degree of individual variability across the population. Several statistical methods for adjusting for individual differences in overall cranial or brain size have been used in the literature, but critical differences exist between them. Using agreement among those methods as an indication of stronger support of a hypothesis is dangerous given that each requires a different set of assumptions be met. Here we examine the theoretical underpinnings of three of these adjustment methods (proportion, residual, and analysis of covariance) and apply them to a volumetric MRI data set. These three methods used for adjusting for brain size are specific cases of a generalized approach which we propose as a recommended modeling strategy. We assess the level of agreement among methods and provide graphical tools to assist researchers in determining how they differ in the types of relationships they can unmask, and provide a useful method by which researchers may tease out important relationships in volumetric MRI data. We conclude with the recommended procedure involving the use of graphical analyses to help uncover potential relationships the ROI volumes may have with head size and give a generalized modeling strategy by which researchers can make such adjustments that include as special cases the three commonly employed methods mentioned above. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [O'Brien, Liam M.] Colby Coll, Dept Math & Stat, Waterville, ME 04901 USA. [Ziegler, David A.; Locascio, Joseph J.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Deutsch, Curtis K.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Deutsch, Curtis K.] Eunice Kennedy Shriver Ctr Mental Retardat Inc, Waltham, MA USA. [Deutsch, Curtis K.] McLean Hosp, Belmont, MA 02178 USA. [Frazier, Jean A.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Herbert, Martha R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Herbert, Martha R.; Locascio, Joseph J.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP O'Brien, LM (reprint author), Colby Coll, Dept Math & Stat, 5838 Mayflower Hill, Waterville, ME 04901 USA. EM lobrien@colby.edu FU Division of Natural Sciences at Colby College FX This work was supported, in part, by a grant from the Division of Natural Sciences at Colby College. We would like to thank two anonymous reviewers and the Editor for their helpful and constructive suggestions. NR 44 TC 23 Z9 23 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD AUG 30 PY 2011 VL 193 IS 2 BP 113 EP 122 DI 10.1016/j.pscychresns.2011.01.007 PG 10 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 799CA UT WOS:000293259900008 PM 21684724 ER PT J AU Lee, JM Pinto, RM Gillis, T St Claire, JC Wheeler, VC AF Lee, Jong-Min Pinto, Ricardo Mouro Gillis, Tammy St Claire, Jason C. Wheeler, Vanessa C. TI Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver SO PLOS ONE LA English DT Article ID HUNTINGTONS-DISEASE; TRINUCLEOTIDE REPEAT; LENGTH; MOUSE; MUTATION; CELLS; GENE; VULNERABILITY; NEURONS; BRAIN AB Background: Age at onset of Huntington's disease (HD) is largely determined by the CAG trinucleotide repeat length in the HTT gene. Importantly, the CAG repeat undergoes tissue-specific somatic instability, prevalent in brain regions that are disease targets, suggesting a potential role for somatic CAG repeat instability in modifying HD pathogenesis. Thus, understanding underlying mechanisms of somatic CAG repeat instability may lead to discoveries of novel therapeutics for HD. Investigation of the dynamics of the CAG repeat size changes over time may provide insights into the mechanisms underlying CAG repeat instability. Methodology/Principal Findings: To understand how the HTT CAG repeat length changes over time, we quantified somatic instability of the CAG repeat in Huntington's disease CAG knock-in mice from 2-16 months of age in liver, striatum, spleen and tail. The HTT CAG repeat in spleen and tail was very stable, but that in liver and striatum expanded over time at an average rate of one CAG per month. Interestingly, the patterns of repeat instability were different between liver and striatum. Unstable CAG repeats in liver repeatedly gained similar sizes of additional CAG repeats (approximately two CAGs per month), maintaining a distinct population of unstable repeats. In contrast, unstable CAG repeats in striatum gained additional repeats with different sizes resulting in broadly distributed unstable CAG repeats. Expanded CAG repeats in the liver were highly enriched in polyploid hepatocytes, suggesting that the pattern of liver instability may reflect the restriction of the unstable repeats to a unique cell type. Conclusions/Significance: Our results are consistent with repeat expansion occurring as a consequence of recurrent small repeat insertions that differ in different tissues. Investigation of the specific mechanisms that underlie liver and striatal instability will contribute to our understanding of the relationship between instability and disease and the means to intervene in this process. C1 [Lee, Jong-Min; Pinto, Ricardo Mouro; Gillis, Tammy; St Claire, Jason C.; Wheeler, Vanessa C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM jlee51@partners.org; wheeler@chgr.mgh.harvard.edu FU National Institute of Neurological Disorders and Stroke [NS049206] FX This work is supported by National Institute of Neurological Disorders and Stroke grant NS049206 to VCW. The funder had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 15 Z9 15 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 29 PY 2011 VL 6 IS 8 AR e23647 DI 10.1371/journal.pone.0023647 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 817MF UT WOS:000294676900014 PM 21897851 ER PT J AU Zhang, EZ Vakoc, BJ AF Zhang, Ellen Ziyi Vakoc, Benjamin J. TI Polarimetry noise in fiber-based optical coherence tomography instrumentation SO OPTICS EXPRESS LA English DT Article ID POLARIZATION-MODE DISPERSION; BIREFRINGENCE; TISSUE; OCT; COLLAGEN AB High noise levels in fiber-based polarization-sensitive optical coherence tomography (PS-OCT) have broadly limited its clinical utility. In this study we investigate contribution of polarization mode dispersion (PMD) to the polarimetry noise. We develop numerical models of the PS-OCT system including PMD and validate these models with empirical data. Using these models, we provide a framework for predicting noise levels, for processing signals to reduce noise, and for designing an optimized system. (C) 2011 Optical Society of America C1 [Zhang, Ellen Ziyi] Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zhang, EZ (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. EM zzhang0@partners.org FU US National Institutes of Health [K25-CA127465]; Center for Integration of Medicine & Innovative Technology (CIMIT) FX We would like to thank Zhongxi Zhang at University of Ottawa for valuable discussion on simulation of polarization mode dispersion. This research was supported in part by US National Institutes of Health grant K25-CA127465 and Center for Integration of Medicine & Innovative Technology (CIMIT). NR 27 TC 19 Z9 19 U1 0 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD AUG 29 PY 2011 VL 19 IS 18 BP 16830 EP 16842 DI 10.1364/OE.19.016830 PG 13 WC Optics SC Optics GA 814XE UT WOS:000294489700011 PM 21935044 ER PT J AU Medyouf, H Gusscott, S Wang, HF Tseng, JC Wai, C Nemirovsky, O Trumpp, A Pflumio, F Carboni, J Gottardis, M Pollak, M Kung, AL Aster, JC Holzenberger, M Weng, AP AF Medyouf, Hind Gusscott, Samuel Wang, Hongfang Tseng, Jen-Chieh Wai, Carol Nemirovsky, Oksana Trumpp, Andreas Pflumio, Francoise Carboni, Joan Gottardis, Marco Pollak, Michael Kung, Andrew L. Aster, Jon C. Holzenberger, Martin Weng, Andrew P. TI High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; GAMMA-SECRETASE INHIBITORS; C-MYC; GLUCOCORTICOID RESISTANCE; GENE-EXPRESSION; STEM-CELLS; GROWTH; PTEN; ACTIVATION; RECEPTOR AB T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of Notch1 and PI3K-Akt pathways. Although mutations that activate PI3K-Akt signaling have previously been identified, the relative contribution of growth factor-dependent activation is unclear. We show here that pharmacologic inhibition or genetic deletion of insulin-like growth factor 1 receptor (IGF1R) blocks the growth and viability of T-ALL cells, whereas moderate diminution of IGF1R signaling compromises leukemia-initiating cell (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, IGF1R is a Notch1 target, and Notch1 signaling is required to maintain IGF1R expression at high levels in T-ALL cells. These findings suggest effects of Notch on LIC activity may be mediated in part by enhancing the responsiveness of T-ALL cells to ambient growth factors, and provide strong rationale for use of IGF1R inhibitors to improve initial response to therapy and to achieve long-term cure of patients with T-ALL. C1 [Medyouf, Hind; Gusscott, Samuel; Wai, Carol; Nemirovsky, Oksana; Weng, Andrew P.] BC Canc Agcy, Dept Pathol, Terry Fox Lab, Vancouver, BC V52 1L3, Canada. [Wang, Hongfang; Aster, Jon C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Tseng, Jen-Chieh; Kung, Andrew L.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Trumpp, Andreas] German Canc Res Ctr, Heidelberg Inst Stem Cell Technol & Expt Med HI S, D-69120 Heidelberg, Germany. [Trumpp, Andreas] German Canc Res Ctr, Div Stem Cells & Canc, D-69120 Heidelberg, Germany. [Pflumio, Francoise] Univ Paris 07, CEA, INSERM, U967,LSHL IRCM, F-92265 Fontenay Aux Roses, France. [Carboni, Joan; Gottardis, Marco] Bristol Myers Squibb Co, Oncol Drug Discovery, Princeton, NJ 08543 USA. [Pollak, Michael] McGill Univ, Dept Oncol, Montreal, PQ H3T 1E2, Canada. [Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kung, Andrew L.] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. [Holzenberger, Martin] Univ Paris 06, Ctr Rech Inst Natl Sante & Rech Med St Antoine, F-75571 Paris, France. RP Weng, AP (reprint author), BC Canc Agcy, Dept Pathol, Terry Fox Lab, Vancouver, BC V52 1L3, Canada. EM h.medyouf@dkfz-heidelberg.de; aweng@bccrc.ca RI Pollak, Michael/G-9094-2011; Weng, Andrew/I-5015-2014; Pflumio, Francoise/E-2074-2017; OI Pollak, Michael/0000-0003-3047-0604; Kung, Andrew/0000-0002-9091-488X; Medyouf, Hind/0000-0003-4652-9455 FU Canadian Cancer Society Research Institute/Terry Fox Foundation; US National Cancer Institute [K22CA112538, P01CA119070]; Leukemia and Lymphoma Society of Canada; Lymphoma Foundation Canada; Cancer Research Society; Agence Nationale de la Recherche [NT05-3 42491]; Human Frontier Science Program Fellowship; Leukemia and Lymphoma Society; William Lawrence Foundation FX This work was funded by grants from the Canadian Cancer Society Research Institute/Terry Fox Foundation, US National Cancer Institute (K22CA112538, P01CA119070), Leukemia and Lymphoma Society of Canada, Lymphoma Foundation Canada, Cancer Research Society, and Agence Nationale de la Recherche (NT05-3 42491). H. Medyouf is supported by a Human Frontier Science Program Fellowship. J.C. Aster is supported by grants from the Leukemia and Lymphoma Society and the William Lawrence Foundation. A.P. Weng is a Michael Smith Foundation for Health Research Scholar. NR 66 TC 65 Z9 68 U1 1 U2 8 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 29 PY 2011 VL 208 IS 9 BP 1809 EP 1822 DI 10.1084/jem.20110121 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 812YD UT WOS:000294329600008 PM 21807868 ER PT J AU Bradner, J AF Bradner, James TI Chemical inhibition of human bromdomains SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Bradner, James] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM james_bradner@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 92-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300815 ER PT J AU Chen, O Popovic, Z Liu, WH Chauhan, V Fukumura, D Jain, R Bawendi, M AF Chen, Ou Popovic, Zoran Liu, Wenhao Chauhan, Vikash Fukumura, Dai Jain, Rakesh Bawendi, Moungi TI Nanoparticle size and shape series for in vivo fluorescence imaging SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Chen, Ou; Popovic, Zoran; Liu, Wenhao; Bawendi, Moungi] MIT, Cambridge, MA 02139 USA. [Chauhan, Vikash; Fukumura, Dai; Jain, Rakesh] Massachusetts Gen Hosp, Boston, MA 02139 USA. [Chauhan, Vikash; Fukumura, Dai; Jain, Rakesh] Harvard Univ, Sch Med, Boston, MA 02139 USA. EM chenou@mit.edu NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 223-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378301637 ER PT J AU Gray, NS AF Gray, Nathanael S. TI Overcoming kinase inhibitor resistance: EGFR, Bcr-Abl, and b-Raf SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Gray, Nathanael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. EM Nathanael_gray@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 94-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378300817 ER PT J AU Knutson, CG Sarkar, U Wishnok, JS Korzenik, JR Tannenbaum, SR AF Knutson, Charles G. Sarkar, Ujjal Wishnok, John S. Korzenik, Joshua R. Tannenbaum, Steven R. TI Use of an aldehyde reactive probe to capture protein carbonyls SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Knutson, Charles G.; Sarkar, Ujjal; Wishnok, John S.; Tannenbaum, Steven R.] MIT, Cambridge, MA 02139 USA. [Korzenik, Joshua R.] Massachusetts Gen Hosp, Crohns & Colitis Ctr, Boston, MA 02114 USA. EM knutson@mit.edu NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 17-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378307482 ER PT J AU Liong, M Tassa, C Shaw, SY Lee, H Weissleder, R AF Liong, Monty Tassa, Carlos Shaw, Stanley Y. Lee, Hakho Weissleder, Ralph TI Multiplexed magnetic labeling amplification SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Liong, Monty; Tassa, Carlos; Shaw, Stanley Y.; Lee, Hakho; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM liong.monty@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 360-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378301777 ER PT J AU Fang, PA Conway, JF Margolis, HC Simmer, JP Beniash, E AF Ping An Fang Conway, James F. Margolis, Henry C. Simmer, James P. Beniash, Elia TI Supramolecular assemblies of amelogenin guide organization of calcium phosphate prenucleation clusters into highly ordered mesostructures SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Ping An Fang; Beniash, Elia] Univ Pittsburgh, Dept Oral Biol, Pittsburgh, PA 15261 USA. [Conway, James F.] Univ Pittsburgh, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Margolis, Henry C.] Forsyth Inst, Dept Biomineralizat, Cambridge, MA 02142 USA. [Simmer, James P.] Univ Michigan, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. EM ebeniash@pitt.edu NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 26-GEOC PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378303448 ER PT J AU Thomas, CJ Boxer, MB Jiang, JK Vander Heiden, MG Walsh, MJ Brimacombe, K Shen, M Skoumbourdis, AP Park, HW Cantley, LC Auld, DS AF Thomas, Craig J. Boxer, Matthew B. Jiang, Jian-Kang Vander Heiden, Matthew G. Walsh, Martin J. Brimacombe, Kyle Shen, Min Skoumbourdis, Amanda P. Park, Hee Won Cantley, Lewis C. Auld, Douglas S. TI Discovery, development, and utility of activators of the human M2 isoform of pyruvate kinase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA USA. [Vander Heiden, Matthew G.; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Cambridge, MA 02138 USA. [Vander Heiden, Matthew G.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Park, Hee Won] Univ Toronto, Struct Genom Consortium, Toronto, ON M5S 1A1, Canada. [Park, Hee Won] Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A1, Canada. [Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA USA. EM craigt@mail.nih.gov RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 NR 0 TC 1 Z9 1 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 233-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304543 ER PT J AU Vander Heiden, MG AF Vander Heiden, Matthew G. TI Modulation of pyruvate kinase activity and its role in cell metabolism SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 242nd National Meeting of the American-Chemical-Society (ACS) CY AUG 28-SEP 01, 2011 CL Denver, CO SP Amer Chem Soc (ACS) C1 [Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA USA. EM mvh@mit.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2011 VL 242 MA 232-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 880BE UT WOS:000299378304542 ER PT J AU Koffie, RM Hyman, BT Spires-Jones, TL AF Koffie, Robert M. Hyman, Bradley T. Spires-Jones, Tara L. TI Alzheimer's disease: synapses gone cold SO MOLECULAR NEURODEGENERATION LA English DT Review DE Alzheimer's disease; amyloid-beta; synapse loss; long-term depression; long-term potentiation; cognitive decline ID AMYLOID-BETA-PROTEIN; LONG-TERM POTENTIATION; HIPPOCAMPAL SYNAPTIC PLASTICITY; CELLULAR PRION PROTEIN; REVERSIBLE MEMORY LOSS; DENDRITIC SPINE LOSS; APP TRANSGENIC MICE; RAT DENTATE GYRUS; A-BETA; IN-VIVO AB Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (A beta), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. A beta oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric A beta has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how A beta impacts synapses. C1 [Koffie, Robert M.; Hyman, Bradley T.; Spires-Jones, Tara L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Koffie, Robert M.] Harvard Biophys Program, Boston, MA 02115 USA. RP Spires-Jones, TL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. EM tspires@partners.org OI Spires-Jones, Tara/0000-0003-2530-0598 FU Alzheimer's disease Drug Discovery Foundation/Association for Frontotemporal Dementias [K99 AG033670-01A1, P50 AG005134, AG12406, AG08487]; NIH [T32 GM07753]; Paul and Daisy Soros Foundation FX This work was supported by K99 AG033670-01A1, Alzheimer's disease Drug Discovery Foundation/Association for Frontotemporal Dementias, P50 AG005134, AG12406, and AG08487. RMK is supported by the Harvard Biophysics and Medical Scientist Training Programs (NIH T32 GM07753) and the Paul and Daisy Soros Foundation. NR 142 TC 80 Z9 83 U1 1 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD AUG 26 PY 2011 VL 6 AR 63 DI 10.1186/1750-1326-6-63 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 828UY UT WOS:000295530100001 PM 21871088 ER PT J AU Rynkiewicz, D Rathkopf, M Sim, I Waytes, AT Hopkins, RJ Giri, L DeMuria, D Ransom, J Quinn, J Nabors, GS Nielsen, CJ AF Rynkiewicz, Dianna Rathkopf, Melinda Sim, Iain Waytes, A. Thomas Hopkins, Robert J. Giri, Lallan DeMuria, Deborah Ransom, Janet Quinn, James Nabors, Gary S. Nielsen, Carl J. TI Marked enhancement of the immune response to BioThrax (R) (Anthrax Vaccine Adsorbed) by the TLR9 agonist CPG 7909 in healthy volunteers SO VACCINE LA English DT Article DE BioThrax; Anthrax Vaccine Adsorbed; CPG 7909; CpG; Oligodeoxynucleotide; Clinical trial; Adjuvant ID LETHAL TOXIN NEUTRALIZATION; INHALATIONAL ANTHRAX; BACILLUS-ANTHRACIS; POSTEXPOSURE PROPHYLAXIS; PROTECTIVE ANTIGEN; IMMUNOGLOBULIN-G; ADVERSE EVENTS; UNITED-STATES; OLIGONUCLEOTIDES; ADJUVANT AB Immunization with BioThrax (R) (Anthrax Vaccine Adsorbed) is a safe and effective means of preventing anthrax. Animal studies have demonstrated that the addition of CpG DNA adjuvants to BioThrax can markedly increase the immunogenicity of the vaccine, increasing both serum anti-protective antigen (PA) antibody and anthrax toxin-neutralizing antibody (TNA) concentrations. The immune response to CpG-adjuvanted BioThrax in animals was not only stronger, but was also more rapid and led to higher levels of protection in spore challenge models. The B-class CpG DNA adjuvant CPG 7909, a 24-base synthetic, single-strand oligodeoxynucleotide, was evaluated for its safety profile and adjuvant properties in a Phase 1 clinical trial. A double-blind study was performed in which 69 healthy subjects, age 18-45 years, were randomized to receive three doses of either: (1) BioThrax alone, (2)1 mg of CPG 7909 alone or (3) BioThrax plus 1 mg of CPG 7909, all given intramuscularly on study days 0, 14 and 28. Subjects were monitored for IgG to PA by ELISA and for TNA titers through study day 56 and for safety through month 6. CPG 7909 increased the antibody response by 6-8-fold at peak, and accelerated the response by 3 weeks compared to the response seen in subjects vaccinated with BioThrax alone. No serious adverse events related to study agents were reported, and the combination was considered to be reasonably well tolerated. The marked acceleration and enhancement of the immune response seen by combining BioThrax and CPG 7909 offers the potential to shorten the course of immunization and reduce the time to protection, and may be particularly useful in the setting of post-exposure prophylaxis. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Waytes, A. Thomas; Hopkins, Robert J.; Giri, Lallan; Nabors, Gary S.] Emergent BioSolut Inc, Gaithersburg, MD 20879 USA. [Waytes, A. Thomas; Hopkins, Robert J.; Giri, Lallan; Nabors, Gary S.] Emergent BioSolut Inc, Lansing, MI USA. [Rynkiewicz, Dianna] Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX USA. [Rynkiewicz, Dianna] Vet Adm Hosp, San Antonio, TX USA. [Rathkopf, Melinda; Quinn, James] USAF, Med Ctr, San Antonio, TX USA. [Sim, Iain; DeMuria, Deborah] Coley Pharmaceut Grp Inc, Wellesley, MA USA. [Ransom, Janet] Fast Track Drugs & Biol, Potomac, MD USA. [Nielsen, Carl J.] DARPA DSO, Arlington, VA USA. RP Nabors, GS (reprint author), Emergent BioSolut Inc, Gaithersburg, MD 20879 USA. EM iain.s.sim@gmail.com; ddemuria@gmail.com; naborsg@ebsi.com FU Defense Advanced Research Projects Administration (DARPA) [DAAD1903C0002]; U.S. Army Research Office FX The authors would like to acknowledge the support of the Defense Advanced Research Projects Administration (DARPA; contract DAAD1903C0002) and the U.S. Army Research Office. The authors also acknowledge the assistance of Drs. John Carney and Joseph Bielitzki who served as Program Managers during this study and Dr. Brett Giroir, Deputy Director, DARPA/DSO. In addition, the authors would like to thank the clinical staff and the volunteers of the U.S.A.F. Medical Center Wilford Hall and the University of Texas Medical Center and Veterans' Administration Center; Drs. Arthur Krieg, John Whisnant, and Mohamed El Adhami (Coley); Drs. Paul Hine and David Willis, and Cheryl Enger (Emergent BioSolutions); Capt. (Dr.) Robb Rowley (U.S.A.F.); Wendy Johnson for serological testing (USAMRIID); and Dr. Rob Carnes (BioSciences Intl., now Battelle). The authors dedicate this work to the late Drs. Carl Nielsen and Dianna Rynkiewicz. NR 42 TC 36 Z9 39 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 26 PY 2011 VL 29 IS 37 BP 6313 EP 6320 DI 10.1016/j.vaccine.2011.05.047 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 825AR UT WOS:000295243800021 PM 21624418 ER PT J AU Garg, S Sharma, M Ung, C Tuli, A Barral, DC Hava, DL Veerapen, N Besra, GS Hacohen, N Brenner, MB AF Garg, Salil Sharma, Mahak Ung, Cindy Tuli, Amit Barral, Duarte C. Hava, David L. Veerapen, Natacha Besra, Gurdyal S. Hacohen, Nir Brenner, Michael B. TI Lysosomal Trafficking, Antigen Presentation, and Microbial Killing Are Controlled by the Arf-like GTPase Arl8b SO IMMUNITY LA English DT Article ID T-CELL DEVELOPMENT; CD1D; EXPRESSION; RAB; LOCALIZATION; MOLECULES; PATHWAYS; REVEALS; EVASION; PROTEIN AB Antigen presentation and microbial killing are critical arms of host defense that depend upon cargo trafficking into lysosomes. Yet, the molecular regulators of traffic into lysosomes are only partly understood. Here, using a lysosome-dependent immunological screen of a trafficking shRNA library, we identified the Art-like GTPase Arl8b as a critical regulator of cargo delivery to lysosomes. Homotypic fusion and vacuole protein sorting (HOPS) complex members were identified as effectors of Arl8b and were dependent on Arl8b for recruitment to lysosomes, suggesting that Arl8b-HOPS plays a general role in directing traffic to lysosomes. Moreover, the formation of CD1 antigen-presenting complexes in lysosomes, their delivery to the plasma membrane, and phagosome-lysosome fusion were all markedly impaired in Arl8b silenced cells resulting in corresponding defects in T cell activation and microbial killing. Together, these results define Arl8b as a key regulator of lysosomal cellular and immunological functions. C1 [Sharma, Mahak; Ung, Cindy; Tuli, Amit; Barral, Duarte C.; Hava, David L.; Brenner, Michael B.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Garg, Salil] Harvard Div Med Sci, Grad Program Immunol, Boston, MA 02115 USA. [Garg, Salil] Harvard MIT MD PhD Program, Boston, MA 02115 USA. [Veerapen, Natacha; Besra, Gurdyal S.] Univ Birmingham, Sch Biosci, Birmingham, W Midlands, England. [Hacohen, Nir] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. RP Brenner, MB (reprint author), Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. EM mbrenner@rics.bwh.harvard.edu RI Barral, Duarte/E-7548-2013; OI Barral, Duarte/0000-0001-8867-2407; Besra, Gurdyal/0000-0002-5605-0395 FU Medical Council; Wellcome Trust [084923/B/08/7]; NIH [AI028973, AI063428] FX The authors would like to acknowledge S. Silver and G. Cowley of the Broad Institute RNAi Platform. We would like to acknowledge S. Porcelli (Albert Einstein) for the gift of L363 antibody and V. Hsu for helpful discussions regarding trafficking. We would like to thank J. Neefjes (Netherlands Cancer Institute), J.W. Harper (Harvard University), V. Faundez (Emory University), R.C. Piper (University of Iowa), and A. Edinger (University of California Irvine) for their general gifts of molecular constructs. S.G. would also like to thank A. Sant (University of Rochester) for helpful discussions and previous mentorship. M.S. would like to thank S. Caplan and N. Naslavsky (University of Nebraska) for their mentorship and gifts of molecular constructs. G.B. acknowledges support from J. Badrick, the Medical Council, and The Wellcome Trust (084923/B/08/7). N.H. is a recipient of the NIH Director's New Innovator Award. This work was primarily funded by NIH grants AI028973 and AI063428 to M.B. NR 30 TC 56 Z9 56 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 26 PY 2011 VL 35 IS 2 BP 182 EP 193 DI 10.1016/j.immuni.2011.06.009 PG 12 WC Immunology SC Immunology GA 813SC UT WOS:000294387900009 PM 21802320 ER PT J AU West, EE Youngblood, B Tan, WG Jin, HT Araki, K Alexe, G Konieczny, BT Calpe, S Freeman, GJ Terhorst, C Haining, WN Ahmed, R AF West, Erin E. Youngblood, Ben Tan, Wendy G. Jin, Hyun-Tak Araki, Koichi Alexe, Gabriela Konieczny, Bogumila T. Calpe, Silvia Freeman, Gordon J. Terhorst, Cox Haining, W. Nicholas Ahmed, Rafi TI Tight Regulation of Memory CD8(+) T Cells Limits Their Effectiveness during Sustained High Viral Load SO IMMUNITY LA English DT Article ID NK-ASSOCIATED RECEPTORS; IN-VIVO; PROTECTIVE IMMUNITY; MEDIATED-IMMUNITY; NAIVE RATHER; 2B4 CD244; INFECTION; PERSISTENCE; EXHAUSTION; DIFFERENTIATION AB To design successful vaccines for chronic diseases, an understanding of memory CD8(+) T cell responses to persistent antigen restimulation is critical. However, most studies comparing memory and naive cell responses have been performed only in rapidly cleared acute infections. Herein, by comparing the responses of memory and naive CD8(+) T cells to acute and chronic lymphocytic choriomeningitis virus infection, we show that memory cells dominated over naive cells and were protective when present in sufficient numbers to quickly reduce infection. In contrast, when infection was not rapidly reduced, because of high antigen load or persistence, memory cells were quickly lost, unlike naive cells. This loss of memory cells was due to a block in sustaining cell proliferation, selective regulation by the inhibitory receptor 2B4, and increased reliance on CD4(+) T cell help. Thus, emphasizing the importance of designing vaccines that elicit effective CD4(+) T cell help and rapidly control infection. C1 [West, Erin E.; Youngblood, Ben; Tan, Wendy G.; Jin, Hyun-Tak; Araki, Koichi; Konieczny, Bogumila T.; Ahmed, Rafi] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [West, Erin E.; Youngblood, Ben; Tan, Wendy G.; Jin, Hyun-Tak; Araki, Koichi; Konieczny, Bogumila T.; Ahmed, Rafi] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Alexe, Gabriela] Broad Inst, Cambridge, MA 02142 USA. [Calpe, Silvia; Terhorst, Cox] Harvard Univ, Sch Med, Div Immunol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Haining, W. Nicholas] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. RP Ahmed, R (reprint author), Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM rahmed@emory.edu FU National Institutes of Health (NIH) [R01 AI030048]; American Cancer Society (ACS) [PF-09-134-01-MPC] FX We thank R. Karaffa and S. Durham for FACS sorting at the Emory University School of Medicine Flow Cytometry Core Facility, and we thank the members of the R.A. lab for helpful discussions. We also thank R. Akondy for initial help with the microarray analysis. This work was supported by the National Institutes of Health (NIH) grant R01 AI030048 (to R.A.) and the American Cancer Society (ACS) postdoctoral fellowship PF-09-134-01-MPC (to B.Y.). NR 54 TC 74 Z9 76 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 26 PY 2011 VL 35 IS 2 BP 285 EP 298 DI 10.1016/j.immuni.2011.05.017 PG 14 WC Immunology SC Immunology GA 813SC UT WOS:000294387900017 PM 21856186 ER PT J AU Stransky, N Egloff, AM Tward, AD Kostic, AD Cibulskis, K Sivachenko, A Kryukov, GV Lawrence, MS Sougnez, C McKenna, A Shefler, E Ramos, AH Stojanov, P Carter, SL Voet, D Cortes, ML Auclair, D Berger, MF Saksena, G Guiducci, C Onofrio, RC Parkin, M Romkes, M Weissfeld, JL Seethala, RR Wang, L Rangel-Escareno, C Fernandez-Lopez, JC Hidalgo-Miranda, A Melendez-Zajgla, J Winckler, W Ardlie, K Gabriel, SB Meyerson, M Lander, ES Getz, G Golub, TR Garraway, LA Grandis, JR AF Stransky, Nicolas Egloff, Ann Marie Tward, Aaron D. Kostic, Aleksandar D. Cibulskis, Kristian Sivachenko, Andrey Kryukov, Gregory V. Lawrence, Michael S. Sougnez, Carrie McKenna, Aaron Shefler, Erica Ramos, Alex H. Stojanov, Petar Carter, Scott L. Voet, Douglas Cortes, Maria L. Auclair, Daniel Berger, Michael F. Saksena, Gordon Guiducci, Candace Onofrio, Robert C. Parkin, Melissa Romkes, Marjorie Weissfeld, Joel L. Seethala, Raja R. Wang, Lin Rangel-Escareno, Claudia Carlos Fernandez-Lopez, Juan Hidalgo-Miranda, Alfredo Melendez-Zajgla, Jorge Winckler, Wendy Ardlie, Kristin Gabriel, Stacey B. Meyerson, Matthew Lander, Eric S. Getz, Gad Golub, Todd R. Garraway, Levi A. Grandis, Jennifer R. TI The Mutational Landscape of Head and Neck Squamous Cell Carcinoma SO SCIENCE LA English DT Article ID TUMOR-SUPPRESSOR; STEM-CELLS; E-CADHERIN; CANCER; NOTCH; SKIN; DIFFERENTIATION; GENOME; KERATINOCYTES; INACTIVATION AB Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms. C1 [Stransky, Nicolas; Tward, Aaron D.; Kostic, Aleksandar D.; Cibulskis, Kristian; Sivachenko, Andrey; Kryukov, Gregory V.; Lawrence, Michael S.; Sougnez, Carrie; McKenna, Aaron; Shefler, Erica; Ramos, Alex H.; Stojanov, Petar; Carter, Scott L.; Voet, Douglas; Cortes, Maria L.; Auclair, Daniel; Berger, Michael F.; Saksena, Gordon; Guiducci, Candace; Onofrio, Robert C.; Parkin, Melissa; Winckler, Wendy; Ardlie, Kristin; Gabriel, Stacey B.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Golub, Todd R.; Garraway, Levi A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Egloff, Ann Marie; Grandis, Jennifer R.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15213 USA. [Egloff, Ann Marie; Seethala, Raja R.; Wang, Lin; Grandis, Jennifer R.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. [Tward, Aaron D.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Tward, Aaron D.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Kostic, Aleksandar D.; Kryukov, Gregory V.; Meyerson, Matthew; Lander, Eric S.; Golub, Todd R.; Garraway, Levi A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Romkes, Marjorie] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. [Romkes, Marjorie] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15261 USA. [Weissfeld, Joel L.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15232 USA. [Weissfeld, Joel L.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA. [Seethala, Raja R.; Wang, Lin] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Rangel-Escareno, Claudia; Carlos Fernandez-Lopez, Juan; Hidalgo-Miranda, Alfredo; Melendez-Zajgla, Jorge] Inst Nacl Med Genom, Mexico City 01900, DF, Mexico. [Meyerson, Matthew; Garraway, Levi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Meyerson, Matthew; Golub, Todd R.; Garraway, Levi A.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Lander, Eric S.] MIT, Cambridge, MA 02142 USA. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Grandis, Jennifer R.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. RP Garraway, LA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM levi_garraway@dfci.harvard.edu; grandisjr@upmc.edu RI Meyerson, Matthew/E-7123-2012; Fernandez, Juan Carlos/C-4976-2013; Hidalgo-Miranda, Alfredo/B-2123-2010; Rangel-Escareno, Claudia/F-4587-2012; Kryukov, Gregory/A-9592-2008 OI Fernandez, Juan Carlos/0000-0003-3680-4193; Hidalgo-Miranda, Alfredo/0000-0003-2315-3977; Rangel-Escareno, Claudia/0000-0003-1303-0834; Kostic, Aleksandar/0000-0002-0837-4360; FU Carlos Slim Health Institute; International Cancer Genome Consortium; National Human Genome Research Institute; National Cancer Institute; Starr Cancer Consortium; Novartis Institutes for BioMedical Research; Howard Hughes Medical Institute; American Cancer Society; NIH FX We thank the Broad Institute Sequencing Platform for the generation of sequencing data, the staff of the Biological Samples Platform and the Genetic Analysis Platform at the Broad Institute, and J. Aster for helpful discussions. This work was conducted as part of the Slim Initiative for Genomic Medicine, a joint U.S.-Mexico project funded by the Carlos Slim Health Institute, and is part of a global effort in collaboration with the International Cancer Genome Consortium. The work was also supported by grants from the National Human Genome Research Institute (S.B.G., E.S.L.), the National Cancer Institute (M.M., S.B.G., L.A.G., J.R.G., A.M.E.), the Starr Cancer Consortium (L.A.G.), the Novartis Institutes for BioMedical Research (N.S.), the Howard Hughes Medical Institute (T.R.G.), the American Cancer Society (J.R.G.), and the NIH Director's New Innovator Award (L.A.G.). L.A.G. and M.M. are paid consultants for and equity holders in Foundation Medicine, a genomics-based oncology diagnostics company, and are also paid consultants for Novartis. M.F.B. is a paid consultant for Foundation Medicine. E.S.L. is an equity holder in Foundation Medicine. The compressed binary Sequence Alignment/Map files (BAM) and SNP array data are available in dbGaP under accession no. phs000370.v1.p1. NR 33 TC 896 Z9 907 U1 16 U2 117 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 26 PY 2011 VL 333 IS 6046 BP 1157 EP 1160 DI 10.1126/science.1208130 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811VM UT WOS:000294244300052 PM 21798893 ER PT J AU Rinehart, J Vazquez, N Kahle, KT Hodson, CA Ring, AM Gulcicek, EE Louvi, A Bobadilla, NA Gamba, G Lifton, RP AF Rinehart, Jesse Vazquez, Norma Kahle, Kristopher T. Hodson, Caleb A. Ring, Aaron M. Gulcicek, Erol E. Louvi, Angeliki Bobadilla, Norma A. Gamba, Gerardo Lifton, Richard P. TI WNK2 Kinase Is a Novel Regulator of Essential Neuronal Cation-Chloride Cotransporters SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID K-CL COTRANSPORTER; ALANINE-RICH KINASE; PROTEIN-KINASE; CELL-VOLUME; NERVOUS-SYSTEM; BLOOD-PRESSURE; NA+-K+-2CL(-) COTRANSPORTER; INHERITED HYPERTENSION; MAMMALIAN-CELLS; IN-VIVO AB NKCC1 and KCC2, related cation-chloride cotransporters (CCC), regulate cell volume and gamma-aminobutyric acid (GABA)-ergic neurotranmission by modulating the intracellular concentration of chloride [Cl(-)]. These CCCs are oppositely regulated by serine-threonine phosphorylation, which activates NKCC1 but inhibits KCC2. The kinase(s) that performs this function in the nervous system are not known with certainty. WNK1 and WNK4, members of the WNK(with no lysine [(K) under bar]) kinase family, either directly or via the downstream SPAK/OSR1 Ste 20-type kinases, regulate the furosemide-sensitive NKCC2 and the thiazide-sensitive NCC, kidney-specific CCCs. What role the novel WNK2 kinase plays in this regulatory cascade, if any, is unknown. Here, we show that WNK2, unlike other WNKs, is not expressed in kidney; rather, it is a neuron-enriched kinase primarily expressed in neocortical pyramidal cells, thalamic relay cells, and cerebellar granule and Purkinje cells in both the developing and adult brain. Bumetanide-sensitive and Cl(-)-dependent (86)Rb(+) uptake assays in Xenopus laevis oocytes revealed that WNK2 promotes Cl(-) accumulation by reciprocally activating NKCC1 and inhibiting KCC2 in a kinase-dependent manner, effectively bypassing normal tonicity requirements for cotransporter regulation. TiO(2) enrichment and tandem mass spectrometry studies demonstrate WNK2 forms a protein complex in the mammalian brain with SPAK, a known phosphoregulator of NKCC1. In this complex, SPAK is phosphorylated at Ser-383, a consensus WNK recognition site. These findings suggest a role for WNK2 in the regulation of CCCs in the mammalian brain, with implications for both cell volume regulation and/or GABAergic signaling. C1 [Vazquez, Norma; Bobadilla, Norma A.; Gamba, Gerardo] Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mol Physiol Unit, Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City 14000, DF, Mexico. [Rinehart, Jesse; Hodson, Caleb A.; Ring, Aaron M.; Louvi, Angeliki; Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, New Haven, CT 06510 USA. [Vazquez, Norma; Bobadilla, Norma A.; Gamba, Gerardo] Inst Nacl Cardiol Ignacio Chavez, Mexico City 14000, DF, Mexico. [Kahle, Kristopher T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Kahle, Kristopher T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Gulcicek, Erol E.] Yale Univ, Keck Biotechnol Resource Lab, New Haven, CT 06510 USA. RP Gamba, G (reprint author), Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mol Physiol Unit, Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City 14000, DF, Mexico. EM gamba@biomedicas.unam.mx; richard.lifton@yale.edu FU NIDA, National Institutes of Health [2P30DA018343]; Leducq Foundation Transatlantic Network on Hypertension; el Consejo Nacional de Ciencia y Tecnologia (CONACYT-Mexico) [59992] FX This work was supported, in whole or in part, by NIDA, National Institutes of Health Grant 2P30DA018343 (to J. R., E. E. G., and R. P. L.), the Leducq Foundation Transatlantic Network on Hypertension (to G. G. and R. P. L.), and el Consejo Nacional de Ciencia y Tecnologia (CONACYT-Mexico) Grant 59992 (to G. G.). NR 64 TC 32 Z9 36 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 26 PY 2011 VL 286 IS 34 BP 30171 EP 30180 DI 10.1074/jbc.M111.222893 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 809IU UT WOS:000294046600074 PM 21733846 ER PT J AU Phillips, MA Colonnese, MT Goldberg, J Lewis, LD Brown, EN Constantine-Paton, M AF Phillips, Marnie A. Colonnese, Matthew T. Goldberg, Julie Lewis, Laura D. Brown, Emery N. Constantine-Paton, Martha TI A Synaptic Strategy for Consolidation of Convergent Visuotopic Maps SO NEURON LA English DT Article ID RAT SUPERIOR COLLICULUS; CAT VISUAL-CORTEX; NMDA RECEPTOR; PYRAMIDAL NEURONS; IN-VIVO; SENSORY EXPERIENCE; NEURAL MAP; PLASTICITY; MICE; COMPETITION AB The mechanisms by which experience guides refinement of converging afferent pathways are poorly understood. We describe a vision-driven refinement of corticocollicular inputs that determines the consolidation of retinal and visual cortical (VC) synapses on individual neurons in the superficial superior colliculus (sSC). Highly refined corticocollicular terminals form 1-2 days after eye-opening (EO), accompanied by VC-dependent filopodia sprouting on proximal dendrites, and PSD-95 and VC-dependent quadrupling of functional synapses. Delayed EO eliminates synapses, corticocollicular terminals, and spines on VC-recipient dendrites. Awake recordings after EO show that VC and retina cooperate to activate sSC neurons, and VC light responses precede sSC responses within intervals promoting potentiation. Eyelid closure is associated with more protracted cortical visual responses, causing the majority of VC spikes to follow those of the colliculus. These data implicate spike-timing plasticity as a mechanism for cortical input survival, and support a cooperative strategy for retinal and cortical coinnervation of the sSC. C1 [Phillips, Marnie A.; Constantine-Paton, Martha] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Phillips, Marnie A.; Goldberg, Julie; Lewis, Laura D.; Brown, Emery N.; Constantine-Paton, Martha] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Constantine-Paton, Martha] MIT, Dept Biol, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Colonnese, Matthew T.] Aix Marseille Univ, INSERM, U901, INMED,Fac Sci, F-13273 Marseille, France. [Brown, Emery N.] Massachusetts Gen Hosp, Neurosci Stat Res Lab, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Phillips, MA (reprint author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM marnie.a.phillips@gmail.com OI Colonnese, Matthew/0000-0002-2480-1270 FU NIH [EY006039]; Agence Nationale de Recherche, France FX We would like to thank R. Desimone for helpful comments, C. Yee and A. Birdsey-Benton for technical assistance, W. Lee for transferring mutant mice, and C. Tunca for biochemistry advice. This work was supported by NIH grant EY006039 to M.C.-P. M.T.C. was supported by a grant to Rustem Khazipov (INSERM, France) from the Agence Nationale de Recherche, France. NR 58 TC 14 Z9 14 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 25 PY 2011 VL 71 IS 4 BP 710 EP 724 DI 10.1016/j.neuron.2011.06.023 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 815JJ UT WOS:000294521600015 PM 21867886 ER PT J AU Lemieux, ME Cheng, ZM Zhou, Q White, R Cornell, J Kung, AL Rebel, VI AF Lemieux, Madeleine E. Cheng, Ziming Zhou, Qing White, Ruth Cornell, John Kung, Andrew L. Rebel, Vivienne I. TI Inactivation of a Single Copy of Crebbp Selectively Alters Pre-mRNA Processing in Mouse Hematopoietic Stem Cells SO PLOS ONE LA English DT Article ID ADULT BONE-MARROW; BINDING-PROTEIN; GENE-EXPRESSION; SELF-RENEWAL; GLUCOCORTICOID-RECEPTOR; FETAL LIVER; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; LYMPHOCYTE DEVELOPMENT; ERYTHROID PROGENITORS AB Global expression analysis of fetal liver hematopoietic stem cells (FL HSCs) revealed the presence of unspliced pre-mRNA for a number of genes in normal FL HSCs. In a subset of these genes, Crebbp(+/-) FL HSCs had less unprocessed pre-mRNA without a corresponding reduction in total mRNA levels. Among the genes thus identified were the key regulators of HSC function Itga4, Msi2 and Tcf4. A similar but much weaker effect was apparent in Ep300(+/-) FL HSCs, indicating that, in this context as in others, the two paralogs are not interchangeable. As a group, the down-regulated intronic probe sets could discriminate adult HSCs from more mature cell types, suggesting that the underlying mechanism is regulated with differentiation stage and is active in both fetal and adult hematopoiesis. Consistent with increased myelopoiesis in Crebbp hemizygous mice, targeted reduction of CREBBP abundance by shRNA in the multipotent EML cell line triggered spontaneous myeloid differentiation in the absence of the normally required inductive signals. In addition, differences in protein levels between phenotypically distinct EML subpopulations were better predicted by taking into account not only the total mRNA signal but also the amount of unspliced message present. CREBBP thus appears to selectively influence the timing and degree of pre-mRNA processing of genes essential for HSC regulation and thereby has the potential to alter subsequent cell fate decisions in HSCs. C1 [Lemieux, Madeleine E.; Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Lemieux, Madeleine E.; Rebel, Vivienne I.] Harvard Univ, Sch Med, Boston, MA USA. [Cheng, Ziming; Zhou, Qing; Rebel, Vivienne I.] Univ Texas Hlth Sci Ctr San Antonio, GCCRI, San Antonio, TX 78229 USA. [White, Ruth] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR 97201 USA. [Cornell, John] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Rebel, Vivienne I.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. RP Lemieux, ME (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM rebel@uthscsa.edu OI Lemieux, Madeleine/0000-0001-6355-8691; Kung, Andrew/0000-0002-9091-488X FU Greehey Children's Cancer Research Institute/University of Texas Health Science Center in San Antonio (UTHSCSA); National Cancer Institute-Cancer Center [2P30 CA054174-17] FX This work was supported with funding from the Greehey Children's Cancer Research Institute/University of Texas Health Science Center in San Antonio (UTHSCSA) and a National Cancer Institute-Cancer Center Support Grant (2P30 CA054174-17) for the UTHSCSA Flow Cytometry Core. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 5 Z9 5 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 25 PY 2011 VL 6 IS 8 AR e24153 DI 10.1371/journal.pone.0024153 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 812MQ UT WOS:000294298000049 PM 21901164 ER PT J AU Narla, A Dutt, S McAuley, JR Al-Shahrour, F Hurst, S McConkey, M Neuberg, D Ebert, BL AF Narla, Anupama Dutt, Shilpee McAuley, J. Randall Al-Shahrour, Fatima Hurst, Slater McConkey, Marie Neuberg, Donna Ebert, Benjamin L. TI Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis SO BLOOD LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; HEMATOPOIETIC STEM-CELLS; BLOOD-GROUP SYSTEM; MYELODYSPLASTIC SYNDROME; DELETION 5Q; MULTIPLE-MYELOMA; GENE; DEFICIENCY; RECEPTOR; DIFFERENTIATION AB Corticosteroids and lenalidomide decrease red blood cell transfusion dependence in patients with Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome (MDS), respectively. We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Both agents promote erythropoiesis, increasing the absolute number of erythroid cells produced from normal CD34(+) cells and from CD34(+) cells with the types of ribosome dysfunction found in DBA and del(5q) MDS. However, the drugs had distinct effects on the production of erythroid progenitor colonies; dexamethasone selectively increased the number of burst-forming units-erythroid (BFU-E), whereas lenalidomide specifically increased colony-forming unit-erythroid (CFU-E). Use of the drugs in combination demonstrated that their effects are not redundant. In addition, dexamethasone and lenalidomide induced distinct gene-expression profiles. In coculture experiments, we examined the role of the microenvironment in response to both drugs and found that the presence of macrophages, the central cells in erythroblastic islands, accentuated the effects of both agents. Our findings indicate that dexamethasone and lenalidomide promote different stages of erythropoiesis and support the potential clinical utility of combination therapy for patients with bone marrow failure. (Blood. 2011; 118(8): 2296-2304) C1 [Narla, Anupama; Dutt, Shilpee; McAuley, J. Randall; Al-Shahrour, Fatima; Hurst, Slater; McConkey, Marie; Ebert, Benjamin L.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Narla, Anupama; Al-Shahrour, Fatima; Ebert, Benjamin L.] Broad Inst, Cambridge, MA USA. [Narla, Anupama; Neuberg, Donna; Ebert, Benjamin L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Narla, Anupama] Childrens Hosp, Boston, MA 02115 USA. RP Ebert, BL (reprint author), Brigham & Womens Hosp, Dept Med, Karp Res Bldg,CHRB 05-210,1 Blackfan Cir, Boston, MA 02115 USA. EM bebert@partners.org FU National Institutes of Health [5R01 HL082945, P01 CA108631]; Burroughs-Wellcome Fund (CAMS) FX This work was funded by the National Institutes of Health (grants 5R01 HL082945 and P01 CA108631) and by the Burroughs-Wellcome Fund (CAMS) to B.L.E. NR 48 TC 30 Z9 30 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 25 PY 2011 VL 118 IS 8 BP 2296 EP 2304 DI 10.1182/blood-2010-11-318543 PG 9 WC Hematology SC Hematology GA 811ZR UT WOS:000294258000032 PM 21527522 ER PT J AU Nishino, HT Tambouret, RH Wilbur, DC AF Ha Thanh Nishino Tambouret, Rosemary H. Wilbur, David C. TI Testing for Human Papillomavirus in Cervical Cancer Screening SO CANCER CYTOPATHOLOGY LA English DT Review DE HPV testing; human papillomavirus; cervical cancer screening ID HIGH-RISK HPV; ATYPICAL SQUAMOUS-CELLS; DNA TEST; INTRAEPITHELIAL NEOPLASIA; UNDETERMINED SIGNIFICANCE; CLINICAL-PERFORMANCE; MESSENGER-RNA; ASC-US; P16(INK4A); CYTOLOGY AB High-risk human papillomavirus (hrHPV) testing has become an integral component of cervical cancer screening, given that persistent infection with hrHPV was recognized as a significant risk factor for most precancers and cancers of the cervix. Particularly, testing for hrHPV types (in conjunction with cervical cytology) has been approved for primary screening in women over 30 years of age and for cost-effective triaging of equivocal cervical cytology results. HPV was a small double-stranded DNA virus that cannot be cultured in vitro; so, different types of tests have been developed to detect its presence. Various molecular techniques were available for detecting the presence and/or quantity of hrHPV. In this review, the testing options for hrHPV and its surrogates, with an emphasis on those approved by the US Food and Drug Administration (FDA), were detailed. Cancer (Cancer Cytopathol) 2011;119:219-27. (C) 2011 American Cancer Society. C1 [Ha Thanh Nishino] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Lab Pathol, Boston, MA 02114 USA. RP Nishino, HT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Lab Pathol, 55 Fruit St,Warren 125, Boston, MA 02114 USA. EM hnishino@partners.org NR 52 TC 16 Z9 16 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD AUG 25 PY 2011 VL 119 IS 4 BP 219 EP 227 DI 10.1002/cncy.20161 PG 9 WC Oncology; Pathology SC Oncology; Pathology GA 810FJ UT WOS:000294110600002 PM 21717588 ER PT J AU Graham, BM Richardson, R AF Graham, B. M. Richardson, R. TI MEMORY OF FEARFUL EVENTS: THE ROLE OF FIBROBLAST GROWTH FACTOR-2 IN FEAR ACQUISITION AND EXTINCTION SO NEUROSCIENCE LA English DT Article DE fibroblast growth factor-2; fear conditioning; fear extinction; anxiety; memory; long-term potentiation ID LONG-TERM POTENTIATION; ACTIVATED PROTEIN-KINASE; RAT HIPPOCAMPAL-NEURONS; GATED CALCIUM-CHANNELS; MEDIAL PREFRONTAL CORTEX; FGF-2 GENE-EXPRESSION; CONDITIONED FEAR; FACTOR RECEPTOR-1; BASOLATERAL AMYGDALA; CORTICAL-NEURONS AB Research during the past decade has led to a tremendous growth in our understanding of how fear memories are acquired and subsequently inhibited on a neural and molecular level. Such research has contributed to significant developments in the treatment of anxiety disorders, and has considerably advanced our understanding of the neurobiology of learning and memory in general. A number of recent studies have examined the role of growth factors in the formation of long-term memory for fearful events, due to their ability to cause morphological neural changes in response to environmental stimulation. In this review we first describe physiological evidence that fibroblast growth factor-2 (FGF2) receptors are highly expressed in the neural circuitry regulating fear acquisition and extinction, and that FGF2 modulates the molecular signals known to be involved in the formation of fear memories. Then we present emerging behavioral research that demonstrates that exogenous FGF2 can enhance the formation of fear conditioning and extinction memories. Finally, we briefly discuss how research into the role of FGF2 in learning and memory may be of clinical benefit, particularly in the treatment of anxiety disorders. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Graham, B. M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02129 USA. [Graham, B. M.] Massachusetts Gen Hosp, Boston, MA 02129 USA. [Richardson, R.] UNSW, Sch Psychol, Sydney, NSW 2052, Australia. RP Graham, BM (reprint author), Harvard Univ, Sch Med, Dept Psychiat, 149 13th St Charlestown, Boston, MA 02129 USA. EM bmgraham@nmr.mgh.harvard.edu OI Richardson, Rick/0000-0003-1833-9777 FU Australian Research Council [DP0985554] FX Preparation of this manuscript was supported by a Discovery Project grant from the Australian Research Council (DP0985554) to R.R. NR 128 TC 11 Z9 12 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG 25 PY 2011 VL 189 BP 156 EP 169 DI 10.1016/j.neuroscience.2011.05.041 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 809XT UT WOS:000294090700015 PM 21624434 ER PT J AU Albert, RK Connett, J Bailey, WC Casaburi, R Cooper, JAD Criner, GJ Curtis, JL Dransfield, MT Han, MLK Lazarus, SC Make, B Marchetti, N Martinez, FJ Madinger, NE McEvoy, C Niewoehner, DE Porsasz, J Price, CS Reilly, J Scanlon, PD Sciurba, FC Scharf, SM Washko, GR Woodruff, PG Anthonisen, NR AF Albert, Richard K. Connett, John Bailey, William C. Casaburi, Richard Cooper, J. Allen D., Jr. Criner, Gerard J. Curtis, Jeffrey L. Dransfield, Mark T. Han, MeiLan K. Lazarus, Stephen C. Make, Barry Marchetti, Nathaniel Martinez, Fernando J. Madinger, Nancy E. McEvoy, Charlene Niewoehner, Dennis E. Porsasz, Janos Price, Connie S. Reilly, John Scanlon, Paul D. Sciurba, Frank C. Scharf, Steven M. Washko, George R. Woodruff, Prescott G. Anthonisen, Nicholas R. CA COPD Clinical Res Network TI Azithromycin for Prevention of Exacerbations of COPD SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; FLUTICASONE PROPIONATE; CYSTIC-FIBROSIS; HEALTH OUTCOMES; TIOTROPIUM; SALMETEROL; ERYTHROMYCIN; MANAGEMENT; FREQUENCY AB Background Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases. Methods We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval. Results A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P < 0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P = 0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P< 0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [+/- SD] decrease of 2.8 +/- 12.8 vs. 0.6 +/- 11.4, P = 0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P = 0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P = 0.04). Conclusions Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials. gov number, NCT00325897.) C1 Denver Hlth, Med Serv, Denver, CO USA. [Albert, Richard K.; Price, Connie S.] Univ Colorado Denver, Hlth Sci Ctr, Dept Med, Denver, CO USA. Natl Jewish Hlth, Div Pulm Med, Denver, CO USA. [Madinger, Nancy E.; Price, Connie S.] Univ Colorado Denver, Dept Med, Div Infect Dis, Denver, CO USA. [Connett, John] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Niewoehner, Dennis E.; Reilly, John] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Niewoehner, Dennis E.; Reilly, John] Minneapolis Vet Affairs VA Med Ctr, Med Serv, Div Pulm Med, Minneapolis, MN USA. [Bailey, William C.; Cooper, J. Allen D., Jr.; Dransfield, Mark T.] Univ Alabama, Dept Med, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Dransfield, Mark T.] Birmingham VA Med Ctr, Pulm Sect, Birmingham, AL USA. [Casaburi, Richard; Porsasz, Janos] Harbor UCLA Med Ctr, Dept Med, Div Resp & Crit Care Physiol & Med, Torrance, CA 90509 USA. [Criner, Gerard J.; Marchetti, Nathaniel] Temple Univ, Div Pulm & Crit Care Med, Dept Med, Philadelphia, PA 19122 USA. [Curtis, Jeffrey L.; Han, MeiLan K.; Martinez, Fernando J.] Univ Michigan, Dept Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Curtis, Jeffrey L.] Ann Arbor VA Med Ctr, Div Pulm & Crit Care Med, Ann Arbor, MI USA. [Lazarus, Stephen C.; Woodruff, Prescott G.] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA. [Lazarus, Stephen C.; Woodruff, Prescott G.] Univ Calif San Francisco, Inst Cardiovasc Res, San Francisco, CA USA. [McEvoy, Charlene] HealthPartners Res Fdn, Pulm Crit Care & Sleep Dept, St Paul, MN USA. [Scanlon, Paul D.] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA. [Sciurba, Frank C.] Univ Pittsburgh, Dept Med, Div Pulm & Crit Care Med, Pittsburgh, PA USA. [Scharf, Steven M.] Univ Maryland, Dept Med, Div Pulm & Crit Care, Baltimore, MD 21201 USA. [Washko, George R.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Anthonisen, Nicholas R.] Resp Hosp, Winnipeg, MB, Canada. RP Albert, RK (reprint author), Dr Albert Denver Hlth, 777 Bannock St,MC 4000, Denver, CO 80204 USA. EM ralbert@dhha.org RI Gough, Ethan/B-8633-2012; Wendt, Chris/C-6823-2012; OI Curtis, Jeffrey/0000-0001-5191-4847 FU National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health [U10 HL074407, U10 HL074408, U10 HL074409, U10 HL074416, U10 HL074418, U10 HL074422, U10 HL074424, U10 HL074428, U10 HL074431, U10 HL074439, U10 HL074441]; Division of Lung Diseases of the NHLBI; National Center for Research Resources [M01]; Gilead Sciences; Elsevier; Novartis Pharmaceuticals; Forest Pharmaceuticals; Theratechnologies; Breathe Technologies; Medtronic Spinal and Biologics; Boehringer Ingelheim; Philips Respironics; Novartis; Actelion Pharmaceuticals; AstraZeneca; Pfizer; Roche; Osiris Therapeutics; GlaxoSmithKline; Watkins; Louri; Roll and Change; Lawrence R. Dry Associates; Starnes Davis Florie LLP; Walker; Tipps Malone PLC; Moore; Ingram Johnson Steele; Farris; Riley Pitt, LLP; Phillips Pharmaceuticals; Uptake Medical; Dey; Boston Scientific; CSL Behring; Astellas Pharma; Talecris Biotherapeutics; Chiesi Pharmaceuticals; MedImmune-Astra Zeneca; Merck; Pearl Therapeutics; UBC; Mpex Pharmaceuticals and Ikaria; Forest-Almirall; Nycomed-Forest; Bayer; Schering-Plough (Merck); HLS; Comgeniz; fb Communications; BoomComm; Elan; Genzyme; Quark Pharmaceuticals; Sanofi-Aventis; Associates in Medical Marketing and Castle Connolly; National Association for Continuing Education; Med-Ed; Potomac Pharma; Vox Medica; WebMD; Epocrates; Altana-Nycomed; Global; Johnson & Johnson-Centocor Ortho Biotech; MicroPhage; Cubist Pharmaceuticals; Quintiles; Sanofi Pasteur; BioCryst Pharmaceuticals; Accelr8 Technology; Robert Michael; Baxter Healthcare; Altana; Lippincott Williams Wilkins; Wolters Kluwer; Genentech FX Supported by grants (U10 HL074407, U10 HL074408, U10 HL074409, U10 HL074416, U10 HL074418, U10 HL074422, U10 HL074424, U10 HL074428, U10 HL074431, U10 HL074439, and U10 HL074441) from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. The COPD Clinical Research Network is supported by a Cooperative Agreement from the Division of Lung Diseases of the NHLBI. At some sites, General Clinical Research Center facilities were used; their M01 grants from the National Center for Research Resources are listed in the Supplementary Appendix.; Dr. Albert reports receiving consulting fees from Gilead Sciences, fees for expert testimony from the Bruce Fagel Law Firm, and royalties from Elsevier, and being named on a patent pending for a device that provides continuous monitoring of the elevation of the head of the bed (Denver Health and the University of Colorado); Dr. Casaburi, receiving payment for service on the advisory boards of Novartis Pharmaceuticals and Forest Pharmaceuticals, consulting fees from Theratechnologies, Breathe Technologies, Medtronic Spinal and Biologics, Boehringer Ingelheim, Philips Respironics, Novartis, and Actelion Pharmaceuticals, lecture fees from Boehringer Ingelheim, AstraZeneca, and Pfizer, holding stock in Inogen, and receiving grant support from Novartis, Roche, Boehringer Ingelheim, Osiris Therapeutics, Forest Pharmaceuticals, and GlaxoSmithKline, Breathe Technologies (pending), and Theratechnologies (pending); Dr. Cooper, receiving fees for expert testimony from Watkins, Louri, Roll and Change; Lawrence R. Dry & Associates; Starnes Davis Florie LLP; Walker, Tipps & Malone PLC; Moore, Ingram Johnson & Steele; and Farris, Riley & Pitt, LLP; and grant support from GlaxoSmithKline and Novartis; Dr. Criner, receiving consulting fees from Phillips Pharmaceuticals, GlaxoSmithKline, Uptake Medical, and Dey, grant support from Philips Respironics, GlaxoSmithKline, Boehringer Ingelheim, Novartis, and AstraZeneca, and royalties from Springer; Dr. Curtis, receiving grant support from Boehringer Ingelheim; Dr. Dransfield, receiving consulting fees from GlaxoSmithKline, Boehringer Ingelheim, and Forest Pharmaceuticals, grant support from GlaxoSmithKline, Boehringer Ingelheim, and Boston Scientific, and lecture fees from GlaxoSmithKline and Boehringer Ingelheim; Dr. Han, receiving payment for service on the advisory boards of CSL Behring, GlaxoSmithKline, and Boehringer Ingelheim, consulting fees from Genentech and Novartis, lecture fees from GlaxoSmithKline, CSL Behring, Boehringer Ingelheim, and Pfizer, royalties from UpToDate, and meeting expenses from AstraZeneca; Dr. Madinger, receiving honoraria in conjunction with the Merck Study Monitoring Antimicrobial Resistance Trends (SMART), the JMI Laboratories Sentry study, and the Eurofins Medinet Trust study; Dr. Make, receiving payment for service on the advisory boards of Forest Pharmaceuticals, AstraZeneca, Novartis, Dey, Nycomed, Philips Respironics, Schering-Plough (now Merck), SeQual, Embryon, Boehringer Ingelheim, Pfizer, and GlaxoSmithKline, consulting fees from Astellas Pharma, Talecris Biotherapeutics, and Chiesi Pharmaceuticals, lecture fees from GlaxoSmithKline, Boehringer Ingelheim, Pfizer, and Forest Pharmaceuticals, payment for manuscript preparation from AstraZeneca, payment for video presentation preparation from Boehringer Ingelheim and Pfizer, payment for document reviews from Spiration, and grant support from AstraZeneca, GlaxoSmithKline, Pfizer, Nabi Biopharmaceuticals, Boehringer Ingelheim, and Sunovion; Dr.; Martinez, receiving payment for service on the advisory boards of GlaxoSmithKline, MedImmune-Astra Zeneca, Merck, Pearl Therapeutics, Novartis, UBC, Mpex Pharmaceuticals and Ikaria, consulting fees from Forest-Almirall, Boehringer Ingelheim, Nycomed-Forest, Roche, Bayer, Schering-Plough (Merck), HLS, Talecris Biotherapeutics, Comgeniz, fb Communications, BoomComm, Actelion Pharmaceuticals, Elan, Genzyme, Quark Pharmaceuticals, Merck, Pfizer, and Sanofi-Aventis, royalties from Associates in Medical Marketing and Castle Connolly, lecture fees from GlaxoSmithKline, National Associaion for Continuing Education, Med-Ed, Potomac Pharma, Pfizer, Boehringer Ingelheim, Schering-Plough (Merck), Vox Medica, WebMD, Epocrates, AstraZeneca, and Altana-Nycomed, payment for development of educational presentations for HIT Global and UpToDate, and grant support from Boehringer Ingelheim, Gilead, Johnson & Johnson-Centocor Ortho Biotech, and Actelion Pharmaceuticals; Dr. McEvoy, receiving grant support from Boston Scientific and GlaxoSmithKline and lecture fees from Boehringer Ingelheim and GlaxoSmithKline; Dr. Niewoehner, receiving consulting fees from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Forest Research, Merck, Sanofi-Aventis, Bayer Schering Pharma, Nycomed, ProtAffin, and Pfizer; Dr. Porszasz, receiving consulting fees from Breathe Technologies, Boehringer Ingelheim, Novartis, and Forest Pharmaceuticals, and grant support from Boehringer Ingelheim, Forest Pharmaceuticals, Breathe Technologies (pending), and Novartis; Dr. Price, receiving consulting fees from Astellas Pharma, Cubist Pharmaceuticals, and Merck, providing expert testimony on transmission of hospital-associated infections, management of musculoskeletal infections, aminoglycoside toxicity, and diagnosis of infection, receiving grant support from MicroPhage, Cubist Pharmaceuticals, Quintiles, Sanofi Pasteur, BioCryst Pharmaceuticals, and Accelr8 Technology, and lecture fees from Robert Michael (a CME vendor), Cubist Pharmaceuticals, and Baxter Healthcare; Dr. Scanlon, receiving grant support from Altana, Boehringer Ingelheim, Dey, Forest Pharmaceuticals, GlaxoSmithKline, Novartis, and Pfizer and royalties from Lippincott Williams & Wilkins and Wolters Kluwer; Dr. Sciurba, receiving consulting fees from Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline and grant support from Pfizer and GlaxoSmithKline; Dr. Washko, receiving consulting fees from MedImmune and Spiration and being married to an employee of Merck Research Laboratories Division of Clinical Pharmacology; and Dr. Woodruff, receiving consulting fees from MedImmune, grant support from Genentech, and being a coinventor on a patent held jointly by his institution and Genentech. No other potential conflict of interest relevant to this article was reported. NR 42 TC 384 Z9 395 U1 5 U2 46 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 25 PY 2011 VL 365 IS 8 BP 689 EP 698 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 811JM UT WOS:000294205300004 PM 21864166 ER PT J AU Paul, E Thiele, EA Shailam, R Rosales, AM Sadow, PM AF Paul, Elahna Thiele, Elizabeth Anne Shailam, Randheer Rosales, Ana Maria Sadow, Peter M. TI Case 26-2011: A 7-Year-Old Boy with a Complex Cyst in the Kidney SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; RENAL-CELL CARCINOMA; CONTIGUOUS GENE SYNDROME; DISEASE; ANGIOMYOLIPOMA; EPILEPSY; EMBOLIZATION; PROGNOSIS; TSC2 C1 [Paul, Elahna] Massachusetts Gen Hosp, Dept Pediat Nephrol, Boston, MA 02114 USA. [Thiele, Elizabeth Anne] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Shailam, Randheer] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rosales, Ana Maria] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Sadow, Peter M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Paul, Elahna] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Thiele, Elizabeth Anne] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Shailam, Randheer] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Rosales, Ana Maria] Harvard Univ, Sch Med, Dept Cardiol, Boston, MA USA. [Sadow, Peter M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Paul, E (reprint author), Massachusetts Gen Hosp, Dept Pediat Nephrol, Boston, MA 02114 USA. NR 31 TC 4 Z9 4 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 25 PY 2011 VL 365 IS 8 BP 743 EP 751 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 811JM UT WOS:000294205300012 PM 21864169 ER PT J AU Gupta, K Strymish, JM Lawler, E AF Gupta, Kalpana Strymish, Judith M. Lawler, Elizabeth TI Transmission of Resistant Bacteria in Intensive Care SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Gupta, Kalpana; Strymish, Judith M.] VA Boston Healthcare Syst, Boston, MA 02132 USA. [Lawler, Elizabeth] Massachusetts Vet Epidemiol Res Informat Ctr, Boston, MA USA. RP Gupta, K (reprint author), VA Boston Healthcare Syst, Boston, MA 02132 USA. EM kalpana.gupta@va.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 25 PY 2011 VL 365 IS 8 BP 763 EP 763 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 811JM UT WOS:000294205300022 PM 21864173 ER PT J AU Lee, KH Shim, MS Kim, JY Jung, HK Lee, E Carlson, BA Xu, XM Park, JM Hatfield, DL Park, T Lee, BJ AF Lee, Kwang Hee Shim, Myoung Sup Kim, Jin Young Jung, Hee Kyoung Lee, Eunji Carlson, Bradley A. Xu, Xue-Ming Park, Jin Mo Hatfield, Dolph L. Park, Taesung Lee, Byeong Jae TI Drosophila selenophosphate synthetase 1 regulates vitamin B6 metabolism: prediction and confirmation SO BMC GENOMICS LA English DT Article ID SELENOCYSTEINE BIOSYNTHESIS; SELENOPROTEIN SYNTHESIS; 5'-PHOSPHATE OXIDASE; ESCHERICHIA-COLI; GENE ONTOLOGY; SELENIUM; SYNTHASE; HOMOLOG; PATHWAY; IDENTIFICATION AB Background: There are two selenophosphate synthetases (SPSs) in higher eukaryotes, SPS1 and SPS2. Of these two isotypes, only SPS2 catalyzes selenophosphate synthesis. Although SPS1 does not contain selenophosphate synthesis activity, it was found to be essential for cell growth and embryogenesis in Drosophila. The function of SPS1, however, has not been elucidated. Results: Differentially expressed genes in Drosophila SL2 cells were identified using two-way analysis of variance methods and clustered according to their temporal expression pattern. Gene ontology analysis was performed against differentially expressed genes and gene ontology terms related to vitamin B6 biosynthesis were found to be significantly affected at the early stage at which megamitochondria were not formed (day 3) after SPS1 knockdown. Interestingly, genes related to defense and amino acid metabolism were affected at a later stage (day 5) following knockdown. Levels of pyridoxal phosphate, an active form of vitamin B6, were decreased by SPS1 knockdown. Treatment of SL2 cells with an inhibitor of pyridoxal phosphate synthesis resulted in both a similar pattern of expression as that found by SPS1 knockdown and the formation of megamitochondria, the major phenotypic change observed by SPS1 knockdown. Conclusions: These results indicate that SPS1 regulates vitamin B6 synthesis, which in turn impacts various cellular systems such as amino acid metabolism, defense and other important metabolic activities. C1 [Lee, Kwang Hee; Shim, Myoung Sup; Kim, Jin Young; Jung, Hee Kyoung; Lee, Byeong Jae] Seoul Natl Univ, Dept Biol Sci, Seoul 151742, South Korea. [Lee, Kwang Hee; Lee, Eunji; Park, Taesung; Lee, Byeong Jae] Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea. [Lee, Eunji; Park, Taesung] Seoul Natl Univ, Dept Stat, Seoul 151742, South Korea. [Carlson, Bradley A.; Xu, Xue-Ming; Hatfield, Dolph L.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Park, Jin Mo] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Park, Jin Mo] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Dept Biol Sci, Seoul 151742, South Korea. EM imbglmg@snu.ac.kr FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2009-0094020, 2011-0012947]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; Korea Ministry of Education and Human Resources Development FX This work was supported by the Priority Research Centers Program and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant Nos 2009-0094020 and 2011-0012947 to BJL) and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. MSS, JYK, KHL and HKJ were supported by Brain Korea 21 Research Fellowship from the Korea Ministry of Education and Human Resources Development. NR 45 TC 6 Z9 6 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 24 PY 2011 VL 12 AR 426 DI 10.1186/1471-2164-12-426 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 848KG UT WOS:000297049900001 PM 21864351 ER PT J AU Magnee, MJCM de Gelder, B van Engeland, H Kemner, C AF Magnee, Maurice J. C. M. de Gelder, Beatrice van Engeland, Herman Kemner, Chantal TI Multisensory Integration and Attention in Autism Spectrum Disorder: Evidence from Event-Related Potentials SO PLOS ONE LA English DT Article ID PERVASIVE DEVELOPMENTAL DISORDERS; AUDIOVISUAL SPEECH INTEGRATION; AUDITORY-VISUAL INTEGRATION; SELECTIVE ATTENTION; FACE; PERCEPTION; VOICE; SCHIZOPHRENIA; HUMANS; ERP AB Successful integration of various simultaneously perceived perceptual signals is crucial for social behavior. Recent findings indicate that this multisensory integration (MSI) can be modulated by attention. Theories of Autism Spectrum Disorders (ASDs) suggest that MSI is affected in this population while it remains unclear to what extent this is related to impairments in attentional capacity. In the present study Event-related potentials (ERPs) following emotionally congruent and incongruent face-voice pairs were measured in 23 high-functioning, adult ASD individuals and 24 age-and IQ-matched controls. MSI was studied while the attention of the participants was manipulated. ERPs were measured at typical auditory and visual processing peaks, namely, P2 and N170. While controls showed MSI during divided attention and easy selective attention tasks, individuals with ASD showed MSI during easy selective attention tasks only. It was concluded that individuals with ASD are able to process multisensory emotional stimuli, but this is differently modulated by attention mechanisms in these participants, especially those associated with divided attention. This atypical interaction between attention and MSI is also relevant to treatment strategies, with training of multisensory attentional control possibly being more beneficial than conventional sensory integration therapy. C1 [Magnee, Maurice J. C. M.; van Engeland, Herman; Kemner, Chantal] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Child & Adolescent Psychiat, Utrecht, Netherlands. [Magnee, Maurice J. C. M.; de Gelder, Beatrice] Tilburg Univ, Lab Cognit & Affect Neurosci, NL-5000 LE Tilburg, Netherlands. [de Gelder, Beatrice] Harvard Univ, Sch Med, Charlestown, MA USA. [de Gelder, Beatrice] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Kemner, Chantal] Univ Utrecht, Dept Dev Psychol, Utrecht, Netherlands. RP Magnee, MJCM (reprint author), Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Child & Adolescent Psychiat, Utrecht, Netherlands. EM M.J.C.M.Magnee@umcutrecht.nl FU Netherlands Organization for Scientific Research (NWO) [402-01-094]; Utrecht University FX The work described was supported by an Innovational Research Incentives grant (VIDI-scheme, 402-01-094) of the Netherlands Organization for Scientific Research (NWO) and a Neuroscience and Cognition Utrecht (NCU) grant from Utrecht University to Chantal Kemner. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 17 Z9 18 U1 3 U2 47 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 24 PY 2011 VL 6 IS 8 AR e24196 DI 10.1371/journal.pone.0024196 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 832TW UT WOS:000295832000095 PM 21887382 ER PT J AU Sekeres, MA Steensma, DP AF Sekeres, Mikkael A. Steensma, David P. TI The Road Warriors SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Sekeres, Mikkael A.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sekeres, MA (reprint author), Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. EM sekerem@ccf.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 24 PY 2011 VL 306 IS 8 BP 805 EP 806 DI 10.1001/jama.2011.1191 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 810VY UT WOS:000294157300001 PM 21862735 ER PT J AU Murff, HJ FitzHenry, F Matheny, ME Gentry, N Kotter, KL Crimin, K Dittus, RS Rosen, AK Elkin, PL Brown, SH Speroff, T AF Murff, Harvey J. FitzHenry, Fern Matheny, Michael E. Gentry, Nancy Kotter, Kristen L. Crimin, Kimberly Dittus, Robert S. Rosen, Amy K. Elkin, Peter L. Brown, Steven H. Speroff, Theodore TI Automated Identification of Postoperative Complications Within an Electronic Medical Record Using Natural Language Processing SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PATIENT-SAFETY-INDICATORS; QUALITY IMPROVEMENT PROGRAM; ADMINISTRATIVE DATA; ADVERSE EVENTS; TIME; CARE AB Context Currently most automated methods to identify patient safety occurrences rely on administrative data codes; however, free-text searches of electronic medical records could represent an additional surveillance approach. Objective To evaluate a natural language processing search-approach to identify postoperative surgical complications within a comprehensive electronic medical record. Design, Setting, and Patients Cross-sectional study involving 2974 patients undergoing inpatient surgical procedures at 6 Veterans Health Administration (VHA) medical centers from 1999 to 2006. Main Outcome Measures Postoperative occurrences of acute renal failure requiring dialysis, deep vein thrombosis, pulmonary embolism, sepsis, pneumonia, or myocardial infarction identified through medical record review as part of the VA Surgical Quality Improvement Program. We determined the sensitivity and specificity of the natural language processing approach to identify these complications and compared its performance with patient safety indicators that use discharge coding information. Results The proportion of postoperative events for each sample was 2% (39 of 1924) for acute renal failure requiring dialysis, 0.7% (18 of 2327) for pulmonary embolism, 1% (29 of 2327) for deep vein thrombosis, 7% (61 of 866) for sepsis, 16% (222 of 1405) for pneumonia, and 2% (35 of 1822) for myocardial infarction. Natural language processing correctly identified 82% (95% confidence interval [CI], 67%-91%) of acute renal failure cases compared with 38% (95% CI, 25%-54%) for patient safety indicators. Similar results were obtained for venous thromboembolism (59%, 95% CI, 44%-72% vs 46%, 95% CI, 32%-60%), pneumonia (64%, 95% CI, 58%-70% vs 5%, 95% CI, 3%-9%), sepsis (89%, 95% CI, 78%-94% vs 34%, 95% CI, 24%-47%), and postoperative myocardial infarction (91%, 95% CI, 78%-97%) vs 89%, 95% CI, 74%-96%). Both natural language processing and patient safety indicators were highly specific for these diagnoses. Conclusion Among patients undergoing inpatient surgical procedures at VA medical centers, natural language processing analysis of electronic medical records to identify postoperative complications had higher sensitivity and lower specificity compared with patient safety indicators based on discharge coding. JAMA. 2011;306(8):848-855 www.jama.com C1 [Murff, Harvey J.; FitzHenry, Fern; Matheny, Michael E.; Gentry, Nancy; Dittus, Robert S.; Brown, Steven H.; Speroff, Theodore] Vet Affairs Med Ctr, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. [Murff, Harvey J.; Matheny, Michael E.; Dittus, Robert S.; Speroff, Theodore] Vanderbilt Univ, Div Gen Internal Med & Publ Hlth, Nashville, TN USA. [FitzHenry, Fern; Matheny, Michael E.; Brown, Steven H.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN USA. [Kotter, Kristen L.; Crimin, Kimberly; Speroff, Theodore] Vanderbilt Univ, Dept Biostat, Nashville, TN USA. [Rosen, Amy K.] Boston Univ, Sch Publ Hlth, Ctr Org Leadership & Management Res, VA Boston Healthcare Syst, Boston, MA USA. [Rosen, Amy K.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Elkin, Peter L.] Mt Sinai Sch Med, New York, NY USA. RP Murff, HJ (reprint author), Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, 2525 W End Ave,Ste 600,6th Floor, Nashville, TN 37203 USA. EM harvey.j.murff@vanderbilt.edu OI Matheny, Michael/0000-0003-3217-4147 FU Veterans Health Administration [CDA-08-020]; Veterans Health Consortium for Health Informatics Research (CHIR) [HIR 09-001, HIR 09-003]; National Institutes of Health; Department of Veterans Affairs [SAF-03-223] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interests. Dr Matheny reported that he is supported by the Veterans Health Administration HSR&D Career Development Award CDA-08-020. Drs Matheny and Speroff reported that they are supported by the Veterans Health Consortium for Health Informatics Research (CHIR) awards HIR 09-001 and HIR 09-003. Dr Elkins reported that a pending grant gfrom the National Institutes of Health. No other disclosures were made.; This study was supported by grant SAF-03-223 from the Department of Veterans Affairs. NR 27 TC 109 Z9 109 U1 1 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 24 PY 2011 VL 306 IS 8 BP 848 EP 855 DI 10.1001/jama.2011.1204 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 810VY UT WOS:000294157300022 PM 21862746 ER PT J AU Ryan, C Leonardi, CL Krueger, JG Kimball, AB Strober, BE Gordon, KB Langley, RG de Lemos, JA Daoud, Y Blankenship, D Kazi, S Kaplan, DH Friedewald, VE Menter, A AF Ryan, Caitriona Leonardi, Craig L. Krueger, James G. Kimball, Alexa B. Strober, Bruce E. Gordon, Kenneth B. Langley, Richard G. de Lemos, James A. Daoud, Yahya Blankenship, Derek Kazi, Salahuddin Kaplan, Dan H. Friedewald, Vincent E. Menter, Alan TI Association Between Biologic Therapies for Chronic Plaque Psoriasis and Cardiovascular Events A Meta-analysis of Randomized Controlled Trials SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; PLACEBO-CONTROLLED TRIAL; OPEN-LABEL EXTENSION; TO-SEVERE PSORIASIS; PHASE-III TRIAL; DOUBLE-BLIND; IN-VIVO; INFLIXIMAB INDUCTION; DEFICIENT MICE; EFFICACY AB Context Ustekinumab and briakinumab, monoclonal antibodies to the shared p40 subunit of interleukin (IL)-12 and IL-23, have shown efficacy in treating chronic plaque psoriasis (CPP). Preliminary reports of major adverse cardiovascular events (MACEs) in psoriasis patients receiving anti-IL-12/23 agents have prompted concern. Objective To evaluate a possible association between biologic therapies for CPP and MACEs via meta-analysis. Data Sources Randomized controlled trials (RCTs) of anti-IL-12/23 (ustekinumab and briakinumab) agents and anti-tumor necrosis factor alpha (TNF-alpha) agents (adalimumab, etanercept, and infliximab) used in treating CPP were reviewed using the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Ovid MEDLINE from database inception to May 2011. The results of registered nonpublished completed studies were procured through abstract publications or poster presentations. Study Selection Randomized, placebo-controlled, double-blind, monotherapy studies (with safety outcome data for MACE) of IL-12/23 antibodies and anti-TNF-alpha agents in adults. Studies of psoriatic arthritis were excluded. Data Extraction Two investigators independently searched data while 6 investigators reviewed the abstracted data. Results A total of 22 RCTs comprising 10 183 patients met the predefined inclusion criteria. The primary outcome measure was MACE, a composite end point of myocardial infarction, cerebrovascular accident, or cardiovascular death during the placebocontrolled phase of treatment in patients receiving at least 1 dose of study agent or placebo. Absolute risk differences were used as an effect measure. There was no evidence of statistical heterogeneity across the studies using the I-2 statistic (I-2=0), allowing for combination of trial results using the Mantel-Haenszel fixed-effects method. During the placebo-controlled phases of the anti-IL-12/23 studies, 10 of 3179 patients receiving anti-IL-12/23 therapies experienced MACEs compared with zero events in 1474 patients receiving placebo (Mantel-Haenszel risk difference, 0.012 events/ person-year; 95% confidence interval [CI], -0.001 to 0.026; P=.12). In the anti-TNF-alpha trials, only 1 of 3858 patients receiving anti-TNF-alpha agents experienced a MACE compared with 1 of 1812 patients receiving placebo (Mantel-Haenszel risk difference, -0.0005 events/person-year; 95% CI, -0.010 to 0.009; P=.94). Conclusions Compared with placebo, there was no significant difference in the rate of MACEs observed in patients receiving anti-IL-12/IL-23 antibodies or anti-TNF-alpha treatments. This study may have been underpowered to identify a significant difference. JAMA. 2011;306(8):864-871 www.jama.com C1 [Ryan, Caitriona; Menter, Alan] Baylor Res Inst, Dept Dermatol, Dallas, TX 75246 USA. [Leonardi, Craig L.] St Louis Univ, Dept Dermatol, St Louis, MO 63103 USA. [Krueger, James G.] Rockefeller Univ, Lab Investigat Dermatol, New York, NY 10021 USA. [Kimball, Alexa B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Strober, Bruce E.] Univ Connecticut, Dept Dermatol, Farmington, CT USA. [Gordon, Kenneth B.] Univ Chicago, Pritzker Sch Med, Div Dermatol, Chicago, IL 60637 USA. [Langley, Richard G.] Dalhousie Univ, Dept Dermatol, Halifax, NS, Canada. [de Lemos, James A.] Univ Texas SW Med Ctr Dallas, Donald W Reynolds Cardiovasc Res Ctr, Dallas, TX 75390 USA. [de Lemos, James A.] Univ Texas SW Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA. [Daoud, Yahya; Blankenship, Derek] Baylor Univ, Med Ctr, Dept Res & Improvement Educ, Dallas, TX USA. [Kazi, Salahuddin] VA N Texas Hlth Care Syst, Dept Rheumatol, Dallas, TX USA. [Kaplan, Dan H.] Univ Minnesota, Dept Dermatol, Ctr Immunol, Minneapolis, MN 55455 USA. [Friedewald, Vincent E.] Univ Notre Dame, Dept Cardiol, Notre Dame, IN 46556 USA. RP Ryan, C (reprint author), Baylor Res Inst, Dept Dermatol, 3900 Junius St,Ste 125, Dallas, TX 75246 USA. EM caitriona.ryan@baylorhealth.edu RI Kaplan, Daniel/N-2779-2013; OI Kaplan, Daniel/0000-0002-7851-7320; Ryan, Caitriona/0000-0003-1915-546X FU Abbott; Centocor; Amgen; Eli Lilly; Baylor Research Institute FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ryan reports acting as a speaker for Jansen-Cilag and Pfizer; serving as an advisory board member for Galderma; and receiving grant support from Abbott. Dr Leonardi reports acting as a consultant for Abbott, Amgen, Centocor, Pfizer, and Eli Lilly; investigating for Abbott, Amgen, Celgene, Centocor, Genentech, Eli Lilly, Galderma, Genzyme, GlaxoSmithKline, Incyte, Pfizer, Incyte, Schering Plough, Sirtris, Stiefel, Novartis, Novo Nordisk, Vascular Biogenics, and Wyeth (now Pfizer); and serving on speakers' bureaus for Abbott, Amgen, and Centocor. Dr Krueger reports being a consultant to or participant on advisory boards for Amgen, Wyeth (now Pfizer), and Centocor. Dr Kimball reports acting as a consultant and investigator for Abbott, Amgen, Centocor, Idera, VBL, Neostrata, Galderma; investigating for Pfizer, Boehringer Ingleheim, Stiefel, Cytochroma, and Schering Plough; speaking for Johnson and Johnson; receiving fellowship funding from Centocor; and consulting for Novartis, Lilly, Celgene, Combinatorix, Canfite, Serentis, Incyte, Array Biopharma, and Warner Chilcott. Dr Strober reports acting as a consultant for Amgen, Abbott, Centocor, Pfizer, Celgene, and Novartis; as a speaker for Amgen, Abbott, and Centocor; and receiving grant support from Amgen, Abbott, and Centocor. Dr Gordon reports receiving research support or honoraria from Abbott, Amgen, Centocor, and Eli Lilly, and consulting for Abbott, Amgen, Centocor, Eli Lilly, Merck, and Pfizer. Dr Langley reports acting as an investigator, scientific advisory board member, or speaker for Abbott, Amgen, Biogen-IDEC, Celgene, Centocor, Leo, Schering, Merck, Novartis, Ortho Biotec, and Pfizer. Dr de Lemos reports consulting for Johnson and Johnson and AstraZeneca. Dr Kazi reports acting as a speaker for Centocor and Genentech. Dr Friedewald reports acting as a consultant for AstraZeneca. Dr Menter reports receiving research support and consulting or lecturing for Abbott, Amgen, Astellas, Asubio, Celgene, Centocor, DUSA, Eli Lilly, Galderma, Genentech, Novartis, Novo-Nordisk, Merck-Serono, Pfizer, Promius, Stiefel, Syntrix Biosystems, Warner Chilcott, and Wyeth (now Pfizer). All other authors report no disclosures.; No external funding was received for this study. Statistical support was funded internally by Baylor Research Institute discretionary funds. Mr Daoud and Dr Blankenship are full-time employees of Baylor Research Institute and were reimbursed for their time spent working on this project. NR 59 TC 123 Z9 125 U1 1 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 24 PY 2011 VL 306 IS 8 BP 864 EP 871 DI 10.1001/jama.2011.1211 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 810VY UT WOS:000294157300024 PM 21862748 ER PT J AU Jha, AK AF Jha, Ashish K. TI The Promise of Electronic Records Around the Corner or Down the Road? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PHYSICIAN ORDER ENTRY; HEALTH RECORDS; QUALITY; SAFETY C1 [Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Div Gen Med,Brigham & Womens Hosp, Boston, MA 02115 USA. [Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. RP Jha, AK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM ajha@hsph.harvard.edu NR 10 TC 33 Z9 34 U1 2 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 24 PY 2011 VL 306 IS 8 BP 880 EP 881 DI 10.1001/jama.2011.1219 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 810VY UT WOS:000294157300029 PM 21862751 ER PT J AU Bell, AH Malecek, NJ Morin, EL Hadj-Bouziane, F Tootell, RBH Ungerleider, LG AF Bell, Andrew H. Malecek, Nicholas J. Morin, Elyse L. Hadj-Bouziane, Fadila Tootell, Roger B. H. Ungerleider, Leslie G. TI Relationship between Functional Magnetic Resonance Imaging-Identified Regions and Neuronal Category Selectivity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INFERIOR TEMPORAL CORTEX; POSTERIOR INFEROTEMPORAL CORTEX; DISTRIBUTED ORGANIZATION; OBJECT REPRESENTATIONS; BEHAVING MONKEYS; NEURAL RESPONSES; CONTRAST AGENT; BODY PARTS; MACAQUE; FACE AB Functional magnetic resonance imaging (fMRI) has been used extensively to identify regions in the inferiortemporal (IT) cortex that are selective for categories of visual stimuli. However, comparatively little is known about the neuronal responses relative to these fMRI-defined regions. Here, we compared in nonhuman primates the distribution and response properties of IT neurons recorded within versus outside fMRI regions selective for four different visual categories: faces, body parts, objects, and places. Although individual neurons that preferred each of the four categories were found throughout the sampled regions, they were most concentrated within the corresponding fMRI region, decreasing significantly within 1-4 mm from the edge of these regions. Furthermore, the correspondence between fMRI and neuronal distributions was specific to neurons that increased their firing rates in response to the visual stimuli but not to neurons suppressed by visual stimuli, suggesting that the processes associated with inhibiting neuronal activity did not contribute strongly to the fMRI signal in this experiment. C1 [Bell, Andrew H.; Malecek, Nicholas J.; Morin, Elyse L.; Hadj-Bouziane, Fadila; Tootell, Roger B. H.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Tootell, Roger B. H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Tootell, Roger B. H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Bell, AH (reprint author), MRC, Cognit & Brain Sci Unit, 15 Chaucer Rd, Cambridge CB2 7EF, England. EM andrew.bell@mrc-cbu.cam.ac.uk RI Hadj-Bouziane, Fadila/A-1180-2013; OI Bell, Andrew/0000-0001-8420-4622 FU National Institutes of Health [R01 MH67529, R01 EY017081]; Athinoula A. Martinos Center for Biomedical Imaging; National Center for Research Resources; National Institute of Mental Health FX This work was supported by National Institutes of Health Grants R01 MH67529 and R01 EY017081 (R.B.H.T.), the Athinoula A. Martinos Center for Biomedical Imaging, the National Center for Research Resources, and the National Institute of Mental Health Intramural Research Program (A.H.B., N.J.M., E.L.M., F.H-B., and L.G.U.). We thank the following individuals: Wim Vanduffel, Hauke Kolster, and Leeland Ekstrom for their invaluable assistance with the imaging experiments conducted while at Massachusetts General Hospital, and Lucy Guillory for her assistance with animal training and collection of the imaging data. NR 51 TC 47 Z9 47 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 24 PY 2011 VL 31 IS 34 BP 12229 EP 12240 DI 10.1523/JNEUROSCI.5865-10.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 811IU UT WOS:000294202900018 PM 21865466 ER PT J AU Premereur, E Vanduffel, W Janssen, P AF Premereur, Elsie Vanduffel, Wim Janssen, Peter TI Functional Heterogeneity of Macaque Lateral Intraparietal Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID POSTERIOR PARIETAL CORTEX; AREA LIP; PERCEPTUAL DECISION; TARGET SELECTION; PRIORITY MAP; NEURAL BASIS; ATTENTION; MONKEY; INTENTION; SACCADE AB The macaque lateral intraparietal area (LIP) has been implicated in many cognitive processes, ranging from saccade planning and spatial attention to timing and categorization. Importantly, different research groups have used different criteria for including LIP neurons in their studies. While some research groups have selected LIP neurons based on the presence of memory-delay activity, other research groups have used other criteria such as visual, presaccadic, and/or memory activity. We recorded from LIP neurons that were selected based on spatially selective saccadic activity but regardless of memory-delay activity in macaque monkeys. To test anticipatory climbing activity, we used a delayed visually guided saccade task with a unimodal schedule of go-times, for which the conditional probability that the go-signal will occur rises monotonically as a function of time. A subpopulation of LIP neurons showed anticipatory activity that mimicked the subjective hazard rate of the go-signal when the animal was planning a saccade toward the receptive field. A large subgroup of LIP neurons, however, did not modulate their firing rates according to the subjective hazard function. These non-anticipatory neurons were strongly influenced by salient visual stimuli appearing in their receptive field, but less so by the direction of the impending saccade. Thus, LIP contains a heterogeneous population of neurons related to saccade planning or visual salience, and these neurons are spatially intermixed. Our results suggest that between-study differences in neuronal selection may have contributed significantly to the findings of different research groups with respect to the functional role of area LIP. C1 [Premereur, Elsie; Vanduffel, Wim; Janssen, Peter] Katholieke Univ Leuven, Lab Neuro & Psychofysiol, B-3000 Louvain, Belgium. [Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02129 USA. RP Janssen, P (reprint author), Katholieke Univ Leuven, Lab Neuro & Psychofysiol, Campus Gasthuisberg,O&N 2,Herestr 49,Bus 1021, B-3000 Louvain, Belgium. EM Peter.Janssen@med.kuleuven.be FU Geneeskundige Stichting Koningin Elisabeth, Fonds voor Wetenschappelijk Onderzoek [G.0713.09, G.0622.08, G.0831.11]; Interuniversity Attraction Poles [P6/29]; Excellentie Financiering [EF/05/014]; National Science Foundation [BCS-0745436]; Programma Financiering [PFV/10/008]; Geconcerteerde Onderzoeksacties [GOA/10/19] FX This work was supported by Geneeskundige Stichting Koningin Elisabeth, Fonds voor Wetenschappelijk Onderzoek (G.0713.09, G.0622.08, and G.0831.11), Interuniversity Attraction Poles (P6/29), Excellentie Financiering (EF/05/014), National Science Foundation (BCS-0745436), Programma Financiering (PFV/10/008), and Geconcerteerde Onderzoeksacties (GOA/10/19). We thank Stijn Verstraeten, Piet Kayenbergh, Gerrit Meulemans, Marc De Paep, Inez Puttemans, and Marjan Docx for assistance. We thank Steve Raiguel for comments on a previous version of this manuscript. NR 42 TC 27 Z9 27 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 24 PY 2011 VL 31 IS 34 BP 12307 EP 12317 DI 10.1523/JNEUROSCI.2241-11.2011 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 811IU UT WOS:000294202900025 PM 21865473 ER PT J AU Thadhani, R Kisner, T Hagmann, H Bossung, V Noack, S Schaarschmidt, W Jank, A Kribs, A Cornely, OA Kreyssig, C Hemphill, L Rigby, AC Khedkar, S Lindner, TH Mallmann, P Stepan, H Karumanchi, SA Benzing, T AF Thadhani, Ravi Kisner, Tuelay Hagmann, Henning Bossung, Verena Noack, Stefanie Schaarschmidt, Wiebke Jank, Alexander Kribs, Angela Cornely, Oliver A. Kreyssig, Claudia Hemphill, Linda Rigby, Alan C. Khedkar, Santosh Lindner, Tom H. Mallmann, Peter Stepan, Holger Karumanchi, S. Ananth Benzing, Thomas TI Pilot Study of Extracorporeal Removal of Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia SO CIRCULATION LA English DT Article DE angiogenic factor; apheresis; preeclampsia ID DENSITY-LIPOPROTEIN APHERESIS; HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; GROWTH-FACTOR RECEPTOR-1; RANDOMIZED CONTROLLED-TRIAL; EXPECTANT MANAGEMENT; CITRATE ANTICOAGULATION; VEGF RECEPTOR-1; HEPARIN-BINDING; WEEKS GESTATION; PREGNANCY AB Background-Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (<32 weeks) preeclampsia. Methods and Results-We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. Conclusions-This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting. (Circulation. 2011;124:940-950.) C1 [Thadhani, Ravi; Hemphill, Linda] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol,Dept Med, Boston, MA USA. [Kisner, Tuelay; Hagmann, Henning; Benzing, Thomas] Univ Cologne, Div Renal, Cologne, Germany. [Kisner, Tuelay; Hagmann, Henning; Benzing, Thomas] Univ Cologne, Dept Med, Cologne, Germany. [Kisner, Tuelay; Hagmann, Henning; Benzing, Thomas] Univ Cologne, Ctr Mol Med, Cologne, Germany. [Bossung, Verena; Mallmann, Peter] Univ Cologne, Dept Obstet & Gynecol, Cologne, Germany. [Kribs, Angela] Univ Cologne, Dept Neonatol, Cologne, Germany. [Cornely, Oliver A.] Univ Cologne, Dept Internal Med, Cologne, Germany. [Cornely, Oliver A.] Univ Cologne, Clin Trials Ctr, ZKS Koln, Cologne, Germany. [Schaarschmidt, Wiebke; Jank, Alexander; Stepan, Holger] Univ Hosp Leipzig, Dept Obstet, Leipzig, Germany. [Kreyssig, Claudia; Lindner, Tom H.] Univ Hosp Leipzig, Div Nephrol, Dept Internal Med Neurol & Dermatol, Leipzig, Germany. [Rigby, Alan C.; Khedkar, Santosh; Karumanchi, S. Ananth] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Thadhani, R (reprint author), Bullfinch 127, Boston, MA 02114 USA. EM thadhani.r@mgh.harvard.edu; Thomas.Benzing@uk-koeln.de FU Department of Medicine, Massachusetts General Hospital; several federal and foundation grants; Forschungspool Klinische Studien, Faculty of Medicine, University of Cologne; German Federal Ministry of Research and Education (Bundesministerium fur Bildung und Forschung) [01KN1106]; German Research Foundation [BE2212]; Howard Hughes Medical Institute FX This work was funded by the Discovery Fund from the Department of Medicine, Massachusetts General Hospital, to Dr Thadhani. Dr Thadhani's salary is supported by several federal and foundation grants. This work also received support from Forschungspool Klinische Studien, Faculty of Medicine, University of Cologne. Dr Cornely is supported by the German Federal Ministry of Research and Education (Bundesministerium fur Bildung und Forschung Grant 01KN1106). Dr Benzing received funding from the German Research Foundation (BE2212). Dr Karumanchi is supported by the Howard Hughes Medical Institute. NR 55 TC 138 Z9 141 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 23 PY 2011 VL 124 IS 8 BP 940 EP U178 DI 10.1161/CIRCULATIONAHA.111.034793 PG 18 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 810JC UT WOS:000294120600017 PM 21810665 ER PT J AU Cermelli, S Ruggieri, A Marrero, JA Ioannou, GN Beretta, L AF Cermelli, Silvia Ruggieri, Anna Marrero, Jorge A. Ioannou, George N. Beretta, Laura TI Circulating MicroRNAs in Patients with Chronic Hepatitis C and Non-Alcoholic Fatty Liver Disease SO PLOS ONE LA English DT Article ID HEPATOCELLULAR-CARCINOMA; IN-VIVO; MIR-122; CANCER; VIRUS; EXPRESSION; TRANSLATION; BIOMARKERS; STEATOSIS; INFECTION AB MicroRNAs miR-122, miR-34a, miR-16 and miR-21 are commonly deregulated in liver fibrosis and hepatocellular carcinoma. This study examined whether circulating levels of these miRNAs correlate with hepatic histological disease severity in patients with chronic hepatitis C infection (CHC) or non-alcoholic fatty-liver disease (NAFLD) and can potentially serve as circulating markers for disease stage assessment. We first used an in vitro model of hepatitis C virus (HCV) infection to measure the extracellular levels of these four miRNAs. Whereas miR-21 extracellular levels were unchanged, extracellular levels of miR-122, miR-34a and to a lesser extent miR-16, steadily increased during the course of HCV infection, independently of viral replication and production. Similarly, in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher than in control individuals, while miR-21 levels were unchanged. There was no correlation between the serum levels of any of these microRNAs and HCV viral loads. In contrast, miR-122 and miR-34a levels positively correlated with disease severity. Identical results were obtained in an independent cohort of CHC patients. We extended the study to patients with NAFLD. As observed in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher in NAFLD patients than in controls, while miR-21 levels were unchanged. Again, miR-122 and miR-34a levels positively correlated with disease severity from simple steatosis to steatohepatitis. In both CHC and NAFLD patient groups, serum levels of miR-122 and miR-34a correlated with liver enzymes levels, fibrosis stage and inflammation activity. miR-122 levels also correlated with serum lipids in NAFLD patients. Conclusion: Serum levels of miR-34a and miR-122 may represent novel, noninvasive biomarkers of diagnosis and histological disease severity in patients with CHC or NAFLD. C1 [Cermelli, Silvia; Ruggieri, Anna; Beretta, Laura] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Ruggieri, Anna] Ist Super Sanita, Dept Infect Parasit & Immune Mediated Dis, I-00161 Rome, Italy. [Marrero, Jorge A.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Gastroenterol, Seattle, WA USA. [Ioannou, George N.] Univ Washington, Seattle, WA 98195 USA. RP Cermelli, S (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM lberetta@fhcrc.org RI ruggieri, anna/C-9950-2015 FU National Institutes of Health [DK066840] FX This work was supported by grant DK066840 from the National Institutes of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 205 Z9 212 U1 1 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 23 PY 2011 VL 6 IS 8 AR e23937 DI 10.1371/journal.pone.0023937 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811YA UT WOS:000294253500040 PM 21886843 ER PT J AU Kaplan, GB Leite-Morris, KA Fan, WY Young, AJ Guy, MD AF Kaplan, Gary B. Leite-Morris, Kimberly A. Fan, WenYing Young, Angela J. Guy, Marsha D. TI Opiate Sensitization Induces FosB/Delta FosB Expression in Prefrontal Cortical, Striatal and Amygdala Brain Regions SO PLOS ONE LA English DT Article ID MESOLIMBIC DOPAMINE RELEASE; VENTRAL TEGMENTAL AREA; DELTA-FOSB; NUCLEUS-ACCUMBENS; BEHAVIORAL SENSITIZATION; LOCOMOTOR-ACTIVITY; DISTINCT PATTERNS; CHRONIC COCAINE; C-FOS; MORPHINE AB Sensitization to the effects of drugs of abuse and associated stimuli contributes to drug craving, compulsive drug use, and relapse in addiction. Repeated opiate exposure produces behavioral sensitization that is hypothesized to result from neural plasticity in specific limbic, striatal and cortical systems. Delta FosB and FosB are members of the Fos family of transcription factors that are implicated in neural plasticity in addiction. This study examined the effects of intermittent morphine treatment, associated with motor sensitization, on FosB/Delta FosB levels using quantitative immunohistochemistry. Motor sensitization was tested in C57BL/6 mice that received six intermittent pre-treatments (on days 1, 3, 5, 8, 10, 12) with either subcutaneous morphine (10 mg/kg) or saline followed by a challenge injection of morphine or saline on day 16. Mice receiving repeated morphine injections demonstrated significant increases in locomotor activity on days 8, 10, and 12 of treatment (vs. day 1), consistent with development of locomotor sensitization. A morphine challenge on day 16 significantly increased locomotor activity of saline pre-treated mice and produced even larger increases in motor activity in the morphine pre-treated mice, consistent with the expression of opiate sensitization. Intermittent morphine pre-treatment on these six pre-treatment days produced a significant induction of FosB/Delta FosB, measured on day 16, in multiple brain regions including prelimbic (PL) and infralimbic (IL) cortex, nucleus accumbens (NAc) core, dorsomedial caudate-putamen (CPU), basolateral amygdala (BLA) and central nucleus of the amygdala (CNA) but not in a motor cortex control region. Opiate induced sensitization may develop via Fos/Delta FosB plasticity in motivational pathways (NAc), motor outputs (CPU), and associative learning (PL, IL, BLA) and stress pathways (CNA). C1 [Kaplan, Gary B.] VA Boston Healthcare Syst, Mental Hlth Serv, Boston, MA USA. [Kaplan, Gary B.; Leite-Morris, Kimberly A.; Fan, WenYing; Young, Angela J.; Guy, Marsha D.] VA Boston Healthcare Syst, Res Serv, Boston, MA USA. [Leite-Morris, Kimberly A.; Fan, WenYing] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Leite-Morris, Kimberly A.; Fan, WenYing] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA. RP Kaplan, GB (reprint author), VA Boston Healthcare Syst, Mental Hlth Serv, Boston, MA USA. EM Gary.Kaplan@va.gov; kleitemo@bu.edu FU Department of Veterans Affairs; Department of Defense FX This work was supported by a Merit Review Grant from the Department of Veterans Affairs and from the Department of Defense to G.B.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 16 Z9 17 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 23 PY 2011 VL 6 IS 8 AR e23574 DI 10.1371/journal.pone.0023574 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811YA UT WOS:000294253500016 PM 21886798 ER PT J AU Fang, PA Conway, JF Margolis, HC Simmer, JP Beniash, E AF Fang, Ping-An Conway, James F. Margolis, Henry C. Simmer, James P. Beniash, Elia TI Hierarchical self-assembly of amelogenin and the regulation of biomineralization at the nanoscale SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AMORPHOUS CALCIUM-PHOSPHATE; IN-VITRO; OCTACALCIUM PHOSPHATE; CRYSTAL-GROWTH; ENAMEL MATRIX; HYDROXYAPATITE; APATITE; PH; ORGANIZATION; AGGREGATION AB Enamel is a highly organized hierarchical nanocomposite, which consists of parallel arrays of elongated apatitic crystallites forming an intricate three-dimensional microstructure. Amelogenin, the major extracellular matrix protein of dental enamel, regulates the formation of these crystalline arrays via cooperative interactions with forming mineral phase. Using cryoelectron microscopy, we demonstrate that amelogenin undergoes stepwise hierarchical self-assembly. Furthermore, our results indicate that interactions between amelogenin hydrophilic C-terminal telopeptides are essential for oligomer formation and for subsequent steps of hierarchical self-assembly. We further show that amelogenin assemblies stabilize mineral prenucleation clusters and guide their arrangement into linear chains that organize as parallel arrays. The prenucleation clusters subsequently fuse together to form needle-shaped mineral particles, leading to the formation of bundles of crystallites, the hallmark structural organization of the forming enamel at the nanoscale. These findings provide unique insight into the regulation of biological mineralization by specialized macromolecules and an inspiration for bottom-up strategies for the materials design. C1 [Fang, Ping-An; Beniash, Elia] Univ Pittsburgh, Dept Oral Biol, Ctr Craniofacial Regenerat, McGowan Inst Regenerat Med, Pittsburgh, PA 15261 USA. [Conway, James F.] Univ Pittsburgh, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Margolis, Henry C.] Forsyth Inst, Dept Biomineralizat, Cambridge, MA 02142 USA. [Simmer, James P.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Beniash, E (reprint author), Univ Pittsburgh, Dept Oral Biol, Ctr Craniofacial Regenerat, McGowan Inst Regenerat Med, 3501 Terrace St, Pittsburgh, PA 15261 USA. EM ebeniash@pitt.edu RI Fang, PINGAN/A-2461-2009 FU National Institutes of Health [R01DE016376, R01DE016703]; Commonwealth of Pennsylvania [SAP 4100031302] FX Support for this work was provided by National Institutes of Health Grants R01DE016376 (to H.C.M.) and R01DE016703 (to E.B.) and by the Commonwealth of Pennsylvania Grant SAP 4100031302 (to J.F.C.). NR 39 TC 65 Z9 66 U1 5 U2 61 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 23 PY 2011 VL 108 IS 34 BP 14097 EP 14102 DI 10.1073/pnas.1106228108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810XO UT WOS:000294163500050 PM 21825148 ER PT J AU Massie, BM AF Massie, Barry M. TI Globalization of Clinical Trials How Should We Interpret Differences in Outcomes? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE beta-blocker; clinical trials; geography; heart failure; mortality ID CONGESTIVE-HEART-FAILURE; BUCINDOLOL; SURVIVAL C1 [Massie, Barry M.] San Francisco VA Med Ctr, Div Cardiol, San Francisco, CA USA. [Massie, Barry M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Massie, BM (reprint author), VA Med Ctr, Cardiol Div 111C, 4150 Clement St, San Francisco, CA 94121 USA. EM barry.massie@va.gov NR 13 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 23 PY 2011 VL 58 IS 9 BP 923 EP 924 DI 10.1016/j.jacc.2011.04.027 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 808BC UT WOS:000293947100007 PM 21851880 ER PT J AU Talbot, AL Bullock, GC Delehanty, LL Sattler, M Zhao, ZJ Goldfarb, AN AF Talbot, Anne-Laure Bullock, Grant C. Delehanty, Lorrie L. Sattler, Martin Zhao, Zhizhuang Joe Goldfarb, Adam N. TI Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling SO PLOS ONE LA English DT Article ID ACTIVATED PROTEIN-KINASE; IRON-SULFUR CLUSTER; MYELOPROLIFERATIVE NEOPLASMS; ERYTHROID-DIFFERENTIATION; POLYCYTHEMIA-VERA; MITOCHONDRIAL-DNA; EXPRESSION; CELLS; MICE; PHOSPHORYLATION AB Background: Erythroid development requires the action of erythropoietin (EPO) on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy. Methodology/Principal Findings: In C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition. Conclusions/Significance: Direct aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera. C1 [Talbot, Anne-Laure; Bullock, Grant C.; Delehanty, Lorrie L.; Goldfarb, Adam N.] Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA. [Sattler, Martin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zhao, Zhizhuang Joe] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. RP Talbot, AL (reprint author), Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA. EM ang3x@virginia.edu FU NIH [2T32GM007267-32, CA134660]; Ruth L. Kirschstein National Research Service Award [F32 HL0860046]; University of Virginia; NIDDK [R01 DK079924]; Roche Foundation for Anemia Research FX This work was supported by a NIH MSTP grant (grant 2T32GM007267-32, A.-L. T.), by a Ruth L. Kirschstein National Research Service Award (grant F32 HL0860046, G.C.B.), by a University of Virginia K12 Clinical Translational Career Development Award (G.C.B.), by the NIDDK (grant R01 DK079924, A.N.G.), and by the Roche Foundation for Anemia Research (A.N.G). Dr. Martin Sattler is supported by NIH grant CA134660. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 5 Z9 5 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 22 PY 2011 VL 6 IS 8 AR e23850 DI 10.1371/journal.pone.0023850 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811XK UT WOS:000294251800036 PM 21887333 ER PT J AU Cal-Gonzalez, J Herraiz, JL Espana, S Vicente, E Herranz, E Desco, M Vaquero, JJ Udias, JM AF Cal-Gonzalez, J. Herraiz, J. L. Espana, S. Vicente, E. Herranz, E. Desco, M. Vaquero, J. J. Udias, J. M. TI Study of CT-based positron range correction in high resolution 3D PET imaging SO NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT LA English DT Article DE Positron emission tomography; Computed tomography; Positron range; Image quality; Monte Carlo simulation ID RECONSTRUCTION; TOMOGRAPHY; SCANNER AB Positron range limits the spatial resolution of PET images and has a different effect for different isotopes and positron propagation materials. Therefore it is important to consider it during image reconstruction, in order to obtain optimal image quality. Positron range distributions for most common isotopes used in PET in different materials were computed using the Monte Carlo simulations with PeneloPET. The range profiles were introduced into the 3D OSEM image reconstruction software FIRST and employed to blur the image either in the forward projection or in the forward and backward projection. The blurring introduced takes into account the different materials in which the positron propagates. Information on these materials may be obtained, for instance, from a segmentation of a CT image. The results of introducing positron blurring in both forward and backward projection operations was compared to using it only during forward projection. Further, the effect of different shapes of positron range profile in the quality of the reconstructed images with positron range correction was studied. For high positron energy isotopes, the reconstructed images show significant improvement in spatial resolution when positron range is taken into account during reconstruction, compared to reconstructions without positron range modeling. (C) 2010 Elsevier B.V. All rights reserved. C1 [Cal-Gonzalez, J.; Herraiz, J. L.; Vicente, E.; Herranz, E.; Udias, J. M.] Univ Complutense Madrid, Dpto Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. [Espana, S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Espana, S.] Harvard Univ, Sch Med, Boston, MA USA. [Vicente, E.] CSIC, Inst Estructura Mat, E-28006 Madrid, Spain. [Desco, M.] Hosp Gen Univ Gregorio Maranon, Unidad Med & Cirugia Expt, Madrid, Spain. [Vaquero, J. J.] Univ Carlos III Madrid, Dpto Bioingn & Ingn Espacial, Madrid, Spain. RP Cal-Gonzalez, J (reprint author), Univ Complutense Madrid, Dpto Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. EM jacobo@nuclear.fis.ucm.es RI Vaquero, Juan Jose/D-3033-2009; LOPEZ HERRAIZ, JOAQUIN/E-9234-2010; Desco, Manuel/D-2822-2009; Espana, Samuel/E-9240-2010; Udias, Jose/A-7523-2010 OI Vaquero, Juan Jose/0000-0001-9200-361X; LOPEZ HERRAIZ, JOAQUIN/0000-0001-7208-8863; Desco, Manuel/0000-0003-0989-3231; Espana, Samuel/0000-0001-9092-4597; Udias, Jose/0000-0003-3714-764X FU MEC [FPA2007-62216]; UCM (Grupos UCM) [910059]; CPAN (Consolider-Ingenio) [CSPD-2007-00042]; RECAVA-RETIC network; ARTEMIS [S2009/DPI-1802]; European Regional Development; ENTEPRASE [PSE-300000-2009-5]; Ministerio de Ciencia e Innovacion, Spanish Government FX This work has been supported by the MEC (FPA2007-62216), the UCM (Grupos UCM, 910059), the CPAN (Consolider-Ingenio 2010) CSPD-2007-00042, the RECAVA-RETIC network, ARTEMIS S2009/DPI-1802, the European Regional Development and ENTEPRASE grant, PSE-300000-2009-5 and the Ministerio de Ciencia e Innovacion, Spanish Government. NR 17 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-9002 J9 NUCL INSTRUM METH A JI Nucl. Instrum. Methods Phys. Res. Sect. A-Accel. Spectrom. Dect. Assoc. Equip. PD AUG 21 PY 2011 VL 648 SU S1 BP S172 EP S175 DI 10.1016/j.nima.2010.12.041 PG 4 WC Instruments & Instrumentation; Nuclear Science & Technology; Physics, Nuclear; Physics, Particles & Fields SC Instruments & Instrumentation; Nuclear Science & Technology; Physics GA 960GV UT WOS:000305376900045 ER PT J AU Herraiz, JL Espana, S Cal-Gonzalez, J Vaquero, JJ Desco, M Udias, JM AF Herraiz, J. L. Espana, S. Cal-Gonzalez, J. Vaquero, J. J. Desco, M. Udias, J. M. TI Fully 3D GPU PET reconstruction SO NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT LA English DT Article DE Tomographic reconstruction; Positron emission tomography; Graphics processing unit ID IMAGE-RECONSTRUCTION; PROJECTION DATA; ALGORITHM; SOFTWARE AB Fully 3D iterative tomographic image reconstruction is computationally very demanding. Graphics Processing Unit (GPU) has been proposed for many years as potential accelerators in complex scientific problems, but it has not been used until the recent advances in the programmability of GPUs that the best available reconstruction codes have started to be implemented to be run on GPUs. This work presents a GPU-based fully 3D PET iterative reconstruction software. This new code may reconstruct sinogram data from several commercially available PET scanners. The most important and time-consuming parts of the code, the forward and backward projection operations, are based on an accurate model of the scanner obtained with the Monte Carlo code PeneloPET and they have been massively parallelized on the GPU. For the PET scanners considered, the GPU-based code is more than 70 times faster than a similar code running on a single core of a fast GPU, obtaining in both cases the same images. The code has been designed to be easily adapted to reconstruct sinograms from any other PET scanner, including scanner prototypes. (C) 2010 Elsevier B.V. All rights reserved. C1 [Herraiz, J. L.; Cal-Gonzalez, J.; Udias, J. M.] Univ Complutense Madrid, Dept Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. [Espana, S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Espana, S.] Harvard Univ, Sch Med, Boston, MA USA. [Vaquero, J. J.; Desco, M.] Univ Carlos III Madrid, Dept Bioingn & Ingn Espacial, Madrid, Spain. [Desco, M.] Hosp Gen Univ Gregorio Maranon, Unidad Med & Cirugia Expt, Madrid, Spain. RP Herraiz, JL (reprint author), Univ Complutense Madrid, Dept Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. EM joaquin@nuclear.fis.ucm.es RI Udias, Jose/A-7523-2010; Vaquero, Juan Jose/D-3033-2009; LOPEZ HERRAIZ, JOAQUIN/E-9234-2010; Desco, Manuel/D-2822-2009; Espana, Samuel/E-9240-2010 OI Udias, Jose/0000-0003-3714-764X; Vaquero, Juan Jose/0000-0001-9200-361X; LOPEZ HERRAIZ, JOAQUIN/0000-0001-7208-8863; Desco, Manuel/0000-0003-0989-3231; Espana, Samuel/0000-0001-9092-4597 FU MEC [FPA2007-62216]; UCM (Grupos UCM) [910059]; CPAN (Consolider-Ingenio) [CSPD-2007-00042]; RECAVA-RETIC network; ARTEMIS [S2009/DPI-1802]; European Regional Development; ENTEPRASE [PSE-300000-2009-5]; Ministerio de Ciencia e Innovacion, Spanish Government [TEC2008-0675-C02-01] FX The authors would like to thank Dr. R. Cabido and Dr. A.S. Montemayor for their advice in some GPU-related technical issues. This work has been supported by MEC (FPA2007-62216), UCM (Grupos UCM, 910059), CPAN (Consolider-Ingenio 2010) CSPD-2007-00042, the RECAVA-RETIC network, ARTEMIS S2009/DPI-1802, European Regional Development, ENTEPRASE grant, PSE-300000-2009-5 and TEC2008-0675-C02-01, Ministerio de Ciencia e Innovacion, Spanish Government. NR 14 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-9002 J9 NUCL INSTRUM METH A JI Nucl. Instrum. Methods Phys. Res. Sect. A-Accel. Spectrom. Dect. Assoc. Equip. PD AUG 21 PY 2011 VL 648 SU S1 BP S169 EP S171 DI 10.1016/j.nima.2010.12.043 PG 3 WC Instruments & Instrumentation; Nuclear Science & Technology; Physics, Nuclear; Physics, Particles & Fields SC Instruments & Instrumentation; Nuclear Science & Technology; Physics GA 960GV UT WOS:000305376900044 ER PT J AU Attanasi, F Knopf, A Parodi, K Paganetti, H Bortfeld, T Rosso, V Del Guerra, A AF Attanasi, F. Knopf, A. Parodi, K. Paganetti, H. Bortfeld, T. Rosso, V. Del Guerra, A. TI Extension and validation of an analytical model for in vivo PET verification of proton therapy-a phantom and clinical study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID BEAM RANGE VERIFICATION; MONTE-CARLO SIMULATIONS; DOSE DISTRIBUTIONS; FILTERING APPROACH; POSITRON-EMISSION; RADIATION-THERAPY; ACTIVATION; WASHOUT; RABBIT AB The interest in positron emission tomography (PET) as a tool for treatment verification in proton therapy has become widespread in recent years, and several research groups worldwide are currently investigating the clinical implementation. After the first off-line investigation with a PET/CT scanner at MGH (Boston, USA), attention is now focused on an in-room PET application immediately after treatment in order to also detect shorter-lived isotopes, such as O(15) and N(13), minimizing isotope washout and avoiding patient repositioning errors. Clinical trials are being conducted by means of commercially available PET systems, and other tests are planned using application-dedicated tomographs. Parallel to the experimental investigation and new hardware development, great interest has been shown in the development of fast procedures to provide feedback regarding the delivered dose from reconstructed PET images. Since the thresholds of inelastic nuclear reactions leading to tissue beta(+)-activation fall within the energy range of 15-20 MeV, the distal activity fall-off is correlated, but not directly matched, to the distal fall-off of the dose distribution. Moreover, the physical interactions leading to beta(+)-activation and energy deposition are of a different nature. All these facts make it essential to further develop accurate and fast methodologies capable of predicting, on the basis of the planned dose distribution, expected PET images to be compared with actual PET measurements, thus providing clinical feedback on the correctness of the dose delivery and of the irradiation field position. The aim of this study has been to validate an analytical model and to implement and evaluate it in a fast and flexible framework able to locally predict such activity distributions directly taking the reference planning CT and planned dose as inputs. The results achieved in this study for phantoms and clinical cases highlighted the potential of the implemented method to predict expected activity distributions with great accuracy. Thus, the analytical model can be used as a powerful substitute method to the sensitive and time-consuming Monte Carlo approach. C1 [Attanasi, F.; Rosso, V.; Del Guerra, A.] Univ Pisa, Dept Phys, I-56100 Pisa, Italy. [Attanasi, F.; Rosso, V.; Del Guerra, A.] Ist Nazl Fis Nucl, Pisa, Italy. [Knopf, A.] Univ Heidelberg, Heidelberg, DE, Germany. [Parodi, K.] Univ Clin Heidelberg, Heidelberg Ion Therapy Ctr, Dept Radiat Oncol, Heidelberg, Germany. [Paganetti, H.; Bortfeld, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Paganetti, H.; Bortfeld, T.] Harvard Univ, Sch Med, Boston, MA USA. RP Attanasi, F (reprint author), Univ Pisa, Dept Phys, I-56100 Pisa, Italy. EM francesca.attanasi@pi.infn.it NR 23 TC 22 Z9 22 U1 0 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD AUG 21 PY 2011 VL 56 IS 16 BP 5079 EP 5098 DI 10.1088/0031-9155/56/16/001 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 818VV UT WOS:000294784900002 PM 21775794 ER PT J AU Teerlink, JR Clarke, CP Saikali, KG Lee, JH Chen, MM Escandon, RD Elliott, L Bee, R Habibzadeh, MR Goldman, JH Schiller, NB Malik, FI Wolff, AA AF Teerlink, John R. Clarke, Cyril P. Saikali, Khalil G. Lee, Jacqueline H. Chen, Michael M. Escandon, Rafael D. Elliott, Lyndsey Bee, Rachel Habibzadeh, Mohammad Reza Goldman, Jonathan H. Schiller, Nelson B. Malik, Fady I. Wolff, Andrew A. TI Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study SO LANCET LA English DT Article ID DECOMPENSATED HEART-FAILURE; TIME INTERVALS; ASSOCIATION; DIAGNOSIS; SURVIVE; UPDATE AB Background Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. Methods In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0.005 to 1.0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223. Findings The maximum tolerated dose of omecamtiv mecarbil was 0.5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0.99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0.0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0.625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. Interpretation These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. C1 [Teerlink, John R.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA. [Habibzadeh, Mohammad Reza; Schiller, Nelson B.] Univ Calif San Francisco, Div Cardiol, San Francisco, CA 94121 USA. [Clarke, Cyril P.] ICON Dev Solut, UK Clin Res Unit, Manchester, Lancs, England. [Clarke, Cyril P.] Univ Manchester, Manchester, Lancs, England. [Saikali, Khalil G.; Lee, Jacqueline H.; Chen, Michael M.; Escandon, Rafael D.; Malik, Fady I.; Wolff, Andrew A.] Cytokinetics Inc, San Francisco, CA USA. [Elliott, Lyndsey; Bee, Rachel; Goldman, Jonathan H.] ICON Med Imaging, Warrington, PA USA. RP Teerlink, JR (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA. EM john.teerlink@ucsf.edu RI Teerlink, John/D-2986-2012 FU Amgen; Corthera; Cytokinetics; Merck; Novartis; Scios; Bayer; Nile Therapeutics; Cytokinetics (South San Francisco, CA, USA); Cytokinetics Inc. FX JRT has received research grants from Amgen, Corthera, Cytokinetics, Merck, Novartis, and Scios; and consulting fees from Bayer, Corthera, Cytokinetics, Merck, Nile Therapeutics, and Novartis. CPC is an employee of ICON Development Solutions (formerly Medeval). LE and RB are employees of ICON Medical Imaging. KGS, JHL, MMC, RDE, FIM, and AAW are employees of Cytokinetics, the sponsor of this study. MRH and NBS received research grants from ICON Medical Imaging. JHG is an employee of ICON Clinical Research, and formerly of ICON Medical Imaging, the echocardiogram core laboratory for this study.; This study was funded by Cytokinetics (South San Francisco, CA, USA).; Funding Cytokinetics Inc. NR 23 TC 72 Z9 75 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 20 PY 2011 VL 378 IS 9792 BP 667 EP 675 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 815EW UT WOS:000294509900026 PM 21856480 ER PT J AU Cleland, JGF Teerlink, JR Senior, R Nifontov, EM Mc Murray, JJV Lang, CC Tsyrlin, VA Greenberg, BH Mayet, J Francis, DP Shaburishvili, T Monaghan, M Saltzberg, M Neyses, L Wasserman, SM Lee, JH Saikali, KG Clarke, CP Goldman, JH Wolff, AA Malik, FI AF Cleland, John G. F. Teerlink, John R. Senior, Roxy Nifontov, Evgeny M. Mc Murray, John J. V. Lang, Chim C. Tsyrlin, Vitaly A. Greenberg, Barry H. Mayet, Jamil Francis, Darrel P. Shaburishvili, Tamaz Monaghan, Mark Saltzberg, Mitchell Neyses, Ludwig Wasserman, Scott M. Lee, Jacqueline H. Saikali, Khalil G. Clarke, Cyril P. Goldman, Jonathan H. Wolff, Andrew A. Malik, Fady I. TI The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial SO LANCET LA English DT Article ID RESYNCHRONIZATION THERAPY; CONSCIOUS DOGS; MILRINONE; MORTALITY AB Background Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. Methods We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. Findings 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9.7 mL) were recorded, associated with a small reduction in heart rate (up to 2.7 beats per min; p<0.0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0.0026) and end-diastolic volumes (16 mL, p=0.0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. Interpretation Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. C1 [Cleland, John G. F.] Univ Hull, Dept Cardiol, Hull York Med Sch, Kingston Upon Hull HU6 7RX, N Humberside, England. [Teerlink, John R.] Univ Calif San Francisco, Cardiol Sect, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Senior, Roxy] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Senior, Roxy] Royal Brompton Hosp, London SW3 6LY, England. [Senior, Roxy] Northwick Pk Hosp & Clin Res Ctr, Harrow HA1 3UJ, Middx, England. [Nifontov, Evgeny M.] St Petersburg State Med Univ, St Petersburg, Russia. [Mc Murray, John J. V.] Univ Glasgow, Western Infirm, Glasgow G11 6NT, Lanark, Scotland. [Mc Murray, John J. V.] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow G11 6NT, Lanark, Scotland. [Lang, Chim C.] Univ Dundee, Ctr Cardiovasc & Lung Biol, Div Med Sci, Dundee DD1 4HN, Scotland. [Tsyrlin, Vitaly A.] Almazov Fed Heart Blood & Endocrinol Ctr, St Petersburg, Russia. [Greenberg, Barry H.] Univ Calif San Diego Med Ctr, San Diego, CA USA. [Mayet, Jamil; Francis, Darrel P.] St Marys Hosp, London, England. [Shaburishvili, Tamaz] Diagnost Serv Clin, Tbilisi, Rep of Georgia. [Monaghan, Mark] Kings Coll Hosp London, London, England. [Saltzberg, Mitchell] Jefferson Med Coll, Christiana Care Hlth Syst, Newark, DE USA. [Neyses, Ludwig; Clarke, Cyril P.] Univ Manchester, Manchester, Lancs, England. [Neyses, Ludwig] Manchester Royal Infirm, Manchester Acad Hlth Sci Ctr, Manchester M13 9WL, Lancs, England. [Wasserman, Scott M.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Clarke, Cyril P.] ICON Dev Solut, UK Clin Res Unit, Manchester, Lancs, England. [Goldman, Jonathan H.] ICON Med Imaging, Warrington, PA USA. [Lee, Jacqueline H.; Saikali, Khalil G.; Wolff, Andrew A.; Malik, Fady I.] Cytokinetics Inc, San Francisco, CA USA. RP Cleland, JGF (reprint author), Univ Hull, Dept Cardiol, Hull York Med Sch, Castle Hill Hosp, Med Res Bldg, Kingston Upon Hull HU16 5JQ, East Yorkshire, England. EM j.g.cleland@hull.ac.uk RI Teerlink, John/D-2986-2012; mcmurray, john/B-2467-2013; Nifontov, Evgeniy/A-5954-2017; OI Cleland, John/0000-0002-1471-7016; mcmurray, john/0000-0002-6317-3975 FU Cytokinetics; Amgen; Cytokinetics Inc. FX JGFC, JRT, JJVM, and BHG have received research grants and consulting fees from Cytokinetics and Amgen, which is a licensee of omecamtiv mecarbil. RS, EMN, CCL, VAT, JM, DPF, TS, MM, MS, and LN have received research grants and consulting fees from Cytokinetics. SMW is an employee of Amgen. CPC is an employee of ICON Development Solutions (formerly Medeval, Manchester, UK). (HG is an employee of ICON Clinical Research, and formerly of ICON Medical Imaging, the echocardiogram core laboratory for this study. JHL, KGS, AAW, and FIM are employees of Cytokinetics, the sponsor of this study.; Funding: Cytokinetics Inc. NR 16 TC 110 Z9 116 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 20 PY 2011 VL 378 IS 9792 BP 676 EP 683 DI 10.1016/S0140-6736(11)61126-4 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 815EW UT WOS:000294509900027 PM 21856481 ER PT J AU Krum, H Teerlink, JR AF Krum, Henry Teerlink, John R. TI Heart Failure 2 Medical therapy for chronic heart failure SO LANCET LA English DT Article ID PLACEBO-CONTROLLED TRIAL; VENTRICULAR EJECTION FRACTION; RANDOMIZED CONTROLLED-TRIAL; CARDIAC-INSUFFICIENCY BISOPROLOL; ANGIOTENSIN-RECEPTOR BLOCKER; CONVERTING ENZYME-INHIBITOR; GISSI-HF TRIAL; DOUBLE-BLIND; CLINICAL-TRIALS; VASOPRESSIN ANTAGONIST AB Understanding of contemporary pharmacological therapy for chronic heart failure continues to evolve. In this Review, we discuss how findings from clinical trials have caused the roles of old therapies to be expanded and past treatment algorithms to be challenged. Several trials investigating preserved ejection fraction as a measure of heart failure had disappointing results, although important studies are in progress. Many novel therapeutic approaches for heart failure have emerged and are discussed in this review. The pharmacological treatments for heart failure continue to change, with many exciting possibilities for the future. C1 [Teerlink, John R.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA. [Krum, Henry] Monash Univ, Monash Ctr Cardiovasc Res & Educ Therapeut, Melbourne, Vic 3004, Australia. [Teerlink, John R.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA. EM john.teerlink@ucsf.edu RI Teerlink, John/D-2986-2012 FU Amgen; Vifor; Novartis; Servier; Bayer; Cytokinetics; Bristol-Myers Squibb; National Institutes of Health FX HK has received research grants from Amgen, Vifor, Novartis and Servier; and consulting fees from Novartis, Bayer and Amgen. JRT has received research grants from Amgen and Cytokinetics, Bristol-Myers Squibb, National Institutes of Health, and Novartis; and consulting fees from Amgen and Cytokinetics, and Novartis. NR 78 TC 36 Z9 43 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 20 PY 2011 VL 378 IS 9792 BP 713 EP 721 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 815EW UT WOS:000294509900031 PM 21856485 ER PT J AU Wen, PY Schiff, D Cloughesy, TF Reardon, DA Batchelor, TT Chabner, BA Flaherty, K de Groot, JF Gilbert, MR Galanis, E Chang, SM Schwartz, GK Peereboom, D Mehta, MP Yung, WKA Grossman, SA Prados, MD DeAngelis, LM AF Wen, Patrick Y. Schiff, David Cloughesy, Timothy F. Reardon, David A. Batchelor, Tracy T. Chabner, Bruce A. Flaherty, Keith de Groot, John F. Gilbert, Mark R. Galanis, Evanthia Chang, Susan M. Schwartz, Gary K. Peereboom, David Mehta, Minesh P. Yung, W. K. Alfred Grossman, Stuart A. Prados, Michael D. DeAngelis, Lisa M. TI It Is Time to Include Patients With Brain Tumors in Phase I Trials in Oncology SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RECURRENT MALIGNANT GLIOMAS; HIGH-GRADE GLIOMAS; GLIOBLASTOMA-MULTIFORME; PROGRESSION; CRITERIA; THERAPY C1 [Wen, Patrick Y.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schiff, David] Univ Virginia, Neurooncol Ctr, Charlottesville, VA USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, David Geffen Sch Med, Neurooncol Program, Los Angeles, CA 90095 USA. [Reardon, David A.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Chabner, Bruce A.; Flaherty, Keith] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [de Groot, John F.; Gilbert, Mark R.; Yung, W. K. Alfred] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Galanis, Evanthia] Mayo Clin, Rochester, MN USA. [Chang, Susan M.; Prados, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Peereboom, David] Cleveland Clin, Cleveland, OH 44106 USA. [Mehta, Minesh P.] Northwestern Univ, Chicago, IL 60611 USA. [Grossman, Stuart A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [DeAngelis, Lisa M.] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10021 USA. RP Wen, PY (reprint author), Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RI Gilbert, Mark/J-7494-2016; OI Gilbert, Mark/0000-0003-2556-9722; mehta, minesh/0000-0002-4812-5713 FU NCI NIH HHS [U01 CA137443] NR 13 TC 10 Z9 10 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2011 VL 29 IS 24 BP 3211 EP 3213 DI 10.1200/JCO.2011.36.6328 PG 3 WC Oncology SC Oncology GA 808VD UT WOS:000294008500012 PM 21768451 ER PT J AU Abrams, TA Brightly, R Mao, JB Kirkner, G Meyerhardt, JA Schrag, D Fuchs, CS AF Abrams, Thomas A. Brightly, Rick Mao, Jianbin Kirkner, Gregory Meyerhardt, Jeffrey A. Schrag, Deborah Fuchs, Charles S. TI Patterns of Adjuvant Chemotherapy Use in a Population-Based Cohort of Patients With Resected Stage II or III Colon Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLORECTAL-CANCER; CLINICAL-PRACTICE; FINAL REPORT; HIGH-RISK; FLUOROURACIL; THERAPY; LEUCOVORIN; AGE; OXALIPLATIN; LEVAMISOLE AB Purpose Previous studies have examined predictors for initiation of adjuvant chemotherapy in stages II and III colon cancer. However, little is known regarding the use of specific chemotherapy regimens or treatment duration. Patients and Methods We studied treatment records for 2,560 patients with stage II or III colon cancer who received adjuvant chemotherapy between January 2004 and April 2010 at US cancer care facilities participating in a nationwide, commercially available chemotherapy order entry system that captures patient demographics, stage, and details of chemotherapy treatment. Multivariate analyses of prospectively recorded patient and provider characteristics identified predictors of specific therapeutic approaches. Results The addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy increased during the study period (P trend < .001), and this combination represented 78% and 90% of adjuvant chemotherapy in stage II or III disease, respectively, by 2007. Older patients, those with diminished performance status, and those treated in a private practice setting were significantly less likely to receive oxaliplatin. Thirty percent of patients discontinued adjuvant therapy after less than 3 months. Older age, oxaliplatin-containing therapy, and receipt of treatment from a physician with a low volume of patients were each independently associated with premature discontinuation. Six percent of patients received bevacizumab as part of their adjuvant regimen. Conclusion After 2004, oxaliplatin and fluoropyrimidine-based therapy rapidly became the predominant adjuvant treatment for both stage II and stage III colon cancer in this large US cohort. Both increasing patient age and lower volume of an oncologist's practice were associated with early termination of adjuvant therapy. J Clin Oncol 29:3255-3262. (C) 2011 by American Society of Clinical Oncology C1 [Abrams, Thomas A.; Meyerhardt, Jeffrey A.; Schrag, Deborah; Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kirkner, Gregory; Fuchs, Charles S.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Kirkner, Gregory; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA USA. [Brightly, Rick; Mao, Jianbin] IntrinsiQ, Burlington, MA USA. RP Abrams, TA (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Thomas_Abrams@dfci.harvard.edu NR 33 TC 21 Z9 22 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2011 VL 29 IS 24 BP 3255 EP 3262 DI 10.1200/JCO.2011.35.0058 PG 8 WC Oncology SC Oncology GA 808VD UT WOS:000294008500018 PM 21768462 ER PT J AU Sequist, LV von Pawel, J Garmey, EG Akerley, WL Brugger, W Ferrari, D Chen, YP Costa, DB Gerber, DE Orlov, S Ramlau, R Arthur, S Gorbachevsky, I Schwartz, B Schiller, JH AF Sequist, Lecia V. von Pawel, Joachim Garmey, Edward G. Akerley, Wallace L. Brugger, Wolfram Ferrari, Dora Chen, Yinpu Costa, Daniel B. Gerber, David E. Orlov, Sergey Ramlau, Rodryg Arthur, Susan Gorbachevsky, Igor Schwartz, Brian Schiller, Joan H. TI Randomized Phase II Study of Erlotinib Plus Tivantinib Versus Erlotinib Plus Placebo in Previously Treated Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; GENE COPY NUMBER; MET AMPLIFICATION; TYROSINE KINASE; GEFITINIB; MUTATIONS; RESISTANCE; SENSITIVITY; TUMORS; CARBOPLATIN AB Purpose c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor. Methods Previously treated patients with EGFR TKI-naive advanced NSCLC were randomly assigned to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP). The primary end point was progression-free survival (PFS). At the time of progression, cross-over from EP to erlotinib plus tivantinib (ET) was permitted. Archival tumor tissue specimens were required. Results One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio [HR], 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms. Conclusion The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned. J Clin Oncol 29:3307-3315. (C) 2011 by American Society of Clinical Oncology C1 [Sequist, Lecia V.] Massachusetts Gen Hosp, Dept Thorac Oncol, Ctr Canc, Boston, MA 02114 USA. [Sequist, Lecia V.; Costa, Daniel B.] Harvard Univ, Sch Med, Boston, MA USA. [Costa, Daniel B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Garmey, Edward G.; Ferrari, Dora; Chen, Yinpu; Schwartz, Brian] ArQule, Woburn, MA USA. [von Pawel, Joachim] Asklepios Fachkliniken, Munich, Germany. [Brugger, Wolfram] Univ Freiburg, Schwarzwald Baar Clin, Acad Teaching Hosp, Villingen Schwenningen, Germany. [Akerley, Wallace L.] Huntsman Canc Inst, Salt Lake City, UT USA. [Gerber, David E.; Schiller, Joan H.] Univ Texas SW Med Ctr Dallas, Harold C Simmons Canc Ctr, Dallas, TX 75390 USA. [Orlov, Sergey] Pavlov State Med Univ, St Petersburg, Russia. [Ramlau, Rodryg] Karol Marcinkowski Univ Med Sci, Reg Lung Dis Ctr, Poznan, Poland. [Ramlau, Rodryg] Karol Marcinkowski Univ Med Sci, Wielkopolskie Ctr Pulmonol & Torakochirurg, Poznan, Poland. [Arthur, Susan] ICON Clin Res, Dublin, Ireland. [Gorbachevsky, Igor] Daiichi Sankyo, Edison, NJ USA. RP Sequist, LV (reprint author), Massachusetts Gen Hosp, Dept Thorac Oncol, Ctr Canc, 55 Fruit St,POB 212, Boston, MA 02114 USA. EM lvsequist@partners.org OI Costa, Daniel/0000-0002-0689-395X FU ArQule FX Lecia V. Sequist, ArQule; Wallace L. Akerley, ArQule; Wolfram Brugger, ArQule; Daniel B. Costa, ArQule; Sergey Orlov, ArQule; Joan H. Schiller, ArQule NR 28 TC 213 Z9 221 U1 0 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2011 VL 29 IS 24 BP 3307 EP 3315 DI 10.1200/JCO.2010.34.0570 PG 9 WC Oncology SC Oncology GA 808VD UT WOS:000294008500025 PM 21768463 ER PT J AU Burstein, HJ Mangu, PB Somerfield, MR Schrag, D Samson, D Holt, L Zelman, D Ajani, JA AF Burstein, Harold J. Mangu, Pamela B. Somerfield, Mark R. Schrag, Deborah Samson, David Holt, Lawrence Zelman, Debra Ajani, Jaffer A. TI American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Chemotherapy Sensitivity and Resistance Assays SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID OVARIAN-CANCER; DIRECTED CHEMOTHERAPY; CHEMORESPONSE ASSAY; PREDICTIVE-VALUE; TRIAL AB Purpose To update the American Society of Clinical Oncology (ASCO) Technology Assessment guidelines on chemotherapy sensitivity and resistance assays (CSRAs) published in 2004. Methods An Update Working Group reviewed data published between December 1, 2003, and May 31, 2010. MEDLINE and the Cochrane Library were searched. The literature search yielded 11,313 new articles. The limits for "human and English" were used, and then standard ASCO search strings for randomized controlled trials, meta-analyses, guidelines, and reviews were added, yielding 1,298 articles for abstract review. Of these, only 21 articles met predefined inclusion criteria and underwent full text review, and five reports of randomized controlled trials were included for data extraction. Results Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice. Recommendations The use of CSRAs to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations based on published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority. J Clin Oncol 29: 3328-3330. (C) 2011 by American Society of Clinical Oncology C1 [Burstein, Harold J.; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Burstein, Harold J.; Mangu, Pamela B.; Somerfield, Mark R.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Samson, David] Technol Evaluat Ctr, Blue Cross Blue Shield Assoc, Chicago, IL USA. [Holt, Lawrence] Coastal Canc Ctr, Myrtle Beach, SC USA. [Zelman, Debra] Debbies Dream Fdn, Davie, FL USA. [Ajani, Jaffer A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Burstein, HJ (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 7 TC 54 Z9 58 U1 0 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2011 VL 29 IS 24 BP 3328 EP 3330 DI 10.1200/JCO.2011.36.0354 PG 3 WC Oncology SC Oncology GA 808VD UT WOS:000294008500028 PM 21788567 ER PT J AU Ng, K Hollis, BW Fuchs, CS AF Ng, Kimmie Hollis, Bruce W. Fuchs, Charles S. TI Evaluating Vitamin D Status in Ill Patients Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID COLORECTAL-CANCER; PROGNOSTIC FACTORS; LIVER METASTASES; BINDING PROTEIN; ALBUMIN; SERUM; 25-HYDROXYVITAMIN-D; SURVIVAL C1 [Ng, Kimmie; Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hollis, Bruce W.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Ng, K (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2011 VL 29 IS 24 BP 3338 EP 3339 DI 10.1200/JCO.2011.36.6880 PG 3 WC Oncology SC Oncology GA 808VD UT WOS:000294008500037 ER PT J AU Wood, AC Glasser, S Garvey, WT Kabagambe, EK Borecki, IB Tiwari, HK Tsai, MY Hopkins, PN Ordovas, JM Arnett, DK AF Wood, Alexis C. Glasser, Stephen Garvey, W. Timothy Kabagambe, Edmond K. Borecki, Ingrid B. Tiwari, Hemant K. Tsai, Michael Y. Hopkins, Paul N. Ordovas, Jose M. Arnett, Donna K. TI Lipoprotein Lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS SO LIPIDS IN HEALTH AND DISEASE LA English DT Article DE GOLDN; lipoprotein; lipoprotein lipase; Metabolic syndrome ID GENE; DISEASE; RISK; LPL AB Background: Previous analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified groups (N = 251), similar to 75% of individuals met Adult Treatment Panel III criteria for the metabolic syndrome (MetS). Both showed small LDL diameter (mean = 19.9 nm); however, group 1 (N = 200) had medium VLDL diameter (mean = 53.1 nm) while group 2 had very large VLDL diameter (mean = 65.74 nm). Group 2 additionally showed significantly more insulin resistance (IR), and accompanying higher waist circumference and fasting glucose and triglycerides (all P < .01). Since lipoprotein lipase hydrolyzes triglyceride in the VLDL-LDL cascade, we examined whether these two patterns of lipoprotein diameter were associated with differences across two lipoprotein lipase (LPL) gene variants: D9N (rs1801177) and S447X (rs328). Findings: Mixed linear models that controlled for age, sex, center of data collection, and family pedigree revealed no differences between the two groups for the D9N polymorphism (P = .36). However, group 2 contained significantly more carriers (25%) of the 447X variant than group 1 (14%; P = .04). Conclusions: This was the first study this kind to show an association between LPL and large VLDL particle size within the MetS, a pattern associated with higher IR. Future work should extend this to larger samples to confirm these findings, and examine the long term outcomes of those with this lipoprotein diameter pattern. C1 [Wood, Alexis C.; Kabagambe, Edmond K.; Arnett, Donna K.] Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL USA. [Wood, Alexis C.; Tiwari, Hemant K.] Univ Alabama, Sch Publ Hlth, Sect Stat Genet, Dept Biostat, Birmingham, AL USA. [Glasser, Stephen] Univ Alabama, Div Prevent Med, Dept Med, Birmingham, AL USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Kabagambe, Edmond K.; Arnett, Donna K.] Univ Alabama, Sch Publ Hlth, Nutr Obes Res Ctr, Birmingham, AL USA. [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Hopkins, Paul N.] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Ordovas, Jose M.] Tufts Univ, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Ordovas, Jose M.] Ctr Nacl Invest Cardiovasc Madrid, Dept Epidemiol & Populat Genet, Madrid, Spain. RP Wood, AC (reprint author), Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL USA. EM LekkiWood@Gmail.com RI Frazier-Wood, Alexis (Lekki)/B-8053-2010; OI Frazier-Wood, Alexis (Lekki)/0000-0001-7616-2119; Ordovas, Jose/0000-0002-7581-5680 FU NHLBI [U01HL072524] FX This study was funded by NHLBI grant number U01HL072524. Financial disclosures: None to declare. Disclosure: All authors declare that they have no conflicts of interests. NR 11 TC 2 Z9 5 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-511X J9 LIPIDS HEALTH DIS JI Lipids Health Dis. PD AUG 19 PY 2011 VL 10 AR 143 DI 10.1186/1476-511X-10-143 PG 4 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 828RN UT WOS:000295520300001 PM 21854610 ER PT J AU Welander, H Bontha, SV Nasstrom, T Karlsson, M Nikolajeff, F Danzer, K Kostka, M Kalimo, H Lannfelt, L Ingelsson, M Bergstrom, J AF Welander, Hedvig Bontha, Sai Vineela Nasstrom, Thomas Karlsson, Mikael Nikolajeff, Fredrik Danzer, Karin Kostka, Marcus Kalimo, Hannu Lannfelt, Lars Ingelsson, Martin Bergstrom, Joakim TI Gelsolin co-occurs with Lewy bodies in vivo and accelerates alpha-synuclein aggregation in vitro SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE alpha-Synuclein; Gelsolin; Lewy body; Dementia with Lewy bodies; Parkinson's disease; Aggregation ID PARKINSONS-DISEASE; MUTATION; ALZHEIMERS; PROTEINS; VARIANT; CELLS AB Deposition of fibrillar alpha-synuclein as Lewy bodies is the neuropathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Apart from alpha-synuclein, these intraneuronal inclusions contain over 250 different proteins. The actin binding protein gelsolin, has previously been suggested to be part of the Lewy body, but its potential role in alpha-synuclein aggregation remains unknown. Here, we studied the association between gelsolin and alpha-synuclein in brain tissue from PD and DLB patients as well as in a cell model for alpha-synuclein aggregation. Moreover, the potential effect of gelsolin on alpha-synuclein fibrillization was also investigated. Our data demonstrate that gelsolin co-occured with alpha-synuclein in Lewy bodies from affected human brain as well as with Lewy body-like inclusions in alpha-synuclein over expressing cells. Furthermore, in the presence of calcium chloride, gelsolin was found to enhance the aggregation rate of alpha-synuclein in vitro. Moreover, no apparent structural differences could be observed between fibrils formed in the presence or absence of gelsolin. Further studies on gelsolin and other Lewy body associated proteins are warranted to learn more about their potential role in the alpha-synuclein aggregation process. (C) 2011 Elsevier Inc. All rights reserved. C1 [Welander, Hedvig; Bontha, Sai Vineela; Nasstrom, Thomas; Lannfelt, Lars; Ingelsson, Martin; Bergstrom, Joakim] Uppsala Univ, Rudbeck Lab, Dept Publ Hlth Mol Geriatr, SE-75125 Uppsala, Sweden. [Karlsson, Mikael; Nikolajeff, Fredrik] Uppsala Univ, Angstrom Lab, Dept Engn Sci, SE-75121 Uppsala, Sweden. [Danzer, Karin; Kostka, Marcus] Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, Germany. [Danzer, Karin] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Boston, MA 02129 USA. [Kalimo, Hannu] Univ Helsinki, Haartman Inst, Dept Pathol, FI-00014 Helsinki, Finland. RP Bergstrom, J (reprint author), Uppsala Univ, Rudbeck Lab, Dept Publ Hlth Mol Geriatr, SE-75125 Uppsala, Sweden. EM joakim.bergstrom@pubcare.uu.se FU Swedish Brain Power, Gun and Bertil Stohne's Foundation; Lars Hierta Memorial Foundation; Swedish Research Council [2006-2822, 2006-6326, 2006-3464]; Uppsala Berzelii Technology Center for Neurodiagnostics; Swedish Alzheimer Foundation; Swedish Society of Medicine; Hans and Helen Danielsson; Lennart and Christina Kalen; Soderstrom-Konigska Foundation; Swedish Dementia Foundation; Magn Bergwall Foundation; Thore Nilsson Foundation; Old Servant's Foundation; Ahlen Foundation; Loo and Hans Osterman's Foundation; Jeansson's Foundation; Larsson-Rost's Foundation; Golje's Foundation; Bjorklund's Foundation for ALS Research; Swedish Brain Foundation; Swedish Parkinson Foundation; E. Wessler's Foundation; Hospital District of Helsinki and Uusimaa FX We are grateful to Alex Kasrayan and Monica Ekberg (BioArctic Neuroscience AB, Stockholm, Sweden) for preparation of recombinant alpha- synuclein. This study was supported by Grants from Swedish Brain Power, Gun and Bertil Stohne's Foundation, The Lars Hierta Memorial Foundation, The Swedish Research Council (2006-2822 (L.L.) and 2006-6326 and 2006-3464 (M.I.)), Uppsala Berzelii Technology Center for Neurodiagnostics, Swedish Alzheimer Foundation, Swedish Society of Medicine, Hans and Helen Danielsson, Lennart and Christina Kalen, Soderstrom-Konigska Foundation, Swedish Dementia Foundation, Magn Bergwall Foundation, Thore Nilsson Foundation, Old Servant's Foundation, Ahlen Foundation, Loo and Hans Osterman's Foundation, Jeansson's Foundation, Larsson-Rost's Foundation, Golje's Foundation, Bjorklund's Foundation for ALS Research, Swedish Brain Foundation, The Swedish Parkinson Foundation, E. Wessler's Foundation and EVO research Grant from Hospital District of Helsinki and Uusimaa. NR 24 TC 1 Z9 1 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 19 PY 2011 VL 412 IS 1 BP 32 EP 38 DI 10.1016/j.bbrc.2011.07.027 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 815EN UT WOS:000294509000006 PM 21798243 ER PT J AU Elpek, KG Bellemare-Pelletier, A Malhotra, D Reynoso, ED Lukacs-Kornek, V DeKruyff, RH Turley, SJ AF Elpek, Kutlu G. Bellemare-Pelletier, Angelique Malhotra, Deepali Reynoso, Erika D. Lukacs-Kornek, Veronika DeKruyff, Rosemarie H. Turley, Shannon J. TI Lymphoid Organ-Resident Dendritic Cells Exhibit Unique Transcriptional Fingerprints Based on Subset and Site SO PLOS ONE LA English DT Article ID IN-VIVO; RETINOIC ACID; CROSS-PRESENTATION; T-CELLS; REGULATORY FACTOR-4; ADAPTIVE IMMUNITY; GENE-EXPRESSION; SELF-ANTIGENS; DYING CELLS; MOUSE AB Lymphoid organ-resident DC subsets are thought to play unique roles in determining the fate of T cell responses. Recent studies focusing on a single lymphoid organ identified molecular pathways that are differentially operative in each DC subset and led to the assumption that a given DC subset would more or less exhibit the same genomic and functional profiles throughout the body. Whether the local milieu in different anatomical sites can also influence the transcriptome of DC subsets has remained largely unexplored. Here, we interrogated the transcriptional relationships between lymphoid organ-resident DC subsets from spleen, gut-and skin-draining lymph nodes, and thymus of C57BL/6 mice. For this purpose, major resident DC subsets including CD4 and CD8 DCs were sorted at high purity and gene expression profiles were compared using microarray analysis. This investigation revealed that lymphoid organ-resident DC subsets exhibit divergent genomic programs across lymphoid organs. Interestingly, we also found that transcriptional and biochemical properties of a given DC subset can differ between lymphoid organs for lymphoid organ-resident DC subsets, but not plasmacytoid DCs, suggesting that determinants of the tissue milieu program resident DCs for essential site-specific functions. C1 [Elpek, Kutlu G.; Bellemare-Pelletier, Angelique; Malhotra, Deepali; Reynoso, Erika D.; Lukacs-Kornek, Veronika; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Malhotra, Deepali] Harvard Univ, Sch Med, Div Med Sci, Boston, MA USA. [DeKruyff, Rosemarie H.] Harvard Univ, Sch Med, Div Immunol, Childrens Hosp Boston, Boston, MA USA. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. RP Elpek, KG (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM shannon_turley@dfci.harvard.edu OI Malhotra, Deepali/0000-0002-8215-7639 FU AACR; Baruj Benacerraf Postdoctoral Fellowship; American Cancer Society; National Institutes of Health (NIH) [R01 DK074500, P01 AI045757, R24 AI072073] FX This study was supported in part by research funding from the AACR Centennial Postdoctoral Fellowship in Cancer Research to KGE, Baruj Benacerraf Postdoctoral Fellowship to VLK, American Cancer Society Research Scholar Award, National Institutes of Health (NIH) grants (R01 DK074500 and P01 AI045757) to SJT and NIH R24 AI072073 to the Immunological Genome Project. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 13 Z9 13 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 19 PY 2011 VL 6 IS 8 AR e23921 DI 10.1371/journal.pone.0023921 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810LZ UT WOS:000294128100041 PM 21886840 ER PT J AU Yi, CH Pan, HL Seebacher, J Jang, IH Hyberts, SG Heffron, GJ Vander Heiden, MG Yang, RL Li, FP Locasale, JW Sharfi, H Zhai, B Rodriguez-Mias, R Luithardt, H Cantley, LC Daley, GQ Asara, JM Gygi, SP Wagner, G Liu, CF Yuan, JY AF Yi, Caroline H. Pan, Heling Seebacher, Jan Jang, Il-Ho Hyberts, Sven G. Heffron, Gregory J. Vander Heiden, Matthew G. Yang, Renliang Li, Fupeng Locasale, Jason W. Sharfi, Hadar Zhai, Bo Rodriguez-Mias, Ricard Luithardt, Harry Cantley, Lewis C. Daley, George Q. Asara, John M. Gygi, Steven P. Wagner, Gerhard Liu, Chuan-Fa Yuan, Junying TI Metabolic Regulation of Protein N-Alpha-Acetylation by Bcl-xL Promotes Cell Survival SO CELL LA English DT Article ID QUANTITATIVE PROTEOMICS; HISTONE ACETYLATION; BCL-X(L) PREVENTS; CYTOCHROME-C; APOPTOSIS; DEATH; CASPASE-2; CYCLE; (-)-HYDROXYCITRATE; ACCUMULATION AB Previous experiments suggest a connection between the N-alpha-acetylation of proteins and sensitivity of cells to apoptotic signals. Here, we describe a biochemical assay to detect the acetylation status of proteins and demonstrate that protein N-alpha-acetylation is regulated by the availability of acetylCoA. Because the antiapoptotic protein Bcl-xL is known to influence mitochondrial metabolism, we reasoned that Bcl-xL may provide a link between protein N-alpha-acetylation and apoptosis. Indeed, Bcl-xL overexpression leads to a reduction in levels of acetyl-CoA and N-alpha-acetylated proteins in the cell. This effect is independent of Bax and Bak, the known binding partners of Bcl-xL. Increasing cellular levels of acetyl-CoA by addition of acetate or citrate restores protein N-alpha-acetylation in Bcl-xL-expressing cells and confers sensitivity to apoptotic stimuli. We propose that acetyl-CoA serves as a signaling molecule that couples apoptotic sensitivity to metabolism by regulating protein N-alpha-acetylation. C1 [Yi, Caroline H.; Pan, Heling; Seebacher, Jan; Zhai, Bo; Gygi, Steven P.; Yuan, Junying] Beth Israel Deaconess Med Ctr, Dept Cell Biol, Boston, MA 02115 USA. [Hyberts, Sven G.; Heffron, Gregory J.; Rodriguez-Mias, Ricard; Wagner, Gerhard] Beth Israel Deaconess Med Ctr, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Vander Heiden, Matthew G.; Locasale, Jason W.; Sharfi, Hadar; Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Dept Syst Biol, Boston, MA 02115 USA. [Jang, Il-Ho; Daley, George Q.] Beth Israel Deaconess Med Ctr, Childrens Hosp Boston, Boston, MA 02115 USA. [Cantley, Lewis C.; Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. [Cantley, Lewis C.; Asara, John M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Vander Heiden, Matthew G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Vander Heiden, Matthew G.] MIT, Koch Inst, Cambridge, MA 02142 USA. [Yang, Renliang; Li, Fupeng; Liu, Chuan-Fa] Nanyang Technol Univ, Sch Biol Sci, Div Chem Biol & Biotechnol, Singapore 637551, Singapore. [Luithardt, Harry] Solut Labs, Cambridge, MA 02139 USA. RP Yuan, JY (reprint author), Beth Israel Deaconess Med Ctr, Dept Cell Biol, Boston, MA 02115 USA. EM jyuan@hms.harvard.edu RI Cantley, Lewis/D-1800-2014; OI Cantley, Lewis/0000-0002-1298-7653; Liu, Chuan Fa/0000-0001-7433-2081; Locasale, Jason/0000-0002-7766-3502 FU U.S. Army [DAMD17-02-1-0403]; National Institute of Aging [R37-012859]; National Institutes of Health (NIH) [DK070299, GM47467, 5P01CA120964-03]; National Institute of Neurological Disorders and Stroke [1F31NS057872-01] FX We are indebted to Alfred Goldberg, Tom Rapoport, Andrew Steele, Marta Lipinski, and Benedicte Py for critical reading of the manuscript, to Pere Puigserver, Harvey Lodish, Kristin White, and Danny Chou for helpful discussions, and to Xuemei Yang for help in acquiring mass spectrometry metabolomics data. We thank Thomas Arnesen and Johan Lillehaug (University of Bergen) for anti-NATH and for help in designing caspase-2 N-alpha-acetylation mutants. We also thank Tullia Lindsten and Craig Thompson (University of Pennsylvania) for providing anti-Bcl-xL as well as Bcl-xL+/+ and Bcl-xL-/- MEFs. VSV-RAIDD and Bcl-xL mutant constructs were generously provided by Jurg Tschopp (University of Lausanne) and Emily Cheng (Washington University), respectively. This work was supported in part by an Innovator's Award from the U.S. Army Breast Cancer Research Program (grant DAMD17-02-1-0403), a grant from the National Institute of Aging (R37-012859) and a National Institutes of Health (NIH) Director's Pioneer Award to J.Y., NIH grants (DK070299 and GM47467) to G. W., a NIH grant (5P01CA120964-03) to J.M.A., and a Kirchstein National Research Service Award from the National Institute of Neurological Disorders and Stroke (grant 1F31NS057872-01) to C.H.Y. NR 43 TC 84 Z9 86 U1 1 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 19 PY 2011 VL 146 IS 4 BP 607 EP 620 DI 10.1016/j.cell.2011.06.050 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 809HY UT WOS:000294043600015 PM 21854985 ER PT J AU Tanioka, T Tamura, Y Fukaya, M Shinozaki, S Mao, J Kim, M Shimizu, N Kitamura, T Kaneki, M AF Tanioka, Toshihiro Tamura, Yoshiaki Fukaya, Makiko Shinozaki, Shohei Mao, Ji Kim, Minhye Shimizu, Nobuyuki Kitamura, Tadahiro Kaneki, Masao TI Inducible Nitric-oxide Synthase and Nitric Oxide Donor Decrease Insulin Receptor Substrate-2 Protein Expression by Promoting Proteasome-dependent Degradation in Pancreatic beta-Cells INVOLVEMENT OF GLYCOGEN SYNTHASE KINASE-3 beta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NONOBESE DIABETIC MICE; HIGH-FAT DIET; ISLET TRANSPLANTATION; GLUCOSE-HOMEOSTASIS; NOD MICE; KINASE-B; RESISTANCE; MASS; INHIBITOR; SECRETION AB Insulin receptor substrate-2 (IRS-2) plays a critical role in the survival and function of pancreatic beta-cells. Gene disruption of IRS-2 results in failure of the beta-cell compensatory mechanism and diabetes. Nonetheless, the regulation of IRS-2 protein expression in beta-cells remains largely unknown. Inducible nitricoxide synthase (iNOS), a major mediator of inflammation, has been implicated in beta-cell damage in type 1 and type 2 diabetes. The effects of iNOS on IRS-2 expression have not yet been investigated in beta-cells. Here, we show that iNOS and NO donor decreased IRS-2 protein expression in INS-1/832 insulinoma cells and mouse islets, whereas IRS-2 mRNA levels were not altered. Interleukin-1 beta (IL-1 beta), alone or in combination with interferon-gamma(IFN-gamma), reduced IRS-2 protein expression in an iNOS-dependent manner without altering IRS-2 mRNA levels. Proteasome inhibitors, MG132 and lactacystin, blocked the NO donor-induced reduction in IRS-2 protein expression. Treatment with NO donor led to activation of glycogen synthase kinase-3 beta (GSK-3 beta) and c-Jun N-terminal kinase (JNK/SAPK) in beta-cells. Inhibition of GSK-3 beta by pharmacological inhibitors or siRNA-mediated knockdown significantly prevented NO donor-induced reduction in IRS-2 expression in beta-cells. In contrast, a JNK inhibitor, SP600125, did not effectively block reduced IRS-2 expression in NO donor-treated beta-cells. These data indicate that iNOS-derived NO reduces IRS-2 expression by promoting protein degradation, at least in part, through a GSK-3 beta-dependent mechanism. Our findings suggest that iNOS-mediated decreased IRS-2 expresssion may contribute to the progression and/or exacerbation of beta-cell failure in diabetes. C1 [Tanioka, Toshihiro; Tamura, Yoshiaki; Fukaya, Makiko; Shinozaki, Shohei; Mao, Ji; Kim, Minhye; Shimizu, Nobuyuki; Kaneki, Masao] Harvard Univ, Shriners Hosp Children, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med,Med Sch, Charlestown, MA 02129 USA. [Kitamura, Tadahiro] Gunma Univ, Inst Mol & Cellular Regulat, Metab Signal Res Ctr, Gunma 3718512, Japan. RP Kaneki, M (reprint author), 149 13th St,Rm 6604, Charlestown, MA 02129 USA. EM mkaneki@helix.mgh.harvard.edu FU National Institutes of Health [R01DK05827, P30NS045776, 5 u42 RR006042]; American Diabetes Association [7-08-RA-77] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01DK05827 (to M. K.) and P30NS045776 (to the Microscopy and Image Analysis Core of Massachusetts General Hospital). This work was also supported by American Diabetes Association Grant 7-08-RA-77 (to M. K.).; We are grateful to Dr. C. B. Newgard for providing INS-1/832 cells. We acknowledge use of human islets provided by the National Disease Research Interchange, with support from National Institutes of Health Grant 5 u42 RR006042. NR 55 TC 12 Z9 14 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 19 PY 2011 VL 286 IS 33 BP 29388 EP 29396 DI 10.1074/jbc.M110.192732 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 806TY UT WOS:000293837000073 PM 21700708 ER PT J AU Baughman, JM Perocchi, F Girgis, HS Plovanich, M Belcher-Timme, CA Sancak, Y Bao, XR Strittmatter, L Goldberger, O Bogorad, RL Koteliansky, V Mootha, VK AF Baughman, Joshua M. Perocchi, Fabiana Girgis, Hany S. Plovanich, Molly Belcher-Timme, Casey A. Sancak, Yasemin Bao, X. Robert Strittmatter, Laura Goldberger, Olga Bogorad, Roman L. Koteliansky, Victor Mootha, Vamsi K. TI Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter SO NATURE LA English DT Article ID RAT KIDNEY MITOCHONDRIA; OXIDATIVE-PHOSPHORYLATION; RNAI THERAPEUTICS; PROTEIN TOPOLOGY; TRANSPORT; DELIVERY; RESPIRATION; INHIBITION; LIBRARY; COMPLEX AB Mitochondria from diverse organisms are capable of transporting large amounts of Ca(2+) via a ruthenium-red-sensitive, membrane-potential-dependent mechanism called the uniporter(1-4). Although the uniporter's biophysical properties have been studied extensively, its molecular composition remains elusive. We recently used comparative proteomics to identify MICU1 (also known as CBARA1), an EF-hand-containing protein that serves as a putative regulator of the uniporter(5). Here, we use whole-genome phylogenetic profiling, genome-wide RNA co-expression analysis and organelle-wide protein coexpression analysis to predict proteins functionally related to MICU1. All three methods converge on a novel predicted transmembrane protein, CCDC109A, that we now call 'mitochondrial calcium uniporter' (MCU). MCU forms oligomers in the mitochondrial inner membrane, physically interacts with MICU1, and resides within a large molecular weight complex. Silencing MCU in cultured cells or in vivo in mouse liver severely abrogates mitochondrial Ca(2+) uptake, whereas mitochondrial respiration and membrane potential remain fully intact. MCU has two predicted transmembrane helices, which are separated by a highly conserved linker facing the intermembrane space. Acidic residues in this linker are required for its full activity. However, an S259A point mutation retains function but confers resistance to Ru360, the most potent inhibitor of the uniporter. Our genomic, physiological, biochemical and pharmacological data firmly establish MCU as an essential component of the mitochondrial Ca(2+) uniporter. C1 [Baughman, Joshua M.; Perocchi, Fabiana; Girgis, Hany S.; Plovanich, Molly; Belcher-Timme, Casey A.; Sancak, Yasemin; Bao, X. Robert; Strittmatter, Laura; Goldberger, Olga; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. [Baughman, Joshua M.; Perocchi, Fabiana; Girgis, Hany S.; Plovanich, Molly; Belcher-Timme, Casey A.; Sancak, Yasemin; Bao, X. Robert; Strittmatter, Laura; Goldberger, Olga; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Baughman, Joshua M.; Perocchi, Fabiana; Girgis, Hany S.; Plovanich, Molly; Belcher-Timme, Casey A.; Sancak, Yasemin; Bao, X. Robert; Strittmatter, Laura; Goldberger, Olga; Mootha, Vamsi K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Baughman, Joshua M.; Perocchi, Fabiana; Girgis, Hany S.; Plovanich, Molly; Belcher-Timme, Casey A.; Sancak, Yasemin; Bao, X. Robert; Strittmatter, Laura; Goldberger, Olga; Mootha, Vamsi K.] Broad Inst, Cambridge, MA 02142 USA. [Bogorad, Roman L.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Koteliansky, Victor] Alnylam Pharmaceut Inc, Cambridge, MA 02142 USA. RP Mootha, VK (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. EM vamsi@hms.harvard.edu RI Bogorad, Roman/G-2609-2011; OI Bao, Xiaoyan/0000-0001-7931-2944 FU National Science Foundation; National Institutes of Health [GM0077465, DK080261] FX We thank R. Nilsson, J. Engreitz and S. Calvo for bioinformatics assistance; D. Root and S. Silver for assistance in lentiviral RNAi; B. R. Bettencourt, K. Charisse, S. Kuchimanchi and L. Speciner for siRNA design, synthesis and formulation; M. Blower, J. Avruch and R. Ward for advice; and members of the Mootha laboratory for valuable feedback. J. M. B. and L. S. were supported by graduate student fellowships from the National Science Foundation. This work was supported by grants from the National Institutes of Health (GM0077465, DK080261) awarded to V.K.M. NR 28 TC 534 Z9 546 U1 9 U2 68 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 18 PY 2011 VL 476 IS 7360 BP 341 EP U111 DI 10.1038/nature10234 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811JV UT WOS:000294206500040 PM 21685886 ER PT J AU Possemato, R Marks, KM Shaul, YD Pacold, ME Kim, D Birsoy, K Sethumadhavan, S Woo, HK Jang, HG Jha, AK Chen, WW Barrett, FG Stransky, N Tsun, ZY Cowley, GS Barretina, J Kalaany, NY Hsu, PP Ottina, K Chan, AM Yuan, B Garraway, LA Root, DE Mino-Kenudson, M Brachtel, EF Driggers, EM Sabatini, DM AF Possemato, Richard Marks, Kevin M. Shaul, Yoav D. Pacold, Michael E. Kim, Dohoon Birsoy, Kivanc Sethumadhavan, Shalini Woo, Hin-Koon Jang, Hyun G. Jha, Abhishek K. Chen, Walter W. Barrett, Francesca G. Stransky, Nicolas Tsun, Zhi-Yang Cowley, Glenn S. Barretina, Jordi Kalaany, Nada Y. Hsu, Peggy P. Ottina, Kathleen Chan, Albert M. Yuan, Bingbing Garraway, Levi A. Root, David E. Mino-Kenudson, Mari Brachtel, Elena F. Driggers, Edward M. Sabatini, David M. TI Functional genomics reveal that the serine synthesis pathway is essential in breast cancer SO NATURE LA English DT Article ID GENE-EXPRESSION SIGNATURE; NEOPLASTIC RAT-TISSUES; EMBRYONIC STEM-CELLS; XENOGRAFT MODEL; METABOLISM; IDENTIFICATION; DEHYDROGENASE; ACTIVATION; SCREEN; TUMORS AB Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation(1,2). RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes(3). Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of alpha-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent on increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets. C1 [Possemato, Richard; Shaul, Yoav D.; Pacold, Michael E.; Kim, Dohoon; Birsoy, Kivanc; Chen, Walter W.; Barrett, Francesca G.; Tsun, Zhi-Yang; Kalaany, Nada Y.; Hsu, Peggy P.; Ottina, Kathleen; Chan, Albert M.; Yuan, Bingbing; Sabatini, David M.] Nine Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Possemato, Richard; Shaul, Yoav D.; Pacold, Michael E.; Kim, Dohoon; Birsoy, Kivanc; Chen, Walter W.; Tsun, Zhi-Yang; Kalaany, Nada Y.; Hsu, Peggy P.; Ottina, Kathleen; Chan, Albert M.; Sabatini, David M.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Possemato, Richard; Shaul, Yoav D.; Pacold, Michael E.; Kim, Dohoon; Birsoy, Kivanc; Chen, Walter W.; Stransky, Nicolas; Cowley, Glenn S.; Barretina, Jordi; Kalaany, Nada Y.; Hsu, Peggy P.; Ottina, Kathleen; Chan, Albert M.; Garraway, Levi A.; Root, David E.; Sabatini, David M.] MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Possemato, Richard; Shaul, Yoav D.; Pacold, Michael E.; Kim, Dohoon; Birsoy, Kivanc; Chen, Walter W.; Barrett, Francesca G.; Stransky, Nicolas; Tsun, Zhi-Yang; Cowley, Glenn S.; Barretina, Jordi; Kalaany, Nada Y.; Hsu, Peggy P.; Ottina, Kathleen; Chan, Albert M.; Garraway, Levi A.; Root, David E.; Sabatini, David M.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Shaul, Yoav D.; Pacold, Michael E.; Kim, Dohoon; Birsoy, Kivanc; Chen, Walter W.; Tsun, Zhi-Yang; Kalaany, Nada Y.; Hsu, Peggy P.; Ottina, Kathleen; Chan, Albert M.; Sabatini, David M.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Marks, Kevin M.; Sethumadhavan, Shalini; Woo, Hin-Koon; Jha, Abhishek K.; Driggers, Edward M.] Agios Pharmaceut, Cambridge, MA 02139 USA. [Pacold, Michael E.] Brigham & Womens Hosp, Harvard Radiat Oncol Program, Boston, MA 02114 USA. [Barretina, Jordi; Garraway, Levi A.] Dept Med Oncol, Boston, MA 02115 USA. [Barretina, Jordi; Garraway, Levi A.] Ctr Canc Genome Discovery, Dana Farber Canc Inst, Boston, MA 02115 USA. [Barretina, Jordi; Garraway, Levi A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mino-Kenudson, Mari; Brachtel, Elena F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mino-Kenudson, Mari; Brachtel, Elena F.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Sabatini, DM (reprint author), Nine Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. EM sabatini@wi.mit.edu OI Possemato, Richard/0000-0002-2401-0030 FU S. G. Komen for the Cure; Life Science Research Foundation; Keck Foundation; David H. Koch Institute for Integrative Cancer Research at MIT; Alexander and Margaret Stewart Trust; NIH [CA103866] FX We thank members of the D. M. S. laboratory, M. Kwon, B. Luo and F. Reinhardt for assistance. This research is supported by fellowships from S. G. Komen for the Cure to R. P. and the Life Science Research Foundation to Y.D.S. and grants from the Keck Foundation, the David H. Koch Institute for Integrative Cancer Research at MIT, The Alexander and Margaret Stewart Trust Fund, and NIH Grant CA103866 to D. M. S. D. M. S. is an investigator of the Howard Hughes Medical Institute. NR 26 TC 423 Z9 429 U1 14 U2 89 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 18 PY 2011 VL 476 IS 7360 BP 346 EP U119 DI 10.1038/nature10350 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 811JV UT WOS:000294206500041 PM 21760589 ER PT J AU Friedman, RA Nierenberg, AA AF Friedman, Richard A. Nierenberg, Andrew A. TI 'The Illusions of Psychiatry': An Exchange SO NEW YORK REVIEW OF BOOKS LA English DT Letter C1 [Friedman, Richard A.] Weill Cornell Med Coll, Psychopharmacol Clin, New York, NY USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Bipolar Clin, Cambridge, MA USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Res Program, Cambridge, MA USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Depress Clin & Res Program, Cambridge, MA USA. [Nierenberg, Andrew A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Friedman, RA (reprint author), Weill Cornell Med Coll, Psychopharmacol Clin, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NEW YORK REVIEW PI NEW YORK PA 1755 BROADWAY, 5TH FLOOR, NEW YORK, NY 10019 USA SN 0028-7504 J9 NEW YORK REV BOOKS JI N. Y. Rev. Books PD AUG 18 PY 2011 VL 58 IS 13 BP 82 EP 82 PG 1 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 802YR UT WOS:000293547400033 ER PT J AU Evans, CL Abu-Yousif, AO Park, YJ Klein, OJ Celli, JP Rizvi, I Zheng, X Hasan, T AF Evans, Conor L. Abu-Yousif, Adnan O. Park, Yong Jin Klein, Oliver J. Celli, Jonathan P. Rizvi, Imran Zheng, Xiang Hasan, Tayyaba TI Killing Hypoxic Cell Populations in a 3D Tumor Model with EtNBS-PDT SO PLOS ONE LA English DT Article ID PHOTODYNAMIC THERAPY; OVARIAN-CANCER; IN-VITRO; 3-DIMENSIONAL MODEL; OXYGEN-CONSUMPTION; DRUG-RESISTANCE; MURINE SARCOMAS; SOLID TUMORS; BENZOPHENOTHIAZINE; EFFICACY AB An outstanding problem in cancer therapy is the battle against treatment-resistant disease. This is especially true for ovarian cancer, where the majority of patients eventually succumb to treatment-resistant metastatic carcinomatosis. Limited perfusion and diffusion, acidosis, and hypoxia play major roles in the development of resistance to the majority of front-line therapeutic regimens. To overcome these limitations and eliminate otherwise spared cancer cells, we utilized the cationic photosensitizer EtNBS to treat hypoxic regions deep inside in vitro 3D models of metastatic ovarian cancer. Unlike standard regimens that fail to penetrate beyond similar to 150 mu m, EtNBS was found to not only penetrate throughout the entirety of large (>200 mu m) avascular nodules, but also concentrate into the nodules' acidic and hypoxic cores. Photodynamic therapy with EtNBS was observed to be highly effective against these hypoxic regions even at low therapeutic doses, and was capable of destroying both normoxic and hypoxic regions at higher treatment levels. Imaging studies utilizing multiphoton and confocal microscopies, as well as time-lapse optical coherence tomography (TL-OCT), revealed an inside-out pattern of cell death, with apoptosis being the primary mechanism of cell killing. Critically, EtNBS-based photodynamic therapy was found to be effective against the model tumor nodules even under severe hypoxia. The inherent ability of EtNBS photodynamic therapy to impart cytotoxicity across a wide range of tumoral oxygenation levels indicates its potential to eliminate treatment-resistant cell populations. C1 [Evans, Conor L.; Abu-Yousif, Adnan O.; Klein, Oliver J.; Celli, Jonathan P.; Rizvi, Imran; Zheng, Xiang; Hasan, Tayyaba] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02115 USA. [Park, Yong Jin] Korea Adv Inst Sci & Technol, Dept Chem & Biomol Engn, Taejon 305701, South Korea. RP Evans, CL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02115 USA. EM thasan@partners.org OI Rizvi, Imran/0000-0001-9673-4700 FU F32 fellowship [F32 CA138153]; Wellman graduate fellowship; HST-KAIST; National Institutes of Health [NIH RC1 CA146337, DP2 OD007096] FX CLE was supported by a F32 fellowship (F32 CA138153). IR was supported by the Wellman graduate fellowship. YJP was supported by the HST-KAIST summer internship program. Funding for this work came from National Institutes of Health grant NIH RC1 CA146337 to TH and an NIH New Innovator Award DP2 OD007096 to CLE. Information on the New Innovator Award Program is at http://nihroadmap.nih.gov/newinnovator/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 43 Z9 44 U1 3 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 18 PY 2011 VL 6 IS 8 AR e23434 DI 10.1371/journal.pone.0023434 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810LN UT WOS:000294126900023 PM 21876751 ER PT J AU Merzaban, JS Burdick, MM Gadhoum, SZ Dagia, NM Chu, JT Fuhlbrigge, RC Sackstein, R AF Merzaban, Jasmeen S. Burdick, Monica M. Gadhoum, S. Zeineb Dagia, Nilesh M. Chu, Julia T. Fuhlbrigge, Robert C. Sackstein, Robert TI Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells SO BLOOD LA English DT Article ID COLON-CARCINOMA CELLS; MAJOR E-SELECTIN; BONE-MARROW; P-SELECTIN; T-CELLS; ADHESION MOLECULE-1; PROGENITOR CELLS; IN-VIVO; ENDOTHELIAL SELECTINS; CD43 FUNCTIONS AB Although well recognized that expression of E-selectin on marrow microvessels mediates osteotropism of hematopoietic stem/progenitor cells (HSPCs), our knowledge regarding the cognate E-selectin ligand(s) on HSPCs is incomplete. Flow cytometry using E-selectin-Ig chimera (E-Ig) shows that human marrow cells enriched for HSPCs (CD34(+) cells) display greater E-selectin binding than those obtained from mouse (lin(-)/Sca-1(+)/c-kit(-) [LSK] cells). To define the relevant glycoprotein E-selectin ligands, lysates from human CD34(+) and KG1a cells and from mouse LSK cells were immunoprecipitated using E-Ig and resolved by Western blot using E-Ig. In both human and mouse cells, E-selectin ligand reactivity was observed at similar to 120- to 130-kDa region, which contained two E-selectin ligands, the P-selectin glycoprotein ligand-1 glycoform "CLA," and CD43. Human, but not mouse, cells displayed a prominent similar to 100-kDa band, exclusively comprising the CD44 glycoform "HCELL." E-Ig reactivity was most prominent on CLA in mouse cells and on HCELL in human cells. To further assess HCELL's contribution to E-selectin adherence, complementary studies were performed to silence (via CD44 siRNA) or enforce its expression (via exoglycosylation). Under physiologic shear conditions, CD44/HCELL-silenced human cells showed striking decreases (> 50%) in E-selectin binding. Conversely, enforced HCELL expression of LSK cells profoundly increased E-selectin adherence, yielding > 3-fold more marrow homing in vivo. These data define the key glycoprotein E-selectin ligands of human and mouse HSPCs, unveiling critical species-intrinsic differences in both the identity and activity of these structures. (Blood. 2011; 118(7): 1774-1783) C1 [Merzaban, Jasmeen S.; Burdick, Monica M.; Gadhoum, S. Zeineb; Dagia, Nilesh M.; Chu, Julia T.; Fuhlbrigge, Robert C.; Sackstein, Robert] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Merzaban, Jasmeen S.; Burdick, Monica M.; Gadhoum, S. Zeineb; Dagia, Nilesh M.; Chu, Julia T.; Fuhlbrigge, Robert C.; Sackstein, Robert] Harvard Univ, Sch Med, Harvard Skin Dis Res Ctr, Boston, MA USA. [Sackstein, Robert] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Sackstein, Robert] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Sackstein, R (reprint author), Harvard Inst Med, 77 Ave Louis Pasteur,Rm 671, Boston, MA 02115 USA. EM rsackstein@rics.bwh.harvard.edu OI Merzaban, Jasmeen/0000-0002-7276-2907 FU National Institutes of Health National Heart, Lung, and Blood Institute [RO1 HL60528, RO1 HL073714]; National Institutes of Health; American Medical Association; American Society of Hematology; Howard Hughes Medical Institute FX This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute (grants RO1 HL60528 and RO1 HL073714, R. S.), the National Institutes of Health (NRSA Training Grant, M. M. B.), the American Medical Association (Research Seed Grant Award, J.T.C.), the American Society of Hematology (Training Fellowship, J.T.C.), and the Howard Hughes Medical Institute (Medical Student Research Training Fellowship, J.T.C.). NR 55 TC 32 Z9 32 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 18 PY 2011 VL 118 IS 7 BP 1774 EP 1783 DI 10.1182/blood-2010-11-320705 PG 10 WC Hematology SC Hematology GA 808WC UT WOS:000294011500016 PM 21659548 ER PT J AU Jena, AB Seabury, S Lakdawalla, D Chandra, A AF Jena, Anupam B. Seabury, Seth Lakdawalla, Darius Chandra, Amitabh TI Malpractice Risk According to Physician Specialty SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TORT REFORMS; DEFENSIVE MEDICINE; CLAIMS; COSTS AB BACKGROUND Data are lacking on the proportion of physicians who face malpractice claims in a year, the size of those claims, and the cumulative career malpractice risk according to specialty. METHODS We analyzed malpractice data from 1991 through 2005 for all physicians who were covered by a large professional liability insurer with a nationwide client base (40,916 physicians and 233,738 physician-years of coverage). For 25 specialties, we reported the proportion of physicians who had malpractice claims in a year, the proportion of claims leading to an indemnity payment (compensation paid to a plaintiff), and the size of indemnity payments. We estimated the cumulative risk of ever being sued among physicians in high- and low-risk specialties. RESULTS Each year during the study period, 7.4% of all physicians had a malpractice claim, with 1.6% having a claim leading to a payment (i.e., 78% of all claims did not result in payments to claimants). The proportion of physicians facing a claim each year ranged from 19.1% in neurosurgery, 18.9% in thoracic-cardiovascular surgery, and 15.3% in general surgery to 5.2% in family medicine, 3.1% in pediatrics, and 2.6% in psychiatry. The mean indemnity payment was $274,887, and the median was $111,749. Mean payments ranged from $117,832 for dermatology to $520,923 for pediatrics. It was estimated that by the age of 65 years, 75% of physicians in low-risk specialties had faced a malpractice claim, as compared with 99% of physicians in high-risk specialties. CONCLUSIONS There is substantial variation in the likelihood of malpractice suits and the size of indemnity payments across specialties. The cumulative risk of facing a malpractice claim is high in all specialties, although most claims do not lead to payments to plaintiffs. (Funded by the RAND Institute for Civil Justice and the National Institute on Aging.) C1 [Chandra, Amitabh] Harvard Univ, Harvard Kennedy Sch, Cambridge, MA 02138 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam B.] Harvard Univ, Sch Med, Boston, MA USA. [Seabury, Seth] RAND Corp, Santa Monica, CA USA. [Lakdawalla, Darius] Univ So Calif, Schaeffer Ctr Hlth Policy & Econ, Los Angeles, CA USA. [Lakdawalla, Darius] Univ So Calif, Sch Policy Planning & Dev, Los Angeles, CA USA. RP Chandra, A (reprint author), Harvard Univ, Harvard Kennedy Sch, 79 JFK St, Cambridge, MA 02138 USA. EM amitabh_chandra@harvard.edu OI Lakdawalla, Darius/0000-0001-5934-8042 FU RAND Institute for Civil Justice; National Institute on Aging [7R01AG031544, 1RC4AG039036-01, P01 AG19783-02]; National Institute on Aging Roybal Center at the University of Southern California [5P30AG024968] FX Supported by the RAND Institute for Civil Justice; grants (7R01AG031544, to Dr. Seabury; 7R01AG031544 and 1RC4AG039036-01, to Dr. Lakdawalla; and P01 AG19783-02, to Dr. Chandra) from the National Institute on Aging; and a grant (5P30AG024968, to Dr. Lakdawalla) from the National Institute on Aging Roybal Center at the University of Southern California. NR 23 TC 208 Z9 211 U1 1 U2 22 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 18 PY 2011 VL 365 IS 7 BP 629 EP 636 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 808ER UT WOS:000293960500010 PM 21848463 ER PT J AU Benz, EJ Wu, CC Sohani, AR AF Benz, Edward J. Wu, Carol C. Sohani, Aliyah R. TI A Woman with Anemia and Paraspinal Masses Thalassemia (hemoglobin H disease) with extramedullary hematopoiesis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SICKLE-CELL-DISEASE; VITAMIN-D DEFICIENCY; PREVALENCE C1 [Benz, Edward J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wu, Carol C.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Benz, Edward J.] Harvard Univ, Sch Med, Dept Med Pediat & Genet, Boston, MA USA. [Wu, Carol C.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sohani, Aliyah R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Benz, EJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. NR 14 TC 0 Z9 0 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 18 PY 2011 VL 365 IS 7 BP 648 EP 658 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 808ER UT WOS:000293960500014 PM 21848466 ER PT J AU Yu, S Vit, A Devenish, S Mahanty, HK Itzen, A Goody, RS Blankenfeldt, W AF Yu, Shen Vit, Allegra Devenish, Sean Mahanty, H. Khris Itzen, Aymelt Goody, Roger S. Blankenfeldt, Wulf TI Atomic resolution structure of EhpR: phenazine resistance in Enterobacter agglomerans Eh1087 follows principles of bleomycin/mitomycin C resistance in other bacteria SO BMC STRUCTURAL BIOLOGY LA English DT Article ID D-ALANYLGRISEOLUTEIC ACID; PSEUDOMONAS-AERUGINOSA; MACROMOLECULAR STRUCTURES; CRYSTAL-STRUCTURE; PROTEIN FOSA; REFINEMENT; PYOCYANIN; CRYSTALLOGRAPHY; BIOSYNTHESIS; INFECTION AB Background: The phenazines are redox-active secondary metabolites that a large number of bacterial strains produce and excrete into the environment. They possess antibiotic activity owing to the fact that they can reduce molecular oxygen to toxic reactive oxygen species. In order to take advantage of this activity, phenazine producers need to protect themselves against phenazine toxicity. Whereas it is believed that phenazine-producing pseudomonads possess highly active superoxide dismutases and catalases, it has recently been found that the plant-colonizing bacterium Enterobacter agglomerans expresses a small gene ehpR to render itself resistant towards D-alanyl-griseoluteic acid, the phenazine antibiotic produced by this strain. Results: To understand the resistance mechanism installed by EhpR we have determined its crystal structure in the apo form at 2.15 angstrom resolution and in complex with griseoluteic acid at 1.01 angstrom, respectively. While EhpR shares a common fold with glyoxalase-I/bleomycin resistance proteins, the ligand binding site does not contain residues that some related proteins employ to chemically alter their substrates. Binding of the antibiotic is mediated by pi-stacking interactions of the aromatic moiety with the side chains of aromatic amino acids and by a few polar interactions. The dissociation constant K(D) between EhpR and griseoluteic acid was quantified as 244 +/- 45 mu M by microscale thermophoresis measurements. Conclusions: The data accumulated here suggest that EhpR confers resistance by binding D-alanyl-griseoluteic acid and acting as a chaperone involved in exporting the antibiotic rather than by altering it chemically. It is tempting to speculate that EhpR acts in concert with EhpJ, a transport protein of the major facilitator superfamily that is also encoded in the phenazine biosynthesis operon of E. agglomerans. The low affinity of EhpR for griseoluteic acid may be required for its physiological function. C1 [Yu, Shen; Itzen, Aymelt; Goody, Roger S.; Blankenfeldt, Wulf] Max Planck Inst Mol Physiol, Dept Phys Biochem, D-44227 Dortmund, Germany. [Yu, Shen] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Vit, Allegra; Blankenfeldt, Wulf] Univ Bayreuth, Lehrstuhl Biochem, D-95447 Bayreuth, Germany. [Devenish, Sean; Mahanty, H. Khris] Univ Canterbury, Sch Biol Sci, Christchurch 1, New Zealand. [Devenish, Sean] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England. RP Blankenfeldt, W (reprint author), Max Planck Inst Mol Physiol, Dept Phys Biochem, Otto Hahn Str 11, D-44227 Dortmund, Germany. EM wulf.blankenfeldt@uni-bayreuth.de RI Itzen, Aymelt/F-5157-2014; Goody, Roger/J-8845-2014; Blankenfeldt, Wulf/F-8877-2010 OI Itzen, Aymelt/0000-0002-4249-5617; Goody, Roger/0000-0002-0772-0444; Blankenfeldt, Wulf/0000-0001-9886-9668 FU International Max Planck Research School in Chemical Biology FX The authors thank Natalia Kholod for help with cloning experiments and Ingrid Hoffmann and Irina Weber for technical assistance. The x-ray communities at the Max Planck Institutes of Molecular Physiology and for Medical Research (Dortmund and Heidelberg, Germany) are acknowledged for help with data collection at the European Synchrotron Radiation Facility (Grenoble, France), which provided generous access their beamlines. SY was supported by the International Max Planck Research School in Chemical Biology. NR 44 TC 3 Z9 4 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6807 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD AUG 17 PY 2011 VL 11 AR 33 DI 10.1186/1472-6807-11-33 PG 10 WC Biophysics SC Biophysics GA 822GW UT WOS:000295033000001 PM 21849072 ER PT J AU Chuang, PY Dai, Y Liu, RJ He, HL Kretzler, M Jim, B Cohen, CD He, JC AF Chuang, Peter Y. Dai, Yan Liu, Ruijie He, Helen Kretzler, Matthias Jim, Belinda Cohen, Clemens D. He, John C. TI Alteration of Forkhead Box O (Foxo4) Acetylation Mediates Apoptosis of Podocytes in Diabetes Mellitus SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR ACETYLATION; GENE-EXPRESSION; GLOMERULAR-DISEASE; OXIDATIVE STRESS; OXIDANT STRESS; SIRT1; NEPHROPATHY; ACTIVATION; GLYCATION; INJURY AB The number of kidney podocytes is reduced in diabetic nephropathy. Advanced glycation end products (AGEs) accumulate in patients with diabetes and promote the apoptosis of podocyte by activating the forkhead box O4 (Foxo4) transcription factor to increase the expression of a pro-apoptosis gene, Bcl2l11. Using chromatin immunoprecipitation we demonstrate that AGE-modified bovine serum albumin (AGE-BSA) enhances Foxo4 binding to a forkhead binding element in the promoter of Bcl2lll. AGE-BSA also increases the acetylation of Foxo4. Lysine acetylation of Foxo4 is required for Foxo4 binding and transcription of Bcl2l11 in podocytes treated with AGE-BSA. The expression of a protein deacetylase that targets Foxo4 for deacetylation, sirtuin (Sirt1), is down regulated in cultured podocytes by AGE-BSA treatment and in glomeruli of diabetic patients. SIRT1 over expression in cultured murine podocytes prevents AGE-induced apoptosis. Glomeruli isolated from diabetic db/db mice have increased acetylation of Foxo4, suppressed expression of Sirt1, and increased expression of Bcl2l11 compared to non-diabetic littermates. Together, our data provide evidence that alteration of Foxo4 acetylation and down regulation of Sirt1 expression in diabetes promote podocyte apoptosis. Strategies to preserve Sirt1 expression or reduce Foxo4 acetylation could be used to prevent podocyte loss in diabetes. C1 [Chuang, Peter Y.; Dai, Yan; He, Helen; He, John C.] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. [Dai, Yan; He, John C.] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 1, Dept Nephrol, Shanghai 200030, Peoples R China. [Liu, Ruijie] James J Peters VA Med Ctr, Bronx, NY USA. [Kretzler, Matthias] Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Jim, Belinda] Albert Einstein Coll Med, Jacobi Med Ctr, Dept Med, Div Nephrol, Bronx, NY 10467 USA. [Cohen, Clemens D.] Univ Zurich, Div Nephrol, Zurich, Switzerland. [Cohen, Clemens D.] Univ Zurich, Inst Physiol, Zurich, Switzerland. RP Chuang, PY (reprint author), Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. EM peter.chuang@mssm.edu FU NIH [DK082760R01]; Else Kroner-Fresenius Foundation [P09/05//A62/04]; U.S. Department of Veterans Affairs [1I01BX000345] FX This work is supported by an NIH career development award (DK082760R01) to P.Y.C., the Else Kroner-Fresenius Foundation (P09/05//A62/04) award to C. D. C., and a U.S. Department of Veterans Affairs Merit Review Award (1I01BX000345) to J.C.H. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 34 Z9 37 U1 3 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 17 PY 2011 VL 6 IS 8 AR e23566 DI 10.1371/journal.pone.0023566 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810JJ UT WOS:000294121300061 PM 21858169 ER PT J AU Korenstein, D Keyhani, S Mendelson, A Ross, JS AF Korenstein, Deborah Keyhani, Salomeh Mendelson, Ali Ross, Joseph S. TI Adherence of Pharmaceutical Advertisements in Medical Journals to FDA Guidelines and Content for Safe Prescribing SO PLOS ONE LA English DT Article ID DRUG ADVERTISEMENTS; ACCURACY; QUALITY; PATIENT; LAW AB Background: Physician-directed pharmaceutical advertising is regulated in the United States by the Food and Drug Administration (FDA); adherence to current FDA guidelines is unknown. Our objective was to determine adherence rates of physician-directed print advertisements in biomedical journals to FDA guidelines and describe content important for safe prescribing. Methods and Findings: Cross-sectional analysis of November 2008 pharmaceutical advertisements within top U. S.-based biomedical journals publishing original research. We excluded advertisements for devices, over the counter medications, and disease awareness. We utilized FDA guideline items identifying unique forms of advertisement bias to categorize advertisements as adherent to FDA guidelines, possibly non-adherent to at least 1 item, or non-adherent to at least 1 item. We also evaluated advertisement content important for safe prescribing, including benefit quantification, risk information and verifiable references. All advertisements were evaluated by 2 or more investigators, with differences resolved by discussion. Twelve journals met inclusion criteria. Nine contained pharmaceutical advertisements, including 192 advertisements for 82 unique products; median 2 per product (range 1-14). Six "teaser" advertisements presented only drug names, leaving 83 full unique advertisements. Fifteen advertisements (18.1%) adhered to all FDA guidelines, 41 (49.4%) were non-adherent with at least one form of FDA-described bias, and 27 (32.5%) were possibly non-adherent due to incomplete information. Content important for safe prescribing was often incomplete; 57.8% of advertisements did not quantify serious risks, 48.2% lacked verifiable references and 28.9% failed to present adequate efficacy quantification. Study limitations included its focus on advertisements from a single month, the subjectivity of FDA guidelines themselves, and the necessary subjectivity of determinations of adherence. Conclusions: Few physician-directed print pharmaceutical advertisements adhere to all FDA guidelines; over half fail to quantify serious risks. The FDA could better protect public health by creating new more objective advertisement guidelines requiring transparent presentation of basic safety and efficacy information. C1 [Korenstein, Deborah] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Keyhani, Salomeh] Mt Sinai Sch Med, Dept Hlth Evidence & Policy, New York, NY USA. [Keyhani, Salomeh] James J Peters VA Med Ctr, HSR&D Res Enhancement Award Program, Bronx, NY USA. [Keyhani, Salomeh] James J Peters VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. [Mendelson, Ali] Weill Cornell Med Coll, New York, NY USA. [Ross, Joseph S.] Yale Univ, Sch Med, Dept Med, Gen Internal Med Sect, New Haven, CT 06510 USA. [Ross, Joseph S.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. RP Korenstein, D (reprint author), Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. EM deborah.korenstein@mssm.edu FU NIA NIH HHS [K08 AG032886] NR 25 TC 8 Z9 8 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 17 PY 2011 VL 6 IS 8 AR e23336 DI 10.1371/journal.pone.0023336 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 810JJ UT WOS:000294121300037 PM 21858076 ER PT J AU Ommaya, AK Kupersmith, J AF Ommaya, Alexander K. Kupersmith, Joel TI Challenges Facing the US Patient-Centered Outcomes Research Institute SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CLINICAL-RESEARCH ENTERPRISE C1 [Ommaya, Alexander K.; Kupersmith, Joel] US Dept Vet Affairs, Off Res & Dev, Washington, DC 20420 USA. RP Ommaya, AK (reprint author), US Dept Vet Affairs, Off Res & Dev, 810 Vermont Ave NW, Washington, DC 20420 USA. EM alex.ommaya@va.gov NR 8 TC 5 Z9 5 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 17 PY 2011 VL 306 IS 7 BP 756 EP 757 DI 10.1001/jama.2011.1171 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 807LP UT WOS:000293900000026 PM 21846858 ER PT J AU Singer, S Shortell, SM AF Singer, Sara Shortell, Stephen M. TI Implementing Accountable Care Organizations Ten Potential Mistakes and How to Learn From Them SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Shortell, Stephen M.] Univ Calif Berkeley, Sch Publ Hlth, Div Hlth Policy & Management, Berkeley, CA 94720 USA. [Singer, Sara] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management,Dept Med, Sch Med,Massachusetts Gen Hosp,Mongan Inst Publ H, Boston, MA 02115 USA. RP Shortell, SM (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Hlth Policy & Management, 417E Univ Hall, Berkeley, CA 94720 USA. EM shortell@berkeley.edu NR 9 TC 23 Z9 24 U1 2 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 17 PY 2011 VL 306 IS 7 BP 758 EP 759 DI 10.1001/jama.2011.1180 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 807LP UT WOS:000293900000027 PM 21828308 ER PT J AU Chan, ST Yuen, JWM Gohel, MDI Chung, CP Wong, HC Kwong, KK AF Chan, Suk-tak Yuen, John W. M. Gohel, Mayur-Danny I. Chung, Chi-ping Wong, Ho-cheong Kwong, Kenneth K. TI Guasha-induced hepatoprotection in chronic active hepatitis B: A case study SO CLINICA CHIMICA ACTA LA English DT Article DE Guasha; Hepatitis; Heme oxygenase; Human ID HEME OXYGENASE-1; SHA; THERAPY; INJURY AB Background: Heme oxygenase-1 (HO-1) has demonstrated hepatoprotective effect in animal hepatitis models. HO-1 was also reported to be upregulated with Guasha, an ancient therapeutic technique which applies instrument assisted press-stroking to treat many disorders. Methods: We report a case on the changes of liver function, plasma HO-1 and T-helper (Th) cytokine balance in a chronic active hepatitis B carrier before and after Guasha. The patient presented with increased activities of liver enzymes (ALT and AST), indicating inflammatory damage in liver before Guasha. Results: Forty-eight hours after receiving Guasha, the patient showed changes in a number of serum markers: a decline of liver enzymes (ALT and AST) indicating reduced chronic inflammation, an elevated plasma HO-1, and a modulation of T-helper (Th)1/Th2 balance. Conclusions: Guasha was shown to transiently reduce the inflammatory markers of liver injury in human, together with an enhancement of HO-1 which might be responsible for the hepatoprotective action. (C) 2011 Elsevier B.V. All rights reserved. C1 [Chan, Suk-tak; Kwong, Kenneth K.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Yuen, John W. M.] Hong Kong Polytech Univ, Sch Nursing, Hong Kong, Hong Kong, Peoples R China. [Gohel, Mayur-Danny I.] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. [Chung, Chi-ping] Dr Vio & Partners, Hong Kong, Hong Kong, Peoples R China. [Wong, Ho-cheong] Hong Kong Polytech Univ, Univ Hlth Serv, Hong Kong, Hong Kong, Peoples R China. RP Chan, ST (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Bldg 149,13th St,Mailcode 149-2301, Charlestown, MA 02129 USA. EM phoebe@nmr.mgh.harvard.edu RI Chan, Suk-tak/G-5846-2015; Yuen, John Wai-Man/A-4963-2011 OI Yuen, John Wai-Man/0000-0003-1681-233X FU Hong Kong Polytechnic University [5-ZD64] FX This work was supported by the Hong Kong Polytechnic University (5-ZD64). We thank the subject for his participation in this study. NR 22 TC 5 Z9 5 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD AUG 17 PY 2011 VL 412 IS 17-18 BP 1686 EP 1688 DI 10.1016/j.cca.2011.05.009 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 795SW UT WOS:000292997100034 PM 21616064 ER PT J AU Zafar, SY Malin, JL Grambow, SC Abbott, DH Schrag, D Kolimaga, JT Zullig, LL Weeks, JC Fouad, MN Ayanian, JZ Wallace, R Kahn, KL Ganz, PA Catalano, P West, DW Provenzale, D AF Zafar, S. Yousuf Malin, Jennifer L. Grambow, Steven C. Abbott, David H. Schrag, Deborah Kolimaga, Jane T. Zullig, Leah L. Weeks, Jane C. Fouad, Mona N. Ayanian, John Z. Wallace, Robert Kahn, Katherine L. Ganz, Patricia A. Catalano, Paul West, Dee W. Provenzale, Dawn CA Canc Care Outcomes Res TI Early dissemination of bevacizumab for advanced colorectal cancer: a prospective cohort study SO BMC CANCER LA English DT Article ID CARE OUTCOMES RESEARCH; ADJUVANT CHEMOTHERAPY; ADVERSE EVENTS; OVARIAN-CANCER; POPULATION; IRINOTECAN; FLUOROURACIL; LEUCOVORIN; MANAGEMENT; MORTALITY AB Background: We describe early dissemination patterns for first-line bevacizumab given for metastatic colorectal cancer treatment. Methods: We analyzed patient surveys and medical records for a population-based cohort with metastatic colorectal cancer treated in multiple regions and health systems in the United States (US). Eligible patients were diagnosed with metastatic colorectal cancer and initiated first-line chemotherapy after US Food & Drug Administration (FDA) bevacizumab approval in February 2004. First-line bevacizumab therapy was defined as receiving bevacizumab within 8 weeks of starting chemotherapy for metastatic colorectal cancer. We evaluated factors associated with first-line bevacizumab treatment using logistic regression. Results: Among 355 patients, 31% received first-line bevacizumab in the two years after FDA approval, including 26% of men, 41% of women, and 16% of those >= 75 years. Use rose sharply within 6 months after FDA approval, then plateaued. 20% of patients received bevacizumab in combination with irinotecan; 53% received it with oxaliplatin. Men were less likely than women to receive bevacizumab (adjusted OR 0.55; 95% CI 0.32-0.93; p = 0.026). Patients >= 75 years were less likely to receive bevacizumab than patients < 55 years (adjusted OR 0.13; 95% CI 0.04-0.46; p = 0.001). Conclusions: One-third of eligible metastatic colorectal cancer patients received first-line bevacizumab shortly after FDA approval. Most patients did not receive bevacizumab as part of the regimen used in the pivotal study leading to FDA approval. C1 [Zafar, S. Yousuf] Duke Univ, Med Ctr, Dept Med, Div Med Oncol, Durham, NC 27710 USA. [Zafar, S. Yousuf; Grambow, Steven C.; Abbott, David H.; Kolimaga, Jane T.; Zullig, Leah L.; Provenzale, Dawn] DDurham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Malin, Jennifer L.] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. [Malin, Jennifer L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Med Oncol, Los Angeles, CA 90095 USA. [Grambow, Steven C.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Weeks, Jane C.] Dana Farber Canc Inst, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Kolimaga, Jane T.; Provenzale, Dawn] Duke Univ, Med Ctr, Dept Med, Div Gastroenterol, Durham, NC 27710 USA. [Zullig, Leah L.] Univ N Carolina, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Fouad, Mona N.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Ayanian, John Z.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Wallace, Robert] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Kahn, Katherine L.] RAND Corp, Santa Monica, CA USA. [Kahn, Katherine L.] Univ Calif Los Angeles, Dept Med, Div Gen Internal Med, Los Angeles, CA 90024 USA. [Kahn, Katherine L.] Univ Calif Los Angeles, Dept Med, Div Hlth Serv Res, Los Angeles, CA 90024 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Catalano, Paul] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [West, Dee W.] No Calif Canc Ctr, Fremont, CA USA. [West, Dee W.] Stanford Sch Med, Stanford, CA USA. RP Zafar, SY (reprint author), Duke Univ, Med Ctr, Dept Med, Div Med Oncol, Durham, NC 27710 USA. EM yousuf.zafar@duke.edu RI Grambow, Steven/E-1422-2015; OI Grambow, Steven/0000-0001-6037-3253; Zafar, S. Yousuf/0000-0002-9039-5258 FU National Cancer Institute [U01 CA093344, U01 CA093332, U01 CA093324, U01 CA093348, U01 CA093329, U01 CA093339, U01 CA 093326]; Agency for Healthcare Research Quality [03-438MO-03]; Department of Veterans Affairs [HSRD CRS 02-164]; Genentech FX This work and the CanCORS Consortium are supported by grants from the National Cancer Institute to the Statistical Coordinating Center (grant number U01 CA093344) and the National Cancer Institute-supported Primary Data Collection and Research Centers (Dana-Farber Cancer Institute/Cancer Research Network (grant number U01 CA093332); Harvard Medical School/Northern California Cancer Center (grant number U01 CA093324); RAND/UCLA (grant number U01 CA093348); University of Alabama at Birmingham (grant number U01 CA093329); University of Iowa (grant number U01 CA093339); and the University of North Carolina (U01 CA 093326); the Agency for Healthcare Research Quality (grant number 03-438MO-03); and by a Department of Veterans Affairs grant to the Durham VA Medical Center (grant number HSRD CRS 02-164). The study sponsors (National Cancer Institute, the Agency for Healthcare Research Quality, and the Department of Veterans Affairs) played no role in study design, data collection, analysis, interpretation, writing, or decision to submit for publication.; SYZ discloses receipt of honoraria from Genentech. PC discloses receipt of research funding from Genentech. Other authors have no conflicts of interest to disclose. All other authors declare no competing interests. NR 35 TC 4 Z9 4 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 16 PY 2011 VL 11 AR 354 DI 10.1186/1471-2407-11-354 PG 12 WC Oncology SC Oncology GA 821BS UT WOS:000294950400001 PM 21846341 ER PT J AU Wilson, TR Lee, DY Berry, L Shames, DS Settleman, J AF Wilson, Timothy R. Lee, Diana Y. Berry, Leanne Shames, David S. Settleman, Jeff TI Neuregulin-1-Mediated Autocrine Signaling Underlies Sensitivity to HER2 Kinase Inhibitors in a Subset of Human Cancers SO CANCER CELL LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; ANAPLASTIC LYMPHOMA KINASE; SQUAMOUS-CELL CARCINOMA; ERBB RECEPTORS; BREAST-CANCER; LUNG-CANCER; TARGETED THERAPY; LAPATINIB; REVEALS; HEAD AB HER2 kinase inhibitors, such as lapatinib, have demonstrated clinical efficacy in HER2-amplified breast cancers. By profiling nearly 700 human cancer cell lines, we identified a subset of non-HER2 amplified cancer cells with striking sensitivity to HER2 kinase inhibition particularly from head and neck tumors. These cells were found to depend on a neuregulin-1 (NRG1)-mediated autocrine loop driving HER3 activation, which can be disrupted by lapatinib. Elevated NRG1 expression and activated HER3 are strongly associated with lapatinib sensitivity in vitro, and these biomarkers were enriched in a subset of primary head and neck cancer samples. The findings suggest that patients with NRG1-driven tumors lacking HER2 amplification may derive significant clinical benefit from HER2:HER3-directed therapies. C1 [Wilson, Timothy R.; Lee, Diana Y.; Settleman, Jeff] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Wilson, Timothy R.; Lee, Diana Y.; Settleman, Jeff] Harvard Univ, Med School, Boston, MA 02129 USA. [Wilson, Timothy R.; Berry, Leanne; Shames, David S.; Settleman, Jeff] Genentech Inc, San Francisco, CA 94080 USA. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Boston, MA 02129 USA. EM settleman.jeffrey@gene.com RI Wilson, Timothy/F-8210-2012 NR 38 TC 80 Z9 81 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 16 PY 2011 VL 20 IS 2 BP 158 EP 172 DI 10.1016/j.ccr.2011.07.011 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 810BF UT WOS:000294099700006 PM 21840482 ER PT J AU McEvoy, J Flores-Otero, J Zhang, JK Nemeth, K Brennan, R Bradley, C Krafcik, F Rodriguez-Galindo, C Wilson, M Xiong, SB Lozano, G Sage, J Fu, L Louhibi, L Trimarchi, J Pani, A Smeyne, R Johnson, D Dyer, MA AF McEvoy, Justina Flores-Otero, Jacqueline Zhang, Jiakun Nemeth, Katie Brennan, Rachel Bradley, Cori Krafcik, Fred Rodriguez-Galindo, Carlos Wilson, Matthew Xiong, Shunbin Lozano, Guillermina Sage, Julien Fu, Ligia Louhibi, Lotfi Trimarchi, Jeff Pani, Amar Smeyne, Richard Johnson, Dianna Dyer, Michael A. TI Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis SO CANCER CELL LA English DT Article ID AMACRINE CELLS; S-ANTIGEN; EXPRESSION; RETINA; DIFFERENTIATION; INVITRO; TUMOR; MEDULLOBLASTOMA; HETEROGENEITY; PHENOTYPE AB It is widely believed that the molecular and cellular features of a tumor reflect its cell of origin and can thus provide clues about treatment targets. The retinoblastoma cell of origin has been debated for over a century. Here, we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type-specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Furthermore, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro. C1 [McEvoy, Justina; Flores-Otero, Jacqueline; Zhang, Jiakun; Nemeth, Katie; Brennan, Rachel; Bradley, Cori; Krafcik, Fred; Pani, Amar; Smeyne, Richard; Dyer, Michael A.] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Rodriguez-Galindo, Carlos] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Wilson, Matthew; Johnson, Dianna] Univ Tennessee, Hlth Sci Ctr, Dept Ophthalmol, Memphis, TN 38163 USA. [Xiong, Shunbin; Lozano, Guillermina] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Sage, Julien] Stanford Univ, Med Ctr, Dept Pediat & Genet, Stanford, CA 94305 USA. [Fu, Ligia] Hosp Ninos, Dept Hematol Oncol, Tegucigalpa 11101, Honduras. [Louhibi, Lotfi] Inst Curie, F-75005 Paris, France. [Trimarchi, Jeff] Iowa State Univ, Dept Genet Dev & Cell Biol, Ames, IA 50011 USA. [Dyer, Michael A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Dyer, MA (reprint author), St Jude Childrens Hosp, Dept Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM michael.dyer@stjude.org OI McEvoy, Justina/0000-0003-0382-1288; Trimarchi, Jeffrey/0000-0001-7923-1538 FU NCI [CA21765]; NIH [EY014867, EY018599]; American Cancer Society; Research to Prevent Blindness Foundation; American Lebanese Syrian Associated Charities (ALSAC); [CA114102] FX We thank Kip Guy and Anang Shelat for assistance with high-throughput screening and cheminformatics; Sharon Erase and Marina Kedrov for assistance with electron microscopy and morphometric scoring; Geoff Neale for assistance with bioinformatics, Connie Cepko for sharing data, methods, and reagents and for many helpful discussions; David Cobrinik for providing the MSKCC176 cells and for helpful discussions; Justin Thurman for assistance with the animal colony and sectioning; Angela McArthur for editing the manuscript; and Wei Zhao for assistance with biostatistics. This work was supported in part by Cancer Center Support (CA21765) from the NCI; grants to M.A.D from the NIH (EY014867 and EY018599), the American Cancer Society, and Research to Prevent Blindness Foundation; a grant to J.S. (CA114102); and the American Lebanese Syrian Associated Charities (ALSAC). M.A.D. is a Howard Hughes Medical Institute Early Career Scientist. NR 44 TC 38 Z9 40 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG 16 PY 2011 VL 20 IS 2 BP 260 EP 275 DI 10.1016/j.ccr.2011.07.005 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 810BF UT WOS:000294099700013 PM 21840489 ER PT J AU Liesa, M Luptak, I Qin, FZ Hyde, BB Sahin, E Siwik, DA Zhu, ZK Pimentel, DR Xu, XJ Ruderman, NB Huffman, KD Doctrow, SR Richey, L Colucci, WS Shirihai, OS AF Liesa, Marc Luptak, Ivan Qin, Fuzhong Hyde, Brigham B. Sahin, Ergun Siwik, Deborah A. Zhu, Zhengkun Pimentel, David R. Xu, X. Julia Ruderman, Neil B. Huffman, Karl D. Doctrow, Susan R. Richey, Lauren Colucci, Wilson S. Shirihai, Orian S. TI Mitochondrial Transporter ATP Binding Cassette Mitochondrial Erythroid Is a Novel Gene Required for Cardiac Recovery After Ischemia/Reperfusion SO CIRCULATION LA English DT Article DE ABCB10; ischemia; mitochondria; oxidative stress; reperfusion ID ISCHEMIA-REPERFUSION INJURY; OXIDATIVE STRESS; RAT-HEART; TRANSGENIC MICE; MOUSE HEARTS; COMPLEX-I; ABC-ME; OVEREXPRESSION; DYSFUNCTION; PROTECTS AB Background-Oxidative stress and mitochondrial dysfunction are central mediators of cardiac dysfunction after ischemia/reperfusion. ATP binding cassette mitochondrial erythroid (ABC-me; ABCB10; mABC2) is a mitochondrial transporter highly induced during erythroid differentiation and predominantly expressed in bone marrow, liver, and heart. Until now, ABC-me function in heart was unknown. Several lines of evidence demonstrate that the yeast ortholog of ABC-me protects against increased oxidative stress. Therefore, ABC-me is a potential modulator of the outcome of ischemia/reperfusion in the heart. Methods and Results-Mice harboring 1 functional allele of ABC-me (ABC-me(+/-)) were generated by replacing ABC-me exons 2 and 3 with a neomycin resistance cassette. Cardiac function was assessed with Langendorff perfusion and echocardiography. Under basal conditions, ABC-me(+/-) mice had normal heart structure, hemodynamic function, mitochondrial respiration, and oxidative status. However, after ischemia/reperfusion, the recovery of hemodynamic function was reduced by 50% in ABC-me(+/-) hearts as a result of impairments in both systolic and diastolic function. This reduction was associated with impaired mitochondrial bioenergetic function and with oxidative damage to both mitochondrial lipids and sarcoplasmic reticulum calcium ATPase after reperfusion. Treatment of ABC-me(+/-) hearts with the superoxide dismutase/catalase mimetic EUK-207 prevented oxidative damage to mitochondria and sarcoplasmic reticulum calcium ATPase and restored mitochondrial and cardiac function to wild-type levels after reperfusion. Conclusions-Inactivation of 1 allele of ABC-me increases the susceptibility to oxidative stress induced by ischemia/reperfusion, leading to increased oxidative damage to mitochondria and sarcoplasmic reticulum calcium ATPase and to impaired functional recovery. Thus, ABC-me is a novel gene that determines the ability to tolerate cardiac ischemia/reperfusion. (Circulation. 2011;124:806-813.) C1 [Liesa, Marc; Hyde, Brigham B.; Xu, X. Julia; Ruderman, Neil B.; Shirihai, Orian S.] Boston Univ, Sch Med, Dept Med, Obes Res Ctr,Mitochondria ARC, Boston, MA 02118 USA. [Liesa, Marc; Hyde, Brigham B.; Xu, X. Julia; Ruderman, Neil B.; Shirihai, Orian S.] Boston Univ, Sch Med, Mitochondria ARC, Diabet Res Ctr,Dept Med, Boston, MA 02118 USA. [Luptak, Ivan; Qin, Fuzhong; Siwik, Deborah A.; Zhu, Zhengkun; Pimentel, David R.; Colucci, Wilson S.] Boston Univ, Sch Med, Cardiovasc Sect, Mitochondria ARC, Boston, MA 02118 USA. [Huffman, Karl D.; Doctrow, Susan R.] Boston Univ, Sch Med, Ctr Pulm, Mitochondria ARC, Boston, MA 02118 USA. [Sahin, Ergun] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Richey, Lauren] Tufts Univ, Div Lab Anim Med, Boston, MA 02111 USA. RP Shirihai, OS (reprint author), Boston Univ, Sch Med, Evans Biomed Res Ctr, 650 Albany St,Room 804, Boston, MA 02118 USA. EM shirihai@bu.edu RI Ji, Haofeng/G-6206-2012; OI Xu, Julia/0000-0002-2564-8052; Siwik, Deborah/0000-0002-7166-327X; Liesa Roig, Marc/0000-0002-5909-8570; Ruderman, Neil/0000-0002-6589-6587; Luptak, Ivan/0000-0001-7498-7694 FU Evans Center; mitochondria-Affinity Research Collaborative (mtARC); National Institutes of Health [R01 HL071629-03, R01DK074778, HL-061639, HL-064750, GM57770, P01-HL-068758]; American Diabetes Association; Fundacion Ramon Areces FX We are thankful to Dani Dagan, PhD for comments on the manuscript, Richard A. Cohen, MD for SERCA antibodies, Janice M. Weinberg, ScD for advice on statistics, Wuhbet Abraham for technical assistance, and the rest of the members in Dr Shirihai's laboratory. This work was supported by the Evans Center and the mitochondria-Affinity Research Collaborative (mtARC).; This work was supported by National Institutes of Health grants R01 HL071629-03 and R01DK074778 to Dr Shirihai; HL-061639 and HL-064750 to Dr Colucci; GM57770 to Dr Doctrow; and P01-HL-068758 to Dr Ruderman. Dr Xu is a recipient of a mentor based grant from American Diabetes Association. Dr Liesa is a recipient of a postdoctoral fellowship from Fundacion Ramon Areces. NR 37 TC 30 Z9 30 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 16 PY 2011 VL 124 IS 7 BP 806 EP U136 DI 10.1161/CIRCULATIONAHA.110.003418 PG 26 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 807GR UT WOS:000293884900016 PM 21788586 ER PT J AU Gupta, RM Weiner, RB Baggish, AL Fifer, MA AF Gupta, Rajat M. Weiner, Rory B. Baggish, Aaron L. Fifer, Michael A. TI Still a Kid at Heart Hypertrophic Cardiomyopathy in the Elderly SO CIRCULATION LA English DT Article DE hypertrophic cardiomyopathy; myectomy ID BINDING PROTEIN-C; SEPTAL ABLATION; GENE-MUTATIONS; GRADIENT; SPECTRUM; FEATURES; MYECTOMY C1 [Weiner, Rory B.; Baggish, Aaron L.; Fifer, Michael A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Gupta, Rajat M.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. RP Fifer, MA (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,GRB 800, Boston, MA 02114 USA. EM mfifer@partners.org NR 25 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 16 PY 2011 VL 124 IS 7 BP 857 EP 863 DI 10.1161/CIRCULATIONAHA.111.037135 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 807GR UT WOS:000293884900022 PM 21844092 ER PT J AU Lin, WC Cao, J Liu, JY Beshiri, ML Fujiwara, Y Francis, J Cherniack, AD Geisen, C Blair, LP Zou, MR Shen, XH Kawamori, D Liu, ZZ Grisanzio, C Watanabe, H Minamishima, YA Zhang, Q Kulkarni, RN Signoretti, S Rodig, SJ Bronson, RT Orkin, SH Tuck, DP Benevolenskaya, EV Meyerson, M Kaelin, WG Yan, Q AF Lin, Wenchu Cao, Jian Liu, Jiayun Beshiri, Michael L. Fujiwara, Yuko Francis, Joshua Cherniack, Andrew D. Geisen, Christoph Blair, Lauren P. Zou, Mike R. Shen, Xiaohua Kawamori, Dan Liu, Zongzhi Grisanzio, Chiara Watanabe, Hideo Minamishima, Yoji Andrew Zhang, Qing Kulkarni, Rohit N. Signoretti, Sabina Rodig, Scott J. Bronson, Roderick T. Orkin, Stuart H. Tuck, David P. Benevolenskaya, Elizaveta V. Meyerson, Matthew Kaelin, William G., Jr. Yan, Qin TI Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mouse model; histone methyltransferase; chromatin modifier; neuroendocrine tumor; islet cell tumor ID MULTIPLE ENDOCRINE NEOPLASIA; HUMAN CANCER; METHYLTRANSFERASE COMPLEX; CELLULAR-DIFFERENTIATION; REPRESSES TRANSCRIPTION; LYSINE METHYLATION; PROSTATE-CANCER; GENE-EXPRESSION; ACUTE-LEUKEMIA; BREAST-CANCER AB Aberrations in epigenetic processes, such as histone methylation, can cause cancer. Retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) can demethylate tri- and dimethylated lysine 4 in histone H3, which are epigenetic marks for transcriptionally active chromatin, whereas the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor promotes H3K4 methylation. Previous studies suggested that inhibition of RBP2 contributed to tumor suppression by the retinoblastoma protein (pRB). Here, we show that genetic ablation of Rbp2 decreases tumor formation and prolongs survival in Rb1(+/-) mice and Men1-defective mice. These studies link RBP2 histone demethylase activity to tumorigenesis and nominate RBP2 as a potential target for cancer therapy. C1 [Lin, Wenchu; Liu, Jiayun; Francis, Joshua; Cherniack, Andrew D.; Geisen, Christoph; Grisanzio, Chiara; Watanabe, Hideo; Minamishima, Yoji Andrew; Zhang, Qing; Signoretti, Sabina; Meyerson, Matthew; Kaelin, William G., Jr.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cao, Jian; Blair, Lauren P.; Zou, Mike R.; Liu, Zongzhi; Tuck, David P.; Yan, Qin] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Beshiri, Michael L.; Benevolenskaya, Elizaveta V.] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Fujiwara, Yuko; Shen, Xiaohua; Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Fujiwara, Yuko; Shen, Xiaohua; Orkin, Stuart H.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. [Meyerson, Matthew] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Geisen, Christoph; Orkin, Stuart H.; Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Kawamori, Dan; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Med,Dept Med, Boston, MA 02115 USA. [Grisanzio, Chiara; Signoretti, Sabina; Rodig, Scott J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. RP Meyerson, M (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM matthew_meyerson@dfci.harvard.edu; william_kaelin@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; Yan, Qin/E-8893-2012; Cao, Jian/K-2440-2014; Minamishima, Yoji/E-5380-2010 OI Yan, Qin/0000-0003-4077-453X; Minamishima, Yoji/0000-0001-7995-9318 FU National Institutes of Health [CA138631, CA076120, CA16359]; Raymond and Beverly Sackler Fund for the Arts and Sciences; Caring for Carcinoid Foundation; V Scholar Award FX We thank members of the E. V. B., W. G. K., M. M., S.H.O., and Q.Y. laboratories for their kind help and valuable discussions. We thank Dr. Lili Yamasaki for her valuable comments. We also thank the laboratory members of Dr. David Stern for their kind help. We thank Dr. Ronald DePinho for providing Cre-ER transgenic mice and Dr. Seung Kim for providing RIP-Cre mice. We thank Dr. Edward Fox and the Dana-Farber Cancer Institute microarray core facility and Yale Center for Genome Analysis for gene expression profiling studies. We also thank Harvard rodent histology core, Harvard specialized histopatholology core, Dr. Alexander Vortmeyer, and the Yale research histology facility for histological analysis. This work was supported by National Institutes of Health Grants CA138631 (to E. V. B.), CA076120 (to W. G. K.), and CA16359 (to Yale Comprehensive Cancer Center), the Raymond and Beverly Sackler Fund for the Arts and Sciences (M. M.), the Caring for Carcinoid Foundation (M. M), and the V Scholar Award (to Q.Y.). W. G. K. is a Howard Hughes Medical Institute Investigator and a Doris Duke Distinguished Scientist. Q.Y. is a Breast Cancer Alliance Young Investigator and an Alexander and Margaret Stewart Trust Fellow. NR 71 TC 51 Z9 51 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 16 PY 2011 VL 108 IS 33 BP 13379 EP 13386 DI 10.1073/pnas.1110104108 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 807KC UT WOS:000293895100014 PM 21788502 ER PT J AU Trevino, SG Zhang, N Elenko, MP Luptak, A Szostak, JW AF Trevino, Simon G. Zhang, Na Elenko, Mark P. Luptak, Andrej Szostak, Jack W. TI Evolution of functional nucleic acids in the presence of nonheritable backbone heterogeneity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE abiogenesis; genetic takeover; RNA progenitor; origin of life ID IN-VITRO SELECTION; STRUCTURAL BASIS; RNA APTAMERS; LIGAND-BINDING; DNA APTAMER; LIFE; TNA; ATP; RECOGNITION; POLYMERASE AB Multiple lines of evidence support the hypothesis that the early evolution of life was dominated by RNA, which can both transfer information from generation to generation through replication directed by base-pairing, and carry out biochemical activities by folding into functional structures. To understand how life emerged from prebiotic chemistry we must therefore explain the steps that led to the emergence of the RNA world, and in particular, the synthesis of RNA. The generation of pools of highly pure ribonucleotides on the early Earth seems unlikely, but the presence of alternative nucleotides would support the assembly of nucleic acid polymers containing nonheritable backbone heterogeneity. We suggest that homogeneous monomers might not have been necessary if populations of heterogeneous nucleic acid molecules could evolve reproducible function. For such evolution to be possible, function would have to be maintained despite the repeated scrambling of backbone chemistry from generation to generation. We have tested this possibility in a simplified model system, by using a T7 RNA polymerase variant capable of transcribing nucleic acids that contain an approximately 1: 1 mixture of deoxy-and ribonucleotides. We readily isolated nucleotide-binding aptamers by utilizing an in vitro selection process that shuffles the order of deoxy-and ribonucleotides in each round. We describe two such RNA/DNA mosaic nucleic acid aptamers that specifically bind ATP and GTP, respectively. We conclude that nonheritable variations in nucleic acid backbone structure may not have posed an insurmountable barrier to the emergence of functionality in early nucleic acids. C1 [Trevino, Simon G.; Zhang, Na; Elenko, Mark P.; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Howard Hughes Med Inst, Boston, MA 02144 USA. [Trevino, Simon G.; Zhang, Na; Elenko, Mark P.; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Simches Res Ctr, Boston, MA 02144 USA. [Luptak, Andrej] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA 92697 USA. [Luptak, Andrej] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA. [Luptak, Andrej] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Howard Hughes Med Inst, Boston, MA 02144 USA. EM szostak@molbio.mgh.harvard.edu FU National Science Foundation FX We thank T. McAllister for the generous gift of a plasmid containing histidine-tagged Y639F T7 RNA polymerase gene; G. Ruvkun, D. P. Bartel, A. M. van Oijen, R. Bruckner, A. Ricardo, I. Budin, and D. Treco for helpful discussions. This work was supported in part by a grant from the National Science Foundation. J.W.S. is an Investigator of the Howard Hughes Medical Institute. NR 51 TC 24 Z9 24 U1 3 U2 32 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 16 PY 2011 VL 108 IS 33 BP 13492 EP 13497 DI 10.1073/pnas.1107113108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 807KC UT WOS:000293895100033 PM 21825162 ER PT J AU Kawasumi, M Lemos, B Bradner, JE Thibodeau, R Kim, YS Schmidt, M Higgins, E Koo, SW Angle-Zahn, A Chen, A Levine, D Nguyen, L Heffernan, TP Longo, I Mandinova, A Lu, YP Conney, AH Nghiem, P AF Kawasumi, Masaoki Lemos, Bianca Bradner, James E. Thibodeau, Renee Kim, Yong-son Schmidt, Miranda Higgins, Erin Koo, Sang-wahn Angle-Zahn, Aimee Chen, Adam Levine, Douglas Lynh Nguyen Heffernan, Timothy P. Longo, Isabel Mandinova, Anna Lu, Yao-Ping Conney, Allan H. Nghiem, Paul TI Protection from UV-induced skin carcinogenesis by genetic inhibition of the ataxia telangiectasia and Rad3-related (ATR) kinase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE skin cancer prevention; squamous cell carcinoma; xeroderma pigmentosum ID DNA-DAMAGE RESPONSE; ONCOGENE-INDUCED SENESCENCE; CELL-CYCLE CHECKPOINTS; INDUCED APOPTOSIS; ADULT MICE; GENOMIC INSTABILITY; SYNTHETIC LETHALITY; TOPICAL APPLICATION; PROMOTES APOPTOSIS; HAIRLESS MOUSE AB Multiple human epidemiologic studies link caffeinated (but not decaffeinated) beverage intake with significant decreases in several types of cancer, including highly prevalent UV-associated skin carcinomas. The mechanism by which caffeine protects against skin cancer is unknown. Ataxia telangiectasia and Rad3-related (ATR) is a replication checkpoint kinase activated by DNA stresses and is one of several targets of caffeine. Suppression of ATR, or its downstream target checkpoint kinase 1 (Chk1), selectively sensitizes DNA-damaged and malignant cells to apoptosis. Agents that target this pathway are currently in clinical trials. Conversely, inhibition of other DNA damage response pathways, such as ataxia telangiectasia mutated (ATM) and BRCA1, promotes cancer. To determine the effect of replication checkpoint inhibition on carcinogenesis, we generated transgenic mice with diminished ATR function in skin and crossed them into a UV-sensitive background, Xpc(-/-). Unlike caffeine, this genetic approach was selective and had no effect on ATM activation. These transgenic mice were viable and showed no histological abnormalities in skin. Primary keratinocytes from these mice had diminished UV-induced Chk1 phosphorylation and twofold augmentation of apoptosis after UV exposure (P = 0.006). With chronic UV treatment, transgenic mice remained tumor-free for significantly longer (P = 0.003) and had 69% fewer tumors at the end of observation of the full cohort (P = 0.019), compared with littermate controls with the same genetic background. This study suggests that inhibition of replication checkpoint function can suppress skin carcinogenesis and supports ATR inhibition as the relevant mechanism for the protective effect of caffeinated beverage intake in human epidemiologic studies. C1 [Lu, Yao-Ping; Conney, Allan H.] Rutgers State Univ, Ernest Mario Sch Pharm, Susan Lehman Cullman Lab Canc Res, Piscataway, NJ 08854 USA. [Kawasumi, Masaoki; Lemos, Bianca; Thibodeau, Renee; Schmidt, Miranda; Higgins, Erin; Lynh Nguyen; Nghiem, Paul] Univ Washington, Dept Med, Div Dermatol, Seattle, WA 98109 USA. [Kawasumi, Masaoki; Bradner, James E.; Kim, Yong-son; Koo, Sang-wahn; Angle-Zahn, Aimee; Chen, Adam; Levine, Douglas; Lynh Nguyen; Heffernan, Timothy P.; Longo, Isabel; Mandinova, Anna; Nghiem, Paul] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Kawasumi, Masaoki; Bradner, James E.; Kim, Yong-son; Koo, Sang-wahn; Angle-Zahn, Aimee; Chen, Adam; Levine, Douglas; Lynh Nguyen; Heffernan, Timothy P.; Longo, Isabel; Mandinova, Anna; Nghiem, Paul] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Bradner, James E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nghiem, Paul] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. RP Conney, AH (reprint author), Rutgers State Univ, Ernest Mario Sch Pharm, Susan Lehman Cullman Lab Canc Res, Piscataway, NJ 08854 USA. EM aconney@pharmacy.rutgers.edu; pnghiem@uw.edu RI Nghiem, Paul/A-9210-2011 OI Nghiem, Paul/0000-0003-2784-963X FU National Institutes of Health [R01-AR049832, R01-CA130857] FX We thank Dr. Elaine Fuchs for providing the human beta-globin intron-containing keratin-14 promoter construct. This work was supported by National Institutes of Health Grants R01-AR049832 (to P.N.) and R01-CA130857 (to A.H.C.). NR 48 TC 25 Z9 25 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 16 PY 2011 VL 108 IS 33 BP 13716 EP 13721 DI 10.1073/pnas.1111378108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 807KC UT WOS:000293895100071 PM 21844338 ER PT J AU Hung, WW Morrison, RS AF Hung, William W. Morrison, R. Sean TI Hip Fracture: A Complex Illness Among Complex Patients SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID PROXIMAL FEMORAL FRACTURES; HOSPITAL DISCHARGE; RISK-FACTORS; OUTCOMES; SURGERY; MORTALITY; CARE; SURVIVAL; PAIN C1 [Hung, William W.; Morrison, R. Sean] Mt Sinai Sch Med, 1 Gustave L Levy Pl,Box 1070, New York, NY 10029 USA. [Hung, William W.] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Hung, WW (reprint author), Mt Sinai Sch Med, 1 Gustave L Levy Pl,Box 1070, New York, NY 10029 USA. FU NIA NIH HHS [K24 AG022345, R01AG030141]; PHS HHS [AGK24AG022345] NR 20 TC 9 Z9 9 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 16 PY 2011 VL 155 IS 4 BP 267 EP + DI 10.7326/0003-4819-155-4-201108160-00012 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 807KN UT WOS:000293896400009 PM 21844553 ER PT J AU Peterson, PN Rumsfeld, JS AF Peterson, Pamela N. Rumsfeld, John S. TI The Evolving Story of Guidelines and Health Care: Does Being NICE Help? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID CHRONIC HEART-FAILURE; TASK-FORCE; ASSOCIATION; RECOMMENDATIONS; COLLABORATION; MANAGEMENT; DIAGNOSIS; SOCIETY; ADULTS; COSTS C1 [Rumsfeld, John S.] Denver VA Med Ctr, 1055 Clermont St, Denver, CO 80220 USA. [Peterson, Pamela N.] Denver Hlth Med Ctr, Denver, CO 80204 USA. RP Rumsfeld, JS (reprint author), Denver VA Med Ctr, 1055 Clermont St, Denver, CO 80220 USA. EM John.Rumsfeld@va.gov NR 18 TC 2 Z9 2 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 16 PY 2011 VL 155 IS 4 BP 269 EP + DI 10.7326/0003-4819-155-4-201108160-00013 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 807KN UT WOS:000293896400010 PM 21844554 ER PT J AU Litvan, I Aarsland, D Adler, CH Goldman, JG Kulisevsky, J Mollenhauer, B Rodriguez-Oroz, MC Troster, AI Weintraub, D AF Litvan, Irene Aarsland, Dag Adler, Charles H. Goldman, Jennifer G. Kulisevsky, Jaime Mollenhauer, Brit Rodriguez-Oroz, Maria C. Troester, Alexander I. Weintraub, Daniel TI MDS Task Force on Mild Cognitive Impairment in Parkinson's Disease: Critical Review of PD-MCI SO MOVEMENT DISORDERS LA English DT Review DE mild cognitive impairment; Parkinson's disease; systematic review ID PROGRESSIVE SUPRANUCLEAR PALSY; CSF AMYLOID-BETA; REVISED CAMCOG-R; QUALITY-OF-LIFE; LEWY BODIES; CEREBROSPINAL-FLUID; DIFFERENTIAL-DIAGNOSIS; COMMUNITY POPULATION; NORWEGIAN PARKWEST; CLINICAL-FEATURES AB There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinson's disease. The Movement Disorder Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinson's disease-mild cognitive impairment and its association with dementia. A comprehensive PubMed literature review was conducted using systematic inclusion and exclusion criteria. A mean of 26.7% (range, 18.9%-38.2%) of nondemented patients with Parkinson's disease have mild cognitive impairment. The frequency of Parkinson's disease-mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, nonamnestic is more common than amnestic impairment. A high proportion of patients with Parkinson's disease-mild cognitive impairment progress to dementia in a relatively short period of time. The primary conclusions of the Task Force are that: (1) Parkinson's disease-mild cognitive impairment is common, (2) there is significant heterogeneity within Parkinson's disease-mild cognitive impairment in the number and types of cognitive domain impairments, (3) Parkinson's disease-mild cognitive impairment appears to place patients at risk of progressing to dementia, and (4) formal diagnostic criteria for Parkinson's disease-mild cognitive impairment are needed. (C)2011 Movement Disorder Society C1 [Litvan, Irene] Univ Louisville, Sch Med, Dept Neurol, Div Movement Disorders, Louisville, KY 40241 USA. [Litvan, Irene] Frazier Rehab Neurosci Inst, Movement Disorders Program, Louisville, KY USA. [Aarsland, Dag] Stavanger Univ Hosp, Ctr Age Related Med, Oslo, Norway. [Aarsland, Dag] Univ Oslo, Akershus Univ Hosp, Oslo, Norway. [Adler, Charles H.] Mayo Clin, Dept Neurol, Parkinsons Dis & Movement Disorders Ctr, Scottsdale, AZ USA. [Goldman, Jennifer G.] Rush Univ, Med Ctr, Sect Parkinson Dis & Movement Disorders, Dept Neurol Sci, Chicago, IL 60612 USA. [Kulisevsky, Jaime] St Pau Hosp, Dept Neurol, Movement Disorders Unit, Madrid, Spain. [Kulisevsky, Jaime] Univ Autonoma Barcelona, Inst Biomed Res IIB St Pau, Madrid, Spain. [Kulisevsky, Jaime; Rodriguez-Oroz, Maria C.] Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain. [Mollenhauer, Brit] Univ Gottingen, Paracelsus Elena Klin, Gottingen, Germany. [Rodriguez-Oroz, Maria C.] Univ Navarra Clin, Dept Neurol, Sch Med, Ctr Neurosci,CIMA, Pamplona, Spain. [Troester, Alexander I.] Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC 27599 USA. [Weintraub, Daniel] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, PADRECC, Philadelphia, PA USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, MIRECC, Philadelphia, PA USA. RP Litvan, I (reprint author), Univ Louisville, Sch Med, Dept Neurol, Div Movement Disorders, 220 Abraham Flexner Way,Ste 1503, Louisville, KY 40241 USA. EM i.litvan@louisville.edu OI Litvan, Irene/0000-0002-3485-3445; Aarsland, Dag/0000-0001-6314-216X FU Arizona Biomedical Research Commission; Michael J. Fox Foundation; National Parkinson Foundation; GlaxoSmithKline; Medtronic, Inc.; [5R01AG024040-04] FX Irene Litvan was funded by 5R01AG024040-04. Charles Adler has been a consultant for Ipsen and Merck Serono, has been on the advisory boards of Biogen Idec, Eli Lilly, Medtronic, and Merz, and has received grants from the Arizona Biomedical Research Commission and the Michael J. Fox Foundation. Alexander I. Troster has been a consultant for Medtronic, Inc., St. Jude, and Boston Scientific, has been on the advisory boards of Medtronic, Inc. and St. Jude, has received honoraria from Medtronic and Boehringer Ingelheim, and has received grants from the National Parkinson Foundation, GlaxoSmithKline, and Medtronic, Inc. NR 109 TC 205 Z9 213 U1 6 U2 40 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2011 VL 26 IS 10 BP 1814 EP 1824 DI 10.1002/mds.23823 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 822DS UT WOS:000295024700006 PM 21661055 ER PT J AU Schwarzschild, MA Marek, K Eberly, S Oakes, D Shoulson, I Jennings, D Seibyl, J Ascherio, A AF Schwarzschild, Michael A. Marek, Kenneth Eberly, Shirley Oakes, David Shoulson, Ira Jennings, Danna Seibyl, John Ascherio, Alberto CA Parkinson Study Grp PRECEPT TI Serum Urate and Probability of Dopaminergic Deficit in Early "Parkinson's Disease" SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; urate; dopamine transporter; neuroimaging; diagnosis; biomarker ID URIC-ACID LEVELS; FOLLOW-UP; PLASMA URATE; RISK; PROGRESSION; DIAGNOSIS; PREDICTOR; LEVODOPA; SWEDDS; SCANS AB The objective of this study was to investigate whether higher levels of urate, an antioxidant linked to a lower likelihood of developing Parkinson's disease, is also a predictor of having a dopamine transporter brain scan without evidence of dopaminergic deficit. In a cross-sectional study of 797 mildly affected, untreated parkinsonian subjects diagnosed with early Parkinson's disease in the Parkinson Research Examination of CEP-1347 Trial, we investigated the relationship at baseline between serum urate and striatal dopamine transporter density, determined by single-photon emission computed tomography of iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane uptake. A scan without evidence of dopaminergic deficit was defined as lowest putamen iodine-123-labeled 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane > 80% age-expected putamen dopamine transporter density. The odds of having a scan without evidence of dopaminergic deficit rose across increasing quintiles of urate level, with an age- and sex-adjusted odds ratio of 3.2 comparing the highest to the lowest urate quintile (95% confidence interval, 1.5-7.2; P for trend = .0003), and remained significant after adjusting for potential confounding factors. The association was significant in men but not women, regardless of whether common or sex-specific quintiles of urate were used. Higher levels of urate were associated with a greater likelihood of a scan without evidence of dopaminergic deficit among subjects with early untreated parkinsonism in the Parkinson Research Examination of CEP-1347 Trial. The findings support the diagnostic utility of urate in combination with other determinants. (C)2011 Movement Disorder Society C1 [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Marek, Kenneth; Jennings, Danna; Seibyl, John] Inst Neurodegenerat Disorders, New Haven, CT USA. [Eberly, Shirley; Oakes, David; Shoulson, Ira] Univ Rochester, Dept Neurol, Rochester, NY USA. [Eberly, Shirley; Oakes, David; Shoulson, Ira] Univ Rochester, Dept Biostat, Rochester, NY USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Ascherio, A (reprint author), 655 Huntington Ave,3rd Floor, Boston, MA 02115 USA. EM aascheri@hsph.harvard.edu FU NIH [R01NS061858, K24NS060991]; DoD [W81XWH-06-1-0679]; RJG Foundation; Cephalon, Inc. (Frazer, PA); H. Lundbeck A/S (Copenhagen, Denmark) FX The present study was supported by the NIH (R01NS061858, K24NS060991), DoD (W81XWH-06-1-0679), and RJG Foundation.; The present study is a secondary analysis of the database of a clinical trial PRECEPT, which was sponsored by Cephalon, Inc. (Frazer, PA), and H. Lundbeck A/S (Copenhagen, Denmark). Dr. Ira Shoulson had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Kenneth Marek is a consultant/AD board member for GE Healthcare, Alseres, EMD Serono, Lilly, Bayer Healthcare, Sanofi, and Biogen and has an ownership interest in Molecular NeuroImaging, LLC. Dr. John Seibyl is a consultant/AD board member for Bayer Healthcare, GE Healthcare, and Neurologica and has an equity interest in Molecular NeuroImaging, LLC. NR 26 TC 15 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2011 VL 26 IS 10 BP 1864 EP 1868 DI 10.1002/mds.23741 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 822DS UT WOS:000295024700012 PM 21538532 ER PT J AU Mashhoon, Y Janes, AC Jensen, JE Prescot, AP Pachas, G Renshaw, PF Fava, M Evins, AE Kaufman, MJ AF Mashhoon, Yasmin Janes, Amy C. Jensen, J. Eric Prescot, Andrew P. Pachas, Gladys Renshaw, Perry F. Fava, Maurizio Evins, A. Eden Kaufman, Marc J. TI Anterior cingulate proton spectroscopy glutamate levels differ as a function of smoking cessation outcome SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Dorsal anterior cingulate cortex; Glutamate; Nicotine; Relapse; Smoking; Spectroscopy ID SUSTAINED-RELEASE BUPROPION; RANDOMIZED CONTROLLED-TRIAL; RECEPTOR PARTIAL AGONIST; MENSTRUAL-CYCLE; 4 TESLA; CORTEX; ADDICTION; VARENICLINE; ABSTINENCE; REACTIVITY AB Background: Cigarette smoking is the leading preventable cause of death. Unfortunately, the majority of smokers who attempt to quit smoking relapse within weeks. Abnormal dorsal anterior cingulate cortex (dACC) function may contribute to tobacco smoking relapse vulnerability. Growing evidence suggests that glutamate neurotransmission is involved in mediating nicotine dependence. We hypothesized that prior to a cessation attempt, dACC glutamate levels would be lower in relapse vulnerable smokers. Methods: Proton magnetic resonance spectra (MRS) were obtained from dACC and a control region, the parieto-occipital cortex (POC), using two-dimensional J-resolved MRS at 4 T and analyzed using LCModel. Nine nicotine-dependent women were scanned prior to making a quit attempt. Subjects then were divided into two groups; those able to maintain subsequent abstinence aided by nicotine replacement therapy (NRT) and those who slipped while on NRT (smoked any part of a cigarette after attaining at least 24 h of abstinence). Results: Slip subjects exhibited significantly reduced dACC MRS glutamate (Glu/Cr) levels (p<0.03) compared to abstinent subjects. This effect was not observed in the POC control region. Conclusions: Our preliminary findings suggest that dACC Glu levels as measured with MRS may help identify and/or be a biomarker for relapse vulnerable smokers. Future research following up on these findings may help clarify the role of dACC Glu in smoking dependence that may lead to new treatment strategies. (C) 2011 Elsevier Inc. All rights reserved. C1 [Pachas, Gladys; Fava, Maurizio; Evins, A. Eden] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Mashhoon, Yasmin; Janes, Amy C.; Jensen, J. Eric; Prescot, Andrew P.; Renshaw, Perry F.; Kaufman, Marc J.] Harvard Univ, McLean Hosp, Sch Med, Belmont, MA 02478 USA. RP Mashhoon, Y (reprint author), Harvard Univ, McLean Hosp, Sch Med, 115 Mill St, Belmont, MA 02478 USA. EM ymashhoon@mclean.harvard.edu RI Janes, Amy/A-5322-2013 OI Janes, Amy/0000-0002-3749-5006 FU National Institute of Health [U01DA019378, R01DA022276, R01DA014674, R01DA09448, K01DA029645, K02DA017324, T32DA015036, S10RR13938]; Counter-Drug Technology Assessment Center (CTAC); Office of National Drug Control Policy (ONDCP) via Army Contracting Agency [DABT63-99-C, DABK39-03-C-0075]; GlaxoSmithKline (GSK) FX This study was funded in part by National Institute of Health grants U01DA019378, R01DA022276, R01DA014674, R01DA09448, K01DA029645, K02DA017324, T32DA015036, and S10RR13938; by funding from the Counter-Drug Technology Assessment Center (CTAC), an office within the Office of National Drug Control Policy (ONDCP) via Army Contracting Agency Contracts DABT63-99-C and DABK39-03-C-0075; and by research support from GlaxoSmithKline (GSK). The content of the information does not necessarily reflect the position or the policy of the Government and no official endorsement should be inferred. Funding sponsors had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the research report; or in the decision to submit the manuscript for publication. NR 29 TC 12 Z9 12 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD AUG 15 PY 2011 VL 35 IS 7 BP 1709 EP 1713 DI 10.1016/j.pnpbp.2011.05.006 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 820YK UT WOS:000294941800027 PM 21616118 ER PT J AU Cauley, S Luisier, M Balakrishnan, V Klimeck, G Koh, CK AF Cauley, Stephen Luisier, Mathieu Balakrishnan, Venkataramanan Klimeck, Gerhard Koh, Cheng-Kok TI Distributed non-equilibrium Green's function algorithms for the simulation of nanoelectronic devices with scattering SO JOURNAL OF APPLIED PHYSICS LA English DT Article ID CONJUGATE-GRADIENT METHOD; BAND MATRICES; DECAY-RATES; INVERSE AB Through the non-equilibrium Green's function (NEGF) formalism, quantum-scale device simulation can be performed with the inclusion of electron-phonon scattering. However, the simulation of realistically sized devices under the NEGF formalism typically requires prohibitive amounts of memory and computation time. Two of the most demanding computational problems for NEGF simulation involve mathematical operations with structured matrices called semiseparable matrices. In this work, we present parallel approaches for these computational problems which allow for efficient distribution of both memory and computation based upon the underlying device structure. This is critical when simulating realistically sized devices due to the aforementioned computational burdens. First, we consider determining a distributed compact representation for the retarded Green's function matrix G(R). This compact representation is exact and allows for any entry in the matrix to be generated through the inherent semiseparable structure. The second parallel operation allows for the computation of electron density and current characteristics for the device. Specifically, matrix products between the distributed representation for the semiseparable matrix G(R) and the self-energy scattering terms in Sigma(<) produce the less-than Green's function G(<). As an illustration of the computational efficiency of our approach, we stably generate the mobility for nanowires with cross-sectional sizes as large as 4.5 nm, assuming an atomistic model with scattering. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3624612] C1 [Cauley, Stephen] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Luisier, Mathieu; Balakrishnan, Venkataramanan; Klimeck, Gerhard; Koh, Cheng-Kok] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. RP Cauley, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RI Cauley, Stephen/P-1386-2014; Klimeck, Gerhard/A-1414-2012 OI Klimeck, Gerhard/0000-0001-7128-773X FU NSF [EEC-0228390, 0749140]; National Center for Computational Sciences [DE-AC05-00OR22725] FX This work was partially supported by NSF Grant No. EEC-0228390, by NSF PetaApps Grant No. 0749140, by NSF through TeraGrid resources provided by the National Institute for Computational Sciences, and by DOE resources provided by the National Center for Computational Sciences under Contract No. DE-AC05-00OR22725. NR 28 TC 5 Z9 5 U1 0 U2 3 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-8979 J9 J APPL PHYS JI J. Appl. Phys. PD AUG 15 PY 2011 VL 110 IS 4 AR 043713 DI 10.1063/1.3624612 PG 14 WC Physics, Applied SC Physics GA 814VC UT WOS:000294484300073 ER PT J AU Park, KS Liang, MC Raiser, DM Zamponi, R Roach, RR Curtis, SJ Walton, Z Schaffer, BE Roake, CM Zmoos, AF Kriegel, C Wong, KK Sage, J Kim, CF AF Park, Kwon-Sik Liang, Mei-Chih Raiser, David M. Zamponi, Raffaella Roach, Rebecca R. Curtis, Stephen J. Walton, Zandra Schaffer, Bethany E. Roake, Caitlin M. Zmoos, Anne-Flore Kriegel, Christina Wong, Kwok-Kin Sage, Julien Kim, Carla F. TI Characterization of the cell of origin for small cell lung cancer SO CELL CYCLE LA English DT Article DE Rb; p53; SCLC; cell of origin; cancer; lung; neuroendocrine ID ONCOGENIC K-RAS; STEM-CELLS; PROGENITOR CELLS; MOUSE MODEL; SOMATIC INACTIVATION; EXPRESSION ANALYSIS; GENE-EXPRESSION; RB DELETION; IN-VIVO; RETINOBLASTOMA AB Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer that affects more than 200,000 people worldwide every year with a very high mortality rate. Here, we used a mouse genetics approach to characterize the cell of origin for SCLC; in this mouse model, tumors are initiated by the deletion of the Rb and p53 tumor suppressor genes in the lung epithelium of adult mice. We found that mouse SCLCs often arise in the lung epithelium where neuroendocrine cells are located and that the majority of early lesions were composed of proliferating neuroendocrine cells. In addition, mice in which Rb and p53 are deleted in a variety of non-neuroendocrine lung epithelial cells did not develop SCLC. These data indicate that SCLC likely arises from neuroendocrine cells in the lung. C1 [Park, Kwon-Sik; Schaffer, Bethany E.; Roake, Caitlin M.; Zmoos, Anne-Flore; Sage, Julien] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Park, Kwon-Sik; Schaffer, Bethany E.; Roake, Caitlin M.; Zmoos, Anne-Flore; Sage, Julien] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA. [Liang, Mei-Chih; Walton, Zandra; Wong, Kwok-Kin] Harvard Canc Ctr, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Liang, Mei-Chih; Walton, Zandra; Wong, Kwok-Kin] Harvard Canc Ctr, Dana Farber Canc Inst, Ludwig Ctr, Boston, MA USA. [Liang, Mei-Chih; Walton, Zandra; Wong, Kwok-Kin] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Raiser, David M.; Zamponi, Raffaella; Roach, Rebecca R.; Curtis, Stephen J.; Kriegel, Christina; Kim, Carla F.] Childrens Hosp Boston, Stem Cell Program, Boston, MA USA. [Raiser, David M.; Zamponi, Raffaella; Roach, Rebecca R.; Curtis, Stephen J.; Kriegel, Christina; Kim, Carla F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Raiser, David M.; Zamponi, Raffaella; Roach, Rebecca R.; Curtis, Stephen J.; Kriegel, Christina; Kim, Carla F.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Sage, J (reprint author), Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. EM Julien.Sage@stanford.edu; Carla.Kim@childrens.harvard.edu OI wong, kwok kin/0000-0001-6323-235X FU American Lung Association [NCI CA140594]; Parker B. Francis Fellowship Program; Damon Runyon Cancer Research Foundation; American Cancer Society [RSG-10-071-TBG, RSG-08-082-01-MGO]; National Institute of Health [RO1 HL090136, U01 HL100402]; Harvard Stem Cell Institute; United Against Lung Cancer FX We are grateful to Dr. Jeff Whitsett for the SFTPC-rtTA/(tetO)7-Cre mouse lines and the proSP-C antibodies and to Dr. Deming Gou for the gift of the SP-C promoter plasmid. We also thank Dr. Anton Berns for the generous gift of the Rb and p53 conditional mutant mice. We thank the American Lung Association (K.P.,J.S.), the Parker B. Francis Fellowship Program (K.P.), the Damon Runyon Cancer Research Foundation (J.S.), the American Cancer Society (Research scholar awards RSG-10-071-TBG for J.S. and RSG-08-082-01-MGO for C.F.K.), the National Institute of Health (C.F.K. RO1 HL090136 and U01 HL100402), the Harvard Stem Cell Institute (D.M.R., C.F.K.), United Against Lung Cancer (K.K.W.) and the American Lung Association (K.K.W.) NCI CA140594 (KKW). NR 52 TC 41 Z9 44 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD AUG 15 PY 2011 VL 10 IS 16 BP 2806 EP 2815 DI 10.4161/cc.10.16.17012 PG 10 WC Cell Biology SC Cell Biology GA 810VK UT WOS:000294155600035 PM 21822053 ER PT J AU Jacobson, KR Theron, D Victor, TC Streicher, EM Warren, RM Murray, MB AF Jacobson, Karen R. Theron, Danie Victor, Thomas C. Streicher, Elizabeth M. Warren, Robin M. Murray, Megan B. TI Treatment Outcomes of Isoniazid-Resistant Tuberculosis Patients, Western Cape Province, South Africa SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material AB We report treatment outcomes from a retrospective cohort of patients with isoniazid-monoresistant tuberculosis in rural South Africa. Sixteen percent of patients had poor outcomes, 61% of whom progressed to multidrug-resistant tuberculosis. These data reveal the need for early identification and aggressive follow-up of isoniazid monoresistance to increase treatment success. C1 [Jacobson, Karen R.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Theron, Danie] Brewelskloof Hosp, Worcester, MA USA. [Victor, Thomas C.; Streicher, Elizabeth M.; Warren, Robin M.] Univ Stellenbosch, Dept Sci & Technol, Natl Res Fdn Ctr Excellence Biomed TB Res, Med Res Council Ctr Mol & Cellular Biol, Cape Town, South Africa. [Murray, Megan B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Jacobson, KR (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,GRJ5-5, Boston, MA 02114 USA. EM krjacobson@partners.org OI Streicher, Elizabeth/0000-0003-3901-1981; Jacobson, Karen/0000-0003-4239-3685 FU NIAID NIH HHS [T32 AI007387, T32 AI07387] NR 12 TC 33 Z9 33 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2011 VL 53 IS 4 BP 369 EP 372 DI 10.1093/cid/cir406 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 804DW UT WOS:000293635500009 PM 21810750 ER PT J AU Hess, DR MacIntyre, NR AF Hess, Dean R. MacIntyre, Neil R. TI Ventilator Discontinuation: Why Are We Still Weaning? SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID MECHANICAL VENTILATION; CONTROLLED-TRIAL; SUPPORT C1 [Hess, Dean R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02215 USA. [MacIntyre, Neil R.] Duke Univ, Med Ctr, Durham, NC USA. RP Hess, DR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02215 USA. NR 16 TC 13 Z9 13 U1 0 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 15 PY 2011 VL 184 IS 4 BP 392 EP 394 DI 10.1164/rccm.201105-0894ED PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 808EL UT WOS:000293959600004 PM 21844511 ER PT J AU Penuelas, O Frutos-Vivar, F Fernandez, C Anzueto, A Epstein, SK Apezteguia, C Gonzalez, M Nin, N Raymondos, K Tomicic, V Desmery, P Arabi, Y Pelosi, P Kuiper, M Jibaja, M Matamis, D Ferguson, ND Esteban, A AF Penuelas, Oscar Frutos-Vivar, Fernando Fernandez, Cristina Anzueto, Antonio Epstein, Scott K. Apezteguia, Carlos Gonzalez, Marco Nin, Nicolas Raymondos, Konstantinos Tomicic, Vinko Desmery, Pablo Arabi, Yaseen Pelosi, Paolo Kuiper, Michael Jibaja, Manuel Matamis, Dimitros Ferguson, Niall D. Esteban, Andres CA Ventila Grp TI Characteristics and Outcomes of Ventilated Patients According to Time to Liberation from Mechanical Ventilation SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE mechanical ventilation; weaning; outcome; extubation ID CRITICAL ILLNESS POLYNEUROPATHY; SPONTANEOUS BREATHING TRIAL; ACUTE RESPIRATORY-DISTRESS; DURATION; SEDATION; PROTOCOL; FAILURE AB Rationale: A new classification of patients based on the duration of liberation of mechanical ventilation has been proposed. Objectives: To analyze outcomes based on the new weaning classification in a cohort of mechanically ventilated patients. Methods: Secondary analysis included 2,714 patients who were weaned and underwent scheduled extubation from a cohort of 4,968 adult patients mechanically ventilated for more than 12 hours. Measurements and Main Results: Patients were classified according to a new weaning classification: 1,502 patients (55%) as simple weaning, 1,058 patients (39%) as difficult weaning, and 154 (6%) as prolonged weaning. Variables associated with prolonged weaning(>7 d) were: severity at admission (odds ratio [OR] per unit of Simplified Acute Physiology Score II, 1.01; 95% confidence interval [CI], 1.001-1.02), duration of mechanical ventilation before first attempt of weaning (OR per day, 1.10; 95% CI, 1.06-1.13), chronic pulmonary disease other than chronic obstructive pulmonary disease (OR, 13.23; 95% CI, 3.44-51.05), pneumonia as the reason to start mechanical ventilation (OR, 1.82; 95% CI, 1.07-3.08), and level of positive end-expiratory pressure applied before weaning (OR per unit, 1.09; 95% CI, 1.04-1.14). The prolonged weaning group had a nonsignificant trend toward a higher rate of reintubation (P = 0.08), tracheostomy (P = 0.15), and significantly longer length of stay and higher mortality in the intensive care unit (OR for death, 1.97; 95% CI, 1.17-3.31). The adjusted probability of death remained constant until Day 7, at which point it increased to 12.1%. Conclusions: Only patients who need more than 7 days for weaning have an increased mortality. C1 [Esteban, Andres] Hosp Univ Getafe, Intens Care Unit, Madrid 28905, Spain. [Penuelas, Oscar; Frutos-Vivar, Fernando; Nin, Nicolas; Esteban, Andres] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Fernandez, Cristina] Hosp Clin San Carlos, Dept Clin Epidemiol & Prevent Med, Madrid, Spain. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Anzueto, Antonio] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Ferguson, Niall D.] Univ Toronto, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Ferguson, Niall D.] Univ Hlth Network, Interdept Div Crit Care Med, Toronto, ON, Canada. [Ferguson, Niall D.] Univ Hlth Network, Div Respirol, Dept Med, Toronto, ON, Canada. [Epstein, Scott K.] Tufts Univ, Sch Med, Off Educ Affairs, Boston, MA 02111 USA. [Apezteguia, Carlos] Hosp Prof A Posadas, Buenos Aires, DF, Argentina. [Gonzalez, Marco] Univ Pontificia Bolivariana, Medellin, Colombia. [Gonzalez, Marco] Clin Medellin, Medellin, Colombia. [Raymondos, Konstantinos] Hannover Med Sch, D-30623 Hannover, Germany. [Tomicic, Vinko] Clin Las Lilas, Santiago, Chile. [Desmery, Pablo] Sanat Mitre, Buenos Aires, DF, Argentina. [Arabi, Yaseen] King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia. [Pelosi, Paolo] Univ Genoa, Dipartimento Sci Chirurg & Diagnost Int, Genoa, Italy. [Kuiper, Michael] Med Ctr Leeuwarden, Leeuwarden, Netherlands. [Jibaja, Manuel] Hosp Mil Quito, Quito, Ecuador. [Matamis, Dimitros] Papageorgiou Gen Hosp, Thessaloniki, Greece. RP Esteban, A (reprint author), Hosp Univ Getafe, Intens Care Unit, Carretera Toledo,Km 12,500, Madrid 28905, Spain. EM aesteban@ucigetafe.com RI Pesenti, Antonio/H-7483-2012; koca, ugur/F-1265-2016; Malbrain, Manu/B-3680-2017; OI koca, ugur/0000-0002-2949-4265; Malbrain, Manu/0000-0002-1816-5255; Severgnini, Paolo/0000-0001-8027-0059; Frutos-Vivar, Fernando/0000-0002-4648-9636; Ost, David/0000-0001-6351-5552; Kuiper, Michael/0000-0001-6201-7332; Ferguson, Niall/0000-0002-6213-5264; CHIUMELLO, DAVIDE ALBERTO/0000-0001-9260-3930 FU CIBER Enfermedades Respiratorias from Instituto de Salud Carlos III, Spain; Canadian Institutes of Health Research (Ottawa, Canada); Best Spanish Clinical Researcher, Lilly Award (Spain) FX Supported by CIBER Enfermedades Respiratorias from Instituto de Salud Carlos III, Spain. N.D.F. is supported by a Canadian Institutes of Health Research New Investigator Award (Ottawa, Canada). A. E. is supported by the Best Spanish Clinical Researcher, Lilly Award (Spain). NR 21 TC 73 Z9 81 U1 0 U2 10 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 15 PY 2011 VL 184 IS 4 BP 430 EP 437 DI 10.1164/rccm.201011-1887OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 808EL UT WOS:000293959600013 PM 21616997 ER PT J AU Righi, E Kashiwagi, S Yuan, JP Santosuosso, M Leblanc, P Ingraham, R Forbes, B Edelblute, B Collette, B Xing, DY Kowalski, M Mingari, MC Vianello, F Birrer, M Orsulic, S Dranoff, G Poznansky, MC AF Righi, Elda Kashiwagi, Satoshi Yuan, Jianping Santosuosso, Michael Leblanc, Pierre Ingraham, Rachel Forbes, Benjamin Edelblute, Beth Collette, Brian Xing, Deyin Kowalski, Magdalena Mingari, Maria Cristina Vianello, Fabrizio Birrer, Michael Orsulic, Sandra Dranoff, Glenn Poznansky, Mark C. TI CXCL12/CXCR4 Blockade Induces Multimodal Antitumor Effects That Prolong Survival in an Immunocompetent Mouse Model of Ovarian Cancer SO CANCER RESEARCH LA English DT Article ID REGULATORY T-CELLS; CHEMOKINE RECEPTOR EXPRESSION; BREAST-CANCER; TUMOR-CELLS; CXCR4 ANTAGONIST; IN-VIVO; GROWTH; IMMUNOTHERAPY; METASTASIS; CARCINOMA AB The chemokine CXCL12 and its receptor CXCR4 are expressed widely in human cancers, including ovarian cancer, in which they are associated with disease progression at the levels of tumor cell proliferation, invasion, and angiogenesis. Here, we used an immunocompetent mouse model of intraperitoneal papillary epithelial ovarian cancer to show that modulation of the CXCL12/CXCR4 axis in ovarian cancer has multimodal effects on tumor pathogenesis associated with induction of antitumor immunity. siRNA-mediated knockdown of CXCL12 in BR5-1 cells that constitutively express CXCL12 and CXCR4 reduced cell proliferation in vitro, and tumor growth in vivo. Similarly, treatment of BR5-1-derived tumors with AMD3100, a selective CXCR4 antagonist, resulted in increased tumor apoptosis and necrosis, reduction in intraperitoneal dissemination, and selective reduction of intratumoral FoxP3(+) regulatory T cells (Treg). Compared with controls, CXCR4 blockade greatly increased T-cell-mediated antitumor immune responses, conferring a significant survival advantage to AMD3100-treated mice. In addition, the selective effect of CXCR4 antagonism on intratumoral Tregs was associated with both higher CXCR4 expression and increased chemotactic responses to CXCL12, a finding that was also confirmed in a melanoma model. Together, our findings reinforce the concept of a critical role for the CXCL12/CXCR4 axis in ovarian cancer pathogenesis, and they offer a definitive preclinical validation of CXCR4 as a therapeutic target in this disease. Cancer Res; 71(16); 5522-34. (c) 2011 AACR. C1 [Righi, Elda; Kashiwagi, Satoshi; Yuan, Jianping; Santosuosso, Michael; Leblanc, Pierre; Ingraham, Rachel; Forbes, Benjamin; Edelblute, Beth; Collette, Brian; Kowalski, Magdalena; Poznansky, Mark C.] Massachusetts Gen Hosp, Vaccine & Immunotherapy Ctr, Charlestown, MA USA. [Xing, Deyin; Orsulic, Sandra] Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02114 USA. [Birrer, Michael] Massachusetts Gen Hosp, Gynecol Oncol Canc Ctr, Boston, MA 02114 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Righi, Elda; Mingari, Maria Cristina] Univ Genoa, Dept Expt Med & IST Canc Res, Genoa, Italy. [Vianello, Fabrizio] Padua Univ Hosp, Dept Haematol, Padua, Italy. [Kowalski, Magdalena] Clare Coll, Dept Zool, Cambridge, England. [Orsulic, Sandra] Cedars Sinai Med Ctr, Womens Canc Res Inst, Los Angeles, CA 90048 USA. RP Kashiwagi, S (reprint author), Massachusetts Gen Hosp E, Vaccine & Immunotherapy Ctr, Charlestown, MA 02129 USA. EM skashiwagi@partners.org; mpoznansky@partners.org RI Vianello, Fabrizio/M-5211-2016; OI Vianello, Fabrizio/0000-0002-7174-4651; Collette, Brian/0000-0002-9993-8423 FU Public Health Service [RO1 AI49757]; Marsha Rivkin Center for Ovarian Cancer Research; Friends of VIC; Garber Award FX M.C. Poznansky, S. Kashiwagi, and E. Righi were supported by Public Health Service grant RO1 AI49757, the Marsha Rivkin Center for Ovarian Cancer Research, and philanthropic funds from Friends of VIC. S. Orsulic was supported by the Marsha Rivkin Center for Ovarian Cancer Research and the Garber Award. NR 53 TC 63 Z9 65 U1 1 U2 18 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2011 VL 71 IS 16 BP 5522 EP 5534 DI 10.1158/0008-5472.CAN-10-3143 PG 13 WC Oncology SC Oncology GA 806SN UT WOS:000293831500018 PM 21742774 ER PT J AU Fotovati, A Abu-Ali, S Wang, PS Deleyrolle, LP Lee, C Triscott, J Chen, JY Franciosi, S Nakamura, Y Sugita, Y Uchiumi, T Kuwano, M Leavitt, BR Singh, SK Jury, A Jones, C Wakimoto, H Reynolds, BA Pallen, CJ Dunn, SE AF Fotovati, Abbas Abu-Ali, Samah Wang, Pei-Shan Deleyrolle, Loic P. Lee, Cathy Triscott, Joanna Chen, James Y. Franciosi, Sonia Nakamura, Yasuhiro Sugita, Yasuo Uchiumi, Takeshi Kuwano, Michihiko Leavitt, Blair R. Singh, Sheila K. Jury, Alexa Jones, Chris Wakimoto, Hiroaki Reynolds, Brent A. Pallen, Catherine J. Dunn, Sandra E. TI YB-1 Bridges Neural Stem Cells and Brain Tumor-Initiating Cells via Its Roles in Differentiation and Cell Growth SO CANCER RESEARCH LA English DT Article ID STAGE EMBRYONIC-DEVELOPMENT; BOX-BINDING PROTEIN; PROGENITOR CELLS; HUMAN GLIOBLASTOMA; DRUG-RESISTANCE; EXPRESSION; CANCER; ZONE; TEMOZOLOMIDE; PRECURSORS AB The Y-box binding protein 1 (YB-1) is upregulated in many human malignancies including glioblastoma (GBM). It is also essential for normal brain development, suggesting that YB-1 is part of a neural stem cell (NSC) network. Here, we show that YB-1 was highly expressed in the subventricular zone (SVZ) of mouse fetal brain tissues but not in terminally differentiated primary astrocytes. Conversely, YB-1 knockout mice had reduced Sox-2, nestin, and musashi-1 expression in the SVZ. Although primary murine neurospheres were rich in YB-1, its expression was lost during glial differentiation. Glial tumors often express NSC markers and tend to loose the cellular control that governs differentiation; therefore, we addressed whether YB-1 served a similar role in cancer cells. YB-1, Sox-2, musashi-1, Bmi-1, and nestin are coordinately expressed in SF188 cells and 9/9 GBM patient-derived primary brain tumor-initiating cells (BTIC). Silencing YB-1 with siRNA attenuated the expression of these NSC markers, reduced neurosphere growth, and triggered differentiation via coordinate loss of GSK3-beta. Furthermore, differentiation of BTIC with 1% serum or bone morphogenetic protein-4 suppressed YB-1 protein expression. Likewise, YB-1 expression was lost during differentiation of normal human NSCs. Consistent with these observations, YB-1 expression increased with tumor grade (n = 49 cases). YB-1 was also coexpressed with Bmi-1 (Spearmans 0.80, P > 0.001) and Sox-2 (Spearmans 0.66, P > 0.001) based on the analysis of 282 cases of high-grade gliomas. These proteins were highly expressed in 10/15 (67%) of GBM patients that subsequently relapsed. In conclusion, YB-1 correlatively expresses with NSC markers where it functions to promote cell growth and inhibit differentiation. Cancer Res; 71(16); 5569-78. (c) 2011 AACR. C1 [Fotovati, Abbas; Abu-Ali, Samah; Wang, Pei-Shan; Lee, Cathy; Triscott, Joanna; Chen, James Y.; Franciosi, Sonia; Leavitt, Blair R.; Pallen, Catherine J.; Dunn, Sandra E.] Univ British Columbia, Vancouver, BC V5Z 4H4, Canada. [Deleyrolle, Loic P.; Reynolds, Brent A.] Univ Florida, Gainesville, FL USA. [Nakamura, Yasuhiro] St Marys Hosp, Kurume, Fukuoka, Japan. [Sugita, Yasuo] Kurume Univ, Kurume, Fukuoka 830, Japan. [Uchiumi, Takeshi; Kuwano, Michihiko] Kyushu Univ, Fukuoka 812, Japan. [Singh, Sheila K.] McMaster Univ, Hamilton, ON, Canada. [Jury, Alexa; Jones, Chris] Royal Marsden Hosp, Inst Canc Res, Surrey, England. [Wakimoto, Hiroaki] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dunn, SE (reprint author), Univ British Columbia, Vancouver, BC V5Z 4H4, Canada. EM fotovati@hotmail.com; sedunn@mail.ubc.ca RI Leavitt, Blair/G-1934-2012; OI Pallen, Catherine/0000-0002-3576-5295 FU Canadian Institutes of Health Research (CIHR); Michael Cuccione Foundation; JoyUp Biomedical Co. LtD (Tokyo, Japan); CIHR [MOP-62759]; BC Brain Care; Michael Smith Foundation for Health Research; Hannah's Heroes Foundation; Multiple Sclerosis Society of Canada; NHS FX Funding was provided by the Canadian Institutes of Health Research (CIHR), and the Michael Cuccione Foundation (S.E. Dunn), a JU-2 research grant from JoyUp Biomedical Co. LtD (Tokyo, Japan; S. Abu-Ali), CIHR (MOP-62759, C.J. Pallen), and BC Brain Care (S.E. Dunn and A. Fotovati). Michael Smith Foundation for Health Research provided a scholarship to C. Lee. Hannah's Heroes Foundation provided support to S.E. Dunn and C. Lee. P.S. Wang was supported by the Multiple Sclerosis Society of Canada. C. Jones and A. Jury acknowledge NHS funding to the NIHR Biomedical Research Centre. NR 45 TC 39 Z9 42 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2011 VL 71 IS 16 BP 5569 EP 5578 DI 10.1158/0008-5472.CAN-10-2805 PG 10 WC Oncology SC Oncology GA 806SN UT WOS:000293831500022 PM 21730024 ER PT J AU May, KF Gulley, JL Drake, CG Dranoff, G Kantoff, PW AF May, Kenneth F., Jr. Gulley, James L. Drake, Charles G. Dranoff, Glenn Kantoff, Philip W. TI Prostate Cancer Immunotherapy SO CLINICAL CANCER RESEARCH LA English DT Article ID CD8(+) T-CELLS; CTLA-4 BLOCKADE; COMBINATION IMMUNOTHERAPY; ANDROGEN-DEPRIVATION; ANTITUMOR IMMUNITY; TUMOR; PD-1; EFFECTOR; THERAPY; MICE AB The interaction between the immune system and prostate cancer has been an area of research interest for several decades. The recent U. S. Food and Drug Administration approval of 2 first-in-class proof-of-concept immunotherapies (sipuleucel-T and ipilimumab) has stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies that have garnered the most interest are the therapeutic vaccination strategies, exemplified by sipuleucel-T and PROSTVAC-VF, and immune checkpoint blockade of CTLA-4 and PD-1. Improved understanding of the immune responses generated by these strategies and development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide building blocks for future immunotherapies. Clin Cancer Res; 17(16); 5233-8. (C)2011 AACR. C1 [May, Kenneth F., Jr.; Dranoff, Glenn; Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [May, Kenneth F., Jr.; Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02215 USA. [May, Kenneth F., Jr.; Dranoff, Glenn; Kantoff, Philip W.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [May, Kenneth F., Jr.; Dranoff, Glenn; Kantoff, Philip W.] Harvard Univ, Sch Med, Boston, MA USA. [Gulley, James L.] NCI, Clin Trials Grp, Tumor Immunol & Biol Lab, Med Oncol Branch,Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Drake, Charles G.] Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Dept Urol,Dept Oncol, Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP May, KF (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Smith 353, Boston, MA 02215 USA. EM kmay1@partners.org RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Prostate Cancer Foundation; NIH, National Cancer Institute; Center for Cancer Research; NIH [R01 CA127153, 1P50CA58236-15, CA143083, CA78378, 5P01CA089021-10, 5P50CA090381-09]; Patrick C. Walsh Fund; OneInSix Foundation; Leukemia & Lymphoma Society; Melanoma Research Alliance; Alliance for Cancer Gene Therapy; Research Foundation for the Treatment of Ovarian Cancer; Department of Defense FX Prostate Cancer Foundation Young Investigator Award (K. F. May); Intramural Research Program of the NIH, National Cancer Institute, and Center for Cancer Research (J.L. Gulley); NIH R01 CA127153 and 1P50CA58236-15, the Patrick C. Walsh Fund, the OneInSix Foundation, and the Prostate Cancer Foundation (C. G. Drake); NIH CA143083 and CA78378, Leukemia & Lymphoma Society, Melanoma Research Alliance, Alliance for Cancer Gene Therapy, and Research Foundation for the Treatment of Ovarian Cancer (G. Dranoff); NIH 5P01CA089021-10 and 5P50CA090381-09, Prostate Cancer Foundation, and Department of Defense (P. W. Kantoff). NR 52 TC 35 Z9 35 U1 2 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2011 VL 17 IS 16 BP 5233 EP 5238 DI 10.1158/1078-0432.CCR-10-3402 PG 6 WC Oncology SC Oncology GA 806VN UT WOS:000293843700004 PM 21700764 ER PT J AU Chauhan, D Tian, Z Zhou, B Kuhn, D Orlowski, R Raje, N Richardson, P Anderson, KC AF Chauhan, Dharminder Tian, Ze Zhou, Bin Kuhn, Deborah Orlowski, Robert Raje, Noopur Richardson, Paul Anderson, Kenneth C. TI In Vitro and In Vivo Selective Antitumor Activity of a Novel Orally Bioavailable Proteasome Inhibitor MLN9708 against Multiple Myeloma Cells SO CLINICAL CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; GENETIC ABNORMALITIES; INDUCED APOPTOSIS; DRUG-RESISTANCE; CANCER CELLS; BORTEZOMIB; THERAPY; GROWTH; P53; COMBINATION AB Purpose: The success of bortezomib therapy for treatment of multiple myeloma (MM) led to the development of structurally and pharmacologically distinct novel proteasome inhibitors. In the present study, we evaluated the efficacy of one such novel orally bioactive proteasome inhibitor MLN9708/MLN2238 in MM using well-established in vitro and in vivo models. Experimental Design: MM cell lines, primary patient cells, and the human MM xenograft animal model were used to study the antitumor activity of MN2238. Results: Treatment of MM cells with MLN2238 predominantly inhibits chymotrypsin-like activity of the proteasome and induces accumulation of ubiquitinated proteins. MLN2238 inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal cells. In animal tumor model studies, MLN2238 is well tolerated and inhibits tumor growth with significantly reduced tumor recurrence. A head-to-head analysis of MLN2238 versus bortezomib showed a significantly longer survival time in mice treated with MLN2238 than mice receiving bortezomib. Immununostaining of MM tumors from MLN2238-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Mechanistic studies showed that MLN2238-triggered apoptosis is associated with activation of caspase-3, caspase-8, and caspase-9; increase in p53, p21, NOXA, PUMA, and E2F; induction of endoplasmic reticulum (ER) stress response proteins Bip, phospho-eIF2-alpha, and CHOP; and inhibition of nuclear factor kappa B. Finally, combining MLN2238 with lenalidomide, histone deacetylase inhibitor suberoylanilide hydroxamic acid, or dexamethasone triggers synergistic anti-MM activity. Conclusion: Our preclinical study supports clinical evaluation of MLN9708, alone or in combination, as a potential MM therapy. Clin Cancer Res; 17(16); 5311-21. (C)2011 AACR. C1 [Chauhan, Dharminder; Tian, Ze; Raje, Noopur; Richardson, Paul; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Chauhan, Dharminder; Tian, Ze; Raje, Noopur; Richardson, Paul; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Myeloma Ctr,Dept Med Oncol, Boston, MA 02115 USA. [Zhou, Bin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai, Peoples R China. [Zhou, Bin] Childrens Hosp, Boston, MA 02115 USA. [Kuhn, Deborah; Orlowski, Robert] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA. RP Anderson, KC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, M561,450 Brookline Ave, Boston, MA 02115 USA. EM Dharminder_Chauhan@dfci.harvard.edu; Kenneth_Anderson@dfci.harvard.edu FU NIH [SPORE-P50100707, PO1-CA078378, RO1CA050947] FX This investigation was supported by NIH grants SPORE-P50100707, PO1-CA078378, and RO1CA050947 (to D. Chauhan, P. Richardson, and K. C. Anderson, respectively). K. C. Anderson is an American Cancer Society clinical research professor. NR 54 TC 124 Z9 128 U1 1 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2011 VL 17 IS 16 BP 5311 EP 5321 DI 10.1158/1078-0432.CCR-11-0476 PG 11 WC Oncology SC Oncology GA 806VN UT WOS:000293843700012 PM 21724551 ER PT J AU Tanaka, M Butler, MO Ansen, S Imataki, O Berezovskaya, A Nadler, LM Hirano, N AF Tanaka, Makito Butler, Marcus O. Ansen, Sascha Imataki, Osamu Berezovskaya, Alla Nadler, Lee M. Hirano, Naoto TI Induction of HLA-DP4-Restricted Anti-Survivin Th1 and Th2 Responses Using an Artificial Antigen-Presenting Cell SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-ASSOCIATED ANTIGEN; CD8(+) T-CELLS; SPLICE VARIANTS; CANCER-PATIENTS; DIFFERENTIAL EXPRESSION; IMMUNE-RESPONSES; BREAST-CANCER; II MOLECULE; CD4(+); PEPTIDE AB Purpose: In previous cancer vaccine clinical trials targeting survivin, induction of specific CD8(+) T-cell responses did not consistently lead to clinical responses. Considering the critical role of CD4(+) T-cell help in generating antitumor immunity, integration of anti-survivin CD4(+) T-cell responses may enhance the efficacy of anti-survivin cancer immunotherapy. Human leukocyte antigen (HLA)-DP4 is emerging as an attractive MHC target allele of CD4(+) T cell-mediated immunotherapy, because it is one of the most frequent HLA alleles in many ethnic groups. In this article, we aimed to elucidate DP4-restricted CD4(+) T-cell responses against survivin in cancer patients. Experimental Design: We generated a human cell-based artificial antigen-presenting cell (aAPC) expressing HLA-DP4, CD80, and CD83 and induced DP4-restricted antigen-specific CD4(+) T cells. The number, phenotype, effector function, and in vitro longevity of generated CD4(+) T cells were determined. Results: We first determined previously unknown DP4-restricted CD4(+) T-cell epitopes derived from cytomegalovirus pp65, to which sustained Th1-biased recall responses were induced in vitro by using DP4-aAPC. In contrast, DP4-aAPC induced in vitro both Th1 and Th2 long-lived anti-survivin CD4(+) T cells from cancer patients. Both survivin-specific Th1 and Th2 cells were able to recognize survivin-expressing tumors in a DP4-restricted manner. Neither survivin-specific interleukin 10 secreting Tr1 cells nor Th17 cells were induced by DP4-aAPC. Conclusions: DP4-restricted anti-survivin Th1 and Th2 immunity with sufficient functional avidity can be induced from cancer patients. The development of strategies to concurrently induce both CD4(+) and CD8(+) T-cell responses against survivin is warranted for optimal anti-survivin cancer immunotherapy. Clin Cancer Res; 17(16); 5392-401. (C)2011 AACR. C1 [Hirano, Naoto] Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada. [Hirano, Naoto] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [Tanaka, Makito; Butler, Marcus O.; Ansen, Sascha; Imataki, Osamu; Berezovskaya, Alla; Nadler, Lee M.; Hirano, Naoto] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Tanaka, Makito; Butler, Marcus O.; Ansen, Sascha; Imataki, Osamu; Nadler, Lee M.; Hirano, Naoto] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Tanaka, Makito; Butler, Marcus O.; Ansen, Sascha; Imataki, Osamu; Nadler, Lee M.; Hirano, Naoto] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Hirano, N (reprint author), Princess Margaret Hosp, Ontario Canc Inst, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM nhirano@uhnresearch.ca FU Cancer Research Institute; NIH [K22CA129240, R01CA148673]; American Society of Hematology FX M. Tanaka, M.O. Butler, O. Imataki, and L. M. Nadler were supported with funds from the Cancer Research Institute. N. Hirano was funded by NIH grants, K22CA129240 and R01CA148673, and the American Society of Hematology Scholar Award. NR 50 TC 16 Z9 16 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2011 VL 17 IS 16 BP 5392 EP 5401 DI 10.1158/1078-0432.CCR-10-3083 PG 10 WC Oncology SC Oncology GA 806VN UT WOS:000293843700019 PM 21705450 ER PT J AU Manola, J Royston, P Elson, P McCormack, JB Mazumdar, M Negrier, S Escudier, B Eisen, T Dutcher, J Atkins, M Heng, DYC Choueiri, TK Motzer, R Bukowski, R AF Manola, Judith Royston, Patrick Elson, Paul McCormack, Jennifer Bacik Mazumdar, Madhu Negrier, Sylvie Escudier, Bernard Eisen, Tim Dutcher, Janice Atkins, Michael Heng, Daniel Y. C. Choueiri, Toni K. Motzer, Robert Bukowski, Ronald CA Int Kidney Canc Working Grp TI Prognostic Model for Survival in Patients with Metastatic Renal Cell Carcinoma: Results from the International Kidney Cancer Working Group SO CLINICAL CANCER RESEARCH LA English DT Article ID REGRESSION-MODELS; PROGRESSION; CYTOKINE; THERAPY AB Purpose: To develop a single validated model for survival in metastatic renal cell carcinoma (mRCC) using a comprehensive international database. Experimental Design: A comprehensive database of 3,748 patients including previously reported clinical prognostic factors was established by pooling patient-level data from clinical trials. Following quality control and standardization, descriptive statistics were generated. Univariate analyses were conducted using proportional hazards models. Multivariable analysis using a log-logistic model stratified by center and multivariable fractional polynomials was conducted to identify independent predictors of survival. Missing data were handled using multiple imputation methods. Three risk groups were formed using the 25th and 75th percentiles of the resulting prognostic index. The model was validated using an independent data set of 645 patients treated with tyrosine kinase inhibitor (TKI) therapy. Results: Median survival in the favorable, intermediate and poor risk groups was 26.9 months, 11.5 months, and 4.2 months, respectively. Factors contributing to the prognostic index included treatment, performance status, number of metastatic sites, time from diagnosis to treatment, and pretreatment hemoglobin, white blood count, lactate dehydrogenase, alkaline phosphatase, and serum calcium. The model showed good concordance when tested among patients treated with TKI therapy (C statistic = 0.741, 95% CI: 0.714-0.768). Conclusions: Nine clinical factors can be used to model survival in mRCC and form distinct prognostic groups. The model shows utility among patients treated in the TKI era. Clin Cancer Res; 17(16); 5443-50. (C)2011 AACR. C1 [Manola, Judith] Dana Farber Canc Inst, Eastern Cooperat Oncol Grp, Stat Off, Boston, MA 02215 USA. [Atkins, Michael] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Elson, Paul; Bukowski, Ronald] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [McCormack, Jennifer Bacik] EMMES Corp, Rockville, MD USA. [Dutcher, Janice] St Lukes Roosevelt Hosp, Continuum Canc Ctr, New York, NY 10025 USA. [Motzer, Robert] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Mazumdar, Madhu] Weill Cornell Med Coll, New York, NY USA. [Royston, Patrick] MRC, Clin Trials Unit, London, England. [Royston, Patrick] UCL, London, England. [Eisen, Tim] Cambridge Biomed Res Ctr, Cambridge, England. [Negrier, Sylvie] Univ Lyon, Ctr Leon Berard, Lyon, France. [Escudier, Bernard] Inst Gustave Roussy, Villejuif, France. [Heng, Daniel Y. C.] Tom Baker Canc Clin, Calgary, AB, Canada. RP Manola, J (reprint author), Dana Farber Canc Inst, Eastern Cooperat Oncol Grp, Stat Off, CLSB11003,450 Brookline Ave, Boston, MA 02215 USA. EM jmanola@jimmy.harvard.edu FU Bayer; Pfizer; AZ; Kidney Cancer Association; family of Maita Lyn Gerber FX T. Eisen has other commercial research support from Bayer, Pfizer, and AZ and has honoraria from Bayer, Pfizer, AZ, Roche, Boehringer, Ingleheim, and BMS. The other authors disclosed no potential conflicts of interest.; The authors would like to thank the Kidney Cancer Association for its support, and in particular the family of Maita Lyn Gerber, who provided financial support for the project. We are grateful to Wanling Xie and the contributors of the International mRCC Database Consortium for their contributions related to the external validation database. The advice of Hajime Uno in the use and interpretation of concordance statistics was valuable. Finally, we extend sincere appreciation to the groups who contributed data and to the patients who were treated on the clinical trials. NR 21 TC 65 Z9 70 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2011 VL 17 IS 16 BP 5443 EP 5450 DI 10.1158/1078-0432.CCR-11-0553 PG 8 WC Oncology SC Oncology GA 806VN UT WOS:000293843700024 PM 21828239 ER PT J AU Vaezi, A Wang, XZ Buch, S Gooding, W Wang, L Seethala, RR Weaver, DT D'Andrea, AD Argiris, A Romkes, M Niedernhofer, LJ Grandis, JR AF Vaezi, Alec Wang, XiaoZhe Buch, Shama Gooding, William Wang, Lin Seethala, Raja R. Weaver, David T. D'Andrea, Alan D. Argiris, Athanassios Romkes, Marjorie Niedernhofer, Laura J. Grandis, Jennifer R. TI XPF Expression Correlates with Clinical Outcome in Squamous Cell Carcinoma of the Head and Neck SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 04-08, 2010 CL Chicago, IL SP Amer Soc Clin Oncol ID NUCLEOTIDE EXCISION-REPAIR; ADVANCED LARYNGEAL-CANCER; GROWTH-FACTOR RECEPTOR; LOCALLY ADVANCED HEAD; DNA-REPAIR; INDUCTION CHEMOTHERAPY; LUNG-CANCER; GENE POLYMORPHISMS; ORGAN PRESERVATION; PATHWAY GENES AB Purpose: Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC). Experimental Design: Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms (SNP) in the XPF gene by using a custom array. The primary endpoint was progression-free survival (PFS). Results: XPF expression was higher in tumors from the oral cavity than from the other sites (P < 0.01). High XPF expression correlated with early time to progression both by univariate (HR 1.87, P = 0.03) and multivariate analysis (HR = 1.83, P = 0.05). The one year PFS for high expressers was 47% (95% CI = 31-62) compared with 72% (95% CI = 55-83) for low expressers. In addition, we identified four XPF SNPs that showed marginal association with treatment failure. Conclusions: Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next generation personalized cancer therapy. Clin Cancer Res; 17(16); 5513-22. (C)2011 AACR. C1 [Vaezi, Alec] Univ Pittsburgh, Inst Eye & Ear, Dept Otolaryngol Head & Neck Surg, Sch Med, Pittsburgh, PA 15213 USA. [Niedernhofer, Laura J.] Univ Pittsburgh, Dept Microbiol & Mol Genet, Sch Med, Pittsburgh, PA 15213 USA. [Argiris, Athanassios] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. [Buch, Shama; Romkes, Marjorie] Univ Pittsburgh, Dept Med, Ctr Clin Pharmacol, Pittsburgh, PA 15213 USA. [Wang, Lin; Seethala, Raja R.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Grandis, Jennifer R.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Gooding, William] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Wang, XiaoZhe; Weaver, David T.] On Q Ity Inc, Waltham, MA USA. [D'Andrea, Alan D.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Vaezi, A (reprint author), Univ Pittsburgh, Inst Eye & Ear, Dept Otolaryngol Head & Neck Surg, Sch Med, 200 Lothrop St,Suite 500, Pittsburgh, PA 15213 USA. EM vaeziae@upmc.edu FU NCI NIH HHS [P50 CA097190, T32 CA060397, P50 CA097190-05S6]; NIDCD NIH HHS [T32 DC000066-10, T32 DC000066]; NIEHS NIH HHS [R01 ES016114, R01 ES016114-05] NR 48 TC 24 Z9 26 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2011 VL 17 IS 16 BP 5513 EP 5522 DI 10.1158/1078-0432.CCR-11-0086 PG 10 WC Oncology SC Oncology GA 806VN UT WOS:000293843700031 PM 21737503 ER PT J AU Conkrite, K Sundby, M Mukai, S Thomson, JM Mu, D Hammond, SM MacPherson, D AF Conkrite, Karina Sundby, Maggie Mukai, Shizuo Thomson, J. Michael Mu, David Hammond, Scott M. MacPherson, David TI miR-17 similar to 92 cooperates with RB pathway mutations to promote retinoblastoma SO GENES & DEVELOPMENT LA English DT Article DE retinoblastoma; Rb; retina; microRNA; cancer; miR-17 similar to 92 ID MIR-17-92 CLUSTER; PROGENITOR CELLS; GENE; MOUSE; DIFFERENTIATION; EXPRESSION; MICE; PROLIFERATION; AMPLIFICATION; PROGRESSION AB The miR-17 similar to 92 cluster is a potent microRNA-encoding oncogene. Here, we show that miR-17 similar to 92 synergizes with loss of Rb family members to promote retinoblastoma. We observed miR-17 similar to 92 genomic amplifications in murine retinoblastoma and high expression of miR-17 similar to 92 in human retinoblastoma. While miR-17 similar to 92 was dispensable for mouse retinal development, miR-17 similar to 92 overexpression, together with deletion of Rb and p107, led to rapid emergence of retinoblastoma with frequent metastasis to the brain. miR-17 similar to 92 oncogenic function in retinoblastoma was not mediated by a miR-19/PTEN axis toward apoptosis suppression, as found in lymphoma/leukemia models. Instead, miR-17 similar to 92 increased the proliferative capacity of Rb/p107-deficient retinal cells. We found that deletion of Rb family members led to compensatory up-regulation of the cyclin-dependent kinase inhibitor p21Cip1. miR-17 similar to 92 overexpression counteracted p21Cip1 up-regulation, promoted proliferation, and drove retinoblastoma formation. These results demonstrate that the oncogenic determinants of miR-17 similar to 92 are context-specific and provide new insights into miR-17 similar to 92 function as an RB-collaborating gene in cancer. C1 [Conkrite, Karina; Sundby, Maggie; MacPherson, David] Carnegie Inst, Dept Embryol, Baltimore, MD 21218 USA. [Mukai, Shizuo] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Thomson, J. Michael; Hammond, Scott M.] Univ N Carolina Sch, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA. [Mu, David] Penn State Univ, Coll Med, Dept Pathol, Hershey, PA 17033 USA. [Mu, David] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. RP MacPherson, D (reprint author), Carnegie Inst, Dept Embryol, Baltimore, MD 21218 USA. EM macpherson@ciwemb.edu RI Mu, David/E-8933-2011 OI Mu, David/0000-0002-7762-0182 FU NIH [5R01CA148867]; Pearle Vision Foundation; Knights Templar Eye Foundation FX We are grateful to Klaus Rajewsky, Andrea Ventura, Tyler Jacks, Andreas Trumpp, and Peter Gruss for generously providing mouse strains used in the analysis. We thank Vuk Stambolic for providing Pten-/- fibroblasts. We thank Mike Sepanski for TEM analyses, and Nick Ingolia for help with microRNA deep-sequencing analyses. D. MacPherson designed experiments, executed experiments, and wrote the manuscript. K. C. and M. S. executed experiments. S. M. provided critical human retinoblastoma samples. D. Mu oversaw ROMA analyses and analyzed data. J.M.T. performed microarray experiments, and S. H. oversaw microRNA microarray analyses and analyzed data. All authors critically discussed the results and the manuscript. D. MacPherson was supported by NIH grant 5R01CA148867 from the National Cancer Institute as well as grants from the Pearle Vision Foundation and the Knights Templar Eye Foundation. S. M. was supported by gifts to the Mukai Fund, Massachusetts Eye and Ear Infirmary. NR 43 TC 88 Z9 92 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2011 VL 25 IS 16 BP 1734 EP 1745 DI 10.1101/gad.17027411 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 808UF UT WOS:000294003800008 PM 21816922 ER PT J AU Lyons, JL Uno, H Ancuta, P Kamat, A Moore, DJ Singer, EJ Morgello, S Gabuzda, D AF Lyons, Jennifer L. Uno, Hajime Ancuta, Petronela Kamat, Anupa Moore, David J. Singer, Elyse J. Morgello, Susan Gabuzda, Dana TI Plasma sCD14 Is a Biomarker Associated With Impaired Neurocognitive Test Performance in Attention and Learning Domains in HIV Infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; AIDS; HIV-associated neurocognitive disorders; HCV; biomarkers; drug abuse ID HEPATITIS-C VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; NERVOUS-SYSTEM; MICROBIAL TRANSLOCATION; IMMUNE ACTIVATION; AIDS DEMENTIA; SOLUBLE CD14; DRUG-USERS; HAART ERA; DISEASE AB Objective: Mild forms of HIV-associated neurocognitive disorders (HAND) remain prevalent in the era of combination antiretroviral therapy (cART). Although elevated lipopolysaccharide (LPS) and immune activation are implicated in HAND pathogenesis, relationships of LPS and inflammatory markers to mild forms of HAND or impairment in specific cognitive domains are unknown. To examine these relationships, we compared plasma soluble CD14 (sCD14), CCL2, and LPS levels with neurocognitive test scores in a cART era cohort. Methods: We analyzed plasma from HIV+ subjects (n = 97) with nadir CD4 counts <300 and high frequency of hepatitis C virus coinfection and illicit drug use for relationships between sCD14, CCL2, and LPS levels and neurocognitive test scores. Results: Plasma sCD14 levels were higher in subjects with test scores indicating global impairment (P = 0.007), particularly in attention and learning domains (P = 0.015 and P = 0.03, respectively), regardless of HAND diagnosis. Plasma sCD14 levels correlated inversely with global, attention, and learning T scores (P = 0.036, 0.047, and 0.007, respectively) and yielded higher area under receiver operating characteristic values for predicting impaired scores than single-marker models based on plasma or cerebrospinal fluid viral load or CD4 count (area under receiver operating characteristic values = 0.71, 0.81, and 0.71, respectively) and in 4-marker models based on plasma sCD14 and 3 conventional markers compared with the 3-marker models. Conclusions: Plasma sCD14 is a biomarker associated with impaired neurocognitive testing in attention and learning domains in HIV-infected individuals with advanced disease, suggesting involvement of cortical and limbic pathways by inflammatory processes in the cART era. Plasma sCD14 is a potential biomarker to monitor HAND progression and therapeutic responses. C1 [Lyons, Jennifer L.; Uno, Hajime; Kamat, Anupa; Gabuzda, Dana] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ancuta, Petronela] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada. [Ancuta, Petronela] INSERM, U743, Montreal, PQ, Canada. [Moore, David J.] Univ Calif San Diego, Sch Med, Dept Psychiat, San Diego, CA 92103 USA. [Singer, Elyse J.] Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. [Morgello, Susan] Mt Sinai Sch Med, Dept Pathol, New York, NY USA. [Morgello, Susan] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. RP Gabuzda, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,CLS 1010, Boston, MA 02115 USA. EM dana_gabuzda@dfci.harvard.edu FU National Institutes of Health [DA26322, MH083588, U01MH083501, R24MH59724, U01MH083506, R24MH59745, U01MH083507, R24NS45491, 5U01MH083500, NS38841, U01MH083545, N01MH32002]; Mount Sinai Institute for NeuroAIDS Disparities (MSINAD) [R25MH080663]; Harvard Center for AIDS Research; Dana-Farber Cancer Institute/Harvard Center for Cancer Research; [N01MH22005] FX Supported by National Institutes of Health Grant DA26322 and MH083588 to D. G. and a Mount Sinai Institute for NeuroAIDS Disparities (MSINAD) Scholar Grant (funded through R25MH080663) to J.L.L. Core facilities were supported by the Harvard Center for AIDS Research and Dana-Farber Cancer Institute/Harvard Center for Cancer Research grants. National NeuroAIDS Tissue Consortium (NNTC) sites were supported by National Institutes of Health Grants U01MH083501, R24MH59724, U01MH083506, R24MH59745, U01MH083507, R24NS45491, 5U01MH083500, NS38841, U01MH083545, and N01MH32002. CNS HIV Antiretroviral Therapy Effects Research (CHARTER) was supported by N01MH22005. NR 44 TC 64 Z9 64 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2011 VL 57 IS 5 BP 371 EP 379 DI 10.1097/QAI.0b013e3182237e54 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 800RE UT WOS:000293381300011 PM 21646912 ER PT J AU Kulkarni, H Okulicz, JF Grandits, G Crum-Cianflone, NF Landrum, ML Hale, B Wortmann, G Tramont, E Polis, M Dolan, M Lifson, AR Agan, BK Ahuja, SK Marconi, VC AF Kulkarni, Hemant Okulicz, Jason F. Grandits, Greg Crum-Cianflone, Nancy F. Landrum, Michael L. Hale, Braden Wortmann, Glenn Tramont, Edmund Polis, Michael Dolan, Matthew Lifson, Alan R. Agan, Brian K. Ahuja, Sunil K. Marconi, Vincent C. TI Early Postseroconversion CD4 Cell Counts Independently Predict CD4 Cell Count Recovery in HIV-1-Postive Subjects Receiving Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE CD4 count; highly active antiretroviral therapy; outcomes; predictors; treatment response ID PLASMA HIV RNA; VIROLOGICAL RESPONSES; HIV-1-INFECTED PATIENTS; IMMUNOLOGICAL RESPONSE; DISEASE PROGRESSION; PROTEASE INHIBITOR; INFECTED PATIENTS; IMMUNODEFICIENCY; SUPPRESSION; INTERRUPTION AB Background: The relationship between CD4(+) T-cell counts determined soon after seroconversion with HIV-1 (baseline CD4), nadir CD4, and CD4 levels attained during highly active antiretroviral therapy (HAART) is unknown. Methods: Longitudinal, including baseline (at or soon after HIV diagnosis), intermediate (nadir), and distal (post-HAART) CD4(+) T-cell counts were assessed in 1085 seroconverting subjects who achieved viral load suppression from a large well-characterized cohort. The association of baseline with post-HAART CD4(+) T-cell count was determined after adjustment for other relevant covariates. Results: A higher baseline CD4(+) T-cell count predicted a greater postHAART CD4(+) T-cell count, independent of the nadir and other explanatory variables. Together, baseline and nadir strongly predicted the post-HAART CD4(+) count such that a high baseline and lower nadir were associated with a maximal immune recovery after HAART. Likelihood of recovery of the baseline count after HAART was significantly higher when the nadir/ baseline count ratio was consistently >= 0.6. Conclusions: Among viral load suppressing seroconverters, the absolute CD4(+) T-cell count attained post-HAART is highly dependent on both baseline and nadir CD4(+) T-cell counts. These associations further support the early diagnosis and initiation of HAART among HIV-infected persons. C1 [Kulkarni, Hemant; Ahuja, Sunil K.] S Texas Vet Hlth Care Syst, Vet Adm Res Ctr AIDS & HIV Infect 1, San Antonio, TX USA. [Kulkarni, Hemant; Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Okulicz, Jason F.; Grandits, Greg; Crum-Cianflone, Nancy F.; Landrum, Michael L.; Hale, Braden; Wortmann, Glenn; Tramont, Edmund; Polis, Michael; Agan, Brian K.; Marconi, Vincent C.] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Okulicz, Jason F.; Landrum, Michael L.] Brooke Army Med Ctr, San Antonio Mil Med Ctr, Infect Dis Serv, Ft Sam Houston, TX 78234 USA. [Grandits, Greg] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Crum-Cianflone, Nancy F.; Hale, Braden] USN, Infect Dis Clin, San Diego Med Ctr, San Diego, CA 92152 USA. [Wortmann, Glenn] Walter Reed Army Med Ctr, Infect Dis Serv, Washington, DC 20307 USA. [Tramont, Edmund; Polis, Michael] NIAID, NIH, Bethesda, MD 20892 USA. [Dolan, Matthew] Wilford Hall USAF Med Ctr, Henry M Jackson Fdn, Lackland AFB, TX 78236 USA. [Lifson, Alan R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol & Biochem, San Antonio, TX 78229 USA. [Marconi, Vincent C.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. RP Kulkarni, H (reprint author), 12023 Waterway Rdg, San Antonio, TX USA. EM kulkarnih@uthscsa.edu RI Marconi, Vincent/N-3210-2014; OI Marconi, Vincent/0000-0001-8409-4689; Polis, Michael/0000-0002-9151-2268; Agan, Brian/0000-0002-5114-1669 FU Infectious Disease Clinical Research Program (IDCRP) [IDCRP-000-03]; Department of Defense; National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) [Y1-AI-5072]; Veterans Administration Center on AIDS and HIV infection of the South Texas Veterans Health Care System; NIH [R37046326]; VA MERIT award; Elizabeth Glaser Scientist Award; Burroughs Wellcome Clinical Scientist Award in Translational Research; Doris Duke Distinguished Clinical Scientist Award FX Support for this work (IDCRP-000-03) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072. This work was also supported by the Veterans Administration Center on AIDS and HIV infection of the South Texas Veterans Health Care System, and a MERIT (R37046326) award from the NIH to S. K. A. S. K. A. is also supported by a VA MERIT award and is a recipient of the Elizabeth Glaser Scientist Award, the Burroughs Wellcome Clinical Scientist Award in Translational Research, and the Doris Duke Distinguished Clinical Scientist Award. The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the NIH or the Department of Health and Human Services, the Department of Defense or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government. NR 45 TC 9 Z9 9 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2011 VL 57 IS 5 BP 387 EP 395 DI 10.1097/QAI.0b013e3182219113 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 800RE UT WOS:000293381300013 PM 21546844 ER PT J AU Tucker, JD Yang, LG Yang, B Zheng, HP Chang, H Wang, C Shen, SY Zhu, ZJ Yin, YP Subramanian, SV Chen, XS Cohen, MS AF Tucker, Joseph D. Yang, Li-Gang Yang, Bin Zheng, He-Ping Chang, Helena Wang, Cheng Shen, Song-Ying Zhu, Zheng-Jun Yin, Yue-Pin Subramanian, S. V. Chen, Xiang-Sheng Cohen, Myron S. TI A Twin Response to Twin Epidemics: Integrated HIV/Syphilis Testing at STI Clinics in South China SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE China; HIV; multilevel modeling; syphilis; STI clinic; testing ID MULTILEVEL ANALYSIS; GUANGDONG PROVINCE; PREGNANT-WOMEN; HIV; SYPHILIS; HEALTH; INFECTION; ACCEPTANCE; SHENZHEN AB Background: HIV testing is still stigmatized among many high-risk groups in China, whereas routine syphilis testing has been widely accepted at sexually transmitted infection (STI) clinics. This project used the platform of a rapid syphilis screening test to expand HIV test uptake. The objective of this study was to use multilevel modeling to analyze determinants of syphilis and HIV-testing uptake at STI clinics in China. Methods: 2061 STI patients at 6 clinics in Guangdong Province were offered free rapid syphilis and free rapid HIV testing. Test uptake was defined by patient receipt of results and a multilevel model was used to analyze predictors of uptake. Results: This was the first syphilis or HIV test for the large majority (1388, 77.7%) of participants. Syphilis test uptake and HIV test uptake were high (1681, 81.6%, syphilis test uptake; 1673, 81.2% HIV test uptake). HIV test uptake was significantly concordant with syphilis test uptake (tau b = 0.89, P < 0.001). The most parsimonious model of refusing HIV test uptake included the following variables: being married, having a previous HIV test, being unaccompanied, and participating in the last 2 months of the study. Conclusions: STI clinic-based screening for syphilis and HIV represents an excellent opportunity for scaling up integrated services, especially in South China where syphilis and sexually transmitted HIV cases are both rapidly increasing. Effective integration of HIV testing into routine clinical practice requires an understanding not only of individual test uptake but also of the broader social context of HIV testing. C1 [Tucker, Joseph D.; Yang, Li-Gang; Yang, Bin; Zheng, He-Ping; Wang, Cheng; Shen, Song-Ying] Guangdong Prov Ctr Skin Dis & STD Control, STD Control Dept, Guangzhou 510500, Guangdong, Peoples R China. [Tucker, Joseph D.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Tucker, Joseph D.; Chang, Helena; Cohen, Myron S.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Zhu, Zheng-Jun] Jiangmen Municipal Skin Hosp, Jiangmen, Peoples R China. [Yin, Yue-Pin; Chen, Xiang-Sheng] Chinese Acad Med Sci, Natl Ctr STD Control, Nanjing, Peoples R China. [Yin, Yue-Pin; Chen, Xiang-Sheng] Peking Union Med Coll, Inst Dermatol, Nanjing, Peoples R China. [Subramanian, S. V.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP Tucker, JD (reprint author), Guangdong Prov Ctr Skin Dis & STD Control, STD Control Dept, 10 Xianlie Dong Heng Rd, Guangzhou 510500, Guangdong, Peoples R China. EM jtucker4@partners.org FU NIH (US NIH) [1K01TW008200-01A1]; UNC Fogarty AIDS (NIH FIC) [D43 TW01039]; UNC Social Science Research on HIV/AIDS in China (NIH NICHD) [R24 HD056670-01]; UNC Center for AIDS Research; China-Australia Health and HIV/AIDS [HIV 04]; UNICEF/ UNDP/World Bank/WHO [A70577]; Harvard Institute for Global Health; Burroughs Wellcome Fund/American Society of Tropical Medicine; Hygiene Wellcome Postdoctoral Fellowship FX Supported by NIH Fogarty K01 Award (US NIH 1K01TW008200-01A1; JT), the UNC Fogarty AIDS International Research and Training Program (NIH FIC D43 TW01039), the UNC Social Science Research on HIV/AIDS in China (NIH NICHD R24 HD056670-01), the UNC Center for AIDS Research, the China-Australia Health and HIV/AIDS Facility Project (HIV 04), the WHO Rapid Syphilis Test Project (UNICEF/ UNDP/World Bank/WHO A70577), the Harvard Institute for Global Health, and Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene Wellcome Postdoctoral Fellowship in Tropical Infectious Diseases. NR 41 TC 12 Z9 12 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2011 VL 57 IS 5 BP E106 EP E111 DI 10.1097/QAI.0b013e31821d3694 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 800RE UT WOS:000293381300003 PM 21522016 ER PT J AU Baggish, AL Hale, A Weiner, RB Lewis, GD Systrom, D Wang, F Wang, TJ Chan, SY AF Baggish, Aaron L. Hale, Andrew Weiner, Rory B. Lewis, Gregory D. Systrom, David Wang, Francis Wang, Thomas J. Chan, Stephen Y. TI Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID HUMAN SKELETAL-MUSCLE; GENE-EXPRESSION; RESISTANCE EXERCISE; ENDURANCE EXERCISE; DISEASE; CANCER; INFLAMMATION; ANGIOGENESIS; PROTEINS; INJURY AB MicroRNAs (miRNAs) are intracellular mediators of essential biological functions. Recently, plasma-based 'circulating' miRNAs (c-miRNAs) have been shown to control cellular processes, but the c-miRNA response to human exercise remains unknown. We sought to determine whether c-miRNAs are dynamically regulated in response to acute exhaustive cycling exercise and sustained rowing exercise training using a longitudinal, repeated measures study design. Specifically, c-miRNAs involved in angiogenesis (miR-20a, miR-210, miR-221, miR-222, miR-328), inflammation (miR-21, miR-146a), skeletal and cardiac muscle contractility (miR-21, miR-133a), and hypoxia/ischaemia adaptation (miR-21, miR-146a, and miR-210) were measured at rest and immediately following acute exhaustive cycling exercise in competitive male rowers (n = 10, age = 19.1 +/- 0.6 years) before and after a 90 day period of rowing training. Distinct patterns of c-miRNA response to exercise were observed and adhered to four major profiles: (1) c-miRNA up-regulated by acute exercise before and after sustained training (miR-146a and miR-222), (2) c-miRNA responsive to acute exercise before but not after sustained training (miR-21 and miR-221), (3) c-miRNA responsive only to sustained training (miR-20a), and (4) non-responsive c-miRNA (miR-133a, miR-210, miR-328). Linear correlations were observed between peak exercise levels of miR-146a and ((V) over dot(O2max)) (r = 0.63, P = 0.003) and between changes in resting miR-20a and changes in ((V) over dot(O2max)) (pre-training vs. post-training, r = 0.73; P = 0.02). Although future work is required, these results suggest the potential value of c-miRNAs as exercise biomarkers and their possible roles as physiological mediators of exercise-induced cardiovascular adaptation. C1 [Baggish, Aaron L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Performance Program,Div Cardiol,Dept M, Boston, MA 02114 USA. [Hale, Andrew; Chan, Stephen Y.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA 02114 USA. [Wang, Francis] Harvard Univ Hlth Serv, Cambridge, MA USA. RP Baggish, AL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Performance Program,Div Cardiol,Dept M, Yawkey Suite 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org OI Systrom, David/0000-0002-9610-6330 FU American Society of Echocardiography; American Heart Association [09FTF2220328, 0825906D]; NIH [K08]; Pulmonary Hypertension Association FX We thank J. Loscalzo (fruitful discussions); S. K. Chan (critical reading of the manuscript); and S. Tribuna (administrative assistance). This work was supported by the American Society of Echocardiography and the American Heart Association grant 09FTF2220328 (A. L. B) and by the American Heart Association (grant 0825906D), NIH (K08), and the Pulmonary Hypertension Association (S. Y. C.). The authors have no conflicts of interest to report. NR 54 TC 112 Z9 117 U1 0 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 15 PY 2011 VL 589 IS 16 BP 3983 EP 3994 DI 10.1113/jphysiol.2011.213363 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 807OP UT WOS:000293909600010 PM 21690193 ER PT J AU Brauns, S Gollub, RL Roffman, JL Yendild, A Ho, BC Wassink, TH Heinz, A Ehrlich, S AF Brauns, Stefan Gollub, Randy L. Roffman, Joshua L. Yendild, Anastasia Ho, Beng-Choon Wassink, Thomas H. Heinz, Andreas Ehrlich, Stefan TI DISC1 is associated with cortical thickness and neural efficiency SO NEUROIMAGE LA English DT Article DE Cortical thickness; Single nucleotide polymorphism; DISC1; Functional MRI; Working memory; Schizophrenia ID DORSOLATERAL PREFRONTAL CORTEX; WORKING-MEMORY PERFORMANCE; 1ST EPISODE SCHIZOPHRENIA; SURFACE-BASED ANALYSIS; GRAY-MATTER; CEREBRAL-CORTEX; BRAIN STRUCTURE; 1ST-DEGREE RELATIVES; ONSET SCHIZOPHRENIA; BIPOLAR DISORDER AB Background: Disrupted in schizophrenia 1 (DISC1) is known to play a major role during brain development and is a candidate gene for schizophrenia. Cortical thickness is highly heritable and several MRI studies have shown widespread reductions of cortical thickness in patients with schizophrenia. Here, we investigated the effects of variation in DISC] on cortical thickness. In a subsequent analysis we tested whether the identified DISCI risk variant is also associated with neural activity during working memory functioning. Methods: We acquired structural MRI (sMRI), functional MRI (fMRI) and genotype data from 96 healthy volunteers. Separate cortical statistical maps for five single nucleotide polymorphisms (SNP) of DISCI were generated to detect differences of cortical thickness in genotype groups across the entire cortical surface. Working-memory related load-dependent activation was measured during the Sternberg Item Recognition Paradigm and analyzed using a region-of-interest approach. Results: Phe allele carriers of the DISC] SNP Leu607Phe had significantly reduced cortical thickness in the left supramarginal gyrus compared to Leu/Leu homozygotes. Neural activity in the left dorsolateral prefrontal cortex (DLPFC) during working memory task was increased in Phe allele carriers, whereas working memory performance did not differ between genotype groups. Conclusions: This study provides convergent evidence for the effect of DISCI risk variants on two independent brain-based intermediate phenotypes of schizophrenia. The same risk variant was associated with cortical thickness reductions and signs of neural inefficiency during a working memory task. Our findings provide further evidence for a neurodevelopmental model of schizophrenia. (C) 2011 Elsevier Inc. All rights reserved. C1 [Brauns, Stefan; Gollub, Randy L.; Roffman, Joshua L.; Yendild, Anastasia; Ehrlich, Stefan] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Gollub, Randy L.; Roffman, Joshua L.; Ehrlich, Stefan] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Brauns, Stefan; Heinz, Andreas] Univ Med Berlin, Charite, Dept Psychiat, Berlin, Germany. [Ho, Beng-Choon; Wassink, Thomas H.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Ehrlich, Stefan] Tech Univ Dresden, Univ Hosp CG Carus, Dept Child & Adolescent Psychiat, Dresden, Germany. RP Ehrlich, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Psychiat Neuroimaging Res Program, Athinoula A Martinos Ctr Biomed Imaging, CNY Bldg 120,Suite 100, Charlestown, MA 02129 USA. EM stefan@nmr.mgh.harvard.edu RI Ho, Beng-Choon/D-6959-2011; OI Ho, Beng-Choon/0000-0003-3976-1555; Ehrlich, Stefan/0000-0003-2132-4445; Gollub, Randy L./0000-0002-9434-4044 FU NIH [MH068380]; NARSAD; Ortho-McNeil Janssen Scientific Affairs; BMS; Lilly; Janssen-Cilag; Astra-Zeneca; Servier; NIH/NCRR [P41RR14075]; Department of Energy [DE-FG02-99ER62764]; MIND Research Network; NIH; NCRR [MO1 RR025758-01]; Deutsche Forschungsgemeinschaft; Biomedical Science Exchange Program FX In the last two years, Dr. Ho has received grant support from NIH (MH068380), NARSAD and Ortho-McNeil Janssen Scientific Affairs. Dr. Heinz received unrestricted grants and speaker honoraria from BMS, Lilly, Janssen-Cilag, Astra-Zeneca and Servier. All other authors declare that there are no conflicts of interest in relation to the subject of this study.; This work was supported by NIH/NCRRP41RR14075, Department of Energy DE-FG02-99ER62764, MIND Research Network, Morphometry BIRN1U24, RR021382A, Function BIRNU24RR021992-01, NIH. NCRR MO1 RR025758-01, the Deutsche Forschungsgemeinschaft (Research Fellowship to S Ehrlich) and the Biomedical Science Exchange Program (Scholarship to S Brauns). NR 111 TC 29 Z9 31 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2011 VL 57 IS 4 BP 1591 EP 1600 DI 10.1016/j.neuroimage.2011.05.058 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 796LZ UT WOS:000293054100032 PM 21642004 ER PT J AU Wu, W Chen, Z Gao, SK Brown, EN AF Wu, Wei Chen, Zhe Gao, Shangkai Brown, Emery N. TI hierarchical bayesian approach for learning sparse spatio-temporal decomposition of multichannel EEG (vol 56, pg 1929, 2011) SO NEUROIMAGE LA English DT Correction C1 [Wu, Wei; Chen, Zhe; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Wu, Wei; Gao, Shangkai] Tsinghua Univ, Dept Biomed Engn, Beijing 100084, Peoples R China. [Wu, Wei; Chen, Zhe; Brown, Emery N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Stat Res Lab,Dept Anesthesia Crit Care &, Boston, MA 02114 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Wu, W (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM weiwu@neurostat.mit.edu NR 1 TC 1 Z9 1 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2011 VL 57 IS 4 BP 1631 EP 1631 DI 10.1016/j.neuroimage.2011.05.042 PG 1 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 796LZ UT WOS:000293054100038 ER PT J AU Gather, MC Yun, SH AF Gather, Malte C. Yun, Seok Hyun TI Lasing from Escherichia coli bacteria genetically programmed to express green fluorescent protein SO OPTICS LETTERS LA English DT Article ID LASER ACTION; TISSUES AB We report on lasing action from colonies of Escherichia coli bacteria that are genetically programmed to synthesize the green fluorescent protein (GFP). When embedded in a Fabry-Perot type cavity and excited by ns-pulses of blue light (465 nm), the bacteria generate green laser emission (similar to 520 nm). Broad illumination of pump light yields simultaneous lasing over a large area in bacterial colonies. (C) 2011 Optical Society of America C1 [Yun, Seok Hyun] Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Yun, SH (reprint author), Harvard Univ, Sch Med, 50 Blossom St,BAR-8, Boston, MA 02114 USA. EM syun@hms.harvard.edu OI Gather, Malte/0000-0002-4857-5562 FU National Science Foundation (NSF) [ECCS-1101947]; Bullock-Wellman Fellowship FX We thank K. Leosson and J. Halldorsson (University of Iceland) for support with SEM. This work was supported in part by the National Science Foundation (NSF) (ECCS-1101947). M. C. G. acknowledges financial support from the Bullock-Wellman Fellowship. NR 12 TC 34 Z9 34 U1 1 U2 26 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD AUG 15 PY 2011 VL 36 IS 16 BP 3299 EP 3301 PG 3 WC Optics SC Optics GA 807IT UT WOS:000293890800096 PM 21847240 ER PT J AU Zhang, XH Smith-Warner, SA Chan, AT Wu, K Spiegelman, D Fuchs, CS Willett, WC Giovannucci, EL AF Zhang, Xuehong Smith-Warner, Stephanie A. Chan, Andrew T. Wu, Kana Spiegelman, Donna Fuchs, Charles S. Willett, Walter C. Giovannucci, Edward L. TI Aspirin Use, Body Mass Index, Physical Activity, Plasma C-Peptide, and Colon Cancer Risk in US Health Professionals SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE additive model; aspirin; body mass index; cohort studies; colonic neoplasms; C-peptide; motor activity; multiplicative model ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLORECTAL-CANCER; ACTIVITY QUESTIONNAIRE; UNITED-STATES; WOMEN; ALCOHOL; MEN; PREVENTION; REPRODUCIBILITY; VALIDITY AB Aspirin use decreases colon cancer risk, but this association may vary among population subgroups. The aspirin-colon cancer association was evaluated according to body mass index and physical activity in 1,701 incident colon cancer cases diagnosed during follow-up of 139,310 participants for up to 26 years in 2 US prospective cohort studies that began in 1980 and 1992, respectively. Whether plasma C-peptide levels modified the association was examined by using a nested case-control design (n = 384 cases, 749 controls). Multiplicative and additive interactions were tested. Body mass index did not modify the association; pooled multivariable relative risks for regular aspirin use versus nonuse ranged from 0.74 to 0.75 in the normal weight and obese groups (test for multiplicative interaction, P = 0.75; test for additive interaction, P = 0.66). Pooled multivariable relative risks for regular aspirin use were 0.86 (95% confidence interval (CI): 0.66, 1.11) in the low and 0.67 (95% CI: 0.58, 0.77) in the high physical activity groups with no interaction evident on either the multiplicative or additive scale (P > 0.10). Plasma C-peptide levels also did not modify the aspirin-colon cancer association, with multivariable relative risks of 0.74 (95% CI: 0.50, 1.10) for the low and 0.65 (95% CI: 0.46, 0.92) for the high group. Reductions in colon cancer risk associated with aspirin use were not significantly modified by body mass index, physical activity, or plasma C-peptide level in this study. C1 [Zhang, Xuehong; Smith-Warner, Stephanie A.; Wu, Kana; Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Zhang, Xuehong; Smith-Warner, Stephanie A.; Spiegelman, Donna; Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Zhang, Xuehong; Chan, Andrew T.; Wu, Kana; Fuchs, Charles S.; Willett, Walter C.; Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Zhang, Xuehong; Chan, Andrew T.; Wu, Kana; Fuchs, Charles S.; Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Zhang, XH (reprint author), Channing Lab Landmark Ctr, West Wing,401 Pk Dr, Boston, MA 02115 USA. EM xuehong.zhang@channing.harvard.edu RI Zhang, Xuehong/E-6219-2012 FU National Institutes of Health [CA137178, CA55075] FX The research for this article was funded by grants CA137178 and CA55075 from the National Institutes of Health. NR 55 TC 13 Z9 13 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2011 VL 174 IS 4 BP 459 EP 467 DI 10.1093/aje/kwr115 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 803QH UT WOS:000293595300010 PM 21673123 ER PT J AU Shinagare, AB Guo, MY Hatabu, H Krajewski, KM Andriole, K Van den Abbeele, AD DiPiro, PJ Nishino, M AF Shinagare, Atul B. Guo, Mengye Hatabu, Hiroto Krajewski, Katherine M. Andriole, Katherine Van den Abbeele, Annick D. DiPiro, Pamela J. Nishino, Mizuki TI Incidence of Pulmonary Embolism in Oncologic Outpatients at a Tertiary Cancer Center SO CANCER LA English DT Article DE cancer; pulmonary embolism; oncology; outpatient; anticoagulation ID ROW SPIRAL CT; VENOUS THROMBOEMBOLISM; BREAST-CANCER; RISK-FACTORS; LUNG-CANCER; HELICAL CT; THROMBOSIS; PREVALENCE; SURVIVAL; IMPACT AB Incidence of pulmonary embolism (PE) for different cancer types in oncology outpatients is unknown. The purposes of the current study is to determine the incidence of PE in oncology outpatients and to investigate whether the incidence for PE is higher in certain cancers. METHODS: A cohort of oncology outpatients who had imaging studies at Dana-Farber Cancer Institute, a tertiary outpatient cancer institute, from January 2004 through December 2009 was identified using research patient data registry. Radiology reports were reviewed to identify patients who developed PE. Incidences of PE in the total population and in each of 16 predefined cancer groups were calculated. Risk of PE for each cancer was compared using Fisher exact test. RESULTS: A total of 13,783 patients was identified, of which 395 (2.87%; 95% confidence interval [CI] 2.59-3.16) developed PE. The incidence of PE was highest in the central nervous system ([CNS] 12.90%; 95% CI, 8.45-18.59), hepatobiliary (6.85%; 95% CI, 3.33-12.24), pancreatic (5.81%; 95% CI, 3.59-8.84), and upper gastrointestinal (5.81%; 95% CI, 3.96-8.20) malignancies. The risk of PE was significantly higher for CNS (P < .0001; odds ratio [OR], 5.28), pancreatic (P=.0027; OR, 2.15), upper gastrointestinal (P=.0002; OR, 2.18), and lung/pleural malignancies (P=.0028; OR, 1.45). There was significantly lower risk of PE for hematologic (incidence, 1.16%; 95% CI, 0.79-1.64; P < .0001; OR, 0.35) and breast malignancies (incidence, 1.50%; 95% CI, 1.02-2.11; P < .0001; OR, 0.47). CONCLUSIONS: The incidence of PE in oncology outpatients in a tertiary cancer center during a 6-year period was 2.87%. CNS, pancreatic, upper gastrointestinal, and lung/pleural malignancies had a significantly higher risk for PE than other malignancies, whereas hematologic and breast malignancies had a significantly lower risk. Cancer 2011;117:3860-6. (C) 2011 American Cancer Society. C1 [Shinagare, Atul B.; Guo, Mengye; Krajewski, Katherine M.; Van den Abbeele, Annick D.; DiPiro, Pamela J.; Nishino, Mizuki] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Shinagare, Atul B.; Hatabu, Hiroto; Krajewski, Katherine M.; Andriole, Katherine; Van den Abbeele, Annick D.; DiPiro, Pamela J.; Nishino, Mizuki] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Nishino, M (reprint author), Dana Farber Canc Inst, Dept Imaging, 44 Binney St, Boston, MA 02115 USA. EM Mizuki_Nishino@dfci.harvard.edu FU Agfa HealthCare/RSNA; National Institutes of Health [5R21 CA11627-02] FX The investigators were supported by 2009-11 Agfa HealthCare/RSNA Research Scholar Grant (Mizuki Nishino), and 5R21 CA11627-02 (Hiroto Hatabu) from the National Institutes of Health. NR 46 TC 23 Z9 26 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2011 VL 117 IS 16 BP 3860 EP 3866 DI 10.1002/cncr.25941 PG 7 WC Oncology SC Oncology GA 804RW UT WOS:000293672700028 PM 21319153 ER PT J AU Zhang, YQ Gan, BY Liu, D Paik, JH AF Zhang, Yuqing Gan, Boyi Liu, Debra Paik, Ji-hye TI FoxO family members in cancer SO CANCER BIOLOGY & THERAPY LA English DT Review DE FOXO; cancer; RTK-PI3K-AKT-mTORC1; feedback regulation; therapeutic resistance; tumor suppressor; homeostasis; survival ID FORKHEAD TRANSCRIPTION FACTOR; STEM-CELL HOMEOSTASIS; TUMOR SUPPRESSION; OXIDATIVE STRESS; PROTEIN-KINASE; PHOSPHOINOSITIDE 3-KINASE; PROSTATE-CANCER; DOWN-REGULATION; LEUKEMIC-CELLS; MLL GENE AB The PI3K-Akt-FoxO signaling pathway plays a central role in diverse physiological processes including cellular energy storage, growth and survival, among others. As an important effector of this pathway, FoxO is involved in versatile activities that protect organisms from stress and aging. Recent studies on mammalian FoxO have established a direct role for this transcription factor family in cellular proliferation, oxidative stress response and tumorigenesis. The review will focus on the recent developments pertaining to the function of FoxO as well as discuss the various contexts in which FoxO exerts distinct biological activity such as drug resistance and autophagy in cancer pathogenesis and therapy. C1 [Zhang, Yuqing; Liu, Debra; Paik, Ji-hye] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. [Gan, Boyi] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gan, Boyi] Harvard Univ, Sch Med, Boston, MA USA. RP Paik, JH (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. EM jep2025@med.cornell.edu FU Ellison Medical Foundation [AG-NS-0646-10]; Department of Defense [PC100356] FX This work is supported by the Ellison Medical Foundation (AG-NS-0646-10 to J.H.P.) and the Department of Defense (PC100356 to B.G.). NR 90 TC 61 Z9 64 U1 2 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG 15 PY 2011 VL 12 IS 4 BP 253 EP 259 DI 10.4161/cbt.12.4.15954 PG 7 WC Oncology SC Oncology GA 806WN UT WOS:000293847500001 PM 21613825 ER PT J AU Dicker, DT Kahn, N Flaherty, KT Lerner, J El-Deiry, WS AF Dicker, David T. Kahn, Nadia Flaherty, Keith T. Lerner, Jeremy El-Deiry, Wafik S. TI A non-invasive method of imaging melanoma lesions in a patient with stage IV melanoma, being treated with a RAF inhibitor SO CANCER BIOLOGY & THERAPY LA English DT Article DE hyperspectral imaging; multispectral imaging; melanoma; spectral library; non-invasive spectral imaging ID SKIN; BRAF; DIFFERENTIATION; CANCER; SYSTEM AB Utilizing a macroscopic Prism and Reflectance Imaging Spectroscopy System (MACRO-PARISS), spectral data are taken from human skin using a fiber optic light probe. The subject was an oncology patient at the University of Pennsylvania, with biopsy proven melanoma, who underwent chemotherapy with a novel small molecule BRAF inhibitor as part of a Phase I clinical trial. The BRAF mutation had been previously identified in this patient. Cutaneous lesions were identified by a clinical oncologist, and lesions were imaged periodically over a 1 mo period of time. Spectra are classified using a linearity-independent algorithm over a wavelength range of 450-920 nm. Spectral signatures, or characteristic features, of generated spectra correlate with gross features of lesions that are readily observable. Using PARISS we demonstrated differences between spectral signatures of treated lesions over a treatment course, indicating spectral data correlation with changes in disease. PARISS may be useful to better establish a noninvasive means of following disease progression, and ultimately establish characteristic spectral signatures to define disease presence in the future. C1 [Dicker, David T.; El-Deiry, Wafik S.] Penn State Hershey Canc Inst, Hershey, PA USA. [Kahn, Nadia] Georgetown Univ Hosp, Washington, DC 20007 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp Canc Ctr, Boston, MA USA. [Lerner, Jeremy] Lightform Inc, Asheville, NC USA. RP El-Deiry, WS (reprint author), Penn State Hershey Canc Inst, Hershey, PA USA. EM wafik.eldeiry@gmail.com NR 16 TC 5 Z9 5 U1 2 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG 15 PY 2011 VL 12 IS 4 BP 326 EP 334 DI 10.4161/cbt.12.4.17142 PG 9 WC Oncology SC Oncology GA 806WN UT WOS:000293847500009 PM 21768778 ER PT J AU Rothschild, SC Francescatto, L Drummond, IA Tombes, RM AF Rothschild, Sarah C. Francescatto, Ludmila Drummond, Iain A. Tombes, Robert M. TI CaMK-II is a PKD2 target that promotes pronephric kidney development and stabilizes cilia SO DEVELOPMENT LA English DT Article DE CaMK-II; PKD2; Cilia; Kidney; ADPKD; Zebrafish ID PROTEIN-KINASE-II; LEFT-RIGHT AXIS; ZEBRAFISH PRONEPHROS; KUPFFERS VESICLE; EMBRYONIC-DEVELOPMENT; CELL MOTILITY; DISEASE; POLYCYSTIN-2; CALCIUM; GENES AB Intracellular Ca(2+) signals influence gastrulation, neurogenesis and organogenesis through pathways that are still being defined. One potential Ca(2+) mediator of many of these morphogenic processes is CaMK-II, a conserved calmodulin-dependent protein kinase. Prolonged Ca(2+) stimulation converts CaMK-II into an activated state that, in the zebrafish, is detected in the forebrain, ear and kidney. Autosomal dominant polycystic kidney disease has been linked to mutations in the Ca(2+)-conducting TRP family member PKD2, the suppression of which in vertebrate model organisms results in kidney cysts. Both PKD2-deficient and CaMK-II-deficient zebrafish embryos fail to form pronephric ducts properly, and exhibit anterior cysts and destabilized cloacal cilia. PKD2 suppression inactivates CaMK-II in pronephric cells and cilia, whereas constitutively active CaMK-II restores pronephric duct formation in pkd2 morphants. PKD2 and CaMK-II deficiencies are synergistic, supporting their existence in the same genetic pathway. We conclude that CaMK-II is a crucial effector of PKD2 Ca(2+) that both promotes morphogenesis of the pronephric kidney and stabilizes primary cloacal cilia. C1 [Tombes, Robert M.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Drummond, Iain A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. RP Tombes, RM (reprint author), Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. EM rtombes@vcu.edu FU National Science Foundation [IOS-0817658] FX The authors gratefully acknowledge Jamie Lahvic, Bennett Childs, Jamie McLeod, Alexandra Myers and Amritha Yelamilli for their assistance with this study; and Becky Burdine, Alan Davidson, Amanda Dickinson, James Lister, Lila Solnica-Krezel and Joe Yost for sharing useful reagents and advice. Supported by National Science Foundation grant IOS-0817658. NR 76 TC 15 Z9 15 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD AUG 15 PY 2011 VL 138 IS 16 BP 3387 EP 3397 DI 10.1242/dev.066340 PG 11 WC Developmental Biology SC Developmental Biology GA 797KB UT WOS:000293123500005 PM 21752935 ER PT J AU Wang, HX Kolesnikova, TV Denison, C Gygi, SP Hemler, ME AF Wang, Hong-Xing Kolesnikova, Tatiana V. Denison, Carilee Gygi, Steven P. Hemler, Martin E. TI The C-terminal tail of tetraspanin protein CD9 contributes to its function and molecular organization SO JOURNAL OF CELL SCIENCE LA English DT Article DE CD9; Tetraspanin; SILAC; Microvilli; Cell adhesion; Cell spreading ID DIPHTHERIA-TOXIN BINDING; CELL-SURFACE; GAMETE FUSION; TRANSMEMBRANE DOMAINS; ENRICHED MICRODOMAINS; CD9-DEFICIENT MICE; VLA INTEGRINS; BREAST-CANCER; UP-REGULATION; AMINO-ACIDS AB Tetraspanin protein CD9 supports sperm-egg fusion, and regulates cell adhesion, motility, metastasis, proliferation and signaling. The large extracellular loop and transmembrane domains of CD9 engage in functionally important interactions with partner proteins. However, neither functional nor biochemical roles have been shown for the CD9 C-terminal tail, despite it being highly conserved throughout vertebrate species. To gain new insight into the CD9 tail, three C-terminal amino acids (Glu-Met-Val) were replaced with residues corresponding to C-terminal amino acids from tetraspanin protein CD82 (Pro-Lys-Tyr). Wild-type and mutant CD9 were then stably expressed in MOLT-4, K562, U937, RD and HT1080 cells. Whereas wild-type CD9 inhibited cell adhesion and spreading on fibronectin, mutant CD9 did not. Wild-type CD9 also promoted homotypic cell-cell aggregation and microvilli formation, whereas mutant CD9 did not. Protein interactions of wild-type and mutant CD9 were compared quantitatively using stable isotope labeling with amino acids in cell culture (SILAC) in conjunction with liquid-chromatography-tandem mass spectrometry (LC-MS/MS) technology. SILAC results showed that, despite wild-type and mutant CD9 having identical expression levels, mutant CD9 and its major transmembrane interacting partners were recovered in substantially reduced amounts from 1% Brij 96 lysates. Immunoprecipitation experiments confirmed that mutant CD9 recovery was decreased in Brij 96, but not in more stringent Triton X-100 detergent. Additionally, compared with wild-type CD9 complexes, mutant CD9 complexes were larger and more oligomerized in Brij 96 detergent, consistent with decreased Brij 96 solubility, perhaps due to more membrane domains packing more tightly together. In conclusion, multiple CD9 functions depend on its C-terminal tail, which affects the molecular organization of CD9 complexes, as manifested by their altered solubilization in Brij 96 and organization on the cell surface. C1 [Wang, Hong-Xing; Kolesnikova, Tatiana V.; Hemler, Martin E.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Wang, Hong-Xing; Kolesnikova, Tatiana V.; Hemler, Martin E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Denison, Carilee; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Hemler, ME (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM martin_hemler@dfci.harvard.edu FU National Institutes of Health [GM38903] FX We thank C. E. Bakalarski for his help with the Vista algorithm. This work was supported by a grant from the National Institutes of Health (GM38903) to M.E.H. Deposited in PMC for release after 12 months. NR 72 TC 19 Z9 19 U1 2 U2 8 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 15 PY 2011 VL 124 IS 16 BP 2702 EP 2710 DI 10.1242/jcs.085449 PG 9 WC Cell Biology SC Cell Biology GA 800IK UT WOS:000293352800005 PM 21771881 ER PT J AU Vezys, V Penaloza-MacMaster, P Barber, DL Ha, SJ Konieczny, B Freeman, GJ Mittler, RS Ahmed, R AF Vezys, Vaiva Penaloza-MacMaster, Pablo Barber, Daniel L. Ha, Sang-Jun Konieczny, Bogumila Freeman, Gordon J. Mittler, Robert S. Ahmed, Rafi TI 4-1BB Signaling Synergizes with Programmed Death Ligand 1 Blockade To Augment CD8 T Cell Responses during Chronic Viral Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID THERAPEUTIC VACCINATION; PD-1 BLOCKADE; CD137 4-1BB; IN-VIVO; COSTIMULATION; EXHAUSTION; EFFECTOR; MEMORY; PROLIFERATION; SUPPRESSION AB Previous studies have identified the inhibitory role that the programmed death 1 (PD-1) pathway plays during chronic infection. Blockade of this pathway results in rescue of viral-specific CD8 T cells, as well as reduction of viral loads in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). We tested the effect of combining PD ligand 1 (PD-L1) blockade with an agonistic regimen that induces 4-1BB costimulation during chronic LCMV infection. There is a boosting effect in the rescue of LCMV-specific CD8 T cell responses after dual treatment with PD-L1 blockade and 4-1BB agonistic Abs when the amount and timing of 4-1BB costimulation are carefully controlled. When PD-L1-blocking Abs are given together with a single low dose of anti-4-1BB agonistic Abs, there is an enhanced and stable expansion of viral-specific CD8 T cells. Conversely, when blocking Abs to PD-L1 are given with a repetitive high dose of anti-4-1BB, there is an initial synergistic expansion of viral-specific CD8 T cells by day 7, followed by dramatic apoptosis by day 14. Viral control paralleled CD8 T cell kinetics after dual treatment. By day 7 posttreatment, viral titers were lower in both of the combined regimens (compared with PD-L1 blockade alone). However, whereas the high dose of anti-4-1BB plus PD-L1 blockade resulted in rebound of viral titers to original levels, the low dose of anti-4-1BB plus PD-L1 blockade resulted in a stable reduction of viral loads. These findings demonstrate the importance of carefully manipulating the balance between activating and inhibitory signals to enhance T cell responses during chronic infection. The Journal of Immunology, 2011, 187: 1634-1642. C1 [Vezys, Vaiva; Penaloza-MacMaster, Pablo; Barber, Daniel L.; Ha, Sang-Jun; Konieczny, Bogumila; Mittler, Robert S.; Ahmed, Rafi] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30329 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ahmed, R (reprint author), Emory Univ, Emory Vaccine Ctr, 1510 Clifton Rd, Atlanta, GA 30329 USA. EM rahmed@emory.edu RI vezys, vaiva/N-3144-2013; OI Vezys, Vaiva/0000-0002-2520-809X; Ha, Sang-Jun/0000-0002-1192-6031 FU National Institutes of Health [AI3004] FX This work was supported by National Institutes of Health Grant AI3004 (to R.A.). NR 42 TC 40 Z9 40 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2011 VL 187 IS 4 BP 1634 EP 1642 DI 10.4049/jimmunol.1100077 PG 9 WC Immunology SC Immunology GA 800RX UT WOS:000293384600015 PM 21742975 ER PT J AU Kaufman, DR De Calisto, J Simmons, NL Cruz, AN Villablanca, EJ Mora, JR Barouch, DH AF Kaufman, David R. De Calisto, Jaime Simmons, Nathaniel L. Cruz, Ashley N. Villablanca, Eduardo J. Mora, J. Rodrigo Barouch, Dan H. TI Vitamin A Deficiency Impairs Vaccine-Elicited Gastrointestinal Immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL DEPLETION; ANTIBODY-RESPONSE; DENDRITIC CELLS; RETINOIC-ACID; EXPANDED PROGRAM; SIV INFECTION; SUPPLEMENTATION; IMMUNIZATION; TRAFFICKING; LYMPHOCYTES AB Vitamin A deficiency is highly prevalent in much of the developing world, where vaccination programs are of paramount importance to public health. However, the impact of vitamin A deficiency on the immunogenicity and protective efficacy of vaccines has not been defined previously. In this article, we show that the vitamin A metabolite retinoic acid is critical for trafficking of vaccine-elicited T lymphocytes to the gastrointestinal mucosa and for vaccine protective efficacy in mice. Moderate vitamin A deficiency abrogated Ag-specific T lymphocyte trafficking to the gastrointestinal tract, gastrointestinal cellular immune responses, and protection against a mucosal challenge following immunization with a recombinant adenovirus vaccine vector. Oral vitamin A supplementation as well as retinoic acid administration fully restored the mucosal immune responses and vaccine protective efficacy. These data suggest that oral vitamin A supplementation may be important for optimizing the success of vaccines against HIV-1 and other mucosal pathogens in the developing world, highlighting a critical relationship between host nutritional status and vaccine efficacy. The Journal of Immunology, 2011, 187: 1877-1883. C1 [Kaufman, David R.; Simmons, Nathaniel L.; Cruz, Ashley N.; Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Div Vaccine Res, Boston, MA 02215 USA. [De Calisto, Jaime; Villablanca, Eduardo J.; Mora, J. Rodrigo] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Barouch, Dan H.] Ragon Inst MGH MIT & Harvard Univ, Boston, MA 02114 USA. RP Barouch, DH (reprint author), Beth Israel Deaconess Med Ctr, Div Vaccine Res, 330 Brookline Ave, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu RI Villablanca, Eduardo/E-1380-2016 OI Villablanca, Eduardo/0000-0001-9522-9729 FU National Institutes of Health [K08 AI083079, U19 AI066305, U19 AI078526, R01 AI066924]; Bill and Melinda Gates Foundation [38614] FX This work was supported by National Institutes of Health Grant K08 AI083079 (to D. R. K.) and by National Institutes of Health Grants U19 AI066305, U19 AI078526, and R01 AI066924 and Bill and Melinda Gates Foundation Grant 38614 (to D.H.B.). NR 46 TC 24 Z9 24 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2011 VL 187 IS 4 BP 1877 EP 1883 DI 10.4049/jimmunol.1101248 PG 7 WC Immunology SC Immunology GA 800RX UT WOS:000293384600039 PM 21765014 ER PT J AU Clancy, CJ Nguyen, MH AF Clancy, Cornelius J. Nguyen, M. Hong TI At What Cost Echinocandin Resistance? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID CANDIDA-ALBICANS; DRUG-RESISTANCE; INVASIVE CANDIDIASIS; FITNESS; EVOLUTION; SUSCEPTIBILITY; MECHANISMS C1 [Clancy, Cornelius J.; Nguyen, M. Hong] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Clancy, Cornelius J.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Clancy, CJ (reprint author), 3550 Terrace St,Scaife Hall 867, Pittsburgh, PA 15261 USA. EM cjc76@pitt.edu NR 19 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2011 VL 204 IS 4 BP 499 EP 501 DI 10.1093/infdis/jir355 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 799RS UT WOS:000293304400003 PM 21791650 ER PT J AU Powis, KM Kitch, D Ogwu, A Hughes, MD Lockman, S Leidner, J van Widenfelt, E Moffat, C Moyo, S Makhema, J Essex, M Shapiro, RL AF Powis, Kathleen M. Kitch, Douglas Ogwu, Anthony Hughes, Michael D. Lockman, Shahin Leidner, Jean van Widenfelt, Erik Moffat, Claire Moyo, Sikhulile Makhema, Joseph Essex, Max Shapiro, Roger L. TI Increased Risk of Preterm Delivery Among HIV-Infected Women Randomized to Protease Versus Nucleoside Reverse Transcriptase Inhibitor-Based HAART During Pregnancy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID 4-MILLION NEONATAL DEATHS; LOW-BIRTH-WEIGHT; ANTIRETROVIRAL THERAPY; RECEIVING ZIDOVUDINE; PREMATURE DELIVERY; PREVENTION; SURVIVAL; DRUGS; AGE AB Background. Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies. Methods. HIV-infected, HAART-naive pregnant women with CD4+ counts >= 200 cells/mm(3) were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (< 37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression. Results. Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26-3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen. Conclusions. PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study. C1 [Powis, Kathleen M.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Powis, Kathleen M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Powis, Kathleen M.; Lockman, Shahin; Leidner, Jean; Moffat, Claire; Makhema, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Powis, Kathleen M.; Hughes, Michael D.; Lockman, Shahin; van Widenfelt, Erik] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Kitch, Douglas; Lockman, Shahin; Essex, Max] Brigham & Womens Hosp, Infect Dis Unit, Boston, MA 02115 USA. [Ogwu, Anthony] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Moyo, Sikhulile; Shapiro, Roger L.] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. RP Powis, KM (reprint author), Massachusetts Gen Hosp, Dept Internal Med, 175 Cambridge St,5th floor, Boston, MA 02114 USA. EM kpowis@partners.org OI Moyo, Sikhulile/0000-0003-3821-4592 FU Harvard University Center for AIDS Research; Global Infections Diseases Program; Harvard Institute for Global Health; National Institute of Allergy and Infectious Diseases [U01-AI066454]; Brigham and Women's Global Women's Health Fellowship; Fogarty AITRP grant [D43 TW000004] FX This work was supported by a grant from the Harvard University Center for AIDS Research, the Global Infections Diseases Program, and the Global Health Scholars Program at Harvard Institute for Global Health (to K. M. P.) for the preterm delivery study. Mma Bana study was supported by a grant (U01-AI066454) from the National Institute of Allergy and Infectious Diseases. Funding support from Brigham and Women's Global Women's Health Fellowship supported K. M. P.'s salary during the Mma Bana study. Funding from Fogarty AITRP grant (D43 TW000004) provided funding for A. O., C. M., and S. M. Study drugs were provided by Abbott Pharmaceuticals, GlaxoSmithKline, and the government of Botswana. NR 26 TC 71 Z9 71 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2011 VL 204 IS 4 BP 506 EP 514 DI 10.1093/infdis/jir307 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 799RS UT WOS:000293304400005 PM 21791651 ER PT J AU Gong, DP Farley, K White, M Hartshorn, KL Benarafa, C Remold-O'Donnell, E AF Gong, Dapeng Farley, Kalamo White, Mitchell Hartshorn, Kevan L. Benarafa, Charaf Remold-O'Donnell, Eileen TI Critical Role of SerpinB1 in Regulating Inflammatory Responses in Pulmonary Influenza Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID SURFACTANT PROTEIN D; A VIRUS-INFECTION; DENDRITIC CELLS; T-CELLS; SERINE PROTEASES; H5N1 INFLUENZA; PANDEMIC VIRUS; GAMMA; MICE; CYTOKINES AB Background. Excessive inflammatory host response increases morbidity and mortality associated with seasonal respiratory influenza, and highly pathogenic virus strains are characterized by massive infiltration of monocytes and/or macrophages that produce a storm of injurious cytokines. Methods. Here, we examined the role in respiratory influenza of serpinB1, an endogenous inhibitor of the serine proteases elastase, cathepsin G, and proteinase-3, increasingly recognized as regulators of inflammation. Results. After challenge with high-dose surfactant protein-D (SP-D)-sensitive influenza A/Philadelphia/82 (H3N2), serpinB1(-/-) mice died earlier and in greater numbers than did wild-type mice. Sublethally infected animals suffered increased morbidity, delayed resolution of epithelial injury, and increased immune cell death. Viral clearance and SP-D/SP-A upregulation were unimpaired and so were early virus-induced cytokine and chemokine burst and influx of large numbers of neutrophils and monocytes. Whereas initial cytokines and chemokines rapidly cleared in wild-type mice, TNF-alpha, IL-6, KC/CXCL1, G-CSF, IL-17A, and MCP-1/CCL2 remained elevated in serpinB1(-/-) mice. Monocyte-derived cells were the dominant immune cells in influenza-infected lungs, and those from serpinB1(-/-) mice produced excessive IL-6 and TNF-alpha when tested ex vivo. Pulmonary gamma delta T-cells that produced IL-17A were also increased. Conclusions. Because viral clearance was unimpaired, the study highlights the critical role of serpinB1 in mitigating inflammation and restricting pro-inflammatory cytokine production in influenza infection. C1 [Gong, Dapeng; Farley, Kalamo; Benarafa, Charaf; Remold-O'Donnell, Eileen] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Gong, Dapeng; Farley, Kalamo; Benarafa, Charaf; Remold-O'Donnell, Eileen] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Gong, Dapeng; Farley, Kalamo; Benarafa, Charaf; Remold-O'Donnell, Eileen] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [White, Mitchell; Hartshorn, Kevan L.] Boston Med Ctr, Dept Hematol & Med Oncol, Boston, MA USA. RP Remold-O'Donnell, E (reprint author), Childrens Hosp, Immune Dis Inst, 3 Blackfan Circle, Boston, MA 02115 USA. EM remold@idi.harvard.edu OI Hartshorn, Kevan/0000-0002-7196-7433; Benarafa, Charaf/0000-0002-2049-7769 FU National Institutes of Health [R21 AI-072552, R01 HL-066548, RO1 AI-8322, RHL069031]; Parker B. Francis Fellowship FX This work was supported by National Institutes of Health (R21 AI-072552 to E. R. O. and C. B., R01 HL-066548 to E. R. O., RO1 AI-8322 to K. L. H., and RHL069031 to K. L. H.) and Parker B. Francis Fellowship in Pulmonary Research (to C. B.). NR 44 TC 21 Z9 23 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2011 VL 204 IS 4 BP 592 EP 600 DI 10.1093/infdis/jir352 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 799RS UT WOS:000293304400016 PM 21791661 ER PT J AU Peng, LF Schaefer, EAK Maloof, N Skaff, A Berical, A Belon, CA Heck, JA Lin, WY Frick, DN Allen, TM Miziorko, HM Schreiber, SL Chung, RT AF Peng, Lee F. Schaefer, Esperance A. K. Maloof, Nicole Skaff, Andrew Berical, Andrew Belon, Craig A. Heck, Julie A. Lin, Wenyu Frick, David N. Allen, Todd M. Miziorko, Henry M. Schreiber, Stuart L. Chung, Raymond T. TI Ceestatin, a Novel Small Molecule Inhibitor of Hepatitis C Virus Replication, Inhibits 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIGH-THROUGHPUT SCREEN; COENZYME-A SYNTHASE; RNA REPLICATION; CELL-CULTURE; GERANYLGERANYLATION; IDENTIFICATION; PURIFICATION; ENZYMES; YEAST AB Background. Hepatitis C virus (HCV) chronically infects >170 million persons worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. The identification of more effective and better-tolerated agents for treating HCV is a high priority. We have reported elsewhere the discovery of the anti-HCV compound ceestatin using a high-throughput screen of a small molecule library. Methods. To identify host or viral protein targets in an unbiased fashion, we performed affinity chromatography, using tandem liquid chromatography/mass spectrometry to identify specific potential targets. Results. Ceestatin binds to 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase and irreversibly inhibits HMG-CoA synthase in a dose-dependent manner. Ceestatin's anti-HCV effects are reversed by addition of HMG-CoA, mevalonic acid, or geranylgeraniol. Treatment with small interfering RNA against HMG-CoA synthase led to a substantial reduction in HCV replication, further validating HMG-CoA synthase as an enzyme essential for HCV replication. Conclusions. Ceestatin therefore exerts its anti-HCV effects through inhibition of HMG-CoA synthase. It may prove useful as an antiviral agent, as a probe to study HCV replication, and as a cholesterol-lowering agent. The logical stepwise process employed to discover the mechanism of action of ceestatin can serve as a general experimental strategy to uncover the targets on which novel uncharacterized anti-HCV compounds act. C1 [Peng, Lee F.; Schaefer, Esperance A. K.; Lin, Wenyu; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Boston, MA 02114 USA. [Peng, Lee F.; Maloof, Nicole; Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Peng, Lee F.; Maloof, Nicole; Schreiber, Stuart L.] Broad Inst Harvard & MIT, Cambridge, England. [Berical, Andrew; Allen, Todd M.] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. [Skaff, Andrew; Miziorko, Henry M.] Univ Missouri, Sch Biol Sci, Div Mol Biol & Biochem, Kansas City, MO 64110 USA. [Belon, Craig A.; Heck, Julie A.; Frick, David N.] New York Med Coll, Dept Biochem & Mol Biol, Valhalla, NY 10595 USA. [Schreiber, Stuart L.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Warren 10,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org RI Allen, Todd/F-5473-2011 FU National Institutes of Health [R01 AI069939, K24 DK078772, K08 DK088951]; American Gastroenterological Association; American Liver Foundation FX This work was supported by the National Institutes of Health (grants R01 AI069939 and K24 DK078772 to R. T. C. and K08 DK088951 to L. F. P.), the American Gastroenterological Association (L. F. P.), and the American Liver Foundation (L. F. P.). S. L. S. is a Howard Hughes Medical Institute Investigator. NR 22 TC 8 Z9 9 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2011 VL 204 IS 4 BP 609 EP 616 DI 10.1093/infdis/jir303 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 799RS UT WOS:000293304400018 PM 21791663 ER PT J AU Antoniou, AC Kartsonaki, C Sinilnikova, OM Soucy, P McGuffog, L Healey, S Lee, A Peterlongo, P Manoukian, S Peissel, B Zaffaroni, D Cattaneo, E Barile, M Pensotti, V Pasini, B Dolcetti, R Giannini, G Putignano, AL Varesco, L Radice, P Mai, PL Greene, MH Andrulis, IL Glendon, G Ozcelik, H Thomassen, M Gerdes, AM Kruse, TA Jensen, UB Cruger, DG Caligo, MA Laitman, Y Milgrom, R Kaufman, B Paluch-Shimon, S Friedman, E Loman, N Harbst, K Lindblom, A Arver, B Ehrencrona, H Melin, B Nathanson, KL Domchek, SM Rebbeck, T Jakubowska, A Lubinski, J Gronwald, J Huzarski, T Byrski, T Cybulski, C Gorski, B Osorio, A Cajal, TRY Fostira, F Andres, R Benitez, J Hamann, U Hogervorst, FB Rookus, MA Hooning, MJ Nelen, MR van der Luijt, RB van Os, TAM van Asperen, CJ Devilee, P Meijers-Heijboer, HEJ Garcia, EBG Peock, S Cook, M Frost, D Platte, R Leyland, J Evans, DG Lalloo, F Eeles, R Izatt, L Adlard, J Davidson, R Eccles, D Ong, KR Cook, J Douglas, F Paterson, J Kennedy, MJ Miedzybrodzka, Z Godwin, A Stoppa-Lyonnet, D Buecher, B Belotti, M Tirapo, C Mazoyer, S Barjhoux, L Lasset, C Leroux, D Faivre, L Bronner, M Prieur, F Nogues, C Rouleau, E Pujol, P Coupier, I Frenay, M Hopper, JL Daly, MB Terry, MB John, EM Buys, SS Yassin, Y Miron, A Goldgar, D Singer, CF Tea, MK Pfeiler, G Dressler, AC Hansen, TV Jonson, L Ejlertsen, B Barkardottir, RB Kirchhoff, T Offit, K Piedmonte, M Rodriguez, G Small, L Boggess, J Blank, S Basil, J Azodi, M Toland, AE Montagna, M Tognazzo, S Agata, S Imyanitov, E Janavicius, R Lazaro, C Blanco, I Pharoah, PDP Sucheston, L Karlan, BY Walsh, CS Olah, E Bozsik, A Teo, SH Seldon, JL Beattie, MS van Rensburg, EJ Sluiter, MD Diez, O Schmutzler, RK Wappenschmidt, B Engel, C Meindl, A Ruehl, I Varon-Mateeva, R Kast, K Deissler, H Niederacher, D Arnold, N Gadzicki, D Schonbuchner, I Caldes, T de la Hoya, M Nevanlinna, H Aittomaki, K Dumont, M Chiquette, J Tischkowitz, M Chen, XQ Beesley, J Spurdle, AB Neuhausen, SL Ding, YC Fredericksen, Z Wang, X Pankratz, VS Couch, F Simard, J Easton, DF Chenevix-Trench, G AF Antoniou, Antonis C. Kartsonaki, Christiana Sinilnikova, Olga M. Soucy, Penny McGuffog, Lesley Healey, Sue Lee, Andrew Peterlongo, Paolo Manoukian, Siranoush Peissel, Bernard Zaffaroni, Daniela Cattaneo, Elisa Barile, Monica Pensotti, Valeria Pasini, Barbara Dolcetti, Riccardo Giannini, Giuseppe Putignano, Anna Laura Varesco, Liliana Radice, Paolo Mai, Phuong L. Greene, Mark H. Andrulis, Irene L. Glendon, Gord Ozcelik, Hilmi Thomassen, Mads Gerdes, Anne-Marie Kruse, Torben A. Jensen, Uffe Birk Crueger, Dorthe G. Caligo, Maria A. Laitman, Yael Milgrom, Roni Kaufman, Bella Paluch-Shimon, Shani Friedman, Eitan Loman, Niklas Harbst, Katja Lindblom, Annika Arver, Brita Ehrencrona, Hans Melin, Beatrice Nathanson, Katherine L. Domchek, Susan M. Rebbeck, Timothy Jakubowska, Ania Lubinski, Jan Gronwald, Jacek Huzarski, Tomasz Byrski, Tomasz Cybulski, Cezary Gorski, Bohdan Osorio, Ana Ramon y Cajal, Teresa Fostira, Florentia Andres, Raquel Benitez, Javier Hamann, Ute Hogervorst, Frans B. Rookus, Matti A. Hooning, Maartje J. Nelen, Marcel R. van der Luijt, Rob B. van Os, Theo A. M. van Asperen, Christi J. Devilee, Peter Meijers-Heijboer, Hanne E. J. Garcia, Encarna B. Gomez Peock, Susan Cook, Margaret Frost, Debra Platte, Radka Leyland, Jean Evans, D. Gareth Lalloo, Fiona Eeles, Ros Izatt, Louise Adlard, Julian Davidson, Rosemarie Eccles, Diana Ong, Kai-ren Cook, Jackie Douglas, Fiona Paterson, Joan Kennedy, M. John Miedzybrodzka, Zosia Godwin, Andrew Stoppa-Lyonnet, Dominique Buecher, Bruno Belotti, Muriel Tirapo, Carole Mazoyer, Sylvie Barjhoux, Laure Lasset, Christine Leroux, Dominique Faivre, Laurence Bronner, Myriam Prieur, Fabienne Nogues, Catherine Rouleau, Etienne Pujol, Pascal Coupier, Isabelle Frenay, Marc Hopper, John L. Daly, Mary B. Terry, Mary B. John, Esther M. Buys, Saundra S. Yassin, Yosuf Miron, Alexander Goldgar, David Singer, Christian F. Tea, Muy-Kheng Pfeiler, Georg Dressler, Anne Catharina Hansen, Thomas v. O. Jonson, Lars Ejlertsen, Bent Barkardottir, Rosa Bjork Kirchhoff, Tomas Offit, Kenneth Piedmonte, Marion Rodriguez, Gustavo Small, Laurie Boggess, John Blank, Stephanie Basil, Jack Azodi, Masoud Toland, Amanda Ewart Montagna, Marco Tognazzo, Silvia Agata, Simona Imyanitov, Evgeny Janavicius, Ramunas Lazaro, Conxi Blanco, Ignacio Pharoah, Paul D. P. Sucheston, Lara Karlan, Beth Y. Walsh, Christine S. Olah, Edith Bozsik, Aniko Teo, Soo-Hwang Seldon, Joyce L. Beattie, Mary S. van Rensburg, Elizabeth J. Sluiter, Michelle D. Diez, Orland Schmutzler, Rita K. Wappenschmidt, Barbara Engel, Christoph Meindl, Alfons Ruehl, Ina Varon-Mateeva, Raymonda Kast, Karin Deissler, Helmut Niederacher, Dieter Arnold, Norbert Gadzicki, Dorothea Schoenbuchner, Ines Caldes, Trinidad de la Hoya, Miguel Nevanlinna, Heli Aittomaki, Kristiina Dumont, Martine Chiquette, Jocelyne Tischkowitz, Marc Chen, Xiaoqing Beesley, Jonathan Spurdle, Amanda B. Neuhausen, Susan L. Ding, Yuan Chun Fredericksen, Zachary Wang, Xianshu Pankratz, Vernon S. Couch, Fergus Simard, Jacques Easton, Douglas F. Chenevix-Trench, Georgia CA SWE-BRCA HEBON EMBRACE CEMO Study Collaborators Breast Canc Family Registry kConFab Investigators CIMBA TI Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ESTROGEN-RECEPTOR; CONFER SUSCEPTIBILITY; GENETIC MODIFIERS; VARIANTS; LOCUS; POPULATION; 2Q35 AB Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women. C1 [Antoniou, Antonis C.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. [Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England. [Sinilnikova, Olga M.; CEMO Study Collaborators] Ctr Hosp Univ Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Sinilnikova, Olga M.; Mazoyer, Sylvie; Barjhoux, Laure] Univ Lyon, Ctr Leon Berard, CNRS, Equipe Labellisee LIGUE 2008,UMR5201, Lyon, France. [Simard, Jacques] Ctr Hosp Univ Quebec, Canc Genom Lab, Canada Res Chair Oncogenet, Quebec City, PQ, Canada. Univ Laval, Quebec City, PQ, Canada. [Healey, Sue; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [kConFab Investigators] Peter MacCallum Canc Ctr, kConFab Kathleen Cuningham Consortium Res Familial, Melbourne, Vic, Australia. [Peterlongo, Paolo; Radice, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predicted Med, Unit Med Genet, Milan, Italy. [Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. Univ Milan, Dept Med Surg & Dent, Milan, Italy. [Barile, Monica] IEO, Div Canc Prevent & Genet, Milan, Italy. [Pensotti, Valeria] Cogentech, Consortium Genom Technol, Milan, Italy. [Pasini, Barbara] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Dolcetti, Riccardo] IRCCS, Ctr Riferimento Oncol, Canc Bioimmunotherapy Unit, Aviano, PN, Italy. [Giannini, Giuseppe] Univ Roma La Sapienza, Dept Expt Med, Rome, Italy. [Putignano, Anna Laura] Univ Florence, Dept Clin Physiopathol, Florence, Italy. [Putignano, Anna Laura] Fiorgen Fdn Pharmacogen, Sesto Fiorentino, Italy. [Varesco, Liliana] Ist Nazl Ric Canc IST, Dept Epidemiol Prevent & Special Funct, Unit Hereditary Canc, Genoa, Italy. [Mai, Phuong L.; Greene, Mark H.] US Natl Canc Inst, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Andrulis, Irene L.; Ozcelik, Hilmi] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.; Ozcelik, Hilmi] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Andrulis, Irene L.; Glendon, Gord; CIMBA] Canc Care Ontario, Toronto, ON, Canada. [Thomassen, Mads; Kruse, Torben A.] Odense Univ Hosp, DK-5000 Odense C, Denmark. [Gerdes, Anne-Marie] Rigshosp, DK-2100 Copenhagen, Denmark. [Jensen, Uffe Birk] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Crueger, Dorthe G.] Vejle Hosp, Vejle, Denmark. [Caligo, Maria A.] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy. [Caligo, Maria A.] Univ Hosp Pisa, Pisa, Italy. [Laitman, Yael; Milgrom, Roni; Friedman, Eitan] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel. [Kaufman, Bella; Paluch-Shimon, Shani] Sheba Med Ctr, Inst Oncol, Breast Canc Unit, Tel Hashomer, Israel. [Loman, Niklas; Harbst, Katja] Univ Lund Hosp, Dept Oncol, S-22185 Lund, Sweden. [Lindblom, Annika; SWE-BRCA] Karolinska Univ Hosp, Dept Clin Genet, S-17176 Stockholm, Sweden. [Arver, Brita] Karolinska Univ Hosp, Dept Oncol, S-17176 Stockholm, Sweden. [Ehrencrona, Hans] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, S-75185 Uppsala, Sweden. [Melin, Beatrice] Umea Univ, Dept Radiat Sci, S-90185 Umea, Sweden. [Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy] Univ Penn, Philadelphia, PA 19104 USA. [Jakubowska, Ania; Lubinski, Jan; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Gorski, Bohdan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Osorio, Ana; Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain. [Ramon y Cajal, Teresa] Hosp Santa Creu & Sant Pau, Oncol Serv, Barcelona, Spain. [Fostira, Florentia] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece. [Andres, Raquel] Hosp Clin Univ Lozano Blesa, Oncol unit, Zaragoza, Spain. [Hamann, Ute] Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. [Hogervorst, Frans B.] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Rookus, Matti A.; HEBON] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Hooning, Maartje J.] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Nelen, Marcel R.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet 849, NL-6525 ED Nijmegen, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [van Os, Theo A. M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [van Asperen, Christi J.] Leiden Univ, Med Ctr Leiden, Dept Clin Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr Leiden, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr Leiden, Dept Pathol, Leiden, Netherlands. [Meijers-Heijboer, Hanne E. J.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Garcia, Encarna B. Gomez] MUMC, Sch Oncol, Dept Clin Genet, Maastricht, Netherlands. [Garcia, Encarna B. Gomez] MUMC, Sch Oncol, GROM, Maastricht, Netherlands. [Evans, D. Gareth; Lalloo, Fiona] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eeles, Ros] Inst Canc Res, Oncogenet Team, Surrey, England. [Eeles, Ros] Royal Marsden NHS Fdn Trust, Surrey, England. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, London, England. [Adlard, Julian] Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England. [Davidson, Rosemarie] Yorkhill Hosp, Ferguson Smith Ctr Clin Genet, Glasgow, Lanark, Scotland. [Eccles, Diana] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Ong, Kai-ren] Birmingham Womens Hosp Healthcare NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Cook, Jackie] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Douglas, Fiona] Newcastle Tyne Hosp NHS Trust, Ctr Life, Inst Human Genet, Newcastle Upon Tyne, Tyne & Wear, England. [Paterson, Joan] Addenbrookes Hosp, E Anglian Reg Genet Serv, Dept Clin Genet, Cambridge, England. [Kennedy, M. John] Trinity Coll Dublin, Acad Unit Clin & Mol Oncol, Dublin, Ireland. [Kennedy, M. John] St James Hosp, Dublin, Ireland. [Miedzybrodzka, Zosia] NHS Grampian & Univ Aberdeen, N Scotland Reg Genet Serv, Aberdeen, Scotland. [Godwin, Andrew] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Stoppa-Lyonnet, Dominique; Buecher, Bruno; Belotti, Muriel; Tirapo, Carole] Inst Curie, Serv Genet Oncol, Paris, France. [Stoppa-Lyonnet, Dominique] Inst Curie, INSERM, Unite U830, Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Fac Med, Paris, France. [Lasset, Christine] Univ Lyon 1, CNRS, UMR5558, F-69365 Lyon, France. [Lasset, Christine] Ctr Leon Berard, Unite Prevent & Epidemiol Genet, F-69373 Lyon, France. [Leroux, Dominique] CHU Grenoble, Dept Genet, F-38043 Grenoble, France. [Leroux, Dominique] Univ Grenoble, Inst Albert Bonniot, Grenoble, France. [Faivre, Laurence] CHU Dijon, Ctr Genet, Dijon, France. [Faivre, Laurence] Ctr Lutte Canc Georges Francois Leclerc, Dijon, France. [Bronner, Myriam] Nancy Univ, Ctr Hosp Reg & Univ, Med Genet Lab, Vandoeuvre Les Nancy, France. Ctr Hosp Univ St Etienne, Serv Genet Clin Chromos & Mol, St Etienne, France. [Rouleau, Etienne] Hop Rene Huguenin, Inst Curie, Lab Oncogenet, St Cloud, France. [Nogues, Catherine] Hop Rene Huguenin, Inst Curie, Oncogenet Clin, St Cloud, France. [Pujol, Pascal; Coupier, Isabelle] CHU Arnaud de Villeneuve, Unite Oncogenet, Montpellier, France. [Pujol, Pascal] CRCM Val dAurelle, INSERM 896, Montpellier, France. [Coupier, Isabelle] CRLCC Val dAurelle, Unite Oncogenet, Montpellier, France. [Prieur, Fabienne; Frenay, Marc] Ctr Antoine Lacassagne, F-06054 Nice, France. [Hopper, John L.] Univ Melbourne, Melbourne, Vic, Australia. [Daly, Mary B.] Fox Chase Canc Ctr, Dept Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA. [Terry, Mary B.] Columbia Univ, New York, NY USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford Canc Ctr, Stanford, CA 94305 USA. [Buys, Saundra S.] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Salt Lake City, UT USA. [Yassin, Yosuf; Miron, Alexander] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldgar, David] Univ Utah, Dept Dermatol, Salt Lake City, UT USA. [Singer, Christian F.; Tea, Muy-Kheng; Pfeiler, Georg; Dressler, Anne Catharina] Med Univ Vienna, Dept Obstet Gynecol, Vienna, Austria. [Hansen, Thomas v. O.; Jonson, Lars] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Allerod, Denmark. [Ejlertsen, Bent] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Allerod, Denmark. [Barkardottir, Rosa Bjork] Landspitali Univ Hosp, Dept Pathol, Cell Biol Lab, Tromso, Norway. [Barkardottir, Rosa Bjork] Univ Iceland, Fac Med, Reykjavik, Iceland. [Kirchhoff, Tomas; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Sucheston, Lara] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Rodriguez, Gustavo] Evanston NW Healthcare, Evanston, IL USA. [Small, Laurie] Maine Med Ctr, Scarborough, ME USA. [Boggess, John] Univ N Carolina, Chapel Hill, NC USA. [Blank, Stephanie] NYU, Sch Med, New York, NY USA. [Basil, Jack] St Elizabeth Hosp, Edgewood, KY USA. [Azodi, Masoud] Yale Univ, Sch Med, New Haven, CT USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Montagna, Marco; Tognazzo, Silvia; Agata, Simona] Ist Oncol Veneto IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy. [Imyanitov, Evgeny] NN Petrov Inst Oncol, St Petersburg 197758, Russia. [Janavicius, Ramunas] Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, Vilnius, Lithuania. [Janavicius, Ramunas] State Res Inst Inovat Med Ctr, Vilnius, Lithuania. [Lazaro, Conxi; Blanco, Ignacio] Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain. [Karlan, Beth Y.; Walsh, Christine S.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Res Inst, Los Angeles, CA 90048 USA. [Olah, Edith; Bozsik, Aniko] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Teo, Soo-Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia. [Teo, Soo-Hwang] Univ Malaya, Canc Res Inst, Kuala Lumpur, Malaysia. [Seldon, Joyce L.] Univ Calif Los Angeles, Canc Genet Program, CLA Jonsson Comp Canc Ctr, Santa Monica, CA USA. [Beattie, Mary S.] Univ Calif San Francisco, UCSF Canc Risk Program, San Francisco, CA 94143 USA. [Beattie, Mary S.] Univ Calif San Francisco, UCSF Dept Med, San Francisco, CA 94143 USA. [Beattie, Mary S.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Beattie, Mary S.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [van Rensburg, Elizabeth J.; Sluiter, Michelle D.] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa. [Diez, Orland] Univ Hosp Vall dHebron, Oncogenet Lab, Barcelona, Spain. [Diez, Orland] VHIO, Barcelona, Spain. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, CIO, Cologne, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Obstet & Gynaecol, D-8000 Munich, Germany. [Ruehl, Ina] Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Varon-Mateeva, Raymonda] Campus Virchov Klinikum, Inst Human Genet, Charite, Berlin, Germany. [Kast, Karin] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Obstet & Gynaecol, Dresden, Germany. [Deissler, Helmut] Univ Hosp Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Niederacher, Dieter] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Obstet & Gynaecol, Dusseldorf, Germany. [Arnold, Norbert] Univ Kiel, Dept Obstet & Gynaecol, Univ Hosp Schleswigholstein, Kiel, Germany. [Gadzicki, Dorothea] Hannover Med Sch, Inst Cell & Mol Pathol, D-3000 Hannover, Germany. [Schoenbuchner, Ines] Univ Wurzburg, Inst Human Genet, Dept Med Genet, Ctr Familial Breast & Ovarian Canc, D-8700 Wurzburg, Germany. [Caldes, Trinidad; de la Hoya, Miguel] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Chiquette, Jocelyne] Univ Quebec, Ctr Hosp, Ctr Rech FRSQ, Unite Rech Sante Populat,Ctr Malad Sein Deschenes, Quebec City, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Tischkowitz, Marc] McGill Univ, Jewish Gen Hosp, Segal Canc Ctr, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Neuhausen, Susan L.; Ding, Yuan Chun] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Fredericksen, Zachary; Pankratz, Vernon S.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Wang, Xianshu; Couch, Fergus] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. RP Antoniou, AC (reprint author), Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England. EM antonis@srl.cam.ac.uk RI Ehrencrona, Hans/M-5619-2014; Jakubowska, Anna/O-8050-2014; GLADIEFF, Laurence/O-5129-2014; Nelen, Marcel/L-4542-2015; Dolcetti, Riccardo/O-3832-2015; Ligtenberg, Marjolijn/N-9666-2013; Gronwald, Jacek/A-4576-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; Rahman, Nazneen/D-2802-2013; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Oosterwijk, Jan C./G-5770-2011; Blanco, Ignacio/D-2565-2013; Arnold, Norbert/E-3012-2010; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Giannini, Giuseppe/B-5672-2013; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Leroux, Dominique/G-7309-2014; Teo, Soo-hwang/H-2353-2014; Osorio, Ana/I-4324-2014; BYRSKI, Tomasz/I-2844-2014; Spurdle, Amanda/A-4978-2011; OI Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719; Dolcetti, Riccardo/0000-0003-1625-9853; Ligtenberg, Marjolijn/0000-0003-1290-1474; Gronwald, Jacek/0000-0002-3643-2871; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Janavicius, Ramunas/0000-0002-3773-8485; Nordling, Margareta/0000-0002-4047-4994; Rahman, Nazneen/0000-0003-4376-0440; Blanco, Ignacio/0000-0002-7414-7481; Arnold, Norbert/0000-0003-4523-8808; montagna, marco/0000-0002-4929-2150; Giannini, Giuseppe/0000-0003-0299-4056; Osorio, Ana/0000-0001-8124-3984; Eeles, Rosalind/0000-0002-3698-6241; Barton, David E/0000-0002-2031-9719; Nathanson, Katherine/0000-0002-6740-0901; Spurdle, Amanda/0000-0003-1337-7897; PUTIGNANO, Anna Laura/0000-0001-9434-1612; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364; Evans, Gareth/0000-0002-8482-5784; Kruse, Inken/0000-0001-7176-6300 FU Cancer Research UK [C12292/A11174, C1287/A10118]; European Community [223175 (HEALTH-F22009-223175)]; Associazione Italiana per la Ricerca sul Cancro FX This work was supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F22009-223175). NR 44 TC 42 Z9 42 U1 2 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2011 VL 20 IS 16 BP 3304 EP 3321 DI 10.1093/hmg/ddr226 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 796CF UT WOS:000293027100017 PM 21593217 ER PT J AU Porcheray, F Miklos, DB Floyd, BH Sarantopoulos, S Bellucci, R Soiffer, RJ Antin, JH Alyea, EP Ritz, J Zorn, E AF Porcheray, Fabrice Miklos, David B. Floyd, Blair H. Sarantopoulos, Stefanie Bellucci, Roberto Soiffer, Robert J. Antin, Joseph H. Alyea, Edwin P. Ritz, Jerome Zorn, Emmanuel TI Combined CD4 T-Cell and Antibody Response to Human Minor Histocompatibility Antigen DBY After Allogeneic Stem-Cell Transplantation SO TRANSPLANTATION LA English DT Article DE Hematopoietic stem-cell transplantation; H-Y antigens; Antibodies; CD4+T cells ID VERSUS-HOST-DISEASE; H-Y-ANTIGEN; B-CELL; GRAFT-REJECTION; GENE CODES; RECOGNITION; CONTAINS; CYSTEINE; DFFRY AB Background. Antibody responses to HY antigens in male recipients are frequent after transplantation of stem cells from female donors (Miklos et al., Blood 2005; 105: 2973; Miklos et al., Blood 2004; 103: 353). However, evidence that this B-cell immunity is accompanied by T-cell responses to the cognate antigens is scarce. Here, we examined T- and B-cell responses to DBY antigen in a male patient who received hematopoietic stem cells from a human leukocyte antigen-identical female sibling. Materials and Methods. We used 93 overlapping peptides representing the entire DBY protein to detect and characterize T-cell and antibody responses to DBY by enzyme-linked immunosorbent spot (ELISPOT) and enzyme-linked immunosorbent assay. Results. High frequency CD4+ T cells specific for a unique DBY peptide were detected in the patient blood. We isolated the corresponding T-cell clone and characterized the recognized epitope as an 18-mer peptide restricted by human leukocyte antigen-DRB1(star)0101. Upon stimulation, this clone produced cytokines with no evidence of Th1 or Th2 polarization. Remarkably, this clone also recognized the DBX homologue peptide and responded to female donor dendritic cells stimulated with poly I/C or lipopolysaccharide, indicating that the peptide was endogenously processed in these cells. High titer DBY-specific antibodies were also found in the patient serum which, in contrast to the T-cell response, did not cross-react with DBX. Conclusion. We show here the development of a coordinated B and T-cell response to DBY in a recipient of sex mismatched allogeneic hematopoietic stem-cell transplantation. Our findings support a role for CD4+ T cells in the development of humoral immunity to minor histocompatibility antigens. C1 [Porcheray, Fabrice; Floyd, Blair H.; Bellucci, Roberto; Soiffer, Robert J.; Antin, Joseph H.; Alyea, Edwin P.; Ritz, Jerome; Zorn, Emmanuel] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Miklos, David B.] Stanford Univ, Med Ctr, Dept Med, Stanford, CA 94305 USA. [Sarantopoulos, Stefanie] Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol Oncol, Med Ctr, Chapel Hill, NC 27599 USA. RP Zorn, E (reprint author), Massachusetts Gen Hosp, Wellman Thier 815,55 Fruit St, Boston, MA 02114 USA. EM ezorn@partners.org RI porcheray, fabrice/B-9505-2012; OI Ritz, Jerome/0000-0001-5526-4669 FU NIH [CA142106, AI29530] FX This work was supported by NIH grants CA142106 and AI29530. NR 19 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 15 PY 2011 VL 92 IS 3 BP 359 EP 365 DI 10.1097/TP.0b013e3182244cc3 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 798BM UT WOS:000293176300021 PM 21709606 ER PT J AU Laha, M Panizzi, P Nahrendorf, M Bock, PE AF Laha, Malabika Panizzi, Peter Nahrendorf, Matthias Bock, Paul E. TI Engineering streptokinase for generation of active site-labeled plasminogen analogs SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Plasminogen; Streptokinase; Fluorescence probes; Binding; Kinetics; Plasminogen receptors ID PEPTIDE CHLOROMETHYL KETONES; BLOOD-COAGULATION PROTEINASES; ENDOTHELIAL-CELL RECEPTOR; ANNEXIN-II; FLUORESCENCE PROBES; CONFORMATIONAL ACTIVATION; AFFINITY-CHROMATOGRAPHY; SERINE PROTEINASES; ZYMOGEN ACTIVATION; KINETIC MECHANISM AB We previously demonstrated that streptokinase (SK) can be used to generate active site-labeled fluorescent analogs of plasminogen (Pg) by virtue of its nonproteolytic activation of the zymogen. The method is versatile and allows stoichiometric and active site-specific incorporation of any one of many molecular probes. The limitation of the labeling approach is that it is both time-consuming and low yield. Here we demonstrate an improved method for the preparation of labeled Pg analogs by the use of an engineered SK mutant fusion protein with both COOH- and NH(2)-terminal His(6) tags. The NH(2)-terminal tag is followed by a tobacco etch virus proteinase cleavage site to ensure that the SK Ile(1) residue, essential for conformational activation of Pg, is preserved. The SK COOH-terminal Lys(414) residue and residues Arg253-Leu260 in the SK beta-domain were deleted to prevent cleavage by plasmin (Pm) and to disable Pg substrate binding to the SK.Pg*/Pm catalytic complexes, respectively. Near elimination of Pm generation with the SK Delta(R253-L260)Delta K414-His(6) mutant increased the yield of labeled Pg 2.6-fold and reduced the time required more than 2-fold. The versatility of the labeling method was extended to the application of Pg labeled with a near-infrared probe to quantitate Pg receptors on immune cells by flow cytometry. (C) 2011 Elsevier Inc. All rights reserved. C1 [Laha, Malabika; Bock, Paul E.] Vanderbilt Univ, Sch Med, Dept Pathol, Nashville, TN 37232 USA. [Panizzi, Peter] Auburn Univ, Harrison Sch Pharm, Dept Pharmacal Sci, Auburn, AL 36849 USA. [Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02129 USA. RP Bock, PE (reprint author), Vanderbilt Univ, Sch Med, Dept Pathol, Nashville, TN 37232 USA. EM paul.bock@vanderbilt.edu OI Panizzi, Peter/0000-0003-0141-8807 FU National Institutes of Health from the National Heart, Lung, and Blood Institute [RO1 HL056181]; American Heart Association [0835623D]; [F32 HL094010]; [K99 HL094533]; [RO1 HL096576-01] FX This work was supported in part by National Institutes of Health Grant RO1 HL056181 from the National Heart, Lung, and Blood Institute to P.E.B., Grants F32 HL094010 and K99 HL094533 to P.P., and Grant RO1 HL096576-01 and an American Heart Association Grant (0835623D) to M.N. We thank Laura Mizoue of the Vanderbilt University Center for Structural Biology for the TEV proteinase construct and Jonathan Creamer for his work in optimizing TEV proteinase purification. We thank Virna Cortez-Retamozo and Cedric Berger for their help in acquiring the flow cytometry data. We also thank the Molecular Structure Facility at the University of California, Davis, for performing NH2-terminal sequencing and the Vanderbilt DNA Sequencing Facility for DNA sequencing. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. The funding organizations played no role in the decision to publish or the content. NR 64 TC 1 Z9 1 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 15 PY 2011 VL 415 IS 2 BP 105 EP 115 DI 10.1016/j.ab.2011.04.025 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 781BD UT WOS:000291904700003 PM 21570944 ER PT J AU Walsh, CO Ziniel, SI Delichatsios, HK Ludwig, DS AF Walsh, Carolyn O. Ziniel, Sonja I. Delichatsios, Helen K. Ludwig, David S. TI Nutrition attitudes and knowledge in medical students after completion of an integrated nutrition curriculum compared to a dedicated nutrition curriculum: a quasi-experimental study SO BMC MEDICAL EDUCATION LA English DT Article ID PRIMARY PREVENTION; EDUCATION; SCHOOLS; PROFICIENCY; PREVALENCE; PHYSICIANS; CONSENSUS; CHILDREN; DISEASE; UPDATE AB Background: Nutrition education has presented an ongoing challenge to medical educators. In the 2007-2008 academic year, Harvard Medical School replaced its dedicated Preventive Medicine and Nutrition course with an integrated curriculum. The objective of the current study was to assess the effect of the curriculum change on medical student attitudes and knowledge about nutrition. Methods: A survey was administered in a quasi-experimental design to students in the last class of the dedicated curriculum (n = 131) and the first class of the integrated curriculum (n = 135) two years after each class completed the required nutrition course. Main measures were attitude scores based on modified Nutrition in Patient care Survey and satisfaction ratings, performance on a nutrition knowledge test, and demographic variables. Two-tailed t-tests were performed. Results: Response rates were 50.4% and 42.2%. There were no differences between the groups in attitude scores from the Nutrition in Patient care Survey (p = 0.43) or knowledge scores (p = 0.63). Students with the integrated curriculum were less satisfied with both the quantity (p < 0.0001) and quality (p = 0.008) of their nutrition education, and were more likely to have completed optional online nutrition training modules (p = 0.0089). Conclusions: Medical student attitudes and knowledge about nutrition were not affected by the model of nutrition education they receive, though students in an integrated curriculum may feel their education is inadequate and seek additional training. C1 [Walsh, Carolyn O.] Childrens Hosp Boston, Boston Combined Residency Program Pediat, Boston, MA 02115 USA. [Ziniel, Sonja I.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Ziniel, Sonja I.] Childrens Hosp Boston, Clin Res Program, Boston, MA 02115 USA. [Delichatsios, Helen K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ludwig, David S.] Childrens Hosp Boston, Optimal Weight Life Program, Boston, MA 02115 USA. RP Walsh, CO (reprint author), Childrens Hosp Boston, Boston Combined Residency Program Pediat, 300 Longwood Ave, Boston, MA 02115 USA. EM carolyn_walsh@post.harvard.edu FU Harvard Medical School; New Balance Foundation; Harvard PASTEUR Program; Harvard Office of Enrichment Programs; Harvard Clinical and Translational Science Center (Catalyst); National Institute of Diabetes, Digestive and Kidney Diseases [R03DK073335, K24DK082730]; Thrasher Research Fund; National Institutes of Health (Beth Israel Deaconess Medical Center General Clinical Research Center) [M01-RR01032] FX This work was funded by the Clinical Research Fellowship Program at Harvard Medical School offered by the Doris Duke Charitable Foundation, the New Balance Foundation, the Harvard PASTEUR Program, the Harvard Office of Enrichment Programs, the Harvard Clinical and Translational Science Center (Catalyst), the National Institute of Diabetes, Digestive and Kidney Diseases (R03DK073335), the Thrasher Research Fund, and the National Institutes of Health (M01-RR01032, Beth Israel Deaconess Medical Center General Clinical Research Center). DSL was supported in part by grant K24DK082730 from the National Institute of Diabetes, Digestive and Kidney Diseases. The funders were not involved in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. NR 25 TC 8 Z9 8 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6920 J9 BMC MED EDUC JI BMC Med. Educ. PD AUG 12 PY 2011 VL 11 AR 58 DI 10.1186/1472-6920-11-58 PG 7 WC Education & Educational Research; Education, Scientific Disciplines SC Education & Educational Research GA 820KS UT WOS:000294905200001 PM 21835040 ER PT J AU Noskova, L Stranecky, V Hartmannova, H Pristoupilova, A Baresova, V Ivanek, R Hulkova, H Jahnova, H van der Zee, J Staropoli, JF Sims, KB Tyynela, J Van Broeckhoven, C Nijssen, PCG Mole, SE Elleder, M Kmoch, S AF Noskova, Lenka Stranecky, Viktor Hartmannova, Hana Pristoupilova, Anna Baresova, Veronika Ivanek, Robert Hulkova, Helena Jahnova, Helena van der Zee, Julie Staropoli, John F. Sims, Katherine B. Tyynela, Jaana Van Broeckhoven, Christine Nijssen, Peter C. G. Mole, Sara E. Elleder, Milan Kmoch, Stanislav TI Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID KUFS-DISEASE; CSP-ALPHA; CHAPERONE COMPLEX; FORM; PALMITOYLATION; COLOCALIZATION; DEGENERATION; DEFICIENCY; DOMAIN AB Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSP alpha). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSP alpha in neuronal cells. The resulting depletion of functional CSP alpha might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSP alpha in humans and demonstrates the need for detailed investigation of CSP alpha in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation. C1 [Noskova, Lenka; Stranecky, Viktor; Hartmannova, Hana; Pristoupilova, Anna; Baresova, Veronika; Ivanek, Robert; Hulkova, Helena; Jahnova, Helena; Elleder, Milan; Kmoch, Stanislav] Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Prague 12000, Czech Republic. [Noskova, Lenka; Stranecky, Viktor; Hartmannova, Hana; Pristoupilova, Anna; Baresova, Veronika; Ivanek, Robert; Elleder, Milan; Kmoch, Stanislav] Charles Univ Prague, Fac Med 1, Ctr Appl Genom, Prague 12000, Czech Republic. [van der Zee, Julie; Van Broeckhoven, Christine] VIB, Neurodegenerat Brain Dis Grp, Dept Mol Genet, B-2610 Antwerp, Belgium. [van der Zee, Julie; Van Broeckhoven, Christine] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2610 Antwerp, Belgium. [Staropoli, John F.; Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Staropoli, John F.; Sims, Katherine B.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Tyynela, Jaana] Univ Helsinki, Inst Biomed Biochem & Dev Biol, FIN-00014 Helsinki, Finland. [Nijssen, Peter C. G.] St Elizabeth Hosp, Dept Neurol, NL-5022 Tilburg, Netherlands. [Mole, Sara E.] UCL, MRC Lab Mol Cell Biol, Inst Child Hlth, London WC1E 6BT, England. [Mole, Sara E.] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. RP Kmoch, S (reprint author), Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Prague 12000, Czech Republic. EM skmoch@lf1.cuni.cz RI Ivanek, Robert/A-8852-2008; Pristoupilova, Anna/F-4990-2017; OI Pristoupilova, Anna/0000-0003-0047-9405; Mole, Sara/0000-0003-4385-4957 FU Grant Agency of Charles University of Prague [299911]; Ministry of Education of the Czech Republic [1M6837805002, MSM0021620806]; Belgian Science Policy Office Interuniversity Attraction Poles [P6/43]; Flemish Government Methusalem Excellence; Research Foundation Flanders; Batten Disease Support and Research Association FX This work was supported by the Grant Agency of Charles University of Prague (project 299911), the Ministry of Education of the Czech Republic (projects 1M6837805002 and MSM0021620806), Belgian Science Policy Office Interuniversity Attraction Poles program P6/43, Flemish Government Methusalem Excellence grant, Research Foundation Flanders (J.v.d.Z, postdoctoral fellowship), and the Batten Disease Support and Research Association. We thank clinical colleagues and families who contributed samples used in this study, especially John Morris and Joanne Porter (UCL563), David Sleat and the late Krystyna Wisniewski (UCL519), and Aristotle Siakotos (UCL328). NR 35 TC 116 Z9 120 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG 12 PY 2011 VL 89 IS 2 BP 241 EP 252 DI 10.1016/j.ajhg.2011.07.003 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 810TA UT WOS:000294148800004 PM 21820099 ER PT J AU Sirbu, BM Lachmayer, SJ Wulfing, V Marten, LM Clarkson, KE Lee, LW Gheorghiu, L Zou, L Powell, SN Dahm-Daphi, J Willers, H AF Sirbu, Bianca M. Lachmayer, Sarah J. Wuelfing, Verena Marten, Lara M. Clarkson, Katie E. Lee, Linda W. Gheorghiu, Liliana Zou, Lee Powell, Simon N. Dahm-Daphi, Jochen Willers, Henning TI ATR-p53 Restricts Homologous Recombination in Response to Replicative Stress but Does Not Limit DNA Interstrand Crosslink Repair in Lung Cancer Cells SO PLOS ONE LA English DT Article ID WILD-TYPE P53; STRAND BREAK REPAIR; TRANSACTIVATION DOMAIN; HOLLIDAY JUNCTIONS; BLM HELICASE; MUTANT P53; PROTEIN-A; CHECKPOINT; PHOSPHORYLATION; DAMAGE AB Homologous recombination (HR) is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB). However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The cellular factors that restrict HR processes in mammalian cells are only beginning to be elucidated. The tumor suppressor p53 has been implicated in the suppression of HR though it has remained unclear why p53, as the guardian of the genome, would impair an error-free repair process. Here, we show for the first time that p53 downregulates foci formation of the RAD51 recombinase in response to replicative stress in H1299 lung cancer cells in a manner that is independent of its role as a transcription factor. We find that this downregulation of HR is not only completely dependent on the binding site of p53 with replication protein A but also the ATR/ATM serine 15 phosphorylation site. Genetic analysis suggests that ATR but not ATM kinase modulates p53's function in HR. The suppression of HR by p53 can be bypassed under experimental conditions that cause DSB either directly or indirectly, in line with p53's role as a guardian of the genome. As a result, transactivation-inactive p53 does not compromise the resistance of H1299 cells to the interstrand crosslinking agent mitomycin C. Altogether, our data support a model in which p53 plays an anti-recombinogenic role in the ATR-dependent mammalian replication checkpoint but does not impair a cell's ability to use HR for the removal of DSB induced by cytotoxic agents. C1 [Sirbu, Bianca M.; Lachmayer, Sarah J.; Wuelfing, Verena; Marten, Lara M.; Clarkson, Katie E.; Lee, Linda W.; Gheorghiu, Liliana; Willers, Henning] Massachusetts Gen Hosp, Ctr Canc, Lab Cellular & Mol Radiat Oncol, Charlestown, MA 02129 USA. [Lachmayer, Sarah J.; Wuelfing, Verena; Marten, Lara M.; Dahm-Daphi, Jochen] Univ Hamburg, Dept Radiat Oncol, Hamburg, Germany. [Zou, Lee] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA USA. [Powell, Simon N.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. [Zou, Lee; Dahm-Daphi, Jochen] Univ Marburg, Inst Radiobiol & Mol Radiat Oncol, Marburg, Germany. [Willers, Henning] Harvard Univ, Sch Med, Boston, MA USA. RP Sirbu, BM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Lab Cellular & Mol Radiat Oncol, Charlestown, MA 02129 USA. EM hwillers@partners.org FU NCI [R01 CA58985, R01 GM076388]; NCI Dana-Farber/Harvard Cancer Center SPORE in Lung Cancer [P50 CA090578]; Department of Defense [W81XWH-06-1-0309]; Massachusetts General Hospital [C06 CA059267]; Proton Therapy Research and Treatment Center; Deutsche Krebshilfe (German Cancer Aid) [10-1843-Da] FX This work was supported by NCI grants R01 CA58985 (SNP) and R01 GM076388 (LZ), the NCI Dana-Farber/Harvard Cancer Center SPORE in Lung Cancer P50 CA090578 (HW, LZ), Department of Defense W81XWH-06-1-0309 (HW), Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center (HW), and Deutsche Krebshilfe (German Cancer Aid) 10-1843-Da (JDD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 8 Z9 8 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 12 PY 2011 VL 6 IS 8 AR e23053 DI 10.1371/journal.pone.0023053 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 808CT UT WOS:000293953500016 PM 21857991 ER PT J AU Hannun, YA Obeid, LM AF Hannun, Yusuf A. Obeid, Lina M. TI Many Ceramides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID NECROSIS-FACTOR-ALPHA; RADIATION-INDUCED APOPTOSIS; LONGEVITY ASSURANCE GENE-1; TANDEM MASS-SPECTROMETRY; SQUAMOUS-CELL CARCINOMAS; SPHINGOLIPID METABOLISM; SACCHAROMYCES-CEREVISIAE; SPHINGOSINE 1-PHOSPHATE; SYNTHASE 6; NEUTRAL SPHINGOMYELINASE-2 AB Intensive research over the past 2 decades has implicated ceramide in the regulation of several cell responses. However, emerging evidence points to dramatic complexities in ceramide metabolism and structure that defy the prevailing unifying hypothesis on ceramide function that is based on the understanding of ceramide as a single entity. Here, we develop the concept that "ceramide" constitutes a family of closely related molecules, subject to metabolism by >28 enzymes and with >200 structurally distinct mammalian ceramides distinguished by specific structural modifications. These ceramides are synthesized in a combinatorial fashion with distinct enzymes responsible for the specific modifications. These multiple pathways of ceramide generation led to the hypothesis that individual ceramide molecular species are regulated by specific biochemical pathways in distinct subcellular compartments and execute distinct functions. In this minireview, we describe the "many ceramides" paradigm, along with the rationale, supporting evidence, and implications for our understanding of bioactive sphingolipids and approaches for unraveling these pathways. C1 [Hannun, Yusuf A.; Obeid, Lina M.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Obeid, Lina M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Obeid, Lina M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Hannun, YA (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. EM hannun@musc.edu; obeidl@musc.edu OI obeid, lina/0000-0002-0734-0847 FU National Institutes of Health [R01AG016583, R01GM062887]; NCI [R01GM43825, R01GM63265, P01CA097132]; Office of Research and Development, Department of Veterans Affairs; Ralph H. Johnson Veterans Affairs Medical Center (Charleston, SC) FX This work was support, in whole or in part, by National Institutes of Health Grants R01AG016583 and R01GM062887 (to L. M. O.) and R01GM43825, R01GM63265, and P01CA097132 from NCI (to Y. A. H.) and in part by a MERIT Award (to L. M. O.) from the Office of Research and Development, Department of Veterans Affairs, Ralph H. Johnson Veterans Affairs Medical Center (Charleston, SC). This minireview will be reprinted in the 2011 Minireview Compendium, which will be available in January, 2012. NR 96 TC 197 Z9 199 U1 0 U2 22 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 12 PY 2011 VL 286 IS 32 BP 27855 EP 27862 DI 10.1074/jbc.R111.254359 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 803CJ UT WOS:000293557800002 PM 21693702 ER PT J AU Li, X Yeung, DF Fiegen, AM Sodroski, J AF Li, Xing Yeung, Darwin F. Fiegen, Ann M. Sodroski, Joseph TI Determinants of the Higher Order Association of the Restriction Factor TRIM5 beta and Other Tripartite Motif (TRIM) Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; B-BOX 2; RETROVIRAL RESTRICTION; TRIM5-ALPHA PROTEIN; RHESUS TRIM5-ALPHA; B30.2(SPRY) DOMAIN; MONKEY TRIM5-ALPHA; CYTOPLASMIC BODIES; HIV-1 INFECTION; CAPSID BINDING AB Many tripartite motif (TRIM) proteins self-associate, forming dimers and higher order complexes. For example, dimers of TRIM5 alpha, a host factor that restricts retrovirus infection, assemble into higher order arrays on the surface of the viral capsid, resulting in an increase in avidity. Here we show that the higher order association of different TRIM proteins exhibits a wide range of efficiencies. Homologous association (self-association) was more efficient than the heterologous association of different TRIM proteins, indicating that specificity determinants of higher order self-association exist. To investigate the structural determinants of higher order self-association, we studied TRIM mutants and chimeras. These studies revealed the following: 1) the RING domain contributes to the efficiency of higher order self-association, which enhances the binding of TRIM5 alpha to the human immunodeficiency virus (HIV-1) capsid; 2) the RING and B-box 2 domains work together as a homologous unit to promote higher order association of dimers; 3) dimerization is probably required for efficient higher order self-association; 4) the Linker 2 region contributes to higher order self-association, independently of effects of Linker 2 changes on TRIM dimerization; and 5) for efficiently self-associating TRIM proteins, the B30.2(SPRY) domain is not required for higher order self-association. These results support a model in which both ends of the core TRIM dimer (RING-B-box 2 at one end and Linker 2 at the other) contribute to the formation of higher order arrays. C1 [Li, Xing; Yeung, Darwin F.; Fiegen, Ann M.; Sodroski, Joseph] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Canc Immunol & AIDS, 450 Brookline Ave,CLS 1010, Boston, MA 02215 USA. EM joseph_sodroski@dfci.harvard.edu FU National Institutes of Health [AI063987, AI076094]; Center for AIDS Research [AI06354]; International AIDS Vaccine Initiative FX This work was supported, in whole or in part, by National Institutes of Health Grants AI063987 and AI076094 and Center for AIDS Research Award AI06354. This work was also supported by the International AIDS Vaccine Initiative and the late William F. McCarty-Cooper. NR 46 TC 27 Z9 31 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 12 PY 2011 VL 286 IS 32 BP 27959 EP 27970 DI 10.1074/jbc.M111.260406 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 803CJ UT WOS:000293557800014 PM 21680743 ER PT J AU Zou, CB Ellis, BM Smith, RM Chen, BB Zhao, YT Mallampalli, RK AF Zou, Chunbin Ellis, Bryon M. Smith, Rebecca M. Chen, Bill B. Zhao, Yutong Mallampalli, Rama K. TI Acyl-CoA:Lysophosphatidylcholine Acyltransferase I (Lpcat1) Catalyzes Histone Protein O-Palmitoylation to Regulate mRNA Synthesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHATIDYLCHOLINE SYNTHESIS; CHROMATIN-STRUCTURE; PHOSPHORYLATION; MAINTENANCE; DROSOPHILA; STABILITY; HORMONE; YEAST; COA AB The enzyme acyl-CoA:lysophosphatidylcholine acyltransferase (Lpcat1) is a critical cytosolic enzyme needed for lung surfactant synthesis that catalyzes an acyltransferase reaction by adding a palmitate to the sn-2 position of lysophospholipids. Here we report that histone H4 protein is subject to palmitoylation catalyzed by Lpcat1 in a calcium-regulated manner. Cytosolic Lpcat1 was observed to shift into the nucleus in lung epithelia in response to exogenous Ca(2+). Nuclear Lpcat1 colocalizes with and binds to histone H4, where it catalyzes histone H4 palmitoylation. Mutagenesis studies demonstrated that Ser(47) within histone H4 serves as a putative acceptor site, indicative of Lpcat1-mediated O-palmitoylation. Lpcat1 knockdown or expression of a histone H4 Ser(47A) mutant protein in cells decreased cellular mRNA synthesis. These findings provide the first evidence of a protein substrate for Lpcat1 and reveal that histone lipidation may occur through its O-palmitoylation as a novel post-translational modification. This epigenetic modification regulates global gene transcriptional activity. C1 [Zou, Chunbin] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. RP Zou, CB (reprint author), Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Acute Lung Injury Ctr Excellence, BST E1 103,200 Lathrop St, Pittsburgh, PA 15213 USA. EM zouc@upmc.edu FU National Institutes of Health [R01 HL096376, HL097376, HL098174]; United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; United States Department of Veterans Affairs FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 HL096376, HL097376, and HL098174 (to R. K. M.). This material is based upon work supported, in part, by the United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. This work was also supported by a Merit Review Award from the United States Department of Veterans Affairs. NR 30 TC 26 Z9 27 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 12 PY 2011 VL 286 IS 32 BP 28019 EP 28025 DI 10.1074/jbc.M111.253385 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 803CJ UT WOS:000293557800020 PM 21685381 ER PT J AU Unternaehrer, JJ Daley, GQ AF Unternaehrer, Juli J. Daley, George Q. TI Induced pluripotent stem cells for modelling human diseases SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE induced pluripotent stem cells; disease modelling; reprogramming; embryonic stem cells ID FRAGILE-X-SYNDROME; LONG-QT SYNDROME; DIRECTED DIFFERENTIATION; PARKINSONS-DISEASE; MOTOR-NEURONS; PATIENT; GENERATION; ANEMIA; PATHOGENESIS; FIBROBLASTS AB Research into the pathophysiological mechanisms of human disease and the development of targeted therapies have been hindered by a lack of predictive disease models that can be experimentally manipulated in vitro. This review describes the current state of modelling human diseases with the use of human induced pluripotent stem (iPS) cell lines. To date, a variety of neurodegenerative diseases, haematopoietic disorders, metabolic conditions and cardiovascular pathologies have been captured in a Petri dish through reprogramming of patient cells into iPS cells followed by directed differentiation of disease-relevant cells and tissues. However, realizing the true promise of iPS cells for advancing our basic understanding of disease and ultimately providing novel cell-based therapies will require more refined protocols for generating the highly specialized cells affected by disease, coupled with strategies for drug discovery and cell transplantation. C1 [Unternaehrer, Juli J.; Daley, George Q.] Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Daley, George Q.] Childrens Hosp, Howard Hughes Med Inst, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Unternaehrer, Juli J.; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Unternaehrer, Juli J.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Daley, George Q.] Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, 300 Longwood Ave, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu FU NIH [RO1-DK70055, RO1-DK59279, UO1-HL100001, T32-HL07623-23]; ARRA stimulus package [RC2-HL102815]; Roche Foundation for Anemia Research; Alex's Lemonade Stand; Burroughs Wellcome Fund; Leukaemia and Lymphoma Society FX G.Q.D. is supported by grants from the NIH (RO1-DK70055, RO1-DK59279, UO1-HL100001, and special funds from the ARRA stimulus package RC2-HL102815), the Roche Foundation for Anemia Research, and Alex's Lemonade Stand. G. Q. D. is a recipient of Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukaemia and Lymphoma Society, and is an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. J.J.U. is supported by a grant from the NIH (T32-HL07623-23). We thank M. Willy Lensch for critical review of the manuscript, Patrick Cahan for contribution to the figure and Wolfgang Unternaehrer for assistance in preparing the table. NR 45 TC 45 Z9 47 U1 2 U2 16 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD AUG 12 PY 2011 VL 366 IS 1575 BP 2274 EP 2285 DI 10.1098/rstb.2011.0017 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 786RD UT WOS:000292324700010 PM 21727133 ER PT J AU Shadrach, JL Wagers, AJ AF Shadrach, Jennifer L. Wagers, Amy J. TI Stem cells for skeletal muscle repair SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE satellite cell; muscular dystrophy; sarcopenia; muscle degeneration; myogenesis ID DUCHENNE MUSCULAR-DYSTROPHY; SATELLITE CELLS; SELF-RENEWAL; INFLAMMATORY PROCESSES; MYOGENIC PROGENITORS; STEM/PROGENITOR CELLS; PHYSICAL-ACTIVITY; ADULT MYOGENESIS; BONE-MARROW; DISEASE AB Skeletal muscle is a highly specialized tissue composed of non-dividing, multi-nucleated muscle fibres that contract to generate force in a controlled and directed manner. Skeletal muscle is formed during embryogenesis from a subset of muscle precursor cells, which generate both differentiated muscle fibres and specialized muscle-forming stem cells known as satellite cells. Satellite cells remain associated with muscle fibres after birth and are responsible for muscle growth and repair throughout life. Failure in satellite cell function can lead to delayed, impaired or failed recovery after muscle injury, and such failures become increasingly prominent in cases of progressive muscle disease and in old age. Recent progress in the isolation of muscle satellite cells and elucidation of the cellular and molecular mediators controlling their activity indicate that these cells represent promising therapeutic targets. Such satellite cell-based therapies may involve either direct cell replacement or development of drugs that enhance endogenous muscle repair mechanisms. Here, we discuss recent breakthroughs in understanding both the cell intrinsic and extrinsic regulators that determine the formation and function of muscle satellite cells, as well as promising paths forward to realizing their full therapeutic potential. C1 [Wagers, Amy J.] Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. Bauer Ctr, Joslin Diabet Ctr, Cambridge, MA 02138 USA. RP Wagers, AJ (reprint author), Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, 7 Divin Ave, Cambridge, MA 02138 USA. EM amy.wagers@joslin.harvard.edu FU NIH [AG033053]; Jain Foundation; WM Keck Foundation FX Amy Wagers is an Early Career Scientist of the Howard Hughes Medical Institute. Work discussed here was supported in part by grants from the NIH (AG033053), the Jain Foundation, and the WM Keck Foundation. The authors thank Sara Jurga and Massimiliano Cerletti for the provision of unpublished images and data for this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies. NR 87 TC 35 Z9 36 U1 0 U2 15 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD AUG 12 PY 2011 VL 366 IS 1575 BP 2297 EP 2306 DI 10.1098/rstb.2011.0027 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 786RD UT WOS:000292324700012 PM 21727135 ER PT J AU Elfiky, AA Aziz, SA Conrad, PJ Siddiqui, S Hackl, W Maira, M Robert, CL Kluger, HM AF Elfiky, Aymen A. Aziz, Saadia A. Conrad, Patricia J. Siddiqui, Summar Hackl, Wolfgang Maira, Michel Robert, Camp L. Kluger, Harriet M. TI Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in renal cell cancer SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE/AKT PATHWAY; DUAL PI3K/MTOR INHIBITOR; PHASE-III TRIAL; PANCREATIC-CANCER; ANTITUMOR-ACTIVITY; SIGNALING PATHWAY; INTERFERON-ALPHA; IN-VIVO; CARCINOMA; NVP-BEZ235 AB Background: PI3K and mTOR are key components of signal transduction pathways critical for cell survival. Numerous PI3K inhibitors have entered clinical trials, while mTOR is the target of approved drugs for metastatic renal cell carcinoma (RCC). We characterized expression of p85 and p110 alpha PI3K subunits and mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules in vitro. Methods: We employed tissue microarrays containing 330 nephrectomy cases using a novel immunofluorescence-based method of Automated Quantitative Analysis (AQUA) of in situ protein expression. In RCC cell lines we assessed synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235, which co-targets PI3K and mTOR. Results: p85 expression was associated with high stage and grade (P < 0.0001 for both). High p85 and high mTOR expression were strongly associated with decreased survival, and high p85 was independently prognostic on multivariable analysis. Strong co-expression of both PI3K subunits and mTOR was found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were highly synergistic in all six RCC cell lines studied. Similar synergism was seen with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in vitro with IC(50)s in the low eta M range and resultant PARP cleavage. Conclusions: High PI3K and mTOR expression in RCC defines populations with decreased survival, suggesting that they are good drug targets in RCC. These targets tend to be co-expressed, and co-targeting these molecules is synergistic. NVP-BEZ235 is active in RCC cells in vitro; suggesting that concurrent PI3K and mTOR targeting in RCC warrants further investigation. C1 [Aziz, Saadia A.; Conrad, Patricia J.; Kluger, Harriet M.] Yale Univ, Yale Canc Ctr, Sect Med Oncol, New Haven, CT 06520 USA. [Elfiky, Aymen A.] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02215 USA. [Siddiqui, Summar; Robert, Camp L.] Yale Univ, Dept Pathol, New Haven, CT 06520 USA. [Hackl, Wolfgang; Maira, Michel] Novartis Inst Biomed Res AG, CH-4002 Basel, Switzerland. RP Kluger, HM (reprint author), Yale Univ, Yale Canc Ctr, Sect Med Oncol, 333 Cedar St, New Haven, CT 06520 USA. EM Harriet.Kluger@yale.edu FU American Society of Clinical Oncology; NIH [R21 CA116265, RO-1 R0-1 CA158167, R0-1 CA129034]; American Cancer Society [M130572] FX AAE is supported by a Young Investigator Award from the American Society of Clinical Oncology. RLC is supported by NIH Grant R21 CA116265. HMK is supported by NIH grants RO-1 R0-1 CA158167 (to H. Kluger) R0-1 CA129034 (to F. Waldman) and by American Cancer Society Award M130572 (to H. Kluger). NR 52 TC 21 Z9 21 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD AUG 11 PY 2011 VL 9 AR 133 DI 10.1186/1479-5876-9-133 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 819QG UT WOS:000294843300001 PM 21834980 ER PT J AU Huang, XM Auinger, P Eberly, S Oakes, D Schwarzschild, M Ascherio, A Mailman, R Chen, HL AF Huang, Xuemei Auinger, Peggy Eberly, Shirley Oakes, David Schwarzschild, Michael Ascherio, Alberto Mailman, Richard Chen, Honglei CA Parkinson Study Grp DATATOP TI Serum Cholesterol and the Progression of Parkinson's Disease: Results from DATATOP SO PLOS ONE LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; INCREASES DOPAMINE RELEASE; RAT NUCLEUS-ACCUMBENS; IN-VITRO; RISK; STATINS; COHORT; DISABILITY; MORPHINE AB Background: Recent studies have suggested that higher serum cholesterol may be associated with lower occurrence of Parkinson's disease (PD). This study is to test the hypothesis that higher serum cholesterol correlates with slower PD progression. Methods: Baseline non-fasting serum total cholesterol was measured in 774 of the 800 subjects with early PD enrolled between 1987 and 1988 in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. Participants were followed for up to two years, with clinical disability requiring levodopa therapy as the primary endpoint. Hazard ratios (HRs) and 95% confidence intervals (CI) were determined for increasing serum cholesterol concentration (in quintiles) for clinical disability requiring levodopa therapy, after adjusting for confounders. At baseline, only nine subjects reported use of cholesterol-lowering agents (two with statins). Results: The overall mean cholesterol level was 216 mg/dL (range 100-355). The HR of progressing to the primary endpoint decreased with increasing serum cholesterol concentrations. Compared to the lowest quintile, the HRs (95% CI), for each higher quintile (in ascending order) are 0.83 (0.59-1.16); 0.86 (0.61-1.20); 0.84 (0.60-1.18); and 0.75 (0.52-1.09). The HR for one standard deviation (SD) increase = 0.90 [(0.80-1.01), p for trend = 0.09]. This trend was found in males (HR per SD = 0.88 [(0.77-1.00), p for trend = 0.05], but not in females [ HR = 1.03 (0.81-1.32)]. Conclusions: This secondary analysis of the DATATOP trial provides preliminary evidence that higher total serum cholesterol concentrations may be associated with a modest slower clinical progression of PD, and this preliminary finding needs confirmation from larger prospective studies. C1 [Huang, Xuemei; Mailman, Richard] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Huang, Xuemei; Mailman, Richard] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. [Auinger, Peggy] Univ Rochester, Sch Med & Dent, Dept Neurol, Ctr Human Expt Therapeut, Rochester, NY 14642 USA. [Eberly, Shirley; Oakes, David] Univ Rochester, Sch Med & Dent, Dept Biostat, Rochester, NY USA. [Schwarzschild, Michael] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. RP Huang, XM (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. EM Xuemei@psu.edu OI Mailman, Richard/0000-0003-1353-2738; Chen, Honglei/0000-0003-3446-7779 FU Parkinson's Disease Foundation; National Institutes of Health [NS060722]; Pennsylvania Tobacco Settlement Fund; National Institute of Environmental Health Sciences [Z01-ES-101986] FX This work was supported, in part, by Parkinson's Disease Foundation, National Institutes of Health (NS060722 to XH), the Pennsylvania Tobacco Settlement Fund, and the intramural research program of the National Institute of Environmental Health Sciences (Z01-ES-101986 to HC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation. NR 34 TC 16 Z9 16 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 11 PY 2011 VL 6 IS 8 AR e22854 DI 10.1371/journal.pone.0022854 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 808CS UT WOS:000293953400015 PM 21853051 ER PT J AU Tang, M Gonen, M Quintas-Cardama, A Cortes, J Kantarjian, H Field, C Hughes, TP Branford, S Michor, F AF Tang, Min Gonen, Mithat Quintas-Cardama, Alfonso Cortes, Jorge Kantarjian, Hagop Field, Chani Hughes, Timothy P. Branford, Susan Michor, Franziska TI Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells SO BLOOD LA English DT Article ID ABL TYROSINE KINASE; COMPLETE MOLECULAR REMISSION; CHRONIC MYELOGENOUS LEUKEMIA; STOCHASTIC GENE-EXPRESSION; EARLY CHRONIC-PHASE; IMATINIB MESYLATE; CML PATIENTS; TRANSPLANTATION; DISCONTINUATION; INTERLEUKIN-3 AB Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitors (TKIs) imatinib mesylate and nilotinib represents a successful application of molecularly targeted anticancer therapy. However, the effect of TKIs on leukemic stem cells remains incompletely understood. On the basis of a statistical modeling approach that used the 10-year imatinib mesylate treatment response of patients with CML and a patient cohort receiving first-line nilotinib therapy, we found that successful long-term therapy results in a triphasic exponential decline of BCR-ABL1 transcripts in many patients. Within our framework, the first slope of -0.052 +/- 0.018 (imatinib mesylate) and -0.042 +/- 0.015 (nilotinib) per day represents the turnover rate of leukemic differentiated cells, whereas the second slope of -0.0057 +/- 0.0038 (imatinib mesylate) and -0.0019 +/- 0.0013 (nilotinib) per day represents the turnover rate of leukemic progenitor cells. The third slope allows an inference of the behavior of immature leukemic cells, potentially stem cells. This third slope is negative in most patients, positive in others, and not observable in some patients. This variability in response may be because of insufficient follow-up, missing data, disease heterogeneity, inconsistent compliance to drug, or acquired resistance. Our approach suggests that long-term TKI therapy may reduce the abundance of leukemic stem cells in some patients. (Blood. 2011;118(6):1622-1631) C1 [Tang, Min; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tang, Min; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Gonen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Biostat & Epidemiol, New York, NY 10021 USA. [Quintas-Cardama, Alfonso; Cortes, Jorge; Kantarjian, Hagop] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Field, Chani; Hughes, Timothy P.; Branford, Susan] SA Pathol, Dept Genet & Mol Pathol, Adelaide, SA, Australia. [Field, Chani; Hughes, Timothy P.; Branford, Susan] Univ Adelaide, Adelaide, SA, Australia. RP Michor, F (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02115 USA. EM michor@jimmy.harvard.edu RI Tang, Min/A-9311-2012; Gonen, Mithat/E-4826-2012 FU NCI NIH HHS [P30 CA016672] NR 44 TC 30 Z9 32 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 11 PY 2011 VL 118 IS 6 BP 1622 EP 1631 DI 10.1182/blood-2011-02-339267 PG 10 WC Hematology SC Hematology GA 806DW UT WOS:000293787300029 PM 21653938 ER PT J AU Hendricks, JA Keliher, EJ Marinelli, B Reiner, T Weissleder, R Mazitschek, R AF Hendricks, J. Adam Keliher, Edmund J. Marinelli, Brett Reiner, Thomas Weissleder, Ralph Mazitschek, Ralph TI In Vivo PET Imaging of Histone Deacetylases by F-18-Suberoylanilide Hydroxamic Acid (F-18-SAHA) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID INHIBITORS; CELLS; MALIGNANCIES; DISEASE; CANCER; BRAIN AB Histone deacetylases (HDACs) are a group of enzymes that modulate gene expression and cell state by deacetylation of both histone and non-histone proteins. A variety of HDAC inhibitors (HDACi) have already undergone clinical testing in cancer. Real-time in vivo imaging of HDACs and their inhibition would be invaluable; however, the development of appropriate imaging agents has remained a major challenge. Here, we describe the development and evaluation of F-18-suberoylanilide hydroxamic acid (F-18-SAHA 1a), a close analogue of the most clinically relevant HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). We demonstrate that 1a has near identical biochemical activity profiles to that of SAHA and report findings from pharmacokinetic studies. Using a murine ovarian. cancer model, we likewise show that HDAC inhibitor target binding efficacy can be quantitated within 24 h of administration. 1a thus represents the first F-18-positron emission tomography (PET) HDAC imaging agent, which also exhibits low nanomolar potency and is pharmacologically analogous to a clinically relevant HDAC inhibitor. C1 [Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu; rmazitschek@mgh.harvard.edu RI Mazitschek, Ralph/E-3741-2013; OI Mazitschek, Ralph/0000-0002-1105-689X; Reiner, Thomas/0000-0002-7819-5480 FU NCI [P50CA086355, T32CA079443, U24CA092782]; Deutschen Akademie der Wissenschaften Leopoldina [LPDS 2009-24] FX Financial support from the NCI (Grants P50CA086355, T32CA079443, and U24CA092782) is gratefully acknowledged. T.R received a stipend from the Deutschen Akademie der Wissenschaften Leopoldina (Grant LPDS 2009-24). NR 26 TC 21 Z9 21 U1 4 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 11 PY 2011 VL 54 IS 15 BP 5576 EP 5582 DI 10.1021/jm200620f PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 801EK UT WOS:000293419400027 PM 21721525 ER PT J AU Grelotti, DJ Kaptchuk, TJ AF Grelotti, David J. Kaptchuk, Ted J. TI Placebo by proxy SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID METAANALYSIS; CHILDREN C1 [Grelotti, David J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Grelotti, David J.] Harvard Univ, Sch Med, McLean Hosp, Boston, MA 02114 USA. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Program Placebo Studies, Boston, MA 02114 USA. RP Grelotti, DJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM david_grelotti@hms.harvard.edu FU NCCIH NIH HHS [K24 AT004095] NR 12 TC 16 Z9 17 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD AUG 11 PY 2011 VL 343 AR d4345 DI 10.1136/bmj.d4345 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 808DP UT WOS:000293956900001 PM 21835868 ER PT J AU Sawcer, S Hellenthal, G Pirinen, M Spencer, CCA Patsopoulos, NA Moutsianas, L Dilthey, A Su, Z Freeman, C Hunt, SE Edkins, S Gray, E Booth, DR Potter, SC Goris, A Band, G Oturai, AB Strange, A Saarela, J Bellenguez, C Fontaine, B Gillman, M Hemmer, B Gwilliam, R Zipp, F Jayakumar, A Martin, R Leslie, S Hawkins, S Giannoulatou, E D'alfonso, S Blackburn, H Boneschi, FM Liddle, J Harbo, HF Perez, ML Spurkland, A Waller, MJ Mycko, MP Ricketts, M Comabella, M Hammond, N Kockum, I McCann, OT Ban, M Whittaker, P Kemppinen, A Weston, P Hawkins, C Widaa, S Zajicek, J Dronov, S Robertson, N Bumpstead, SJ Barcellos, LF Ravindrarajah, R Abraham, R Alfredsson, L Ardlie, K Aubin, C Baker, A Baker, K Baranzini, SE Bergamaschi, L Bergamaschi, R Bernstein, A Berthele, A Boggild, M Bradfield, JP Brassat, D Broadley, SA Buck, D Butzkueven, H Capra, R Carroll, WM Cavalla, P Celius, EG Cepok, S Chiavacci, R Clerget-Darpoux, F Clysters, K Comi, G Cossburn, M Cournu-Rebeix, I Cox, MB Cozen, W Cree, BAC Cross, AH Cusi, D Daly, MJ Davis, E de Bakker, PIW Debouverie, M D'hooghe, MB Dixon, K Dobosi, R Dubois, B Ellinghaus, D Elovaara, I Esposito, F Fontenille, C Foote, S Franke, A Galimberti, D Ghezzi, A Glessner, J Gomez, R Gout, O Graham, C Grant, SFA Guerini, FR Hakonarson, H Hall, P Hamsten, A Hartung, HP Heard, RN Heath, S Hobart, J Hoshi, M Infante-Duarte, C Ingram, G Ingram, W Islam, T Jagodic, M Kabesch, M Kermode, AG Kilpatrick, TJ Kim, C Klopp, N Koivisto, K Larsson, M Lathrop, M Lechner-Scott, JS Leone, MA Leppa, V Liljedahl, U Bomfim, IL Lincoln, RR Link, J Liu, JJ Lorentzen, AR Lupoli, S Macciardi, F Mack, T Marriott, M Martinelli, V Mason, D McCauley, JL Mentch, F Mero, IL Mihalova, T Montalban, X Mottershead, J Myhr, KM Naldi, P Ollier, W Page, A Palotie, A Pelletier, J Piccio, L Pickersgill, T Piehl, F Pobywajlo, S Quach, HL Ramsay, PP Reunanen, M Reynolds, R Rioux, J Rodegher, M Roesner, S Rubio, JP Ruckert, IM Salvetti, M Salvi, E Santaniello, A Schaefer, CA Schreiber, S Schulze, C Scott, RJ Sellebjerg, F Selmaj, KW Sexton, D Shen, L Simms-Acuna, B Skidmore, S Sleiman, PMA Smestad, C Sorensen, PS Sondergaard, HB Stankovich, J Strange, RC Sulonen, AM Sundqvist, E Syvanen, AC Taddeo, F Taylor, B Blackwell, JM Tienari, P Bramon, E Tourbah, A Brown, MA Tronczynska, E Casas, JP Tubridy, N Corvin, A Vickery, J Jankowski, J Villoslada, P Markus, HS Wang, K Mathew, CG Wason, J Palmer, CNA Wichmann, HE Plomin, R Willoughby, E Rautanen, A Winkelmann, J Wittig, M Trembath, RC Yaouanq, J Viswanathan, AC Zhang, HT Wood, NW Zuvich, R Deloukas, P Langford, C Duncanson, A Oksenberg, JR Pericak-Vance, MA Haines, JL Olsson, T Hillert, J Ivinson, AJ De Jager, PL Peltonen, L Stewart, GJ Hafler, DA Hauser, SL McVean, G Donnelly, P Compston, A AF Sawcer, Stephen Hellenthal, Garrett Pirinen, Matti Spencer, Chris C. A. Patsopoulos, Nikolaos A. Moutsianas, Loukas Dilthey, Alexander Su, Zhan Freeman, Colin Hunt, Sarah E. Edkins, Sarah Gray, Emma Booth, David R. Potter, Simon C. Goris, An Band, Gavin Oturai, Annette Bang Strange, Amy Saarela, Janna Bellenguez, Celine Fontaine, Bertrand Gillman, Matthew Hemmer, Bernhard Gwilliam, Rhian Zipp, Frauke Jayakumar, Alagurevathi Martin, Roland Leslie, Stephen Hawkins, Stanley Giannoulatou, Eleni D'alfonso, Sandra Blackburn, Hannah Boneschi, Filippo Martinelli Liddle, Jennifer Harbo, Hanne F. Perez, Marc L. Spurkland, Anne Waller, Matthew J. Mycko, Marcin P. Ricketts, Michelle Comabella, Manuel Hammond, Naomi Kockum, Ingrid McCann, Owen T. Ban, Maria Whittaker, Pamela Kemppinen, Anu Weston, Paul Hawkins, Clive Widaa, Sara Zajicek, John Dronov, Serge Robertson, Neil Bumpstead, Suzannah J. Barcellos, Lisa F. Ravindrarajah, Rathi Abraham, Roby Alfredsson, Lars Ardlie, Kristin Aubin, Cristin Baker, Amie Baker, Katharine Baranzini, Sergio E. Bergamaschi, Laura Bergamaschi, Roberto Bernstein, Allan Berthele, Achim Boggild, Mike Bradfield, Jonathan P. Brassat, David Broadley, Simon A. Buck, Dorothea Butzkueven, Helmut Capra, Ruggero Carroll, William M. Cavalla, Paola Celius, Elisabeth G. Cepok, Sabine Chiavacci, Rosetta Clerget-Darpoux, Francoise Clysters, Katleen Comi, Giancarlo Cossburn, Mark Cournu-Rebeix, Isabelle Cox, Mathew B. Cozen, Wendy Cree, Bruce A. C. Cross, Anne H. Cusi, Daniele Daly, Mark J. Davis, Emma de Bakker, Paul I. W. Debouverie, Marc D'hooghe, Marie Beatrice Dixon, Katherine Dobosi, Rita Dubois, Benedicte Ellinghaus, David Elovaara, Irina Esposito, Federica Fontenille, Claire Foote, Simon Franke, Andre Galimberti, Daniela Ghezzi, Angelo Glessner, Joseph Gomez, Refujia Gout, Olivier Graham, Colin Grant, Struan F. A. Guerini, Franca Rosa Hakonarson, Hakon Hall, Per Hamsten, Anders Hartung, Hans-Peter Heard, Rob N. Heath, Simon Hobart, Jeremy Hoshi, Muna Infante-Duarte, Carmen Ingram, Gillian Ingram, Wendy Islam, Talat Jagodic, Maja Kabesch, Michael Kermode, Allan G. Kilpatrick, Trevor J. Kim, Cecilia Klopp, Norman Koivisto, Keijo Larsson, Malin Lathrop, Mark Lechner-Scott, Jeannette S. Leone, Maurizio A. Leppa, Virpi Liljedahl, Ulrika Bomfim, Izaura Lima Lincoln, Robin R. Link, Jenny Liu, Jianjun Lorentzen, Aslaug R. Lupoli, Sara Macciardi, Fabio Mack, Thomas Marriott, Mark Martinelli, Vittorio Mason, Deborah McCauley, Jacob L. Mentch, Frank Mero, Inger-Lise Mihalova, Tania Montalban, Xavier Mottershead, John Myhr, Kjell-Morten Naldi, Paola Ollier, William Page, Alison Palotie, Aarno Pelletier, Jean Piccio, Laura Pickersgill, Trevor Piehl, Fredrik Pobywajlo, Susan Quach, Hong L. Ramsay, Patricia P. Reunanen, Mauri Reynolds, Richard Rioux, Johnd. Rodegher, Mariaemma Roesner, Sabine Rubio, Justin P. Rueckert, Ina-Maria Salvetti, Marco Salvi, Erika Santaniello, Adam Schaefer, Catherine A. Schreiber, Stefan Schulze, Christian Scott, Rodney J. Sellebjerg, Finn Selmaj, Krzysztof W. Sexton, David Shen, Ling Simms-Acuna, Brigid Skidmore, Sheila Sleiman, Patrick M. A. Smestad, Cathrine Sorensen, Per Soelberg Sondergaard, Helle Bach Stankovich, Jim Strange, Richard C. Sulonen, Anna-Maija Sundqvist, Emilie Syvaenen, Ann-Christine Taddeo, Francesca Taylor, Bruce Blackwell, Jenefer M. Tienari, Pentti Bramon, Elvira Tourbah, Ayman Brown, Matthew A. Tronczynska, Ewa Casas, Juan P. Tubridy, Niall Corvin, Aiden Vickery, Jane Jankowski, Janusz Villoslada, Pablo Markus, Hugh S. Wang, Kai Mathew, Christopher G. Wason, James Palmer, Colin N. A. Wichmann, H-Erich Plomin, Robert Willoughby, Ernest Rautanen, Anna Winkelmann, Juliane Wittig, Michael Trembath, Richard C. Yaouanq, Jacqueline Viswanathan, Ananth C. Zhang, Haitao Wood, Nicholas W. Zuvich, Rebecca Deloukas, Panos Langford, Cordelia Duncanson, Audrey Oksenberg, Jorge R. Pericak-Vance, Margaret A. Haines, Jonathan L. Olsson, Tomas Hillert, Jan Ivinson, Adrian J. De Jager, Philip L. Peltonen, Leena Stewart, Graeme J. Hafler, David A. Hauser, Stephen L. McVean, Gil Donnelly, Peter Compston, Alastair CA Int Multiple Sclerosis Genetics Co Wellcome Trust Case Control Consor TI Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; HETEROGENEITY; HAPLOTYPES; VARIANTS; ALLELES AB Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability(1). Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals(2,3), and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk(4). Modestly powered genome-wide association studies (GWAS)(5-10) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility(11). Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. C1 [Sawcer, Stephen; Ban, Maria; Kemppinen, Anu; Baker, Amie; Skidmore, Sheila; Compston, Alastair] Univ Cambridge, Dept Clin Neurosci, Addenbrookes Hosp, Cambridge CB2 0QQ, England. [Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C. A.; Su, Zhan; Freeman, Colin; Band, Gavin; Strange, Amy; Bellenguez, Celine; Giannoulatou, Eleni; Rautanen, Anna; McVean, Gil; Donnelly, Peter] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Patsopoulos, Nikolaos A.; de Bakker, Paul I. W.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet,Dept Med, Boston, MA 02115 USA. [Patsopoulos, Nikolaos A.; Ardlie, Kristin; Aubin, Cristin; Daly, Mark J.; de Bakker, Paul I. W.; De Jager, Philip L.; Hafler, David A.] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Patsopoulos, Nikolaos A.; Pobywajlo, Susan; De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Ctr Neurol Dis, Boston, MA 02115 USA. [Moutsianas, Loukas; Dilthey, Alexander; Donnelly, Peter] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Hunt, Sarah E.; Edkins, Sarah; Gray, Emma; Potter, Simon C.; Gillman, Matthew; Gwilliam, Rhian; Jayakumar, Alagurevathi; Blackburn, Hannah; Liddle, Jennifer; Perez, Marc L.; Waller, Matthew J.; Ricketts, Michelle; Hammond, Naomi; McCann, Owen T.; Whittaker, Pamela; Weston, Paul; Widaa, Sara; Dronov, Serge; Bumpstead, Suzannah J.; Ravindrarajah, Rathi; Palotie, Aarno; Deloukas, Panos; Langford, Cordelia] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Booth, David R.; Heard, Rob N.; Stewart, Graeme J.] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2145, Australia. [Goris, An; Clysters, Katleen; Dobosi, Rita; Dubois, Benedicte] Katholieke Univ Leuven, Sect Expt Neurol, Lab Neuroimmunol, B-3000 Louvain, Belgium. [Oturai, Annette Bang; Sellebjerg, Finn; Sorensen, Per Soelberg; Sondergaard, Helle Bach] Rigshosp, Copenhagen Univ Hosp, Dept Neurol, Danish Multiple Sclerosis Ctr, DK-2100 Copenhagen, Denmark. [Saarela, Janna; Leppa, Virpi; Palotie, Aarno; Sulonen, Anna-Maija] Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland. [Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Fontenille, Claire] UPMC, AP HP, INSERM UMR S CRICM 975, Dept Neurol Pitie Salpetriere, F-75013 Paris, France. [Hemmer, Bernhard; Berthele, Achim; Buck, Dorothea; Cepok, Sabine; Hoshi, Muna; Winkelmann, Juliane] Tech Univ Munich, Klinikum Rechts Isar, Dept Neurol, D-81675 Munich, Germany. [Zipp, Frauke] Johannes Gutenberg Univ Mainz, Univ Med Mainz, Dept Neurol, D-55131 Mainz, Germany. [Zipp, Frauke; Martin, Roland] Max Delbrueck Ctr Mol Med, D-13092 Berlin, Germany. [Roesner, Sabine] Ctr Mol Neurobiol, Inst Neuroimmunol & Clin MS Res Inims, D-20251 Hamburg, Germany. [Leslie, Stephen] Univ Oxford, Dept Clin Pharmacol, Oxford OX3 7DQ, England. [Hawkins, Stanley] Queens Univ Belfast, Belfast BT7 1NN, Antrim, North Ireland. [D'alfonso, Sandra; Bergamaschi, Laura] Univ Piemonte Orientale, Dept Med Sci, I-28100 Novara, Italy. [D'alfonso, Sandra; Bergamaschi, Laura] Univ Piemonte Orientale, IRCAD, I-28100 Novara, Italy. [Boneschi, Filippo Martinelli; Comi, Giancarlo; Esposito, Federica; Martinelli, Vittorio; Rodegher, Mariaemma] Ist Sci San Raffaele, Dept Neurol, Inst Expt Neurol INSPE, Div Neurosci, I-20132 Milan, Italy. [Harbo, Hanne F.; Celius, Elisabeth G.; Mero, Inger-Lise; Smestad, Cathrine] Oslo Univ Hosp, Dept Neurol, N-0407 Oslo, Norway. [Harbo, Hanne F.; Lorentzen, Aslaug R.] Univ Oslo, Dept Neurol, N-0318 Oslo, Norway. [Spurkland, Anne] Univ Oslo, Inst Basal Med Sci, N-0317 Oslo, Norway. [Mycko, Marcin P.; Selmaj, Krzysztof W.; Tronczynska, Ewa] Med Univ Lodz, Lab Neuroimmunol, Dept Neurol, PL-90153 Lodz, Poland. [Comabella, Manuel; Montalban, Xavier] Vall dHebron Univ Hosp, Multiple Sclerosis Ctr Catalonia CEM Cat, Clin Neuroinmunol Unit, Barcelona 08035, Spain. [Kockum, Ingrid; Jagodic, Maja; Bomfim, Izaura Lima; Link, Jenny; Piehl, Fredrik; Sundqvist, Emilie; Olsson, Tomas; Hillert, Jan] Karolinska Inst, Karolinska Univ Hosp, Ctr Mol Med CMM, Dept Clin Neurosci, SE-17176 Stockholm, Sweden. [Hawkins, Clive; Abraham, Roby; Mihalova, Tania; Strange, Richard C.] Keele Univ, Sch Med, Stoke On Trent ST4 7NY, Staffs, England. [Zajicek, John; Hobart, Jeremy; Ingram, Wendy; Vickery, Jane] Univ Exeter, Peninsula Coll Med & Dent, Plymouth PL6 8BX, Devon, England. [Zajicek, John; Hobart, Jeremy; Ingram, Wendy; Vickery, Jane] Univ Plymouth, Clin Neurol Res Grp, Plymouth PL6 8BX, Devon, England. [Robertson, Neil; Baker, Katharine; Cossburn, Mark; Ingram, Gillian; Pickersgill, Trevor] Univ Wales Hosp, Dept Neurol, Cardiff CF14 4XW, S Glam, Wales. [Barcellos, Lisa F.; Quach, Hong L.; Ramsay, Patricia P.] Univ Calif Berkeley, Genet Epidemiol & Genom Lab, Div Epidemiol, Sch Publ Hlth, Berkeley, CA 94720 USA. [Barcellos, Lisa F.; Bernstein, Allan; Schaefer, Catherine A.; Shen, Ling; Simms-Acuna, Brigid] Kaiser Permanente No Calif Div Res, Oakland, CA 94612 USA. [Alfredsson, Lars] Karolinska Inst, Inst Expt Med, S-17177 Stockholm, Sweden. [Baranzini, Sergio E.; Cree, Bruce A. C.; Gomez, Refujia; Lincoln, Robin R.; Santaniello, Adam; Oksenberg, Jorge R.; Hauser, Stephen L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Bergamaschi, Roberto] IRCCS, Neurol Inst C Mondino, I-27100 Pavia, Italy. [Boggild, Mike] Walton Ctr Neurol & Neurosurg, Liverpool L7 9LJ, Merseyside, England. [Bradfield, Jonathan P.; Chiavacci, Rosetta; Glessner, Joseph; Grant, Struan F. A.; Hakonarson, Hakon; Kim, Cecilia; Mentch, Frank; Sleiman, Patrick M. A.; Wang, Kai; Zhang, Haitao] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Brassat, David] INSERM, U1043, F-31059 Toulouse, France. [Brassat, David] Hop Purpan, F-31059 Toulouse, France. [Broadley, Simon A.] Griffith Univ, Sch Med, Gold Coast, Qld 4222, Australia. [Butzkueven, Helmut; Kilpatrick, Trevor J.; Marriott, Mark; Rubio, Justin P.] Univ Melbourne, Florey Neurosci Inst, Melbourne, Vic 3010, Australia. [Butzkueven, Helmut; Kilpatrick, Trevor J.; Marriott, Mark; Tubridy, Niall] Royal Melbourne Hosp, Parkville, Vic 3050, Australia. [Butzkueven, Helmut] Monash Univ, Box Hill Hosp, Clayton, Vic 3800, Australia. [Butzkueven, Helmut] Univ Melbourne, Dept Med, RMH Cluster, Melbourne, Vic 3010, Australia. [Capra, Ruggero] Osped Civili Brescia, Dept Neurol, Multiple Sclerosis Ctr, I-25018 Brescia, Italy. [Carroll, William M.; Kermode, Allan G.] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Perth, WA 6009, Australia. [Cavalla, Paola] Univ Turin, AOU San Giovanni Battista, Dept Neurosci, I-10126 Turin, Italy. [Clerget-Darpoux, Francoise] Univ Paris 11, INSERM, U669, F-94800 Villejuif, France. [Cox, Mathew B.; Lechner-Scott, Jeannette S.; Scott, Rodney J.] Univ Newcastle, Callaghan, NSW 2308, Australia. [Cozen, Wendy; Islam, Talat; Mack, Thomas] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cross, Anne H.; Piccio, Laura] Washington Univ, Dept Neurol, St Louis, MO 63110 USA. [Cusi, Daniele; Lupoli, Sara; Macciardi, Fabio; Salvi, Erika] Univ Milan, Filarete Fdn, AO San Paolo, Dept Med Surg & Dent, I-20139 Milan, Italy. [Daly, Mark J.; Ivinson, Adrian J.; De Jager, Philip L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Davis, Emma; Dixon, Katherine; Ollier, William] Univ Manchester, UK DNA Banking Network, Ctr Integrated Genom Med Res, Manchester M13 9PT, Lancs, England. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Div Biomed Genet, Dept Med Genet, NL-3508 GA Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3508 GA Utrecht, Netherlands. [Debouverie, Marc] Hop Cent, Serv Neurol, F-54035 Nancy, France. [D'hooghe, Marie Beatrice] Natl Multiple Sclerosis Ctr, B-1820 Melsbroek, Belgium. [Ellinghaus, David; Franke, Andre; Schreiber, Stefan; Wittig, Michael] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany. [Elovaara, Irina] Tampere Univ Hosp, Dept Neurol, FIN-33014 Tampere, Finland. [Elovaara, Irina] Univ Tampere, Sch Med, Tampere 33014, Finland. [Foote, Simon; Stankovich, Jim; Taylor, Bruce] Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas 7000, Australia. [Galimberti, Daniela] Univ Milan, Fdn Ca Granda, Ctr Dino Ferrari, Dept Neurol Sci,Osped Maggiore Policlin, I-20122 Milan, Italy. [Ghezzi, Angelo] Osped Gallarate, Ctr Studi Sclerosi Multipla, I-21013 Gallarate, VA, Italy. [Gout, Olivier] Fdn Ophtalmol Adolphe de Rothschild, Serv Neurol, F-75019 Paris, France. [Graham, Colin] Belfast Hlth & Social Care Trust, City Hosp, Belfast BT9 7AB, Antrim, North Ireland. [Grant, Struan F. A.; Hakonarson, Hakon; Sleiman, Patrick M. A.; Wang, Kai; Zhang, Haitao] Childrens Hosp Philadelphia, Div Genet, Philadelphia, PA 19104 USA. [Grant, Struan F. A.; Hakonarson, Hakon] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Guerini, Franca Rosa] Don C Gnocchi Fdn IRCCS, Lab Mol Med & Biotechnol, I-20148 Milan, Italy. [Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Hamsten, Anders; Larsson, Malin] Karolinska Inst, Karolinska Univ, Dept Med Solna, Atherosclerosis Res Unit, S-17176 Stockholm, Sweden. [Hartung, Hans-Peter] Univ Dusseldorf, Dept Neurol, D-40225 Dusseldorf, Germany. [Heath, Simon; Lathrop, Mark] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, F-91057 Evry, France. [Infante-Duarte, Carmen] Univ Med Berlin, Charite, Expt & Clin Res Ctr, D-13125 Berlin, Germany. [Infante-Duarte, Carmen] Max Delbrueck Ctr Mol Med, D-13125 Berlin, Germany. [Kabesch, Michael] Hannover Med Sch, Dept Paediat Pneumol Allergy & Neonatol, D-30625 Hannover, Germany. [Kilpatrick, Trevor J.] Univ Melbourne, Ctr Neurosci, Melbourne, Vic 3010, Australia. [Klopp, Norman; Rueckert, Ina-Maria; Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, D-85764 Munich, Germany. [Koivisto, Keijo] Seinajoki Cent Hosp, Seinajoki 60220, Finland. [Lechner-Scott, Jeannette S.] John Hunter Hosp, Hunter Med Res Inst, New Lambton, NSW 2305, Australia. [Leone, Maurizio A.; Naldi, Paola] Maggiore della Carita Hosp, SCDU Neurol, I-28100 Novara, Italy. [Leppa, Virpi; Sulonen, Anna-Maija] Natl Inst Hlth & Welf, Unit Publ Hlth Genom, Helsinki 00290, Finland. [Liljedahl, Ulrika; Syvaenen, Ann-Christine] Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Univ Hosp,Res Dept 2, S-75185 Uppsala, Sweden. [Liu, Jianjun] Genome Inst Singapore, Singapore 138672, Singapore. [Lorentzen, Aslaug R.; Mero, Inger-Lise] Oslo Univ Hosp, Inst Immunol, N-0027 Oslo, Norway. [Lupoli, Sara] Ist Sci San Raffaele, Inst Expt Neurol INSPE, I-20132 Milan, Italy. [Macciardi, Fabio] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92617 USA. [Mason, Deborah] Univ Otago, Christchurch Sch Med, Christchurch 8041, New Zealand. [McCauley, Jacob L.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [McCauley, Jacob L.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA. [Mottershead, John] Hope Hosp, Greater Manchester Ctr Clin Neurosci, Salford M6 8HD, Lancs, England. [Mottershead, John] Dunedin Publ Hosp, Dept Neurol, Otago 9016, New Zealand. [Myhr, Kjell-Morten] Haukeland Hosp, Dept Neurol, Norwegian Multiple Sclerosis Competence Ctr, N-5021 Bergen, Norway. [Myhr, Kjell-Morten] Univ Bergen, Dept Clin Med, N-5021 Bergen, Norway. [Page, Alison] Derriford Hosp, Dept Neurol, Plymouth Hosp NHS Trust, Plymouth PL6 8DH, Devon, England. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki 00014, Finland. [Palotie, Aarno] Univ Cent Hosp, Helsinki 00014, Finland. [Palotie, Aarno] Broad Inst MIT & Harvard, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA 02142 USA. [Pelletier, Jean] Hop La Timone, Serv Neurol, Pole Neurosci Clin, F-13005 Marseille, France. [Reunanen, Mauri] Oulu Univ Hosp, Dept Neurol, Oulu 90029, Finland. [Reynolds, Richard] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Wolfson Neurosci Labs, UK MS Tissue Bank, London W12 0NN, England. [Rioux, Johnd.] Univ Montreal, Montreal, PQ H1T 1C8, Canada. [Rioux, Johnd.] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Salvetti, Marco] Univ Roma La Sapienza, Ctr Expt Neurol Therapy CENTERS, I-00189 Rome, Italy. [Salvi, Erika; Taddeo, Francesca] KOS Genet Srl, I-20123 Milan, Italy. [Schreiber, Stefan] Univ Kiel, Univ Hosp, Dept Gen Internal Med, D-24105 Kiel, Germany. [Schulze, Christian] Ctr Mol Neurobiol, D-20251 Hamburg, Germany. [Sexton, David; Zuvich, Rebecca; Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN 37232 USA. [Blackwell, Jenefer M.] Univ Western Australia, Ctr Child Hlth Res, Telethon Inst Child Hlth Res, Subiaco, WA 6008, Australia. [Blackwell, Jenefer M.] Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Cambridge CB2 0XY, England. [Tienari, Pentti] Univ Helsinki, Cent Hosp, Dept Neurol, FIN-00290 Helsinki, Finland. [Blackwell, Jenefer M.; Tienari, Pentti] Univ Helsinki, Biomedicum, Mol Neurol Programme, FIN-00290 Helsinki, Finland. [Bramon, Elvira] Kings Coll London, Inst Psychiat, Biomed Res Ctr Mental Hlth, Div Psychol Med & Psychiat, London SE5 8AF, England. [Bramon, Elvira] S London & Maudsley NHS Fdn Trust, London SE5 8AF, England. [Tourbah, Ayman] Univ Reims, Serv Neurol, F-51100 Reims, France. [Tourbah, Ayman] Univ Reims, Fac Med Reims, F-51100 Reims, France. [Brown, Matthew A.] Univ Queensland, Brisbane, Qld 4102, Australia. [Brown, Matthew A.] Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld 4102, Australia. [Casas, Juan P.] Univ London London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1E 7HT, England. [Tubridy, Niall] St Vincents Univ Hosp, Dublin 4, Ireland. [Corvin, Aiden] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin 2, Eire, Ireland. [Jankowski, Janusz] Barts & London Queen Marys Sch Med & Dent, Ctr Gastroenterol, London E1 2AT, England. [Villoslada, Pablo] Hosp Clin Barcelona, Inst Biomed Res August Pi Sunyer IDIBAPS, Dept Neurosci, Barcelona 08036, Spain. [Markus, Hugh S.] St Georges Univ London, London SW17 0RE, England. [Mathew, Christopher G.; Trembath, Richard C.] Kings Coll London, Guys Hosp, Sch Med, Dept Med & Mol Genet, London SE1 9RT, England. [Wason, James] Med Res Council Biostat Unit, Cambridge CB2 0SR, England. [Palmer, Colin N. A.] Univ Dundee, Inst Biomed Res, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Scotland. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Wichmann, H-Erich] Klinikum Grosshadern, D-81377 Munich, Germany. [Plomin, Robert] Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London SE5 8AF, England. [Willoughby, Ernest] Auckland City Hosp, Dept Neurol, Auckland 1010, New Zealand. [Winkelmann, Juliane] Tech Univ Munich, Inst Humangenet, D-81675 Munich, Germany. [Winkelmann, Juliane] Helmholtz Zentrum Munchen, Inst Humangenet, D-85764 Munich, Germany. [Wittig, Michael] Univ Kiel, Popgen Biobank, D-24105 Kiel, Germany. [Yaouanq, Jacqueline] CHU Pontchaillou, F-35033 Rennes, France. [Viswanathan, Ananth C.] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr Ophthalmol, London EC1V 2PD, England. [Viswanathan, Ananth C.] UCL Inst Ophthalmol, London EC1V 2PD, England. [Wood, Nicholas W.] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Duncanson, Audrey] Wellcome Trust Res Labs, London NW1 2BE, England. [Ivinson, Adrian J.] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr, Boston, MA 02115 USA. [Hafler, David A.] Yale Univ, Sch Med, Dept Neurol & Immunol, New Haven, CT 06520 USA. RP Compston, A (reprint author), Univ Cambridge, Dept Clin Neurosci, Addenbrookes Hosp, BOX 165,Hills Rd, Cambridge CB2 0QQ, England. EM donnelly@well.ox.ac.uk; alastair.compston@medschl.cam.ac.uk RI Mathew, Christopher/G-3434-2015; Macciardi, Fabio/N-3768-2014; Hauser, Stephen/J-2978-2016; Esposito, Federica/K-6537-2016; Mycko, Marcin Przemyslaw/S-9386-2016; Franke, Andre/B-2151-2010; D'hooghe, Marie/G-3423-2013; de Bakker, Paul/B-8730-2009; Schreiber, Stefan/B-6748-2008; Plomin, Robert/B-8911-2008; D'Alfonso, Sandra/K-7295-2014; Salvi, Erika/C-1033-2015; Goris, An/F-2943-2010; Zipp, Frauke/C-9968-2015; brassat, david/L-2173-2014; Wood, Nicholas/C-2505-2009; Jankowski, Janusz/H-2706-2012; Blackwell, Jenefer/H-3015-2015; Rioux, John/A-9599-2015; Baranzini, Sergio/A-9422-2013; Deloukas, Panos/B-2922-2013; Piehl, Fredrik/E-3451-2013; Foote, Simon/F-2802-2013; Palmer, Colin/C-7053-2008; turton, miranda/F-4682-2011; Tienari, Pentti/A-4893-2012; Haines, Jonathan/C-3374-2012; Guerini, Franca Rosa/G-8055-2012; Martinelli Boneschi, Filippo/H-8592-2012; Link, Jenny/J-1629-2012; Lima Bomfim, Izaura/J-3462-2012; Heath, Simon/J-4138-2012; Ellinghaus, David/G-4467-2012 OI Butzkueven, Helmut/0000-0003-3940-8727; Kilpatrick, Trevor/0000-0003-3999-085X; Pirinen, Matti/0000-0002-1664-1350; Gillman, Matthew/0000-0002-2340-6930; Foote, Simon/0000-0002-9142-2107; Winkelmann, Juliane/0000-0003-2667-9691; Plomin, Robert/0000-0002-0756-3629; McVean, Gil/0000-0002-5012-4162; Villoslada, Pablo/0000-0002-8735-6119; Trembath, Richard/0000-0003-0550-3400; RUBIO, JUSTIN/0000-0003-3750-917X; Leone, Maurizio/0000-0002-6339-5738; Corvin, Aiden/0000-0001-6717-4089; Link, Jenny/0000-0002-6134-9404; Hunt, Sarah/0000-0002-8350-1235; Brown, Matthew A/0000-0003-0538-8211; Potter, Simon/0000-0003-4208-4102; Spurkland, Anne/0000-0003-4421-0766; Cavalla, Paola/0000-0003-4589-4864; Giannoulatou, Eleni/0000-0002-7084-6736; Mathew, Christopher/0000-0003-4178-1838; Macciardi, Fabio/0000-0003-0537-4266; Esposito, Federica/0000-0003-2550-0805; Franke, Andre/0000-0003-1530-5811; Lima Bomfim, Izaura/0000-0003-0890-3872; Saarela, Janna/0000-0002-0853-6219; D'hooghe, Marie/0000-0002-0917-4176; Alfredsson, Lars/0000-0003-1688-6697; galimberti, daniela/0000-0002-9284-5953; de Bakker, Paul/0000-0001-7735-7858; Schreiber, Stefan/0000-0003-2254-7771; D'Alfonso, Sandra/0000-0002-3983-9925; Salvi, Erika/0000-0002-2724-2291; Goris, An/0000-0002-1276-6682; Zipp, Frauke/0000-0002-1231-1928; Wood, Nicholas/0000-0002-9500-3348; Jankowski, Janusz/0000-0003-2130-9181; Rioux, John/0000-0001-7560-8326; Baranzini, Sergio/0000-0003-0067-194X; Deloukas, Panos/0000-0001-9251-070X; Palmer, Colin/0000-0002-6415-6560; Guerini, Franca Rosa/0000-0001-9461-5927; FU Wellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 075491/Z/04/Z, 068545/Z/02]; National Institutes of Health [AI076544, NS032830, NS049477, NS19142, NS049510, NS26799, NS43559, NS067305, CA104021, RR020092, RR024992, K23N/S048869]; US National Multiple Sclerosis Society [RG 4201-A-1]; Nancy Davis Foundation; Cambridge NIHR Biomedical Research Centre; UK Medical Research Council [G0700061, G0000934]; Multiple Sclerosis Society of Great Britain and Northern Ireland [898/08]; Wolfson Royal Society; Peter Doherty fellowship; Lagrange Fellowship; Harry Weaver Neuroscience Scholarships; Australian National Health and Medical Research Council (NHMRC); Australian Research Council; JHH Charitable Trust; Multiple Sclerosis Research Australia; Health Research Council New Zealand; National MS Society of New Zealand; Wetenschappelijk Onderzoek Multiple Sclerose; Bayer Chair on Fundamental Genetic Research; Biogen Idec Chair Translational Research in Multiple Sclerosis; FWO-Vlaanderen; Belgian Neurological Society; Danish Multiple Sclerosis Society; Neuropromise EU [LSHM-CT-2005-018637]; Center of Excellence for Disease Genetics of the Academy of Finland; Sigrid Juselius Foundation; Helsinki University Central Hospital Research Foundation; Bundesministerium fur Bildung und Technologie (KKNMS consortium Control MS); Deutsche Forschungsgemeinschaft; Institut National de la Sante et de la Recherche Medicale (INSERM); Association pour la Recherche sur la Sclerose En Plaques (ARSEP); Association Francaise contre les Myopathies (AFM); Italian Foundation for Multiple Sclerosis [2002/R/40, 2005/R/10, 2008/R/11, 2008/R/15]; Italian Ministry of Health [Giovani Ricercatori 2007-D.lgs 502/92]; Regione Piemonte [2003, 2004, 2008, 2009]; CRT Foundation; Turin; Moorfields/UCL Institute of Ophthalmology NIHR Biomedical Research Centre; Norwegian MS Register and Biobank; Research Council of Norway; South-Eastern and Western Norway regional Health Authories; Ulleval University Hospital Scientific Advisory Council; Haukeland University Hospital; Amici Centro Sclerosi Multipla del San Raffaele (ACESM); Association of British Neurologists; Spanish Ministry of Health [FISPI060117]; Bibbi and Niels Jensens Foundation; Montel Williams foundation; Hjarnfonden and Swedish medical research council [8691]; Stockholm County Council [562183]; Swedish Council for Working life and Social Research; Gemeinnutzige Hertie Stiftung; Northern California Kaiser Permanente members and Polpharma Foundation; Washington University Institute of Clinical and Translational Sciences-Brain, Behavioral and Performance Unit; German Ministry of Education and Research; Helmholtz Zentrum Munchen-National Research Center; German National Genome Research Network (NGFN); LMUinnovativ; Knut and Alice Wallenberg Foundation; Children's Hospital of Philadelphia; Agency for Science & Technology and Research of Singapore; Susan G. Komen Breast Cancer Foundation FX The principal funding for this study was provided by the Wellcome Trust (085475/B/08/Z, 085475/Z/08/Z, 075491/Z/04/Z and 068545/Z/02). The work was also supported by National Institutes of Health (AI076544, NS032830, NS049477, NS19142, NS049510, NS26799, NS43559, NS067305, CA104021, RR020092, RR024992 and K23N/S048869), US National Multiple Sclerosis Society (RG 4201-A-1), Nancy Davis Foundation, Cambridge NIHR Biomedical Research Centre, UK Medical Research Council (G0700061, G0000934), Multiple Sclerosis Society of Great Britain and Northern Ireland (898/08), Wolfson Royal Society Merit Award, Peter Doherty fellowship, Lagrange Fellowship, Harry Weaver Neuroscience Scholarships, Australian National Health and Medical Research Council (NHMRC), Australian Research Council Linkage Program Grant, JHH Charitable Trust Fund, Multiple Sclerosis Research Australia, Health Research Council New Zealand, National MS Society of New Zealand, Wetenschappelijk Onderzoek Multiple Sclerose, Bayer Chair on Fundamental Genetic Research regarding the Neuroimmunological Aspects of Multiple Sclerosis, Biogen Idec Chair Translational Research in Multiple Sclerosis, FWO-Vlaanderen, Belgian Neurological Society, Danish Multiple Sclerosis Society, Neuropromise EU grant (LSHM-CT-2005-018637), Center of Excellence for Disease Genetics of the Academy of Finland, Sigrid Juselius Foundation, Helsinki University Central Hospital Research Foundation, Bundesministerium fur Bildung und Technologie (KKNMS consortium Control MS), Deutsche Forschungsgemeinschaft, Institut National de la Sante et de la Recherche Medicale (INSERM), Association pour la Recherche sur la Sclerose En Plaques (ARSEP), Association Francaise contre les Myopathies (AFM), Italian Foundation for Multiple Sclerosis (FISM grants 2002/R/40, 2005/R/10, 2008/R/11 and 2008/R/15), Italian Ministry of Health (grant Giovani Ricercatori 2007-D.lgs 502/92), Regione Piemonte (grants 2003, 2004, 2008, 2009), CRT Foundation, Turin, Moorfields/UCL Institute of Ophthalmology NIHR Biomedical Research Centre, Norwegian MS Register and Biobank, Research Council of Norway, South-Eastern and Western Norway regional Health Authories, Ulleval University Hospital Scientific Advisory Council, Haukeland University Hospital, Amici Centro Sclerosi Multipla del San Raffaele (ACESM), Association of British Neurologists, Spanish Ministry of Health (FISPI060117), Bibbi and Niels Jensens Foundation, Montel Williams foundation, Hjarnfonden and Swedish medical research council (8691), Stockholm County Council (562183), Swedish Council for Working life and Social Research, Gemeinnutzige Hertie Stiftung, Northern California Kaiser Permanente members and Polpharma Foundation, and Washington University Institute of Clinical and Translational Sciences-Brain, Behavioral and Performance Unit. We acknowledge use of data from the British 1958 Birth Cohort, the UK National Blood Service, the popgen biobank, the KORA and MONICA Augsburg studies, the Accelerated Cure Project, the Brigham & Women's Hospital PhenoGenetic Project, the Swedish CAD project, the Norwegian Bone Marrow Donor Registry, the Children's Hospital of Philadelphia (CHOP), the Swedish Breast Cancer study, BRC-REFGENSEP (Pitie-Salpetriere Centre d'Investigation Clinique (CIC) and Genethon) and HYPERGENES (HEALTH-F4-2007-201550).; Projects received support from the German Ministry of Education and Research, the Helmholtz Zentrum Munchen-National Research Center, the German National Genome Research Network (NGFN), the LMUinnovativ, the Knut and Alice Wallenberg Foundation, the Cener for Applied Genomics from the Children's Hospital of Philadelphia Development Award, the Agency for Science & Technology and Research of Singapore, and the Susan G. Komen Breast Cancer Foundation. We thank S. Bertrand, J. Bryant, S. L. Clark, L. Collimedaglia, G. Coniglio, J. S. Conquer, B. Colombo, T. Dibling, G. Eckstein, J. C. Eldred, G. Fischer, S. Gamble, P. Gregersen, R. Guerrero, C. Hind, P. Lichtner, L. Moiola, H. Mousavi, R. Naismith, R. J. Parks, R. Pearson, V. Pilato, M. Radaelli, E. Scarpini, C. R. Stribling, T. Strom, S. Taylor, D. Vukcevic and A. Wilk for their help and support. Detailed acknowledgements are available in Supplementary Information. This manuscript is dedicated to the memory of L. Peltonen, a member of both the IMSGC and the WTCCC2, in recognition of her contributions to, and her leadership in, human genetics. NR 26 TC 1034 Z9 1042 U1 27 U2 273 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 11 PY 2011 VL 476 IS 7359 BP 214 EP 219 DI 10.1038/nature10251 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 805MU UT WOS:000293731900038 ER PT J AU Goldfine, AB Kaul, S Hiatt, WR AF Goldfine, Allison B. Kaul, Sanjay Hiatt, William R. TI Fibrates in the Treatment of Dyslipidemias - Time for a Reassessment SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TYPE-2 DIABETES-MELLITUS; CORONARY-HEART-DISEASE; SECONDARY PREVENTION; GEMFIBROZIL; CHOLESTEROL; THERAPY; TRIAL; MEN C1 [Goldfine, Allison B.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Goldfine, Allison B.] Harvard Univ, Sch Med, Boston, MA USA. [Kaul, Sanjay] Univ Calif Los Angeles, Los Angeles, CA USA. [Kaul, Sanjay] Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. [Hiatt, William R.] Univ Colorado, Div Cardiol, Sch Med, Aurora, CO USA. [Hiatt, William R.] CPC Clin Res, Aurora, CO USA. RP Goldfine, AB (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. NR 8 TC 22 Z9 24 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 11 PY 2011 VL 365 IS 6 BP 481 EP 484 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 805MW UT WOS:000293732100001 PM 21830963 ER PT J AU Bienfang, DC McKenna, MJ Papaliodis, GN Gonzalez, RG Stemmer-Rachamimov, A AF Bienfang, Don C. McKenna, Michael J. Papaliodis, George N. Gonzalez, R. Gilberto Stemmer-Rachamimov, Anat TI Case 24-2011: A 36-Year-Old Man with Headache, Memory Loss, and Confusion Anatomical Diagnosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PLACOID PIGMENT EPITHELIOPATHY; RETINAL ARTERIOLAR OCCLUSIONS; OF-THE-LITERATURE; SUSAC-SYNDROME; LYME-DISEASE; HEARING-LOSS; NEUROLOGIC ABNORMALITIES; WHIPPLES DISEASE; MICROANGIOPATHY; ENCEPHALOPATHY C1 [Bienfang, Don C.] Brigham & Womens Hosp, Div Neuroophthalmol, Boston, MA 02115 USA. [McKenna, Michael J.] Massachusetts Eye & Ear Infirm, Otol & Neurotol Serv, Boston, MA 02114 USA. [Papaliodis, George N.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bienfang, Don C.; Papaliodis, George N.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [McKenna, Michael J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Gonzalez, R. Gilberto] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Stemmer-Rachamimov, Anat] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Bienfang, DC (reprint author), Brigham & Womens Hosp, Div Neuroophthalmol, 75 Francis St, Boston, MA 02115 USA. NR 28 TC 8 Z9 8 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 11 PY 2011 VL 365 IS 6 BP 549 EP 559 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 805MW UT WOS:000293732100012 PM 21830970 ER PT J AU Hsieh, KC Gvilia, I Kumar, S Uschakov, A McGinty, D Alam, MN Szymusiak, R AF Hsieh, K. -C. Gvilia, I. Kumar, S. Uschakov, A. McGinty, D. Alam, M. N. Szymusiak, R. TI c-FOS EXPRESSION IN NEURONS PROJECTING FROM THE PREOPTIC AND LATERAL HYPOTHALAMIC AREAS TO THE VENTROLATERAL PERIAQUEDUCTAL GRAY IN RELATION TO SLEEP STATES SO NEUROSCIENCE LA English DT Article DE median preoptic nucleus; ventrolateral preoptic area; perifornical lateral hypothalamus; sleep deprivation ID WAKING DISCHARGE PATTERNS; EYE-MOVEMENT SLEEP; REM-SLEEP; IMMUNOREACTIVE NEURONS; PARADOXICAL SLEEP; STRIA TERMINALIS; OREXIN NEURONS; PARAVENTRICULAR NUCLEUS; HOMEOSTATIC REGULATION; BEHAVING ANIMALS AB The ventrolateral division of the periaqueductal gray (vIPAG) and the adjacent deep mesencephalic reticular nucleus have been implicated in the control of sleep. The preoptic hypothalamus, which contains populations of sleep-active neurons, is an important source of afferents to the vIPAG. The perifornical lateral hypothalamus (LH) contains populations of wake-active neurons and also projects strongly to the vIPAG. We examined nonREM and REM sleep-dependent expression of c-Fos protein in preoptic-vIPAG and LH-vIPAG projection neurons identified by retrograde labeling with Fluorogold (FG). Separate groups of rats (n=5) were subjected to 3 h total sleep deprivation (TSD) followed by 1 h recovery sleep (RS), or to 3 h of selective REM sleep deprivation (RSD) followed by RS. A third group of rats (n=5) was subjected to TSD without opportunity for RS (awake group). In the median preoptic nucleus (MnPN), the percentage of FG+ neurons that were also Fos+ was higher in TSD-RS animals compared to both RSD-RS rats and awake rats. There were significant correlations between time spent in deep nonREM sleep during the 1 h prior to sacrifice across groups and the percentage of double-labeled cells in MnPN and ventrolateral preoptic area (VLPO). There were no significant correlations between percentage of double-labeled neurons and time spent in REM sleep for any of the preoptic nuclei examined. In the LH, percentage of double-labeled neurons was highest in awake rats, intermediate in TSD-RS rats and lowest in the RSD-RS group. These results suggest that neurons projecting from MnPN and VLPO to the vIPAG are activated during nonREM sleep and support the hypothesis that preoptic neurons provide inhibitory input to vIPAG during sleep. Suppression of excitatory input to the vIPAG from the LH during sleep may have a permissive effect on REM sleep generation. Published by Elsevier Ltd on behalf of IBRO. C1 [Hsieh, K. -C.; Gvilia, I.; Kumar, S.; Uschakov, A.; McGinty, D.; Alam, M. N.; Szymusiak, R.] VA Greater Los Angeles, Res Serv, Los Angeles, CA 91343 USA. [Hsieh, K. -C.; Kumar, S.; Uschakov, A.; Szymusiak, R.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Hsieh, K. -C.; Kumar, S.; Uschakov, A.; Szymusiak, R.] Univ Calif Los Angeles, Sch Med, Dept Neurobiol, Los Angeles, CA 90024 USA. [Gvilia, I.] Beritashvili Inst Physiol, Tbilisi, GA USA. [McGinty, D.; Alam, M. N.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. RP Szymusiak, R (reprint author), VA Greater Los Angeles Healthcare Syst, Res Serv 151A3, 16111 Plummer St, North Hills, CA 91343 USA. EM rszym@ucla.edu FU Department of Veterans Affairs; NIH [MH63323] FX Supported by the Department of Veterans Affairs and NIH Grant MH63323. The authors thank Ms. Keng-Tee Chow and Mr. Bryan Angara for their excellent technical assistance. NR 69 TC 13 Z9 14 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD AUG 11 PY 2011 VL 188 BP 55 EP 67 DI 10.1016/j.neuroscience.2011.05.016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 783GL UT WOS:000292069400006 PM 21601616 ER PT J AU Ortiz, T Poch, J Santos, JM Requena, C Martinez, AM Ortiz-Teran, L Turrero, A Barcia, J Nogales, R Calvo, A Martinez, JM Cordoba, JL Pascual-Leone, A AF Ortiz, Tomas Poch, Joaquin Santos, Juan M. Requena, Carmen Martinez, Ana M. Ortiz-Teran, Laura Turrero, Agustin Barcia, Juan Nogales, Ramon Calvo, Agustin Martinez, Jose M. Cordoba, Jose L. Pascual-Leone, Alvaro TI Recruitment of Occipital Cortex during Sensory Substitution Training Linked to Subjective Experience of Seeing in People with Blindness SO PLOS ONE LA English DT Article ID CROSS-MODAL PLASTICITY; VISUAL-CORTEX; CONGENITALLY BLIND; EFFECTIVE CONNECTIVITY; ACTIVATION PATTERNS; CORTICAL ACTIVITY; HUMAN BRAIN; HUMANS; PERCEPTION; TACTILE AB Over three months of intensive training with a tactile stimulation device, 18 blind and 10 blindfolded seeing subjects improved in their ability to identify geometric figures by touch. Seven blind subjects spontaneously reported 'visual qualia', the subjective sensation of seeing flashes of light congruent with tactile stimuli. In the latter subjects tactile stimulation evoked activation of occipital cortex on electroencephalography (EEG). None of the blind subjects who failed to experience visual qualia, despite identical tactile stimulation training, showed EEG recruitment of occipital cortex. None of the blindfolded seeing humans reported visual-like sensations during tactile stimulation. These findings support the notion that the conscious experience of seeing is linked to the activation of occipital brain regions in people with blindness. Moreover, the findings indicate that provision of visual information can be achieved through non-visual sensory modalities which may help to minimize the disability of blind individuals, affording them some degree of object recognition and navigation aid. C1 [Ortiz, Tomas; Santos, Juan M.; Martinez, Ana M.; Ortiz-Teran, Laura] Univ Complutense, Fac Med, Dept Psychiat, E-28040 Madrid, Spain. [Poch, Joaquin] Hosp Clin Univ San Carlos, Dept Ear Nose & Throat ENT, Madrid, Spain. [Santos, Juan M.] Spanish Res Network Mental Hlth, CIBERSAM Ctr Invest Biomed Red Salud Mental, Madrid, Spain. [Requena, Carmen] Univ Leon, Dept Psychol, E-24071 Leon, Spain. [Ortiz-Teran, Laura] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. [Turrero, Agustin] Univ Complutense, Fac Med, Dept Stat, E-28040 Madrid, Spain. [Barcia, Juan] Hosp Clin Univ San Carlos, Dept Neurosurg, Madrid, Spain. [Nogales, Ramon; Calvo, Agustin; Martinez, Jose M.; Cordoba, Jose L.] Univ Complutense, Fac Med, Vis Tactile Project, E-28040 Madrid, Spain. [Pascual-Leone, Alvaro] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat,Dept N, Boston, MA 02215 USA. [Pascual-Leone, Alvaro] Univ Autonoma Barcelona, Inst Guttman Neurorehabil, E-08193 Barcelona, Spain. RP Ortiz, T (reprint author), Univ Complutense, Fac Med, Dept Psychiat, E-28040 Madrid, Spain. EM tortiz@med.ucm.es RI Requena, Carmen/J-6849-2014 OI Requena, Carmen/0000-0003-2427-8608 FU Fundacion Esther Koplowitz [EK-4131306]; Instituto Madrileno de Desarrollo (IMADE)/Madrid Regional Government (Spain) [IMADE-4131307] FX This research has been made possible through grants from the Fundacion Esther Koplowitz (grant #EK-4131306) and Instituto Madrileno de Desarrollo (IMADE)/Madrid Regional Government (Spain) (grant #IMADE-4131307). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 23 Z9 23 U1 3 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 10 PY 2011 VL 6 IS 8 AR e23264 DI 10.1371/journal.pone.0023264 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 827UM UT WOS:000295454200059 PM 21853098 ER PT J AU Morrow, PK Wulf, GM Ensor, J Booser, DJ Moore, JA Flores, PR Xiong, Y Zhang, SY Krop, IE Winer, EP Kindelberger, DW Coviello, J Sahin, AA Nunez, R Hortobagyi, GN Yu, DH Esteva, FJ AF Morrow, Phuong K. Wulf, Gerburg M. Ensor, Joe Booser, Daniel J. Moore, Julia A. Flores, Peter R. Xiong, Yan Zhang, Siyuan Krop, Ian E. Winer, Eric P. Kindelberger, David W. Coviello, Jeanna Sahin, Aysegul A. Nunez, Rodolfo Hortobagyi, Gabriel N. Yu, Dihua Esteva, Francisco J. TI Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RESISTANCE; INHIBITION; RAPAMYCIN; DISEASE AB Purpose Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. Patients and Methods This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. Results Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. Conclusion Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC. C1 [Morrow, Phuong K.; Ensor, Joe; Booser, Daniel J.; Moore, Julia A.; Flores, Peter R.; Xiong, Yan; Zhang, Siyuan; Sahin, Aysegul A.; Nunez, Rodolfo; Hortobagyi, Gabriel N.; Yu, Dihua; Esteva, Francisco J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77005 USA. [Krop, Ian E.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA USA. [Kindelberger, David W.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Esteva, FJ (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Box 1354, Houston, TX 77005 USA. EM fjesteva@mdanderson.org RI Zhang, Siyuan/A-1276-2014; OI Zhang, Siyuan/0000-0003-0910-3666; Ensor, Joe/0000-0003-3533-4388; Esteva, Francisco/0000-0003-2437-3920 FU National Cancer Institute (NCI) [1 P50 CA116199-01, 1P50 CA089393]; Novartis Pharmaceuticals; AVON foundation; Genentech FX Supported by Grant No. 1 P50 CA116199-01 from the National Cancer Institute (NCI) Breast Cancer SPORE (Specialized Program of Research Excellence) and Novartis Pharmaceuticals (to The University of Texas MD Anderson Cancer Center); and Grant No. 1P50 CA089393 NCI Breast Cancer SPORE, the AVON foundation, and Novartis Pharmaceuticals (to Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, and Brigham and Women's Hospital).; Research Funding: Phuong Khanh Morrow, Novartis; Ian E. Krop, Genentech; Eric P. Winer, Genentech; Gabriel N. Hortobagyi, Novartis; Francisco J. Esteva, Novartis NR 17 TC 125 Z9 130 U1 0 U2 12 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2011 VL 29 IS 23 BP 3126 EP 3132 DI 10.1200/JCO.2010.32.2321 PG 7 WC Oncology SC Oncology GA 804BJ UT WOS:000293628400012 PM 21730275 ER PT J AU de Jong, MC Nathan, H Sotiropoulos, GC Paul, A Alexandrescu, S Marques, H Pulitano, C Barroso, E Clary, BM Aldrighetti, L Ferrone, CR Zhu, AX Bauer, TW Walters, DM Gamblin, TC Nguyen, KT Turley, R Popescu, I Hubert, C Meyer, S Schulick, RD Choti, MA Gigot, JF Mentha, G Pawlik, TM AF de Jong, Mechteld C. Nathan, Hari Sotiropoulos, Georgios C. Paul, Andreas Alexandrescu, Sorin Marques, Hugo Pulitano, Carlo Barroso, Eduardo Clary, Bryan M. Aldrighetti, Luca Ferrone, Cristina R. Zhu, Andrew X. Bauer, Todd W. Walters, Dustin M. Gamblin, T. Clark Nguyen, Kevin T. Turley, Ryan Popescu, Irinel Hubert, Catherine Meyer, Stephanie Schulick, Richard D. Choti, Michael A. Gigot, Jean-Francois Mentha, Gilles Pawlik, Timothy M. TI Intrahepatic Cholangiocarcinoma: An International Multi-Institutional Analysis of Prognostic Factors and Lymph Node Assessment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SEER DATABASE ANALYSIS; STAGING SYSTEM; SURVIVAL; EXPERIENCE; MANAGEMENT; CARCINOMA; RESECTION; SURGERY; TRENDS AB Purpose To identify factors associated with outcome after surgical management of intrahepatic cholangio-carcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. Patients and Methods From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. Results Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). Conclusion Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis. C1 [de Jong, Mechteld C.; Nathan, Hari; Schulick, Richard D.; Choti, Michael A.; Pawlik, Timothy M.] Johns Hopkins Univ Sch Med, Baltimore, MD USA. [Sotiropoulos, Georgios C.; Paul, Andreas] Univ Hosp Essen, Essen, Germany. [Alexandrescu, Sorin; Popescu, Irinel] Inst Digest Dis & Liver Transplantat Fundeni, Bucharest, Romania. [Marques, Hugo; Barroso, Eduardo] Curry Cabral Hosp, Lisbon, Portugal. [Pulitano, Carlo; Aldrighetti, Luca] Univ Milan, Osped San Raffaele, I-20127 Milan, Italy. [Clary, Bryan M.; Turley, Ryan] Duke Med Ctr, Durham, NC USA. [Ferrone, Cristina R.; Zhu, Andrew X.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bauer, Todd W.; Walters, Dustin M.] Univ Virginia, Charlottesville, VA USA. [Gamblin, T. Clark; Nguyen, Kevin T.] Univ Pittsburgh, Pittsburgh, PA USA. [Hubert, Catherine; Gigot, Jean-Francois] Clin Univ St Luc, B-1200 Brussels, Belgium. [Meyer, Stephanie; Mentha, Gilles] Hop Univ Geneve, Geneva, Switzerland. RP Pawlik, TM (reprint author), Dept Surg, Harvey 611,600 N Wolfe St, Baltimore, MD 21287 USA. EM tpawlik1@jhmi.edu RI POPESCU, IRINEL/B-3048-2008 NR 22 TC 144 Z9 145 U1 1 U2 14 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2011 VL 29 IS 23 BP 3140 EP 3145 DI 10.1200/JCO.2011.35.6519 PG 6 WC Oncology SC Oncology GA 804BJ UT WOS:000293628400014 PM 21730269 ER PT J AU Niedzwiecki, D Bertagnolli, MM Warren, RS Compton, CC Kemeny, NE Benson, AB Eckhardt, SG Alberts, S Porjosh, GN Kerr, DJ Fields, A Rougier, P Pipas, JM Schwartz, JH Atkins, J O'Rourke, M Perry, MC Goldberg, RM Mayer, RJ Colacchio, TA AF Niedzwiecki, Donna Bertagnolli, Monica M. Warren, Robert S. Compton, Carolyn C. Kemeny, Nancy E. Benson, Al Bowen, III Eckhardt, S. Gail Alberts, Steven Porjosh, Gity N. Kerr, David J. Fields, Anthony Rougier, Philippe Pipas, J. Marc Schwartz, Joel H. Atkins, James O'Rourke, Mark Perry, Michael C. Goldberg, Richard M. Mayer, Robert J. Colacchio, Thomas A. TI Documenting the Natural History of Patients With Resected Stage II Adenocarcinoma of the Colon After Random Assignment to Adjuvant Treatment With Edrecolomab or Observation: Results From CALGB 9581 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLORECTAL-CANCER; MONOCLONAL-ANTIBODIES; FOLINIC ACID; DOSE LEUCOVORIN; COMPETING RISK; FLUOROURACIL; THERAPY; SURVIVAL; TRIAL; CHEMOTHERAPY AB Purpose We conducted a randomized trial comparing adjuvant treatment with edrecolomab versus observation in patients with resected, low-risk, stage II colon cancer. This study also prospectively studied patient-and tumor-specific markers of treatment outcome. Patients and Methods After surgical resection, patients with stage II colon cancer were randomly assigned to either five infusions of edrecolomab at 28-day intervals or observation without adjuvant therapy. Results Final accrual included 1,738 patients; 865 patients received edrecolomab, and 873 patients were observed without adjuvant treatment. Median follow-up time was 7.9 years. There were no significant outcome differences between study arms (overall survival [OS], P = .71; disease-free survival, P = .64). The combined 5-year all-cause OS was 0.86 (95% CI, 0.84 to 0.88), and the combined 5-year disease-specific OS was 0.93 (95% CI, 0.91 to 0.94). The relationships between demographic and histopathologic factors and survival differed for all-cause and disease-specific survival outcomes, but no combined prognostic factor model was found to adequately classify patients at higher risk of recurrence or death as a result of colon cancer. Conclusion Edrecolomab did not prolong survival. Consequently, this large study with a long duration of follow-up provided unique data concerning the natural history of resected stage II colon cancer. Prognostic factors identified in previous retrospective and pooled analyses were associated with survival outcomes in this stage II patient cohort. Results from ongoing molecular marker studies may enhance our ability to determine the risk profile of these patients. C1 [Niedzwiecki, Donna] Duke Univ Med Ctr, Canc & Leukemia Grp Stat Ctr B, Durham, NC 27705 USA. SE Canc Control Consortium, Goldsboro, NC USA. Univ N Carolina, Chapel Hill, NC USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Eastern Cooperat Oncol Grp, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. N Shore Canc Ctr, Danvers, MA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NCI, Bethesda, MD 20892 USA. Natl Canc Inst Expanded Participat Project, Rockville, MD USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. SW Oncol Grp, San Antonio, TX USA. N Cent Canc Treatment Grp, Rochester, MN USA. Inova Res Ctr, Falls Church, VA USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Canc Ctr Carolinas, Greenville, SC USA. Univ Missouri Ellis Fischel Canc Ctr, Columbia, MO USA. Canc Res Clin Trials Unit, Birmingham, W Midlands, England. Oxford Canc Trials Off, Oxford, England. Natl Canc Inst Canada Clin Trials Grp, Kingston, ON, Canada. European Org Res Treatment Canc, Brussels, Belgium. Hop Europeen Georges Pompidou, Paris, France. RP Niedzwiecki, D (reprint author), Duke Univ Med Ctr, Canc & Leukemia Grp Stat Ctr B, Hock Plaza,2424 Erwin Rd,Room 8040, Durham, NC 27705 USA. EM niedz001@mc.duke.edu RI Goldberg , Richard/M-1311-2013 FU Centocor; GlaxoSmithKline FX Research Funding: David J. Kerr, Centocor; Anthony Fields, GlaxoSmithKline NR 44 TC 25 Z9 27 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2011 VL 29 IS 23 BP 3146 EP 3152 DI 10.1200/JCO.2010.32.5357 PG 7 WC Oncology SC Oncology GA 804BJ UT WOS:000293628400015 PM 21747085 ER PT J AU Bertagnolli, MM Redston, M Compton, CC Niedzwiecki, D Mayer, RJ Goldberg, RM Colacchio, TA Saltz, LB Warren, RS AF Bertagnolli, Monica M. Redston, Mark Compton, Carolyn C. Niedzwiecki, Donna Mayer, Robert J. Goldberg, Richard M. Colacchio, Thomas A. Saltz, Leonard B. Warren, Robert S. TI Microsatellite Instability and Loss of Heterozygosity at Chromosomal Location 18q: Prospective Evaluation of Biomarkers for Stages II and III Colon Cancer-A Study of CALGB 9581 and 89803 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLORECTAL-CANCER; ALLELIC LOSS; ADJUVANT CHEMOTHERAPY; GENETIC ALTERATIONS; PROGNOSTIC MARKER; FLUOROURACIL; SURVIVAL; CARCINOMA; TUMOR; LEUCOVORIN AB Purpose Colorectal cancer (CRC) develops as a result of a series of accumulated genomic changes that produce oncogene activation and tumor suppressor gene loss. These characteristics may classify CRC into subsets of distinct clinical behaviors. Patients and Methods We studied two of these genomic defects-mismatch repair deficiency (MMR-D) and loss of heterozygosity at chromosomal location 18q (18qLOH)-in patients enrolled onto two phase III cooperative group trials for treatment of potentially curable colon cancer. These trials included prospective secondary analyses to determine the relationship between these markers and treatment outcome. A total of 1,852 patients were tested for MMR status and 955 (excluding patients with MMR-D tumors) for 18qLOH. Results Compared with stage III, more stage II tumors were MMR-D (21.3% v 14.4%; P < .001) and were intact at 18q (24.2% v 15.1%; P = .001). For the combined cohort, patients with MMR-D tumors had better 5-year disease-free survival (DFS; 0.76 v 0.67; P < .001) and overall survival (OS; 0.81 v 0.78; P = .029) than those with MMR intact (MMR-I) tumors. Among patients with MMR-I tumors, the status of 18q did not affect outcome, with 5-year values for patients with 18q intact versus 18qLOH tumors of 0.74 versus 0.65 (P = .18) for DFS and 0.81 versus 0.77 (P = .18) for OS. Conclusion We conclude that MMR-D tumor status, but not the presence of 18qLOH, has prognostic value for stages II and III colon cancer. C1 [Bertagnolli, Monica M.; Redston, Mark] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bertagnolli, Monica M.; Mayer, Robert J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Niedzwiecki, Donna] Duke Univ Med Ctr, Canc & Leukemia Grp Stat Ctr B, Durham, NC USA. [Goldberg, Richard M.] Univ N Carolina, Chapel Hill, NC USA. [Compton, Carolyn C.] NCI, Bethesda, MD 20892 USA. [Colacchio, Thomas A.] Dartmouth Hitchcock Med Ctr, Hanover, NH USA. [Saltz, Leonard B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Warren, Robert S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Bertagnolli, MM (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM mbertagnolli@partners.org RI Goldberg , Richard/M-1311-2013 FU National Cancer Institute, Bethesda, MD [CA31946, CA33601] FX Supported in part by Grants No. CA31946 from the National Cancer Institute, Bethesda, MD, to CALGB (M.M.B.) and No. CA33601 to the CALGB Statistical Center (Daniel J. Sargent, Group Statistician and principal investigator). NR 35 TC 57 Z9 57 U1 1 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2011 VL 29 IS 23 BP 3153 EP 3162 DI 10.1200/JCO.2010.33.0092 PG 10 WC Oncology SC Oncology GA 804BJ UT WOS:000293628400016 PM 21747089 ER PT J AU Peralta, CA Shlipak, MG AF Peralta, Carmen A. Shlipak, Michael G. TI Biomarkers for Detecting and Risk-Stratifying Chronic Kidney Disease Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CYSTATIN-C; SERUM CYSTATIN; CREATININE C1 [Peralta, Carmen A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Peralta, CA (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM carmenalicia.peralta@ucsf.edu NR 4 TC 0 Z9 0 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 10 PY 2011 VL 306 IS 6 BP 611 EP 612 DI 10.1001/jama.2011.1112 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 804XD UT WOS:000293687300021 ER PT J AU Yaffe, K Laffan, AM Harrison, SL Redline, S Spira, AP Ensrud, KE Ancoli-Israel, S Stone, KL AF Yaffe, Kristine Laffan, Alison M. Harrison, Stephanie Litwack Redline, Susan Spira, Adam P. Ensrud, Kristine E. Ancoli-Israel, Sonia Stone, Katie L. TI Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MINI-MENTAL-STATE; HEART HEALTH; CARDIOVASCULAR-DISEASE; INTERMITTENT HYPOXIA; ALZHEIMERS-DISEASE; INSULIN-RESISTANCE; NOCTURNAL HYPOXIA; ANIMAL-MODELS; APNEA; FRAGMENTATION AB Context Sleep-disordered breathing (characterized by recurrent arousals from sleep and intermittent hypoxemia) is common among older adults. Cross-sectional studies have linked sleep-disordered breathing to poor cognition; however, it remains unclear whether sleep-disordered breathing precedes cognitive impairment in older adults. Objectives To determine the prospective relationship between sleep-disordered breathing and cognitive impairment and to investigate potential mechanisms of this association. Design, Setting, and Participants Prospective sleep and cognition study of 298 women without dementia (mean [SD] age: 82.3 [3.2] years) who had overnight polysomnography measured between January 2002 and April 2004 in a substudy of the Study of Osteoporotic Fractures. Sleep-disordered breathing was defined as an apnea-hypopnea index of 15 or more events per hour of sleep. Multivariate logistic regression was used to determine the independent association of sleep-disordered breathing with risk of mild cognitive impairment or dementia, adjusting for age, race, body mass index, education level, smoking status, presence of diabetes, presence of hypertension, medication use (antidepressants, benzodiazepines, or nonbenzodiazepine anxiolytics), and baseline cognitive scores. Measures of hypoxia, sleep fragmentation, and sleep duration were investigated as underlying mechanisms for this relationship. Main Outcome Measures Adjudicated cognitive status (normal, dementia, or mild cognitive impairment) based on data collected between November 2006 and September 2008. Results Compared with the 193 women without sleep-disordered breathing, the 105 women (35.2%) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (31.1% [n=60] vs 44.8% [n=47]; adjusted odds ratio [AOR], 1.85; 95% confidence interval [CI], 1.11-3.08). Elevated oxygen desaturation index (>= 15 events/hour) and high percentage of sleep time (>7%) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR, 1.71 [95% CI, 1.04-2.83] and AOR, 2.04 [95% CI, 1.10-3.78], respectively). Measures of sleep fragmentation (arousal index and wake after sleep onset) or sleep duration (total sleep time) were not associated with risk of cognitive impairment. Conclusion Among older women, those with sleep-disordered breathing compared with those without sleep-disordered breathing had an increased risk of developing cognitive impairment. JAMA. 2011;306(6):613-619 www.jama.com C1 [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94121 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Laffan, Alison M.; Harrison, Stephanie Litwack; Stone, Katie L.] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, San Francisco, CA USA. [Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Sleep Med, Boston, MA 02115 USA. [Redline, Susan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. [Spira, Adam P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Ensrud, Kristine E.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Ensrud, Kristine E.] Univ Minnesota, Dept Epidemiol, Minneapolis, MN 55455 USA. [Ensrud, Kristine E.] Univ Minnesota, Dept Community Hlth, Minneapolis, MN 55455 USA. [Ensrud, Kristine E.] Vet Affairs Med Ctr, Minneapolis, MN USA. [Ancoli-Israel, Sonia] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, Box 181,4150 Clement St, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu FU National Institutes of Health; Alzheimer Association; Department of Defense; American Health Assistance Foundation; Beeson Scientific; Japan Geriatrics Society; Wake Forest University; State of California Department of Human Services; National Institute on Aging [AG05407, AR35582, AG05394, AR35584, AR35583, R01 AG005407, R01 AG027576-22, 2 R01 AG005394-22A1, 2 R01 AG027574-22A1, AG026720, K24AG031155, AG08415]; NIA [1K01AG033195] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Yaffe reported that she is a consultant for Novartis Inc; serves on data and safety monitoring boards for Pfizer, Medivation, and the National Institute of Mental Health; is a board member for Beeson Scientific Advisory; has grants pending with the National Institutes of Health, the Alzheimer Association, the Department of Defense, and the American Health Assistance Foundation; and has received funding for expenses unrelated to the activites listed from the Alzheimer Association, the National Institutes of Health, Beeson Scientific, Japan Geriatrics Society, Wake Forest University, and the State of California Department of Human Services. Dr Laffan reported that she received salary support and was reimbursed for travel to professional society meetings from the National Institutes of Health. Dr Redline reported that her institution received a California Pacific Medical Center subcontract via a National Institutes of Health grant; she is a board member for the American Academy of Sleep Medicine; her institution has received an endowment for a professorship in sleep medicine from Dr Peter Farrell, CEO of RosMed Inc; and has multiple grants pending with the National Institutes of Health on sleep apnea. Dr Spira reported that he has received honoraria as a clinical editor for the International Journal of Sleep and Wakefulness-Primary Care, which receives pharmaceutical industry support. Dr Ancoli-Israel reported that she is a consultant for Johnson & Johnson, Merck, Purdue Pharma LP, sanofi-aventis, and Pfizer and has grants pending with the National Institutes of Health. No other disclosures were reported.; The Study of Osteoporotic Fractures is supported by funding from the National Institutes of Health. The National Institute on Aging provided support for this study under grants AG05407, AR35582, AG05394, AR35584, AR35583, R01 AG005407, R01 AG027576-22, 2 R01 AG005394-22A1, and 2 R01 AG027574-22A1, AG05407, AR35582, AG05394, AR35584, AR35583, AG026720. In addition, this study was supported by National Institute on Aging grant AG026720. Dr Yaffe is supported in part by National Institute on Aging grant K24AG031155. Dr Spira is supported by a Mentored Research Scientist Development Award (NIA 1K01AG033195). Dr Ancoli-Israel is supported by National Institute on Aging grant AG08415. NR 43 TC 244 Z9 249 U1 10 U2 37 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 10 PY 2011 VL 306 IS 6 BP 613 EP 619 DI 10.1001/jama.2011.1115 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 804XD UT WOS:000293687300022 PM 21828324 ER PT J AU Xu-Wilson, M Tian, J Shadmehr, R Zee, DS AF Xu-Wilson, Minnan Tian, Jing Shadmehr, Reza Zee, David S. TI TMS Perturbs Saccade Trajectories and Unmasks an Internal Feedback Controller for Saccades SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SUPERIOR COLLICULUS; OMNIPAUSE NEURONS; EYE-MOVEMENTS; INTERRUPTED SACCADES; MAGNETIC STIMULATION; ADAPTIVE-CONTROL; GUIDED SACCADES; BURST NEURONS; STARTLE; MONKEY AB When we applied a single pulse of transcranial magnetic stimulation (TMS) to any part of the human head during a saccadic eye movement, the ongoing eye velocity was reduced as early as 45 ms after the TMS, and lasted similar to 32 ms. The perturbation to the saccade trajectory was not due to a mechanical effect of the lid on the eye (e. g., from blinks). When the saccade involved coordinated movements of both the eyes and the lids, e. g., in vertical saccades, TMS produced a synchronized inhibition of the motor commands to both eye and lid muscles. The TMS-induced perturbation of the eye trajectory did not show habituation with repetition, and was present in both pro-saccades and anti-saccades. Despite the perturbation, the eye trajectory was corrected within the same saccade with compensatory motor commands that guided the eyes to the target. This within-saccade correction did not rely on visual input, suggesting that the brain monitored the oculomotor commands as the saccade unfolded, maintained a real-time estimate of the position of the eyes, and corrected for the perturbation. TMS disrupted saccades regardless of the location of the coil on the head, suggesting that the coil discharge engages a nonhabituating startle-like reflex system. This system affects ongoing motor commands upstream of the oculomotor neurons, possibly at the level of the superior colliculus or omnipause neurons. Therefore, a TMS pulse centrally perturbs saccadic motor commands, which are monitored possibly via efference copy and are corrected via internal feedback. C1 [Xu-Wilson, Minnan; Shadmehr, Reza] Johns Hopkins Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. [Tian, Jing; Zee, David S.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Shadmehr, Reza; Zee, David S.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Xu-Wilson, M (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St,9th Floor, Boston, MA 02114 USA. EM manon@alum.mit.edu FU National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH); NIH [UL1 RR 025005, NS37422, EY01849]; Leon Levy Foundation; Helena Rubenstein Foundation; Schwerin Family Foundation; National Institute of Neurological Disorders and Stroke FX This work was supported by the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research (Grant UL1 RR 025005). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. This work was also supported by grants from the NIH (NS37422 and EY01849), the Leon Levy Foundation, the Helena Rubenstein Foundation, and the Schwerin Family Foundation. M.X.W. was supported by National Research Service Award predoctoral fellowships from the National Institute of Neurological Disorders and Stroke. J.T. is the Betty and Paul Cinquegrana Scholar. We thank Dale Roberts and Adrian Lasker for their technical support. We thank Dr. Lance Optican for his valuable input and engaging discussions. The model in this paper was modified from that given to us by Dr. Stefano Ramat and Dr. Lance Optican. NR 46 TC 15 Z9 15 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 10 PY 2011 VL 31 IS 32 BP 11537 EP 11546 DI 10.1523/JNEUROSCI.1584-11.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 805NV UT WOS:000293735900013 PM 21832184 ER PT J AU Draetta, GF DePinho, RA AF Draetta, Giulio F. DePinho, Ronald A. TI Cancer Drug Discovery Faces the FACT SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NF-KAPPA-B; TRANSCRIPTION; P53 AB In this issue of Science Translational Medicine, Gasparian et al. use a clever cell-based screen to identify a family of DNA-binding small molecules-curaxins-that inhibit tumor cell growth and division. The curaxins' mechanism of action pinpoints a new chromatin-remodeling factor as a therapeutic target for cancer. C1 [Draetta, Giulio F.; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. EM ron_depinho@dfci.harvard.edu FU National Cancer Institute, National Institutes of Health; Ivy Foundation; American Italian Cancer Foundation FX This work was supported by grants from the National Cancer Institute, National Institutes of Health; the Ivy Foundation; and the American Italian Cancer Foundation. NR 7 TC 2 Z9 2 U1 1 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 10 PY 2011 VL 3 IS 95 AR 95ps34 DI 10.1126/scitranslmed.3002822 PG 2 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 805OU UT WOS:000293739300002 PM 21832237 ER PT J AU Baffy, G Derdak, Z Robson, SC AF Baffy, G. Derdak, Z. Robson, S. C. TI Mitochondrial recoupling: a novel therapeutic strategy for cancer? SO BRITISH JOURNAL OF CANCER LA English DT Review DE uncoupling proteins; UCP2; aerobic glycolysis; metabolic reprogramming; oxidative stress; p53 ID OXYGEN SPECIES PRODUCTION; BETA-CELL DYSFUNCTION; UNCOUPLING PROTEIN-2; AEROBIC GLYCOLYSIS; INNER MEMBRANE; PROTON LEAK; HEPG2 CELLS; P53; SUPEROXIDE; METABOLISM AB Recent findings link metabolic transformation of cancer cells to aberrant functions of mitochondrial uncoupling proteins (UCPs). By inducing proton leak, UCPs interfere with mitochondrial synthesis of adenosine 5'-triphosphate, which is also a key determinant of glycolytic pathways. In addition, UCP suppress the generation of superoxide, a byproduct of mitochondrial electron transport and a major source of oxidative stress. The near ubiquitous UCP2 becomes highly abundant in some cancers and may advance metabolic reprogramming, further disrupt tumour suppression, and promote chemoresistance. Here we review current evidence to suggest that inhibition of mitochondrial uncoupling may eliminate these responses and reveal novel anti-cancer strategies. British Journal of Cancer (2011) 105, 469-474. doi: 10.1038/bjc. 2011.245 www.bjcancer.com Published online 28 June 2011 (C) 2011 Cancer Research UK C1 [Baffy, G.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Dept Med, Boston, MA 02130 USA. [Baffy, G.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02130 USA. [Derdak, Z.] Brown Univ, Rhode Isl Hosp, Liver Res Ctr, Dept Med, Providence, RI 02903 USA. [Derdak, Z.] Brown Univ, Alpert Sch Med, Providence, RI 02903 USA. [Robson, S. C.] Harvard Univ, Sch Med, Liver Clin, Dept Med,Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Baffy, G (reprint author), Harvard Univ, Sch Med, VA Boston Healthcare Syst, Dept Med, 150 S Huntington Ave,Room A6-46, Boston, MA 02130 USA. EM gbaffy@partners.org FU NHLBI NIH HHS [R01 HL094400, R01 HL094400-01] NR 50 TC 35 Z9 36 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 9 PY 2011 VL 105 IS 4 BP 469 EP 474 DI 10.1038/bjc.2011.245 PG 6 WC Oncology SC Oncology GA 806DB UT WOS:000293784400001 PM 21712825 ER PT J AU Ellenbogen, KA Gold, MR Meyer, TE Lozano, IF Mittal, S Waggoner, AD Lemke, B Singh, JP Spinale, FG Van Eyk, JE Whitehill, J Weiner, S Bedi, M Rapkin, J Stein, KM AF Ellenbogen, Kenneth A. Gold, Michael R. Meyer, Timothy E. Fernandez Lozano, Ignacio Mittal, Suneet Waggoner, Alan D. Lemke, Bernd Singh, Jagmeet P. Spinale, Francis G. Van Eyk, Jennifer E. Whitehill, Jeffrey Weiner, Stanislav Bedi, Maninder Rapkin, Joshua Stein, Kenneth M. TI Response to Letter Regarding Article, "Primary Results From the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial: A Randomized Trial Comparing Empirical, Echocardiography-Guided and Algorithmic Atrioventricular Delay Programming in Cardiac Resynchronization Therapy" SO CIRCULATION LA English DT Letter C1 [Ellenbogen, Kenneth A.] Virginia Commonwealth Univ, Med Ctr, Richmond, VA 23284 USA. [Gold, Michael R.; Spinale, Francis G.] Med Univ S Carolina, Charleston, SC 29425 USA. [Meyer, Timothy E.; Rapkin, Joshua; Stein, Kenneth M.] Boston Sci, St Paul, MN USA. [Fernandez Lozano, Ignacio] Hosp Puerta de Hierro, Madrid, Spain. [Mittal, Suneet] St Lukes Roosevelt Hosp, New York, NY USA. [Waggoner, Alan D.] Washington Univ, Sch Med, St Louis, MO USA. [Lemke, Bernd] Maerkische Kliniken GmbH, Luedenscheid, Germany. [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Whitehill, Jeffrey] Austin Heart Hosp, Austin, TX USA. [Weiner, Stanislav] Tyler Cardiovasc Consultants, Tyler, TX USA. [Bedi, Maninder] Washington Hosp, Washington, PA USA. RP Ellenbogen, KA (reprint author), Virginia Commonwealth Univ, Med Ctr, Richmond, VA 23284 USA. NR 3 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 9 PY 2011 VL 124 IS 6 BP E191 EP E192 DI 10.1161/CIRCULATIONAHA.111.027284 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 804AG UT WOS:000293624800004 ER PT J AU Johansen, KL AF Johansen, Kirsten L. TI Is Predialysis Nephrology Care Worthwhile? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Johansen, Kirsten L.] San Francisco VA Med Ctr, Nephrol Sect, San Francisco, CA 94121 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. RP Johansen, KL (reprint author), San Francisco VA Med Ctr, Nephrol Sect, 4150 Clement St,111J, San Francisco, CA 94121 USA. EM kirsten.johansen@ucsf.edu NR 8 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 8 PY 2011 VL 171 IS 15 BP 1317 EP 1318 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 804GR UT WOS:000293642800002 PM 21824944 ER PT J AU Schuetz, P Chiappa, V Briel, M Greenwald, JL AF Schuetz, Philipp Chiappa, Victor Briel, Matthias Greenwald, Jeffrey L. TI Procalcitonin Algorithms for Antibiotic Therapy Decisions A Systematic Review of Randomized Controlled Trials and Recommendations for Clinical Algorithms SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID RESPIRATORY-TRACT INFECTIONS; COMMUNITY-ACQUIRED PNEUMONIA; CRITICALLY-ILL PATIENTS; HUMAN ADIPOSE-TISSUE; SEVERE SEPSIS; SERUM PROCALCITONIN; SEPTIC PATIENTS; METAANALYSIS; CARE; DIAGNOSIS AB Previous randomized controlled trials suggest that using clinical algorithms based on procalcitonin levels, a marker of bacterial infections, results in reduced antibiotic use without a deleterious effect on clinical outcomes. However, algorithms differed among trials and were embedded primarily within the European health care setting. Herein, we summarize the design, efficacy, and safety of previous randomized controlled trials and propose adapted algorithms for US settings. We performed a systematic search and included all 14 randomized controlled trials (N=4467 patients) that investigated procalcitonin algorithms for antibiotic treatment decisions in adult patients with respiratory tract infections and sepsis from primary care, emergency department (ED), and intensive care unit settings. We found no significant difference in mortality between procalcitonin-treated and control patients overall (odds ratio, 0.91; 95% confidence interval, 0.73-1.14) or in primary care (0.13; 0-6.64), ED (0.95; 0.67-1.36), and intensive care unit (0.89; 0.66-1.20) settings individually. A consistent reduction was observed in antibiotic prescription and/or duration of therapy, mainly owing to lower prescribing rates in low-acuity primary care and ED patients, and shorter duration of therapy in moderate-and high-acuity ED and intensive care unit patients. Measurement of procalcitonin levels for antibiotic decisions in patients with respiratory tract infections and sepsis appears to reduce antibiotic exposure without worsening the mortality rate. We propose specific procalcitonin algorithms for low-, moderate-, and high-acuity patients as a basis for future trials aiming at reducing antibiotic overconsumption. Arch Intern Med. 2011;171(15):1322-1331 C1 [Schuetz, Philipp] Harvard Univ, Sch Publ Hlth, Dept Emergency Med, Boston, MA 02115 USA. [Chiappa, Victor; Greenwald, Jeffrey L.] Massachusetts Gen Hosp, Dept Med, Inpatient Clinician Educ Serv, Boston, MA 02114 USA. [Briel, Matthias] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. RP Schuetz, P (reprint author), Harvard Univ, Sch Publ Hlth, Dept Emergency Med, 667 Huntington Ave, Boston, MA 02115 USA. EM philipp.schuetz@post.harvard.edu FU Swiss Foundation for Grants in Biology and Medicine [PASMP3-127684/1]; BRAHMS USA Inc; santesuisse; Gottfried and Julia Bangerter-Rhyner Foundation FX Dr Schuetz was supported by research grant PASMP3-127684/1 from the Swiss Foundation for Grants in Biology and Medicine and received support from BRAHMS USA Inc and bio-Merieux to attend meetings and to fulfill speaking engagements. Dr Briel is supported by grants from santesuisse and the Gottfried and Julia Bangerter-Rhyner Foundation. NR 41 TC 154 Z9 167 U1 0 U2 22 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 8 PY 2011 VL 171 IS 15 BP 1322 EP 1331 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 804GR UT WOS:000293642800004 PM 21824946 ER PT J AU Kistler, CE Kirby, KA Lee, D Casadei, MA Walter, LC AF Kistler, Christine E. Kirby, Katharine A. Lee, Delia Casadei, Michele A. Walter, Louise C. TI Long-term Outcomes Following Positive Fecal Occult Blood Test Results in Older Adults Benefits and Burdens SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID COMPLETE DIAGNOSTIC EVALUATION; AMERICAN-CANCER-SOCIETY; COLORECTAL-CANCER; ELDERLY-PATIENTS; COLONOSCOPY SURVEILLANCE; COMORBIDITY INDEX; LIFE EXPECTANCY; UNITED-STATES; GUIDELINES; AGE AB Background: In the United States, older adults have low rates of follow-up colonoscopy after a positive fecal occult blood test (FOBT) result. The long-term outcomes of these real world practices and their associated benefits and burdens are unknown. Methods: Longitudinal cohort study of 212 patients 70 years or older with a positive FOBT result at 4 Veteran Affairs (VA) facilities in 2001 and followed up through 2008. We determined the frequency of downstream outcomes during the 7 years of follow-up, including procedures, colonoscopic findings, outcomes of treatment, complications, and mortality based on chart review and national VA and Medicare data. Net burden or benefit from screening and follow-up was determined according to each patient's life expectancy. Life expectancy was classified into 3 categories: best (age, 70-79 years and Charlson-Deyo comorbidity index [CCI], 0), average, and worst (age, 70-84 years and CCI, >= 4 or age, >= 85 years and CCI, >= 1). Results: Fifty-six percent of patients received follow-up colonoscopy (118 of 212), which found 34 sig-nificant adenomas and 6 cancers. Ten percent experienced complications from colonoscopy or cancer treatment (12 of 118). Forty-six percent of those without follow-up colonoscopy died of other causes within 5 years of FOBT (43 of 94), while 3 died of colorectal cancer within 5 years. Eighty-seven percent of patients with worst life expectancy experienced a net burden from screening (26 of 30) as did 70% with average life expectancy (92 of 131) and 65% with best life expectancy (35 of 51) (P=.048 for trend). Conclusions: Over a 7-year period, older adults with best life expectancy were less likely to experience a net burden from current screening and follow-up practices than are those with worst life expectancy. The net burden could be decreased by better targeting FOBT screening and follow-up to healthy older adults. C1 [Kistler, Christine E.] Univ N Carolina, Dept Family Med, Chapel Hill, NC 27599 USA. [Kirby, Katharine A.; Casadei, Michele A.; Walter, Louise C.] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA USA. [Kirby, Katharine A.; Casadei, Michele A.; Walter, Louise C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lee, Delia] Univ Arkansas, Sch Med, Fayetteville, AR 72701 USA. RP Kistler, CE (reprint author), Univ N Carolina, Dept Family Med, 590 Manning Dr,CB 7595, Chapel Hill, NC 27599 USA. EM Christine_Kistler@med.unc.edu FU National Institute on Aging [T32 AG000212-16]; Agency for Healthcare Research and Quality Mentored Career Development Program in Comparative Effectiveness Development [K12 HS19468-01]; Cecil G. Sheps Center for Health Services Research; Lineberger Cancer Center at the University of North Carolina at Chapel Hill; VA Health Services Research and Development [IIR-04-427]; National Cancer Institute [1R01CA134425]; VA Quality Scholars Program FX Work for this research was supported by the VA Quality Scholars Program, National Institute on Aging grant T32 AG000212-16, Agency for Healthcare Research and Quality Mentored Career Development Program in Comparative Effectiveness Development grant K12 HS19468-01, the Cecil G. Sheps Center for Health Services Research, and the Lineberger Cancer Center at the University of North Carolina at Chapel Hill (Dr Kistler); and by VA Health Services Research and Development grant IIR-04-427 and National Cancer Institute grant 1R01CA134425 (Dr Walter). NR 41 TC 16 Z9 16 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 8 PY 2011 VL 171 IS 15 BP 1344 EP 1351 DI 10.1001/archinternmed.2011.206 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 804GR UT WOS:000293642800007 PM 21555655 ER PT J AU Newton, KM Grady, D AF Newton, Katherine M. Grady, Deborah TI Soy Isoflavones for Prevention of Menopausal Bone Loss and Vasomotor Symptoms SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; MILD COGNITIVE IMPAIRMENT; HEALTH INITIATIVE MEMORY; ESTROGEN PLUS PROGESTIN; POSTMENOPAUSAL WOMEN; MINERAL DENSITY; METAANALYSIS; DEMENTIA C1 [Grady, Deborah] Univ Calif San Francisco, Dept Med, San Francisco, CA 94115 USA. [Grady, Deborah] San Francisco VA Med Ctr, Med Serv, San Francisco, CA USA. [Newton, Katherine M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. RP Grady, D (reprint author), Univ Calif San Francisco, Dept Med, 1635 Divisadero St,Ste 600, San Francisco, CA 94115 USA. NR 12 TC 7 Z9 7 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 8 PY 2011 VL 171 IS 15 BP 1369 EP 1370 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 804GR UT WOS:000293642800012 PM 21824951 ER PT J AU Turchin, A Goldberg, SI Breydo, E Shubina, M Einbinder, JS AF Turchin, Alexander Goldberg, Saveli I. Breydo, Eugene Shubina, Maria Einbinder, Jonathan S. TI Copy/Paste Documentation of Lifestyle Counseling and Glycemic Control in Patients With Diabetes: True to Form? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID ELECTRONIC HEALTH RECORDS C1 [Turchin, Alexander; Shubina, Maria] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Einbinder, Jonathan S.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Turchin, Alexander; Breydo, Eugene; Einbinder, Jonathan S.] Harvard Univ, Sch Med, Boston, MA USA. [Turchin, Alexander; Breydo, Eugene; Einbinder, Jonathan S.] Partners HealthCare Syst, Clin Informat Res & Dev, Boston, MA USA. [Goldberg, Saveli I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Turchin, A (reprint author), Brigham & Womens Hosp, Div Endocrinol, 221 Longwood Ave, Boston, MA 02115 USA. EM aturchin@partners.org FU NIDDK NIH HHS [L30 DK081970] NR 8 TC 17 Z9 17 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 8 PY 2011 VL 171 IS 15 BP 1393 EP 1394 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 804GR UT WOS:000293642800019 PM 21606091 ER PT J AU Huang, SL Shen, Q Duong, TQ AF Huang, Shiliang Shen, Qiang Duong, Timothy Q. TI Quantitative prediction of acute ischemic tissue fate using support vector machine SO BRAIN RESEARCH LA English DT Article DE SVM; fMRI; ANN; Perfusion-diffusion mismatch; Predictive model; DWI; PWI; ADC; CBF; Spatial infarction incidence ID NEURAL-NETWORK; CEREBRAL-ISCHEMIA; FOCAL ISCHEMIA; FUNCTIONAL MRI; BRAIN-INJURY; PERFUSION; STROKE; PENUMBRA; CLASSIFICATION; CONSUMPTION AB Accurate and quantitative prediction of ischemic tissue fate could improve decision-making in the clinical treatment of acute stroke. The goal of the present study is to explore the novel use of support vector machine (SVM) to predict infarct on a pixel-by-pixel basis using only acute cerebral blood flow (CBF), apparent diffusion coefficient (ADC) MRI data. The efficacy of SVM prediction model was tested on three stroke groups: 30-min, 60-min, and permanent middle cerebral-artery occlusion (n=12 rats for each group). CBF, ADC and relaxation time constant (T2) were acquired during the acute phase up to 3 h and again at 24 h. Infarct was predicted using only acute (30-min) stroke data. Receiver-operating characteristic (ROC) analysis was used to quantify prediction accuracy. The areas under the receiver-operating curves were 86+/-2.7%, 89+/-1.4%, and 93+/-0.8% using ADC+CBF data for the 30-min, 60-min and permanent middle cerebral artery occlusion (MCAO) group, respectively. Adding neighboring pixel information and spatial infarction incidence improved performance to 88 +/-2.8%, 94+/-0.8%, and 97+/-0.9%, respectively. SVM prediction compares favorably to a previously published artificial neural network (ANN) prediction algorithm operated on the same data sets. SVM prediction model has the potential to provide quantitative frameworks to aid clinical decision-making in the treatment of acute stroke. (C) 2011 Elsevier B.V. All rights reserved. C1 [Huang, Shiliang; Shen, Qiang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu RI Duong, Timothy/B-8525-2008; Shen, Qiang/B-8784-2008; Huang, Shiliang/F-3143-2010 OI Shen, Qiang/0000-0002-4287-3403; FU NIH [R01-NS45879]; American Heart Association [EIA 0940104N, SDG-0430020N, SDG-0830293N] FX This work was supported by the NIH (R01-NS45879) and the American Heart Association (EIA 0940104N, SDG-0430020N and SDG-0830293N). NR 34 TC 12 Z9 12 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 8 PY 2011 VL 1405 BP 77 EP 84 DI 10.1016/j.brainres.2011.05.066 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 807VW UT WOS:000293932100008 PM 21741624 ER PT J AU Lu, L Ladinsky, MS Kirchhausen, T AF Lu, Lei Ladinsky, Mark S. Kirchhausen, Tomas TI Formation of the postmitotic nuclear envelope from extended ER cisternae precedes nuclear pore assembly SO JOURNAL OF CELL BIOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM; MEMBRANE-PROTEINS; LIVING CELLS; COMPLEX; CHROMATIN; MITOSIS; RECRUITMENT; SUBCOMPLEX; STEPS; ORGANIZATION AB During mitosis, the nuclear envelope merges with the endoplasmic reticulum (ER), and nuclear pore complexes are disassembled. In a current model for reassembly after mitosis, the nuclear envelope forms by a reshaping of ER tubules. For the assembly of pores, two major models have been proposed. In the insertion model, nuclear pore complexes are embedded in the nuclear envelope after their formation. In the prepore model, nucleoporins assemble on the chromatin as an intermediate nuclear pore complex before nuclear envelope formation. Using live-cell imaging and electron microscope tomography, we find that the mitotic assembly of the nuclear envelope primarily originates from ER cisternae. Moreover, the nuclear pore complexes assemble only on the already formed nuclear envelope. Indeed, all the chromatin-associated Nup107-160 complexes are in single units instead of assembled prepores. We therefore propose that the postmitotic nuclear envelope assembles directly from ER cisternae followed by membrane-dependent insertion of nuclear pore complexes. C1 [Lu, Lei; Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Lu, Lei; Kirchhausen, Tomas] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Lu, Lei; Kirchhausen, Tomas] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Lu, Lei] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore. [Ladinsky, Mark S.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Ladinsky, Mark S.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. RP Kirchhausen, T (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. EM lulei@ntu.edu.sg; kirchhausen@crystal.harvard.edu RI Lu, Lei/A-2225-2011 OI Lu, Lei/0000-0002-8192-1471 FU National Institutes of Health [GM-075252, U54 AI057159]; SBS [SUG M58080013] FX This work was supported by National Institutes of Health grants GM-075252 (to T. Kirchhausen), U54 AI057159 (New England Regional Center of Excellence in Biodefense and Emerging Infectious Disease, Core Imaging Facility), and SBS SUG M58080013 (to L. Lu). NR 46 TC 50 Z9 51 U1 0 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 8 PY 2011 VL 194 IS 3 BP 425 EP 440 DI 10.1083/jcb.201012063 PG 16 WC Cell Biology SC Cell Biology GA 804YY UT WOS:000293693500009 PM 21825076 ER PT J AU Tomas, E Wood, JA Stanojevic, V Habener, JF AF Tomas, Eva Wood, Jenna A. Stanojevic, Violeta Habener, Joel F. TI GLP-1-derived nonapeptide GLP-1(28-36)amide inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice SO REGULATORY PEPTIDES LA English DT Article DE Glucagon-like peptide-1; Insulin resistance; Obesity; Energy expenditure ID GLUCAGON-LIKE PEPTIDE-1; MEDIATED GLUCOSE-UPTAKE; GLP-1 9-36 AMIDE; METABOLIC SYNDROME; NEUTRAL ENDOPEPTIDASE-24.11; INSULIN-RESISTANCE; OXIDATIVE STRESS; MOUSE MODEL; MELLITUS AB Background: The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1 (28-36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome. Methods and results: Three- to 11-week infusions of GLP-1(28-36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28-36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP-1(28-36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25-70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight. Conclusions: GLP-1(28-36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome. (C) 2011 Elsevier B.V. All rights reserved. C1 [Tomas, Eva; Wood, Jenna A.; Stanojevic, Violeta; Habener, Joel F.] Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. RP Habener, JF (reprint author), Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. EM jhabener@partners.org FU Novo Nordisk FX We thank Zhenghu Liu for helpful comments, Karen McManus for expert experimental assistance, and Ashok Khatri for peptide synthesis. The later studies were supported in part by a grant from Novo Nordisk. NR 27 TC 21 Z9 21 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD AUG 8 PY 2011 VL 169 IS 1-3 BP 43 EP 48 DI 10.1016/j.regpep.2011.04.006 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 787ID UT WOS:000292368900007 PM 21549160 ER PT J AU Sherry, N Hagopian, W Ludvigsson, J Jain, SM Wahlen, J Ferry, RJ Bode, B Aronoff, S Holland, C Carlin, D King, KL Wilder, RL Pillemer, S Bonvini, E Johnson, S Stein, KE Koenig, S Herold, KC Daifotis, AG AF Sherry, Nicole Hagopian, William Ludvigsson, Johnny Jain, Sunil M. Wahlen, Jack Ferry, Robert J., Jr. Bode, Bruce Aronoff, Stephen Holland, Christopher Carlin, David King, Karen L. Wilder, Ronald L. Pillemer, Stanley Bonvini, Ezio Johnson, Syd Stein, Kathryn E. Koenig, Scott Herold, Kevan C. Daifotis, Anastasia G. CA Protege Trial Investigators TI Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial SO LANCET LA English DT Article ID MONOCLONAL-ANTIBODY; INSULIN-SECRETION; IMMUNE THERAPY; MELLITUS AB Background Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve beta-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. Methods In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protege study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0.5 U/kg per day and glycated haemoglobin A(1c) (HbA(1c)) of less than 6-5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. Findings 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19.8% (41/207) in the 14-day full-dose group; 13.7% (14/102) in the 14-day low-dose group; 20.8% (22/106) in the 6-day full-dose group; and 20.4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0.03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). Interpretation Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in beta-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. C1 [Sherry, Nicole] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hagopian, William] NW Diabet Res Inst, Seattle, WA USA. [Ludvigsson, Johnny] Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Div Pediat, Linkoping, Sweden. [Jain, Sunil M.] TOTALL Diabet Hormone Res Inst, Indore, Madhya Pradesh, India. [Wahlen, Jack] Endocrine Res Specialists, Ogden, UT USA. [Ferry, Robert J., Jr.] Le Bonheur Childrens Hosp, Div Pediat Endocrinol & Metab, Memphis, TN USA. [Ferry, Robert J., Jr.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Bode, Bruce] Atlanta Diabet Associates, Atlanta, GA USA. [Aronoff, Stephen] Res Inst Dallas, Dallas, TX USA. [Holland, Christopher; Carlin, David; King, Karen L.; Bonvini, Ezio; Johnson, Syd; Stein, Kathryn E.; Koenig, Scott; Daifotis, Anastasia G.] MacroGenics, Rockville, MD USA. [Wilder, Ronald L.] PAREXEL Int, Durham, NC USA. [Pillemer, Stanley] Amer Biopharma Corp, Gaithersburg, MD USA. [Herold, Kevan C.] Yale Univ, New Haven, CT USA. RP Sherry, N (reprint author), Massachusetts Gen Hosp Children, 175 Cambridge St,Room 537, Boston, MA 02114 USA. EM nsherry@partners.org RI Hanukoglu, Aaron/L-4892-2016; Ferry, Robert/O-6107-2016; OI Hanukoglu, Aaron/0000-0003-1486-6641; Ferry, Robert/0000-0001-9228-3914; Ludvigsson, Johnny/0000-0003-1695-5234 FU MacroGenics; Juvenile Diabetes Research Foundation; Eli Lilly; US National Institutes of Health [R21 HD059292, T35 DK007405]; Le Bonheur Foundation (Memphis TN, USA); Juvenile Diabetes Foundation [2008-502] FX Funding MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.; CH, DC, KLK, EB, SJ, KES, SK, and AGD are employees of MacroGenics and potentially own shares or options in the company. NS, JL, SA, BB, JW, and RJF received research and travel support for this study from MacroGenics. JL has received advisory board support from Johnson & Johnson. RJF has received research support within the past 3 years from Tolerx (to study otelixizumab for recent-onset type 1 diabetes); unrelated research support from the US National Institutes of Health (grants R21 HD059292 and T35 DK007405), Gabrielle's Angel Foundation, Eli Lilly, Diamyd, Pfizer, and Novo Nordisk; and unrestricted research support from Le Bonheur Foundation (Memphis TN, USA). WH chairs the data safety and monitoring board for the BHT-3021-01 insulin plasmid trial (Bayhill Pharmaceuticals). KCH has received research support from MacroGenics, and support from the Juvenile Diabetes Foundation (grant 2008-502) for laboratory studies on patients' samples from Prot g. RLW is a former employee of MacroGenics and holds restricted stock in the company, and is now an employee of Parexel International, the lead contract research organisation that coordinated the Prot g trial globally. SA has received speaking honoraria from Eli Lilly. SP was formerly employed by MacroGenics and received stock options while employed there. SMJ declares that he has no conflicts of interest. NR 20 TC 199 Z9 202 U1 4 U2 26 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 6 PY 2011 VL 378 IS 9790 BP 487 EP 497 DI 10.1016/S0140-6736(11)60931-8 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 809SO UT WOS:000294077200028 PM 21719095 ER PT J AU Olivieri, KC Mukerji, J Gabuzda, D AF Olivieri, Kevin C. Mukerji, Joya Gabuzda, Dana TI Nef-mediated enhancement of cellular activation and human immunodeficiency virus type 1 replication in primary T cells is dependent on association with p21-activated kinase 2 SO RETROVIROLOGY LA English DT Article ID LONG-TERM-NONPROGRESSOR; SRC-FAMILY KINASES; HIV-1 NEF; VIRAL REPLICATION; RHESUS MACAQUES; DISEASE PROGRESSION; DOWN-REGULATION; SH3 DOMAINS; LIPID RAFTS; IN-VIVO AB Background: The HIV-1 accessory protein Nef is an important determinant of lentiviral pathogenicity that contributes to disease progression by enhancing viral replication and other poorly understood mechanisms. Nef mediates diverse functions including downmodulation of cell surface CD4 and MHC Class I, enhancement of viral infectivity, and enhancement of T cell activation. Nef interacts with a multiprotein signaling complex that includes Src family kinases, Vav1, CDC42, and activated PAK2 (p21-activated kinase 2). Although previous studies have attempted to identify a biological role for the Nef-PAK2 signaling complex, the importance of this complex and its constituent proteins in Nef function remains unclear. Results: Here, we show that Nef mutants defective for PAK2-association, but functional for CD4 and MHC Class I downmodulation and infectivity enhancement, are also defective for the ability to enhance viral replication in primary T cells that are infected and subsequently activated by sub-maximal stimuli (1 mu g/ml PHA-P). In contrast, these Nef mutants had little or no effect on HIV-1 replication in T cells activated by stronger stimuli (2 mu g/ml PHAP or anti-CD3/CD28-coated beads). Viruses bearing wild-type Nefs, but not Nef mutants defective for PAK2 association, enhanced NFAT and IL2 receptor promoter activity in Jurkat cells. Moreover, expression of wild-type Nefs, but not mutant Nefs defective for PAK2 association, was sufficient to enhance responsiveness of primary CD4 and CD8 T cells to activating stimuli in Nef-expressing and bystander cells. siRNA knockdown of PAK2 in Jurkat cells reduced NFAT activation induced by anti-CD3/CD28 stimulation both in the presence and absence of Nef, and expression of a PAK2 dominant mutant inhibited Nef-mediated enhancement of CD25 expression. Conclusion: Nef-mediated enhancement of cellular activation and viral replication in primary T cells is dependent on PAK2 and on the strength of the activating stimuli, and correlates with the ability of Nef to associate with PAK2. PAK2 is likely to play a role in Nef-mediated enhancement of viral replication and immune activation in vivo. C1 [Olivieri, Kevin C.; Mukerji, Joya; Gabuzda, Dana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Gabuzda, Dana] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Gabuzda, D (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM dana_gabuzda@dfci.harvard.edu FU NIH [R21 AI73415, R21 AI77464, DP1 DA028994]; Harvard University Center for AIDS Research; DFCI/Harvard Cancer Center; [T32 AI007386]; [T32 AG00222] FX We thank Etienne Gagnon, Kristin Agopian, Vikas Misra, Megan Mefford, and Edana Cassol for advice and discussions, Hillel Haim and Joseph Sodroski for providing the HXB2 Env plasmids, Andreas Baur for providing the pNL4-3 MCS Nef provirus, Damian Purcell for providing the pNL4-3 Delta Nef (Delta XhoI) provirus, and Michel Tremblay for providing the IL2-Luc and NFAT-Luc stable cell lines. The following reagent was obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID: MAGI-CCR5 from Dr. Julie Overbaugh. pHAGE was obtained from the Harvard Gene Therapy Initiative plasmid repository. This work was supported by NIH grants R21 AI73415, R21 AI77464, and DP1 DA028994. K.C.O. was supported in part by T32 AI007386. J.M. was supported in part by T32 AG00222. Core facilities were supported by Harvard University Center for AIDS Research and DFCI/Harvard Cancer Center grants. NR 73 TC 19 Z9 19 U1 3 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD AUG 5 PY 2011 VL 8 AR 64 DI 10.1186/1742-4690-8-64 PG 17 WC Virology SC Virology GA 817OL UT WOS:000294683600001 PM 21819585 ER PT J AU Michael, AM King, MD Ehrlich, S Pearlson, G White, T Holt, DJ Andreasen, NC Sakoglu, U Ho, BC Schulz, SC Calhoun, VD AF Michael, Andrew M. King, Margaret D. Ehrlich, Stefan Pearlson, Godfrey White, Tonya Holt, Daphne J. Andreasen, Nancy C. Sakoglu, Unal Ho, Beng-Choon Schulz, S. Charles Calhoun, Vince D. TI A data-driven investigation of gray matter-function correlations in schizophrenia during a working memory task SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE schizophrenia; structural MRI; functional MRI; correlation; gray matter; working memory ID DORSOLATERAL PREFRONTAL CORTEX; VOXEL-BASED MORPHOMETRY; TEMPORAL-LOBE; BRAIN VOLUMES; FMRI; ABNORMALITIES; PERFORMANCE; METAANALYSIS; DYSFUNCTION; SYMPTOMS AB The brain is a vastly interconnected organ and methods are needed to investigate its long range structure(S)-function(F) associations to better understand disorders such as schizophrenia that are hypothesized to be due to distributed disconnected brain regions. In previous work we introduced a methodology to reduce the whole brain S-F correlations to a histogram and here we reduce the correlations to brain clusters. The application of our approach to sMRI [gray matter (GM) concentration maps] and functional magnetic resonance imaging data (general linear model activation maps during Encode and Probe epochs of a working memory task) from patients with schizophrenia (SZ, n = 100) and healthy controls (HC, n = 100) presented the following results. In HC the whole brain correlation histograms for GM-Encode and GM-Probe overlap for Low and Medium loads and at High the histograms separate, but in SZ the histograms do not overlap for any of the load levels and Medium load shows the maximum difference. We computed GM-F differential correlation clusters using activation for Probe Medium, and they included regions in the left and right superior temporal gyri, anterior cingulate, cuneus, middle temporal gyrus, and the cerebellum. Inter-cluster GM-Probe correlations for Medium load were positive in HC but negative in SZ. Within group inter-cluster GM-Encode and GM-Probe correlation comparisons show no differences in HC but in SZ differences are evident in the same clusters where HC vs. SZ differences occurred for Probe Medium, indicating that the S-F integrity during Probe is aberrant in SZ. Through a data-driven whole brain analysis approach we find novel brain clusters and show how the S-F differential correlation changes during Probe and Encode at three memory load levels. Structural and functional anomalies have been extensively reported in schizophrenia and here we provide evidences to suggest that evaluating S-F associations can provide important additional information. C1 [Michael, Andrew M.; King, Margaret D.; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87106 USA. [Ehrlich, Stefan; Holt, Daphne J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ehrlich, Stefan] Tech Univ Dresden, Dept Child & Adolescent Psychiat, D-8027 Dresden, Germany. [Pearlson, Godfrey; Calhoun, Vince D.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Pearlson, Godfrey; Calhoun, Vince D.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06520 USA. [Pearlson, Godfrey; Calhoun, Vince D.] Inst Living, Olin Ctr, Hartford, CT USA. [White, Tonya] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [White, Tonya; Schulz, S. Charles] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Andreasen, Nancy C.; Ho, Beng-Choon] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Sakoglu, Unal] Univ Texas Dallas, Ctr Vital Longev, Dallas, TX 75230 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. RP Michael, AM (reprint author), Mind Res Network, 1101 Yale Blvd NE, Albuquerque, NM 87106 USA. EM andru4u@gmail.com RI Ho, Beng-Choon/D-6959-2011; OI Ho, Beng-Choon/0000-0003-3976-1555; Ehrlich, Stefan/0000-0003-2132-4445 FU Department of Energy [DE-FG02-99ER62764]; National Institutes of Health [R01EB006841, R01EB005846] FX The data collection was funded by the Department of Energy, grant DE-FG02-99ER62764. The authors would like to thank the University of Iowa Hospital, Massachusetts General Hospital, the University of Minnesota, and the Mind Research Network staff for their efforts during data collection, preprocessing, and analysis. This work was supported by the National Institutes of Health under grants R01EB006841 and R01EB005846. NR 49 TC 13 Z9 13 U1 0 U2 5 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD AUG 5 PY 2011 VL 5 AR 71 DI 10.3389/fnhum.2011.00071 PG 14 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 814RF UT WOS:000294474100002 PM 21886614 ER PT J AU Lakhashe, SK Velu, V Sciaranghella, G Siddappa, NB DiPasquale, JM Hemashettar, G Yoon, JK Rasmussen, RA Yang, F Lee, SJ Montefiori, DC Novembre, FJ Villinger, F Amara, RR Kahn, M Hu, SL Li, SF Li, ZX Frankel, FR Robert-Guroff, M Johnson, WE Lieberman, J Ruprecht, RM AF Lakhashe, Samir K. Velu, Vijayakumar Sciaranghella, Gaia Siddappa, Nagadenahalli B. DiPasquale, Janet M. Hemashettar, Girish Yoon, John K. Rasmussen, Robert A. Yang, Feng Lee, Sandra J. Montefiori, David C. Novembre, Francis J. Villinger, Francois Amara, Rama Rao Kahn, Maria Hu, Shiu-Lok Li, Sufen Li, Zhongxia Frankel, Fred R. Robert-Guroff, Marjorie Johnson, Welkin E. Lieberman, Judy Ruprecht, Ruth M. TI Prime-boost vaccination with heterologous live vectors encoding SIV gag and multimeric HIV-1 gp160 protein: Efficacy against repeated mucosal R5 clade C SHIV challenges SO VACCINE LA English DT Article DE Live attenuated Listeria monocytogenes; Replication-competent adenovirus; Live oral vaccine; HIV/AIDS vaccine; Multimeric HIV clade C gp160; Prime-boost vaccination; alpha 4 beta 7 integrin ID IMMUNODEFICIENCY-VIRUS TYPE-1; CELL-MEDIATED-IMMUNITY; LISTERIA-MONOCYTOGENES; RHESUS MACAQUES; PROTECTIVE EFFICACY; INTEGRIN ALPHA(4)BETA(7); REPLICATION-COMPETENT; CANCER-IMMUNOTHERAPY; SHIV89.6P CHALLENGE; ADENOVIRUS VACCINES AB We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus >90%; these RM also had strong SIV Gag-specific proliferation of CD8(+) T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the alpha 4 beta 7-expressing CD4(+) T cells; the latter have been implicated as preferential virus targets in vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Lakhashe, Samir K.; Sciaranghella, Gaia; Siddappa, Nagadenahalli B.; Hemashettar, Girish; Yoon, John K.; Rasmussen, Robert A.; Yang, Feng; Lee, Sandra J.; Ruprecht, Ruth M.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Lakhashe, Samir K.; Sciaranghella, Gaia; Siddappa, Nagadenahalli B.; Rasmussen, Robert A.; Yang, Feng; Lee, Sandra J.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Velu, Vijayakumar; Novembre, Francis J.; Villinger, Francois; Amara, Rama Rao] Emory Univ, Yerkes Natl Primate Res Ctr, Div Microbiol & Immunol, Atlanta, GA 30329 USA. [Velu, Vijayakumar; Novembre, Francis J.; Amara, Rama Rao] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30329 USA. [DiPasquale, Janet M.; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Villinger, Francois] Emory Univ, Yerkes Natl Primate Res Ctr, Dept Pathol, Atlanta, GA 30329 USA. [Kahn, Maria; Hu, Shiu-Lok] Univ Washington, Seattle, WA 98195 USA. [Li, Sufen; Li, Zhongxia; Frankel, Fred R.] Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Johnson, Welkin E.] New England Primate Res Ctr, Southborough, MA 01772 USA. [Lieberman, Judy] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 450 Brookline Ave, Boston, MA 02215 USA. EM ruth_ruprecht@dfci.harvard.edu RI Lakhashe, Samir/F-1150-2014; Lieberman, Judy/A-2717-2015; Hu, Shiu-Lok/A-3196-2008; OI Hu, Shiu-Lok/0000-0003-4336-7964; Byrareddy, Siddappa /0000-0002-7423-1763; Velu, Vijayakumar/0000-0003-4238-1924 FU NIH [P01 AI054558, P01 AI048240, RR-00165, RR00168]; Center for AIDS Research Immunology [P30 AI060354, P30 AI 050409]; NIH, National Cancer Institute FX We thank Julie Johnson-McGrath for assistance with the preparation of this manuscript, Stephanie Ehnert for the coordination of the primate studies, and Dr. Richard Raybourne (formerly of the Food and Drug Administration) for assistance and protocols to assess anti-Lm immune responses. We thank Stefan Kostense, Crucell Holland B.V., for providing the Ad5-luciferase construct. We thank the NIH AIDS Research and Reference Reagent Program for reagents. This study was supported by NIH grants P01 AI054558 to FF, FJN, RMR and JL and P01 AI048240 to RMR, RR-00165 to the YNPRC, RR00168 to the NEPRC, and by Center for AIDS Research Immunology Core grants, P30 AI060354 and P30 AI 050409, and in part by the Intramural Research Program of the NIH, National Cancer Institute. NR 71 TC 24 Z9 24 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 5 PY 2011 VL 29 IS 34 BP 5611 EP 5622 DI 10.1016/j.vaccine.2011.06.017 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 810RW UT WOS:000294145800006 PM 21693155 ER PT J AU Gerszten, RE Asnani, A Carr, SA AF Gerszten, Robert E. Asnani, Aarti Carr, Steven A. TI Status and Prospects for Discovery and Verification of New Biomarkers of Cardiovascular Disease by Proteomics SO CIRCULATION RESEARCH LA English DT Review DE proteomics; biomarkers; mass spectrometry ID ACUTE CORONARY SYNDROMES; HUMAN PLASMA PROTEOME; PEPTIDE IMMUNOAFFINITY ENRICHMENT; SPECTROMETRY-BASED PROTEOMICS; TARGETED MASS-SPECTROMETRY; TROPONIN-I; MYOCARDIAL-INFARCTION; NATRIURETIC PEPTIDE; MULTIPLEXED ASSAYS; UNSTABLE ANGINA AB Despite unmet needs for cardiovascular biomarkers, few new protein markers have been approved by the US Food and Drug Administration for the diagnosis or screening of cardiovascular diseases. Mass spectrometry-based proteomics technologies are capable of identifying hundreds to thousands of proteins in cells, tissues, and biofluids. Proteomics may therefore provide the opportunity to elucidate new biomarkers and pathways without a prior known association with cardiovascular disease; however, important obstacles remain. In this review, we focus on emerging techniques that may form a coherently integrated pipeline to overcome present limitations to both the discovery and validation processes. (Circ Res. 2011;109:463-474.) C1 [Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Gerszten, Robert E.; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 55 Fruit St, Boston, MA 02114 USA. EM Gerszten.Robert@mgh.harvard.edu; scarr@broad.mit.edu FU National Institutes of Health, National Heart, Lung, and Blood Institute's Proteomics Center [HHSN268201000033C]; [R01HL096738-02] FX The authors gratefully acknowledge support from the National Institutes of Health, National Heart, Lung, and Blood Institute's Proteomics Center Contract (HHSN268201000033C) and R01HL096738-02. NR 67 TC 37 Z9 38 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 5 PY 2011 VL 109 IS 4 BP 463 EP 474 DI 10.1161/CIRCRESAHA.110.225003 PG 12 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 802IV UT WOS:000293504100014 PM 21817166 ER PT J AU Hashimoto, T Adams, KW Fan, ZY McLean, PJ Hyman, BT AF Hashimoto, Tadafumi Adams, Kenneth W. Fan, Zhanyun McLean, Pamela J. Hyman, Bradley T. TI Characterization of Oligomer Formation of Amyloid-beta Peptide Using a Split-luciferase Complementation Assay SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID A-BETA; ALZHEIMERS-DISEASE; IN-VIVO; PROTOFIBRIL FORMATION; SYNAPTIC PLASTICITY; SECRETED OLIGOMERS; PROTEIN OLIGOMERS; SENILE PLAQUES; A-BETA-40; MEMORY AB Amyloid-beta peptide (A beta) is the amyloid component of senile plaques in Alzheimer disease (AD) brains. Recently a soluble oliomeric form of A beta in A beta precursor protein transgenic mouse brains and AD brains was identified as a potential causative molecule for memory impairment, suggesting that soluble A beta oligomers cause neurodegeneration in AD. Further characterization of this species has been hampered, however, because the concentrations are quite small and it is difficult to monitor A beta oligomers specifically. Here we developed a novel method for monitoring A beta oligomers using a split-luciferase complementation assay. In this assay, the Nand C-terminal fragments of Gaussia luciferase (Gluc) are fused separately to A beta. We found that conditioned media from both N- and C-terminal fragments of Gluc-tagged A beta 1-42 doubly transfected HEK293 cells showed strong luminescence. We used gel filtration analyses to analyze the size of oligomers formed by the luciferase complementation assay, and found that it matched closely with oligomers formed by endogenous A beta in Tg2576 neurons. Large oligomers (24-36-mers), 8-mers, trimers, and dimers predominate. In both systems, A beta formed oligomers intracellularly, which then appear to be secreted as oligomers. We then evaluated several factors that might impact oligomer formation. The level of oligomerization of A beta 1-40 was similar to that of A beta 1-42. Homodimers formed more readily than heterodimers. The level of oligomerization of murine A beta 1-42 was similar to that of human A beta 1-42. As expected, the familial AD-linked Arctic mutation (E22G) significantly enhanced oligomer formation. These data suggest that Gluc-tagged A beta enables the analysis of A beta oligomers. C1 [Hashimoto, Tadafumi; Adams, Kenneth W.; Fan, Zhanyun; McLean, Pamela J.; Hyman, Bradley T.] Massachusetts Gen Hosp, Dept Neurol, Alzheimers Dis Res Unit, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Dept Neurol, Alzheimer Dis Res Unit, Bldg 114,16th St, Charlestown, MA 02129 USA. EM bhyman@partners.org RI Hashimoto, Tadafumi/A-7723-2013 FU National Institutes of Health [AG12406]; JSPS; Ellison Medical Foundation/AFAR [2009A059868] FX This work was supported, in whole or in part, by National Institutes of Health Grant AG12406 (to B. T. H.), the JSPS Postdoctoral Fellow for Research Abroad (to T. H.), and the Ellison Medical Foundation/AFAR 2009A059868 (to T. H.). NR 38 TC 27 Z9 28 U1 1 U2 16 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 5 PY 2011 VL 286 IS 31 BP 27081 EP 27091 DI 10.1074/jbc.M111.257378 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 799EZ UT WOS:000293268700003 PM 21652708 ER PT J AU Arnaout, R Lee, W Cahill, P Honan, T Sparrow, T Weiand, M Nusbaum, C Rajewsky, K Koralov, SB AF Arnaout, Ramy Lee, William Cahill, Patrick Honan, Tracey Sparrow, Todd Weiand, Michael Nusbaum, Chad Rajewsky, Klaus Koralov, Sergei B. TI High-Resolution Description of Antibody Heavy-Chain Repertoires in Humans SO PLOS ONE LA English DT Article ID MEMORY B-CELLS; SOMATIC HYPERMUTATION; V(D)J RECOMBINATION; V-H; NEUTRALIZING ANTIBODIES; CAPSULAR POLYSACCHARIDE; IMMUNOGLOBULIN GENES; RECEPTOR DIVERSITY; IMMUNE-RESPONSE; REGION AB Antibodies' protective, pathological, and therapeutic properties result from their considerable diversity. This diversity is almost limitless in potential, but actual diversity is still poorly understood. Here we use deep sequencing to characterize the diversity of the heavy-chain CDR3 region, the most important contributor to antibody binding specificity, and the constituent V, D, and J segments that comprise it. We find that, during the stepwise D-J and then V-DJ recombination events, the choice of D and J segments exert some bias on each other; however, we find the choice of the V segment is essentially independent of both. V, D, and J segments are utilized with different frequencies, resulting in a highly skewed representation of VDJ combinations in the repertoire. Nevertheless, the pattern of segment usage was almost identical between two different individuals. The pattern of V, D, and J segment usage and recombination was insufficient to explain overlap that was observed between the two individuals' CDR3 repertoires. Finally, we find that while there are a near-infinite number of heavy-chain CDR3s in principle, there are about 3-9 million in the blood of an adult human being. C1 [Arnaout, Ramy] Brigham & Womens Hosp, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Arnaout, Ramy; Lee, William; Cahill, Patrick; Honan, Tracey; Sparrow, Todd; Weiand, Michael; Nusbaum, Chad] MIT, Genome Sequencing & Anal Program, Broad Inst, Cambridge, MA 02139 USA. [Rajewsky, Klaus; Koralov, Sergei B.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Rajewsky, Klaus; Koralov, Sergei B.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Arnaout, Ramy; Lee, William; Cahill, Patrick; Honan, Tracey; Sparrow, Todd; Weiand, Michael; Nusbaum, Chad] Harvard Univ, Cambridge, MA 02138 USA. RP Arnaout, R (reprint author), Brigham & Womens Hosp, Dept Pathol, Beth Israel Deaconess Med Ctr, 75 Francis St, Boston, MA 02115 USA. EM rarnaout@bidmc.harvard.edu FU NIH [AI054636]; Ruth L. Kirchstein National Research Service FX KR and SK were supported by NIH grant AI054636. RA was supported by a Ruth L. Kirchstein National Research Service Award Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 89 Z9 90 U1 2 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 4 PY 2011 VL 6 IS 8 AR e22365 DI 10.1371/journal.pone.0022365 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 803DK UT WOS:000293561200015 PM 21829618 ER PT J AU Humphreys, K Grankvist, A Leu, M Hall, P Liu, JJ Ripatti, S Rehnstrom, K Groop, L Klareskog, L Ding, B Gronberg, H Xu, JF Pedersen, NL Lichtenstein, P Mattingsdal, M Andreassen, OA O'Dushlaine, C Purcell, SM Sklar, P Sullivan, PF Hultman, CM Palmgren, J Magnusson, PKE AF Humphreys, Keith Grankvist, Alexander Leu, Monica Hall, Per Liu, Jianjun Ripatti, Samuli Rehnstroem, Karola Groop, Leif Klareskog, Lars Ding, Bo Gronberg, Henrik Xu, Jianfeng Pedersen, Nancy L. Lichtenstein, Paul Mattingsdal, Morten Andreassen, Ole A. O'Dushlaine, Colm Purcell, Shaun M. Sklar, Pamela Sullivan, Patrick F. Hultman, Christina M. Palmgren, Juni Magnusson, Patrik K. E. TI The Genetic Structure of the Swedish Population SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; EUROPEAN POPULATIONS; RISK; SUBSTRUCTURE; CANCER; SNPS; LOCI AB Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise F(st)) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions. C1 [Humphreys, Keith; Grankvist, Alexander; Leu, Monica; Hall, Per; Gronberg, Henrik; Pedersen, Nancy L.; Lichtenstein, Paul; Hultman, Christina M.; Palmgren, Juni; Magnusson, Patrik K. E.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Liu, Jianjun] Genome Inst Singapore, Human Genet Lab, Singapore, Singapore. [Ripatti, Samuli] Inst Mol Med, Helsinki, Finland. [Ripatti, Samuli] Univ Helsinki, FIMM, Helsinki, Finland. [Ripatti, Samuli] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland. [Rehnstroem, Karola] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. [Groop, Leif] Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Klareskog, Lars; Ding, Bo] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Xu, Jianfeng] Wake Forest Univ, Sch Med, Dept Canc Biol, Winston Salem, NC 27109 USA. [Xu, Jianfeng] Wake Forest Univ, Sch Med, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. [Xu, Jianfeng] Wake Forest Univ, Sch Med, Ctr Canc Genom, Winston Salem, NC 27109 USA. [Mattingsdal, Morten; Andreassen, Ole A.] Univ Oslo, Inst Clin Med, Sect Psychiat, Oslo, Norway. [Mattingsdal, Morten] Sorlandet Hosp HF, Kristiansand, Norway. [Andreassen, Ole A.] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [O'Dushlaine, Colm; Purcell, Shaun M.; Sklar, Pamela] MIT, Broad Inst, Cambridge, MA 02139 USA. [O'Dushlaine, Colm; Purcell, Shaun M.; Sklar, Pamela] Harvard Univ, Cambridge, MA 02138 USA. [O'Dushlaine, Colm; Purcell, Shaun M.; Sklar, Pamela] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Palmgren, Juni] Stockholm Univ, Dept Math Stat, S-10691 Stockholm, Sweden. [Palmgren, Juni] Swedish eSci Res Ctr, Stockholm, Sweden. RP Humphreys, K (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM Patrik.Magnusson@ki.se RI Ripatti, Samuli/H-9446-2014; Magnusson, Patrik/C-4458-2017; OI Andreassen, Ole A./0000-0002-4461-3568; Ripatti, Samuli/0000-0002-0504-1202; Palmgren, Juni/0000-0002-9031-8615; lichtenstein, paul/0000-0003-3037-5287; Klareskog, Lars/0000-0001-9601-6186 FU Swedish Research Council [521-2009-2664, M-2005-1112, 523-2006-972]; Swedish Council for Working Life and Social Research [184/2000, 2001-2368]; National Institute of Mental Health [MH077139]; Stanley Center for Psychiatric Research; Stanley Medical Research Institute; Research Council of Norway [167153/V50]; South-East Norway Health Authority [2004-123]; National Institutes of Health [RO1 CA58427]; Agency for Science, Technology and Research (A*STAR; Singapore); Nordic Cancer Society; Marit and Hans Rausing's Initiative against Breast Cancer; Novartis Pharmaceuticals; Sigrid Juselius Foundation; European Commission [QLG2-CT-2002-01254]; Swedish Foundation for Strategic Research; Swedish Heart and Lung Foundation FX We acknowledge support from the Swedish Research Council (grant 521-2009-2664), the Swedish Council for Working Life and Social Research (grants 184/2000, 2001-2368), the National Institute of Mental Health (grant MH077139) and the Stanley Center for Psychiatric Research, Broad Institute from a grant from the Stanley Medical Research Institute. The TOP study was supported by the Research Council of Norway (grant 167153/V50) and the South-East Norway Health Authority (grant 2004-123). The CAHRES study was supported by the National Institutes of Health (grant RO1 CA58427), the Agency for Science, Technology and Research (A*STAR; Singapore), the Nordic Cancer Society, and Marit and Hans Rausing's Initiative against Breast Cancer. The genotyping in the DGI study was funded by an unrestricted grant from Novartis Pharmaceuticals, whereas phenotyping was funded by grants from the Sigrid Juselius Foundation and the Swedish Research Council. The TWINGENE-SW study was supported by the GenomeEUtwin project under the European Commission Programme CEQuality of Life and Management of the Living Resources1 of 5th Framework Programme (grant QLG2-CT-2002-01254), the Swedish Research Council (grant M-2005-1112), Swedish Foundation for Strategic Research and the Swedish Heart and Lung Foundation. KH acknowledges support from the Swedish Research Council (grant 523-2006-972). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 21 Z9 21 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 4 PY 2011 VL 6 IS 8 AR e22547 DI 10.1371/journal.pone.0022547 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 803DK UT WOS:000293561200022 PM 21829632 ER PT J AU Pillai, S AF Pillai, Shiv TI Now you know your ABCs SO BLOOD LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pillai, S (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 4 PY 2011 VL 118 IS 5 BP 1187 EP 1188 DI 10.1182/blood-2011-06-355131 PG 2 WC Hematology SC Hematology GA 802KP UT WOS:000293510000002 PM 21816835 ER PT J AU Cornejo, MG Mabialah, V Sykes, SM Khandan, T Lo Celso, C Lopez, CK Rivera-Munoz, P Rameau, P Tothova, Z Aster, JC DePinho, RA Scadden, DT Gilliland, DG Mercher, T AF Cornejo, Melanie G. Mabialah, Vinciane Sykes, Stephen M. Khandan, Tulasi Lo Celso, Cristina Lopez, Cecile K. Rivera-Munoz, Paola Rameau, Philippe Tothova, Zuzana Aster, Jon C. DePinho, Ronald A. Scadden, David T. Gilliland, D. Gary Mercher, Thomas TI Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; FOXO TRANSCRIPTION FACTORS; SELF-RENEWAL; IN-VIVO; LEUKEMIA; PATHWAYS; PROGENITORS; PTEN; THROMBOPOIETIN; IDENTIFICATION AB The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways. (Blood. 2011;118(5):1264-1273) C1 [Mercher, Thomas] Inst Gustave Roussy, INSERM, U985, F-94800 Villejuif, France. [Cornejo, Melanie G.; Sykes, Stephen M.; Khandan, Tulasi; Tothova, Zuzana; Gilliland, D. Gary; Mercher, Thomas] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Hematol,Dept Med, Boston, MA 02115 USA. [Mabialah, Vinciane; Lopez, Cecile K.; Rivera-Munoz, Paola; Mercher, Thomas] Univ Paris 11, INSERM, U985, Villejuif, France. [Lo Celso, Cristina; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Aster, Jon C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pathol,Dept Med, Boston, MA 02115 USA. [DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA USA. RP Mercher, T (reprint author), Inst Gustave Roussy, INSERM, U985, Pavillon Rech 1,39 Rue Camille Desmoulins, F-94800 Villejuif, France. EM thomas.mercher@inserm.fr RI Mercher, Thomas/J-2446-2014; OI Mercher, Thomas/0000-0003-1552-087X; Lo Celso, Cristina/0000-0002-1163-4207 FU Leukemia & Lymphoma Society; Ligue National Contre le Cancer; Agence Nationale de la Recherche; Fondation Gustave Roussy; EHA FX This work was supported in part by the Leukemia & Lymphoma Society (D. G. G.) and by Ligue National Contre le Cancer, Agence Nationale de la Recherche, and Fondation Gustave Roussy grants, a Leukemia & Lymphoma Society Special Fellowship, and an EHA-Jose Carreras Young Investigator fellowship (T. M.). NR 49 TC 32 Z9 33 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 4 PY 2011 VL 118 IS 5 BP 1264 EP 1273 DI 10.1182/blood-2011-01-328567 PG 10 WC Hematology SC Hematology GA 802KP UT WOS:000293510000018 PM 21653327 ER PT J AU Armenian, SH Sun, CL Kawashima, T Arora, M Leisenring, W Sklar, CA Baker, KS Francisco, L Teh, JB Mills, G Wong, FL Rosenthal, J Diller, LR Hudson, MM Oeffinger, KC Forman, SJ Robison, LL Bhatia, S AF Armenian, Saro H. Sun, Can-Lan Kawashima, Toana Arora, Mukta Leisenring, Wendy Sklar, Charles A. Baker, K. Scott Francisco, Liton Teh, Jennifer Berano Mills, George Wong, F. Lennie Rosenthal, Joseph Diller, Lisa R. Hudson, Melissa M. Oeffinger, Kevin C. Forman, Stephen J. Robison, Leslie L. Bhatia, Smita TI Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS) SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; VERSUS-HOST-DISEASE; QUALITY-OF-LIFE; ALLOGENEIC HEMATOPOIETIC SCT; ACUTE LYMPHOBLASTIC-LEUKEMIA; LATE COMPLICATIONS; ADULT SURVIVORS; FOLLOW-UP; HODGKIN-LYMPHOMA AB HSCT is being increasingly offered as a curative option for children with hematologic malignancies. Although survival has improved, the long-term morbidity ascribed to the HSCT procedure is not known. We compared the risk of chronic health conditions and adverse health among children with cancer treated with HSCT with survivors treated conventionally, as well as with sibling controls. HSCT survivors were drawn from BMTSS (N = 145), whereas conventionally treated survivors (N = 7207) and siblings (N = 4020) were drawn from CCSS. Self-reported chronic conditions were graded with CTCAEv3.0. Fifty-nine percent of HSCT survivors reported >= 2 conditions, and 25.5% reported severe/life-threatening conditions. HSCT survivors were more likely than sibling controls to have severe/life-threatening (relative risk [RR] = 8.1, P < .01) and 2 or more (RR = 5.7, P < .01) conditions, as well as functional impairment (RR = 7.7, P < .01) and activity limitation (RR = 6.3, P < .01). More importantly, compared with CCSS survivors, BMTSS survivors demonstrated significantly elevated risks (severe/life-threatening conditions: RR = 3.9, P < .01; multiple conditions: RR = 2.6, P < .01; functional impairment: RR = 3.5, P < .01; activity limitation: RR = 5.8, P < .01). Unrelated donor HSCT recipients were at greatest risk. Childhood HSCT survivors carry a significantly greater burden of morbidity not only compared with noncancer populations but also compared with conventionally treated cancer patients, providing evidence for close monitoring of this high-risk population. (Blood. 2011; 118(5): 1413-1420) C1 [Armenian, Saro H.; Sun, Can-Lan; Francisco, Liton; Teh, Jennifer Berano; Mills, George; Wong, F. Lennie; Bhatia, Smita] City Hope Natl Med Ctr, Populat Sci, Duarte, CA 91010 USA. [Baker, K. Scott] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Arora, Mukta] Univ Minnesota, Minneapolis, MN USA. [Sklar, Charles A.; Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rosenthal, Joseph] Childrens Hosp Cent Calif, Madera, CA USA. [Diller, Lisa R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hudson, Melissa M.; Robison, Leslie L.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Forman, Stephen J.] City Hope Natl Med Ctr, Hematol & Hematopoiet Cell Transplantat, Duarte, CA 91010 USA. RP Bhatia, S (reprint author), City Hope Natl Med Ctr, Populat Sci, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM sbhatia@coh.org FU National Institutes of Health [R01 CA078938, P01 CA 30206, U24-CA-55727]; Leukemia & Lymphoma Society [2191-02]; American Lebanese Syrian Associated Charities (St Jude Children's Research Hospital) FX This study was supported in part by grants from the National Institutes of Health (R01 CA078938, to S.B.; P01 CA 30206, to S.J.F.; U24-CA-55727, to L.L.R.), Leukemia & Lymphoma Society Scholar Award for Clinical Research (2191-02, to S.B.), and the American Lebanese Syrian Associated Charities (St Jude Children's Research Hospital). NR 46 TC 56 Z9 57 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 4 PY 2011 VL 118 IS 5 BP 1413 EP 1420 DI 10.1182/blood-2011-01-331835 PG 8 WC Hematology SC Hematology GA 802KP UT WOS:000293510000035 PM 21652685 ER PT J AU Alter, G Heckerman, D Schneidewind, A Fadda, L Kadie, CM Carlson, JM Oniangue-Ndza, C Martin, M Li, B Khakoo, SI Carrington, M Allen, TM Altfeld, M AF Alter, Galit Heckerman, David Schneidewind, Arne Fadda, Lena Kadie, Carl M. Carlson, Jonathan M. Oniangue-Ndza, Cesar Martin, Maureen Li, Bin Khakoo, Salim I. Carrington, Mary Allen, Todd M. Altfeld, Marcus TI HIV-1 adaptation to NK-cell-mediated immune pressure SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NATURAL-KILLER-CELLS; MHC CLASS-I; HLA-B; INHIBITORY RECEPTOR; VIRAL PEPTIDES; BINDING-SITE; RECOGNITION; KIR3DL1; RESPONSES AB Natural killer (NK) cells have an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors(1-3). Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory killer immunoglobulin-like receptors (KIRs)(4-7). However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino-acid polymorphisms in the HIV-1 sequence of chronically infected individuals, on a population level. We show that these KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4(+) T cells, and reduce the antiviral activity of KIR-positive NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell-mediated immune pressure by selecting for sequence polymorphisms, as was previously described for virus-specific T cells and neutralizing antibodies(8). NK cells might therefore have a previously underappreciated role in contributing to viral evolution. C1 [Alter, Galit; Schneidewind, Arne; Fadda, Lena; Oniangue-Ndza, Cesar; Li, Bin; Carrington, Mary; Allen, Todd M.; Altfeld, Marcus] Harvard Univ, Ragon Inst MGH MIT & Harvard, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. [Heckerman, David; Kadie, Carl M.; Carlson, Jonathan M.] Microsoft Res, Redmond, WA 98053 USA. [Martin, Maureen; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Khakoo, Salim I.] Univ London Imperial Coll Sci Technol & Med, Div Med, London W2 1PG, England. RP Altfeld, M (reprint author), Harvard Univ, Ragon Inst MGH MIT & Harvard, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. EM maltfeld@partners.org RI Allen, Todd/F-5473-2011; OI Khakoo, Salim/0000-0002-4057-9091 FU National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases [R01 AI067031, PO1 AI074415]; Doris Duke Charitable Foundation; National Cancer Institute (NIH) [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; Wellcome Trust; Microsoft Research; Bill & Melinda Gates Foundation; Mark and Lisa Schwartz Foundation; Phillip T. and Susan M. Ragon Foundation FX These studies were supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants R01 AI067031 (M. A.) and PO1 AI074415 (M. A. and T. M. A.), and by the Doris Duke Charitable Foundation (M. A.). This project was funded in whole or in part with federal funds from the National Cancer Institute (NIH) under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. S. I. K. is a recipient of a Wellcome Trust Senior Clinical Fellowship and M. A. is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation. We thank Microsoft Research, the Bill & Melinda Gates Foundation, the Mark and Lisa Schwartz Foundation and the Phillip T. and Susan M. Ragon Foundation for their support. NR 29 TC 149 Z9 155 U1 1 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 4 PY 2011 VL 476 IS 7358 BP 96 EP + DI 10.1038/nature10237 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 801NR UT WOS:000293447300037 PM 21814282 ER PT J AU Berardi, MJ Shih, WM Harrison, SC Chou, JJ AF Berardi, Marcelo J. Shih, William M. Harrison, Stephen C. Chou, James J. TI Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching SO NATURE LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; LIQUID-CRYSTALLINE PHASE; DIPOLAR COUPLINGS; INDUCED ALIGNMENT; ADP/ATP CARRIER; PROTON CHANNEL; MEMBRANE; SPECTROSCOPY; SECRETION; MECHANISM AB Mitochondrial uncoupling protein 2 (UCP2) is an integral membrane protein in the mitochondrial anion carrier protein family, the members of which facilitate the transport of small molecules across the mitochondrial inner membrane(1,2). When the mitochondrial respiratory complex pumps protons from the mitochondrial matrix to the intermembrane space, it builds up an electrochemical potential(2). A fraction of this electrochemical potential is dissipated as heat, in a process involving leakage of protons back to the matrix(2). This leakage, or 'uncoupling' of the proton electrochemical potential, is mediated primarily by uncoupling proteins(2). However, the mechanism of UCP-mediated proton translocation across the lipid bilayer is unknown. Here we describe a solution-NMR method for structural characterization of UCP2. The method, which overcomes some of the challenges associated with membrane-protein structure determination(3), combines orientation restraints derived from NMR residual dipolar couplings (RDCs) and semiquantitative distance restraints from paramagnetic relaxation enhancement (PRE) measurements. The local and secondary structures of the protein were determined by piecing together molecular fragments from the Protein Data Bank that best fit experimental RDCs from samples weakly aligned in a DNA nanotube liquid crystal. The RDCs also determine the relative orientation of the secondary structural segments, and the PRE restraints provide their spatial arrangement in the tertiary fold. UCP2 closely resembles the bovine ADP/ATP carrier (the only carrier protein of known structure(4)), but the relative orientations of the helical segments are different, resulting in a wider opening on the matrix side of the inner membrane. Moreover, the nitroxide-labelled GDP binds inside the channel and seems to be closer to transmembrane helices 1-4. We believe that this biophysical approach can be applied to other membrane proteins and, in particular, to other mitochondrial carriers, not only for structure determination but also to characterize various conformational states of these proteins linked to substrate transport. C1 [Berardi, Marcelo J.; Harrison, Stephen C.; Chou, James J.] Harvard Univ, Jack & Eileen Connors Struct Biol Lab, Sch Med, Boston, MA 02115 USA. [Berardi, Marcelo J.; Shih, William M.; Harrison, Stephen C.; Chou, James J.] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Sch Med, Boston, MA 02115 USA. [Shih, William M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Shih, William M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02138 USA. [Harrison, Stephen C.] Harvard Univ, Howard Hughes Med Inst, Sch Med, Boston, MA 02115 USA. RP Chou, JJ (reprint author), Harvard Univ, Jack & Eileen Connors Struct Biol Lab, Sch Med, Boston, MA 02115 USA. EM chou@cmcd.hms.harvard.edu RI Chou, James/N-9840-2013 FU NIH [1U54GM094608, 1DP2OD004641] FX We thank K. Oxenoid and R. Sounier for discussions, M. McClintock for help with DNA nanotube preparation, I. Stokes-Rees and P. Sliz for help with computations, and N. Voigt for help with figures. The work was supported by NIH grants 1U54GM094608 (to J.J.C.) and 1DP2OD004641 (to W. M. S.). S. C. H. is an Investigator at the Howard Hughes Medical Institute. NR 37 TC 173 Z9 175 U1 8 U2 75 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 4 PY 2011 VL 476 IS 7358 BP 109 EP 113 DI 10.1038/nature10257 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 801NR UT WOS:000293447300040 PM 21785437 ER PT J AU Volpp, KG Asch, DA Galvin, R Loewenstein, G AF Volpp, Kevin G. Asch, David A. Galvin, Robert Loewenstein, George TI Redesigning Employee Health Incentives - Lessons from Behavioral Economics SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Volpp, Kevin G.; Asch, David A.] Univ Penn, Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Asch, David A.; Loewenstein, George] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Asch, David A.; Loewenstein, George] Univ Penn, Penn CMU Roybal Ctr Behav Econ & Hlth, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Asch, David A.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Asch, David A.] Univ Penn, Wharton Sch, Dept Hlth Care Management, Philadelphia, PA 19104 USA. [Galvin, Robert] Equity Healthcare, Black Stone Grp, New York, NY USA. [Galvin, Robert] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Loewenstein, George] Carnegie Mellon Univ, Dept Social & Decis Sci, Pittsburgh, PA 15213 USA. RP Volpp, KG (reprint author), Univ Penn, Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. FU NIA NIH HHS [P30 AG034546] NR 5 TC 91 Z9 91 U1 2 U2 18 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 4 PY 2011 VL 365 IS 5 BP 388 EP 390 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 801NW UT WOS:000293447800002 PM 21812669 ER PT J AU Seely, EW Ecker, J AF Seely, Ellen W. Ecker, Jeffrey TI Chronic Hypertension in Pregnancy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONVERTING ENZYME-INHIBITORS; HIGH BLOOD-PRESSURE; RISK-FACTORS; DEVELOPMENTAL TOXICITY; PREVENT PREECLAMPSIA; ALDOSTERONE SYSTEM; UNITED-STATES; WOMEN; OUTCOMES; GROWTH AB A 35-year-old woman who has never been pregnant and who has a 5-year history of hypertension wants to become pregnant. She has stopped using contraception. Her only medication is lisinopril at a dose of 10 mg per day. Her blood pressure is 124/68 mm Hg, and her body-mass index (the weight in kilograms divided by the square of the height in meters) is 27. What would you advise? C1 [Seely, Ellen W.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Seely, Ellen W.; Ecker, Jeffrey] Harvard Univ, Sch Med, Boston, MA USA. [Ecker, Jeffrey] Massachusetts Gen Hosp, Div Maternal Fetal Med, Boston, MA 02114 USA. RP Seely, EW (reprint author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 221 Longwood Ave, Boston, MA 02115 USA. EM eseely@partners.org FU Bayer Healthcare FX Dr. Seely reports receiving an investigator-initiated grant from Bayer Healthcare for a study involving postmenopausal women. No other potential conflict of interest relevant to this article was reported. NR 42 TC 37 Z9 40 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 4 PY 2011 VL 365 IS 5 BP 439 EP 446 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 801NW UT WOS:000293447800008 PM 21812673 ER PT J AU Sykes, DB Schroyens, W O'Connell, C AF Sykes, David B. Schroyens, Wilfried O'Connell, Casey TI The TEMPI Syndrome - A Novel Multisystem Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID POLYCYTHEMIA C1 [Sykes, David B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schroyens, Wilfried] Univ Antwerp Hosp, Antwerp, Belgium. [O'Connell, Casey] Univ So Calif, Los Angeles, CA USA. RP Sykes, DB (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM dbsykes@partners.org NR 4 TC 14 Z9 15 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 4 PY 2011 VL 365 IS 5 BP 475 EP 477 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 801NW UT WOS:000293447800035 PM 21812700 ER PT J AU Moorman, AJ Stratton, JR Levy, WC AF Moorman, Alec J. Stratton, John R. Levy, Wayne C. TI Clonidine therapy in patients with heart failure improves exercise efficiency, functional class and symptoms SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Heart failure; Sympathetic nervous system; Exercise; Clonidine ID SYMPATHETIC INHIBITION; MORTALITY C1 [Moorman, Alec J.; Levy, Wayne C.] Univ Washington, Div Cardiol, Dept Med, Sch Med, Seattle, WA 98177 USA. [Stratton, John R.] VA Puget Sound Hlth Care Syst, Dept Med, Div Cardiol, Seattle, WA USA. RP Moorman, AJ (reprint author), Univ Washington, Div Cardiol, Dept Med, Sch Med, Box 356422,1959 NE Pacific St, Seattle, WA 98177 USA. EM amoorman@u.washington.edu NR 9 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG 4 PY 2011 VL 150 IS 3 BP 372 EP 373 DI 10.1016/j.ijcard.2011.05.091 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 795EW UT WOS:000292956200050 PM 21640409 ER PT J AU Yu, LY Hales, CA AF Yu, Lunyin Hales, Charles A. TI Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice SO BMC CANCER LA English DT Article DE hypoxia; tumor growth; metastasis; A549 lung cancer cells; Lewis lung carcinoma; HCT116 colon cancer cells; animals ID INDUCED PULMONARY-HYPERTENSION; ALVEOLAR EPITHELIAL-CELLS; ORTHOTOPIC MURINE MODEL; LYMPH-NODE METASTASIS; GROWTH IN-VIVO; A549 CELLS; CERVICAL-CARCINOMA; GENE-EXPRESSION; ALPHA-1 SUBUNIT; UTERINE CERVIX AB Background: Hypoxia has been identified as a major negative factor for tumor progression in clinical observations and in animal studies. However, the precise role of hypoxia in tumor progression has not been fully explained. In this study, we extensively investigated the effect of long-term exposure to hypoxia on tumor progression in vivo. Methods: Rats bearing transplanted tumors consisting of A549 human lung cancer cells (lung cancer tumor) were exposed to hypoxia for different durations and different levels of oxygen. The tumor growth and metastasis were evaluated. We also treated A549 lung cancer cells (A549 cells) with chronic hypoxia and then implanted the hypoxia-pretreated cancer cells into mice. The effect of exposure to hypoxia on metastasis of Lewis lung carcinoma in mice was also investigated. Results: We found that long-term exposure to hypoxia a) significantly inhibited lung cancer tumor growth in xenograft and orthotopic models in rats, b) significantly reduced lymphatic metastasis of the lung cancer in rats and decreased lung metastasis of Lewis lung carcinoma in mice, c) reduced lung cancer cell proliferation and cell cycle progression in vitro, d) decreased growth of the tumors from hypoxia-pretreated A549 cells, e) decreased Na+-K+ ATPase alpha 1 expression in hypoxic lung cancer tumors, and f) increased expression of hypoxia inducible factors (HIF1 alpha and HIF2 alpha) but decreased microvessel density in the lung cancer tumors. In contrast to lung cancer, the growth of tumor from HCT116 human colon cancer cells (colon cancer tumor) was a) significantly enhanced in the same hypoxia conditions, accompanied by b) no significant change in expression of Na+-K+ ATPase alpha 1, c) increased HIF1 alpha expression (no HIF2 alpha was detected) and d) increased microvessel density in the tumor tissues. Conclusions: This study demonstrated that long-term exposure to hypoxia repressed tumor progression of the lung cancer from A549 cells and that decreased expression of Na+-K+ ATPase was involved in hypoxic inhibition of tumor progression. The results from this study provide new insights into the role of hypoxia in tumor progression and therapeutic strategies for cancer treatment. C1 [Yu, Lunyin; Hales, Charles A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit,Dept Med, Boston, MA 02114 USA. RP Yu, LY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit,Dept Med, Boston, MA 02114 USA. EM lyu3@partners.org FU ATS/Pulmonary Hypertension Research Grant [PH-08-010]; NIH [HL39150]; Susannah Wood Foundation FX This work was supported by ATS/Pulmonary Hypertension Research Grant PH-08-010 (L. Yu) and NIH grants HL39150 (C.A. Hales) and by the Susannah Wood Foundation. NR 52 TC 13 Z9 13 U1 0 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 3 PY 2011 VL 11 AR 331 DI 10.1186/1471-2407-11-331 PG 15 WC Oncology SC Oncology GA 813YR UT WOS:000294407000001 PM 21812995 ER PT J AU Dykstra, AR Halgren, E Thesen, T Carlson, CE Doyle, W Madsen, JR Eskandar, EN Cash, SS AF Dykstra, Andrew R. Halgren, Eric Thesen, Thomas Carlson, Chad E. Doyle, Werner Madsen, Joseph R. Eskandar, Emad N. Cash, Sydney S. TI Widespread brain areas engaged during a classical auditory streaming task revealed by intracranial EEG SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE auditory streaming; auditory scene analysis; auditory cortex; electrocorticography; bistable perception; evoked potentials ID INDEPENDENT COMPONENT ANALYSIS; GOLDFISH CARASSIUS-AURATUS; SUPERIOR TEMPORAL GYRUS; SURFACE-BASED ANALYSIS; PERCEPTUAL ORGANIZATION; SONGBIRD FOREBRAIN; CORTICAL SURFACE; TONE SEQUENCES; COORDINATE SYSTEM; GAMMA ACTIVITY AB The auditory system must constantly decompose the complex mixture of sound arriving at the ear into perceptually independent streams constituting accurate representations of individual sources in the acoustic environment. How the brain accomplishes this task is not well understood. The present study combined a classic behavioral paradigm with direct cortical recordings from neurosurgical patients with epilepsy in order to further describe the neural correlates of auditory streaming. Participants listened to sequences of pure tones alternating in frequency and indicated whether they heard one or two "streams." The intracranial EEG was simultaneously recorded from sub-dural electrodes placed over temporal, frontal, and parietal cortex. Like healthy subjects, patients heard one stream when the frequency separation between tones was small and two when it was large. Robust evoked-potential correlates of frequency separation were observed over widespread brain areas. Waveform morphology was highly variable across individual electrode sites both within and across gross brain regions. Surprisingly, few evoked-potential correlates of perceptual organization were observed after controlling for physical stimulus differences. The results indicate that the cortical areas engaged during the streaming task are more complex and widespread than has been demonstrated by previous work, and that, by-and-large, correlates of bistability during streaming are probably located on a spatial scale not assessed - or in a brain area not examined - by the present study. C1 [Dykstra, Andrew R.] MIT, Harvard Mit Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Dykstra, Andrew R.; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Cort Physiol Lab, Boston, MA 02114 USA. [Dykstra, Andrew R.; Madsen, Joseph R.; Eskandar, Emad N.; Cash, Sydney S.] Harvard Univ, Sch Med, Boston, MA USA. [Halgren, Eric] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Halgren, Eric] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Thesen, Thomas; Carlson, Chad E.; Doyle, Werner] NYU, Sch Med, Comprehens Epilepsy Ctr, New York, NY USA. [Madsen, Joseph R.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Dykstra, AR (reprint author), Harvard Mit Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, 55 Fruit St,Thier 423, Boston, MA 02114 USA. EM adykstra@mit.edu FU NIDCD [T32 DC00038]; NIBIB [T32 EB001680]; Amelia Peabody Charitable Trust; NIH [NS18741]; NINDS [NS062092] FX The authors wish to thank the patients and their families for their participation. The authors also wish to thank hospital staff, particularly Kristy Trip, Kara Houghton, Amy Trongnetrpunya, Olga Felsovalyi, and members of the Cortical Neurophysiology Laboratory at MGH including Alex Chan, Justine Cormier, Corey Keller, and Rodrigo Zepeda. Finally, the authors would like to thank Jennifer Melcher, Peter Cariani, and Barbara Shinn-Cunningham for helpful comments. Work supported by NIDCD grant T32 DC00038 to Andrew R. Dykstra, NIBIB grant T32 EB001680 to Andrew R. Dykstra, an Amelia Peabody Charitable Trust grant to Andrew R. Dykstra, NIH grant NS18741 to Eric Halgren, NINDS grant NS062092 to Sydney S. Cash. NR 81 TC 14 Z9 14 U1 2 U2 8 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD AUG 3 PY 2011 VL 5 AR 74 DI 10.3389/fnhum.2011.00074 PG 14 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 814RM UT WOS:000294474800001 PM 21886615 ER PT J AU Chan, DA Sutphin, PD Nguyen, P Turcotte, S Lai, EW Banh, A Reynolds, GE Chi, JT Wu, J Solow-Cordero, DE Bonnet, M Flanagan, JU Bouley, DM Graves, EE Denny, WA Hay, MP Giaccia, AJ AF Chan, Denise A. Sutphin, Patrick D. Nguyen, Phuong Turcotte, Sandra Lai, Edwin W. Banh, Alice Reynolds, Gloria E. Chi, Jen-Tsan Wu, Jason Solow-Cordero, David E. Bonnet, Muriel Flanagan, Jack U. Bouley, Donna M. Graves, Edward E. Denny, William A. Hay, Michael P. Giaccia, Amato J. TI Targeting GLUT1 and the Warburg Effect in Renal Cell Carcinoma by Chemical Synthetic Lethality SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID DEFICIENCY SYNDROME; CANCER CELLS; HYPOXIA; GLUCOSE; GENE; ADAPTATION; EXPRESSION; INHIBITOR; BINDING; DEATH AB Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [F-18] fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy. C1 [Chan, Denise A.; Nguyen, Phuong; Lai, Edwin W.; Banh, Alice; Graves, Edward E.; Giaccia, Amato J.] Stanford Univ, Sch Med, Dept Radiat Oncol, Stanford, CA 94305 USA. [Chan, Denise A.; Reynolds, Gloria E.] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA. [Sutphin, Patrick D.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02111 USA. [Turcotte, Sandra] Univ Moncton, Moncton, NB E1A 3E9, Canada. [Chi, Jen-Tsan] Duke Med Ctr, Dept Mol Genet & Microbiol, Inst Genome Sci & Policy, Durham, NC 27708 USA. [Wu, Jason; Solow-Cordero, David E.] Stanford Univ, Sch Med, High Throughput Biosci Ctr, Stanford, CA 94305 USA. [Bonnet, Muriel; Flanagan, Jack U.; Denny, William A.; Hay, Michael P.] Univ Auckland, Auckland Canc Soc Res Ctr, Auckland 1142, New Zealand. [Bouley, Donna M.] Stanford Univ, Sch Med, Dept Comparat Med, Stanford, CA 94305 USA. RP Chan, DA (reprint author), Stanford Univ, Sch Med, Dept Radiat Oncol, Stanford, CA 94305 USA. EM giaccia@stanford.edu OI Hay, Michael/0000-0002-7087-9087; Solow-Cordero, David/0000-0002-9886-5058 FU Action to Cure Kidney Cancer/Cecile and Ken Youner Fund for Cancer Research; Association for International Cancer Research [10-0042]; Maurice Wilkins Centre for Biodiscovery; Skippy Frank Translational Medicine and Life Sciences Fund; Silicon Valley Foundation; National Cancer Institute (NCI) [CA-123823, NCI-T32-CA-121940, NCI-CA-67166, NCI-CA-082566] FX This investigation was supported by grants from the Action to Cure Kidney Cancer/Cecile and Ken Youner Fund for Cancer Research, the Association for International Cancer Research 10-0042 (M.B.), the Maurice Wilkins Centre for Biodiscovery (M.P.H. and J.U.F.), the Skippy Frank Translational Medicine and Life Sciences Fund (A.J.G.), the Silicon Valley Foundation (A.J.G.), National Cancer Institute (NCI)-CA-123823 (D.A.C.), NCI-T32-CA-121940 (E.W.L.), NCI-CA-67166 (A.J.G.), and NCI-CA-082566 (M.P.H. and A.J.G.). NR 29 TC 105 Z9 108 U1 4 U2 17 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 3 PY 2011 VL 3 IS 94 AR 94ra70 DI 10.1126/scitranslmed.3002394 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 801SC UT WOS:000293459700004 PM 21813754 ER PT J AU Naar, AM AF Naeaer, Anders M. TI MiRs with a Sweet Tooth SO CELL METABOLISM LA English DT Editorial Material ID LIPID-METABOLISM; MICRORNAS; DISEASE C1 [Naeaer, Anders M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Naeaer, Anders M.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Naeaer, Anders M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Naar, AM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Charlestown, MA 02129 USA. EM naar@helix.mgh.harvard.edu FU NIDDK NIH HHS [R01DK078332, R21DK084459, R01 DK078332, R21 DK084459] NR 10 TC 10 Z9 10 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD AUG 3 PY 2011 VL 14 IS 2 BP 149 EP 150 DI 10.1016/j.cmet.2011.07.005 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 803UE UT WOS:000293606300004 PM 21803284 ER PT J AU Pihlajamaki, J Lerin, C Itkonen, P Boes, T Floss, T Schroeder, J Deane, F Crunkhorn, S Burak, F Jimenez-Chillaron, JC Kuulasmaa, T Miettinen, P Park, PJ Nasser, I Zhao, ZW Zhang, ZY Xu, Y Wurst, W Ren, HM Morris, AJ Stamm, S Goldfine, AB Laakso, M Patti, ME AF Pihlajamaeki, Jussi Lerin, Carles Itkonen, Paula Boes, Tanner Floss, Thomas Schroeder, Joshua Deane, Farrell Crunkhorn, Sarah Burak, Furkan Jimenez-Chillaron, Josep C. Kuulasmaa, Tiina Miettinen, Pekka Park, Peter J. Nasser, Imad Zhao, Zhenwen Zhang, Zhaiyi Xu, Yan Wurst, Wolfgang Ren, Hongmei Morris, Andrew J. Stamm, Stefan Goldfine, Allison B. Laakso, Markku Patti, Mary Elizabeth TI Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis SO CELL METABOLISM LA English DT Article ID GENOME-WIDE ASSOCIATION; PRE-MESSENGER-RNA; ADIPOSE-TISSUE; INSULIN-RESISTANCE; SKELETAL-MUSCLE; DIABETIC MICE; LIPIN; METABOLISM; RECEPTOR; PROTEIN AB Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, downregulated in both obese human liver and muscle and in high-fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic beta isoform of LPIN1. Importantly, LPIN1 beta-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity. C1 [Pihlajamaeki, Jussi; Lerin, Carles; Boes, Tanner; Schroeder, Joshua; Deane, Farrell; Crunkhorn, Sarah; Burak, Furkan; Jimenez-Chillaron, Josep C.; Goldfine, Allison B.; Patti, Mary Elizabeth] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. [Park, Peter J.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. [Nasser, Imad] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Pihlajamaeki, Jussi; Itkonen, Paula; Kuulasmaa, Tiina; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio 70211, Finland. [Pihlajamaeki, Jussi] Univ Eastern Finland, Dept Clin Nutr, Kuopio 70211, Finland. [Miettinen, Pekka] Univ Eastern Finland, Dept Surg, Kuopio 70211, Finland. [Lerin, Carles] IDIBAPS CIBERDEM, Diabet & Obes Lab, Barcelona 08036, Spain. [Floss, Thomas; Wurst, Wolfgang] Tech Univ Munich, Helmholtz Zentrum Munchen, Inst Entwicklungsgenet, D-85764 Neuherberg, Germany. [Zhao, Zhenwen; Xu, Yan] Indiana Univ Sch Med, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA. [Zhang, Zhaiyi; Ren, Hongmei; Morris, Andrew J.; Stamm, Stefan] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. [Wurst, Wolfgang] MPI Psychiat, D-80804 Munich, Germany. [Wurst, Wolfgang] Tech Univ Weihenstephan, Lehrstuhl Entwicklungsgenet, Helmholtz Zentrum Munchen, D-80336 Munich, Germany. [Wurst, Wolfgang] LMU, Adolf Butenandt Inst, DZNE Site Munich, D-80336 Munich, Germany. RP Patti, ME (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. EM mary.elizabeth.patti@joslin.harvard.edu FU NIH [DK062948, DK060837, DK70648]; General Clinical Research Center [M01 RR001032]; Joslin Diabetes and Endocrinology Research Center [D36836]; Lilly Foundation; Graetz Fund; Academy of Finland; Finnish Diabetes Research Foundation; Kuopio University Hospital [5167]; European Union [LSHM-CT-2004-512013]; EURASNET; Sigrid Juselius Foundation; Maud Kuistila Foundation; Northern Savo Cultural Foundation; Viipuri Tuberculosis Foundation; American Heart Association; [RO1GM50388]; [P20RR021964] FX We gratefully acknowledge support from NIH DK062948 (M.E.P.), DK060837 (M.E.P. and A.B.G.), and DK70648 (A.B.G.); M01 RR001032 (General Clinical Research Center), D36836 (Joslin Diabetes and Endocrinology Research Center), Lilly Foundation (M.E.P.), Graetz Fund (M.E.P.), Academy of Finland (M.L. and J.P.), Finnish Diabetes Research Foundation (J.P. and M.L.), EVO Fund of Kuopio University Hospital (5167, M.L.), European Union (EUGENE2 LSHM-CT-2004-512013, M.L.), and EURASNET (S.S.). J.P. also received support from Sigrid Juselius Foundation, Maud Kuistila Foundation, Northern Savo Cultural Foundation, and Viipuri Tuberculosis Foundation. A.M. is supported by RO1GM50388 and P20RR021964. H.R. is the recipient of an American Heart Association postdoctoral fellowship. We thank Amit Khanna for technical help with the minigene construction and EURASNET (S.S.) for funding. We appreciate the assistance of Chris Burge and Xinshu Xiao, Massachusetts Institute of Technology, with computational identification of splicing targets. We also thank Joyclyn Yee and Martha yokes for assistance with microarray analysis. NR 59 TC 37 Z9 40 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD AUG 3 PY 2011 VL 14 IS 2 BP 208 EP 218 DI 10.1016/j.cmet.2011.06.007 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 803UE UT WOS:000293606300011 PM 21803291 ER PT J AU Huang, YT Lin, XH Chirieac, LR McGovern, R Wain, JC Heist, RS Skaug, V Zienolddiny, S Haugen, A Su, L Christiani, DC AF Huang, Yen-Tsung Lin, Xihong Chirieac, Lucian R. McGovern, Ray Wain, John C. Heist, Rebecca S. Skaug, Vidar Zienolddiny, Shanbeh Haugen, Aage Su, Li Christiani, David C. TI Impact on Disease Development, Genomic Location and Biological Function of Copy Number Alterations in Non-Small Cell Lung Cancer SO PLOS ONE LA English DT Article ID EXPRESSION PROFILES; GENETIC ALTERATIONS; CARCINOMA; CARCINOGENESIS; ADENOCARCINOMA; POLYMORPHISM; MUTATION; FREQUENT; EVENT; GAIN AB Lung cancer, of which more than 80% is non-small cell, is the leading cause of cancer-related death in the United States. Copy number alterations (CNAs) in lung cancer have been shown to be positionally clustered in certain genomic regions. However, it remains unclear whether genes with copy number changes are functionally clustered. Using a dense single nucleotide polymorphism array, we performed genome-wide copy number analyses of a large collection of non-small cell lung tumors (n = 301). We proposed a formal statistical test for CNAs between different groups (e. g., non-involved lung vs. tumors, early vs. late stage tumors). We also customized the gene set enrichment analysis (GSEA) algorithm to investigate the overrepresentation of genes with CNAs in predefined biological pathways and gene sets (i.e., functional clustering). We found that CNAs events increase substantially from germline, early stage to late stage tumor. In addition to genomic position, CNAs tend to occur away from the gene locations, especially in germline, non-involved tissue and early stage tumors. Such tendency decreases from germline to early stage and then to late stage tumors, suggesting a relaxation of selection during tumor progression. Furthermore, genes with CNAs in non-small cell lung tumors were enriched in certain gene sets and biological pathways that play crucial roles in oncogenesis and cancer progression, demonstrating the functional aspect of CNAs in the context of biological pathways that were overlooked previously. We conclude that CNAs increase with disease progression and CNAs are both positionally and functionally clustered. The potential functional capabilities acquired via CNAs may be sufficient for normal cells to transform into malignant cells. C1 [Huang, Yen-Tsung; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Huang, Yen-Tsung; Lin, Xihong; McGovern, Ray] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Chirieac, Lucian R.] Massachusetts Gen Hosp, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02114 USA. [Wain, John C.; Heist, Rebecca S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Wain, John C.] Massachusetts Gen Hosp, Thorac Surg Unit, Boston, MA 02114 USA. [Heist, Rebecca S.; Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Skaug, Vidar; Zienolddiny, Shanbeh; Haugen, Aage] Natl Inst Occupat Hlth, Dept Biol & Chem Working Environm, Oslo, Norway. [Christiani, David C.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Huang, YT (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu RI Huang, Yen-Tsung/I-1003-2014; Zienolddiny, Shanbeh/O-7392-2015 FU US National Institutes of Health [CA092824, CA074386, CA090578]; Norwegian Cancer Society FX This study is supported by US National Institutes of Health (http://www.nih.gov/) grants no. CA092824 (D. C. C.), CA074386 (D. C. C.), CA090578 (D. C. C.); and Norwegian Cancer Society (http://www.kreftforeningen.no/english)(A.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 9 Z9 9 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 2 PY 2011 VL 6 IS 8 AR e22961 DI 10.1371/journal.pone.0022961 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802LF UT WOS:000293511900019 PM 21829676 ER PT J AU Pankratz, N Dumitriu, A Hetrick, KN Sun, M Latourelle, JC Wilk, JB Halter, C Doheny, KF Gusella, JF Nichols, WC Myers, RH Foroud, T DeStefano, AL AF Pankratz, Nathan Dumitriu, Alexandra Hetrick, Kurt N. Sun, Mei Latourelle, Jeanne C. Wilk, Jemma B. Halter, Cheryl Doheny, Kimberly F. Gusella, James F. Nichols, William C. Myers, Richard H. Foroud, Tatiana DeStefano, Anita L. TI Copy Number Variation in Familial Parkinson Disease SO PLOS ONE LA English DT Article ID HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; MUTATIONS; GENOME; ASSOCIATION; VARIANTS; GENES; ONSET; RARE; HETEROZYGOSITY AB Copy number variants (CNVs) are known to cause Mendelian forms of Parkinson disease (PD), most notably in SNCA and PARK2. PARK2 has a recessive mode of inheritance; however, recent evidence demonstrates that a single CNV in PARK2 (but not a single missense mutation) may increase risk for PD. We recently performed a genome-wide association study for PD that excluded individuals known to have either a LRRK2 mutation or two PARK2 mutations. Data from the Illumina370Duo arrays were re-clustered using only white individuals with high quality intensity data, and CNV calls were made using two algorithms, PennCNV and QuantiSNP. After quality assessment, the final sample included 816 cases and 856 controls. Results varied between the two CNV calling algorithms for many regions, including the PARK2 locus (genome-wide p = 0.04 for PennCNV and p = 0.13 for QuantiSNP). However, there was consistent evidence with both algorithms for two novel genes, USP32 and DOCK5 (empirical, genome-wide p-values<0.001). PARK2 CNVs tended to be larger, and all instances that were molecularly tested were validated. In contrast, the CNVs in both novel loci were smaller and failed to replicate using real-time PCR, MLPA, and gel electrophoresis. The DOCK5 variation is more akin to a VNTR than a typical CNV and the association is likely caused by artifact due to DNA source. DNA for all the cases was derived from whole blood, while the DNA for all controls was derived from lymphoblast cell lines. The USP32 locus contains many SNPs with low minor allele frequency leading to a loss of heterozygosity that may have been spuriously interpreted by the CNV calling algorithms as support for a deletion. Thus, only the CNVs within the PARK2 locus could be molecularly validated and associated with PD susceptibility. C1 [Pankratz, Nathan; Halter, Cheryl; Foroud, Tatiana] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46204 USA. [Dumitriu, Alexandra; Latourelle, Jeanne C.; Wilk, Jemma B.; Myers, Richard H.; DeStefano, Anita L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Hetrick, Kurt N.; Doheny, Kimberly F.] Johns Hopkins Univ, Sch Med, Inst Med Genet, CIDR, Baltimore, MD USA. [Sun, Mei; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sun, Mei] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Nichols, William C.] Cincinnati Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH USA. [Nichols, William C.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [DeStefano, Anita L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Pankratz, N (reprint author), Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46204 USA. EM npankrat@iupui.edu OI Latourelle, Jeanne/0000-0002-4218-9572; Dumitriu, Alexandra/0000-0002-4467-4803; Myers, Richard/0000-0002-8365-2674; Goldwurm, Stefano/0000-0002-1651-567X FU Robert P. & Judith N. Goldberg Foundation; Bumpus Foundation; Harvard NeuroDiscovery Center; Italian Telethon [GTB07001]; Fondazione Grigioni per il Morbo di Parkinson; National Institutes of Health [HHSN268200782096C]; [R01 NS37167]; [R01 NS036711] FX This project was supported by R01 NS37167, R01 NS036711, the Robert P. & Judith N. Goldberg Foundation, the Bumpus Foundation and the Harvard NeuroDiscovery Center. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), as well as clinical data. DNA samples contributed by the Parkinson Institute - Istituti Clinici di Perfezionamento, Milan, Italy were from the "Human genetic bank of patients affected by PD and parkinsonisms", supported by Italian Telethon grant n. GTB07001 and by the "Fondazione Grigioni per il Morbo di Parkinson". Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 21 Z9 21 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 2 PY 2011 VL 6 IS 8 AR e20988 DI 10.1371/journal.pone.0020988 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 802LF UT WOS:000293511900001 PM 21829596 ER PT J AU Ioannou, GN AF Ioannou, George N. TI Hepatitis B Virus in the United States RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Ioannou, GN (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 2 PY 2011 VL 155 IS 3 BP 205 EP + DI 10.7326/0003-4819-155-3-201108020-00022 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 800DJ UT WOS:000293339600018 ER PT J AU Wiviott, SD AF Wiviott, Stephen D. TI ILLUMINATE Sheds More Light SO CIRCULATION LA English DT Editorial Material DE Editorials; cholesteryl ester transfer protein; diabetes mellitus type 2; HDL cholesterol; insulin ID DIABETES-MELLITUS; HIGH-RISK; TRIAL; SAFETY; TORCETRAPIB; DALCETRAPIB; OUTCOMES; EVENTS; IMPACT C1 Harvard Univ, Sch Med, Div Cardiovasc, Brigham & Womens Hosp,TIMI Study Grp, Boston, MA 02115 USA. RP Wiviott, SD (reprint author), Harvard Univ, Sch Med, Div Cardiovasc, Brigham & Womens Hosp,TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM swiviott@partners.org NR 14 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 2 PY 2011 VL 124 IS 5 BP 536 EP 537 DI 10.1161/CIRCULATIONAHA.111.043323 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 800CZ UT WOS:000293338400010 PM 21768540 ER PT J AU Mahaffey, KW Wojdyla, DM Carroll, K Becker, RC Storey, RF Angiolillo, DJ Held, C Cannon, CP James, S Pieper, KS Horrow, J Harrington, RA Wallentin, L AF Mahaffey, Kenneth W. Wojdyla, Daniel M. Carroll, Kevin Becker, Richard C. Storey, Robert F. Angiolillo, Dominick J. Held, Claes Cannon, Christopher P. James, Stefan Pieper, Karen S. Horrow, Jay Harrington, Robert A. Wallentin, Lars CA PLATO Investigators TI Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial SO CIRCULATION LA English DT Article DE aspirin; acute coronary syndrome; myocardial infarction; outcomes ID ACUTE CORONARY SYNDROMES; ST-SEGMENT ELEVATION; ACUTE MYOCARDIAL-INFARCTION; P2Y(12) RECEPTOR; INTERNATIONAL TRIAL; TASK-FORCE; ASPIRIN; PROSTACYCLIN; AGGREGATION; THROMBOXANE AB Background-In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P = 0.045), with less effect of ticagrelor in North America than in the rest of the world. Methods and Results-Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose >= 300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort. Conclusions-The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin. C1 [Mahaffey, Kenneth W.; Wojdyla, Daniel M.; Becker, Richard C.; Pieper, Karen S.; Harrington, Robert A.] Duke Clin Res Inst, Durham, NC 27715 USA. [Carroll, Kevin; Horrow, Jay] AstraZeneca Res & Dev, Wilmington, DE USA. [Storey, Robert F.] Univ Sheffield, Sheffield, S Yorkshire, England. [Angiolillo, Dominick J.] Univ Florida, Coll Med, Jacksonville, FL USA. [Held, Claes; James, Stefan; Wallentin, Lars] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. RP Mahaffey, KW (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. EM mahaf002@mc.duke.edu OI Held, Claes/0000-0001-9402-7404 FU AstraZeneca; Bayer; Boehringer Ingleheim; Bristol-Myers Squibb; Eli Lilly; GlaxoSmithKline; Johnson Johnson; Merck; Ortho/McNeill; Sanofi-Aventis; Schering-Plough (now Merck); Daiichi Sankyo; Novartis; Portola Pharmaceuticals; Pozen; Regado; Regado Biosciences; Eisai; Teva; Accumetrics; Dynabyte; Bristol-Myers Squibb/Sanofi-Aventis; Otsuka; Boston Scientific; Eli Lilly Co; Daiichi Sankyo, Inc; Portola; Intekrin Therapeutics; Takeda; Medicines Company; CSL Behring; Merck/Schering-Plough FX Dr Mahaffey has received consulting fees from AstraZeneca, Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Ortho/McNeill, Sanofi-Aventis, and Schering-Plough (now Merck); he has also received research funding from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Portola Pharmaceuticals, Pozen, Regado, Sanofi-Aventis, Schering-Plough (now Merck), and The Medicines Company. D. M. Wojdyla has received institutional research grant support from AstraZeneca. K. Carroll is an employee of and has equity ownership in AstraZeneca. Dr Becker has received research support from AstraZeneca, Regado Biosciences, Johnson & Johnson, and Bayer; he is on the speakers' bureau for AstraZeneca and Johnson & Johnson; he has also done consulting for AstraZeneca, Canyon Pharmaceuticals, Daiichi Sankyo, Eli Lilly & Co, Merck & Co, Momenta Pharmaceutical, Regado Biosciences, Boehringer-Ingelheim, and Portola. Dr Storey has received consulting fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, Eisai, Novartis, Teva, The Medicines Company, Sanofi-Aventis, Bristol-Myers Squibb, Accumetrics, and Merck/Schering-Plough; he has received lecture fees from Eli Lilly, Daiichi Sankyo, GlaxoSmithKline, Merck, and AstraZeneca; he has also received institutional grant support from AstraZeneca, Eli Lilly, Daiichi Sankyo, Merck/Schering-Plough, Dynabyte, and Accumetrics. Dr Angiolillo has received honoraria/lectures from Bristol Myers Squibb/Sanofi-Aventis, Eli Lilly Co, and Daiichi Sankyo, Inc; he has received honoraria/advisory board for Bristol Myers Squibb/Sanofi-Aventis, Eli Lilly Co./Daiichi Sankyo, Inc, AstraZeneca, The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, Merck, and Evolva; he has received investigator-initiated research grants/awards from Bristol-Myers Squibb/Sanofi-Aventis, GlaxoSmithKline, Otsuka, Boston Scientific; he also receives sponsored research support from Eli Lilly Co, Daiichi Sankyo, Inc, The Medicines Company, Portola, Accumetrics, Schering-Plough, AstraZeneca, Eisai, and Johnson and Johnson. Dr Held receives institutional research grant from AstraZeneca; he also receives speakers' bureau fees, honoraria, and consulting fees from AstraZeneca. Dr Cannon receives research grants/support from Accumetrics, AstraZeneca, GlaxoSmithKline, Intekrin Therapeutics, Merck, and Takeda; he is on the advisory board for Bristol-Myers Squibb/Sanofi, Novartis, and Alnylam; he receives honorarium from Pfizer and AstraZeneca; he also does consulting for and has equity ownership in Automedics Medical Systems. Dr James has received research grants from AstraZeneca, Eli Lilly, and Bristol-Myers Squibb; he receives honoraria from AstraZeneca, The Medicines Company, and Eli Lilly; he also does consulting for AstraZeneca and The Medicines Company. K. S. Pieper has received an institutional research grant from AstraZeneca. Dr Horrow is an employee of and has equity ownership in AstraZeneca. Dr Harrington receives research support from The Medicines Company, Novartis, AstraZeneca, Sanofi-Aventis, Bristol-Myers Squibb, CSL Behring, GlaxoSmithKline, Portola, and Merck; he does consulting for AstraZeneca, Boehringer Ingelheim, Merck, Bristol-Myers Squibb, CSL Behring, Regado Biosciences, and Sanofi-Aventis. A full listing of relationships with industry for Drs Mahaffey and Harrington is available at dcri.org.; Dr Wallentin receives institutional research grants from AstraZeneca, Boehringer Ingelheim, Brisol-Myers Squibb, GlaxoSmithKline, and Merck/Schering-Plough; he is on the speakers' bureau for AstraZeneca, Boehringer Ingelheim, and Eli Lilly; he receives honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck/Schering-Plough, and Eli Lilly; he also does consulting for Regado Biotechnologies, Athera Biotechnologies, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Eli Lilly. NR 20 TC 188 Z9 200 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 2 PY 2011 VL 124 IS 5 BP 544 EP U78 DI 10.1161/CIRCULATIONAHA.111.047498 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 800CZ UT WOS:000293338400014 PM 21709065 ER PT J AU Reiner, T Thurber, G Gaglia, J Vinegoni, C Liew, CW Upadhyay, R Kohler, RH Li, L Kulkarni, RN Benoist, C Mathis, D Weissleder, R AF Reiner, Thomas Thurber, Greg Gaglia, Jason Vinegoni, Claudio Liew, Chong Wee Upadhyay, Rabi Kohler, Rainer H. Li, Li Kulkarni, Rohit N. Benoist, Christophe Mathis, Diane Weissleder, Ralph TI Accurate measurement of pancreatic islet beta-cell mass using a second-generation fluorescent exendin-4 analog SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CONFOCAL LASER ENDOMICROSCOPY; POSITRON-EMISSION-TOMOGRAPHY; PEPTIDE-1 RECEPTOR; IMAGING AGENTS; IN-VITRO; EXPRESSION; MODEL; TRANSPLANTATION; QUANTIFICATION; ESTABLISHMENT AB The hallmark of type 1 diabetes is autoimmune destruction of the insulin-producing beta-cells of the pancreatic islets. Autoimmune diabetes has been difficult to study or treat because it is not usually diagnosed until substantial beta-cell loss has already occurred. Imaging agents that permit noninvasive visualization of changes in beta-cell mass remain a high-priority goal. We report on the development and testing of a near-infrared fluorescent beta-cell imaging agent. Based on the amino acid sequence of exendin-4, we created a neopeptide via introduction of an unnatural amino acid at the K(12) position, which could subsequently be conjugated to fluorophores via bioorthogonal copper-catalyzed click-chemistry. Cell assays confirmed that the resulting fluorescent probe (E4(x12)-VT750) had a high binding affinity (similar to 3 nM). Its in vivo properties were evaluated using high-resolution intravital imaging, histology, whole-pancreas visualization, and endoscopic imaging. According to intravital microscopy, the probe rapidly bound to beta-cells and, as demonstrated by confocal microscopy, it was internalized. Histology of the whole pancreas showed a close correspondence between fluorescence and insulin staining, and there was an excellent correlation between imaging signals and beta-cell mass in mice treated with streptozotocin, a beta-cell toxin. Individual islets could also be visualized by endoscopic imaging. In short, E4(x12)-VT750 showed strong and selective binding to glucose-like peptide-1 receptors and permitted accurate measurement of beta-cell mass in both diabetic and nondiabetic mice. This near-infrared imaging probe, as well as future radioisotope-labeled versions of it, should prove to be important tools for monitoring diabetes, progression, and treatment in both experimental and clinical contexts. C1 [Gaglia, Jason; Li, Li; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Liew, Chong Wee; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Reiner, Thomas; Thurber, Greg; Vinegoni, Claudio; Upadhyay, Rabi; Kohler, Rainer H.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Mathis, D (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM dm@hms.harvard.edu; rweissleder@mgh.harvard.edu OI Gaglia, Jason/0000-0003-2904-312X; Reiner, Thomas/0000-0002-7819-5480 FU National Institutes of Health (NIH) [P01 AI54904, U24 CA092782, R01 67536, R01 EB006432, 1RL9-EB-008539-01]; Harvard Catalyst, the Harvard Clinical and Translational Science Center (NIH) [KL2 RR 025757]; Harvard, Beth Israel Deaconess Medical Center; German Academy of Sciences Leopoldina [LPDS 2009-24]; [1-K99-DK-090210-01] FX We thank Yoshiko Iwamoto for histology and Rostic Gorbatrov for surgery. This work was supported, in part, by the following grants: National Institutes of Health (NIH) Grants P01 AI54904 (to D. M., C. B., and R. W.), U24 CA092782 (to R. W.), R01 67536 (to R.N.K.), and R01 EB006432 (to C. V.). C. W. L. was supported by Grant 1-K99-DK-090210-01 and NIH Training Grant 1RL9-EB-008539-01. R. U. is a Howard Hughes Medical Institute Medical Research Fellow. J.G. is supported in part by a KL2 Medical Research Investigator Training (MeRIT) award from Harvard Catalyst, the Harvard Clinical and Translational Science Center (NIH Award KL2 RR 025757), and the Harvard, Beth Israel Deaconess Medical Center Clinical Investigator Training Program. T. R. was supported by German Academy of Sciences Leopoldina Grant LPDS 2009-24. NR 39 TC 59 Z9 60 U1 1 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 2 PY 2011 VL 108 IS 31 BP 12815 EP 12820 DI 10.1073/pnas.1109859108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 800SC UT WOS:000293385700057 PM 21768367 ER PT J AU Dey-Guha, I Wolfer, A Yeh, AC Albeck, JG Darp, R Leon, E Wulfkuhle, J Petricoin, EF Wittner, BS Ramaswamy, S AF Dey-Guha, Ipsita Wolfer, Anita Yeh, Albert C. Albeck, John G. Darp, Revati Leon, Eduardo Wulfkuhle, Julia Petricoin, Emanuel F., III Wittner, Ben S. Ramaswamy, Sridhar TI Asymmetric cancer cell division regulated by AKT SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STEM-CELLS; BREAST-CANCER; OXIDATIVE STRESS; SELF-RENEWAL; ACTIVATION; STATE; LYMPHOCYTES; INHIBITION; TRANSITION; QUIESCENT AB Human tumors often contain slowly proliferating cancer cells that resist treatment, but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating "G0-like" progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with small-molecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur. C1 [Dey-Guha, Ipsita; Wolfer, Anita; Darp, Revati; Leon, Eduardo; Wittner, Ben S.; Ramaswamy, Sridhar] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Dey-Guha, Ipsita; Wolfer, Anita; Darp, Revati; Leon, Eduardo; Wittner, Ben S.; Ramaswamy, Sridhar] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Dey-Guha, Ipsita; Wolfer, Anita; Darp, Revati; Leon, Eduardo; Wittner, Ben S.; Ramaswamy, Sridhar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Dey-Guha, Ipsita; Wolfer, Anita; Darp, Revati; Leon, Eduardo; Wittner, Ben S.; Ramaswamy, Sridhar] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Dey-Guha, Ipsita; Wolfer, Anita; Yeh, Albert C.; Albeck, John G.; Wittner, Ben S.; Ramaswamy, Sridhar] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wulfkuhle, Julia; Petricoin, Emanuel F., III] George Mason Univ, Ctr Appl Prote & Mol Med, Manassas, VA 20110 USA. [Ramaswamy, Sridhar] Broad Inst Harvard, Cambridge, MA 02142 USA. [Ramaswamy, Sridhar] MIT, Cambridge, MA 02142 USA. [Ramaswamy, Sridhar] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Ramaswamy, S (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. EM sridhar@mgh.harvard.edu FU Massachusetts General Hospital Cancer Center; National Cancer Institute [K08 CA100339, P50 CA89393, P50 CA127003]; Department of Defense [W81XH-06-2-0033]; Howard Hughes Medical Institute; Sidney Kimmel Foundation; Smith Family Foundation; Swiss National Science Foundation; Emma Muschamp Foundation FX We thank Nick Dyson, Daniel Haber, Raul Mostoslavsky, Shobha Vasudevan, and key anonymous reviewers for valuable advice, criticism, and discussion. We thank Dennis Sgroi for expert pathology advice. We thank Kat Folz-Donahue, Supriya Gupta, Laura Prickett-Rice, and Elizabeth Richardson for expert technical advice and assistance. The human studies described were performed under a Partners Human Research Committee Institutional Review Board-approved protocol (2009-P-002302). This work was supported by the Massachusetts General Hospital Cancer Center, the National Cancer Institute (K08 CA100339, P50 CA89393, P50 CA127003), Department of Defense (W81XH-06-2-0033), Howard Hughes Medical Institute (Physician-Scientist Early Career Award), Sidney Kimmel Foundation (Translational Science Award), Smith Family Foundation (New Investigator Award), Swiss National Science Foundation (postdoctoral award; to A.W.), the Emma Muschamp Foundation (postdoctoral award; to A.W.), and a Howard Hughes Medical Institute Medical Student Research Training Fellowship (to A.C.Y.). NR 35 TC 45 Z9 47 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 2 PY 2011 VL 108 IS 31 BP 12845 EP 12850 DI 10.1073/pnas.1109632108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 800SC UT WOS:000293385700062 PM 21757645 ER PT J AU Lam, CSP Cheng, S Choong, K Larson, MG Murabito, JM Newton-Cheh, C Bhasin, S McCabe, EL Miller, KK Redfield, MM Vasan, RS Coviello, AD Wang, TJ AF Lam, Carolyn S. P. Cheng, Susan Choong, Karen Larson, Martin G. Murabito, Joanne M. Newton-Cheh, Christopher Bhasin, Shalender McCabe, Elizabeth L. Miller, Karen K. Redfield, Margaret M. Vasan, Ramachandran S. Coviello, Andrea D. Wang, Thomas J. TI Influence of Sex and Hormone Status on Circulating Natriuretic Peptides SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE hormones; natriuretic peptides; sex ID CARDIAC ENDOCRINE FUNCTION; TANDEM MASS-SPECTROMETRY; CORONARY HEART-DISEASE; POSTMENOPAUSAL WOMEN; REPLACEMENT THERAPY; BINDING GLOBULIN; MENSTRUAL-CYCLE; FREE TESTOSTERONE; FOLLICULAR PHASE; RISK-FACTORS AB Objectives The aim of this study was to assess the relationship between sex hormones and natriuretic peptide levels in community-based adults. Background Women have higher circulating natriuretic peptide concentrations than men, but the mechanisms for these sex-related differences and the impact of hormone therapy are unclear. Experimental studies suggest that androgens may suppress natriuretic peptide secretion. Methods We measured N-terminal pro-B-type natriuretic peptide (NT-proBNP), total testosterone, and sex hormone-binding globulin plasma levels in 4,056 men and women (mean age 40 +/- 9 years) from the Framingham Heart Study Third-Generation cohort. Sex/hormone status was grouped as: 1) men; 2) post-menopausal women not receiving hormone replacement therapy; 3) pre-menopausal women not receiving hormonal contraceptives; 4) post-menopausal women receiving hormone replacement therapy; and 5) pre-menopausal women receiving hormonal contraceptives. Results Circulating NT-proBNP levels were associated with sex/hormone status (overall p < 0.0001). Men had lower NT-proBNP levels than women of all menopause or hormone groups, and women receiving hormonal contraceptives had higher NT-proBNP levels than women who were not receiving hormone therapy (all p < 0.0001). These relationships remained significant after adjusting for age, body mass index, and cardiovascular risk factors. Across sex/hormone status groups, free testosterone (FT) levels decreased and sex hormone-binding globulin levels increased in tandem with increasing NT-proBNP levels. In sex-specific analyses, NT-proBNP levels decreased across increasing quartiles of FT in men (p for trend < 0.01) and women (p for trend < 0.0001). Adjustment for FT markedly attenuated the association between sex/hormone status and NT-proBNP concentrations. Conclusions These findings suggest that lower levels of circulating androgens and the potentiating effect of exogenous female hormone therapy contribute to the higher circulating NT-proBNP concentrations in women. (J Am Coll Cardiol 2011;58:618-26) (C) 2011 by the American College of Cardiology Foundation C1 [Lam, Carolyn S. P.; Cheng, Susan; Larson, Martin G.; Murabito, Joanne M.; Newton-Cheh, Christopher; McCabe, Elizabeth L.; Vasan, Ramachandran S.; Coviello, Andrea D.; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Cheng, Susan; Newton-Cheh, Christopher; McCabe, Elizabeth L.; Miller, Karen K.; Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Choong, Karen; Bhasin, Shalender; Coviello, Andrea D.] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Choong, Karen; Bhasin, Shalender; Coviello, Andrea D.] Boston Med Ctr, Boston, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Lam, Carolyn S. P.; Redfield, Margaret M.] Mayo Clin, Rochester, MN USA. [Lam, Carolyn S. P.; Vasan, Ramachandran S.; Coviello, Andrea D.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Lam, Carolyn S. P.; Vasan, Ramachandran S.; Coviello, Andrea D.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. RP Lam, CSP (reprint author), Natl Univ Hlth Syst, Tower Block Level 9,1E Kent Ridge Rd, Singapore 119228, Singapore. EM carolyn_lam@nuhs.edu.sg OI Murabito, Joanne/0000-0002-0192-7516; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU NIH/NHLBI [NO1-HC-25195, R01-HL-086875, R01-HL-094755]; [HL-84907] FX This study is from the Framingham Heart Study of the National Heart, Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine, and is supported by NIH/NHLBI NO1-HC-25195, R01-HL-086875, and R01-HL-094755. Dr. Newton-Cheh serves on a scientific advisory board at Merck. Dr. Redfield is supported by HL-84907. All other authors have reported that they have no relationships to disclose. Drs. Coviello and Wang contributed equally to this work. NR 45 TC 27 Z9 28 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 2 PY 2011 VL 58 IS 6 BP 618 EP 626 DI 10.1016/j.jacc.2011.03.042 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 797YV UT WOS:000293167200011 PM 21798425 ER PT J AU Wilson, R Lewis, SA Dicianno, BE AF Wilson, Richard Lewis, Steven A. Dicianno, Brad E. TI Targeted Preventive Care May Be Needed for Adults with Congenital Spine Anomalies SO PM&R LA English DT Article ID PRESSURE ULCERS; HEALTH-CARE; CORD-INJURY; BIFIDA; HOSPITALIZATIONS; GUIDELINES; RISK AB Objective: To compare hospitalizations caused by spina bifida sensitive conditions, ambulatory care sensitive conditions in adults with spina bifida and in the general population, our aim was to provide information about whether preventive health efforts already underway in the hospitalized general population are adequate for preventive care in spina bifida and congenital spine anomalies. Design: Retrospective secondary data analysis. Patients (or Participants): Records of hospitalized individuals who were 18 years of age and older. Methods: Comparison between individuals hospitalized with spina bifida and the general population using data from the California State Inpatient Database from the Healthcare Cost and Utilization Project for 2004 of adults. Main Outcome Measurements: Prevalence of spina bifida sensitive conditions and ambulatory care sensitive conditions as reason for hospitalization and 30-day readmission. Results: As compared with the general population, persons with spina bifida who were hospitalized in 2004 had a significantly greater number of hospitalizations, number of hospitalizations associated with both spina bifida sensitive conditions and ambulatory care sensitive conditions, and number of 30-day readmissions. Stratification by age shows that the admissions for spina bifida sensitive conditions were greater in persons with spina bifida than in the general population for all age groups. In contrast, only in the youngest age group did those with spina bifida experience greater hospitalizations for ambulatory care-sensitive conditions. Conclusions: This study provides further evidence that persons with spina bifida have hospitalizations that are beyond what the general population experiences. These conditions may be potentially preventable with appropriate ambulatory care. This group also had a greater risk for readmission within 30 days of discharge from their last hospitalization. More research is needed on the efficacy of programs aimed at prevention of these conditions. PM R 2011;3:730-738 C1 [Wilson, Richard] Case Western Reserve Univ, Metrohlth Med Ctr, MetroHlth Rehabil Inst Ohio, Cleveland, OH USA. [Wilson, Richard] Cleveland Funct Elect Stimulat Ctr, Cleveland, OH USA. [Lewis, Steven A.] Case Western Reserve Univ, Metrohlth Med Ctr, Ctr Hlth Care Res & Policy, Cleveland, OH USA. [Dicianno, Brad E.] Univ Pittsburgh, Human Engn Res Labs, Pittsburgh, PA USA. [Dicianno, Brad E.] US Dept Vet Affairs, Pittsburgh, PA USA. [Dicianno, Brad E.] Univ Pittsburgh, Adult Spina Bifida Clin, Dept Phys Med & Rehabil, Pittsburgh, PA USA. RP Wilson, R (reprint author), 2500 MetroHlth Dr,S1-107E, Cleveland, OH 44109 USA. EM rwilson@metrohealth.org OI Dicianno, Brad/0000-0003-0738-0192 NR 37 TC 11 Z9 11 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD AUG PY 2011 VL 3 IS 8 BP 730 EP 738 DI 10.1016/j.pmrj.2011.05.021 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 961BD UT WOS:000305438000008 PM 21871417 ER PT J AU Porter, JN Jedema, HP Baeg, EH Bradberry, CW AF Porter, J. N. Jedema, H. P. Baeg, E. H. Bradberry, C. W. TI IMPACT OF COCAINE SELF-ADMINISTRATION ON COGNITIVE FLEXIBILITY AND ATTENTIONAL PERFORMANCE IN RHESUS MONKEYS SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT 14th Biennial Meeting of the European-Behavioural-Pharmacology-Society CY AUG 26-29, 2011 CL Amsterdam, NETHERLANDS SP European Behav Pharmacol Soc C1 Univ Pittsburgh, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD AUG PY 2011 VL 22 SU S BP E11 EP E12 PG 2 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 893OM UT WOS:000300365200043 ER PT J AU Fligner, CL Murray, J Roberts, DJ AF Fligner, Corinne L. Murray, Jill Roberts, Drucilla J. TI Synergism of verbal autopsy and diagnostic pathology autopsy for improved accuracy of mortality data SO POPULATION HEALTH METRICS LA English DT Article ID DISEASE; RATES; DEATH C1 [Fligner, Corinne L.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Murray, Jill] Univ Witwatersrand, Natl Inst Occupat Hlth, Natl Hlth Lab Serv, ZA-2000 Johannesburg, South Africa. [Murray, Jill] Univ Witwatersrand, Fac Hlth Sci, Sch Publ Hlth, ZA-2000 Johannesburg, South Africa. [Roberts, Drucilla J.] Massachusetts Gen Hosp MGH Pathol, Boston, MA USA. [Fligner, Corinne L.] Univ Washington, Sch Med, Dept Lab Med, Seattle, WA USA. RP Fligner, CL (reprint author), Univ Washington, Sch Med, Dept Pathol, Box 356100, Seattle, WA 98195 USA. EM fligner@u.washington.edu NR 12 TC 12 Z9 12 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-7954 J9 POPUL HEALTH METR JI Popul. Health Metr. PD AUG 1 PY 2011 VL 9 AR 25 DI 10.1186/1478-7954-9-25 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 891LO UT WOS:000300218700005 PM 21806831 ER PT J AU Iftimia, N Cizginer, S Deshpande, V Pitman, M Tatli, S Iftimia, NA Hammer, DX Mujat, M Ustun, T Ferguson, RD Brugge, WR AF Iftimia, Nicusor Cizginer, Sevdenur Deshpande, Vikram Pitman, Martha Tatli, Servet Iftimia, Nicolae-Adrian Hammer, Daniel X. Mujat, Mircea Ustun, Teoman Ferguson, R. Daniel Brugge, William R. TI Differentiation of pancreatic cysts with optical coherence tomography (OCT) imaging: an ex vivo pilot study SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID NEOPLASMS; DIAGNOSIS; FEATURES; MASSES; ACCURACY; LESIONS; BENIGN; CANCER; MRI; EUS AB We demonstrate for the first time that optical coherence tomography (OCT) imaging can reliably distinguish between morphologic features of low risk pancreatic cysts (i.e., pseudocysts and serous cystadenomas) and high risk pancreatic cysts (i.e., mucinous cystic neoplasms and intraductal papillary mucinous neoplasms). In our study fresh pancreatectomy specimens (66) from patients with cystic lesions undergoing surgery were acquired and examined with OCT. A training set of 20 pathology-OCT correlated tissue specimens were used to develop criteria for differentiating between low and high risk cystic lesions. A separate (validation) set of 46 specimens were used to test the OCT criteria by three clinicians, blinded to histopathology findings. Histology was finally used as a, gold. standard for testing OCT findings. OCT was able to reveal specific morphologic features of pancreatic cysts and thus to differentiate between low-risk and high-risk cysts with over 95% sensitivity and specificity. This pilot study suggests that OCT could be used by clinicians in the future to more reliably differentiate between benign and potentially malignant pancreatic cysts. However, in vivo use of OCT requires a probe that has to fit the bore of the pancreas biopsy needle. Therefore, we have developed such probes and planned to start an in vivo pilot study within the very near future. (C) 2011 Optical Society of America C1 [Iftimia, Nicusor; Hammer, Daniel X.; Mujat, Mircea; Ustun, Teoman; Ferguson, R. Daniel] Phys Sci Inc, Andover, MA 01810 USA. [Cizginer, Sevdenur; Brugge, William R.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Deshpande, Vikram; Pitman, Martha] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Tatli, Servet] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Iftimia, Nicolae-Adrian] Brandeis Univ, Waltham, MA USA. RP Iftimia, N (reprint author), Phys Sci Inc, 20 New England Business Ctr, Andover, MA 01810 USA. EM iftimia@psicorp.com NR 35 TC 10 Z9 10 U1 0 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD AUG 1 PY 2011 VL 2 IS 8 BP 2372 EP 2382 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886VN UT WOS:000299882100026 PM 21833374 ER PT J AU Antony, B Abramoff, MD Tang, L Ramdas, WD Vingerling, JR Jansonius, NM Lee, K Kwon, YH Sonka, M Garvin, MK AF Antony, Bhavna Abramoff, Michael D. Tang, Li Ramdas, Wishal D. Vingerling, Johannes R. Jansonius, Nomdo M. Lee, Kyungmoo Kwon, Young H. Sonka, Milan Garvin, Mona K. TI Automated 3-D method for the correction of axial artifacts in spectral-domain optical coherence tomography images SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID SEGMENTATION; REGISTRATION; ROTTERDAM AB The 3-D spectral-domain optical coherence tomography (SD-OCT) images of the retina often do not reflect the true shape of the retina and are distorted differently along the x and y axes. In this paper, we propose a novel technique that uses thin-plate splines in two stages to estimate and correct the distinct axial artifacts in SD-OCT images. The method was quantitatively validated using nine pairs of OCT scans obtained with orthogonal fast-scanning axes, where a segmented surface was compared after both datasets had been corrected. The mean unsigned difference computed between the locations of this artifact-corrected surface after the single-spline and dual-spline correction was 23.36 +/- 4.04 mu m and 5.94 +/- 1.09 mu m, respectively, and showed a significant difference (p < 0.001 from two-tailed paired t-test). The method was also validated using depth maps constructed from stereo fundus photographs of the optic nerve head, which were compared to the flattened top surface from the OCT datasets. Significant differences (p < 0.001) were noted between the artifact-corrected datasets and the original datasets, where the mean unsigned differences computed over 30 optic-nerve-head-centered scans (in normalized units) were 0.134 +/- 0.035 and 0.302 +/- 0.134, respectively. (C) 2011 Optical Society of America C1 [Antony, Bhavna; Abramoff, Michael D.; Lee, Kyungmoo; Sonka, Milan; Garvin, Mona K.] Univ Iowa, Dept Elect & Comp Engn, Iowa City, IA 52242 USA. [Abramoff, Michael D.; Tang, Li; Kwon, Young H.; Sonka, Milan] Univ Iowa, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. [Abramoff, Michael D.; Garvin, Mona K.] US Dept Vet Affairs, Iowa City, IA USA. [Ramdas, Wishal D.; Vingerling, Johannes R.] Erasmus MC, Depts Ophthalmol & Epidemiol, Rotterdam, Netherlands. [Jansonius, Nomdo M.] Univ Groningen, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands. RP Antony, B (reprint author), Univ Iowa, Dept Elect & Comp Engn, Iowa City, IA 52242 USA. EM mona-garvin@uiowa.edu RI Abramoff, Michael/A-5836-2009 OI Abramoff, Michael/0000-0002-3490-0037 FU Department of Veterans Affairs; National Institutes of Health [NEI EY017066, R01 EY018853, R01 EY019112]; Research to Prevent Blindness, New York, NY; Marlene S. and Leonard A. Hadley Glaucoma Research Fund; Stichting Lijf en Leven, Krimpen aan de Lek; MD Fonds, Utrecht; Rotterdamse Vereniging Blindenbelangen, Rotterdam; Stichting Oogfonds Nederland, Utrecht; Blindenpenning, Amsterdam; Blindenhulp, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn; Landelijke Stichting voor Blinden en Slechtzienden, Utrecht; Swart van Essen, Rotterdam; Stichting Winckel-Sweep, Utrecht; Henkes Stichting, Rotterdam; Lamris Ootech BV, Nieuwegein; Medical Workshop, de Meern; Topcon Europe BV, Capelle aan de IJssel in the Netherlands; Heidelberg Engineering, Dossenheim, Germany FX This work was supported in part by the Department of Veterans Affairs; the National Institutes of Health grants NEI EY017066, R01 EY018853 and R01 EY019112; Research to Prevent Blindness, New York, NY; Marlene S. and Leonard A. Hadley Glaucoma Research Fund; Stichting Lijf en Leven, Krimpen aan de Lek; MD Fonds, Utrecht; Rotterdamse Vereniging Blindenbelangen, Rotterdam; Stichting Oogfonds Nederland, Utrecht; Blindenpenning, Amsterdam; Blindenhulp, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn; Landelijke Stichting voor Blinden en Slechtzienden, Utrecht; Swart van Essen, Rotterdam; Stichting Winckel-Sweep, Utrecht; Henkes Stichting, Rotterdam; Lamris Ootech BV, Nieuwegein; Medical Workshop, de Meern; Topcon Europe BV, Capelle aan de IJssel, all in the Netherlands, and Heidelberg Engineering, Dossenheim, Germany. NR 24 TC 16 Z9 16 U1 2 U2 6 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD AUG 1 PY 2011 VL 2 IS 8 BP 2403 EP 2416 PG 14 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886VN UT WOS:000299882100029 PM 21833377 ER PT J AU Brunoni, AR Fregni, F Pagano, RL AF Brunoni, Andre Russowsky Fregni, Felipe Pagano, Rosana Lima TI Translational research in transcranial direct current stimulation (tDCS): a systematic review of studies in animals SO REVIEWS IN THE NEUROSCIENCES LA English DT Review DE animal models; brain; direct current; electrical stimulation; neuroplasticity; systematic review; translational research ID NONINVASIVE BRAIN-STIMULATION; CORTICAL SPREADING DEPRESSION; ELECTRICAL-STIMULATION; DC STIMULATION; CLINICAL-TRIAL; MOTOR CORTEX; RATS; EPILEPSY; MEMORY; ELECTROSTIMULATION AB Recent therapeutic human studies testing transcranial direct current stimulation (tDCS) has shown promising results, although many questions remain unanswered. Translational research with experimental animals is an appropriate framework for investigating its mechanisms of action that are still undetermined. Nevertheless, animal and human studies are often discordant. Our aim was to review tDCS animal studies, examining and comparing their main findings with human studies. We performed a systematic review in Medline and other databases, screening for animal studies in vivo that delivered tDCS. Studies in vitro and using other neuromodulatory techniques were excluded. We extracted data according to Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines for reporting in vivo animal research. Thus, we collected data on sample characteristics (size, gender, weight and specimen) and methodology (experimental procedures, experimental animals, housing and husbandry, as well as analysis). We also collected data on methods for delivering tDCS (location, size, current and current density of electrodes and electrode montage), experimental effects (polarity-, intensityand after-effects) and safety. Only 12 of 48 potentially eligible studies met our inclusion criteria and were reviewed. Quality assessment reporting was only moderate and studies were heterogeneous regarding tDCS montage methodology, position of active and reference electrodes, and current density used. Nonetheless, almost all studies demonstrated that tDCS had positive immediate and long-lasting effects. Vis-a-vis human trials, animal studies applied higher current densities (34.2 vs. 0.4 A/m(2), respectively), preferred extra-cephalic positions for reference electrodes (60 % vs. 10 %, respectively) and used electrodes with different sizes more often. Potential implications for translational tDCS research are discussed. C1 [Brunoni, Andre Russowsky] Univ Sao Paulo, Inst Psychol, Dept Neurosci & Behav, BR-05508000 Sao Paulo, Brazil. [Brunoni, Andre Russowsky] Univ Sao Paulo, Univ Hosp, BR-05508000 Sao Paulo, Brazil. [Fregni, Felipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Fregni, Felipe] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp,Lab Neuromodulat, Boston, MA 02114 USA. [Pagano, Rosana Lima] Hosp Sirio Libanes, Lab Neuromodulat & Expt Pain, BR-01308050 Sao Paulo, Brazil. RP Brunoni, AR (reprint author), Univ Sao Paulo, Inst Psychol, Dept Neurosci & Behav, Cidade Univ, BR-05508000 Sao Paulo, Brazil. EM brunoni@usp.br; fregni.felipe@mgh.harvard.edu RI Brunoni, Andre/H-8394-2012 OI Brunoni, Andre/0000-0002-6310-3571 NR 60 TC 17 Z9 19 U1 0 U2 13 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-1763 J9 REV NEUROSCIENCE JI Rev. Neurosci. PD AUG PY 2011 VL 22 IS 4 BP 471 EP 481 DI 10.1515/RNS.2011.042 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 889PB UT WOS:000300084600007 PM 21819264 ER PT J AU Marotta, LLC Polyak, K AF Marotta, Lauren L. C. Polyak, Kornelia TI Unraveling the complexity of basal-like breast cancer SO ONCOTARGET LA English DT Editorial Material ID HETEROGENEITY C1 [Marotta, Lauren L. C.; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Marotta, Lauren L. C.; Polyak, Kornelia] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA USA. [Polyak, Kornelia] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Marotta, LLC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM Kornelia_Polyak@dfci.harvard.edu NR 8 TC 8 Z9 9 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG PY 2011 VL 2 IS 8 BP 588 EP 589 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 880QR UT WOS:000299422500002 PM 21876228 ER PT J AU Lennerz, JKM Chapman, WC Brunt, EM AF Lennerz, Jochen K. M. Chapman, William C. Brunt, Elizabeth M. TI Keratin 19 Epithelial Patterns in Cirrhotic Stroma Parallel Hepatocarcinogenesis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; TO-MESENCHYMAL TRANSITION; SMALL HEPATOCELLULAR CARCINOMAS; PRIMARY BILIARY-CIRRHOSIS; TGF-BETA; LIVER FIBROSIS; DUCTULAR REACTION; E-CADHERIN; DYSPLASTIC NODULES; CELL-DEATH AB Cirrhotic septa harbor vessels and inflammatory, fibrogenic, and ductular epithelial cells, collectively referred to as the ductular reaction (DR). Lack of the DR in the stromal compartment around hepatocellular carcinoma (HCC) has been documented; however, the relationship of epithelial keratin 19 (K19) structures to progression of intralesional carcinogenesis has not been explored. K19 immunoreactivity in the stromal compartment around 176 nodules in cirrhotic explants was examined. Quantitative differences (P < 0.0001) were manifested in three distinct histologically identifiable patterns: "complex" around cirrhotic nodules (CN), "attenuated" around dysplastic nodules (DN), and "absent" around HCC. Markers of necrosis or apoptosis could not explain the perinodular K19 epithelial loss; however, multicolor immunolabeling for K19, vimentin, E-Cadherin, SNAIL, and fibroblast-specific protein 1 (FSP-1) demonstrated discrepancies in immunophenotype and cytomorphologic features. Variability of cellular features was accompanied by an overall decrease in epithelial markers and significantly increased fractions of SNAIL- and FSP-1 positive cells in the DR around DN when compared with CN (P < 0.0001). Immunolabeling of transforming growth factor-beta signaling components (TGF beta R1 SMAD3, and pSMAD2/3) demonstrated increased percentages of pSMAD2/3 around DN when compared with CN (P < 0.0001). These findings collectively suggest marked alterations in cellular identity as an underlying mechanism for the reproducible extralesional K19 pattern that parallels progressive stages of intranodular hepatocarcinogenesis. Paracrine signaling is proposed as a link that emphasizes the importance of the epithelial-stromal compartment in malignant progression of HCC in cirrhosis. (Am J Pathol 2011, 179:1015-1029; DOI: 10.1016/j.ajpath.2011.04.040) C1 [Lennerz, Jochen K. M.; Brunt, Elizabeth M.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 USA. [Lennerz, Jochen K. M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Chapman, William C.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. RP Brunt, EM (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, 660 Euclid Ave, St Louis, MO 63130 USA. EM EBrunt@path.wustl.edu FU Washington University/Barnes-Jewish Hospital; Massachusetts General Hospital/Harvard Medical School FX We thank Julie Gutierrez, Elease Barnes, Shari Jackson, and Mary Madden for administrative assistance; Autumn Watson, Vernetta Layton, Kevin Selle, Don Leahart, Kevin Keith, and Rodney Brown for histotechnical assistance; Jianping Li, Xiaopei Zhu, and Prosperidad Amargo for technical assistance; Joan Rossi and Dr. Jason Mills for microscope use; Walter Clermont, Stacey Yates, Emily Brophy, and Mike Isaacs for slide scanning and information technology support; Dr. James S. Lewis, Jr, and the research histology laboratory; Drs. John D. Pfeifer and Peter Humphrey (Washington University/Barnes-Jewish Hospital) and Drs. Gregory Y. Lauwers and John Gilbertson (Massachusetts General Hospital/Harvard Medical School) for support and thoughtful discussions. NR 101 TC 9 Z9 9 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2011 VL 179 IS 2 BP 1015 EP 1029 DI 10.1016/j.ajpath.2011.04.040 PG 15 WC Pathology SC Pathology GA 865JM UT WOS:000298307200045 PM 21704007 ER PT J AU Garcia-Albeniz, X Chan, AT AF Garcia-Albeniz, X. Chan, A. T. TI Aspirin for the prevention of colorectal cancer SO BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY LA English DT Article DE Aspirin; NSAID; Colorectal cancer; Adenocarcinoma; Adenoma ID LOW-DOSE ASPIRIN; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; FAMILIAL ADENOMATOUS POLYPOSIS; RANDOMIZED CONTROLLED-TRIALS; LONG-TERM USE; TRANSIENT ISCHEMIC ATTACK; CARDIOVASCULAR-DISEASE; CYCLOOXYGENASE-2 INHIBITOR; RESISTANT STARCH; LYNCH SYNDROME AB Over 600,000 people worldwide die of colorectal cancer (CRC) annually, highlighting the importance of developing effective prevention strategies. Among proposed chemopreventive interventions, aspirin is perhaps the agent with the strongest body of evidence that supports wider spread use to significantly reduce the population burden of CRC. Several epidemiological studies, four randomized controlled trials (RCTs) of colorectal polyp recurrence, and RCTs in patients with hereditary colorectal cancer syndromes, have shown that aspirin reduces incidence of colorectal neoplasia. Recently, in a pooled analysis of five cardiovascular-prevention RCTs linked to cancer outcomes, daily aspirin use at any dose reduced the risk of CRC by 24% and of CRC-associated mortality by 35% after a delay of 8-10 years. In an expanded meta-analysis of 8 cardiovascular-prevention RCTs, daily aspirin use at any dose was associated with a 21% lower risk of all cancer death, including CRC, with benefit only apparent after 5 years. In this review, we will summarize human studies of aspirin in CRC prevention as well as discuss the safety profile and mechanism of aspirin in CRC prevention. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Chan, A. T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chan, A. T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Garcia-Albeniz, X.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02114 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St, Boston, MA 02114 USA. EM xgarciad@hsph.harvard.edu; achan@partners.org FU 'La Caixa' fellowship; NCI [R01 CA137178] FX XGA is supported by a 'La Caixa' fellowship. ATC is a Damon Runyon Cancer Foundation Clinical Investigator and supported by NCI R01 CA137178. NR 84 TC 39 Z9 41 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6918 J9 BEST PRACT RES CL GA JI Best Pract. Res. Clin. Gastroenterol. PD AUG-OCT PY 2011 VL 25 IS 4-5 BP 461 EP 472 DI 10.1016/j.bpg.2011.10.015 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 868OL UT WOS:000298532500003 PM 22122763 ER PT J AU Ackerman, KE Davis, B Jacoby, L Misra, M AF Ackerman, Kathryn E. Davis, Brittany Jacoby, Leah Misra, Madhusmita TI DXA surrogates for visceral fat are inversely associated with bone density measures in adolescent athletes with menstrual dysfunction SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE athletes; body composition; bone density; fat mass; lean mass; regional fat; trunk fat ID HORMONE REPLACEMENT THERAPY; MINERAL DENSITY; POSTMENOPAUSAL WOMEN; ANOREXIA-NERVOSA; BODY-COMPOSITION; PREMENOPAUSAL WOMEN; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; YOUNG-ADULTS; MASS AB Objective: Lean mass is associated with bone mineral density (BMD) in athletes, attributable to the anabolic pull of muscle on bone. Fat mass is also important, and subcutaneous fat positively and visceral fat negatively correlates with BMD in obese adolescents. The contribution of regional body composition to low BMD in amenorrheic athletes (AA) has not been elucidated. We hypothesized that in adolescent athletes (runners), BMD is associated positively with total fat (surrogate for subcutaneous fat) and lean mass, and inversely with percent trunk fat and trunk-to-extremity fat ratio (surrogates for visceral fat). Design: Cross-sectional study. Subjects and methods: We examined BMD and body composition using dual energy X-ray absorptiometry (DXA) in 21 AA and 19 eumenorrheic athletes (EA) (12-18 years) (runners). We report total hip and height-adjusted BMD [lumbar bone mineral apparent density (LBMAD) and whole body bone mineral content/height (WBBMC/Ht)]. Results: AA had lower BMD than EA. Lean mass was less strongly associated with hip BMD in AA than EA; fat mass was positively associated with LBMAD in EA. Percent trunk fat and trunk-to-extremity fat ratio were inversely associated with lumbar and WB measures in AA. In a regression model, lean and fat mass were positively, and percent trunk fat and trunk-to-extremity fat ratio negatively associated with LBMAD and WBBMC/Ht for all athletes, even after controlling for serum estradiol. Conclusions: DXA surrogates for visceral fat are inversely associated with bone density in athletes. C1 [Ackerman, Kathryn E.; Davis, Brittany; Jacoby, Leah; Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Ackerman, Kathryn E.; Davis, Brittany; Jacoby, Leah; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Misra, Madhusmita] Mass Gen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, MPH BUL 457,55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org FU NIH [1 UL1 RR025758-01, 1 R01 HD060827-01A1] FX Nothing to declare. This study was supported in part by NIH grants 1 UL1 RR025758-01 and 1 R01 HD060827-01A1. NR 36 TC 13 Z9 13 U1 0 U2 1 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD AUG PY 2011 VL 24 IS 7-8 BP 497 EP 504 DI 10.1515/JPEM.2011.208 PG 8 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 854BE UT WOS:000297468700017 PM 21932588 ER PT J AU Sarris, J Mischoulon, D Schweitzer, I AF Sarris, Jerome Mischoulon, David Schweitzer, Isaac TI Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials SO BIPOLAR DISORDERS LA Welsh DT Review DE adjunctive; bipolar depression; bipolar disorder; depression; mania; mood stabilizers; nutraceuticals; nutrients; omega-3 ID PLACEBO-CONTROLLED-TRIAL; POLYUNSATURATED FATTY-ACIDS; MAJOR DEPRESSIVE DISORDER; OPEN-LABEL TRIAL; DOUBLE-BLIND; DOCOSAHEXAENOIC ACID; RATING-SCALE; MANIA; MOOD; OMEGA-3-FATTY-ACIDS AB Objective: Studies using augmentation of pharmacotherapies with nutraceuticals in bipolar disorder (BD) have been conducted and preliminary evidence in many cases appears positive. To date, however, no specialized systematic review of this area has been conducted. We present the first systematic review of clinical trials using nutrient-based nutraceuticals in combination with standard pharmacotherapies to treat BD. A subsequent aim of this report was to discuss posited underlying mechanisms of action. Methods: PubMed, CINAHL, Web of Science, and Cochrane Library databases, and grey literature were searched during mid-2010 for human clinical trials in English using nutraceuticals such as omega-3, N-acetyl cysteine (NAC), inositol, and vitamins and minerals, in combination with pharmacotherapies to treat bipolar mania and bipolar depression. A review of the results including an effect size analysis (Cohen's d) was subsequently conducted. Results: In treating bipolar depression, positive evidence with large effect sizes were found for NAC (d = 1.04) and a chelated mineral and vitamin formula (d = 1.70). On the outcome of bipolar mania, several nutraceuticals reduced mania with strong clinical effects: a chelated mineral formula (d = 0.83), L-tryptophan (d = 1.47), magnesium (d = 1.44), folic acid (d = 0.40), and branched-chain amino acids (d = 1.60). Mixed, but mainly positive, evidence was found for omega-3 for bipolar depression, while no evidentiary support was found for use in mania. No significant effect on BD outcome scales was found for inositol (possibly due to small samples). Conclusions: BD treatment outcomes may potentially be improved by additional use of certain nutraceuticals with conventional pharmacotherapies. However, caution should be extended in interpreting the large effects of several isolated studies, as they have not yet been replicated in larger trials. C1 [Sarris, Jerome] Univ Melbourne, Melbourne Clin, Dept Psychiat, Fac Med, Richmond, Vic 3121, Australia. [Sarris, Jerome] Swinburne Univ Technol, Ctr Human Psychopharmacol, Melbourne, Vic, Australia. [Mischoulon, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. RP Sarris, J (reprint author), Univ Melbourne, Melbourne Clin, Dept Psychiat, Fac Med, 2 Salisbury St, Richmond, Vic 3121, Australia. EM jsarris@unimelb.edu.au FU Australian National Health and Medical Research Council (NHMRC) [628875]; University of Melbourne; Centre for Human Psychopharmacology at Swinburne University of Technology; Nordic Naturals and Ganeden; Back Bay Scientific for PMS Escape; Lippincott Williams & Wilkins for the textbook Natural Medications for Psychiatric Disorders: Considering the Alternatives; Independent Medical Education grants FX JS is funded by an Australian National Health and Medical Research Council Fellowship (NHMRC funding ID 628875) in a strategic partnership with The University of Melbourne and the Centre for Human Psychopharmacology at Swinburne University of Technology.; DM has received research support from Nordic Naturals and Ganeden; has served as a consultant to Bristol-Myers Squibb; has received writing honoraria from Pamlab; has received royalties from Back Bay Scientific for PMS Escape, and royalties from Lippincott Williams & Wilkins for the textbook Natural Medications for Psychiatric Disorders: Considering the Alternatives; and he has received honoraria from Reed Medical Education (a company working as a logistics collaborator for the MGH Psychiatry Academy). The education programs conducted by the MGH Psychiatry Academy were supported through Independent Medical Education grants from pharmaceutical companies co-supporting programs along with participant tuition. Commercial entities currently supporting the MGH Psychiatry Academy are listed on the Academy's website http://www.mghcme.org. JS and IS have no conflicts of interest to report. NR 66 TC 26 Z9 26 U1 3 U2 18 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD AUG-SEP PY 2011 VL 13 IS 5-6 BP 454 EP 465 DI 10.1111/j.1399-5618.2011.00945.x PG 12 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 848DQ UT WOS:000297029600002 PM 22017215 ER PT J AU Weiner, DL Manzi, SF Briggs, SM Fleisher, GR AF Weiner, Debra L. Manzi, Shannon F. Briggs, Susan M. Fleisher, Gary R. TI Response to Challenges and Lessons Learned From Hurricanes Katrina and Rita: A National Perspective SO PEDIATRICS LA English DT Editorial Material C1 [Weiner, Debra L.; Fleisher, Gary R.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Manzi, Shannon F.] Childrens Hosp, Dept Pharm, Boston, MA 02115 USA. [Briggs, Susan M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. RP Weiner, DL (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM debra.weiner@childrens.harvard.edu NR 10 TC 1 Z9 1 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2011 VL 128 SU 1 BP S31 EP S33 DI 10.1542/peds.2010-3724M PG 3 WC Pediatrics SC Pediatrics GA 846QQ UT WOS:000296918700012 PM 21807712 ER PT J AU Chung, JH Carr, RB Stern, EJ AF Chung, Jonathan H. Carr, Robert B. Stern, Eric J. TI Extrapleural Hematomas Imaging Appearance, Classification, and Clinical Significance SO JOURNAL OF THORACIC IMAGING LA English DT Article DE trauma; extrapleural hematoma; extrapleural fat sign; hemothorax; rib fracture ID FAT SIGN; INJURIES AB Purpose: We sought to identify radiologic and clinical findings associated with extrapleural hematomas (EPHs), to formulate an imaging-based classification system for EPHs, and to identify any radiologic or clinical factors associated with surgical intervention. Materials and Methods: Thirteen cases of EPH were gathered during the clinical review. An EPH was diagnosed on computed tomography (CT) if there was inward displacement of extrapleural fat by an intrathoracic peripheral fluid collection. The location and shape of each EPH were documented. For each case, the chest radiograph obtained in closest proximity to the CT acquisitions was also reviewed. The following additional data were also gathered: coexistent thoracic and nonthoracic injuries; mechanism of injury; treatment; and outcome. Results: In our series, 92% of the patients (12/13) were male. The average age of the affected patients was 61 years. Most cases were related to blunt trauma (85%, 11/13). All these patients had additional injuries; rib fractures were most consistently present (81%, 9/11). All cases could be further categorized based on the appearance of their CT scan as biconvex or nonconvex. Biconvex EPHs tended to be larger than other types (average size of 4211 mL) and required surgical intervention in 80% of patients (4/5). No specific treatment was necessary in patients with nonconvex EPHs. Conclusions: EPHs occur most commonly in high-energy blunt trauma; concomitant injuries are the rule, especially rib fractures. Biconvex hematomas tend to be large, likely resulting from high-pressure bleeding. Consequently, biconvex EPHs more often require surgical intervention. Nonconvex hematomas can usually be managed conservatively. C1 [Chung, Jonathan H.; Carr, Robert B.; Stern, Eric J.] Univ Washington Hosp, Dept Radiol, Seattle, WA USA. RP Chung, JH (reprint author), Massachusetts Gen Hosp, Dept Radiol, 30 Cambridge Pk,Dr 4106, Cambridge, MA 02140 USA. EM jonherochung@yahoo.com FU Siemens AG FX Dr Chung receives grant support from Siemens AG. No other authors have any conflict of interest to declare. NR 12 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0883-5993 J9 J THORAC IMAG JI J. Thorac. Imaging PD AUG PY 2011 VL 26 IS 3 BP 218 EP 223 DI 10.1097/RTI.0b013e3181ebeaba PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 796UW UT WOS:000293079600016 PM 20818277 ER PT J AU Strober, S Spitzer, TR Lowsky, R Sykes, M AF Strober, Samuel Spitzer, Thomas R. Lowsky, Robert Sykes, Megan TI Translational studies in hematopoietic cell transplantation: Treatment of hematologic malignancies as a stepping stone to tolerance induction SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Transplantation; Tolerance; Graft-vs-host disease; Graft-vs-leukemia; Rejection; Kidney transplantation ID TOTAL-LYMPHOID IRRADIATION; VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; RECIPIENT LEUKOCYTE INFUSIONS; KILLER T-CELLS; NONMYELOABLATIVE CONDITIONING REGIMEN; MIXED LYMPHOHEMATOPOIETIC CHIMERISM; DONOR-SPECIFIC TOLERANCE; LOW-DOSE PREDNISONE; LONG-TERM SURVIVAL AB Allogeneic hematopoietic cell transplantation (HCT) has most commonly been used to treat hematologic malignancies, where it is often the only potentially curative option available. The success of HCT has been limited by transplant-associated toxicities related to the conditioning regimens used and to the common immunologic consequence of donor T cell recognition of recipient alloantigens, graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has essentially precluded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. In this paper we review two approaches to HCT involving reduced intensity conditioning regimens that have been associated with improvements in safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting. These strategies have been applied in the first successful pilot studies for the induction of organ allograft tolerance in humans. Thus, we summarize an example of vertical translational research between animal models and humans and horizontal translation between two separate goals that culminated in the use of HCT to achieve allograft tolerance in humans. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Strober, Samuel] Stanford Univ, Dept Med, Sch Med, Div Rheumatol & Immunol, Stanford, CA 94305 USA. [Spitzer, Thomas R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Bone Marrow Transplantat,Dept Med, Boston, MA USA. [Lowsky, Robert] Stanford Univ, Dept Med, Sch Med, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. RP Sykes, M (reprint author), Columbia Univ, Coll Phys & Surg, Columbia Ctr Translat Immunol, Dept Med Surg & Microbiol Immunol,Med Ctr, 650 W 168th St,BB1512, New York, NY 10032 USA. EM megan.sykes@columbia.edu FU NCI, NHLBI, NIAID; Multiple Myeloma Research Foundation; Leukemia and Lymphoma Society; Immune Tolerance Network FX We thank Ms. Shavree Washington for expert assistance with the manuscript. The work was supported by the NCI, NHLBI, NIAID, the Multiple Myeloma Research Foundation, the Leukemia and Lymphoma Society and the Immune Tolerance Network. NR 82 TC 20 Z9 21 U1 0 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD AUG PY 2011 VL 23 IS 4 BP 273 EP 281 DI 10.1016/j.smim.2011.05.001 PG 9 WC Immunology SC Immunology GA 839XW UT WOS:000296403800006 PM 21705229 ER PT J AU Zhang, Y Wey, HY Nateras, OSE Peng, Q De La Garza, BH Duong, TQ AF Zhang, Yi Wey, Hsiao-Ying Nateras, Oscar San Emeterio Peng, Qi De La Garza, Bryan H. Duong, Timothy Q. TI Anatomical, Blood Oxygenation Level-Dependent, and Blood Flow MRI of Nonhuman Primate (Baboon) Retina SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE high-resolution MRI; blood oxygenation level-dependent; blood flow; choroid; retinal diseases; high-resolution fMRI; hyperoxia; hypercapnia ID OPTICAL COHERENCE TOMOGRAPHY; FUNCTIONAL MRI; LAMINAR SPECIFICITY; ENHANCED MRI; RESOLUTION; FMRI; RAT; DEGENERATION; HYPERCAPNIA; HYPEROXIA AB The goal of this study was to demonstrate high-resolution anatomical, blood oxygenation level-dependent, and blood flow MRI on large nonhuman primate retinas using a 3-Tesla clinical scanner as a first step toward translation. Baboon was chosen because of its evolutionary similarity to human. Anesthetized preparation, free of eye-movement artifacts, was used to evaluate clinical scanner hardware feasibility and optimize multimodal protocols for retinal MRI. Anatomical MRI (0.1 x 0.2 x 2.0 mm(3)) before contrast-agent injection detected three alternating bright-dark-bright layers. The hyperintense inner strip nearest to the vitreous was enhanced by an intravascular contrast agent, which likely included the ganglion and bipolar cell layer and the embedded retinal vessels. The hypointense middle strip showed no contrast enhancement, which likely included the avascular outer unclear layer and photoreceptor segments. The hyperintense outer strip showed contrast enhancement, which likely corresponded to the choroid vascular layer. In the posterior retina, the total thickness including the choroid was 617 +/-. 101 mu m ( standard deviation, n = 7). Blood oxygenation level-dependent functional MRI (0.3 x 0.6 x 2.0 mm(3)) of oxygen inhalation relative to air increased the signals by 6.5 +/- 1.4%. Basal blood flow (2 x 2 x 2 mm(3)) was 83 +/- 30 mL/100 g/min (air), and hypercapnia increased blood flow by 25 +/- 9% (P < 0.05). This study demonstrates multimodal MRI to image anatomy, physiology, and function on large nonhuman primate retinas using a clinical scanner, offering encouraging data to explore human applications. Magn Reson Med 66:546-554, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Zhang, Yi; Wey, Hsiao-Ying; Nateras, Oscar San Emeterio; Peng, Qi; De La Garza, Bryan H.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Zhang, Yi; Wey, Hsiao-Ying; Nateras, Oscar San Emeterio; Peng, Qi; De La Garza, Bryan H.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu RI Duong, Timothy/B-8525-2008; Wey, Hsiao-Ying/G-3031-2012 FU NIH/NEI [R01 EY014211, EY018855]; Department of Veterans Affairs; Translational Technology Research Grant via the Clinical Translational Science Award (CTSA) [UL1RR025767]; American Heart Association [EIA 0940104N] FX Grant sponsor: NIH/NEI; Grant numbers: R01 EY014211, EY018855; Grant sponsor: Department of Veterans Affairs; Grant sponsor: Translational Technology Research Grant via the Clinical Translational Science Award (CTSA); Grant number: UL1RR025767; Grant sponsor: American Heart Association's Established Investigator Award; Grant number: EIA 0940104N. NR 46 TC 5 Z9 5 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD AUG PY 2011 VL 66 IS 2 BP 546 EP 554 DI 10.1002/mrm.22853 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 799AV UT WOS:000293256800027 PM 21360746 ER PT J AU Tsai, PH Teng, E Liu, C Mendez, MF AF Tsai, Po-Heng Teng, Edmond Liu, Collin Mendez, Mario F. TI Posterior Cortical Atrophy: Evidence for Discrete Syndromes of Early-Onset Alzheimer's Disease SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE posterior cortical atrophy; Alzheimer's disease; visual processing; visual agnosia; Balint syndrome; Gerstmann syndrome ID METABOLIC DEFICITS; DEMENTIA; MEMORY AB Background: Posterior cortical atrophy (PCA) may represent a discrete syndrome of Alzheimer's disease (AD) rather than amnestic AD with visual deficits. Methods: We separated 30 patients with PCA based on ventral and dorsal visual symptoms using cluster analysis and analyzed the demographic, cognitive, and functional imaging features. Results: This analysis revealed subgroups of 26 dorsal and 4 ventral patients. The ventral subgroup had greater confrontational naming impairment, and the dorsal subgroup had greater hypofunction in the parietal regions. The PCA cohort had memory retrieval rather than encoding deficits, and clinical follow-up showed relative isolation of dorsal and ventral visual manifestations. Conclusion: These results support 2, mostly nonoverlapping syndromes in patients with PCA, with the commonest affecting the dorsal visual pathway; moreover, the memory retrieval difficulty in the patients with PCA was dissimilar to the amnestic pattern in typical AD. These results suggest that, in most cases, PCA syndromes are discrete clinical variants of AD. C1 [Tsai, Po-Heng; Teng, Edmond; Liu, Collin; Mendez, Mario F.] W Los Angeles VA Healthcare Ctr, Neurobehavior Unit, Los Angeles, CA 90073 USA. [Tsai, Po-Heng; Teng, Edmond; Liu, Collin; Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Teng, Edmond] VA Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. RP Tsai, PH (reprint author), W Los Angeles VA Healthcare Ctr, Neurobehavior Unit 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM potsai@ucla.edu FU VA Special Fellowship for Geriatric Neurology; NIA [K08 AG 34628, R01AG034499-03]; AFAR [K08 AG 34628]; John A. Hartford Foundation [K08 AG 34628]; Atlantic Philanthropies [K08 AG 34628]; Starr Foundation [K08 AG 34628]; VA Merit Review FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: P-HT was supported by a VA Special Fellowship for Geriatric Neurology. ET is supported by K08 AG 34628 (jointly sponsored by NIA, AFAR, the John A. Hartford Foundation, the Atlantic Philanthropies, the Starr Foundation, and an anonymous donor). MFM is supported by a VA Merit Review and NIA R01AG034499-03. NR 24 TC 12 Z9 12 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD AUG PY 2011 VL 26 IS 5 BP 413 EP 418 DI 10.1177/1533317511418955 PG 6 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA 836HQ UT WOS:000296102400009 PM 21831859 ER PT J AU Shannon, KM Rodgers, LH Chan-Smutko, G Patel, D Gabree, M Ryan, PD AF Shannon, Kristen M. Rodgers, Linda H. Chan-Smutko, Gayun Patel, Devanshi Gabree, Michele Ryan, Paula D. TI Which individuals undergoing BRACAnalysis need BART testing? SO CANCER GENETICS LA English DT Article DE BRCA1; BRCA2; gene; genetic testing ID OVARIAN-CANCER FAMILIES; NONPOLYPOSIS COLORECTAL-CANCER; PRIMARY-CARE PHYSICIANS; BREAST-CANCER; HIGH-RISK; GENOMIC REARRANGEMENTS; GERMLINE MUTATIONS; COST-EFFECTIVENESS; BRCA1 MUTATIONS; HISTORY AB Deleterious mutations in BRCA1 and BRCA2 include those identified by sequencing technology as well as large genomic rearrangements (LGR). The main testing laboratory in the United States, Myriad Genetics Laboratory (MGL), has defined criteria for inclusion of LGR testing (i.e., BRACAnalysis Rearrangement Test, or BART (TM)) when BRCA1 and BRCA2 testing is ordered. We were interested in determining how many of our patients with LGR mutations in BRCA1 and BRCA2 fulfilled these MGL criteria. A retrospective chart review was performed on all individuals who underwent genetic testing at our institution since August 2006. Individuals who underwent LGR testing were classified as either having or not having a LGR in BRCA1 or BRCA2. Each individual's history was classified as meeting MGL defined LGR criteria, meeting criteria using third-degree relatives, or not meeting criteria. A total of 257 BART tests were ordered at our institution from August 2006 to August 2009. Five individuals (1.9%) had an LGR mutation. Two LGR were identified in patients who met MGL defined LGR criteria. One LGR was identified in a patient that met MGL defined LGR criteria only when using third-degree relatives. Two LGR were identified in individuals who did not meet MGL defined criteria. LGR are present in individuals who do not have a high pretest probability of carrying a mutation in BRCA1 or BRCA2. These data suggest that when BRCA1 and BRCA2 genetic testing is performed, testing should always include LGR testing so that the results are the most comprehensive and reliable. C1 [Shannon, Kristen M.; Rodgers, Linda H.; Chan-Smutko, Gayun; Patel, Devanshi; Gabree, Michele] Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA 02114 USA. [Ryan, Paula D.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP Shannon, KM (reprint author), Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA 02114 USA. EM keshannon@partners.org FU MGH Cancer Center FX This research was funded by the MGH Cancer Center. NR 35 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2210-7762 J9 CANCER GENET-NY JI Cancer Genet. PD AUG PY 2011 VL 204 IS 8 BP 416 EP 422 DI 10.1016/j.cancergen.2011.07.005 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 833SN UT WOS:000295905300001 PM 21962891 ER PT J AU Leitner, H Bose-O'Reilly, S Oberaigner, W Mark, M Brezinka, C Siebert, U AF Leitner, H. Boese-O'Reilly, S. Oberaigner, W. Mark, M. Brezinka, C. Siebert, U. TI Perinatal Mortality by Mother's Country of Origin in Tyrol 2000-2008 SO GESUNDHEITSWESEN LA German DT Article DE perinatal mortality in Tyrol; migration; mother's country of origin; Latina Paradoxon ID INFANT-MORTALITY; NETHERLANDS; MIGRATION; ETHNICITY; CARE; MIGRANTS; DELIVERY; GERMANY; HEALTH; WOMEN AB Introduction: This study analyses for the first time the Tyrolean perinatal mortality stratified by the country of origin of the mother. Data of the Tyrolean birth registry were evaluated from 2000-2008. The aim of our study was to analyse differences in perinatal mortality according to the country of origin of the mother. Methods: 58 787 single births were assessed between the years 2000-2008. Mothers with similar experiences of how to access the healthcare system were aggregated into 5 groups: (1) "Tyrol/Austria", (2) "western Europe/West", (3) "former Yugoslavia/eastern Europe", (4) "Turkey" and (5) "other countries". The odds ratio for perinatal mortality according to the country of origin of the mother was calculated in a multivariate model. The following independent variables were included: age of mother at birth, parity, housewife during pregnancy, week of gestation at the first check-up visit, smoking, preterm delivery and weight of the newborn. Results: The number of mothers of Tyrolean/Austrian origin decreased over the years by 2% whereas the number of mothers from Western Europe/West increased by 3%. The other migration groups remained constant or were slightly decreased. In the multivariate model; the perinatal mortality [odds ratio (CI)] was for the subgroups "Turkey"1.06 (0.61-1.83) and for "western Europe/West"1.09 (0.64-1.86), and therefore almost identical with the reference subgroup "Tyrol/Austria"(OR = 1); the perinatal mortality was significantly increased with 2.14 (1.37-3.34) for the subgroup "former Yugoslavia/eastern Europe and for the subgroup "other countries" 2.54 (1.21-5.36). The variables "age under 18 years"OR 1.99 (0.80-4.93) and "mulitpara"OR 1.30 (0.96-1.74) were not significantly increased. Significantly increased was "preterm delivery"OR 4.53 (2.80-7.33) and "low birthweight" (<1 500 g) OR 53.60 (32.02-89.73) and 1 500 to 2 499 g OR 4.85 (2.96-7.96). There are considerable differences comparing the odds ratios between the 5 subgroups for perinatal mortality. The subgroups "Turkey" and "western Europe/West" have a similar odds ratio compared to the reference group "Tyrol/Austria". The subgroups "former Yugoslavia" and "other countries" have a significantly increased perinatal mortality (OR 2-2.5). Conclusion: The good outcome of the mothers from "Turkey" can be seen as similar to the "Latina paradoxon", which means a better outcome of pregnancy and birth of mothers from "Turkey", even though they are more comparable with other migrant groups in some risk factors, such as a lower socioeconomic standard, late check-ups, language difficulties and cultural factors. A single case analysis would be necessary to examine the exact causes. C1 [Leitner, H.; Oberaigner, W.] IET Inst Klin Epidemiol Tilak, Innsbruck, Austria. [Leitner, H.; Boese-O'Reilly, S.; Oberaigner, W.; Siebert, U.] UMIT Univ Hlth Sci Med Informat & Technol, UMIT Inst Publ Hlth Med Decis Making & Hlth Techn, Dept Publ Hlth Informat Syst & Hlth Technol Asses, Hall I T, Austria. [Mark, M.] TILAK Tiroler Landeskrankenanstalten, Innsbruck, Austria. [Brezinka, C.] Univ Klin Frauenheilkunde & Geburtshilfe, Innsbruck, Austria. [Siebert, U.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Program,Inst Technol Assessment, Boston, MA USA. [Siebert, U.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Siebert, U.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. RP Leitner, H (reprint author), Geburtenregister Osterreich Inst Klin Epidemiol T, Anichstr 35, A-6020 Innsbruck, Austria. EM Hermann.Leitner@tilak.at NR 31 TC 1 Z9 1 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0941-3790 J9 GESUNDHEITSWESEN JI Gesundheitswesen PD AUG PY 2011 VL 73 IS 8-9 BP 469 EP 476 DI 10.1055/s-0030-1270501 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 829VZ UT WOS:000295614600002 PM 21305452 ER PT J AU Zhang, Q Yan, XG Strongman, GE AF Zhang, Quan Yan, Xiangguo Strongman, Gary E. TI Development of motion resistant instrumentation for ambulatory near-infrared spectroscopy SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE wearable; near-infrared spectroscopy; laser; tissue oxygenation; parabolic flight; high altitude; motion artifacts ID VALSALVA MANEUVER; FOCAL CHANGES; OXYGENATION; ELECTROCARDIOGRAPHY; CONSCIOUSNESS; CIRCULATION; PERFORMANCE; TECHNOLOGY; SATURATION; ACCURACY AB Ambulatory near-infrared spectroscopy (aNIRS) enables recording of systemic or tissue-specific hemodynamics and oxygenation during a person's normal activities. It has particular potential for the diagnosis and management of health problems with unpredictable and transient hemodynamic symptoms, or medical conditions requiring continuous, long-duration monitoring. aNIRS is also needed in conditions where regular monitoring or imaging cannot be applied, including remote environments such as during spaceflight or at high altitude. One key to the successful application of aNIRS is reducing the impact of motion artifacts in aNIRS recordings. In this paper, we describe the development of a novel prototype aNIRS monitor, called NINscan, and our efforts to reduce motion artifacts in aNIRS monitoring. Powered by 2 AA size batteries and weighting 350 g, NINscan records NIRS, ECG, respiration, and acceleration for up to 14 h at a 250 Hz sampling rate. The system's performance and resistance to motion is demonstrated by long term quantitative phantom tests, Valsalva maneuver tests, and multiparameter monitoring during parabolic flight and high altitude hiking. To the best of our knowledge, this is the first report of multiparameter aNIRS monitoring and its application in parabolic flight. (C) 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.3615248] C1 [Zhang, Quan; Strongman, Gary E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neural Syst Grp, Charlestown, MA 02129 USA. [Yan, Xiangguo] Xi An Jiao Tong Univ, Educ Minist, Key Lab Biomed Informat Engn, Xian 710049, Shaanxi, Peoples R China. RP Zhang, Q (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neural Syst Grp, 13th St,Bldg 149,Room 2651, Charlestown, MA 02129 USA. EM qzhang@nmr.mgh.harvard.edu FU National Space Biomedical Research Institute (NSBRI) through NASA [NCC 9-58]; NIH [R21-EB002416] FX This work was supported by the National Space Biomedical Research Institute (NSBRI) through NASA NCC 9-58, as well as NIH R21-EB002416. The authors would like to thank Chen Hui and Liu Zhonghua for their help with technology development, Solomon G. Diamond for the helpful discussion of quantification of motion resistance, Dr. Erika Wagner, Dr. Thomas Zeffiro, and Dan Buck land for their extensive assistance coordinating and conducting the parabolic flight experiment, and Dr. Stuart Harris, Erika Williams, Michael Patz and all of Team Uhuru for their help in data acquisition during the ascent of Mt. Kilimanjaro. NR 46 TC 11 Z9 11 U1 0 U2 6 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD AUG PY 2011 VL 16 IS 8 AR 087008 DI 10.1117/1.3615248 PG 12 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 827PX UT WOS:000295441500035 PM 21895335 ER PT J AU Shen, C Beroukhim, R Schumacher, SE Zhou, J Chang, M Signoretti, S Kaelin, WG AF Shen, Chuan Beroukhim, Rameen Schumacher, Steven E. Zhou, Jing Chang, Michelle Signoretti, Sabina Kaelin, William G., Jr. TI Genetic and Functional Studies Implicate HIF1 alpha as a 14q Kidney Cancer Suppressor Gene SO CANCER DISCOVERY LA English DT Article ID RENAL-CELL CARCINOMA; HYPOXIA-INDUCIBLE FACTOR; COPY-NUMBER ALTERATIONS; HIPPEL-LINDAU PROTEIN; FACTOR (HIF)-1-ALPHA; IN-VIVO; EXPRESSION; HIF-2-ALPHA; LINES; HIF AB Kidney cancers often delete chromosome 3p, spanning the VHL tumor suppressor gene, and chromosome 14q, which presumably harbors >= 1 tumor suppressor genes. pVHL inhibits the hypoxia-inducible transcription factor (HIF), and HIF2 alpha is a kidney cancer oncoprotein. In this article, we identify focal, homozygous deletions of the HIF1 alpha locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1 alpha suppresses renal carcinoma growth, but the products of these altered loci do not. Conversely, downregulation of HIF1 alpha in HIF1 alpha-proficient lines promotes tumor growth. HIF1a activity is diminished in 14q-deleted kidney cancers, and all somatic HIF1 alpha mutations identified in kidney cancers tested to date are loss of function. Therefore, HIF1 alpha has the credentials of a kidney cancer suppressor gene. SIGNIFICANCE: Deletion of 14q is a frequent event in clear cell renal carcinoma and portends a poor prognosis. In this study, we provide genetic and functional evidence that HIF1 alpha is a target of 14q loss in kidney cancer. Cancer Discovery; 1(3);222-35. (C) 2011 AACR. C1 [Shen, Chuan; Beroukhim, Rameen; Signoretti, Sabina; Kaelin, William G., Jr.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Beroukhim, Rameen; Schumacher, Steven E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Beroukhim, Rameen; Zhou, Jing; Kaelin, William G., Jr.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Chang, Michelle; Signoretti, Sabina] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Beroukhim, Rameen; Schumacher, Steven E.; Kaelin, William G., Jr.] Broad Inst, Cambridge, MA USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Mayer Bldg,Room 457, Boston, MA 02215 USA. EM william_kaelin@dfci.harvard.edu RI Schumacher, Steven/E-9821-2013 OI Schumacher, Steven/0000-0002-6819-5647 FU NIH; Howard Hughes Medical Institute; Doris Duke Charitable Foundation; Dana-Farber/Harvard Cancer Center; Genentech FX This work was supported by NIH (W. G. Kaelin), Howard Hughes Medical Institute (W. G. Kaelin), Doris Duke Charitable Foundation (W. G. Kaelin), Dana-Farber/Harvard Cancer Center Kidney Cancer Career Development Award (C. Shen; funded by Genentech). W. G. Kaelin is a Doris Duke Distinguished Clinical Investigator and Howard Hughes Medical Institute Investigator. NR 56 TC 108 Z9 109 U1 4 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD AUG PY 2011 VL 1 IS 3 BP 222 EP 235 DI 10.1158/2159-8290.CD-11-0098 PG 14 WC Oncology SC Oncology GA 832DY UT WOS:000295783300020 PM 22037472 ER PT J AU Rodrik-Outmezguine, VS Chandarlapaty, S Pagano, NC Poulikakos, PI Scaltriti, M Moskatel, E Baselga, J Guichard, S Rosen, N AF Rodrik-Outmezguine, Vanessa S. Chandarlapaty, Sarat Pagano, Nen C. Poulikakos, Poulikos I. Scaltriti, Maurizio Moskatel, Elizabeth Baselga, Jose Guichard, Sylvie Rosen, Neal TI mTOR Kinase Inhibition Causes Feedback-Dependent Biphasic Regulation of AKT Signaling SO CANCER DISCOVERY LA English DT Article ID MAMMALIAN TARGET; BREAST-CANCER; TUMOR-CELLS; PATHWAY; RAPAMYCIN; PHOSPHORYLATION; INSULIN; COMPLEX; RICTOR; ACTIVATION AB mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways. SIGNIFICANCE: The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways. Cancer Discovery; 1(3);248-59. (C) 2011 AACR. C1 [Rosen, Neal] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, Dept Med, New York, NY 10065 USA. [Rodrik-Outmezguine, Vanessa S.; Chandarlapaty, Sarat; Pagano, Nen C.; Poulikakos, Poulikos I.; Moskatel, Elizabeth; Rosen, Neal] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10065 USA. [Scaltriti, Maurizio; Baselga, Jose] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Guichard, Sylvie] AstraZeneca, Macclesfield, Cheshire, England. RP Rosen, N (reprint author), Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, Dept Med, 1275 York Ave, New York, NY 10065 USA. EM rosenn@mskcc.org FU NIH [5P01CA094060-08, 5P50CA086438-10, 5P50CA092629-10]; Breast Cancer Research Foundation FX This work is supported by NIH Program Grants 5P01CA094060-08, 5P50CA086438-10, and 5P50CA092629-10 and by the Breast Cancer Research Foundation. NR 44 TC 174 Z9 175 U1 2 U2 17 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD AUG PY 2011 VL 1 IS 3 BP 248 EP 259 DI 10.1158/2159-8290.CD-11-0085 PG 12 WC Oncology SC Oncology GA 832DY UT WOS:000295783300022 PM 22140653 ER PT J AU Liu, XZ Choy, E Hornicek, FJ Yang, SH Yang, C Harmon, D Mankin, H Duan, ZF AF Liu, Xianzhe Choy, Edwin Hornicek, Francis J. Yang, Shuhua Yang, Cao Harmon, David Mankin, Henry Duan, Zhenfeng TI ROCK1 as a Potential Therapeutic Target in Osteosarcoma SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE kinase; osteosarcoma; ROCK1 ID KINASE INHIBITOR; RHO-GTPASES; CANCER; CHEMOTHERAPY; EXTREMITY; SURVIVAL; RELAPSE AB Osteosarcoma is the most common primary malignancy of bone. Patients with localized disease are routinely treated with surgery and chemotherapy. Unfortunately, many of these patients eventually relapse even after high-dose pre- and postoperative chemotherapy. Upon recurrence of the tumor locally or distantly, they have limited treatment options that are usually unsuccessful. Our prior studies screening lentiviral shRNA libraries, searching for kinases involved in osteosarcoma cell growth and proliferation have identified the Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as a possible hit. We show in this study that ROCK1 is highly expressed in various tumor cell lines and tumor tissues from osteosarcoma patients. ROCK1 knockdown by synthetic siRNA decreases cell proliferation, viability and induces apoptosis in osteosarcoma cell lines KHOS and U-2OS. Finally, we established the relationship between expression levels of ROCK1 and clinical prognosis in osteosarcoma patients by using immunohistochemistry. There were significant differences in overall survival between cohorts of patients with ROCK1 levels categorized as high-staining, moderate-staining, and low-staining. High levels of ROCK1 were associated with poor outcomes in clinical osteosarcoma. These findings suggest that knockdown of ROCK1 inhibits proliferation and induces apoptosis in osteosarcoma cell lines. ROCK1 may be a promising therapeutic target for the treatment of osteosarcoma patients. (C) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29: 1259-1266, 2011 C1 [Liu, Xianzhe; Hornicek, Francis J.; Mankin, Henry; Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Liu, Xianzhe; Hornicek, Francis J.; Mankin, Henry; Duan, Zhenfeng] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Liu, Xianzhe; Choy, Edwin; Hornicek, Francis J.; Harmon, David; Mankin, Henry; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. [Liu, Xianzhe; Yang, Shuhua; Yang, Cao] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Orthopaed Surg, Wuhan 430022, Peoples R China. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. EM zduan@partners.org OI Choy, Edwin/0000-0001-9896-8084 FU Gattegno and Wechsler funds; Kenneth Stanton Fund; Jennifer Hunter Yates Foundation; Sarcoma Foundation of America FX This project was supported, in part, by a grant from the Gattegno and Wechsler funds. Support has also been provided by the Kenneth Stanton Fund and the Jennifer Hunter Yates Foundation. Dr. Duan is supported, in part, through a grant from Sarcoma Foundation of America. NR 23 TC 38 Z9 40 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD AUG PY 2011 VL 29 IS 8 BP 1259 EP 1266 DI 10.1002/jor.21403 PG 8 WC Orthopedics SC Orthopedics GA 777KQ UT WOS:000291614800017 PM 21387396 ER PT J AU Qu, J Wang, DY Grosskreutz, CL AF Qu, Juan Wang, Danyi Grosskreutz, Cynthia L. TI Mechanisms of retinal ganglion cell injury and defense in glaucoma SO EXPERIMENTAL EYE RESEARCH LA English DT Reprint DE apoptosis; neuroprotection; caspase; calcineurin; calpain ID NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; OPTIC-NERVE DAMAGE; ELEVATED INTRAOCULAR-PRESSURE; CHRONIC OCULAR HYPERTENSION; EARLY GENE-EXPRESSION; OPEN-ANGLE GLAUCOMA; LONG-TERM SURVIVAL; NEUROTROPHIC FACTOR; ADULT-RATS AB Glaucoma is a disease in which retinal ganglion cells (RGCs) die leading ultimately to blindness. Over the past decade and a half, information has begun to emerge regarding specific molecular responses of the retina to conditions of elevated intraocular pressure (IOP). It is now clear that the state of the RGC in glaucoma depends on a balance of pro-survival and pro-death pathways in the retina and details of these responses are still being worked out. In this review, we will discuss the evidence supporting the involvement of specific apoptotic cascades as well as the insults that trigger RGC apoptosis. In addition, we will present evidence supporting the existence of endogenous protective mechanisms as well as exogenous neuroprotective strategies. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Qu, Juan; Wang, Danyi; Grosskreutz, Cynthia L.] Harvard Univ, Dept Ophthalmol, Howe Lab Ophthalmol, Massachusetts Eye & Ear Infirm,Med Sch, Boston, MA 02114 USA. RP Grosskreutz, CL (reprint author), Novartis Inst Biomed Res, 220 Massachusetts Ave, Cambridge, MA 01239 USA. EM cynthia_grosskreutz@meei.harvard.edu NR 127 TC 0 Z9 0 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD AUG PY 2011 VL 93 IS 2 SI SI BP 48 EP 53 PG 6 WC Ophthalmology SC Ophthalmology GA 824KX UT WOS:000295201900015 ER PT J AU Brunye, TT Ditman, T Mahoney, CR Taylor, HA AF Brunye, Tad T. Ditman, Tali Mahoney, Caroline R. Taylor, Holly A. TI Better you than I: Perspectives and emotion simulation during narrative comprehension SO JOURNAL OF COGNITIVE PSYCHOLOGY LA English DT Article DE Action understanding; Discourse comprehension; Embodied cognition; Emotion; Language; Perspective taking ID LANGUAGE COMPREHENSION; READING-COMPREHENSION; ENVIRONMENTS; MODELS AB Recent studies suggest that readers develop richer multidimensional situation models when they mentally participate as characters in narrative worlds. The present study tested this by examining whether readers differentially represent situational elements when they read narratives using the pronoun "you" or "I" to describe a protagonist, and whether the pronoun "you" would make readers more likely to react to the emotional valence of narratives, embodying the affective states of protagonists. Response times and error rates to comprehension questions demonstrated a richer representation of the spatial organisation of narrative worlds with the pronoun "you" relative to "I". Further, readers were more emotionally reactive to valenced narrative events with the pronoun "you". Results demonstrate that readers differentially represent narrative worlds as a function of perspective, developing richer spatial mental models of layouts and a greater internalisation of emotional events when directly addressed as a protagonist. C1 [Brunye, Tad T.; Ditman, Tali; Mahoney, Caroline R.; Taylor, Holly A.] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Ditman, Tali] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Brunye, Tad T.; Mahoney, Caroline R.] USA, NSRDEC, Natick, MA 01760 USA. RP Brunye, TT (reprint author), Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. NR 22 TC 12 Z9 12 U1 0 U2 9 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 2044-5911 J9 J COGN PSYCHOL JI J. Cogn. Psychol. PD AUG PY 2011 VL 23 IS 5 BP 659 EP 666 DI 10.1080/20445911.2011.559160 PG 8 WC Psychology, Experimental SC Psychology GA 823ST UT WOS:000295147500012 ER PT J AU Sherwood, JE Fraser, S Citron, DM Wexler, H Blakely, G Jobling, K Patrick, S AF Sherwood, Jeffrey E. Fraser, Susan Citron, Diane M. Wexler, Hana Blakely, Garry Jobling, Kelly Patrick, Sheila TI Multi-drug resistant Bacteroides fragilis recovered from blood and severe leg wounds caused by an improvised explosive device (IED) in Afghanistan SO ANAEROBE LA English DT Article DE Bacteroides fragilis; Multi-drug resistance; nimE; Plasmid; Linezolid ID METRONIDAZOLE RESISTANCE; MECHANISM; CFIA AB This report summarizes the case of a 23 year-old otherwise healthy male that was injured in an improvised explosive device (IED) blast in support of Operation Enduring Freedom (OEF). He sustained bilateral open tibia and fibula fractures in the setting of being exposed to water contaminated with raw sewage. Despite long-term carbapenem therapy, the patient's wounds were repeatedly noted to have purulent drainage during surgical debridement and cultures from these wounds were persistently positive for Bacteroides fragilis. Apparent clinical failure persisted despite the addition of metronidazole to his regimen and an eventual trial of tigecycline. Susceptibility testing of the B. fragilis isolate was performed and resistance to penicillin, clindamycin,metronidazole, cefoxitin, meropenem, imipenem, piperacillin/tazobactam, and tigecycline was confirmed. The presence of a nimE gene on a potentially transferrable plasmid was also confirmed by plasmid sequencing. The only antibiotics that displayed in vitro susceptibility were moxifloxacin and linezolid. These antibiotics were initiated in combination with aggressive irrigation and serial surgical debridement. Conversion to left-sided internal fixation became feasible and his left lower extremity was salvaged without residual evidence of infection. The patient completed an eight week course of combination moxifloxacin and linezolid therapy without adverse event. This B. fragilis isolate displayed simultaneous high-level resistance to multiple antibiotics routinely utilized in anaerobic infections. This was evidenced by clinical failure, in vitro susceptibility testing, and demonstration of genes associated with resistance mechanisms. This case warrants review not only due to the rarity of this event but also the potential implications regarding anaerobic infections in traumatic wounds and the success of a novel treatment regimen utilizing combination therapy with moxifloxacin and linezolid. Published by Elsevier Ltd. C1 [Sherwood, Jeffrey E.; Fraser, Susan] Walter Reed Army Med Ctr, Dept Infect Dis, Washington, DC 20307 USA. [Citron, Diane M.] RM Alden Res Lab, Culver City, CA 90230 USA. [Wexler, Hana] W Los Angeles VA Med Ctr, Los Angeles, CA 90076 USA. [Blakely, Garry; Jobling, Kelly] Univ Edinburgh, Inst Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. [Patrick, Sheila] Queens Univ Belfast, Ctr Infect & Immun, Sch Med Dent & Biomed Sci, Belfast BT9 7BL, Antrim, North Ireland. RP Sherwood, JE (reprint author), Walter Reed Army Med Ctr, Dept Infect Dis, Ward 63,6900 Georgia Ave,NW, Washington, DC 20307 USA. EM jeffrey.e.sherwood@us.army.mil; susan.fraser@us.army.mil; d.m.citron@att.net; s.patrick@qub.ac.uk FU George-town University; R.M. Alden Research Laboratory; Walter Reed Army Medical Center FX The authors would like to thank Drs. Itzhak Brook of George-town University, Ellie J.C. Goldstein of the R.M. Alden Research Laboratory, and Gerald Van Horn of Walter Reed Army Medical Center for their contributions, support, and clinical input regarding this case. NR 18 TC 26 Z9 27 U1 2 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1075-9964 J9 ANAEROBE JI Anaerobe PD AUG PY 2011 VL 17 IS 4 SI SI BP 152 EP 155 DI 10.1016/j.anaerobe.2011.02.007 PG 4 WC Microbiology SC Microbiology GA 824ZF UT WOS:000295240000005 PM 21376821 ER PT J AU Rege, TA Wagner, AJ Corless, CL Heinrich, MC Hornick, JL AF Rege, Tanya A. Wagner, Andrew J. Corless, Christopher L. Heinrich, Michael C. Hornick, Jason L. TI "Pediatric-Type" Gastrointestinal Stromal Tumors Are SDHB Negative ("Type 2") GISTs Response SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Letter ID OF-THE-LITERATURE; YOUNG-ADULTS; CHILDREN C1 [Rege, Tanya A.; Hornick, Jason L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Wagner, Andrew J.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Corless, Christopher L.] Portland VA Med Ctr, Dept Pathol, Portland, OR USA. [Heinrich, Michael C.] Portland VA Med Ctr, Div Hematol & Oncol, Portland, OR USA. [Corless, Christopher L.; Heinrich, Michael C.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. RP Rege, TA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. NR 9 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2011 VL 35 IS 8 BP 1247 EP 1248 DI 10.1097/PAS.0b013e3182237757 PG 3 WC Pathology; Surgery SC Pathology; Surgery GA 792GD UT WOS:000292728200023 ER PT J AU Khor, TS Shen, J Lauwers, GY Deshpande, V AF Khor, Tze Sheng Shen, Jian Lauwers, Gregory Y. Deshpande, Vikram TI Comment on the Article by Chetty et al on Combined Classical Carcinoid and Goblet Cell Carcinoid Tumor: A New Morphologic Variant of Carcinoid Tumor of the Appendix. (Am J Surg Pathol 34(8):1163-1167) SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Letter ID CYTOKERATIN-20 C1 [Khor, Tze Sheng; Lauwers, Gregory Y.; Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lauwers, Gregory Y.; Deshpande, Vikram] Harvard Univ, Sch Med, Boston, MA USA. [Shen, Jian] Providence Hlth & Serv, Dept Pathol, Providence Portland Med Ctr, Portland, OR USA. RP Khor, TS (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 7 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2011 VL 35 IS 8 BP 1248 EP 1250 DI 10.1097/PAS.0b013e318223496e PG 4 WC Pathology; Surgery SC Pathology; Surgery GA 792GD UT WOS:000292728200024 PM 21753706 ER PT J AU Li, XK Villard, JW Ouyang, YJ Michalek, JE Jabara, R Sims, D Kemp, N Glynn, T Banas, C Bailey, SR Feldman, MD AF Li, Xiankai Villard, Joseph W. Ouyang, Yongjian Michalek, Joel E. Jabara, Refat Sims, Dan Kemp, Nate Glynn, Tim Banas, Christopher Bailey, Steven R. Feldman, Marc D. TI Safety and efficacy of frequency domain optical coherence tomography in pigs SO EUROINTERVENTION LA English DT Article DE optical coherence tomography; safety; efficacy; frequency domain ID CORONARY STENT SYSTEM; NANOTHIN POLYZENE-F; ARTERY LESIONS; TRIAL; PLAQUES AB Aims: To determine the safety and efficacy of frequency domain OCT, which can scan at much higher rates and make it possible to avoid an occlusion balloon and image during an angiographic injection through guide catheter. The catheters have diameters ranging from 2.7 to 3.5 Fr. The presence of the imaging catheter increases fluid resistance to the injection of viscous solutions necessary for clearing the blood. Methods and results: The Volcano 3.5 Fr frequency domain OCT catheter system was investigated for safety in (a) n=10 porcine studies using acute and 30-day histology, and (b) for efficacy in n=9 in vivo porcine coronary arteries. We found: (a) frequency domain imaging is safe in the porcine model using histology as an endpoint; (b) the addition of a viscous contrast (iodixonal) to saline is superior for lumen clearance compared to saline alone; (c) hand injection, 4 ml/sec, and 6 ml/sec power injection all provided similar vessel wall clearance; (d) the anticipated loss of vessel wall visualisation with left main injection (due to half the injectate in the non-imaged vessel) was not evident in proximal and middle coronary artery OCT catheter positions. Conclusions: Frequency domain OCT is safe and efficacious in the porcine model. C1 [Li, Xiankai; Villard, Joseph W.; Bailey, Steven R.; Feldman, Marc D.] Univ Texas Hlth Sci Ctr San Antonio, Janey Briscoe Div Cardiol, San Antonio, TX 78229 USA. [Li, Xiankai] Tongji Univ, Sch Med, Dept Cardiol, Shanghai Peoples Hosp 10, Shanghai 200092, Peoples R China. [Jabara, Refat] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Jabara, Refat] St Josephs Translat Res Inst, Atlanta, GA USA. [Sims, Dan; Kemp, Nate; Glynn, Tim; Banas, Christopher] Volcano Corp, Billerica, MA USA. [Feldman, Marc D.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Feldman, MD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Janey Briscoe Div Cardiol, 7703 Floyd Curl Dr,Mail Code 7872, San Antonio, TX 78229 USA. EM feldmanm@uthscsa.edu FU Volcano Corporation, San Diego, CA, USA; VA Merit Grant FX This study was supported in part by Volcano Corporation, San Diego, CA, USA and a VA Merit Grant (MDF) NR 18 TC 2 Z9 2 U1 0 U2 1 PU EUROPA EDITION PI TOULOUSE CEDEX 6 PA 5, RUE SAINT-PANTALEON, BP 61508, TOULOUSE CEDEX 6, 31015, FRANCE SN 1774-024X J9 EUROINTERVENTION JI EuroIntervention PD AUG PY 2011 VL 7 IS 4 BP 497 EP 504 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 822EB UT WOS:000295025600014 PM 21764669 ER PT J AU Huang, Q Fan, XS Agoston, AT Feng, AI Yu, HP Lauwers, G Zhang, LH Odze, RD AF Huang, Qin Fan, Xiangshan Agoston, Agoston T. Feng, Anning Yu, Huiping Lauwers, Gregory Zhang, Lihua Odze, Robert D. TI Comparison of gastro-oesophageal junction carcinomas in Chinese versus American patients SO HISTOPATHOLOGY LA English DT Article DE American; carcinoma; Chinese; gastric cardia; gastro-oesophageal; oesophagus; stomach ID BODY-MASS INDEX; GASTRIC CARDIA; ESOPHAGOGASTRIC JUNCTION; BARRETTS-ESOPHAGUS; HELICOBACTER-PYLORI; INTESTINAL METAPLASIA; DISTAL ESOPHAGEAL; REFLUX DISEASE; ADENOCARCINOMA; RISK AB Aims: To compare the clinical and pathological features of gastro-oesophageal junction (GEJ) carcinomas in Chinese and American patients. Methods and results: Eighty consecutive patients with a GEJ carcinoma (43 from mainland China, and 37 from the USA) were evaluated for association with Barrett oesophagus (BO), chronic Helicobacter pylori gastritis, intestinal metaplasia, and outcome. GEJ carcinomas were defined as tumours that were located within 20 mm of, and crossed, the GEJ. Overall, GEJ carcinomas from Chinese patients revealed significantly more frequent location in the proximal stomach, higher pathological stage, larger size, younger patient age, and association with chronic H. pylori gastritis. In contrast, GEJ cancers from American patients showed a strong association with distal oesophageal location, BO, and associated intestinal metaplasia and dysplasia. Pathologically, GEJ carcinomas from American patients were predominantly adenocarcinomas, whereas Chinese patients showed a higher proportion of mucinous, adenosquamous, acinar or neuroendocrine tumours. Overall, 3- and 5-year survival rates were statistically similar between both patient groups, but upon multivariate analysis, Chinese patients showed statistically better survival rates for stage III tumours. Conclusions: Most GEJ carcinomas in patients from China represent proximal gastric cancers associated with chronic H. pylori gastritis, and BO-associated carcinomas are rare among this patient population. C1 [Agoston, Agoston T.; Odze, Robert D.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Huang, Qin; Fan, Xiangshan; Yu, Huiping; Zhang, Lihua] Nanjing Drum Tower Hosp, Dept Pathol, Nanjing, Peoples R China. [Huang, Qin] Boston Vet Affairs Healthcare Syst, Dept Pathol, Boston, MA USA. [Huang, Qin; Lauwers, Gregory; Odze, Robert D.] Harvard Univ, Sch Med, Boston, MA USA. [Feng, Anning] Nanjing Med Univ, Nanjing, Peoples R China. [Lauwers, Gregory] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Odze, RD (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM rodze@partners.org FU Department of Science and Technology [200601050]; Nanjing Drum Tower Hospital, China FX The major findings of this study were presented at the 2009 USCAP annual meeting in Boston, USA, and published in abstract form in Modern Pathology. This project was financed partially by a grant from the Science and Technical Development Project of Nanjing City, Department of Science and Technology (No. 200601050), and a special grant from the Nanjing Drum Tower Hospital, China. NR 46 TC 17 Z9 23 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0309-0167 J9 HISTOPATHOLOGY JI Histopathology PD AUG PY 2011 VL 59 IS 2 BP 188 EP 197 DI 10.1111/j.1365-2559.2011.03924.x PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 818WJ UT WOS:000294786300004 PM 21884197 ER PT J AU Honma, N Arai, T Takubo, K Younes, M Tanaka, N Mieno, MN Tamura, K Ikeda, S Sawabe, M Muramatsu, M AF Honma, Naoko Arai, Tomio Takubo, Kaiyo Younes, Mamoun Tanaka, Noriko Mieno, Makiko Naka Tamura, Kohei Ikeda, Shinobu Sawabe, Motoji Muramatsu, Masaaki TI Oestrogen receptor-beta CA repeat polymorphism is associated with incidence of colorectal cancer among females SO HISTOPATHOLOGY LA English DT Article DE CA repeat polymorphism; colorectal cancer; female; oestrogen receptor-beta ID ABSENT HMLH1 EXPRESSION; BREAST-CANCER; ER-BETA; MICROSATELLITE INSTABILITY; GENE POLYMORPHISM; COLON-CANCER; CARCINOMA; CLONING; ADENOCARCINOMA; SURVIVAL AB Aims: Increasing evidence suggests an association between oestrogens and colorectal cancer. Oestrogen receptor beta, ER-beta, putatively plays a pathobiological role in colorectal cancer as colorectal epithelial cells frequently express ER-beta. The aim was to elucidate the association of the dinucleotide (CA) repeat polymorphism of the ER-beta gene (ESR2) with colorectal cancer. Methods and results: Deoxyribonucleic acids extracted from the renal cortex of 1488 Japanese autopsies with complete clinical/pathological data were studied. CA repeat polymorphism was determined by polymerase chain reaction using fluorescein-labelled primers. Patients were divided into three genotype groups according to the number of CA repeats of each allele S < 22, L 22); SS (with two S alleles), SL (with one each S and L allele) and LL (with two L alleles). The presence/absence of colorectal cancers was determined by examining the clinical records and autopsy material. The incidence of colorectal cancer was significantly different according to the ESR2 CA repeat genotype only among females (SS, 37/202 = 18.3%; SL, 19/332 = 5.7%; LL, 5/155 = 3.2%, P < 0.0001). Immunohistochemically, cancers in females with the SS genotype, but not the SL genotype, frequently expressed the C-terminus portion of ER-beta 1 (wild-type ER-beta). Conclusions: A role for ESR2 CA repeat polymorphism in the pathogenesis of colorectal cancer among females is suggested. C1 [Honma, Naoko] Tokyo Metropolitan Inst Gerontol, Res Team Geriatr Pathol, Itabashi Ku, Tokyo 1730015, Japan. [Arai, Tomio; Sawabe, Motoji] Tokyo Metropolitan Inst Gerontol, Dept Pathol, Tokyo 1730015, Japan. [Younes, Mamoun] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Tanaka, Noriko] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Tanaka, Noriko] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mieno, Makiko Naka] Jichi Med Univ, Ctr Informat, Dept Med Informat, Shimotsuke, Japan. [Tamura, Kohei; Ikeda, Shinobu; Muramatsu, Masaaki] Tokyo Med & Dent Univ, Med Res Inst, Dept Mol Epidemiol, Tokyo, Japan. RP Honma, N (reprint author), Tokyo Metropolitan Inst Gerontol, Res Team Geriatr Pathol, Itabashi Ku, Sakaecho 35-2, Tokyo 1730015, Japan. EM nhonma@tmig.or.jp FU Japan Society for the Promotion of Science [19590376] FX This work was supported by a Grant-in-Aid for Scientific Research no. 19590376 from the Japan Society for the Promotion of Science. We thank Sachiko Nishimura and the technical staff of the Department of Pathology, Tokyo Metropolitan Geriatric Hospital for their excellent technical assistance. NR 32 TC 7 Z9 7 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0309-0167 J9 HISTOPATHOLOGY JI Histopathology PD AUG PY 2011 VL 59 IS 2 BP 216 EP 224 DI 10.1111/j.1365-2559.2011.03914.x PG 9 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 818WJ UT WOS:000294786300007 PM 21884200 ER PT J AU Zhao, XS Fiske, B Kawakami, A Li, JY Fisher, DE AF Zhao, Xiansi Fiske, Brian Kawakami, Akinori Li, Juying Fisher, David E. TI Regulation of MITF stability by the USP13 deubiquitinase SO NATURE COMMUNICATIONS LA English DT Article ID NF-KAPPA-B; TRANSCRIPTION FACTOR; LINEAGE SURVIVAL; MASTER REGULATOR; DNA-DAMAGE; MICROPHTHALMIA; MELANOMA; GENE; EXPRESSION; MELANOCYTES AB The microphthalmia-associated transcription factor (MITF) is essential for melanocyte development. Mutation-induced MAPK pathway activation is common in melanoma and induces MITF phosphorylation, ubiquitination, and proteolysis. Little is known about the enzymes involved in MITF ubiquitination/deubiquitination. Here we report the identification of a deubiquitinating enzyme, named ubiquitin-specific protease 13 (USP13) that appears to be responsible for MITF deubiquitination, utilizing a short hairpin RNA library against known deubiquitinating enzymes. Through deubiquitination, USP13 stabilizes and upregulates MITF protein levels. Conversely, suppression of USP13 (through knockdown) leads to dramatic loss of MITF protein, but not messenger RNA. Through its effects on MITF deubiquitination, USP13 was observed to modulate expression of MITF downstream target genes and, thereby, to be essential for melanoma growth in soft agar and in nude mice. These observations suggest that as a potentially drugable protease, USP13 might be a viable therapeutic target for melanoma. C1 [Zhao, Xiansi; Fiske, Brian; Kawakami, Akinori; Li, Juying; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. [Zhao, Xiansi; Fiske, Brian; Kawakami, Akinori; Li, Juying; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Melanoma Program,Dept Dermatol, Boston, MA 02114 USA. RP Fisher, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. EM dfisher3@partners.org FU NIH (Distinguished Clinical Scholar of the Doris Duke Medical Foundation); Melanoma Research Alliance; Sheldon and Dr Miriam Adelson Medical Research Foundation FX The authors gratefully acknowledge Dr Rene Bernards (Netherlands Cancer Institute), who generously provided the shRNA DUB library, and members of the Fisher lab for useful discussions. This work was supported by grants from NIH (Distinguished Clinical Scholar of the Doris Duke Medical Foundation (DEF)), the Melanoma Research Alliance (DEF) and the Sheldon and Dr Miriam Adelson Medical Research Foundation. NR 35 TC 19 Z9 22 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2011 VL 2 AR 414 DI 10.1038/ncomms1421 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819DV UT WOS:000294806500007 PM 21811243 ER PT J AU Werheid, K McDonald, RS Simmons-Stern, N Ally, BA Budson, AE AF Werheid, Katja McDonald, Rebecca S. Simmons-Stern, Nicholas Ally, Brandon A. Budson, Andrew E. TI Familiar smiling faces in Alzheimer's disease: Understanding the positivity-related recognition bias SO NEUROPSYCHOLOGIA LA English DT Article DE False recognition; Memory; Socioemotional selectivity; Facial emotion; Alzheimer disease ID MILD COGNITIVE IMPAIRMENT; HEALTHY OLDER-ADULTS; FALSE RECOGNITION; EMOTIONAL PICTURES; NEGATIVE AFFECT; MEMORY; RETRIEVAL; DEMENTIA; RECOLLECTION; ENHANCEMENT AB Recent research has revealed a recognition bias favoring positive faces and other stimuli in older compared to younger adults. However, it is yet unclear whether this bias reflects an age-related preference for positive emotional stimuli, or an affirmatory bias used to compensate for episodic memory deficits. To follow up this point, the present study examined recognition of emotional faces and current mood state in patients with mild Alzheimer disease (AD) and healthy controls. Expecting lower overall memory performance, more negative and less positive mood in AD patients, the critical question was whether the positivity-related recognition bias would be increased compared to cognitively unimpaired controls. Eighteen AD patients and 18 healthy controls studied happy, neutral, and angry faces, which in a subsequent recognition task were intermixed with 50% distracter faces. As expected, the patient group showed reduced memory performance, along with a less positive and more negative mood. The recognition bias for positive faces persisted. This pattern supports the view that the positivity-induced recognition bias represents a compensatory, gist-based memory process that is applied when item-based recognition fails. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Werheid, Katja; McDonald, Rebecca S.] Humboldt Univ, Dept Psychol, D-12489 Berlin, Germany. [Simmons-Stern, Nicholas; Budson, Andrew E.] VA Boston Healthcare Syst, Ctr Translat Cognit Neurosci, Geriatr Res Educ Clin Ctr, Boston, MA USA. [Simmons-Stern, Nicholas; Budson, Andrew E.] Boston Univ, Sch Med, Dept Neurol, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Ally, Brandon A.] Vanderbilt Univ, Dept Neurol, Nashville, TN USA. [Ally, Brandon A.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Ally, Brandon A.] Vanderbilt Univ, Dept Psychiat, Nashville, TN USA. RP Werheid, K (reprint author), Humboldt Univ, Dept Psychol, Rudower Chaussee 18, D-12489 Berlin, Germany. EM katja.werheid@hu-berlin.de OI Ally, Brandon/0000-0002-6034-7968 FU National Institute on Aging [K23 AG031925, R01 AG025815, P30 AG13846] FX Many thanks to Maria Schefter for support in programming and for valuable comments. Ellen Beth and Rose Agger assisted in data collection, Katherine Jung helped with data analysis, and Norbert Kathmann generously supported the project. This material is the result of the study supported with resources and the use of facilities at the Edith Nourse Rogers Memorial Veterans Hospital in Bedford, MA. Supported by National Institute on Aging grants K23 AG031925 (BAA), R01 AG025815 (AEB), and P30 AG13846 (AEB). NR 53 TC 12 Z9 12 U1 2 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD AUG PY 2011 VL 49 IS 10 BP 2935 EP 2940 DI 10.1016/j.neuropsychologia.2011.06.022 PG 6 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 820XX UT WOS:000294940500016 PM 21736891 ER PT J AU Kurtz, BP Abrams, AN AF Kurtz, Brian P. Abrams, Annah N. TI Psychiatric Aspects of Pediatric Cancer SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Cancer; Psychosocial issues; Psychiatry; Pediatric; Coping ID ACUTE LYMPHOBLASTIC-LEUKEMIA; NEWLY-DIAGNOSED CANCER; LONG-TERM SURVIVORS; CHRONIC HEPATITIS-C; BONE-MARROW-TRANSPLANTATION; INTERFERON-ALPHA TREATMENT; STEM-CELL TRANSPLANTATION; PLACEBO-CONTROLLED TRIAL; CHILDRENS ONCOLOGY GROUP; MALIGNANT BRAIN-TUMORS AB The diagnosis and treatment of children and adolescents with cancer has a tremendous and lasting effect on the patients, their families, and other individuals in their social network. It carries a host of psychological and behavioral ramifications, from questions of mortality to changes in levels of functioning in multiple domains. In this review the authors address the psychosocial and treatment-related issues that arise in children with cancer, with attention to the adjustment to cancer at different developmental stages, mood and anxiety issues, treatment-related psychiatric sequelae, and the challenges faced by childhood cancer survivors. C1 [Abrams, Annah N.] Massachusetts Gen Hosp, Dept Pediat Hematol Oncol, Boston, MA 02114 USA. [Abrams, Annah N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kurtz, Brian P.; Abrams, Annah N.] Tufts Univ, Sch Med, Dept Psychiat, Boston, MA 02111 USA. [Kurtz, Brian P.] Tufts Med Ctr, Dept Psychiat, Div Pediat Psychiat, Boston, MA 02111 USA. [Kurtz, Brian P.] Tufts Med Ctr, Floating Hosp Children, Boston, MA 02111 USA. RP Abrams, AN (reprint author), Massachusetts Gen Hosp, Dept Child & Adolescent Psychiat, 55 Fruit St,Yawkey 8B, Boston, MA 02114 USA. EM aabrams@partners.org NR 157 TC 5 Z9 5 U1 6 U2 22 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD AUG PY 2011 VL 58 IS 4 BP 1003 EP + DI 10.1016/j.pcl.2011.06.009 PG 22 WC Pediatrics SC Pediatrics GA 818XS UT WOS:000294790600014 PM 21855719 ER PT J AU Curtis, JR Baddley, JW Yang, S Patkar, N Chen, L Delzell, ES Mikuls, TR Saag, KG Singh, J Safford, M Cannon, GW AF Curtis, Jeffrey R. Baddley, John W. Yang, Shuo Patkar, Nivedita Chen, Lang Delzell, Elizabeth S. Mikuls, Ted R. Saag, Kenneth G. Singh, Jasvinder Safford, Monika Cannon, Grant W. TI Validation of a Preliminary Administrative Claims-Based Algorithm for the Effectiveness of Medications for Rheumatoid Arthritis SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Curtis, Jeffrey R.; Baddley, John W.; Yang, Shuo; Patkar, Nivedita; Chen, Lang; Delzell, Elizabeth S.; Saag, Kenneth G.; Singh, Jasvinder; Safford, Monika] Univ Alabama, Birmingham, AL USA. [Baddley, John W.; Singh, Jasvinder] Birmingham VA Med Ctr, Birmingham, AL USA. [Mikuls, Ted R.] Omaha VA Med Ctr, Omaha, NE USA. [Mikuls, Ted R.] Univ Nebraska, Med Ctr, Omaha, NE USA. [Cannon, Grant W.] George E Wahlen VA Med Ctr, Salt Lake City, UT USA. [Cannon, Grant W.] Univ Utah, Salt Lake City, UT USA. RI YANG, SHUO/D-2695-2014 OI YANG, SHUO/0000-0002-4999-0506 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2011 VL 20 SU 1 MA 161 BP S69 EP S70 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 821AG UT WOS:000294946600156 ER PT J AU Lavigne, JE Au, A Rong, J Wang, Y Good, CB Glassman, PA Cunningham, F AF Lavigne, Jill E. Au, Anthony Rong, Jiang Wang, Yu Good, C. B. Glassman, Peter A. Cunningham, Francesca TI Utilization of Prescription Drugs with Warnings of Suicidal Thoughts and Behaviors in the US and the US Department of Veterans Affairs (VA), 2009 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Lavigne, Jill E.] US Dept Vet Affairs, Pharm Benefit Management Grp, Ctr Excellence Suicide Prevent, Canandaigua, NY USA. [Lavigne, Jill E.] St John Fisher Coll, Wegmans Sch Pharm, Rochester, NY 14618 USA. [Au, Anthony; Rong, Jiang; Wang, Yu; Good, C. B.; Cunningham, Francesca] US Dept Vet Affairs, Pharm Benefits Management Serv Ctr Med Safety VAM, Hines, IL USA. [Good, C. B.] Pittsburgh Healthcare Syst, Dept Vet Affairs, Pittsburgh, PA USA. [Glassman, Peter A.] Greater Angeles Healthcare Syst, Dept Vet Affairs, Los Angeles, CA USA. [Good, C. B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2011 VL 20 SU 1 MA 496 BP S216 EP S217 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 821AG UT WOS:000294946600479 ER PT J AU Marcum, ZA Amuan, ME Hanlon, JT Aspinall, SL Handler, SM Ruby, CM Pugh, MJV AF Marcum, Zachary A. Amuan, Megan E. Hanlon, Joseph T. Aspinall, Sherrie L. Handler, Steven M. Ruby, Christine M. Pugh, Mary Jo V. TI Therapeutic Failures and Adverse Drug Withdrawal Events Leading to Hospitalization among Older Outpatient Veterans SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Marcum, Zachary A.; Hanlon, Joseph T.; Aspinall, Sherrie L.; Handler, Steven M.; Ruby, Christine M.] Univ Pittsburgh, Pittsburgh, PA USA. [Marcum, Zachary A.; Hanlon, Joseph T.; Handler, Steven M.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Amuan, Megan E.] Bedford VA Hosp, Bedford, MA USA. [Hanlon, Joseph T.; Aspinall, Sherrie L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Aspinall, Sherrie L.] VA Pharm Benefits Management Serv, VA Ctr Medicat Safety, Hines, IL USA. [Aspinall, Sherrie L.] S Texas Vet Hlth Care Syst, Vet Evidence Based Res Disseminat & Implementat C, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2011 VL 20 SU 1 MA 692 BP S300 EP S301 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 821AG UT WOS:000294946600665 ER PT J AU Williams, JR Crentsil, V Duncan, L Goldstein, S Graham, D Hammer, M Kavanagh, J Kornegay, C Levin, R Weintraub, D Wilkinson, J Kales, H AF Williams, James R. Crentsil, Victor Duncan, Laurie Goldstein, Susanne Graham, David Hammer, Marlene Kavanagh, Janet Kornegay, Cynthia Levin, Robert Weintraub, Daniel Wilkinson, Jayne Kales, Helen TI Retrospective Method To Identify Tardive Dyskinesia in Electronic Medical Records SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Williams, James R.; Kornegay, Cynthia] US FDA, Div Epidemiol, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Crentsil, Victor; Duncan, Laurie; Levin, Robert] US FDA, Div Psychiat Prod, Ctr Drug Evaluat & Res, Off New Drugs,Off Drug Evaluat 1, Silver Spring, MD USA. [Goldstein, Susanne] US FDA, Div Neurol Prod, Ctr Drug Evaluat & Res, Off New Drugs,Off Drug Evaluat 1, Silver Spring, MD USA. [Graham, David; Hammer, Marlene] US FDA, Immediate Off, Ctr Drug Evaluat & Res, Off Surveillance & Epidemiol, Silver Spring, MD USA. [Kavanagh, Janet; Kales, Helen] Ann Arbor Ctr Excellence, Serious Mental Illness Treatment Res & Evaluat Ct, Dept Vet Affairs, Ann Arbor, MI USA. [Kavanagh, Janet; Kales, Helen] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Weintraub, Daniel; Wilkinson, Jayne] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Dept Vet Affairs, Philadelphia, PA USA. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Wilkinson, Jayne] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2011 VL 20 SU 1 MA 807 BP S348 EP S349 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 821AG UT WOS:000294946600772 ER PT J AU Winthrop, KL Baxter, R Liu, LY McFarland, B Austin, DF Varley, CD Radcliffe, L Suhler, EB Choi, D Rosenbaum, JT Herrinton, LJ AF Winthrop, Kevin L. Baxter, Roger Liu, Liyan McFarland, Bentson Austin, Donald F. Varley, Cara D. Radcliffe, LeAnn Suhler, Eric B. Choi, Dongseok Rosenbaum, James T. Herrinton, Lisa J. TI Mycobacterial Disease in Patients Who Use Anti-Tumor Necrosis Factor Therapy SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Winthrop, Kevin L.; McFarland, Bentson; Austin, Donald F.; Varley, Cara D.; Suhler, Eric B.; Choi, Dongseok; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Baxter, Roger; Liu, Liyan; Herrinton, Lisa J.] Kaiser Permanente No Calif, Oakland, CA USA. [Winthrop, Kevin L.; Austin, Donald F.; Radcliffe, LeAnn; Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2011 VL 20 SU 1 MA 198 BP S86 EP S86 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 821AG UT WOS:000294946600192 ER PT J AU Melki, SA Harissi-Dagher, M AF Melki, Samir A. Harissi-Dagher, Mona TI Coaxially sighted intraocular lens light reflex for centration of the multifocal single piece intraocular lens SO CANADIAN JOURNAL OF OPHTHALMOLOGY-JOURNAL CANADIEN D OPHTALMOLOGIE LA English DT Article ID CONTRAST SENSITIVITY; VISUAL PERFORMANCE; CATARACT-SURGERY; IMPLANTATION; DECENTRATION; DISTANCE; VISION; DESIGN; ACUITY; DEPTH AB Centration of multifocal Intraocular lenses (IOL) may be critical to ensure optimal function and prevent untoward side effects. Pharmacologic pupillary dilation and constriction may shift the physiologic location of the pupillary center rendering intraoperative positioning of multifocal IOL challenging. Similarly, the anterior capsular center is difficult to pinpoint and may not correspond to either the visual axis or the pupillary center. The visual axis is the only landmark that can be consistently identified prior, during and after cataract surgery. Centering diffractive multifocal IOL on the visual axis may allow more consistent placement and better outcome measures. In the following, we describe a simple technique to center multifocal single piece acrylic IOLs on the visual axis. C1 [Melki, Samir A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Melki, Samir A.] Boston Eye Grp, Brookline, MA USA. [Harissi-Dagher, Mona] Univ Montreal, Montreal, PQ, Canada. RP Melki, SA (reprint author), 1101 Beacon St,Suite 6 W, Brookline, MA 02446 USA. EM samir_melki@meei.harvard.edu NR 37 TC 5 Z9 5 U1 0 U2 2 PU CANADIAN OPHTHAL SOC PI OTTAWA PA 1525 CARLING AVE SUITE 610, OTTAWA, ONTARIO K1Z 8R9, CANADA SN 0008-4182 J9 CAN J OPHTHALMOL JI Can. J. Opthalmol.-J. Can. Opthalmol. PD AUG PY 2011 VL 46 IS 4 BP 319 EP 321 DI 10.1016/j.jcjo.2011.06.007 PG 3 WC Ophthalmology SC Ophthalmology GA 819AS UT WOS:000294798400006 PM 21816250 ER PT J AU Westaway, SK Reinier, K Huertas-Vazquez, A Evanado, A Teodorescu, C Navarro, J Sinner, MF Gunson, K Jui, J Spooner, P Kaab, S Chugh, SS AF Westaway, Shawn K. Reinier, Kyndaron Huertas-Vazquez, Adriana Evanado, Audrey Teodorescu, Carmen Navarro, Jo Sinner, Moritz F. Gunson, Karen Jui, Jonathan Spooner, Peter Kaab, Stefan Chugh, Sumeet S. TI Common Variants in CASQ2, GPD1L, and NOS1AP Are Significantly Associated With Risk of Sudden Death in Patients With Coronary Artery Disease SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE death, sudden; risk prediction; genomics; variants ID QT-INTERVAL DURATION; POLYMORPHIC VENTRICULAR-TACHYCARDIA; GENOME-WIDE ASSOCIATION; ACUTE MYOCARDIAL-INFARCTION; CARDIAC DEATH; UNEXPECTED DEATH; BRUGADA-SYNDROME; FAMILY-HISTORY; POPULATION; MUTATIONS AB Background-Recent evidence suggests a genetic component for sudden cardiac death (SCD) in subjects with coronary artery disease (CAD). We conducted a systematic candidate-gene approach using haplotype-tagging single nucleotide polymorphisms (htSNPs) to identify genes associated with SCD risk in the context of CAD. Methods and Results-We investigated 1424 htSNPs representing 18 genes with mutations described in patients with ventricular arrhythmias in 291 subjects from the Oregon Sudden Unexpected Death Study (Ore-SUDS). The Ore-SUDS is an ongoing prospective investigation of SCD in the Portland, OR, metropolitan area (population, 1 000 000). SCD cases were ascertained from multiple sources and medical records were reviewed to determine the presence of CAD. A total of 36 SNPs were associated with risk of SCD (uncorrected probability values <0.01) in the initial study sample. These SNPs were subsequently tested for replication in an independent case-control study sample from the Ore-SUDS (n=688). The association analysis in the replication stage revealed 6 SNPs associated with SCD: CASQ2 region (rs17500488, P=0.04; rs3010396, P=0.007; rs7366407; P=0.04), NOS1AP (rs12084280, P=0.04; rs10918859, P=0.02), and 1 SNP located approximate to 26 kb upstream of GPD1L (rs9862154, P=0.04). Conclusions-Common variations in or near CASQ2, GPD1L, and NOS1AP are associated with increased risk of SCD in patients with CAD. These findings provide further evidence for overlap between the genetic architecture of rare and common forms of SCD, and replication in additional populations is warranted. (Circ Cardiovasc Genet. 2011;4:397-402.) C1 [Reinier, Kyndaron; Huertas-Vazquez, Adriana; Evanado, Audrey; Teodorescu, Carmen; Navarro, Jo; Chugh, Sumeet S.] Cedars Sinai Med Ctr, Inst Heart, Los Angeles, CA 90048 USA. [Sinner, Moritz F.; Kaab, Stefan] Univ Munich, Klinikum Grosshadern, Dept Med 1, D-8000 Munich, Germany. [Sinner, Moritz F.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Westaway, Shawn K.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Gunson, Karen] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Jui, Jonathan] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, OR 97201 USA. [Spooner, Peter] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. RP Chugh, SS (reprint author), Cedars Sinai Med Ctr, Inst Heart, 5702 S Tower,8700 Beverly Blvd, Los Angeles, CA 90048 USA. EM sumeet.chugh@cshs.org FU US National Heart, Lung, and Blood Institute, National Institutes of Health (NIH/NHLBI) [R01 HL105170-01, R01 HL088416, R01 HL088416-03S1]; Leducq Foundation Transatlantic network of excellence; German Heart Foundation FX Phenotyping for the Oregon Sudden Unexpected Death Study was funded in part by the US National Heart, Lung, and Blood Institute, National Institutes of Health (NIH/NHLBI R01 HL105170-01, R01 HL088416, and R01 HL088416-03S1 to Dr Chugh). Dr Chugh holds the Pauline and Harold Price Chair in Cardiac Electrophysiology at the Cedars-Sinai Heart Institute, Los Angeles, CA. Genetic analysis was funded by a Leducq Foundation Transatlantic network of excellence grant (to Drs Kaab and Spooner and colleagues). Dr Sinner was supported by the German Heart Foundation. NR 49 TC 30 Z9 35 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD AUG PY 2011 VL 4 IS 4 BP 397 EP 402 DI 10.1161/CIRCGENETICS.111.959916 PG 6 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 807MB UT WOS:000293901300013 PM 21685173 ER PT J AU Wild, PS Zeller, T Schillert, A Szymczak, S Sinning, CR Deiseroth, A Schnabel, RB Lubos, E Keller, T Eleftheriadis, MS Bickel, C Rupprecht, HJ Wilde, S Rossmann, H Diemert, P Cupples, LA Perret, C Erdmann, J Stark, K Kleber, ME Epstein, SE Voight, BF Kuulasmaa, K Li, MY Schafer, AS Klopp, N Braund, PS Sager, H Demissie, S Proust, C Konig, IR Wichmann, HE Reinhard, W Hoffmann, MM Virtamo, J Burnett, MS Siscovick, D Wiklund, PG Qu, LM El Mokthari, NE Thompson, JR Peters, A Smith, AV Yon, E Baumert, J Hengstenberg, C Marz, W Amouyel, P Devaney, J Schwartz, S Saarela, O Mehta, NN Rubin, D Silander, K Hall, AS Ferriers, J Harris, TB Melander, O Kee, F Hakonarson, H Schrezenmeir, J Gudnason, V Elosua, R Arveiler, D Evans, A Rader, DJ Illig, T Schreiber, S Bis, JC Altshuler, D Kavousi, M Witteman, JCM Uitterlinden, AG Hofman, A Folsom, AR Barbalic, M Boerwinkle, E Kathiresan, S Reilly, MP O'Donnell, CJ Samani, NJ Schunkert, H Cambien, F Lackner, KJ Tiret, L Salomaa, V Munzel, T Ziegler, A Blankenberg, S AF Wild, Philipp S. Zeller, Tanja Schillert, Arne Szymczak, Silke Sinning, Christoph R. Deiseroth, Arne Schnabel, Renate B. Lubos, Edith Keller, Till Eleftheriadis, Medea S. Bickel, Christoph Rupprecht, Hans J. Wilde, Sandra Rossmann, Heidi Diemert, Patrick Cupples, L. Adrienne Perret, Claire Erdmann, Jeanette Stark, Klaus Kleber, Marcus E. Epstein, Stephen E. Voight, Benjamin F. Kuulasmaa, Kari Li, Mingyao Schaefer, Arne S. Klopp, Norman Braund, Peter S. Sager, Hendrik Demissie, Serkalem Proust, Carole Koenig, Inke R. Wichmann, Heinz-Erich Reinhard, Wibke Hoffmann, Michael M. Virtamo, Jarmo Burnett, Mary Susan Siscovick, David Wiklund, Per Gunnar Qu, Liming El Mokthari, Nour Eddine Thompson, John R. Peters, Annette Smith, Albert V. Yon, Emmanuelle Baumert, Jens Hengstenberg, Christian Maerz, Winfried Amouyel, Philippe Devaney, Joseph Schwartz, Stephen Saarela, Olli Mehta, Nehal N. Rubin, Diana Silander, Kaisa Hall, Alistair S. Ferriers, Jean Harris, Tamara B. Melander, Olle Kee, Frank Hakonarson, Hakon Schrezenmeir, Juergen Gudnason, Vilmundur Elosua, Roberto Arveiler, Dominique Evans, Alun Rader, Daniel J. Illig, Thomas Schreiber, Stefan Bis, Joshua C. Altshuler, David Kavousi, Maryam Witteman, Jaqueline C. M. Uitterlinden, Andre G. Hofman, Albert Folsom, Aaron R. Barbalic, Maja Boerwinkle, Eric Kathiresan, Sekar Reilly, Muredach P. O'Donnell, Christopher J. Samani, Nilesh J. Schunkert, Heribert Cambien, Francois Lackner, Karl J. Tiret, Laurence Salomaa, Veikko Munzel, Thomas Ziegler, Andreas Blankenberg, Stefan TI A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE coronary artery disease; genome-wide association studies; gene expression; genetic variation; genomics; eQTL; eSNP; LIPA ID LYSOSOMAL ACID LIPASE; LOW-DENSITY-LIPOPROTEIN; MYOCARDIAL-INFARCTION; WOLMAN-DISEASE; HEART-DISEASE; EXPRESSION; RISK; COHORTS; ATHEROSCLEROSIS; CHOLESTEROL AB Background-eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results-In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)). Conclusions-The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.) C1 [Wild, Philipp S.; Zeller, Tanja; Sinning, Christoph R.; Deiseroth, Arne; Schnabel, Renate B.; Lubos, Edith; Keller, Till; Eleftheriadis, Medea S.; Rupprecht, Hans J.; Wilde, Sandra; Munzel, Thomas; Blankenberg, Stefan] Univ Med Ctr Mainz, Dept Med 2, D-55131 Mainz, Germany. [Schillert, Arne; Szymczak, Silke; Koenig, Inke R.; Ziegler, Andreas] Univ Lubeck, Univ Hosp Schleswig Holstein, Inst Med Biometry & Stat, D-23562 Lubeck, Germany. [Bickel, Christoph] Fed Armed Hosp Koblenz, Dept Internal Med, D-56072 Koblenz, Germany. [Rossmann, Heidi; Lackner, Karl J.] Univ Med Ctr Mainz, Inst Clin Chem & Lab Med, D-55131 Mainz, Germany. [Diemert, Patrick; Erdmann, Jeanette; Sager, Hendrik; Schunkert, Heribert] Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Cupples, L. Adrienne; Demissie, Serkalem; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Perret, Claire; Proust, Carole; Yon, Emmanuelle; Cambien, Francois; Tiret, Laurence] Univ Paris 06, INSERM, UMRS937, Paris, France. [Stark, Klaus; Reinhard, Wibke; Hengstenberg, Christian] Univ Hosp Regensburg, Klin & Poliklin Innere Med 2, D-93053 Regensburg, Germany. [Kleber, Marcus E.] LURIC Study Nonprofit LLC, D-79098 Freiburg, Germany. [Epstein, Stephen E.; Burnett, Mary Susan; Devaney, Joseph] MedStar Hlth Res Inst, Cardiovasc Res Inst, Washington, DC 20010 USA. [Voight, Benjamin F.] Broad Inst, Cambridge Ctr 5, Cambridge, MA 02142 USA. [Kuulasmaa, Kari; Virtamo, Jarmo; Saarela, Olli; Silander, Kaisa; Salomaa, Veikko] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland. [Li, Mingyao; Qu, Liming] Univ Penn, Dept Biostat, Philadelphia, PA 19104 USA. [Schaefer, Arne S.; Schreiber, Stefan] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany. [Klopp, Norman; Wichmann, Heinz-Erich; Peters, Annette; Baumert, Jens; Illig, Thomas] Helmholtz Zentrum Munchen, Inst Epidemiol, D-85764 Neuherberg, Germany. [Braund, Peter S.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Braund, Peter S.; Samani, Nilesh J.] Glenfield Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England. [Hoffmann, Michael M.] Univ Med Ctr, Div Clin Chem, Dept Med, D-79075 Freiburg, Germany. [Siscovick, David; Schwartz, Stephen] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Siscovick, David; Schwartz, Stephen] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA. [Wiklund, Per Gunnar] Umea Univ, Dept Publ Hlth & Clin Med, SE-90185 Umea, Sweden. [El Mokthari, Nour Eddine] Univ Med Ctr Schleswig Holstein, Clin Cardiol, D-24105 Kiel, Germany. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Maerz, Winfried] Synlab Ctr Lab Diagnost, D-69037 Heidelberg, Germany. [Amouyel, Philippe] Pasteur Inst Lille, INSERM, Dept Epidemiol & Publ Hlth, U508, F-59019 Lille, France. [Mehta, Nehal N.; Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds LS1 3EX, W Yorkshire, England. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Melander, Olle] Lund Univ, Dept Clin Sci, SE-20502 Lund, Sweden. [Kee, Frank; Evans, Alun] Queens Univ Belfast, UK Clin Res Collaborat Ctr Excellence Publ Hlth, Belfast BT12 6BJ, Antrim, North Ireland. [Hakonarson, Hakon] Univ Penn, Ctr Appl Genom, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Schrezenmeir, Juergen] Max Rubner Inst, Inst Physiol & Biochem Nutr, D-24103 Kiel, Germany. [Elosua, Roberto] IMIM Doctor Aiguader, Grp Epidemiol & Genet Cardiovasc, Barcelona 08003, Spain. [Arveiler, Dominique] Univ Strasbourg, Lab Epidemiol & Sante Publ, F-67085 Strasbourg, France. [Ferriers, Jean] Fac Med Toulouse, Dept Epidemiol, F-31073 Toulouse, France. [Rader, Daniel J.] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Kavousi, Maryam; Witteman, Jaqueline C. M.; Uitterlinden, Andre G.; Hofman, Albert] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Barbalic, Maja; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Perret, Claire; Proust, Carole; Yon, Emmanuelle; Cambien, Francois; Tiret, Laurence] Sch Med, Paris, France. RP Blankenberg, S (reprint author), Univ Klinikum Hamburg Eppendorf, Univ Herzzentrum Hamburg, Martinistr 52, D-20246 Hamburg, Germany. EM s.blankenberg@uke.de RI Erdmann, Jeanette/P-7513-2014; Stark, Klaus/D-3813-2009; Szymczak, Silke/C-6625-2013; Altshuler, David/A-4476-2009; Schreiber, Stefan/B-6748-2008; Schnabel, Renate/F-6527-2014; Peters, Annette/A-6117-2011; Hoffmann, Michael/D-4074-2015; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; OI ELOSUA, ROBERTO/0000-0001-8235-0095; Erdmann, Jeanette/0000-0002-4486-6231; Keller, Till/0000-0002-0895-6491; Ziegler, Andreas/0000-0002-8386-5397; Kuulasmaa, Kari/0000-0003-2165-1411; Kleber, Marcus/0000-0003-0663-7275; Stark, Klaus/0000-0002-7832-1942; Altshuler, David/0000-0002-7250-4107; Schreiber, Stefan/0000-0003-2254-7771; Hoffmann, Michael/0000-0001-8459-6080; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Cupples, L. Adrienne/0000-0003-0273-7965 FU government of Rheinland-Pfalz ("Stiftung Rheinland Pfalz fur Innovation,") [AZ 961-386261/733]; Johannes Gutenberg-University of Mainz; National Genome Network [A3 01GS0833, 01GS0831]; Federal Ministry of Education and Research, Germany; GlaxoSmithKline through an Alternate Drug Discovery Initiative FX The Gutenberg Heart Study is funded through the government of Rheinland-Pfalz ("Stiftung Rheinland Pfalz fur Innovation," contract No. AZ 961-386261/733), the research programs "Wissen schafft Zukunft" and "Schwerpunkt Vaskulare Pravention" of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Heart Study. Specifically, the research reported in this article was supported by the National Genome Network "NGFNplus" (contract No. project A3 01GS0833 and 01GS0831) by the Federal Ministry of Education and Research, Germany.; Drs Reilly and Rader were supported by GlaxoSmithKline through an Alternate Drug Discovery Initiative research alliance award. NR 48 TC 57 Z9 60 U1 0 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD AUG PY 2011 VL 4 IS 4 BP 403 EP U203 DI 10.1161/CIRCGENETICS.110.958728 PG 85 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 807MB UT WOS:000293901300014 PM 21606135 ER PT J AU Arif, SA Poon, H AF Arif, Sally A. Poon, Henry TI Tadalafil: A Long-Acting Phosphodiesterase-5 Inhibitor for the Treatment of Pulmonary Arterial Hypertension SO CLINICAL THERAPEUTICS LA English DT Review DE phosphodiesterase-5 inhibitor; pulmonary arterial hypertension; tadalafil ID HEALTHY MALE-SUBJECTS; QUALITY-OF-LIFE; SILDENAFIL; THERAPY; PHARMACOKINETICS; DYSFUNCTION; RESPONSES; BOSENTAN; SURVIVAL; BLOCKERS AB Background: Tadalafil is a phosphodiesterase-5 (PDE-5) inhibitor that was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of pulmonary arterial hypertension (PAH). Objective: The purpose of this review is to evaluate the pharmacology, pharmacokinetic properties, clinical efficacy, adverse effects, drug interactions, and dosage and administration of tadalafil in patients with PAH. Methods: A literature search of MEDLINE and International Pharmaceutical Abstracts (1960 through September 5, 2010) was conducted with the search terms tadalafil, pulmonary arterial hypertension, and phosphodiesterase-5 inhibitor. Data found from orignial research and case series published in English were screened for relevancy to pharmacology, pharmacokinetics, clinical efficacy and safety, and tolerability. Relevant articles from the bibliographies of the identified published articles were also obtained. Unpublished data and posters were obtained from the manufacturer of tadalafil and the FDA Web site. Results: By selectively inhibiting PDE-5, tadalafil causes nitric oxide mediated vasodilation in the pulmonary vasculature. Tadalafil has a greater affinity (10,000-fold) for PDE-5 compared with the other PDE inhibitors and has a t(1/2) of 17.5 hours. In a controlled clinical study in patients with PAH, patients receiving tadalafil in a total daily dose of 40 mg had significant improvements in their 6-minute walk distance (33 m from baseline) and time to clinical worsening compared with those receiving placebo (both, P < 0.05). Tadalafil had adverse effects similar to placebo, with headache being the most commonly reported (42%). Conclusions: In the small number of studies available, tadalafil was effective and well tolerated when used to treat patients with PAH. Compared with placebo, tadalafil was associated with significant improvements in exercise capacity and reduced time to clinical worsening (68% relative risk reduction; P = 0.038). There is limited evidence comparing tadalafil with sildenafil and vardenafil, and the studies are limited by short treatment durations. (Clin Ther. 2011;33: 993-1004) (C) 2011 Elsevier HS Journals, Inc. All rights reserved. Key C1 [Arif, Sally A.] Midwestern Univ, Chicago Coll Pharm, Dept Pharm Practice, Downers Grove, IL 60515 USA. [Arif, Sally A.] Rush Univ, Dept Pharm, Med Ctr, Chicago, IL 60612 USA. [Poon, Henry] James J Peters VA Med Ctr, Dept Pharm, Bronx, NY USA. RP Arif, SA (reprint author), Midwestern Univ, Chicago Coll Pharm, Dept Pharm Practice, 555 31st St, Downers Grove, IL 60515 USA. EM sarif@midwestern.edu RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 48 TC 15 Z9 17 U1 0 U2 7 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0149-2918 EI 1879-114X J9 CLIN THER JI Clin. Ther. PD AUG PY 2011 VL 33 IS 8 BP 993 EP 1004 DI 10.1016/j.clinthera.2011.06.008 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 818KE UT WOS:000294749800001 PM 21762988 ER PT J AU Laiteerapong, N Karter, AJ Liu, JY Moffet, HH Sudore, R Schillinger, D John, PM Huang, ES AF Laiteerapong, Neda Karter, Andrew J. Liu, Jennifer Y. Moffet, Howard H. Sudore, Rebecca Schillinger, Dean John, Priya M. Huang, Elbert S. TI Correlates of Quality of Life in Older Adults With Diabetes The Diabetes & Aging Study SO DIABETES CARE LA English DT Article ID GERIATRIC SYNDROMES; SELF-MANAGEMENT; PRIMARY-CARE; CHRONIC-PAIN; HEALTH; ASSOCIATION; DISPARITIES; RETIREMENT; COMMUNITY; DISEASES AB OBJECTIVE-To evaluate associations between health-related quality of life (HRQL) and geriatric syndromes, diabetes complications, and hypoglycemia in older adults with diabetes. RESEARCH DESIGN AND METHODS-A race-stratified random sample of 6,317 adults with type 2 or type 1 diabetes, aged 60 to 75 years, enrolled in Kaiser Permanente Northern California, who completed a survey that included a HRQL instrument based on the Short Form 8-item health survey. Administrative records were used to ascertain diagnoses of geriatric syndromes, diabetes complications, and hypoglycemia. Associations were estimated between HRQL and exposures in exposure-specific and combined exposure models (any syndrome, any complication, or hypoglycemia). Conservatively, differences of points were considered the minimally important difference in HRQL scores. RESULTS-HRQL was lower with nearly all exposures of interest. The lowest physical HRQL was associated with amputation. In combined exposure models, geriatric syndromes (-5.3 [95% CI -5.8 to -4.8], P < 0.001) and diabetes complications (-3.5 [-4.0 to -2.9], P < 0.001) were associated with lower physical HRQL. The lowest mental HRQL was associated with depression, underweight (BMI <18 kg/m(2)), amputation, and hypoglycemia. In combined exposure models, only hypoglycemia was associated with lower mental HRQL (-4.0[-7.0 to 1.1], P = 0.008). CONCLUSIONS-Geriatric syndromes and hypoglycemia are associated with lower HRQL to a comparable degree as diabetes complications. Addressing geriatric syndromes and avoiding hypoglycemia should be given as high a priority as preventing diabetes complications in older adults with diabetes. C1 [Laiteerapong, Neda; John, Priya M.; Huang, Elbert S.] Univ Chicago, Dept Med, Gen Internal Med Sect, Chicago, IL 60637 USA. [Karter, Andrew J.; Liu, Jennifer Y.; Moffet, Howard H.] Kaiser Permanente, Div Res, Oakland, CA USA. [Sudore, Rebecca] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA USA. [Sudore, Rebecca] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Schillinger, Dean] Univ Calif San Francisco, San Francisco Gen Hosp, Div Gen Internal Med, San Francisco, CA 94143 USA. [Schillinger, Dean] Univ Calif San Francisco, San Francisco Gen Hosp, Ctr Vulnerable Populat, San Francisco, CA 94143 USA. [Schillinger, Dean] Calif Diabet Program, Calif Dept Publ Hlth, Sacramento, CA USA. RP Laiteerapong, N (reprint author), Univ Chicago, Dept Med, Gen Internal Med Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM nlaiteer@medicine.bsd.uchicago.edu FU National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK-081796, RC1-DK-086178, R01-DK-080726, R01-DK-065664]; National Institute of Child Health and Human Development [R01-HD-46113]; Agency for Healthcare Research and Quality [T32-HS000084]; NIDDK [F32-DK-089973]; NIDDK Diabetes and Research Training Center at the University of Chicago [P60-DK-20595]; NIH [UL1-RR-024131]; Centers for Disease Control and Prevention [1U58-DP-002007-02] FX This work was performed with support by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; grants R01-DK-081796, RC1-DK-086178, R01-DK-080726, R01-DK-065664), and the National Institute of Child Health and Human Development (grant R01-HD-46113). N.L. was supported by the Agency for Healthcare Research and Quality (T32-HS000084) and the NIDDK (F32-DK-089973). N.L., P.M.J., and E.S.H. are members of the NIDDK Diabetes and Research Training Center at the University of Chicago (grant P60-DK-20595). D.S. was supported by the NIH Clinical and Translational Sciences Award (grant UL1-RR-024131) and the Centers for Disease Control and Prevention (grant 1U58-DP-002007-02). NR 26 TC 51 Z9 55 U1 0 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2011 VL 34 IS 8 BP 1749 EP 1753 DI 10.2337/dc10-2424 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 809EU UT WOS:000294035400013 PM 21636795 ER PT J AU Kuenen, JC Borg, R Kuik, DJ Zheng, H Schoenfeld, D Diamant, M Nathan, DM Heine, RJ AF Kuenen, Judith C. Borg, Rikke Kuik, Dirk J. Zheng, Hui Schoenfeld, David Diamant, Michaela Nathan, David M. Heine, Robert J. CA ADAG Study Grp TI Does Glucose Variability Influence the Relationship Between Mean Plasma Glucose and HbA(1c) Levels in Type 1 and Type 2 Diabetic Patients? SO DIABETES CARE LA English DT Article ID OXIDATIVE STRESS; HEMOGLOBIN A1C; BLOOD-GLUCOSE; IN-VITRO; MELLITUS; GLYCOSYLATION; COMPLICATIONS; INSTABILITY; FLUCTUATIONS; ACTIVATION AB OBJECTIVE-The A1C-Derived Average Glucose (ADAG) study demonstrated a linear relationship between HbA(1c) and mean plasma glucose (MPG). As glucose variability (GV) may contribute to glycation, we examined the association of several glucose variability indices and the MPG-HbA(1c) relationship. RESEARCH DESIGN AND METHODS-Analyses included 268 patients with type 1 diabetes and 159 with type 2 diabetes. MPG during 3 months was calculated from 7-point self-monitored plasma glucose and continuous glucose monitoring. We calculated three different measures of GV and used a multiple-step regression model to determine the contribution of the respective GV measures to the MPG-HbA(1c) relationship. RESULTS-GV, as reflected by SD and continuous overlapping net glycemic action, had a significant effect on the MPG-HbA(1c) relationship in type 1 diabetic patients so that high GV led to a higher HbA(1c) level for the same MPG. In type 1 diabetes, the impact of confounding and effect modification of a low versus high SD at an MPG level of 160 mg/dL on the HbA(1c) level is 7.02 vs. 7.43 and 6.96 vs. 7.41. All GV measures showed the same tendency. CONCLUSIONS-In only type 1 diabetic patients, GV shows a significant interaction with MPG in the association with HbA(1c). This effect is more pronounced at higher HbA(1c) levels. However, the impact of GV on the HbA(1c) level in type 1 diabetes is modest, particularly when HbA(1c) is close to the treatment target of 7%. C1 [Kuenen, Judith C.; Diamant, Michaela] Vrije Univ Amsterdam, Med Ctr, Ctr Diabet, Amsterdam, Netherlands. [Borg, Rikke] Steno Diabet Ctr, Copenhagen, Denmark. [Kuik, Dirk J.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Zheng, Hui; Schoenfeld, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA USA. [Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. [Heine, Robert J.] Lilly, Minneapolis, MN USA. RP Kuenen, JC (reprint author), Vrije Univ Amsterdam, Med Ctr, Ctr Diabet, Amsterdam, Netherlands. EM jc.kuenen@me.com FU American Diabetes Association; European Association for the Study of Diabetes; Abbott Diabetes Care; Bayer Healthcare; GlaxoSmithKline; sanofi-aventis Netherlands; Merck Company; LifeScan; Medtronic Minimed FX The ADAG study is supported by research grants from the American Diabetes Association and the European Association for the Study of Diabetes.; Financial support was provided by Abbott Diabetes Care, Bayer Healthcare, GlaxoSmithKline, sanofi-aventis Netherlands, Merck & Company, LifeScan, and Medtronic Minimed. Supplies and equipment were provided by Medtronic Minimed, LifeScan, and Hemocue. R.J.H. is employed by and owns stocks of Eli Lilly and Company. No other potential conflicts of interest relevant to this article were reported. NR 25 TC 22 Z9 22 U1 1 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2011 VL 34 IS 8 BP 1843 EP 1847 DI 10.2337/dc10-2217 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 809EU UT WOS:000294035400031 PM 21700921 ER PT J AU Ram, R Storb, R Sandmaier, BM Maloney, DG Woolfrey, A Flowers, MED Maris, MB Laport, GG Chauncey, TR Lange, T Langston, AA Storer, B Georges, GE AF Ram, Ron Storb, Rainer Sandmaier, Brenda M. Maloney, David G. Woolfrey, Ann Flowers, Mary E. D. Maris, Michael B. Laport, Ginna G. Chauncey, Thomas R. Lange, Thoralf Langston, Amelia A. Storer, Barry Georges, George E. TI Non-myeloablative conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE acute lymphoblastic leukemia; Philadelphia chromosome-positive; allogeneic hematopoietic cell transplantation; non-myeloablative conditioning; imatinib ID 1ST COMPLETE REMISSION; ACUTE LYMPHOCYTIC-LEUKEMIA; VERSUS-HOST-DISEASE; TOTAL-BODY IRRADIATION; TERM-FOLLOW-UP; ADULT PATIENTS; HYPER-CVAD; HEMATOLOGIC MALIGNANCIES; IMATINIB MESYLATE; MYCOPHENOLATE-MOFETIL AB Background Allogeneic hematopoietic cell transplantation is a potentially curative treatment for patients with acute lymphoblastic leukemia. However, the majority of older adults with acute lymphoblastic leukemia are not candidates for myeloablative conditioning regimens. A non-myeloablative preparative regimen is a reasonable treatment option for this group. We sought to determine the outcome of non-myeloablative conditioning and allogeneic transplantation in patients with high-risk acute lymphoblastic leukemia. Design and Methods Fifty-one patients (median age 56 years) underwent allogeneic hematopoietic cell transplantation from sibling or unrelated donors after fludarabine and 2 Gray total body irradiation. Twenty-five patients had Philadelphia chromosome-positive acute lymphoblastic leukemia. Eighteen of these patients received post-grafting imatinib. Results With a median follow-up of 43 months, the 3-year overall survival was 34%. The 3-year relapse/progression and non-relapse mortality rates were 40% and 28%, respectively. The cumulative incidences of grades II and III-IV acute graft-versus-host disease were 53% and 6%, respectively. The cumulative incidence of chronic graft-versus-host disease was 44%. Hematopoietic cell transplantation in first complete remission and post-grafting imatinib were associated with improved survival (P=0.005 and P=0.03, respectively). Three-year overall survival rates for patients with Philadelphia-negative acute lymphoblastic leukemia in first remission and beyond first remission were 52% and 8%, respectively. For patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first remission who received post-grafting imatinib, the 3-year overall survival rate was 62%; for the subgroup without evidence of minimal residual disease at transplantation, the overall survival was 73%. Conclusions For patients with high-risk acute lymphoblastic leukemia in first complete remission, non-myeloablative conditioning and allogeneic hematopoietic cell transplantation, with post-grafting imatinib for Philadelphia chromosome-positive disease, can result in favorable long-term survival. (Clinicaltrials.gov identifier: NCT0036738) C1 [Ram, Ron; Storb, Rainer; Sandmaier, Brenda M.; Maloney, David G.; Woolfrey, Ann; Flowers, Mary E. D.; Storer, Barry; Georges, George E.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Storb, Rainer; Sandmaier, Brenda M.; Maloney, David G.; Woolfrey, Ann; Flowers, Mary E. D.; Chauncey, Thomas R.; Storer, Barry; Georges, George E.] Univ Washington, Sch Med, Seattle, WA USA. [Maris, Michael B.] Rocky Mt Canc Ctr, Denver, CO USA. [Laport, Ginna G.] Stanford Univ, Stanford, CA 94305 USA. [Chauncey, Thomas R.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Lange, Thoralf] Univ Leipzig, Leipzig, Germany. [Langston, Amelia A.] Emory Univ, Atlanta, GA 30322 USA. RP Georges, GE (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,D1-100, Seattle, WA 98109 USA. EM ggeorges@fhcrc.org FU National Institutes of Health, Bethesda, MD [P01CA018029, P01CA078902, P30CA015704]; Davidoff Foundation FX this work was supported by grants from the National Institutes of Health, Bethesda, MD (grants P01CA018029, P01CA078902, and P30CA015704). RR was a recipient of a fellowship award from the Davidoff Foundation. NR 41 TC 49 Z9 52 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD AUG PY 2011 VL 96 IS 8 BP 1113 EP 1120 DI 10.3324/haematol.2011.040261 PG 8 WC Hematology SC Hematology GA 818BA UT WOS:000294722700008 PM 21508120 ER PT J AU Gibson, SE Swerdlow, SH Ferry, JA Surti, U Dal Cin, P Harris, NL Hasserjian, RP AF Gibson, Sarah E. Swerdlow, Steven H. Ferry, Judith A. Surti, Urvashi Dal Cin, Paola Harris, Nancy Lee Hasserjian, Robert P. TI Reassessment of small lymphocytic lymphoma in the era of monoclonal B-cell lymphocytosis SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE chronic lymphocytic leukemia; small lymphocytic lymphoma; monoclonal B-cell lymphocytosis; MBL ID NATURAL-HISTORY; FOLLICULAR LYMPHOMA; NODE HISTOLOGY; LEUKEMIA; SURVIVAL; PROGRESSION; FEATURES; CLONES; MBL; CLL AB Background In the 2008 World Health Organization classification, small lymphocytic lymphoma is defined as a neoplasm with the tissue morphology and immunophenotype of chronic lymphocytic leukemia, but with absence of leukemia. Minimal criteria of tissue involvement to separate small lymphocytic lymphoma from monoclonal B-cell lymphocytosis have not been defined. Design and Methods We reviewed the clinicopathological features of 36 patients with extramedullary tissue biopsies containing chronic lymphocytic leukemia-type cells and less than 5x10(9)/L peripheral blood monoclonal B cells. Pathological features (extent and patterns of involvement, architectural preservation, presence of proliferation centers) as well as cytogenetic and radiological findings were examined in relation to clinical outcome. Results The biopsies were performed to evaluate lymphadenopathy in 20 patients and for other reasons (most frequently staging of a non-hematologic neoplasm) in 16 patients. At latest follow-up (median 23 months), 21 untreated patients had no or stable lymphadenopathy, 3 had regressed lymphadenopathy, and 12 had developed progressive lymphadenopathy and/or received therapy for chronic lymphocytic leukemia/small lymphocytic lymphoma. Features associated with progression/treatment included lymph nodes 1.5 cm or greater on imaging studies (P=0.01) and presence of proliferation centers in the biopsied tissue (P=0.004). Neither the size nor extent of involvement of the excised lymph node correlated with progression/treatment. Conclusions Our findings suggest that biopsies containing chronic lymphocytic leukemia-type cells, but lacking proliferation centers and with non-enlarged or only slightly enlarged lymph nodes on imaging, represent a very indolent disease that may best be considered a tissue equivalent of monoclonal B-cell lymphocytosis rather than overt small lymphocytic lymphoma. We propose that such cases be designated as tissue involvement by chronic lymphocytic leukemia/small lymphocytic lymphoma-like cells of uncertain significance. C1 [Ferry, Judith A.; Harris, Nancy Lee; Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gibson, Sarah E.; Swerdlow, Steven H.; Surti, Urvashi] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Surti, Urvashi] UPMC, Pittsburgh Cytogenet Lab, Magee Womens Hosp, Pittsburgh, PA USA. [Dal Cin, Paola] Brigham & Womens Hosp, Ctr Adv Mol Diagnost, Boston, MA 02115 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM rhasserjian@partners.org FU NCATS NIH HHS [UL1 TR000005] NR 38 TC 30 Z9 35 U1 0 U2 4 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD AUG PY 2011 VL 96 IS 8 BP 1144 EP 1152 DI 10.3324/haematol.2011.042333 PG 9 WC Hematology SC Hematology GA 818BA UT WOS:000294722700012 PM 21546505 ER PT J AU Jakubikova, J Cervi, D Ooi, M Kim, K Nahar, S Klippel, S Cholujova, D Leiba, M Daley, JF Delmore, J Negri, J Blotta, S McMillin, DW Hideshima, T Richardson, PG Sedlak, J Anderson, KC Mitsiades, CS AF Jakubikova, Jana Cervi, David Ooi, Melissa Kim, Kihyun Nahar, Sabikun Klippel, Steffen Cholujova, Dana Leiba, Merav Daley, John F. Delmore, Jake Negri, Joseph Blotta, Simona McMillin, Douglas W. Hideshima, Teru Richardson, Paul G. Sedlak, Jan Anderson, Kenneth C. Mitsiades, Constantine S. TI Anti-tumor activity and signaling events triggered by the isothiocyanates, sulforaphane and phenethyl isothiocyanate, in multiple myeloma SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE isothiocyanates; sulforaphane; phenethyl isothiocyanate; PEITC; multiple myeloma; bone marrow microenvironment; signaling pathways ID PROSTATE-CANCER CELLS; FACTOR-KAPPA-B; CACO-2 CELLS; MEDIATED APOPTOSIS; GROWTH ARREST; IN-VITRO; PHOSPHORYLATION; TRANSCRIPTION; PATHWAYS; VIVO AB Background Isothiocyanates, a family of phytochemicals found in cruciferous vegetables, have cytotoxic effects against several types of tumor cells. Multiple myeloma is a fatal disease characterized by clonal proliferation of plasma cells in the bone marrow. The growing body of preclinical information on the anti-cancer activity of isothiocyanates led us to investigate their anti-myeloma properties. Design and Methods We evaluated the anti-myeloma activity of the isothiocyanates, sulforaphane and phenethyl isothiocyanate, on a panel of human myeloma cell lines as well as primary myeloma tumor cells. Cell viability, apoptosis, cell cycle alterations and cell proliferation were then analyzed in vitro and in a xenograft mouse model in vivo. The molecular sequelae of isothiocyanate treatment in multiple myeloma cells were evaluated by multiplex analyses using bead arrays and western blotting. Results We observed that sulforaphane and phenylethyl isothiocyanate have activity against myeloma cell lines and patients' myeloma cells both in vitro and in vivo using a myeloma xenograft mouse model. Isothiocyanates induced apoptotic death of myeloma cells; depletion of mitochondrial membrane potential; cleavage of PARP and caspases-3 and -9; as well as down-regulation of anti-apoptotic proteins including Mcl-1, X-IAP, c-IAP and survivin. Isothiocyanates induced G2/M cell cycle arrest accompanied by mitotic phosphorylation of histone H3. Multiplex analysis of phosphorylation of diverse components of signaling cascades revealed changes in MAPK activation; increased phosphorylation of c-jun and HSP27; as well as changes in the phosphorylation of Akt, and GSK3 alpha/beta and p53. Isothiocyanates suppressed proliferation of myeloma cells alone and when co-cultured with HS-5 stromal cells. Sulforaphane and phenylethyl isothiocyanate enhanced the in vitro anti-myeloma activity of several conventional and novel therapies used in multiple myeloma. Conclusions Our study shows that isothiocyanates have potent anti-myeloma activities and may enhance the activity of other anti-multiple myeloma agents. These results indicate that isothiocyanates may have therapeutic potential in multiple myeloma and provide the preclinical framework for future clinical studies of isothiocyanates in multiple myeloma. C1 [Jakubikova, Jana; Cervi, David; Ooi, Melissa; Kim, Kihyun; Nahar, Sabikun; Klippel, Steffen; Leiba, Merav; Daley, John F.; Delmore, Jake; Negri, Joseph; Blotta, Simona; McMillin, Douglas W.; Hideshima, Teru; Richardson, Paul G.; Anderson, Kenneth C.; Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, Boston, MA 02115 USA. [Jakubikova, Jana; Cervi, David; Ooi, Melissa; Kim, Kihyun; Nahar, Sabikun; Klippel, Steffen; Leiba, Merav; Daley, John F.; Delmore, Jake; Negri, Joseph; Blotta, Simona; McMillin, Douglas W.; Hideshima, Teru; Richardson, Paul G.; Anderson, Kenneth C.; Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Jakubikova, Jana; Cholujova, Dana; Sedlak, Jan] Slovak Acad Sci, Canc Res Inst, Dept Tumor Immunol, Bratislava, Slovakia. RP Mitsiades, CS (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM kenneth_anderson@dfci.har-vard.edu; constantine_mitsi-ades@dfci.harvard.edu RI Kim, Kihyun/D-5175-2013 OI Kim, Kihyun/0000-0002-5878-8895 FU Dana-Farber Cancer Institute; Chambers Medical Foundation; National Institutes of Health [R01-50947, P0-1-78378]; Slovak RD Agency [VVCE-0001-07] FX this work was supported in part by the "Dunkin Donuts Rising Stars" Program at the Dana-Farber Cancer Institute (CSM), the Chambers Medical Foundation (PGR and CSM), National Institutes of Health Grants R01-50947, P0-1-78378 (KCA) and Slovak R&D Agency grant VVCE-0001-07 (JS). KCA is an American Cancer Society Clinical Research Professor. NR 40 TC 28 Z9 29 U1 0 U2 4 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD AUG PY 2011 VL 96 IS 8 BP 1170 EP 1179 DI 10.3324/haematol.2010.029363 PG 10 WC Hematology SC Hematology GA 818BA UT WOS:000294722700015 PM 21712538 ER PT J AU Hempel, S Rubenstein, LV Shanman, RM Foy, R Golder, S Danz, M Shekelle, PG AF Hempel, Susanne Rubenstein, Lisa V. Shanman, Roberta M. Foy, Robbie Golder, Su Danz, Marjorie Shekelle, Paul G. TI Identifying quality improvement intervention publications - A comparison of electronic search strategies SO IMPLEMENTATION SCIENCE LA English DT Article ID HEALTH-CARE; CONTROLLED-TRIALS; PALLIATIVE CARE; RELEVANT; MEDLINE; FILTER AB Background: The evidence base for quality improvement (QI) interventions is expanding rapidly. The diversity of the initiatives and the inconsistency in labeling these as QI interventions makes it challenging for researchers, policymakers, and QI practitioners to access the literature systematically and to identify relevant publications. Methods: We evaluated search strategies developed for MEDLINE (Ovid) and PubMed based on free text words, Medical subject headings (MeSH), QI intervention components, continuous quality improvement (CQI) methods, and combinations of the strategies. Three sets of pertinent QI intervention publications were used for validation. Two independent expert reviewers screened publications for relevance. We compared the yield, recall rate, and precision of the search strategies for the identification of QI publications and for a subset of empirical studies on effects of QI interventions. Results: The search yields ranged from 2,221 to 216,167 publications. Mean recall rates for reference publications ranged from 5% to 53% for strategies with yields of 50,000 publications or fewer. The 'best case' strategy, a simple text word search with high face validity ('quality' AND 'improv*' AND 'intervention*') identified 44%, 24%, and 62% of influential intervention articles selected by Agency for Healthcare Research and Quality (AHRQ) experts, a set of exemplar articles provided by members of the Standards for Quality Improvement Reporting Excellence (SQUIRE) group, and a sample from the Cochrane Effective Practice and Organization of Care Group (EPOC) register of studies, respectively. We applied the search strategy to a PubMed search for articles published in 10 pertinent journals in a three-year period which retrieved 183 publications. Among these, 67% were deemed relevant to QI by at least one of two independent raters. Forty percent were classified as empirical studies reporting on a QI intervention. Conclusions: The presented search terms and operating characteristics can be used to guide the identification of QI intervention publications. Even with extensive iterative development, we achieved only moderate recall rates of reference publications. Consensus development on QI reporting and initiatives to develop QI-relevant MeSH terms are urgently needed. C1 [Hempel, Susanne; Rubenstein, Lisa V.; Shanman, Roberta M.; Danz, Marjorie; Shekelle, Paul G.] RAND Corp, Santa Monica, CA 90407 USA. [Rubenstein, Lisa V.; Shekelle, Paul G.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Rubenstein, Lisa V.; Shekelle, Paul G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Foy, Robbie] Univ Leeds, Leeds LS2 9JT, W Yorkshire, England. [Golder, Su] Univ York, Ctr Reviews & Disseminat, York YO10 5DD, N Yorkshire, England. RP Hempel, S (reprint author), RAND Corp, Santa Monica, CA 90407 USA. EM susanne_hempel@rand.org OI Kimmel, Ellen K./0000-0002-6473-9491; golder, su/0000-0002-8987-5211 FU RAND Corporation; Veterans Affairs Greater Los Angeles Healthcare System; Robert Wood Johnson Foundation [65113] FX We would like to thank Jeremy Grimshaw and the Cochrane Effective Practice and Organization of Care Group (EPOC) for providing a search strategy and access to the database of registered quality improvement initiative; Greg Ogrinc, Paul Batalden, Seth Landefield, Julia Neily and Frank Davidoff as members of the SQUIRE group for providing us with a selection of pertinent quality improvement publications; Ellen Kimmel, Susanne Salem-Schatz and Heather Woodward-Hagg for assistance with the search strategies, Nancy Wilczynski and Carl Patow for comments on earlier drafts of the manuscript, Breanne Johnsen for assistance in the project and manuscript preparation and Sydne Newberry for manuscript editing. The project was funded by the RAND Corporation, the Veterans Affairs Greater Los Angeles Healthcare System and in parts through a grant from the Robert Wood Johnson Foundation (ID 65113). NR 28 TC 13 Z9 13 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD AUG 1 PY 2011 VL 6 AR 85 DI 10.1186/1748-5908-6-85 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 819GB UT WOS:000294812300001 PM 21806808 ER PT J AU Iovieno, N Tedeschini, E Bentley, KH Evins, AE Papakostas, GI AF Iovieno, Nadia Tedeschini, Enrico Bentley, Kate H. Evins, A. Eden Papakostas, George I. TI Antidepressants for Major Depressive Disorder and Dysthymic Disorder in Patients With Comorbid Alcohol Use Disorders: A Meta-Analysis of Placebo-Controlled Randomized Trials SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DOUBLE-BLIND; EXCLUSION CRITERIA; CLINICAL-TRIALS; COOCCURRING DEPRESSION; ABSTINENT ALCOHOLICS; NEFAZODONE TREATMENT; DIAGNOSTIC CRITERIA; DEPENDENT PATIENTS; EFFICACY TRIALS; SERTRALINE AB Objective: Mood and alcohol use disorders are often co-occurring, each condition complicating the course and outcome of the other. The aim of this study was to examine the efficacy of antidepressants in patients with unipolar major depressive disorder (MDD) and/or dysthymic disorder with comorbid alcohol use disorders and to compare antidepressant and placebo response rates between depressed patients with or without comorbid alcohol use disorders. Data Sources: MEDLINE/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the acute-phase treatment of MDD and/or dysthymic disorder in patients with or without alcohol use disorders. The search term placebo was cross-referenced with each of the antidepressants approved by the US, Canadian, or European Union drug regulatory agencies for the treatment of MDD and/or dysthymic disorder. Study Selection: 195 articles were found eligible for inclusion in our analysis, 11 of which focused on the treatment of MDD/dysthymic disorder in patients with comorbid alcohol use disorders. The search was limited to articles published between January 1, 1980, and March 15, 2009 (inclusive). Results: We found that antidepressant therapy was more effective than placebo in patients with comorbid alcohol use disorders (risk ratio of response = 1.336; P = .021). However, this was not the case when selective serotonin reuptake inhibitor (SSRI) antidepressants were examined alone (P > .05). There was no significant difference in the relative efficacy of antidepressants (versus placebo) when comparing studies in MDD/dysthymic disorder patients with or without alcohol use disorders (P = .973). Meta-regression analyses yielded no significant differences in the risk ratio of responding to antidepressants versus placebo in trials with comorbid alcohol use disorders, whether antidepressants were used alone or adjunctively to psychotherapy, whether they were used in patients actively drinking or recently sober, or whether they were used in pure MDD or in combined MDD and dysthymic disorder populations. Conclusions: These results support the utility of certain antidepressants (tricyclics, nefazodone) in treating depression in patients with comorbid alcohol use disorders. More data on the use of newer antidepressants, including the SSRIs, for this select patient population are needed. J Clin Psychiatry 2011;720:1144-1151 (C) Copyright 2011 Physicians Postgraduate Press, Inc. C1 [Iovieno, Nadia] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Iovieno, Nadia] Univ Pisa, Dept Psychiat, I-56100 Pisa, Italy. [Tedeschini, Enrico] Univ Modena & Reggio Emilia, Dept Psychiat, Modena, Italy. [Iovieno, Nadia; Tedeschini, Enrico; Bentley, Kate H.; Evins, A. Eden; Papakostas, George I.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Iovieno, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, 50 Stanford St,Suite 401, Boston, MA 02114 USA. EM niovieno@partners.org RI Papakostas, George/I-6905-2013 OI Papakostas, George/0000-0002-2465-5103 FU Pfizer; GlaxoSmithKline; Bristol-Myers Squibb; Forest; National Institute of Mental Health; PAMLAB; Ridge Diagnostics FX Dr Evins has served as a consultant for Pfizer and Boehringer-Ingelheim and has received research grant support from Pfizer and GlaxoSmithKline. Dr Papakostas has served as a consultant for Abbott, AstraZeneca, Brainsway, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Evotec, Inflabloc, Jazz, Otsuka, PAMLAB, Pfizer, Pierre Fabre, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire, and Wyeth; has received honoraria from Abbott, Astra Zeneca, Bristol-Myers Squibb, Brainsway, Cephalon, Eli Lilly, Evotec, GlaxoSmithKline, Inflabloc, Jazz, Lundbeck, Otsuka, PAMLAB, Pfizer, Pierre Fabre, Ridge Diagnostics, Shire, Titan, and Wyeth; has received research support from Bristol-Myers Squibb, Forest, National Institute of Mental Health, PAMLAB, Pfizer, and Ridge Diagnostics (formerly known as Precision Human Biolaboratories); and has served (in the past, but not currently) on the speaker's bureau for Bristol-Myers Squibb and Pfizer. Drs Iovieno and Tedeschini and Ms Bentley report no competing interests. NR 50 TC 14 Z9 15 U1 2 U2 13 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2011 VL 72 IS 8 BP 1144 EP 1151 DI 10.4088/JCP.10m06217 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 817FL UT WOS:000294656600015 PM 21536001 ER PT J AU Desseilles, M Witte, J Chang, TE Iovieno, N Dording, CM Ashih, H Nyer, M Freeman, MP Fava, M Mischoulon, D AF Desseilles, Martin Witte, Janet Chang, Trina E. Iovieno, Nadia Dording, Christina M. Ashih, Heidi Nyer, Maren Freeman, Marlene P. Fava, Maurizio Mischoulon, David TI Assessing the Adequacy of Past Antidepressant Trials: A Clinician's Guide to the Antidepressant Treatment Response Questionnaire SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Editorial Material ID TREATMENT-RESISTANT DEPRESSION; DEFINITION C1 [Desseilles, Martin] Univ Liege, Cyclotron Res Ctr, B-4000 Liege, Belgium. [Desseilles, Martin; Witte, Janet; Chang, Trina E.; Iovieno, Nadia; Dording, Christina M.; Ashih, Heidi; Nyer, Maren; Freeman, Marlene P.; Fava, Maurizio; Mischoulon, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Trial Network & Inst, Boston, MA USA. [Desseilles, Martin; Witte, Janet; Chang, Trina E.; Iovieno, Nadia; Dording, Christina M.; Ashih, Heidi; Nyer, Maren; Freeman, Marlene P.; Fava, Maurizio; Mischoulon, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. RP Desseilles, M (reprint author), Univ Liege B30, Cyclotron Res Ctr, 8 Allee,6 Aout, B-4000 Liege, Belgium. EM m.desseilles@ulg.ac.be NR 6 TC 1 Z9 1 U1 0 U2 3 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2011 VL 72 IS 8 BP 1152 EP 1154 DI 10.4088/JCP.11ac07225 PG 3 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 817FL UT WOS:000294656600016 PM 21899818 ER PT J AU Morland, LA Hynes, AK Mackintosh, MA Resick, PA Chard, KM AF Morland, Leslie A. Hynes, Anna K. Mackintosh, Margaret-Anne Resick, Patricia A. Chard, Kathleen M. TI Group Cognitive Processing Therapy Delivered to Veterans via Telehealth: A Pilot Cohort SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NONINFERIORITY TRIAL; TELEPSYCHIATRY AB The authors report clinical findings from the pilot cohort of the first prospective, noninferiority-designed randomized clinical trial evaluating the clinical outcomes of delivering a cognitive-behavioral group intervention for posttraumatic stress disorder (PTSD), cognitive processing therapy (CPT), via video teleconferencing (VT) compared to the in-person modality. The treatment was delivered to 13 veterans with PTSD residing on the Hawaiian Islands. Results support the general feasibility and safety of using VT Both groups showed clinically meaningful reductions in PTSD symptoms and no significant between-group differences on clinical or process outcome variables. In keeping with treatment manual recommendations, a few changes were made to the CPT protocol to accommodate this population. Novel aspects of this trial and lessons learned are discussed. C1 [Morland, Leslie A.; Hynes, Anna K.; Mackintosh, Margaret-Anne] Dept Vet Affairs Pacific Isl Healthcare Syst, Natl Ctr PTSD Pacific Isl Div, Honolulu, HI 96819 USA. [Resick, Patricia A.] Boston Univ, Boston, MA 02215 USA. [Resick, Patricia A.] VA Boston Healthcare Syst, Natl Ctr PTSD Womens Hlth Sci Div, Boston, MA USA. [Chard, Kathleen M.] Univ Cincinnati, Cincinnati, OH 45221 USA. [Chard, Kathleen M.] Cincinnati VA Med Ctr, PTSD, Cincinnati, OH USA. [Chard, Kathleen M.] Cincinnati VA Med Ctr, Anxiety Disorders Div, Cincinnati, OH USA. RP Morland, LA (reprint author), Dept Vet Affairs Pacific Isl Healthcare Syst, Natl Ctr PTSD Pacific Isl Div, 3375 Koapaka St, Honolulu, HI 96819 USA. EM Leslie.Morland@va.gov RI Schueter, nicos/A-3625-2014; OI Mackintosh, Margaret-Anne/0000-0002-2725-3177 NR 20 TC 39 Z9 40 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD AUG PY 2011 VL 24 IS 4 BP 465 EP 469 DI 10.1002/jts.20661 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 816CH UT WOS:000294575800013 PM 21793047 ER PT J AU Venkatesh, V Verdini, D Ghoshhajra, B AF Venkatesh, Vikram Verdini, Daniel Ghoshhajra, Brian TI Normal Magnetic Resonance Imaging of the Thorax SO MAGNETIC RESONANCE IMAGING CLINICS OF NORTH AMERICA LA English DT Article DE Magnetic resonance imaging; Thorax; MR pulse sequences; Intrathoracic structures ID PATENT FORAMEN OVALE; CELL LUNG-CANCER; ATRIAL-FIBRILLATION; PULMONARY VEIN; GASTROESOPHAGEAL JUNCTION; COMPUTED-TOMOGRAPHY; PERICARDIAL DISEASE; CATHETER ABLATION; LYMPH-NODES; MR AB The soft tissue contrast properties of magnetic resonance (MR) allow excellent discrimination of most intrathoracic structures other than the lungs, and allow good insight into normal anatomy. Using MR imaging, the normal cardiorespiratory system, including portions of the lungs and pleural spaces, as well as the mediastinal, chest wall, and cardiac structures can be well depicted. In addition, using newer MR pulse sequences, dynamic ECG-gated imaging can also be achieved, which allows a window into the normal functional processes of these organs. C1 [Venkatesh, Vikram; Verdini, Daniel; Ghoshhajra, Brian] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. RP Ghoshhajra, B (reprint author), Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, 55 Fruit St, Boston, MA 02114 USA. EM bghoshhajra@partners.org RI Ghoshhajra, Brian/J-2114-2016 OI Ghoshhajra, Brian/0000-0002-3865-3432 NR 58 TC 1 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1064-9689 J9 MAGN RESON IMAGING C JI Magn. Reson. Imaging Clin. N. Am. PD AUG PY 2011 VL 19 IS 3 BP 489 EP 506 DI 10.1016/j.mric.2011.05.014 PG 18 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 817ET UT WOS:000294654800006 PM 21816327 ER PT J AU Rosas, HD Reuter, M Doros, G Lee, SY Triggs, T Malarick, K Fischl, B Salat, DH Hersch, SM AF Rosas, H. Diana Reuter, Martin Doros, Gheorghe Lee, Stephanie Y. Triggs, Tyler Malarick, Keith Fischl, Bruce Salat, David H. Hersch, Steven M. TI A Tale of Two Factors: What Determines the Rate of Progression in Huntington's Disease? A Longitudinal MRI Study SO MOVEMENT DISORDERS LA English DT Article DE magnetic resonance imaging longitudinal atrophy; neurodegeneration; phenotypic variability; Huntington's disease ID CAG REPEAT LENGTH; CEREBRAL-CORTEX; CLINICAL PROGRESSION; MITOCHONDRIAL-DNA; BRAIN; RELIABILITY; ACCURATE; VOLUME AB Over the past several years, increased attention has been devoted to understanding regionally selective brain changes that occur in Huntington's disease and their relationships to phenotypic variability. Clinical progression is also heterogeneous, and although CAG repeat length influences age of onset, its role, if any, in progression has been less clear. We evaluated progression in Huntington's disease using a novel longitudinal magnetic resonance imaging analysis. Our hypothesis was that the rate of brain atrophy is influenced by the age of onset of Huntington's disease. We scanned 22 patients with Huntington's disease at approximately 1-year intervals; individuals were divided into 1 of 3 groups, determined by the relative age of onset. We found significant differences in the rates of atrophy of cortex, white matter, and subcortical structures; patients who developed symptoms earlier demonstrated the most rapid rates of atrophy compared with those who developed symptoms during middle age or more advanced age. Rates of cortical atrophy were topologically variable, with the most rapid changes occurring in sensorimotor, posterior frontal, and portions of the parietal cortex. There were no significant differences in the rates of atrophy in basal ganglia structures. Although both CAG repeat length and age influenced the rate of change in some regions, there was no significant correlation in many regions. Rates of regional brain atrophy seem to be influenced by the age of onset of Huntington's disease symptoms and are only partially explained by CAG repeat length. These findings suggest that other genetic, epigenetic, and environmental factors play important roles in neurodegeneration in Huntington's disease. (C) 2011 Movement Disorder Society C1 [Rosas, H. Diana; Reuter, Martin; Lee, Stephanie Y.; Triggs, Tyler; Malarick, Keith; Salat, David H.] Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, Charlestown, MA 02129 USA. [Rosas, H. Diana; Reuter, Martin; Lee, Stephanie Y.; Triggs, Tyler; Malarick, Keith; Hersch, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Rosas, H. Diana; Lee, Stephanie Y.; Triggs, Tyler; Malarick, Keith; Hersch, Steven M.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat, Charlestown, MA 02129 USA. [Rosas, H. Diana; Reuter, Martin; Lee, Stephanie Y.; Triggs, Tyler; Malarick, Keith; Fischl, Bruce; Salat, David H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Reuter, Martin; Fischl, Bruce; Salat, David H.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Reuter, Martin; Fischl, Bruce; Salat, David H.] Harvard Univ, Sch Med, Boston, MA USA. [Reuter, Martin; Fischl, Bruce] MIT, Comp Sci & Al Lab, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Doros, Gheorghe] Boston Univ, Dept Biostat, Boston, MA 02215 USA. RP Rosas, HD (reprint author), Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, 149 13th St,Room 2275, Charlestown, MA 02129 USA. EM rosas@helix.mgh.harvard.edu RI Reuter, Martin/B-3456-2010 OI Reuter, Martin/0000-0002-2665-9693 FU National Institutes of Health, National Institute for Neurological Disorders and Stroke [R01 NS042861, NS058793, NS05792, NS052585, R21NS072652]; National Institute of Nursing Research [NR010827]; National Center for Research Resources [P41-RR14075, BIRN002, U24-01]; National Institute for Biomedical Imaging and Bioengineering [R01EB006758]; National Institute on Aging [AG022381]; CHDI; Ellison Medical Foundation; [RR021382] FX Support for this research was provided in part by the National Institutes of Health, National Institute for Neurological Disorders and Stroke (R01 NS042861, NS058793, NS05792, NS052585, R21NS072652), National Institute of Nursing Research (NR010827), and the National Center for Research Resources (P41-RR14075, and the NCRR BIRN Morphometric Project BIRN002, U24-01). Additional support came from RR021382, the National Institute for Biomedical Imaging and Bioengineering (R01EB006758), and the National Institute on Aging (AG022381). Additional support was provided by CHDI and the Autism & Dyslexia Project, funded by the Ellison Medical Foundation. NR 26 TC 20 Z9 20 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 1 PY 2011 VL 26 IS 9 BP 1691 EP 1697 DI 10.1002/mds.23762 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 812AX UT WOS:000294261200018 PM 21611979 ER PT J AU Kim, D Jensen, JH Wu, EX Feng, L Au, WY Cheung, JS Ha, SY Sheth, SS Brittenham, GM AF Kim, Daniel Jensen, Jens H. Wu, Ed X. Feng, Li Au, Wing-Yan Cheung, Jerry S. Ha, Shau-Yin Sheth, Sujit S. Brittenham, Gary M. TI Rapid monitoring of iron-chelating therapy in thalassemia major by a new cardiovascular MR measure: the reduced transverse relaxation rate SO NMR IN BIOMEDICINE LA English DT Article DE MRI; heart; cardiomyopathy; iron chelation; R(2) ID T2-ASTERISK-CARDIOVASCULAR MAGNETIC-RESONANCE; TRANSFUSION-DEPENDENT THALASSEMIA; SICKLE-CELL-DISEASE; OVERLOAD; HEART; LIVER; FERRITIN; CARDIOMYOPATHY; SEQUENCE; PATHOPHYSIOLOGY AB In iron overload, almost all the excess iron is stored intracellularly as rapidly mobilizable ferritin iron and slowly exchangeable hemosiderin iron. Increases in cytosolic iron may produce oxidative damage that ultimately results in cardiomyocyte dysfunction. Because intracellular ferritin iron is evidently in equilibrium with the low-molecular-weight cytosolic iron pool, measurements of ferritin iron potentially provide a clinically useful indicator of changes in cytosolic iron. The cardiovascular magnetic resonance (CMR) index of cardiac iron used clinically, the effective transverse relaxation rate (R(2)*), is principally influenced by hemosiderin iron and changes only slowly over several months, even with intensive iron-chelating therapy. Another conventional CMR index of cardiac iron, the transverse relaxation rate (R(2)), is sensitive to both hemosiderin iron and ferritin iron. We have developed a new MRI measure, the 'reduced transverse relaxation rate' (RR(2)), and have proposed in previous studies that this measure is primarily sensitive to ferritin iron and largely independent of hemosiderin iron in phantoms mimicking ferritin iron and human liver explants. We hypothesized that RR(2) could detect changes produced by 1 week of iron-chelating therapy in patients with transfusion-dependent thalassemia. We imaged 10 patients with thalassemia major at 1.5 T in mid-ventricular short-axis planes of the heart, initially after suspending iron-chelating therapy for 1 week and subsequently after resuming oral deferasirox. After resuming iron-chelating therapy, significant decreases were observed in the mean myocardial RR(2) (7.8%, p < 0.01) and R(2) (5.5%, p < 0.05), but not in R(2)* (1.7%, p > 0.90). Although the difference between changes in RR(2) and R(2) was not significant (p > 0.3), RR(2) was consistently more sensitive than R(2) (and R(2)*) to the resumption of iron-chelating therapy, as judged by the effect sizes of relaxation rate differences detected. Although further studies are needed, myocardial RR(2) may be a promising investigational method for the rapid assessment of the effects of iron-chelating therapy in the heart. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Kim, Daniel; Jensen, Jens H.] NYU, Dept Radiol, Ctr Biomed Imaging, Sch Med, New York, NY 10016 USA. [Wu, Ed X.] Univ Hong Kong, Dept Elect & Elect Engn, Pokfulam, Hong Kong, Peoples R China. [Feng, Li] NYU, Sch Med, Sackler Inst Grad Biomed Sci, New York, NY 10016 USA. [Au, Wing-Yan] Univ Hong Kong, Dept Med, Pokfulam, Hong Kong, Peoples R China. [Cheung, Jerry S.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Cheung, Jerry S.] Harvard Univ, Sch Med, Charlestown, MA USA. [Ha, Shau-Yin] Univ Hong Kong, Dept Pediat, Pokfulam, Hong Kong, Peoples R China. [Sheth, Sujit S.; Brittenham, Gary M.] Columbia Univ, Dept Pediat, Coll Phys & Surg, New York, NY 10027 USA. [Brittenham, Gary M.] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. RP Kim, D (reprint author), NYU, Dept Radiol, Ctr Biomed Imaging, Sch Med, 660 1st Ave,Room 402, New York, NY 10016 USA. EM kimd10@nyumc.org FU National Institutes of Health [R01 DK069373, R01 DK066251, R37 DK049108]; American Heart Association [0730143N]; Hong Kong Research Grant Council [GRF7794/07M]; Hong Kong Children Thalassaemia Foundation [2007/02] FX The following organizations provided grant support: National Institutes of Health (R01 DK069373, R01 DK066251, R37 DK049108); American Heart Association (0730143N); Hong Kong Research Grant Council (GRF7794/07M); Hong Kong Children Thalassaemia Foundation (2007/02). NR 37 TC 4 Z9 4 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD AUG PY 2011 VL 24 IS 7 BP 771 EP 777 DI 10.1002/nbm.1639 PG 7 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 817PS UT WOS:000294686900002 PM 21190261 ER PT J AU Sattin, A Pekary, AE Blood, J AF Sattin, Albert Pekary, Albert Eugene Blood, James TI Rapid modulation of TRH and TRH-like peptide release in rat brain and peripheral tissues by prazosin SO PEPTIDES LA English DT Article DE Post-traumatic stress disorder; Thyrotropin releasing hormone; Limbic system ID POSTTRAUMATIC-STRESS-DISORDER; AUTONOMIC NERVOUS-SYSTEM; HORMONE TRH; INSULIN-SECRETION; COMBAT VETERANS; IN-VITRO; NOREPINEPHRINE; ACTIVATION; DEPRESSION; PANCREAS AB Hyperresponsiveness to norepinephrine contributes to post-traumatic stress disorder (PTSD). Prazosin, a brain-active blocker of alpha(1)-adrenoceptors, originally used for the treatment of hypertension, has been reported to alleviate trauma nightmares, sleep disturbance and improve global clinical status in war veterans with PTSD. Thyrotropin-releasing hormone (TRH, pGIu-His-Pro-NH(2)) may play a role in the pathophysiology and treatment of neuropsychiatric disorders such as major depression, and PTSD (an anxiety disorder). To investigate whether TRH or TRH-like peptides (pGlu-X-Pro-NH(2), where "X" can be any amino acid residue) participate in the therapeutic effects of prazosin, male rats were injected with prazosin and these peptides then measured in brain and endocrine tissues. Prazosin stimulated TRH and TRH-like peptide release in those tissues with high alpha(1)-adrenoceptor levels suggesting that these peptides may play a role in the therapeutic effects of prazosin. Published by Elsevier Inc. C1 [Sattin, Albert; Pekary, Albert Eugene; Blood, James] VA Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Sattin, Albert] VA Greater Los Angeles Healthcare Syst, Psychiat Serv, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, Dept Biobehav Sci, Los Angeles, CA 90073 USA. [Pekary, Albert Eugene] VA Greater Los Angeles Healthcare Syst, Ctr Ulcer Res & Educ, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90073 USA. [Pekary, Albert Eugene] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. RP Pekary, AE (reprint author), VA Greater Los Angeles Healthcare Syst, Res Serv, Bldg 114,Rm 229,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jpekary@yahoo.com RI Schueter, nicos/A-3625-2014 FU Veterans Administration; Pekary Family Trust FX This work was supported by Veterans Administration Medical Research Funds (AEP and AS) and the Pekary Family Trust. NR 65 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD AUG PY 2011 VL 32 IS 8 BP 1666 EP 1676 DI 10.1016/j.peptides.2011.06.012 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 816BD UT WOS:000294572800015 PM 21718733 ER PT J AU Bell, DW Sikdar, N Lee, KY Price, JC Chatterjee, R Park, HD Fox, J Ishiai, M Rudd, ML Pollock, LM Fogoros, SK Mohamed, H Hanigan, CL Zhang, SY Cruz, P Renaud, G Hansen, NF Cherukuri, PF Borate, B McManus, KJ Stoepel, J Sipahimalani, P Godwin, AK Sgroi, DC Merino, MJ Elliot, G Elkahloun, A Vinson, C Takata, M Mullikin, JC Wolfsberg, TG Hieter, P Lim, DS Myung, K AF Bell, Daphne W. Sikdar, Nilabja Lee, Kyoo-young Price, Jessica C. Chatterjee, Raghunath Park, Hee-Dong Fox, Jennifer Ishiai, Masamichi Rudd, Meghan L. Pollock, Lana M. Fogoros, Sarah K. Mohamed, Hassan Hanigan, Christin L. Zhang, Suiyuan Cruz, Pedro Renaud, Gabriel Hansen, Nancy F. Cherukuri, Praveen F. Borate, Bhavesh McManus, Kirk J. Stoepel, Jan Sipahimalani, Payal Godwin, Andrew K. Sgroi, Dennis C. Merino, Maria J. Elliot, Gene Elkahloun, Abdel Vinson, Charles Takata, Minoru Mullikin, James C. Wolfsberg, Tyra G. Hieter, Philip Lim, Dae-Sik Myung, Kyungjae CA NISC Comparative Sequencing Progra TI Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5 SO PLOS GENETICS LA English DT Article ID REPLICATION-FACTOR-C; COMPARATIVE GENOMIC HYBRIDIZATION; GROSS CHROMOSOMAL REARRANGEMENTS; DNA-POLYMERASE-ETA; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; ENDOMETRIAL CARCINOMA; XERODERMA-PIGMENTOSUM; CELL-LINE; INSTABILITY AB ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5(+/m)) mice that were haploinsuffficient for Atad5. Atad5(+/m) mice displayed high levels of genomic instability in vivo, and Atad5(+/m) mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5(+/m) mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5(+/m) mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis. C1 [Bell, Daphne W.; Price, Jessica C.; Rudd, Meghan L.; Pollock, Lana M.; Fogoros, Sarah K.; Mohamed, Hassan; Hanigan, Christin L.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Sikdar, Nilabja; Lee, Kyoo-young; Park, Hee-Dong; Fox, Jennifer; Lim, Dae-Sik; Myung, Kyungjae] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Chatterjee, Raghunath; Merino, Maria J.; Vinson, Charles] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Park, Hee-Dong; Lim, Dae-Sik] Korea Adv Inst Sci & Technol, Natl Res Lab Genom Stabil, Dept Biol Sci, Taejon 305701, South Korea. [Ishiai, Masamichi; Takata, Minoru] Kyoto Univ, Ctr Radiat Biol, Lab DNA Damage Signaling, Dept Late Effect Studies,Sakyo Ku, Kyoto 606, Japan. [NISC Comparative Sequencing Progra] NIH, NIH Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Zhang, Suiyuan; Cruz, Pedro; Renaud, Gabriel; Hansen, Nancy F.; Cherukuri, Praveen F.; Borate, Bhavesh; Elkahloun, Abdel; Mullikin, James C.; Wolfsberg, Tyra G.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [McManus, Kirk J.; Stoepel, Jan; Sipahimalani, Payal; Hieter, Philip] Univ British Columbia, Michael Smith Labs, Vancouver, BC V5Z 1M9, Canada. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Elliot, Gene] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Bell, DW (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM belldaph@mail.nih.gov; kmyung@mail.nih.gov OI Stoepel, Jan/0000-0002-1559-3852 FU NHGRI, NIH; NCI, NIH; Ministry of Education, Science, Sports, and Culture of Japan; Canadian Institutes of Health Research (CIHR) [MOP-38096]; Korean Research Foundation; NIH [R01 CA140323, RO1-1CA112021-01]; Ovarian Cancer Research Fund; NCI SPORE in breast cancer at Massachusetts General Hospital; Avon Foundation; [U01 CA113916] FX This research was supported by the intramural research program of the NHGRI, NIH, to DWB and KM; the intramural research program of the NCI, NIH, to CV; the Ministry of Education, Science, Sports, and Culture of Japan grant to MT and MI; Canadian Institutes of Health Research (CIHR) grant MOP-38096 (PH); the Korean Research Foundation (KL); NIH R01 CA140323 (AKG); U01 CA113916 (AKG); the Ovarian Cancer Research Fund (AKG); NIH RO1-1CA112021-01 (DCS); the NCI SPORE in breast cancer at Massachusetts General Hospital (DCS); and the Avon Foundation (DCS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 25 Z9 26 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2011 VL 7 IS 8 AR e1002245 DI 10.1371/journal.pgen.1002245 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 812MG UT WOS:000294297000038 PM 21901109 ER PT J AU Cotsapas, C Voight, BF Rossin, E Lage, K Neale, BM Wallace, C Abecasis, GR Barrett, JC Behrens, T Cho, J De Jager, PL Elder, JT Graham, RR Gregersen, P Klareskog, L Siminovitch, KA van Heel, DA Wijmenga, C Worthington, J Todd, JA Hafler, DA Rich, SS Daly, MJ AF Cotsapas, Chris Voight, Benjamin F. Rossin, Elizabeth Lage, Kasper Neale, Benjamin M. Wallace, Chris Abecasis, Goncalo R. Barrett, Jeffrey C. Behrens, Timothy Cho, Judy De Jager, Philip L. Elder, James T. Graham, Robert R. Gregersen, Peter Klareskog, Lars Siminovitch, Katherine A. van Heel, David A. Wijmenga, Cisca Worthington, Jane Todd, John A. Hafler, David A. Rich, Stephen S. Daly, Mark J. CA FOCiS Network Consortia TI Pervasive Sharing of Genetic Effects in Autoimmune Disease SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; CELIAC-DISEASE; SUSCEPTIBILITY LOCI; RISK LOCI; VARIANTS; METAANALYSIS; REPLICATION; ALLELE AB Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis. C1 [Cotsapas, Chris; Voight, Benjamin F.; Rossin, Elizabeth; Neale, Benjamin M.; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Cotsapas, Chris; Voight, Benjamin F.; Rossin, Elizabeth; Lage, Kasper; Neale, Benjamin M.; Daly, Mark J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Cotsapas, Chris; Voight, Benjamin F.; Rossin, Elizabeth; Neale, Benjamin M.; De Jager, Philip L.; Daly, Mark J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Cotsapas, Chris; Hafler, David A.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Cotsapas, Chris; Cho, Judy] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Rossin, Elizabeth] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA. [Rossin, Elizabeth] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA. [Lage, Kasper] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Lage, Kasper] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Wallace, Chris; Todd, John A.] Univ Cambridge, Cambridge Inst Med Res, Juvenile Diabet Res Fdn, Wellcome Trust Diabet & Inflammat Lab,Dept Med Ge, Cambridge, England. [Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Barrett, Jeffrey C.] Wellcome Trust Sanger Inst, Cambridge, England. [Behrens, Timothy; Graham, Robert R.] Genentech Inc, San Francisco, CA 94080 USA. [Cho, Judy] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Cho, Judy] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Elder, James T.] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. [Gregersen, Peter] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Klareskog, Lars] Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden. [Siminovitch, Katherine A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [van Heel, David A.] London Sch Med & Dent, Blizard Inst, London, England. [Wijmenga, Cisca] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Wijmenga, Cisca] Univ Groningen, Groningen, Netherlands. [Worthington, Jane] Univ Manchester, Manchester Acad Hlth Sci Ctr, Sch Translat Med, Arthrit Res UK Epidemiol Unit, Manchester, Lancs, England. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Rossin, Elizabeth] MIT, Boston, MA USA. RP Cotsapas, C (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM mjdaly@atgu.mgh.harvard.edu RI Voight, Benjamin/F-1775-2011; Abecasis, Goncalo/B-7840-2010; Wijmenga, Cisca/D-2173-2009; Siminovitch, Katherine/K-1475-2013; Worthington, Jane/M-9770-2014; OI Cotsapas, Chris/0000-0002-7772-5910; Wallace, Chris/0000-0001-9755-1703; Worthington, Jane/0000-0003-0544-042X; van Heel, David/0000-0002-0637-2265; Klareskog, Lars/0000-0001-9601-6186; Wijmenga, Cisca/0000-0002-5635-1614; Barrett, Jeffrey/0000-0002-1152-370X FU Arthritis Research UK [17552]; NIAMS NIH HHS [R01 AR042742, R01 AR050511, R01 AR054966]; NIDDK NIH HHS [P30 DK043351]; NIGMS NIH HHS [T32 GM007753]; Wellcome Trust [089989, 091157] NR 30 TC 195 Z9 200 U1 2 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2011 VL 7 IS 8 AR e1002254 DI 10.1371/journal.pgen.1002254 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 812MG UT WOS:000294297000043 PM 21852963 ER PT J AU Hamza, TH Chen, HL Hill-Burns, EM Rhodes, SL Montimurro, J Kay, DM Tenesa, A Kusel, VI Sheehan, P Eaaswarkhanth, M Yearout, D Samii, A Roberts, JW Agarwal, P Bordelon, Y Park, Y Wang, LY Gao, JJ Vance, JM Kendler, KS Bacanu, SA Scott, WK Ritz, B Nutt, J Factor, SA Zabetian, CP Payami, H AF Hamza, Taye H. Chen, Honglei Hill-Burns, Erin M. Rhodes, Shannon L. Montimurro, Jennifer Kay, Denise M. Tenesa, Albert Kusel, Victoria I. Sheehan, Patricia Eaaswarkhanth, Muthukrishnan Yearout, Dora Samii, Ali Roberts, John W. Agarwal, Pinky Bordelon, Yvette Park, Yikyung Wang, Liyong Gao, Jianjun Vance, Jeffery M. Kendler, Kenneth S. Bacanu, Silviu-Alin Scott, William K. Ritz, Beate Nutt, John Factor, Stewart A. Zabetian, Cyrus P. Payami, Haydeh TI Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee SO PLOS GENETICS LA English DT Article ID RISK-FACTORS; ASSOCIATION; SMOKING; CAFFEINE; MODEL; TRIAL; ONSET; ISTRADEFYLLINE; METAANALYSIS; VARIANTS AB Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P(2df)=10(-6), GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6x10(-7)) but not in light coffee-drinkers. The a priori Replication hypothesis that "Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers" was confirmed: OR(Replication) = 0.59, P(Replication) = 10(-3); OR(Pooled) = 0.51, P(Pooled) = 7x10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3x10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6x10(-13)). Imputation revealed a block of SNPs that achieved P(2df)<5x10(-8) in GWAIS, and OR = 0.41, P = 3x10(-8) in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients. C1 [Hamza, Taye H.; Hill-Burns, Erin M.; Montimurro, Jennifer; Kay, Denise M.; Kusel, Victoria I.; Sheehan, Patricia; Eaaswarkhanth, Muthukrishnan; Yearout, Dora; Payami, Haydeh] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Chen, Honglei; Gao, Jianjun] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Rhodes, Shannon L.; Ritz, Beate] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Tenesa, Albert] Univ Edinburgh, Roslin Inst, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Yearout, Dora; Samii, Ali; Zabetian, Cyrus P.] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Yearout, Dora; Samii, Ali; Zabetian, Cyrus P.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Roberts, John W.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Agarwal, Pinky] Evergreen Hosp, Med Ctr, Booth Gardner Parkinsons Care Ctr, Kirkland, WA USA. [Bordelon, Yvette; Ritz, Beate] Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Genet, Bethesda, MD 20892 USA. [Wang, Liyong; Vance, Jeffery M.; Scott, William K.] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL 33136 USA. [Wang, Liyong; Vance, Jeffery M.; Scott, William K.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA. [Kendler, Kenneth S.; Bacanu, Silviu-Alin] Virginia Commonwealth Univ, Dept Psychiat, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Ritz, Beate] Univ Calif Los Angeles, Sch Publ Hlth, Ctr Occupat & Environm Hlth, Dept Environm Hlth Sci, Los Angeles, CA 90024 USA. [Nutt, John] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Factor, Stewart A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. RP Hamza, TH (reprint author), New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. EM hpayami@wadsworth.org RI Ritz, Beate/E-3043-2015; OI Kay, Denise/0000-0002-9928-2698; Zabetian, Cyrus/0000-0002-7739-4306; Eaaswarkhanth, Muthukrishnan/0000-0001-9631-8555; Chen, Honglei/0000-0003-3446-7779; Park, Yikyung/0000-0002-6281-489X FU National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS36960, R01 NS067469]; Michael J. Fox Foundation; Department of Veterans Affairs [1I01BX000531]; Close to a Cure Foundation, Research of Foundation for the Carolinas; National Institutes of Health [HHSN268200782096C]; National Institute of Environmental Health Sciences (NIEHS) [R01 ES010544, P01 ES016732]; UCLA Center for Neurodegeneration Science; NINDS [P50 NS038367, P50 NS039764]; NIEHS [Z01-ES-101986]; National Cancer Institute [Z01 CP010196-02] FX NGRC was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) R01 NS36960 and R01 NS067469 (http://www.ninds.nih.gov/) and from the Michael J. Fox Foundation (Edmond J. Safra Global Genetics Consortia) (http://www.michaeljfox.org/). Additional support for subject recruitment was provided by the Department of Veterans Affairs (1I01BX000531) and The Close to a Cure Foundation: A Fund for Parkinson's Research of Foundation for the Carolinas. Genome-wide genotyping was performed at CIDR and funded by the National Institutes of Health (HHSN268200782096C). The PEG study was funded by National Institute of Environmental Health Sciences (NIEHS R01 ES010544 and P01 ES016732), UCLA Center for Neurodegeneration Science, and NINDS (P50 NS038367). The PAGE study was supported by NIEHS (Z01-ES-101986) and the National Cancer Institute (Z01 CP010196-02). HIHG was supported by NINDS (P50 NS039764). Some of the HIHG samples were collected while JMV and WKS were faculty members at Duke University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 80 Z9 80 U1 2 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2011 VL 7 IS 8 AR e1002237 DI 10.1371/journal.pgen.1002237 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 812MG UT WOS:000294297000032 PM 21876681 ER PT J AU Mar, JC Matigian, NA Mackay-Sim, A Mellick, GD Sue, CM Silburn, PA McGrath, JJ Quackenbush, J Wells, CA AF Mar, Jessica C. Matigian, Nicholas A. Mackay-Sim, Alan Mellick, George D. Sue, Carolyn M. Silburn, Peter A. McGrath, John J. Quackenbush, John Wells, Christine A. TI Variance of Gene Expression Identifies Altered Network Constraints in Neurological Disease SO PLOS GENETICS LA English DT Article ID NEURODEVELOPMENTAL HYPOTHESIS; MISSING HERITABILITY; OLFACTORY MUCOSA; COMPLEX DISEASE; STEM-CELLS; SCHIZOPHRENIA; SMOKING; SYSTEM; NOISE AB Gene expression analysis has become a ubiquitous tool for studying a wide range of human diseases. In a typical analysis we compare distinct phenotypic groups and attempt to identify genes that are, on average, significantly different between them. Here we describe an innovative approach to the analysis of gene expression data, one that identifies differences in expression variance between groups as an informative metric of the group phenotype. We find that genes with different expression variance profiles are not randomly distributed across cell signaling networks. Genes with low-expression variance, or higher constraint, are significantly more connected to other network members and tend to function as core members of signal transduction pathways. Genes with higher expression variance have fewer network connections and also tend to sit on the periphery of the cell. Using neural stem cells derived from patients suffering from Schizophrenia (SZ), Parkinson's disease (PD), and a healthy control group, we find marked differences in expression variance in cell signaling pathways that shed new light on potential mechanisms associated with these diverse neurological disorders. In particular, we find that expression variance of core networks in the SZ patient group was considerably constrained, while in contrast the PD patient group demonstrated much greater variance than expected. One hypothesis is that diminished variance in SZ patients corresponds to an increased degree of constraint in these pathways and a corresponding reduction in robustness of the stem cell networks. These results underscore the role that variation plays in biological systems and suggest that analysis of expression variance is far more important in disease than previously recognized. Furthermore, modeling patterns of variability in gene expression could fundamentally alter the way in which we think about how cellular networks are affected by disease processes. C1 [Mar, Jessica C.; Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mar, Jessica C.; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Matigian, Nicholas A.; Mackay-Sim, Alan; Mellick, George D.; McGrath, John J.; Quackenbush, John; Wells, Christine A.] Griffith Univ, Eskitis Inst Cell & Mol Therapies, Natl Ctr Adult Stem Cell Res, Brisbane, Qld 4111, Australia. [Matigian, Nicholas A.] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia. [Sue, Carolyn M.] Royal N Shore Hosp, Kolling Inst Med Res, Dept Neurogenet, Sydney, NSW, Australia. [Sue, Carolyn M.] Univ Sydney, Sydney, NSW 2006, Australia. [Silburn, Peter A.] Univ Queensland, Clin Res Ctr, Brisbane, Qld, Australia. [McGrath, John J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [McGrath, John J.] Univ Queensland, Dept Psychiat, Brisbane, Qld, Australia. [McGrath, John J.] Pk Ctr Mental Hlth, Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia. [Wells, Christine A.] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld, Australia. RP Mar, JC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM jess@jimmy.harvard.edu; john@jimmy.harvard.edu; c.wells@uq.edu.au RI Wells, Christine/A-5071-2010; Matigian, Nicholas/A-4935-2009; McGrath, John/G-5493-2010; Mellick, George/A-7650-2010; Mackay-Sim, Alan/C-3431-2008 OI Wells, Christine/0000-0003-3133-3628; Matigian, Nicholas/0000-0001-7735-9415; McGrath, John/0000-0002-4792-6068; Mellick, George/0000-0002-7211-4651; Mackay-Sim, Alan/0000-0003-4446-5371 FU US National Human Genome Research Institute [P50-HG004233]; Griffith University; Harvard Club of Australia Foundation; US National Library of Medicine [R01-LM010129]; Australian Research Council [LX0882502]; National Health and Medical Research Council Australia [481945]; Australian Stem Cell Centre; Australian Department of Health and Ageing FX JQ and JCM are supported by a grant from the US National Human Genome Research Institute (P50-HG004233). JQ is also supported, in part, by a Jackson Memorial Visiting Fellowship from Griffith University and a Harvard Club of Australia Foundation Fellowship, and from the US National Library of Medicine (R01-LM010129). CAW is supported by the Australian Research Council International linkage scheme (LX0882502), the National Health and Medical Research Council Australia (CDA fellowship 481945), and grants from the Australian Stem Cell Centre. The National Centre for Adult Stem Cell Research is supported by a grant from the Australian Department of Health and Ageing to AM-S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 47 Z9 47 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2011 VL 7 IS 8 AR e1002207 DI 10.1371/journal.pgen.1002207 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 812MG UT WOS:000294297000009 PM 21852951 ER PT J AU Kesarwani, M Hazan, R He, JX Que, YA Apidianakis, Y Lesic, B Xiao, GP Dekimpe, V Milot, S Deziel, E Lepine, F Rahme, LG AF Kesarwani, Meenu Hazan, Ronen He, Jianxin Que, YokAi Apidianakis, Yiorgos Lesic, Biliana Xiao, Gaoping Dekimpe, Valerie Milot, Sylvain Deziel, Eric Lepine, Francois Rahme, Laurence G. TI A Quorum Sensing Regulated Small Volatile Molecule Reduces Acute Virulence and Promotes Chronic Infection Phenotypes SO PLOS PATHOGENS LA English DT Article ID PSEUDOMONAS QUINOLONE SIGNAL; CYSTIC-FIBROSIS PATIENTS; BURKHOLDERIA-PSEUDOMALLEI; DROSOPHILA-MELANOGASTER; HOMOSERINE LACTONES; GENETIC ADAPTATION; AERUGINOSA ENCODES; BACTERIAL; SYSTEM; PATHOGENICITY AB A significant number of environmental microorganisms can cause serious, even fatal, acute and chronic infections in humans. The severity and outcome of each type of infection depends on the expression of specific bacterial phenotypes controlled by complex regulatory networks that sense and respond to the host environment. Although bacterial signals that contribute to a successful acute infection have been identified in a number of pathogens, the signals that mediate the onset and establishment of chronic infections have yet to be discovered. We identified a volatile, low molecular weight molecule, 2-amino acetophenone (2-AA), produced by the opportunistic human pathogen Pseudomonas aeruginosa that reduces bacterial virulence in vivo in flies and in an acute mouse infection model. 2-AA modulates the activity of the virulence regulator MvfR (multiple virulence factor regulator) via a negative feedback loop and it promotes the emergence of P. aeruginosa phenotypes that likely promote chronic lung infections, including accumulation of lasR mutants, long-term survival at stationary phase, and persistence in a Drosophila infection model. We report for the first time the existence of a quorum sensing (QS) regulated volatile molecule that induces bistability phenotype by stochastically silencing acute virulence functions in P. aeruginosa. We propose that 2-AA mediates changes in a subpopulation of cells that facilitate the exploitation of dynamic host environments and promote gene expression changes that favor chronic infections. C1 [Kesarwani, Meenu; Hazan, Ronen; He, Jianxin; Que, YokAi; Apidianakis, Yiorgos; Lesic, Biliana; Xiao, Gaoping; Rahme, Laurence G.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Kesarwani, Meenu; Hazan, Ronen; He, Jianxin; Que, YokAi; Apidianakis, Yiorgos; Lesic, Biliana; Xiao, Gaoping; Rahme, Laurence G.] Massachusetts Gen Hosp, Shriners Burns Inst, Boston, MA 02114 USA. [Dekimpe, Valerie; Milot, Sylvain; Deziel, Eric; Lepine, Francois] INRS Inst Armand Frappier, Laval, PQ, Canada. RP Kesarwani, M (reprint author), Cincinnati Childrens Hosp & Med Ctr, Cincinnati, OH 45229 USA. EM rahme@molbio.mgh.harvard.edu RI Deziel, Eric/A-7678-2008; OI Deziel, Eric/0000-0002-4609-0115; Apidianakis, Yiorgos/0000-0002-7465-3560 FU National Institute of Health [AI063433]; Shriners research grant [8770]; Cystic Fibrosis Foundation [05GO]; Shriners Hospitals [8494]; Swiss National Science Foundation / Swiss Medical Association [PASMP3-123226]; SICPA Foundation FX This work was supported by a National Institute of Health grant (AI063433), a Shriners research grant (#8770), and a Cystic Fibrosis Foundation grant (#05GO) to LGR. RH was supported by a Shriners Hospitals Research Fellowship (#8494). YAQ was supported by a Swiss National Science Foundation / Swiss Medical Association grant (#PASMP3-123226) and a grant from the SICPA Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 34 Z9 34 U1 1 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2011 VL 7 IS 8 AR e1002192 DI 10.1371/journal.ppat.1002192 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 812MR UT WOS:000294298100028 PM 21829370 ER PT J AU Babitt, JL Lin, HY AF Babitt, Jodie L. Lin, Herbert Y. TI The Molecular Pathogenesis of Hereditary Hemochromatosis SO SEMINARS IN LIVER DISEASE LA English DT Review DE Hemochromatosis; iron; hepcidin; bone morphogenetic protein; hemojuvelin; HFE; transferrin receptor 2; ferroportin ID REPULSIVE GUIDANCE MOLECULE; IRON-DEFICIENCY ANEMIA; TRANSFERRIN RECEPTOR 2; AUTOSOMAL-DOMINANT HEMOCHROMATOSIS; MORPHOGENETIC PROTEIN CORECEPTOR; ANTIMICROBIAL PEPTIDE HEPCIDIN; GENOME-WIDE ASSOCIATION; CELL-SURFACE EXPRESSION; JUVENILE HEMOCHROMATOSIS; SERINE-PROTEASE AB Hereditary hemochromatosis is a genetic disorder of iron overload. Over the past 15 years, significant advances have been made in understanding the molecular pathogenesis of this disorder. First, genetic studies linked this disorder to mutations in several genes, including HFE, transferrin receptor 2 (TFR2), hepcidin (HAMP), ferroportin (SLC40A1), and hemojuvelin (HFE2). Recent progress has generated significant insight into the function of these molecules in systemic iron homeostasis, and has revealed that despite the genetic and phenotypic diversity of hereditary hemochromatosis, there are common pathogenic mechanisms underlying this disease. The common downstream mechanism of iron overload in hereditary hemochromatosis is abnormal regulation of the hepcidin-ferroportin axis, leading to a failure to prevent excess iron from entering the circulation. Recent data are starting to unravel the molecular mechanisms by which iron regulates hepcidin production, and has demonstrated a key role for the bone morphogenetic protein-hemojuvelin-SMAD signaling pathway in this process. Future studies will be needed to more fully understand the molecular mechanisms of iron sensing and the roles of HFE and TFR2 in this process. Here, the authors review the current state of knowledge on the molecular pathogenesis of hereditary hemochromatosis. C1 [Babitt, Jodie L.; Lin, Herbert Y.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Program Membrane Biol,Div Nephrol,Ctr Syst Biol, Boston, MA 02114 USA. RP Lin, HY (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Program Membrane Biol,Div Nephrol,Ctr Syst Biol, 185 Cambridge St,CPZN 8216, Boston, MA 02114 USA. EM Lin.herbert@mgh.harvard.edu FU NIH [K08 DK075846, RO1 DK087727, RO1 DK-069533, RO1 DK-071837]; Massachusetts General Hospital FX J.L.B. was supported in part by NIH grants K08 DK075846 and RO1 DK087727, and by a Claflin Distinguished Scholar Award from the Massachusetts General Hospital. H.Y.L. was supported in part by NIH grants RO1 DK-069533 and RO1 DK-071837. NR 151 TC 38 Z9 38 U1 0 U2 10 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 EI 1098-8971 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PD AUG PY 2011 VL 31 IS 3 BP 280 EP 292 DI 10.1055/s-0031-1286059 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 817HF UT WOS:000294661900007 PM 21901658 ER PT J AU Sandefur, BJ Milne, LW AF Sandefur, Benjamin J. Milne, Leslie W. TI IMAGES IN EMERGENCY MEDICINE DIAGNOSIS SO ANNALS OF EMERGENCY MEDICINE LA English DT Editorial Material C1 [Sandefur, Benjamin J.] Harvard Affiliated Emergency Med Residency, Boston, MA USA. [Milne, Leslie W.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Sandefur, BJ (reprint author), Harvard Affiliated Emergency Med Residency, Boston, MA USA. NR 3 TC 1 Z9 1 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD AUG PY 2011 VL 58 IS 2 BP 126 EP + DI 10.1016/j.annemergmed.2011.01.005 PG 2 WC Emergency Medicine SC Emergency Medicine GA 806JN UT WOS:000293803800006 PM 21782550 ER PT J AU Chang, G Weiss, AP Orav, EJ Jones, JA Finn, CT Gitlin, DF Haimovici, F Hazen, E Kosowsky, JM Schechter, MD Rauch, SL AF Chang, Grace Weiss, Anthony P. Orav, Endel John Jones, Jennifer A. Finn, Christine T. Gitlin, David F. Haimovici, Florina Hazen, Eric Kosowsky, Joshua M. Schechter, Mark D. Rauch, Scott L. TI Hospital Variability in Emergency Department Length of Stay for Adult Patients Receiving Psychiatric Consultation: A Prospective Study SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID QUANTILE REGRESSION; VISITS; CARE; TRENDS AB Study objective: We ascertain the components of emergency department (ED) length of stay for adult patients receiving psychiatric evaluation and to examine their variability across 5 hospitals within a health care system. Methods: This was a prospective study of 1,092 adults treated between kine 2008 and May 2009. Research staff abstracted length of stay and clinical information from the medical records. Clinicians completed a time log for each patient contact. Main outcomes were median times for the overall ED length of stay and its 4 components, or time from triage to request for psychiatric evaluation, request to start of psychiatric evaluation, start to completion of psychiatric evaluation with a disposition decision, and disposition decision to discharge from the ED. Results: The overall median length of stay was more than 8 hours. Median times for the components were 1.8 hours from triage to request, 15 minutes from request to start of psychiatric evaluation, 75 minutes from start of psychiatric evaluation to disposition decision, and nearly 3 hours from disposition decision to ED discharge. The median disposition decision to discharge time was substantially shorter for patients who went home (40 minutes) than for patients who were admitted (2.5 hours) or transferred for psychiatric admission at other facilities (6.3 hours). When adjustments for patient and clinical factors were made, differences in ED length of stay persisted between hospitals. Conclusion: ED length of stay for psychiatric patients varied greatly between hospitals, highlighting differences in the organization of psychiatric services and inpatient bed availability. Findings may not generalize to other settings or populations. [Ann Emerg Med. 2011;58:127-136.] C1 [Chang, Grace] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Chang, Grace; Weiss, Anthony P.; Orav, Endel John; Jones, Jennifer A.; Rauch, Scott L.] Partners Psychiat & Mental Hlth, Div Hlth Serv Res, Boston, MA USA. [Chang, Grace; Weiss, Anthony P.; Orav, Endel John; Gitlin, David F.; Haimovici, Florina; Hazen, Eric; Kosowsky, Joshua M.; Schechter, Mark D.] Harvard Univ, Sch Med, Boston, MA USA. [Weiss, Anthony P.; Hazen, Eric] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Finn, Christine T.] Dartmouth Coll, Hitchcock Med Ctr, Lebanon, NH 03756 USA. [Haimovici, Florina] Faulkner Hosp, Jamaica Pl, MA USA. [Hazen, Eric] Newton Wellesley Hosp, Newton, MA USA. [Schechter, Mark D.] N Shore Med Ctr, Salem, MA USA. [Rauch, Scott L.] McLean Hosp, Belmont, MA 02178 USA. RP Chang, G (reprint author), Brigham & Womens Hosp, Dept Psychiat, 221 Longwood Ave, Boston, MA 02115 USA. EM gchang@partners.org FU Partners Psychiatry and Mental Health Division of Health Services Research [K24 AA 000289] FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). This study was supported by the Partners Psychiatry and Mental Health Division of Health Services Research and K24 AA 000289 (Dr. Chang). NR 32 TC 19 Z9 19 U1 2 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD AUG PY 2011 VL 58 IS 2 BP 127 EP 136 DI 10.1016/j.annemergmed.2010.12.003 PG 10 WC Emergency Medicine SC Emergency Medicine GA 806JN UT WOS:000293803800007 PM 21227544 ER PT J AU Pitman, RK Milad, MR Igoe, SA Vangel, MG Orr, SP Tsareva, A Gamache, K Nader, K AF Pitman, Roger K. Milad, Mohammed R. Igoe, Sarah A. Vangel, Mark G. Orr, Scott P. Tsareva, Alina Gamache, Karine Nader, Karim TI Systemic Mifepristone Blocks Reconsolidation of Cue-Conditioned Fear; Propranolol Prevents This Effect SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE memory; conditioning; classical; fear; mifepristone; propranolol ID POSTTRAUMATIC-STRESS-DISORDER; MEMORY RECONSOLIDATION; GLUCOCORTICOID-RECEPTORS; EXTINCTION; AMYGDALA; RETRIEVAL; CORTICOSTERONE; IDENTIFICATION; REACTIVATION; CONTEXT AB Reducing reconsolidation of reactivated traumatic memories may offer a novel pharmacological treatment for posttraumatic stress disorder (PTSD). Preclinical research is needed to identify candidate drugs. We evaluated the ability of postreactivation mifepristone (RU38486, a glucocorticoid antagonist), alone and in combination with propranolol (a beta-adrenergic blocker), both given systemically, to reduce cue-conditioned fear in rats. On Day 1, a 30-s tone conditioned stimulus (CS) was paired with an electric shock unconditioned stimulus (US). On Day 2, the CS was presented without the US (reactivation), and the freezing conditioned response (CR) was measured. This was immediately followed by subcutaneous injection of vehicle, mifepristone 30 mg/kg, propranolol 10 mg/kg, or both. On Day 3, the CR was again measured as a test of postreactivation long-term memory (PR-LTM). On Day 10, the CR was again measured to evaluate spontaneous recovery. On Day 11, the US was presented alone (reinstatement). On Day 12, the CR was again measured. A fifth group received mifepristone without the CS presentation (nonreactivation) on Day 2. A sixth group was tested four hours after the Day 2 mifepristone injection to measure postreactivation short-term memory. Postreactivation, but not nonreactivation, mifepristone produced a decrement in the CR that did not undergo spontaneous recovery and underwent only modest reinstatement. Mifepristone did not exert its effect when administered concurrently with propranolol. Postreactivation mifepristone did not impair short-term memory. Systemic mifepristone blocks the reconsolidation of cue-conditioned fear in rats. Concurrent administration of propranolol prevents this effect. Postreactivation mifepristone may be a promising treatment for PTSD, but not necessarily in combination with propranolol. C1 [Pitman, Roger K.; Milad, Mohammed R.; Igoe, Sarah A.; Vangel, Mark G.; Orr, Scott P.; Tsareva, Alina] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Pitman, Roger K.; Milad, Mohammed R.; Igoe, Sarah A.; Vangel, Mark G.; Orr, Scott P.; Tsareva, Alina] Harvard Med, Boston, MA USA. [Vangel, Mark G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gamache, Karine; Nader, Karim] McGill Univ, Dept Psychol, Montreal, PQ, Canada. RP Pitman, RK (reprint author), MGH E, 120 2nd Ave, Charlestown, MA 02129 USA. EM roger_pitman@hms.harvard.edu FU USARAA [W81XWH-08-2-0126 (PT075809)]; Micro Transponder FX This investigator-initiated study was funded by USARAA Grant #W81XWH-08-2-0126 (PT075809). FINANCIAL DISCLOSURES: All authors receive income from their primary employers. Additionally, Roger Pitman occasionally receives a small royalty for a book chapter on Legal Issues in Post-Traumatic Stress Disorder that he coauthored 14 years ago. He maintains a part-time independent practice of forensic psychiatry and occasionally testifies on matters related to PTSD. Mohammed Milad has received consultation fees from Micro Transponder, a manufacturer of vagal nerve stimulation equipment. Other than the above, no author has received financial support or compensation from any individual corporate entity over the past three years for research or professional service. No author has personal financial holdings that could be perceived as constituting a potential conflict of interest. NR 24 TC 28 Z9 28 U1 0 U2 13 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD AUG PY 2011 VL 125 IS 4 BP 632 EP 638 DI 10.1037/a0024364 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 811VA UT WOS:000294243000016 PM 21688892 ER PT J AU Gandhi, S Sakhuja, R Slovut, DP AF Gandhi, Sanjay Sakhuja, Rahul Slovut, David Paul TI Recent Advances in Percutaneous Management of Iliofemoral and Superficial Femoral Artery Disease SO CARDIOLOGY CLINICS LA English DT Article DE Peripheral arterial disease; Endovascular treatment; Iliac artery; Superficial femoral artery; Percutaneous transluminal angioplasty; Stent ID CUTTING BALLOON ANGIOPLASTY; SINGLE-CENTER EXPERIENCE; CONTROLLED BLUNT MICRODISSECTION; RANDOMIZED CONTROLLED-TRIAL; CHRONIC TOTAL OCCLUSIONS; CRITICAL LIMB ISCHEMIA; STENT IMPLANTATION; TRANSLUMINAL ANGIOPLASTY; MULTICENTER REGISTRY; DISTAL EMBOLIZATION AB Tremendous advances have been made in the endovascular treatment of lower-extremity arterial occlusive disease. New technology has enabled operators to successfully revascularize patients with complex arterial occlusive disease. This article summarizes the latest advances in endovascular therapy of aortoiliac and femoral arteries and reviews the clinical outcomes and costs associated with the use of these treatments. C1 [Slovut, David Paul] Montefiore Med Ctr, Dept Cardiovasc & Thorac Surg, Div Cardiol, Bronx, NY 10467 USA. [Gandhi, Sanjay; Sakhuja, Rahul] Massachusetts Gen Hosp, Div Cardiol, Sect Vasc Med, Boston, MA 02114 USA. RP Slovut, DP (reprint author), Montefiore Med Ctr, Dept Cardiovasc & Thorac Surg, Div Cardiol, 1825 Eastchester Rd, Bronx, NY 10467 USA. EM dslovut@montefiore.org NR 64 TC 2 Z9 4 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8651 J9 CARDIOL CLIN JI Cardiol. Clin. PD AUG PY 2011 VL 29 IS 3 BP 381 EP + DI 10.1016/j.ccl.2011.04.005 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 813MM UT WOS:000294371600008 PM 21803227 ER PT J AU Marroquin, OC Weisbord, S AF Marroquin, Oscar C. Weisbord, Steven TI Cardiovascular Evaluation before Renal Transplantation: To Cath or Not to Cath? SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID MAJOR VASCULAR-SURGERY; MYOCARDIAL-INFARCTION; KIDNEY-TRANSPLANTATION; DISEASE; TRIAL C1 [Marroquin, Oscar C.] Div Cardiol, Pittsburgh, PA 15224 USA. [Marroquin, Oscar C.] UPMC Ctr Heart & Vasc Qual Outcomes & Clin Res, Pittsburgh, PA USA. [Weisbord, Steven] Univ Pittsburgh, Dept Med, Renal Electrolyte Div, Pittsburgh, PA USA. [Marroquin, Oscar C.] Univ Pittsburgh, Med Ctr, Heart & Vasc Ctr Qual Outcomes Clin Res, Pittsburgh, PA USA. [Weisbord, Steven] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Weisbord, Steven] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. RP Marroquin, OC (reprint author), Div Cardiol, Pittsburgh, PA 15224 USA. RI Marroquin, Oscar/F-2214-2015 OI Marroquin, Oscar/0000-0002-0909-0319 NR 13 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD AUG PY 2011 VL 6 IS 8 BP 1807 EP 1809 DI 10.2215/CJN.06420611 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 805IZ UT WOS:000293721400002 PM 21784833 ER PT J AU Srisawat, N Wen, XY Lee, M Kong, L Elder, M Carter, M Unruh, M Finkel, K Vijayan, A Ramkumar, M Paganini, E Singbartl, K Palevsky, PM Kellum, JA AF Srisawat, Nattachai Wen, Xiaoyan Lee, MinJae Kong, Lan Elder, Michele Carter, Melinda Unruh, Mark Finkel, Kevin Vijayan, Anitha Ramkumar, Mohan Paganini, Emil Singbartl, Kai Palevsky, Paul M. Kellum, John A. TI Urinary Biomarkers and Renal Recovery in Critically Ill Patients with Renal Support SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE KIDNEY INJURY; HEPATOCYTE GROWTH-FACTOR; GELATINASE-ASSOCIATED LIPOCALIN; EARLY PREDICTIVE BIOMARKER; INTENSIVE-CARE-UNIT; CYSTATIN-C; REPLACEMENT THERAPY; ADVERSE OUTCOMES; CARDIAC-SURGERY; EARLY MARKER AB Background and objectives Despite significant advances in the epidemiology of acute kidney injury (AKI), prognostication remains a major clinical challenge. Unfortunately, no reliable method to predict renal recovery exists. The discovery of biomarkers to aid in clinical risk prediction for recovery after AKI would represent a significant advance over current practice. Design, setting, participants, & measurements We conducted the Biological Markers of Recovery for the Kidney study as an ancillary to the Acute Renal Failure Trial Network study. Urine samples were collected on days 1, 7, and 14 from 76 patients who developed AM and received renal replacement therapy (RRT) in the intensive care unit. We explored whether levels of urinary neutrophil gelatinase-associated lipocalin (uN-GAL), urinary hepatocyte growth factor (uHGF), urinary cystatin C (uCystatin C), IL-18, neutrophil gelatinase-associated lipocalin/matrix metalloproteinase-9, and urine creatinine could predict subsequent renal recovery. Results We defined renal recovery as alive and free of dialysis at 60 days from the start of RRT. Patients who recovered had higher uCystatin C on day 1 (7.27 versus 6.60 ng/mg(center dot)creatinine) and lower uHGF on days 7 and 14 (2.97 versus 3.48 ng/mg(center dot)creatinine; 2.24 versus 3.40 ng/mg(center dot)creatinine). For predicting recovery, decreasing uNGAL and uHGF in the first 14 days was associated with greater odds of renal recovery. The most predictive model combined relative changes in biomarkers with clinical variables and resulted in an area under the receiver-operator characteristic curve of 0.94. Conclusions We showed that a panel of urine biomarkers can augment clinical risk prediction for recovery after AKI. Clin J Am Soc Nephrol 6: 1815-1823, 2011. doi: 10.2215/CJN.11261210 C1 [Srisawat, Nattachai; Wen, Xiaoyan; Lee, MinJae; Kong, Lan; Elder, Michele; Carter, Melinda; Unruh, Mark; Singbartl, Kai; Palevsky, Paul M.; Kellum, John A.] Univ Pittsburgh, Sch Med, Dept Crit Care Med, CRISMA Clin Res Invest & Syst Modeling Acute Illn, Pittsburgh, PA 15261 USA. [Unruh, Mark; Ramkumar, Mohan; Palevsky, Paul M.; Kellum, John A.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA. [Lee, MinJae; Kong, Lan] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Finkel, Kevin] Univ Texas Houston, Sch Med, Dept Med, Div Renal Dis & Hypertens, Houston, TX 77030 USA. [Vijayan, Anitha] Washington Univ, Dept Med, Div Renal Dis, St Louis, MO USA. [Ramkumar, Mohan; Palevsky, Paul M.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA 15261 USA. [Ramkumar, Mohan; Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Paganini, Emil] Cleveland Clin Fdn, Dept Hypertens & Nephrol, Cleveland, OH 44195 USA. RP Kellum, JA (reprint author), Univ Pittsburgh, Sch Med, Dept Crit Care Med, CRISMA Clin Res Invest & Syst Modeling Acute Illn, 604 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM kellumja@ccm.upmc.edu OI Palevsky, Paul/0000-0002-7334-5400 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK070910, Y1-DK-3508-01]; Department of Veterans Affairs Office of Research and Development [530] FX BioMaRK was supported by a grant (R01DK070910) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of NIDDK or NIH. The VA/NIH ATN study was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development (CSP #530) and by NIDDK by interagency agreement Y1-DK-3508-01. N.S. and X.W. contributed equally to this manuscript. NR 34 TC 52 Z9 57 U1 1 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD AUG PY 2011 VL 6 IS 8 BP 1815 EP 1823 DI 10.2215/CJN.11261210 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 805IZ UT WOS:000293721400005 PM 21757640 ER PT J AU Carvalho, C Isakova, T Collerone, G Olbina, G Wolf, M Westerman, M Gutierrez, OM AF Carvalho, C. Isakova, T. Collerone, G. Olbina, G. Wolf, M. Westerman, M. Gutierrez, O. M. TI Hepcidin and disordered mineral metabolism in chronic kidney disease SO CLINICAL NEPHROLOGY LA English DT Article DE iron; phosphorus; vitamin D ID GLOMERULAR-FILTRATION-RATE; CHRONIC-RENAL-FAILURE; VITAMIN-D DEFICIENCY; HEMODIALYSIS-PATIENTS; PARATHYROID-HORMONE; MAINTENANCE HEMODIALYSIS; INTRAVENOUS CALCITRIOL; HEMOGLOBIN LEVEL; SECONDARY HYPERPARATHYROIDISM; BONE-RESORPTION AB Background: Hepcidin regulates iron homeostasis by blocking iron absorption from the gut and iron release from macrophage and hepatocyte stores. Hepcidin levels are elevated in kidney failure and thus, are thought to contribute to dysregulation of iron homeostasis in chronic kidney disease (CKD). However, the primary factors associated with increased hepcidin levels in CKD patients have not been well-defined. In particular, few studies examined the relationships between hepcidin and disorders of mineral metabolism, which are among the earliest and most common complications of CKD. Methods: We examined the associations between hepcidin, iron indexes, and markers of mineral metabolism in 125 patients from across the spectrum of pre-dialysis CKD. Bioactive hepcidin levels were measured in serum samples by competitive ELISA. Results: Hepcidin was inversely associated with eGFR and linearly associated with ferritin (p < 0.001 for both). In unadjusted analyses, increased serum phosphate and parathyroid hormone (PTH) and decreased 1,25-dihydroxyvitamin D (1,25(OH)(2)D) levels were associated with increased hepcidin. When examined in forward stepwise regression analysis, higher phosphate and PTH levels and lower 1,25(OH)(2)D and FGF23 levels were selected as independent predictors of higher hepcidin levels, whereas there was no association between eGFR and hepcidin. Conclusions: Abnormalities in phosphate and vitamin D metabolism were associated with increased hepcidin levels independently of eGFR in CKD patients. These findings suggest that disorders of mineral metabolism may promote increased hepcidin secretion in CKD. Whether inflammation mediates these associations requires further study. C1 [Carvalho, C.; Wolf, M.; Gutierrez, O. M.] Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Isakova, T.; Collerone, G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Nephrol Div, Boston, MA USA. [Olbina, G.; Westerman, M.] Intrins LifeSci, La Jolla, CA USA. RP Gutierrez, OM (reprint author), Univ Alabama Birmingham, ZRB 614,1530 3rd AVE S, Birmingham, AL 35294 USA. EM ogutierr@uab.edu FU American Kidney Fund Clinical Scientist in Nephrology Fellowship; [K23DK081673]; [R01DK076116]; [R01DK081374] FX Dr. Gutierrez was supported by grant K23DK081673. Dr. Wolf was supported by grants R01DK076116 and R01DK081374. Dr. Isakova was supported by an American Kidney Fund Clinical Scientist in Nephrology Fellowship. NR 47 TC 8 Z9 8 U1 0 U2 15 PU DUSTRI-VERLAG DR KARL FEISTLE PI DEISENHOFEN-MUENCHEN PA BAHNHOFSTRASSE 9 POSTFACH 49, D-82032 DEISENHOFEN-MUENCHEN, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD AUG PY 2011 VL 76 IS 2 BP 90 EP 98 DI 10.5414/CN107018 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 813KD UT WOS:000294364500002 PM 21762639 ER PT J AU Wang, F Bhat, K Doucette, M Zhou, S Gu, Y Law, B Liu, X Wong, ET Kang, JX Hsieh, TC Qian, SY Wu, E AF Wang, F. Bhat, K. Doucette, M. Zhou, S. Gu, Y. Law, B. Liu, X. Wong, E. T. Kang, J. X. Hsieh, T. -C. Qian, S. Y. Wu, E. TI Docosahexaenoic Acid (DHA) Sensitizes Brain Tumor Cells to Etoposide-Induced Apoptosis SO CURRENT MOLECULAR MEDICINE LA English DT Review DE Apoptosis; docosahexaenoic acid; etoposide; glioblastoma; medulloblastoma ID DEPENDENT PROTEIN-KINASE; PROSTATE-CANCER CELLS; SIGNALING PATHWAYS; RAS/MAPK PATHWAY; DNA-PKCS; KAPPA-B; GROWTH; CD44; EXPRESSION; MIGRATION AB In this study, we investigated whether DHA, a nutritionally important n-3 unsaturated fatty acid, modulated the sensitivity of brain tumor cells to the anticancer drug, etoposide (VP16). Medulloblastoma (MB) cell lines, Daoy and D283, and glioblastoma (GBM) cell lines, U138 and U87, were exposed to DHA or VP16 alone or in combination. The effects on cell proliferation and the induction of apoptosis were determined by using MTS and Hoechest 33342/PI double staining. U87 and U138 cells were found to be insensitive to the addition of DHA and VP16, whereas the two MB cell lines showed high sensitivity. DHA or VP16 alone showed little effect on cell proliferation or death in either the MB or GBM cell lines, but pretreatment with DHA enhanced the responsiveness to VP16 in the MB cell lines. To understand the mechanisms of combined DHA and VP16 on MB cells, pathway specific oligo array analyses were performed to dissect possible signaling pathways involved. The addition of DHA and VP16, in comparison to VP16 added alone, resulted in marked suppression in the expression of several genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis, including PRKDC, Survivin, PIK3R1, MAPK14, NF kappa B1, NF kappa BIA, BCL2, CD44, and MAT1. These results suggest (1) that the effects of DHA and VP16 in brain tumor cells are mediated in part by the down regulation of events involved in DNA repair and the PI3K/MAPK signaling pathways and (2) that brain tumors genotypically mimicked by MB cells may benefit from therapies combining DHA with VP16. C1 [Wang, F.; Bhat, K.; Doucette, M.; Zhou, S.; Gu, Y.; Law, B.; Qian, S. Y.; Wu, E.] N Dakota State Univ, Dept Pharmaceut Sci, Fargo, ND 58105 USA. [Liu, X.] Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Amarillo, TX 79106 USA. [Wong, E. T.] Harvard Univ, Sch Med, Brain Tumor Ctr, Boston, MA 02115 USA. [Wong, E. T.] Harvard Univ, Sch Med, Neurooncol Unit, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Kang, J. X.] Massachusetts Gen Hosp, Lab Lipid Med & Technol, Charlestown, MA 02129 USA. [Kang, J. X.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Hsieh, T. -C.] New York Med Coll, Dept Biochem & Mol Biol, Valhalla, NY 10595 USA. RP Wu, E (reprint author), N Dakota State Univ, Dept Pharmaceut Sci, NDSU Dept 2665, 203 Sudro Hall,POB 6050, Fargo, ND 58108 USA. EM erxi.wu@ndsu.edu FU NCI/NIH [1R15CA140833]; NCRR/NIH [5P20 RR015566]; Reason To Ride research fund; ND EPSCoR; North Dakota State University faculty funds; National Center for Research Resources (NCRR), National Institutes of Health (NIH) [NIH P20 RR020151] FX We thank Dr. Chenwen Sun (North Dakota State University) and Dr. Bin Guo (North Dakota State University) for their discussions during this study. We wish to extend our thanks to Mary Pull (North Dakota State University) for her thoughtful reading of the manuscript. This project was supported by NCI/NIH 1R15CA140833 (SQ), NCRR/NIH 5P20 RR015566 (SQ), A Reason To Ride research fund (ETW), ND EPSCoR (EW), North Dakota State University faculty funds (EW), and Pilot Project Grant (EW) from the Centers of Biomedical Research Excellence (COBRE) grant NIH P20 RR020151 from the National Center for Research Resources (NCRR). NCRR is a component of the National Institutes of Health (NIH). The contents of this report are solely the responsibility of the authors and do not necessarily reflect the official views of the NIH or NCRR. NR 49 TC 12 Z9 14 U1 0 U2 6 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD AUG PY 2011 VL 11 IS 6 BP 503 EP 511 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 814AG UT WOS:000294413100007 PM 21663587 ER PT J AU Frullano, L Caravan, P AF Frullano, Luca Caravan, Peter TI Strategies for the Preparation of Bifunctional Gadolinium(III) Chelators SO CURRENT ORGANIC SYNTHESIS LA English DT Article DE Bifunctional chelator; Gadolinium; Magnetic Resonance Imaging; Lanthanide; Bioconjugate; Molecular Imaging; DOTA; DTPA ID MRI CONTRAST AGENTS; HUMAN SERUM-ALBUMIN; MAGNETIC-RESONANCE ANGIOGRAPHY; NEPHROGENIC SYSTEMIC FIBROSIS; LABELED MONOCLONAL-ANTIBODY; FAST WATER EXCHANGE; X-RAY-STRUCTURE; HUMAN COLORECTAL-CARCINOMA; IN-VIVO BIODISTRIBUTION; SOLID-PHASE SYNTHESIS AB The development of gadolinium chelators that can be easily and readily linked to various substrates is of primary importance for the development high relaxation efficiency and/or targeted magnetic resonance imaging (MRI) contrast agents. Over the last 25 years a large number of bifunctional chelators have been prepared. For the most part, these compounds are based on ligands that are already used in clinically approved contrast agents. More recently, new bifunctional chelators have been reported based on complexes that show a more potent relaxation effect, faster complexation kinetics and in some cases simpler synthetic procedures. This review provides an overview of the synthetic strategies used for the preparation of bifunctional chelators for MRI applications. C1 [Caravan, Peter] Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Frullano, Luca] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Caravan, P (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu FU National Institute of Biomedical Imaging and Biomedical Engineering [EB009062-01A1, EB009062-01A1S2, EB009738-01] FX PC acknowledges research support from the National Institute of Biomedical Imaging and Biomedical Engineering through grants EB009062-01A1, EB009062-01A1S2 and EB009738-01. NR 312 TC 30 Z9 30 U1 3 U2 44 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1794 J9 CURR ORG SYNTH JI Curr. Org. Synth. PD AUG PY 2011 VL 8 IS 4 BP 535 EP 565 PG 31 WC Chemistry, Organic SC Chemistry GA 813ZR UT WOS:000294410500006 PM 22375102 ER PT J AU Schwarz, AJ Becerra, L Upadhyay, J Anderson, J Baumgartner, R Coimbra, A Evelhoch, J Hargreaves, R Robertson, B Lyengar, S Tauscher, J Bleakman, D Borsook, D AF Schwarz, Adam J. Becerra, Lino Upadhyay, Jaymin Anderson, Julie Baumgartner, Richard Coimbra, Alexander Evelhoch, Jeff Hargreaves, Richard Robertson, Brigitte Lyengar, Smriti Tauscher, Johannes Bleakman, David Borsook, David TI A procedural framework for good imaging practice in pharmacological fMRI studies applied to drug development #2: protocol optimization and best practices SO DRUG DISCOVERY TODAY LA English DT Review ID QUALITY-ASSURANCE; MULTICENTER FMRI; CLINICAL-TRIALS; MULTISITE FMRI; FUNCTIONAL MRI; CRITICAL PATH; BOLD-FMRI; REPRODUCIBILITY; RECOMMENDATIONS; RELIABILITY AB Functional magnetic resonance imaging (fMRI) experiments are more complex compared with standard radiological imaging, involving additional data streams and hardware along with complex analysis methods. Here, we propose guidelines based around mitigating risks associated with the complexities of the technique at the level of the individual imaging protocol, including workable and effective quality assurance/quality control procedures and rigorous, predefined, analysis pipelines. Our aim is to provide a framework for 'good imaging practice' (GIP), enabling these requirements to be addressed at an appropriate level of detail. The development of a procedural framework for GIP in pharmaceutical fMRI studies could lead to greater acceptance of the method within industry and facilitate validation and, eventually, qualification of the technique as an imaging biomarker. C1 [Schwarz, Adam J.; Becerra, Lino; Upadhyay, Jaymin; Anderson, Julie; Baumgartner, Richard; Coimbra, Alexander; Evelhoch, Jeff; Hargreaves, Richard; Lyengar, Smriti; Tauscher, Johannes; Bleakman, David; Borsook, David] McLean Hosp, Imaging Consortium Drug Dev, Belmont, MA 02478 USA. [Schwarz, Adam J.; Lyengar, Smriti; Tauscher, Johannes; Bleakman, David] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Baumgartner, Richard; Coimbra, Alexander; Evelhoch, Jeff; Hargreaves, Richard] Merck Res Labs, West Point, PA 19486 USA. [Robertson, Brigitte] Sepracor Inc, Marlborough, MA 01752 USA. [Becerra, Lino; Borsook, David] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Becerra, Lino; Upadhyay, Jaymin; Anderson, Julie; Borsook, David] McLean Hosp, PAIN Grp, Brain Imaging Ctr, Belmont, MA 02478 USA. RP Schwarz, AJ (reprint author), McLean Hosp, Imaging Consortium Drug Dev, 115 Mill St, Belmont, MA 02478 USA. EM a.schwarz@lilly.com RI Tauscher, Johannes/M-5976-2016 NR 42 TC 15 Z9 15 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD AUG PY 2011 VL 16 IS 15-16 BP 671 EP 682 DI 10.1016/j.drudis.2011.03.011 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 812SO UT WOS:000294313400005 PM 21477664 ER PT J AU Chen, Q Lv, S Zou, L Gong, Q Dai, G Xue, X Zhou, D AF Chen, Q. Lv, S. Zou, L. Gong, Q. Dai, G. Xue, X. Zhou, D. TI DIFFERENT FUNCTIONAL CONNECTIVITY OF THALAMOHIPPOCAMPUS CIRCUITY IN TEMPORAL LOBE EPILEPSY WITH AND WITHOUT HIPPOCAMAL SCLEROSIS: A RESTING-STATE fMRI STUDY SO EPILEPSIA LA English DT Meeting Abstract CT 29th International Epilepsy Congress CY AUG 28-SEP 01, 2011 CL Rome, ITALY C1 [Chen, Q.; Xue, X.; Zhou, D.] Sichuan Univ, Dept Neurol, W China Hosp, Chengdu 610064, Peoples R China. [Lv, S.; Zou, L.; Gong, Q.] Sichuan Univ, Dept Radiol, W China Hosp, Chengdu 610064, Peoples R China. [Dai, G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD AUG PY 2011 VL 52 SU 6 SI SI BP 181 EP 182 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 811NE UT WOS:000294217200585 ER PT J AU Lieb, W Pencina, MJ Jacques, PF Wang, TJ Larson, MG Levy, D Kannel, WB Vasan, RS AF Lieb, Wolfgang Pencina, Michael J. Jacques, Paul F. Wang, Thomas J. Larson, Martin G. Levy, Daniel Kannel, William B. Vasan, Ramachandran S. TI Higher aldosterone and lower N-terminal proatrial natriuretic peptide as biomarkers of salt sensitivity in the community SO EUROPEAN JOURNAL OF CARDIOVASCULAR PREVENTION & REHABILITATION LA English DT Article DE Salt sensitivity; aldosterone; N-terminal proatrial natriuretic peptide; ANP ID FOOD FREQUENCY QUESTIONNAIRE; METABOLIC RISK-FACTORS; BLOOD-PRESSURE; GLOMERULAR-FILTRATION; SODIUM-INTAKE; HYPERTENSION; ASSOCIATION; POTASSIUM; PLASMA; MICE AB Background: Salt sensitivity, a trait characterized by a pressor blood pressure response to increased dietary salt intake, has been associated with higher rates of cardiovascular target organ damage and cardiovascular disease events. Recent experimental studies have highlighted the potential role of the natriuretic peptides and aldosterone in mediating salt sensitivity. Design: Prospective cohort study. Methods: We evaluated 1575 non-hypertensive Framingham Offspring cohort participants (mean age 55 +/- 9 years, 58% women) who underwent routine measurements of circulating aldosterone and N-terminal proatrial natriuretic peptide (NT-ANP) and assessment of dietary sodium intake. Participants were categorized as potentially 'salt sensitive' if their serum aldosterone was > sex-specific median but plasma NT-ANP was <= sex-specific median value. Dietary sodium intake was categorized as lower versus higher (dichotomized at the sex-specific median). We used multivariable linear regression to relate presence of salt sensitivity (as defined above) to longitudinal changes (Delta) in systolic and diastolic blood pressure on follow-up (median four years). Results: Participants who were 'salt sensitive' (N=437) experienced significantly greater increases in blood pressure (Delta systolic, +4.4 and +2.3 mmHg; Delta diastolic, +1.9 and -0.3 mmHg; on a higher versus lower sodium diet, respectively) as compared to the other participants (Delta systolic, +2.8 and +1.0 mmHg; Delta diastolic, +0.5 and -0.2 mmHg; on higher versus lower sodium diet, respectively; P=0.033 and P=0.0127 for differences between groups in Delta systolic and Delta diastolic blood pressure, respectively). Conclusions: Our observational data suggest that higher circulating aldosterone and lower NT-ANP concentrations may be markers of salt sensitivity in the community. Additional studies are warranted to confirm these observations. C1 [Lieb, Wolfgang; Levy, Daniel; Kannel, William B.; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Pencina, Michael J.; Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Jacques, Paul F.] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer US Dept Agr, Boston, MA 02111 USA. [Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM vasan@bu.edu RI Lieb, Wolfgang/C-1990-2012; OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI [N01-HC-25195, 2 K24 HL04334]; US Department of Agriculture, Agricultural Research Service [58-1950-7-707] FX This work was supported by NHLBI Contract N01-HC-25195 and 2 K24 HL04334 (to RSV); and the US Department of Agriculture, Agricultural Research Service, agreement No. 58-1950-7-707. NR 38 TC 3 Z9 5 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1741-8267 J9 EUR J CARDIOV PREV R JI Eur. J. Cardiovasc. Prev. Rehabil. PD AUG PY 2011 VL 18 IS 4 BP 664 EP 673 DI 10.1177/1741826710389406 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 813ON UT WOS:000294376900018 PM 21450637 ER PT J AU Izar, B Abu Mraheil, M Hain, T AF Izar, Benjamin Abu Mraheil, Mobarak Hain, Torsten TI Identification and Role of Regulatory Non-Coding RNAs in Listeria monocytogenes SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES LA English DT Review DE Listeria monocytogenes; sRNA; asRNA; riboswitch; non-coding RNA; regulatory RNA; RNA-Seq; whole genome tiling arrays; infection; UTR ID GENOME-WIDE ANALYSIS; CONTROLS EXPRESSION; VIRULENCE; GENES; HFQ; STREPTOCOCCUS; SALMONELLA; PREDICTION; PROTEINS; SIGMA(B) AB Bacterial regulatory non-coding RNAs control numerous mRNA targets that direct a plethora of biological processes, such as the adaption to environmental changes, growth and virulence. Recently developed high-throughput techniques, such as genomic tiling arrays and RNA-Seq have allowed investigating prokaryotic cis- and trans-acting regulatory RNAs, including sRNAs, asRNAs, untranslated regions (UTR) and riboswitches. As a result, we obtained a more comprehensive view on the complexity and plasticity of the prokaryotic genome biology. Listeria monocytogenes was utilized as a model system for intracellular pathogenic bacteria in several studies, which revealed the presence of about 180 regulatory RNAs in the listerial genome. A regulatory role of non-coding RNAs in survival, virulence and adaptation mechanisms of L. monocytogenes was confirmed in subsequent experiments, thus, providing insight into a multifaceted modulatory function of RNA/mRNA interference. In this review, we discuss the identification of regulatory RNAs by high-throughput techniques and in their functional role in L. monocytogenes. C1 [Izar, Benjamin; Abu Mraheil, Mobarak; Hain, Torsten] Univ Giessen, Inst Med Microbiol, D-35392 Giessen, Germany. [Izar, Benjamin] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02118 USA. RP Hain, T (reprint author), Univ Giessen, Inst Med Microbiol, Frankfurter Str 107, D-35392 Giessen, Germany. EM Benjamin.Izar@med.uni-giessen.de; Mobarak.Mraheil@mikrobio.med.uni-giessen.de; Torsten.Hain@mikrobio.med.uni-giessen.de FU German Federal Ministry of Education and Research (BMBF ERA-NET Pathogenomics Network) [62080061] FX This work was supported by grants from the German Federal Ministry of Education and Research (BMBF ERA-NET Pathogenomics Network to the sncRNAomics project (62080061) to T.H. NR 40 TC 10 Z9 15 U1 0 U2 8 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1422-0067 J9 INT J MOL SCI JI Int. J. Mol. Sci. PD AUG PY 2011 VL 12 IS 8 BP 5070 EP 5079 DI 10.3390/ijms12085070 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary SC Biochemistry & Molecular Biology; Chemistry GA 811XD UT WOS:000294250800024 PM 21954346 ER PT J AU Courville, EL Lew, M Sadow, PM AF Courville, Elizabeth L. Lew, Madelyn Sadow, Peter M. TI Routine Evaluation of Adult Tonsillectomy Specimens: Toward Establishing a New Standard of Care SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE tonsil; triage; adult; malignancy ID PALATINE TONSIL; PATHOLOGICAL EXAMINATION; MICROSCOPIC EXAMINATION; HISTOLOGIC EXAMINATION; ADENOIDECTOMY; METASTASIS; CHILDREN; ADENOCARCINOMA; MALIGNANCY; CARCINOMA AB Tonsil excision is a common surgery for both children and adults. Prior studies have consistently shown that the rate of malignancy in tonsil specimens is low and that the possibility of true, occult malignancy is remote. Practice trends accept triage of pediatric tonsillectomies for exemption or gross exam only. However, for adults, despite a low malignancy rate, routine histological evaluation of tonsillectomy specimens is standard of care at most health care facilities. The authors performed a retrospective review of all tonsil specimens received in their department over 45 months with categorization of pathological diagnosis and surgical indication. Of 1746 adult tonsillectomy specimens removed during this time, there were no incidental/occult malignancies. These data indicate that gross examination of adult tonsillectomy specimens excised for chronic tonsillitis or sleep apnea is sound practice, and this, taken together with other published data, provides a basis for consensus-derived practice guidelines. C1 [Sadow, Peter M.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Courville, Elizabeth L.; Lew, Madelyn; Sadow, Peter M.] Harvard Univ, Sch Med, Boston, MA USA. [Sadow, Peter M.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Sadow, PM (reprint author), Massachusetts Gen Hosp, Pathol Serv, 55 Fruit St,WRN-219, Boston, MA 02114 USA. EM psadow@partners.org NR 39 TC 3 Z9 3 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD AUG PY 2011 VL 19 IS 4 BP 469 EP 475 DI 10.1177/1066896911402069 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA 814KJ UT WOS:000294449600007 PM 21427094 ER PT J AU Lei, HT Rheaume, MA Velez, G Mukai, S Kazlauskas, A AF Lei, Hetian Rheaume, Marc-Andre Velez, Gisela Mukai, Shizuo Kazlauskas, Andrius TI Expression of PDGFR alpha Is a Determinant of the PVR Potential of ARPE19 Cells SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID EXPERIMENTAL PROLIFERATIVE VITREORETINOPATHY; GROWTH-FACTOR RECEPTOR; RETINAL-DETACHMENT; EPIRETINAL MEMBRANES; EPITHELIAL-CELLS; MODEL AB PURPOSE. Previous studies indicate that the expression of platelet-derived growth factor (PDGF) receptor alpha (PDGFR alpha) dramatically increases the ability of fibroblasts to induce experimental proliferative vitreoretinopathy (PVR). The purpose of this study was to determine whether PDGFR alpha contributed to the PVR potential of retinal pigment epithelial (RPE) cells, one of the most abundant cell types in PVR membranes. METHODS. PDGFR alpha expression in human ARPE19 cells was increased or decreased by stably expressing the PDGFR alpha cDNA or short hairpin (sh) RNA directed at PDGFR alpha, respectively. The level of PDGFR alpha expression in the resulting panel of cell lines was either barely detectable (KD), standard (similar to the level of primary RPE cells), or overexpressed approximately 80-fold. Western blot analysis was used to assess the level of p53 and the activation state of PDGFR alpha and Akt. The following cellular responses were monitored: proliferation, apoptosis, and contraction. The PVR potential of cells was tested in a rabbit model of PVR in which cells were coinjected with platelet-rich plasma into the vitreous. RESULTS. Comparison of KD and overexpressing cells indicated that high-level expression of PDGFR alpha dramatically augmented signaling events, cellular responses, and the PVR potential of ARPE19 cells. However, all these outcomes were also significantly increased, albeit not as robustly, by PDGFR alpha expression to the level typically present in RPE cells. CONCLUSIONS. Even though RPE cells express substantially less PDGFR alpha than fibroblasts, it significantly boosts PVR-related signaling events, cellular responses, and the PVR potential of ARPE19 cells. These studies suggest that inhibiting activation, signaling, or both by PDGFR alpha has the potential to prevent the development of PVR. (Invest Ophthalmol Vis Sci. 2011; 52: 5016-5021) DOI: 10.1167/iovs.11-7442 C1 [Lei, Hetian; Velez, Gisela; Kazlauskas, Andrius] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Rheaume, Marc-Andre; Mukai, Shizuo] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Kazlauskas, A (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM ak@eri.harvard.edu FU National Institutes of Health [EY012509] FX Supported by National Institutes of Health Grant EY012509 (AK). NR 29 TC 25 Z9 28 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2011 VL 52 IS 9 BP 5016 EP 5021 DI 10.1167/iovs.11-7442 PG 6 WC Ophthalmology SC Ophthalmology GA 815SI UT WOS:000294548300002 PM 21642621 ER PT J AU Chowdhury, UR Jea, SY Oh, DJ Rhee, DJ Fautsch, MP AF Chowdhury, Uttio Roy Jea, Seung-Youn Oh, Dong-Jin Rhee, Douglas J. Fautsch, Michael P. TI Expression Profile of the Matricellular Protein Osteopontin in Primary Open-Angle Glaucoma and the Normal Human Eye SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID HUMAN TRABECULAR MESHWORK; INCREASES OUTFLOW RESISTANCE; AQUEOUS-HUMOR; INTRAOCULAR-PRESSURE; GENE-EXPRESSION; EXTRACELLULAR-MATRIX; DEFICIENT MICE; OPTIC-NERVE; CELLS; TISSUE AB PURPOSE. To characterize the role of osteopontin (OPN) in primary open-angle glaucoma (POAG) and normal eyes. METHODS. OPN quantification was performed by enzyme-linked immunosorbent assay in aqueous humor (AH) obtained from human donor eyes (POAG and normal) and surgical samples (POAG and elective cataract removal). OPN expression and localization in whole eye tissue sections and primary normal human trabecular meshwork (NTM) cells were studied by Western blot and immunohistochemistry. Latanoprost-free acid (LFA)-treated NTM cells were analyzed for OPN gene and protein expression. Intraocular pressure was measured by tonometry, and central corneal thickness was measured by optical coherence tomography in young OPN(-/-) and wild-type mice. RESULTS. OPN levels were significantly reduced in donor POAG AH compared with normal AH (0.54 +/- 0.18 ng/mu g [n = 8] vs. 0.77 +/- 0.23 ng/mu g [n = 9]; P = 0.039). A similar trend was observed in surgical AH (1.05 +/- 0.31 ng/mu g [n = 20] vs. 1.43 +/- 0.88 ng/mu g [n = 20]; P = 0.083). OPN was present in the trabecular meshwork, corneal epithelium and endothelium, iris, ciliary body, retina, vitreous humor, and optic nerve. LFA increased OPN gene expression, but minimal change in OPN protein expression was observed. No difference in intraocular pressure (17.5 +/- 2.0 mm Hg [n = 56] vs. 17.3 +/- 1.9 mm Hg [n = 68]) but thinner central corneal thickness (91.7 +/- 3.6 mu m [n = 50] vs. 99.2 +/- 5.5 mu m [n = 70]) was noted between OPN(-/-) and wild-type mice. CONCLUSIONS. OPN is widely distributed in the human eye and was found in lower concentrations in POAG AH. Reduction of OPN in young mice does not affect IOP. (Invest Ophthalmol Vis Sci. 2011; 52: 6443-6451) DOI: 10.1167/iovs.11-7409 C1 [Chowdhury, Uttio Roy; Fautsch, Michael P.] Mayo Clin, Dept Ophthalmol, Rochester, MN 55905 USA. [Jea, Seung-Youn; Oh, Dong-Jin; Rhee, Douglas J.] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Fautsch, MP (reprint author), Mayo Clin, Dept Ophthalmol, 200 1st St SW, Rochester, MN 55905 USA. EM fautsch.michael@mayo.edu FU National Institutes of Health [EY 07065, EY 15736, EY 019654]; Mayo Foundation; Research to Prevent Blindness; Department of Ophthalmology, Mayo Clinic FX Supported in part by National Institutes of Health Research Grants EY 07065 (MPF), EY 15736 (MPF), and EY 019654 (DJR); the Mayo Foundation; and Research to Prevent Blindness (Lew R. Wasserman Merit Award [MPF] and an unrestricted grant [Department of Ophthalmology, Mayo Clinic]). NR 75 TC 9 Z9 9 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2011 VL 52 IS 9 BP 6443 EP 6451 DI 10.1167/iovs.11-7409 PG 9 WC Ophthalmology SC Ophthalmology GA 815SI UT WOS:000294548300013 PM 21743018 ER PT J AU Suzuki, J Manola, A Murakami, Y Morizane, Y Takeuchi, K Kayama, M Miller, JW Sobrin, L Vavvas, DG AF Suzuki, Jun Manola, Akrivi Murakami, Yusuke Morizane, Yuki Takeuchi, Kimio Kayama, Maki Miller, Joan W. Sobrin, Lucia Vavvas, Demetrios G. TI Inhibitory Effect of Aminoimidazole Carboxamide Ribonucleotide (AICAR) on Endotoxin-Induced Uveitis in Rats SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ACTIVATED PROTEIN-KINASE; NF-KAPPA-B; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TOLL-LIKE RECEPTORS; TNF-ALPHA; 5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOSIDE; LIPOPOLYSACCHARIDE; EXPRESSION; CELLS; DISEASE AB PURPOSE. To investigate the anti-inflammatory effect of aminoimidazole carboxamide ribonucleotide (AICAR), an analog of adenosine monophosphate (AMP), in endotoxin-induced uveitis (EIU). METHODS. EIU was induced by subcutaneous injection of lipopolysaccharide (LPS) (200 mu g) in Lewis rats. AICAR (50 mg/kg, intraperitoneally) was given 6 hours prior and at the same time as LPS injection. Clinical uveitis scores, number of anterior chamber (AC) infiltrating cells, anterior chamber protein concentration, retinal vessel leukocyte adhesion, and protein leakage were measured 24 hours later. Protein levels of C-C chemokine ligand-2 (CCL-2)/monocyte chemotactic protein-1 (MCP1), tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) in aqueous humor and retina and nuclear translocation of nuclear factor-kappa B (NF-kappa B) in the retina were determined by enzyme-linked immunosorbent assay (ELISA). Both mRNA and protein levels of CD14 in peripheral blood mononuclear cells were also measured. RESULTS. AICAR treatment significantly reduced EIU clinical severity as well as inflammatory cell infiltration and protein concentration in aqueous humor. Similarly, the number of retinal vessel-adherent leukocytes and protein leakage were decreased by AICAR treatment. Protein levels of TNF-alpha, CCL-2/MCP-1, and ICAM-1 in aqueous humor and CCL-2/MCP-1 and ICAM-1 levels in retina were suppressed with AICAR treatment. AICAR also reduced NF-kappa B translocation and CD14 expression. CONCLUSIONS. AICAR reduces systemic LPS susceptibility and attenuates intraocular inflammation in a rat EIU model by limiting infiltration of leukocytes, suppressing inflammatory mediators, and inhibiting the NF-kappa B pathway. (Invest Ophthalmol Vis Sci. 2011; 52: 6565-6571) DOI: 10.1167/iovs.11-7331 C1 [Suzuki, Jun; Manola, Akrivi; Murakami, Yusuke; Morizane, Yuki; Takeuchi, Kimio; Kayama, Maki; Miller, Joan W.; Sobrin, Lucia; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol,Retina Serv, Boston, MA 02114 USA. RP Vavvas, DG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Dept Ophthalmol,Retina Serv, Boston, MA 02114 USA. EM demetrios_vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 NR 43 TC 13 Z9 14 U1 1 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2011 VL 52 IS 9 BP 6565 EP 6571 DI 10.1167/iovs.11-7331 PG 7 WC Ophthalmology SC Ophthalmology GA 815SI UT WOS:000294548300028 PM 21775660 ER PT J AU Harrison, WW Bearse, MA Schneck, ME Wolff, BE Jewell, NP Barez, S Mick, AB Dolan, BJ Adams, AJ AF Harrison, Wendy W. Bearse, Marcus A., Jr. Schneck, Marilyn E. Wolff, Brian E. Jewell, Nicholas P. Barez, Shirin Mick, Andrew B. Dolan, Bernard J. Adams, Anthony J. TI Prediction, by Retinal Location, of the Onset of Diabetic Edema in Patients with Nonproliferative Diabetic Retinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID MACULAR EDEMA; RISK-FACTORS; MULTIFOCAL ELECTRORETINOGRAM; BLOOD-PRESSURE; THICKNESS; TYPE-1; DELAYS; PHOTOCOAGULATION; COMPLICATIONS; DYSFUNCTION AB PURPOSE. To formulate a model to predict the location of the onset of diabetic retinal edema (DE) in adults with diabetic retinopathy (DR), at risk for DE. METHODS. In all, 46 eyes from 23 patients with DR were included. Subjects were followed semiannually until DE developed or the study concluded. The presence or absence of DE within the central 45 at the final visit was the outcome measure, and data from the prior visit were used as baseline. A logistic regression model was formulated to assess the relationship between DE development and: multifocal electroretinogram (mfERG) implicit time (IT) Z-score, mfERG amplitude (Amp) Z-score, sex, diabetes duration, diabetes type, blood glucose, HbA1c, age, systolic (SBP) and diastolic blood pressure, and grade of retinopathy. A total of 35 retinal zones were constructed from the mfERG elements and each was graded for DE. Data from 52 control subjects were used to calculate the maximum IT and minimum Amp Z-scores for each zone. Receiver operating characteristic curves from a fivefold cross-validation were used to determine the model's predictive properties. RESULTS. Edema developed in 5.2% of all retinal zones and in 35% of the eyes. The mfERG Amp, mfERG IT, SBP, and sex were together predictive of edema onset. Combined, these factors produce a model that has 84% sensitivity and 76% specificity. CONCLUSIONS. Together mfERG, SBP, and sex are good predictors of local edema in patients with DR. The model is a useful tool for assessing risk for edema development and a candidate measure to evaluate novel therapeutics directed at DE. (Invest Ophthalmol Vis Sci. 2011;52:6825-6831) DOI:10.1167/iovs.117533 C1 [Harrison, Wendy W.; Bearse, Marcus A., Jr.; Schneck, Marilyn E.; Wolff, Brian E.; Barez, Shirin; Adams, Anthony J.] Univ Calif Berkeley, Sch Optometry, Grp Vis Sci, Berkeley, CA 94720 USA. [Jewell, Nicholas P.] Univ Calif Berkeley, Dept Stat, Div Biostat, Berkeley, CA 94720 USA. [Mick, Andrew B.; Dolan, Bernard J.] San Francisco Vet Adm Med Ctr, Eye Clin, San Francisco, CA USA. RP Harrison, WW (reprint author), Midwestern Univ, Arizona Coll Optometry, 19555 N 59th Ave, Glendale, AZ 85308 USA. EM wharri@midwestern.edu FU National Institutes of Health-National Eye Institute [EY 007043, EY 02271] FX Supported in part by the National Institutes of Health-National Eye Institute Grants EY 007043 and EY 02271 (AJA). NR 49 TC 15 Z9 15 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2011 VL 52 IS 9 BP 6825 EP 6831 DI 10.1167/iovs.11-7533 PG 7 WC Ophthalmology SC Ophthalmology GA 815SI UT WOS:000294548300060 PM 21743017 ER PT J AU Datta, G Grosclaude, P Kawachi, I Neville, B Datta, N Earle, C AF Datta, G. Grosclaude, P. Kawachi, I. Neville, B. Datta, N. Earle, C. TI BLADDER CANCER SURVIVAL DISPARITIES IN THE UNITED STATES: RESULTS FROM SEER-MEDICARE SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Meeting Abstract C1 [Datta, G.] Univ Montreal, Montreal, PQ, Canada. [Grosclaude, P.] INSERM, U558, Toulouse, France. [Kawachi, I.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Neville, B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Datta, N.] Univ Calif Los Angeles, Los Angeles, CA USA. [Earle, C.] Univ Toronto, Toronto, ON, Canada. RI Grosclaude, Pascale/B-6079-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD AUG PY 2011 VL 65 SU 1 BP A60 EP A60 DI 10.1136/jech.2011.142976b.76 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 807MG UT WOS:000293901800144 ER PT J AU Fick, D Semla, T AF Fick, Donna Semla, Todd TI Improving Medication Use in Gerontological Nursing Now Is the Time for Interdisciplinary Collaboration and Translation SO JOURNAL OF GERONTOLOGICAL NURSING LA English DT Editorial Material ID BEERS CRITERIA; OLDER-ADULTS; INAPPROPRIATE C1 [Fick, Donna] Penn State Univ, Sch Nursing, University Pk, PA 16802 USA. [Semla, Todd] US Dept Vet Affairs, Washington, DC USA. [Semla, Todd] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Semla, Todd] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. RP Fick, D (reprint author), Penn State Univ, Sch Nursing, University Pk, PA 16802 USA. NR 11 TC 2 Z9 4 U1 1 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0098-9134 J9 J GERONTOL NURS JI J. Gerontol. Nurs. PD AUG PY 2011 VL 37 IS 8 BP 3 EP 4 DI 10.3928/00989134-20110603-03 PG 2 WC Geriatrics & Gerontology; Gerontology; Nursing SC Geriatrics & Gerontology; Nursing GA 812DR UT WOS:000294268500001 PM 21800791 ER PT J AU Alter, G Jost, S Rihn, S Reyor, LL Nolan, BE Ghebremichael, M Bosch, R Altfeld, M Lauer, GM AF Alter, Galit Jost, Stephanie Rihn, Suzannah Reyor, Laura L. Nolan, Brian E. Ghebremichael, Musie Bosch, Ronald Altfeld, Marcus Lauer, Georg M. TI Reduced frequencies of NKp30+NKp46+, CD161+, and NKG2D+NK cells in acute HCV infection may predict viral clearance SO JOURNAL OF HEPATOLOGY LA English DT Article DE Hepatitis C virus; Natural killer cells; Innate immunity; CD161; NKp30; NKp46; Resolution of HCV infection; Acute infection ID CHRONIC HEPATITIS-C; NATURAL-KILLER-CELLS; VIRUS ENVELOPE PROTEIN; NK CELL; T-CELLS; EXPRESSION; CYTOTOXICITY; RESPONSES; INDIVIDUALS; ACTIVATION AB Background & Aims: While the majority of HCV-infected patients progress to chronic hepatitis, a small fraction of individuals are able to clear the virus. Resolution of infection occurs within the first few weeks to months of infection, suggesting that innate immune functions may be critical for early control. Epidemiologic data support a role for particular NK cell receptor bearing populations in this control, yet the mechanism by which NK cells respond to HCV early in infection is unknown. Methods: Changes in the phenotype and function of NK cells were investigated in a cohort of 43 individuals identified during various stages of HCV infection with different clinical outcomes. Results: Acute, chronic, and resolved HCV infections were characterized by an expansion of CD56(neg) NK cells. Furthermore, increased levels of HLA-C-binding KIR(+) NK cells were observed in HCV resolvers, while all stages of HCV infection were associated with reduced percentages of NKG2D(+), NKp30(+), and NKp46(+) NK cells, and a slight increase in the ability of NK cells to respond to target cells bearing the ligands for these receptors. In contrast, NKG2A(+) and CD94(+) NK cells were elevated in acute and chronic HCV infection, but not in resolved infection. Most importantly, in acute infection, lower frequencies of NKp30(+), NKp46(+), CD161(+), and NKG2D(+) NK cells were observed in patients who were subsequently able to clear HCV infection than in those becoming chronically infected. Conclusions: These data implicate particular populations of NK cells in the early control and clearance of HCV infection. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Alter, Galit; Jost, Stephanie; Rihn, Suzannah; Ghebremichael, Musie; Altfeld, Marcus] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. [Bosch, Ronald] Harvard Univ, Sch Publ Hlth, CBAR, Boston, MA 02115 USA. [Reyor, Laura L.; Nolan, Brian E.; Lauer, Georg M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. [Ghebremichael, Musie] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Alter, G (reprint author), 149 13th St,Room 6618B, Charlestown, MA 02129 USA. EM galter@partners.org FU NIAID NIH HHS [U19 AI066345] NR 38 TC 48 Z9 54 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2011 VL 55 IS 2 BP 278 EP 288 DI 10.1016/j.jhep.2010.11.030 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 801HL UT WOS:000293429100009 PM 21168454 ER PT J AU Zhang, LL Jilg, N Shao, RX Lin, WY Fusco, DN Zhao, H Goto, K Peng, LF Chen, WC Chung, RT AF Zhang, Leiliang Jilg, Nikolaus Shao, Run-Xuan Lin, Wenyu Fusco, Dahlene N. Zhao, Hong Goto, Kaku Peng, Lee F. Chen, Wen-Chi Chung, Raymond T. TI IL28B inhibits hepatitis C virus replication through the JAK-STAT pathway SO JOURNAL OF HEPATOLOGY LA English DT Article DE HCV; JAK; STAT; IL28B ID ANTIVIRAL RESPONSES; GENETIC-VARIATION; INTERFERON-ALPHA; CELL-CULTURE; LAMBDA; INNATE; IFNS; CLEARANCE; RIBAVIRIN; GENOME AB Background 8: Aims: The combination of pegylated interferon (IFN) alpha and ribavirin (RBV) is the standard therapy for patients with chronic HCV infection. However, it produces a sustained virologic response (SVR) in only half of the treated individuals and is associated with significant side effects. Recently, several single-nucleotide polymorphisms (SNPs) near the IL28B locus, also known as IFN lambda 3, were identified to be strong predictors of SVR in patients receiving PEG-IFN and RBV. We sought to determine whether IL28B was capable of inhibiting HCV replication and to determine the pathway by which IL28B exhibits anti-HCV activity. Methods: Using the full-length HCV replicon OR6 and the infectious HCV clones JFH1 and El, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAR-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAR-STAT pathway inhibitors such as blocking antibodies, a pharmacological inhibitor, and siRNAs. Results: We found that IL28B inhibits HCV replication in a dose- and time-dependent manner. Like IFN alpha, IL28B induces the phosphorylation of STAT1 and STAT2, ISRE-driven transcription, and expression of known ISGs. The anti-HCV effects of IL28A, IL28B, and IL29 were abrogated by an IL10R2 blocking antibody, a pharmacological inhibitor of JAK1/TYK2, and by siRNA against IL28R1, STAT1, STAT2, and IRF9. Conclusions: Our data demonstrate that IL28A, IL28B, and IL29 signal through the JAR-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Zhang, Leiliang; Jilg, Nikolaus; Shao, Run-Xuan; Lin, Wenyu; Fusco, Dahlene N.; Zhao, Hong; Goto, Kaku; Peng, Lee F.; Chen, Wen-Chi; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA 02114 USA. RP Zhang, LL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Warren 1007, Boston, MA 02114 USA. EM armzhang@hotmail.com; rtchung@partners.org FU National Institutes of Health [AI069939, AI082630, DK078772]; Deutsche Forschungsgemeinschaft, Bonn, Germany [Ji 145/1-1] FX This work was supported by grants AI069939, AI082630 and DK078772 (R.T.C.) from the National Institutes of Health. N.J. was supported by Grant Ji 145/1-1 from the Deutsche Forschungsgemeinschaft, Bonn, Germany. NR 26 TC 85 Z9 86 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD AUG PY 2011 VL 55 IS 2 BP 289 EP 298 DI 10.1016/j.jhep.2010.11.019 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 801HL UT WOS:000293429100010 PM 21147189 ER PT J AU Dionne, KR Galvin, JM Schittone, SA Clarke, P Tyler, KL AF Dionne, Kalen R. Galvin, John M. Schittone, Stephanie A. Clarke, Penny Tyler, Kenneth L. TI Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE Reovirus; Virus; Tropism; Interferon; Encephalitis; Brain ID CENTRAL-NERVOUS-SYSTEM; ENCEPHALITIS-VIRUS INFECTION; REGULATORY FACTORS; STIMULATED GENES; TISSUE-INJURY; CELL-DEATH; HOST-CELL; MICE; APOPTOSIS; PROTECTS AB In vivo and ex vivo models of reoviral encephalitis were utilized to delineate the contribution of type I interferon (IFN) to the host's defense against local central nervous system (CNS) viral infection and systemic viral spread. Following intracranial (i.c.) inoculation with either serotype 3 (T3) or serotype 1 (T1) reovirus, increased expression of IFN-alpha, IFN-beta, and myxovirus-resistance protein (Mx1; a prototypical IFN stimulated gene) was observed in mouse brain tissue. Type I IFN receptor deficient mice (IFNAR(-/-)) had accelerated lethality, compared to wildtype (B6wt) controls, following i.c. T1 or T3 challenge. Although viral titers in the brain and eyes of reovirus infected IFNAR(-/-) mice were significantly increased, these mice did not develop neurologic signs or brain injury. In contrast, increased reovirus titers in peripheral tissues (liver, spleen, kidney, heart, and blood) of IFNAR(-/-) mice were associated with severe intestinal and liver injury. These results suggest that reovirus-infected IFNAR(-/-) mice succumb to peripheral disease rather than encephalitis per se. To investigate the potential role of type I IFN in brain tissue, brain slice cultures (BSCs) were prepared from IFNAR(-/-) mice and B6wt controls for ex vivo T3 reovirus infection. Compared to B6wt controls, reoviral replication and virus-induced apoptosis were enhanced in IFNAR(-/-) BSCs indicating that a type I IFN response, initiated by resident CNS cells, mediates innate viral immunity within the brain. T3 reovirus tropism was extended in IFNAR(-/-) brains to include dentate neurons, ependymal cells, and meningeal cells indicating that reovirus tropism within the CNS is dependent upon type I interferon signaling. C1 [Galvin, John M.; Clarke, Penny; Tyler, Kenneth L.] Univ Colorado, Dept Neurol, Aurora, CO 80045 USA. [Tyler, Kenneth L.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. [Tyler, Kenneth L.] Univ Colorado, Dept Med, Aurora, CO 80045 USA. [Schittone, Stephanie A.; Tyler, Kenneth L.] Univ Colorado, Dept Microbiol, Aurora, CO 80045 USA. [Dionne, Kalen R.; Tyler, Kenneth L.] Univ Colorado, Neurosci Program, Aurora, CO 80045 USA. [Dionne, Kalen R.; Tyler, Kenneth L.] Univ Colorado, Med Scientist Training Program, Aurora, CO 80045 USA. RP Tyler, KL (reprint author), Univ Colorado, Dept Neurol, Anschutz Med Campus,Res Complex 2,12700 E 19th Av, Aurora, CO 80045 USA. EM Ken.Tyler@UCDenver.edu OI Tyler, Kenneth/0000-0003-3294-5888 FU VA Merit Grant; institutional MST Program [T32 GM008497]; National Research Service Award [F30 NS071630]; National Research Service [F31 NS06258303]; [RO1NS050138]; [RO1NS051403] FX This work was supported by RO1NS050138 (KLT), RO1NS051403 (KLT), and a VA Merit Grant (KLT). KRD was supported by an institutional MST Program training grant (T32 GM008497) and a National Research Service Award for Individual Predoctoral MD/PhD Fellows (F30 NS071630). SAS was supported by a National Research Service Award for Individual Predoctoral Fellows (F31 NS06258303). The authors extend their gratitude to J. Smith Leser for technical support. We thank Lai Kuan Goh for her critical reading of the manuscript. NR 39 TC 12 Z9 12 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 2011 VL 17 IS 4 BP 314 EP 326 DI 10.1007/s13365-011-0038-1 PG 13 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 813HA UT WOS:000294356200003 PM 21671121 ER PT J AU Gelman, A Nikolajski, C Schwarz, EB Borrero, S AF Gelman, Amanda Nikolajski, Cara Schwarz, Eleanor Bimla Borrero, Sonya TI Racial Disparities in Awareness of the Human Papillomavirus SO JOURNAL OF WOMENS HEALTH LA English DT Article ID HPV VACCINE; COLLEGE-STUDENTS; AFRICAN-AMERICAN; UNITED-STATES; WOMEN; KNOWLEDGE; ATTITUDES; ACCEPTABILITY; ACCEPTANCE; PARENTS AB Background: Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States yet is one of the least recognized among the general public. HPV awareness may be relatively low among minority women. Because HPV awareness is associated with uptake of the HPV vaccine, it is critical to assess HPV awareness in the population and identify any racial/ethnic gaps. Methods: This study used nationally representative data collected by the National Survey of Family Growth between July 2007 and December 2008. A multivariable logistic regression model was used to determine the independent effect of race/ethnicity on HPV awareness while controlling for sociodemographic and clinical confounders in a sample of 4088 women. Stratified multivariable analysis was also conducted to assess the relationship between race/ethnicity and HPV awareness among women in different age groups. Results: After adjusting for confounders, Hispanic and black women overall were significantly less likely to have heard of HPV compared to white women (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.29-0.54 and OR 0.39, 95% CI 0.29-0.54, respectively). Black women aged 15-18 and Hispanic women aged 19-26 had particularly low rates of HPV awareness (OR 0.17, 95% CI 0.07-0.43 and OR 0.18, 95% CI 0.11-0.30, respectively) compared to white women of the same ages. Conclusions: Hispanic and black women have significantly lower levels of HPV awareness than white women. Targeted educational efforts will be important to improve HPV awareness and associated preventive health measures to avoid HPV-related morbidity and mortality. C1 [Gelman, Amanda] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Nikolajski, Cara; Schwarz, Eleanor Bimla; Borrero, Sonya] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA USA. [Nikolajski, Cara; Borrero, Sonya] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Schwarz, Eleanor Bimla] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Schwarz, Eleanor Bimla] Magee Womens Res Inst, Pittsburgh, PA USA. RP Borrero, S (reprint author), 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM borrerosp@upmc.edu OI Schwarz, Eleanor Bimla/0000-0002-9912-8236 FU University of Pittsburgh's Clinical and Translational Sciences Institute (NIH/NCRR/CTSA) [UL1 RR024153]; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [05 KL2 RR024154-05]; NIH Roadmap for Medical Research; NICHD [K23 HD051585] FX We thank Kwonho Jeong from the University of Pittsburgh's Clinical and Translational Sciences Institute (NIH/NCRR/CTSA grant UL1 RR024153) for his help with statistical analysis. This article was made possible by S.B.'s grant (05 KL2 RR024154-05) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. E. B. S. was supported by NICHD grant K23 HD051585 The content of this publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. NR 41 TC 21 Z9 21 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD AUG PY 2011 VL 20 IS 8 BP 1165 EP 1173 DI 10.1089/jwh.2010.2617 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 805MQ UT WOS:000293731500008 PM 21668381 ER PT J AU Chang, RL Ghamsari, L Manichaikul, A Hom, EFY Balaji, S Fu, WQ Shen, Y Hao, T Palsson, BO Salehi-Ashtiani, K Papin, JA AF Chang, Roger L. Ghamsari, Lila Manichaikul, Ani Hom, Erik F. Y. Balaji, Santhanam Fu, Weiqi Shen, Yun Hao, Tong Palsson, Bernhard O. Salehi-Ashtiani, Kourosh Papin, Jason A. TI Metabolic network reconstruction of Chlamydomonas offers insight into light-driven algal metabolism SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE Chlamydomonas reinhardtii; lipid metabolism; metabolic engineering; photobioreactor ID FLUX BALANCE ANALYSIS; ESCHERICHIA-COLI; PROTOCHLOROPHYLLIDE REDUCTASE; CARBONIC-ANHYDRASE; FATTY-ACIDS; REINHARDTII; MODELS; MUTANT; BIOSYNTHESIS; EFFICIENCY AB Metabolic network reconstruction encompasses existing knowledge about an organism's metabolism and genome annotation, providing a platform for omics data analysis and phenotype prediction. The model alga Chlamydomonas reinhardtii is employed to study diverse biological processes from photosynthesis to phototaxis. Recent heightened interest in this species results from an international movement to develop algal biofuels. Integrating biological and optical data, we reconstructed a genome-scale metabolic network for this alga and devised a novel light-modeling approach that enables quantitative growth prediction for a given light source, resolving wavelength and photon flux. We experimentally verified transcripts accounted for in the network and physiologically validated model function through simulation and generation of new experimental growth data, providing high confidence in network contents and predictive applications. The network offers insight into algal metabolism and potential for genetic engineering and efficient light source design, a pioneering resource for studying light-driven metabolism and quantitative systems biology. Molecular Systems Biology 7: 518; published online 2 August 2011; doi:10.1038/msb.2011.52 C1 [Salehi-Ashtiani, Kourosh] New York Univ Abu Dhabi, Abu Dhabi, U Arab Emirates. [Chang, Roger L.; Palsson, Bernhard O.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Ghamsari, Lila; Balaji, Santhanam; Shen, Yun; Hao, Tong; Salehi-Ashtiani, Kourosh] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Ghamsari, Lila; Balaji, Santhanam; Shen, Yun; Hao, Tong; Salehi-Ashtiani, Kourosh] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ghamsari, Lila; Balaji, Santhanam; Shen, Yun; Hao, Tong; Salehi-Ashtiani, Kourosh] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Manichaikul, Ani; Papin, Jason A.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA. [Hom, Erik F. Y.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Fu, Weiqi] Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland. [Salehi-Ashtiani, Kourosh] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. RP Salehi-Ashtiani, K (reprint author), New York Univ Abu Dhabi, Abu Dhabi, U Arab Emirates. EM ksa3@nyu.edu; papin@virginia.edu RI Hom, Erik/B-3889-2008; OI Hom, Erik/0000-0003-0964-0031; Salehi-Ashtiani, Kourosh/0000-0002-6521-5243; Fu, Weiqi/0000-0002-7368-383X; Papin, Jason/0000-0002-2769-5805 FU Office of Science (Biological and Environmental Research); US Department of Energy [DE-FG02-07ER64496]; New York University; Dana-Farber Cancer Institute Strategic Initiative; National Science Foundation [DGE0504645]; Jane Coffin Childs Memorial Fund for Medical Research FX We thank Harish Nagarajan for his critical assessment of this work. This research was supported by the Office of Science (Biological and Environmental Research), US Department of Energy, Grant DE-FG02-07ER64496 (to JP and KS-A), New York University Abu Dhabi Research funds (to KS-A), and Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative (to CCSB). RLC was supported by the National Science Foundation IGERT training Grant DGE0504645, and EFYH was supported by the Jane Coffin Childs Memorial Fund for Medical Research. NR 64 TC 114 Z9 116 U1 0 U2 72 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD AUG PY 2011 VL 7 AR 518 DI 10.1038/msb.2011.52 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 815PP UT WOS:000294537800002 PM 21811229 ER PT J AU Yung, RL Chen, K Abel, GA Gesten, FC Roohan, PJ Boscoe, FP Sinclair, AH Schymura, MJ Schrag, D AF Yung, Rachel L. Chen, Kun Abel, Gregory A. Gesten, Foster C. Roohan, Patrick J. Boscoe, Francis P. Sinclair, Amber H. Schymura, Maria J. Schrag, Deborah TI Cancer Disparities in the Context of Medicaid Insurance: A Comparison of Survival for Acute Myeloid Leukemia and Hodgkin's Lymphoma by Medicaid Enrollment SO ONCOLOGIST LA English DT Article DE Health care disparities; Medicaid; Socioeconomic factors; Neoplasms; Hodgkin's disease; Acute myeloid leukemia ID SOCIOECONOMIC-STATUS; UNITED-STATES; BREAST-CANCER; POPULATION; OUTCOMES; INEQUALITIES; DIAGNOSIS; MORTALITY; DISEASE; WHITES AB Background. Because poverty is difficult to measure, its association with outcomes for serious illnesses such as hematologic cancers remains largely uncharacterized. Using Medicaid enrollment as a proxy for poverty, we aimed to assess potential disparities in survival after a diagnosis of acute myeloid leukemia (AML) or Hodgkin's lymphoma (HL) in a nonelderly population. Methods. We used records from the New York (NY) and California (CA) state cancer registries linked to Medicaid enrollment records for these states to identify Medicaid enrolled and nonenrolled patients aged 21-64 years with incident diagnoses of AML or HL in 2002-2006. We compared overall survival for the two groups using Kaplan-Meier curves and Cox proportional hazards analyses adjusted for sociodemographic and clinical factors. Results. For HL, the adjusted risk for death for Medicaid enrolled compared with nonenrolled patients was 1.98 (95% confidence interval [CI], 1.47-2.68) in NY and 1.89 (95% CI, 1.43-2.49) in CA. In contrast, for AML, Medicaid enrollment had no effect on survival (adjusted hazard ratio, 1.00; 95% CI, 0.84-1.19 in NY and hazard ratio, 1.02; 95% CI, 0.89-1.16 in CA). These results persisted despite adjusting for race/ethnicity and other factors. Conclusions. Poverty does not affect survival for AML patients but does appear to be associated with survival for HL patients, who, in contrast to AML patients, require complex outpatient treatment. Challenges for the poor in adhering to treatment regimens for HL could explain this disparity and merit further study. The Oncologist 2011; 16: 1082-1091 C1 [Yung, Rachel L.; Chen, Kun; Abel, Gregory A.; Schrag, Deborah] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Med Oncol, Boston, MA 02215 USA. [Gesten, Foster C.; Roohan, Patrick J.] New York State Dept Hlth, Office Hlth Insurance Programs, Albany, NY USA. [Boscoe, Francis P.; Sinclair, Amber H.; Schymura, Maria J.] New York State Dept Hlth, New York State Canc Registry, Menands, NY USA. RP Schrag, D (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM deb_schrag@dfci.harvard.edu RI Inov Farmaceutica, Inct/K-2313-2013 FU Association of Schools of Public Health/Centers for Disease Control and Prevention [S3888]; National Cancer Institute [R01-CA131847-01A1] FX Work for this project was supported by Cooperative Agreement S3888 from the Association of Schools of Public Health/Centers for Disease Control and Prevention (awarded to Dr. Schymura) and National Cancer Institute R01-CA131847-01A1 (awarded to Dr. Schrag). NR 30 TC 9 Z9 9 U1 1 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD AUG PY 2011 VL 16 IS 8 BP 1082 EP 1091 DI 10.1634/theoncologist.2011-0126 PG 10 WC Oncology SC Oncology GA 812KH UT WOS:000294291800005 PM 21873583 ER PT J AU Fathi, AT Chabner, BA AF Fathi, Amir T. Chabner, Bruce A. TI FLT3 Inhibition as Therapy in Acute Myeloid Leukemia: A Record of Trials and Tribulations SO ONCOLOGIST LA English DT Article DE FLT3; Acute myeloid leukemia; Internal tandem duplication; Tyrosine kinase inhibitors; Targeted therapy ID RECEPTOR TYROSINE KINASE; INTERNAL TANDEM DUPLICATION; ACUTE MYELOGENOUS LEUKEMIA; HEMATOPOIETIC PROGENITOR CELLS; RISK MYELODYSPLASTIC SYNDROME; HUMAN BONE-MARROW; ACTIVITY IN-VITRO; SIGNAL-TRANSDUCTION; LESTAURTINIB CEP701; GROWTH-FACTOR AB Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prognosis. Approximately one quarter of the patients with AML also carry an internal tandem duplication (ITD) mutation in the gene encoding FMS-like tyrosine kinase 3 (FLT3), which has a significantly deleterious impact on prognosis. The ITD mutation renders FLT3 constitutively active and leads to uncontrolled proliferation of the leukemic blast. Over the course of the last decade, a variety of compounds have been developed in preclinical and clinical studies as potent inhibitors of FLT3. Many of the earlier agents under investigation, such as lestaurtinib, midostaurin, and sunitinib, were initially developed as inhibitors of other tyrosine kinases and as targeted therapies in a variety of malignancies. These compounds have been demonstrated to have some efficacy in clinical trials of AML, mainly manifesting as transient decreases in circulating blasts correlating with effective in vivo suppression of the FLT3 target. Nevertheless, the cumbersome pharmacokinetics of some compounds and the suboptimal specificity and potency of others have limited their therapeutic efficacy. In the last few years, newer, more potent and specific agents have been under investigation, with the leading example being AC220. This agent has shown significant promise in early phases of clinical investigation, and is currently in more advanced clinical trials. Hope remains that FLT3 inhibition will be become an effective therapeutic adjunct to our current treatment approach to AML. The Oncologist 2011; 16: 1162-1174 C1 [Fathi, Amir T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Fathi, AT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Zero Emerson Pl,Suite 118, Boston, MA 02114 USA. EM afathi@partners.org RI Inov Farmaceutica, Inct/K-2313-2013 FU U.S. Government; Actinium Pharmaceuticals; Chroma Therapeutics FX Amir T. Fathi: None; Bruce A. Chabner: Consultant/advisory role: Sanofi, Allergan, Epizyme, PharmaMar, GlaxoSmithKline, Peregrine, Onyx; Honoraria: Eli Lilly; Research funding/contracted research: U.S. Government; Ownership interest: PharmaMar, Gilead, Epizyme, Human Genome Sciences, Onyx.; Section Editor Joseph Jurcic discloses that he serves on the Scientific Advisory Board for Actinium Pharmaceuticals and that he receives research funding from Actinium Pharmaceuticals and Chroma Therapeutics. NR 106 TC 29 Z9 34 U1 1 U2 3 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD AUG PY 2011 VL 16 IS 8 BP 1162 EP 1174 DI 10.1634/theoncologist.2011-0084 PG 13 WC Oncology SC Oncology GA 812KH UT WOS:000294291800014 PM 21765192 ER PT J AU Siddappa, NB Hemashettar, G Shanmuganathan, V Semenya, AA Sweeney, ED Paul, KS Lee, SJ Secor, WE Ruprecht, RM AF Siddappa, Nagadenahalli B. Hemashettar, Girish Shanmuganathan, Vivekanandan Semenya, Amma A. Sweeney, Elizabeth D. Paul, Katherine S. Lee, Sandra J. Secor, W. Evan Ruprecht, Ruth M. TI Schistosoma mansoni Enhances Host Susceptibility to Mucosal but Not Intravenous Challenge by R5 Clade C SHIV SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; POLYMERASE CHAIN-REACTION; RHESUS MACAQUES; GENITAL SCHISTOSOMIASIS; RNA LOAD; INFECTION; TRANSMISSION; HIV-1; AIDS; WOMEN AB Background: The high prevalence of HIV-1/AIDS in areas endemic for schistosomiasis and other helminthic infections has led to the hypothesis that parasites increase host susceptibility to immunodeficiency virus infection. We previously showed that rhesus macaques (RM) with active schistosomiasis were significantly more likely to become systemically infected after intrarectal (i.r.) exposure to an R5-tropic clade C simian-human immunodeficiency virus (SHIV-C) than were parasite-free controls. However, we could not address whether this was due to systemic or mucosal effects. If systemic immunoactivation resulted in increased susceptibility to SHIV-C acquisition, a similarly large difference in host susceptibility would be seen after intravenous (i.v.) SHIV-C challenge. Conversely, if increased host susceptibility was due to parasite-induced immunoactivation at the mucosal level, i.v. SHIV-C challenge would not result in significant differences between parasitized and parasite-free monkeys. Methods and Findings: We enrolled two groups of RM and infected one group with Schistosoma mansoni; the other group was left parasite-free. Both groups were challenged i.v. with decreasing doses of SHIV-C. No statistically significant differences in 50% animal infectious doses (AID(50)) or peak viremia were seen between the two groups. These data strongly contrast the earlier i.r. SHIV-C challenge (using the same virus stock) in the presence/absence of parasites, where we noted a 17-fold difference in AID(50) and one log higher peak viremia in parasitized monkeys (P<0.001 for both). The lack of significant differences after the i.v. challenge implies that the increased host susceptibility is predominantly due to parasite-mediated mucosal upregulation of virus replication and spread, rather than systemic effects. Conclusions: The major impact of schistosome-induced increased host susceptibility is at the mucosal level. Given that >90% of all new HIV-1 infections worldwide are acquired through mucosal contact, parasitic infections that inflame mucosae may play an important role in the spread of HIV-1. C1 [Siddappa, Nagadenahalli B.; Lee, Sandra J.] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Siddappa, Nagadenahalli B.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. [Semenya, Amma A.; Sweeney, Elizabeth D.; Paul, Katherine S.; Secor, W. Evan] Ctr Dis Control & Prevent, Atlanta, GA USA. [Lee, Sandra J.] Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02115 USA. RP Siddappa, NB (reprint author), Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. EM ruth_ruprecht@dfci.harvard.edu OI Byrareddy, Siddappa /0000-0002-7423-1763 FU National Institutes of Health [R56 A1062515, PO1 AI048240] FX This study was supported by National Institutes of Health grants R56 A1062515 and PO1 AI048240. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 15 Z9 15 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2011 VL 5 IS 8 AR e1270 DI 10.1371/journal.pntd.0001270 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 814TJ UT WOS:000294479800025 PM 21829749 ER PT J AU Rattner, DW Hawes, R Schwaitzberg, S Kochman, M Swanstrom, L AF Rattner, David W. Hawes, Robert Schwaitzberg, Steven Kochman, Michael Swanstrom, Lee TI The Second SAGES/ASGE White Paper on natural orifice transluminal endoscopic surgery: 5 years of progress SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article ID ACHALASIA; MYOTOMY AB Background When the concept of Natural Orifice Transluminal Endoscopic Surgery (NOTES (TM)) was first introduced, many physicians could envisage its potential as a less invasive and more cosmetic way to perform surgery. The potential for harm if NOTES was adopted too rapidly was also readily apparent. To ensure the responsible development of these technologies and techniques and to encourage accurate and honest outcome assessment in humans, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and the American Society for Gastrointestinal Endoscopy (ASGE) assembled a Joint Committee to serve as a working group to review the issues involving NOTES. This working group subsequently published the ASGE/SAGES Working Group on Natural Orifice Translumenal Endoscopic Surgery White Paper [1, 2], which laid out the fundamental challenges to be addressed and outlined a pathway for the responsible development and evaluation of NOTES. As part of this mission, the Joint Committee also created an organization called Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR). NOSCAR organized international meetings, developed and sought funding for a research agenda, fostered the translation of research findings into clinical trials, and began development of a human registry to track the clinical adoption of NOTES. C1 [Rattner, David W.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Rattner, David W.] Massachusetts Gen Hosp, Div Gen & Gastrointestinal Surg, Boston, MA 02114 USA. [Hawes, Robert] Med Univ S Carolina, Dept Med, Charleston, SC 29403 USA. [Schwaitzberg, Steven] Cambridge Hlth Alliance, Dept Surg, Cambridge, MA 02139 USA. [Kochman, Michael] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Swanstrom, Lee] Oregon Clin, Gastrointestinal & Minimally Invas Surg Div, Portland, OR 97210 USA. RP Rattner, DW (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM drattner@partners.org NR 16 TC 46 Z9 47 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 J9 SURG ENDOSC JI Surg. Endosc. PD AUG PY 2011 VL 25 IS 8 BP 2441 EP 2448 DI 10.1007/s00464-011-1605-5 PG 8 WC Surgery SC Surgery GA 796AC UT WOS:000293020700002 PM 21359881 ER PT J AU Song, JJ Ott, HC AF Song, Jeremy J. Ott, Harald C. TI Organ engineering based on decellularized matrix scaffolds SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID EXTRACELLULAR-MATRIX; CARDIAC TISSUE; IN-VITRO; BRANCHING MORPHOGENESIS; BIOARTIFICIAL KIDNEY; OXYGEN CARRIERS; GROWTH-FACTORS; RENAL TUBULE; CELLS; CULTURE AB End-organ failure is one of the major healthcare challenges in the Western world. Yet, donor organ shortage and the need for immunosuppression limit the impact of transplantation. The regeneration of whole organs could theoretically overcome these hurdles. Early milestones have been met by combining stem and progenitor cells with increasingly complex scaffold materials and culture conditions. Because the native extracellular matrix (ECM) guides organ development, repair and physiologic regeneration, it provides a promising alternative to synthetic scaffolds and a foundation for regenerative efforts. Perfusion decellularization is a novel technology that generates native ECM scaffolds with intact 3D anatomical architecture and vasculature. This review summarizes achievements to date and discusses the role of native ECM scaffolds in organ regeneration. C1 [Song, Jeremy J.; Ott, Harald C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. RP Ott, HC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 55 Fruit St,GRB425, Boston, MA 02114 USA. EM hott@partners.org NR 87 TC 165 Z9 174 U1 11 U2 121 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 EI 1471-499X J9 TRENDS MOL MED JI Trends Mol. Med PD AUG PY 2011 VL 17 IS 8 BP 424 EP 432 DI 10.1016/j.molmed.2011.03.005 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 816DH UT WOS:000294578400003 PM 21514224 ER PT J AU Lindsley, CW Bates, BS Menon, UN Jadhav, SB Kane, AS Jones, CK Rodriguez, AL Conn, PJ Olsen, CM Winder, DG Emmitte, KA AF Lindsley, Craig W. Bates, Brittney S. Menon, Usha N. Jadhav, Satyawan B. Kane, Alexander S. Jones, Carrie K. Rodriguez, Alice L. Conn, P. Jeffrey Olsen, Christopher M. Winder, Danny G. Emmitte, Kyle A. TI (3-Cyano-5-fluorophenyl)biaryl Negative Allosteric Modulators of mGlu(5): Discovery of a New Tool Compound with Activity in the OSS Mouse Model of Addiction SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE mGlu(5); negative allosteric modulator; noncompetitive antagonist; addiction ID METABOTROPIC GLUTAMATE-RECEPTOR-5 ANTAGONIST; RECEPTOR SUBTYPE-5 ANTAGONISTS; GLUTAMATE RECEPTORS; GASTROESOPHAGEAL-REFLUX; MGLUR5 ANTAGONISTS; NUCLEUS-ACCUMBENS; SQUIRREL-MONKEYS; COCAINE SEEKING; RECENT PROGRESS; DRUG DISCOVERY AB Glutamate is the major excitatory transmitter in the mammalian central nervous system (CNS), exerting its effects through both ionotropic and metabotropic glutamate am receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (group I: mGlu(1) and mGlus; group II: mGlu(2) and mGlu(3); group III: mGlu(4), mGlu(6), mGlu(7), and mGlu(8)). Noncompetitive antagonists, also known as negative allosteric modulators (NAMs), of mGlus offer potential therapeutic applications in diseases such as pain, anxiety, gastresophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of structure activity relationships (SAR) in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro-(5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlus antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu(5) NAM in this novel assay. C1 [Emmitte, Kyle A.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA. [Lindsley, Craig W.; Emmitte, Kyle A.] Vanderbilt Univ, Med Ctr, Dept Chem, Nashville, TN 37232 USA. [Olsen, Christopher M.; Winder, Danny G.] Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Lindsley, Craig W.; Bates, Brittney S.; Menon, Usha N.; Jadhav, Satyawan B.; Kane, Alexander S.; Jones, Carrie K.; Rodriguez, Alice L.; Conn, P. Jeffrey; Emmitte, Kyle A.] US Dept Vet Affairs, Tennesse Valley Healthcare Syst, Nashville, TN 37212 USA. RP Emmitte, KA (reprint author), Vanderbilt Univ, Med Ctr, Dept Pharmacol, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA. EM kyle.a.emmitte@vanderbilt.edu RI Conn, Peter/D-7848-2012; Winder, Danny/H-4857-2013; Olsen, Christopher/C-3542-2008 OI Olsen, Christopher/0000-0003-2700-0310 FU NIH; NIMH; NIDA [RO1 DA023947-01, K99 DA026994]; Alzheimer's Association; Michael J. Fox Foundation; Seaside Therapeutics [VUMC33842]; JohnsonJohnson; Tennessee Valley Healthcare System (U.S. Department of Veteran's Affairs) FX C.W.L. receives funding from NIH, NIMH, NIDA, the Alzheimer's Association, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson&Johnson. C.K.J. receives funding from NIMH and Tennessee Valley Healthcare System (U.S. Department of Veteran's Affairs). P.J.C. receives funding from NIH, NIMH, NIDA, the Michael J. Fox Foundation, Seaside Therapeutics, and Johnson&Johnson. C.M.O. receives funding from NIDA. D.G.W. receives funding from NIH, NIDA, NIAAA, and NIMH. K.A.E. receives funding from NIH. The authors thank NIDA (RO1 DA023947-01) and Seaside Therapeutics (VUMC33842) for their support of our programs in the development of noncompetitive antagonist of mGlu5. The authors also thank NIDA (K99 DA026994) for supporting the development and characterization of OSS. NR 71 TC 17 Z9 17 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD AUG PY 2011 VL 2 IS 8 BP 471 EP 482 DI 10.1021/cn100099n PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA 810ST UT WOS:000294148100001 PM 21927650 ER PT J AU Shaw, ND Srouji, SS Histed, SN Hall, JE AF Shaw, N. D. Srouji, S. S. Histed, S. N. Hall, J. E. TI Differential effects of aging on estrogen negative and positive feedback SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE luteinizing hormone; neuroendocrine; postmenopausal women ID GONADOTROPIN-RELEASING-HORMONE; FOLLICLE-STIMULATING-HORMONE; MIDDLE-AGED RATS; STRENGTH-DURATION CHARACTERISTICS; POSTMENOPAUSAL WOMEN; LUTEINIZING-HORMONE; MENOPAUSAL TRANSITION; STEROID FEEDBACK; PROLACTIN SURGES; MENSTRUAL CYCLES AB Shaw ND, Srouji SS, Histed SN, Hall JE. Differential effects of aging on estrogen negative and positive feedback. Am J Physiol Endocrinol Metab 301: E351-E355, 2011. First published May 10, 2011; doi:10.1152/ajpendo.00150.2011.-Recent studies have demonstrated an age-related decline in gonadotropins and a decrease in pituitary responsiveness to GnRH, indicating that aging influences the neuroendocrine components of the female reproductive axis independently of changes in ovarian function. To determine whether aging might also affect the luteinizing hormone (LH) negative and positive feedback responses to gonadal steroids, we administered a controlled, graded sex steroid infusion to 11 younger (45-56 yr) and nine older (70-80 yr) postmenopausal women (PMW) in whom endogenous ovarian steroids and peptides are uniformly low. The doses of estradiol (E-2) and progesterone (P) were chosen to mimic levels across the normal follicular phase and have been shown previously to induce negative followed by positive feedback on LH. Similar E-2 and P levels were achieved in younger and older PMW (P = 0.4 and 0.3, respectively) and produced a biphasic LH response in all subjects. The early decline in LH to 53% of baseline was not different in older vs. younger PMW. However, the positive feedback effect was attenuated in older compared with younger PMW (peak LH 144.4 +/- 19.5 vs. 226.8 +/- 22.3 IU/l, respectively, P = 0.01). In conclusion, these studies in PMW demonstrate preservation of short-term steroid negative and positive feedback in response to exogenous E-2 and P with aging. Attenuation of positive feedback in older compared with younger PMW is consistent with previous reports of declining GnRH responsiveness with aging. C1 [Shaw, N. D.; Srouji, S. S.; Histed, S. N.; Hall, J. E.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Shaw, N. D.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Hall, JE (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, BHX-5,55 Fruit St, Boston, MA 02114 USA. EM jehall@partners.org OI Shaw, Natalie/0000-0002-0847-9170 FU National Institutes of Health (NIH) [R01-AG-13241, M01-RR-01066, 5T32-HD-007396]; Harvard Clinical and Translational Science Center [UL1 RR 025758]; Harvard University FX This work was supported by National Institutes of Health (NIH) Grants R01-AG-13241 and M01-RR-01066. N. D. Shaw received fellowship support from the NIH (5T32-HD-007396) and from the Scholars in Clinical Science Program of Harvard Catalyst [the Harvard Clinical and Translational Science Center (Award no. UL1 RR 025758) and financial contributions from Harvard University and its affiliated academic health care centers]. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, or its affiliated academic health care centers, the National Center for Research Resources, or the NIH. NR 40 TC 8 Z9 8 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG PY 2011 VL 301 IS 2 BP E351 EP E355 DI 10.1152/ajpendo.00150.2011 PG 5 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 811KZ UT WOS:000294210200014 PM 21558550 ER PT J AU Weng, MQ Raher, MJ Leyton, P Combs, TP Scherer, PE Bloch, KD Medoff, BD AF Weng, Meiqian Raher, Michael J. Leyton, Patricio Combs, Terry P. Scherer, Philipp E. Bloch, Kenneth D. Medoff, Benjamin D. TI Adiponectin Decreases Pulmonary Arterial Remodeling in Murine Models of Pulmonary Hypertension SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE pulmonary hypertension; pulmonary artery smooth muscle cells; metabolism; adiponectin ID SERUM RESPONSE FACTOR; ACTIVATED-RECEPTOR-GAMMA; SMOOTH-MUSCLE-CELL; ALLERGIC AIRWAY INFLAMMATION; GENE-EXPRESSION; CONTRACTILE APPARATUS; INSULIN-RESISTANCE; VASCULAR-DISEASE; GROWTH-FACTORS; MICE AB Remodeling of the pulmonary arteries is a common feature among the heterogeneous disorders that cause pulmonary hypertension. In these disorders, the remodeled pulmonary arteries often demonstrate inflammation and an accumulation of pulmonary artery smooth muscle cells (PASMCs) within the vessels. Adipose tissue secretes multiple bioactive mediators (adipokines) that can influence both inflammation and remodeling, suggesting that adipokines may contribute to the development of pulmonary hypertension. We recently reported on a model of pulmonary hypertension induced by vascular inflammation, in which a deficiency of the adipokine adiponectin (APN) was associated with the extensive proliferation of PASMCs and increased pulmonary artery pressures. Based on these data, we hypothesize that APN can suppress pulmonary hypertension by directly inhibiting the proliferation of PASMCs. Here, we tested the effects of APN overexpression on pulmonary arterial remodeling by using APN-overexpressing mice in a model of pulmonary hypertension induced by inflammation. Consistent with our hypothesis, mice that overexpressed APN manfiested reduced pulmonary hypertension and remodeling compared with wild-type mice, despite developing similar levels of pulmonary vascular inflammation in the model. The overexpression of APN was also protective in a hypoxic model of pulmonary hypertension. Furthermore, APN suppressed the proliferation of PASMCs, and reduced the activity of the serum response factor-serum response element pathway, which is a critical signaling pathway for smooth muscle cell proliferation. Overall, these data suggest that APN can regulate pulmonary hypertension and pulmonary arterial remodeling through its direct effects on PASMCs. Hence, the activation of APN-like activity in the pulmonary vasculature may be beneficial in pulmonary hypertension. C1 [Weng, Meiqian; Medoff, Benjamin D.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Weng, Meiqian; Medoff, Benjamin D.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Raher, Michael J.; Leyton, Patricio; Bloch, Kenneth D.] Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Combs, Terry P.] Univ N Carolina, Sch Med, Dept Nutr, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Scherer, Philipp E.] Univ Texas SW Med Ctr Dallas, Touchstone Diabet Ctr, Dept Internal Med, Dallas, TX 75390 USA. [Scherer, Philipp E.] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. RP Medoff, BD (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, 55 Fruit St,Bulfinch 148, Boston, MA 02114 USA. EM bmedoff@partners.org FU National Institutes of Health [HL088297, T32 HL07874, DK55758, HL074352]; Ikaria LLC; Roche Organ Transplant Research Foundation; Juvenile Diabetes Research Foundation FX This work was supported by National Institutes of Health grants HL088297 (B. D. M.), T32 HL07874 (B. D. M. and M. W.), DK55758 (P. E. S.), and HL074352 (K. D. B.).; K. D. B. received sponsored grants from Ikaria LLC and the National Institutes of Health for more than $100,001 each. B. M. received sponsored grants from the Roche Organ Transplant Research Foundation for $50,001-$100,000 and the National Institutes of Health for more than $100,001. P. E. S. received sponsored grants from the National Institutes of Health and the Juvenile Diabetes Research Foundation for more than $100,001 each. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. NR 71 TC 12 Z9 13 U1 1 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD AUG PY 2011 VL 45 IS 2 BP 340 EP 347 DI 10.1165/rcmb.2010-0316OC PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 808BQ UT WOS:000293948900017 PM 21075862 ER PT J AU Mahon, MJ AF Mahon, Matthew J. TI Vectors bicistronically linking a gene of interest to the SV40 large T antigen in combination with the SV40 origin of replication enhance transient protein expression and luciferase reporter activity SO BIOTECHNIQUES LA English DT Article DE SV40 large T antigen; IRES; luciferase; beta-catenin; mammalian two-hybrid ID CELL-LINES; RECEPTOR AB The simian virus 40 large T antigen (SVLT) induces replication of plasmids bearing the SV40 origin of replication (SV40 on) within mammalian cells. The internal ribosomal entry site (IRES) is an element that allows for the cotranslation of proteins from one polycistronic mRNA. Through the combination of these elements, IRES-dependent coexpression of a protein of interest and the SVLT, either constitutive or regulated, on plasmids bearing the SV40 on generates a positive feedback loop, resulting in enhanced expression. A vector linking red fluorescent protein (RFP) to the IRES-SVLT element enhances fluorescence similar to 10-fold over that demonstrated from a vector lacking this element. In transfection-resistant CV-1 cells, the RFP-IRES-SVLT vector substantially increases the number of cells expressing detectable levels of RFP. Furthermore, inclusion of the IRES-SVLT/SV40 on elements in standard luciferase-based reporter gene constructs and associated effectors results in marked increases in luminescent output and sensitivity, using the beta-catenin/TCF pathway and the mammalian two-hybrid assay as models. Ultimately, vector systems combining these well-established elements (IRES-SVLT/SV40 on) will increase the utility of transient transfection for the production of recombinant proteins, the use of transfection-resistant cell lines, and the effectiveness of luciferase-based high-throughput screening assays. C1 [Mahon, Matthew J.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Mahon, Matthew J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Mahon, MJ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Their 10,50 Blossom St, Boston, MA 02114 USA. EM mahon@helix.mgh.harvard.edu FU National Institutes of Health (NIH) [5P01DK011794-43] FX This work was supported by a grant from the National Institutes of Health (NIH; grant no. 5P01DK011794-43) to John Potts. Special thanks to Marie Demay for the constitutively active beta-catenin plasmid. This paper is subject to the NIH Public Access Policy. NR 15 TC 2 Z9 3 U1 0 U2 2 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 2011 VL 51 IS 2 BP 119 EP + DI 10.2144/000113720 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 810SE UT WOS:000294146600014 PM 21806556 ER PT J AU Chen, WT Lin, YY Fuh, JL Hamalainen, MS Ko, YC Wang, SJ AF Chen, Wei-Ta Lin, Yung-Yang Fuh, Jong-Ling Haemaelaeinen, Matti S. Ko, Yu-Chieh Wang, Shuu-Jiun TI Sustained visual cortex hyperexcitability in migraine with persistent visual aura SO BRAIN LA English DT Article DE migraine; migraine with aura; chronic migraine; persistent aura without infarction; magnetoencephalography ID CORTICAL SPREADING DEPRESSION; CEREBRAL-BLOOD-FLOW; EVOKED-POTENTIALS; MECHANICAL STIMULATION; CALCIUM WAVES; ATTACK; HABITUATION; BRAIN; SUPPRESSION AB Persistent aura without infarction, a rare migraine disorder, is defined by aura symptoms that persist for > 1 week without radiological evidence of cerebral infarction. To unveil its pathophysiological mechanisms, this study used magnetoencephalography to characterize the visual cortex excitability in persistent aura by comparison with episodic and chronic migraine. We recruited six patients with persistent visual aura, 39 patients with episodic migraine [12 in ictal phase; 27 in interictal phase (with aura, n = 9; without aura, n = 18)], 18 patients with chronic migraine and 24 healthy controls. Five sequential blocks of 50 neuromagnetic prominent 100 ms responses were obtained, and the dynamic change in visual cortex excitability was evaluated by the percentage changes of individual mean prominent 100 ms amplitudes at blocks 2-5 compared with block 1, with a significant increase indicating potentiation. We found that in patients with persistent aura, there was significant potentiation during ictal periods (P = 0.009 and 0.006 at blocks 2 and 5, respectively), and the excitability change was inversely correlated with the duration of aura persistence (correlation coefficient -0.812, P = 0.050, block 2). The interictal recordings (n = 3) also showed potentiation. In terms of the other migraine spectrum disorders, persistent aura differed from episodic migraine in the presence of ictal potentiation. Persistent aura further differed from chronic migraine in the absence of interictal potentiation in chronic migraine. There was a higher percentage change of response amplitude at the end of stimulation (block 5) in persistent aura (43.3 +/- 11.7) than in chronic migraine (-7.6 +/- 5.5, P = 0.006) and ictal recordings of episodic migraine (-4.9 +/- 9.6, P = 0.020). Normal control subjects had no significant response changes. This magnetoencephalographic study showed that the visual cortex in patients with persistent visual aura maintains a steady-state hyperexcitability without significant dynamic modulation. The excitability characteristic supports persistent visual aura as a nosological entity in migraine spectrum disorders and suggests a pathophysiological link to sustained excitatory effects possibly related to reverberating cortical spreading depression. C1 [Chen, Wei-Ta; Lin, Yung-Yang; Fuh, Jong-Ling; Wang, Shuu-Jiun] Taipei Vet Gen Hosp, Neurol Inst, Dept Neurol, Taipei 112, Taiwan. [Chen, Wei-Ta; Lin, Yung-Yang; Fuh, Jong-Ling; Ko, Yu-Chieh; Wang, Shuu-Jiun] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Chen, Wei-Ta; Haemaelaeinen, Matti S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Lin, Yung-Yang] Natl Yang Ming Univ, Inst Physiol, Taipei 112, Taiwan. [Lin, Yung-Yang] Natl Yang Ming Univ, Inst Brain Sci, Taipei 112, Taiwan. [Lin, Yung-Yang] Taipei Vet Gen Hosp, Dept Med Res & Educ, Taipei 112, Taiwan. [Ko, Yu-Chieh] Taipei Vet Gen Hosp, Dept Ophthalmol, Taipei 112, Taiwan. RP Wang, SJ (reprint author), Taipei Vet Gen Hosp, Neurol Inst, Dept Neurol, 201 Sect 2,Shih Pai Rd, Taipei 112, Taiwan. EM sjwang@vghtpe.gov.tw RI Hamalainen, Matti/C-8507-2013; OI Fuh, Jong-Ling/0000-0001-9135-3351 FU National Science Council (Taiwan) [NSC 96-2314-B-075-073-MY3, NSC-96-2628-B-010-030-MY3, NSC98-2321-B-010-007, 99-2321-B-010-004-, 99-2628-B-010-011-MY3, 97-2314-B-075-049-MY3, NSC 97-2628-B-010-007-MY3, 98-2314-B-010-019-MY2]; Taipei Veterans General Hospital [V99C1-124, V98ER3-002, VGH-S4-98-001, VGH-ER3-99-006, V99C1-156, V100C-146, V100C-059, VGHUST 100-G7-1-3, V100C-087, VGHUST 100-G7-1-1]; Ministry of Education, Taipei, Taiwan FX National Science Council (Taiwan) (NSC 96-2314-B-075-073-MY3, to W.-T.C.; NSC-96-2628-B-010-030-MY3 and NSC98-2321-B-010-007 and 99-2321-B-010-004- and 99-2628-B-010-011-MY3, to Y.-Y.L.; 97-2314-B-075-049-MY3, to J.-L.F.; NSC 97-2628-B-010-007-MY3 and 98-2314-B-010-019-MY2, to S.-J.W.); Taipei Veterans General Hospital (V99C1-124, to W.-T.C.; V98ER3-002 and VGH-S4-98-001 and VGH-ER3-99-006 and V99C1-156 and V100C-146, to Y.-Y.L.; V100C-059 and VGHUST 100-G7-1-3, to J.-L.F.; V100C-087 and VGHUST 100-G7-1-1, to S.-J.W.); the Ministry of Education (Aim for the Top University Plan), Taipei, Taiwan. NR 40 TC 38 Z9 39 U1 2 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 2011 VL 134 BP 2387 EP 2395 DI 10.1093/brain/awr157 PN 8 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 809OX UT WOS:000294067700023 PM 21729907 ER PT J AU Cecere, LM Littman, AJ Slatore, CG Udris, EM Bryson, CL Boyko, EJ Pierson, DJ Au, DH AF Cecere, Laura M. Littman, Alyson J. Slatore, Christopher G. Udris, Edmunds M. Bryson, Chris L. Boyko, Edward J. Pierson, David J. Au, David H. TI Obesity and COPD: Associated Symptoms, Health-related Quality of Life, and Medication Use SO COPD-JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE LA English DT Article DE Obesity; COPD; Health-related quality of life; Symptoms; Inhaled medications; Exacerbations ID OBSTRUCTIVE PULMONARY-DISEASE; PROGNOSTIC VALUE; LUNG HEALTH; SALMETEROL; WEIGHT; RISK; FLUTICASONE; IPRATROPIUM; FORMOTEROL; MORTALITY AB Background: There is little data about the combined effects of COPD and obesity. We compared dyspnea, health-related quality of life (HRQoL), exacerbations, and inhaled medication use among patients who are overweight and obese to those of normal weight with COPD. Methods: We performed secondary data analysis on 364 Veterans with COPD. We categorized subjects by body mass index (BMI). We assessed dyspnea using the Medical Research Council (MRC) dyspnea scale and HRQoL using the St. George's Respiratory Questionnaire. We identified treatment for an exacerbation and inhaled medication use in the past year. We used multiple logistic and linear regression models as appropriate, with adjustment for age, COPD severity, smoking status, and co-morbidities. Results: The majority of our population was male (n = 355, 98%) and either overweight (n = 115, 32%) or obese (n = 138, 38%). Obese and overweight subjects had better lung function (obese: mean FEV(1) 55.4% +/- 19.9% predicted, overweight: mean FEV(1) 50.0% +/- 20.4% predicted) than normal weight subjects (mean FEV(1) 44.2% +/- 19.4% predicted), yet obese subjects reported increased dyspnea [adjusted OR of MRC score >= 2 = 4.91 (95% CI 1.80, 13.39], poorer HRQoL, and were prescribed more inhaled medications than normal weight subjects. There was no difference in any outcome between overweight and normal weight patients. Conclusions: Despite having less severe lung disease, obese patients reported increased dyspnea and poorer HRQoL than normal weight patients. The greater number of inhaled medications prescribed for obese patients may represent overuse. Obese patients with COPD likely need alternative strategies for symptom control in addition to those currently recommended. C1 [Cecere, Laura M.; Udris, Edmunds M.; Bryson, Chris L.; Au, David H.] Dept Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Cecere, Laura M.; Pierson, David J.; Au, David H.] Univ Washington, Dept Med, Div Pulm & Crit Care Med, Seattle, WA 98101 USA. [Littman, Alyson J.; Boyko, Edward J.] Dept Vet Affairs Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Littman, Alyson J.] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Slatore, Christopher G.] Dept Vet Affairs Med Ctr, Portland, OR USA. [Slatore, Christopher G.] Oregon Hlth & Sci Univ, Dept Med, Div Pulm & Crit Care Med, Portland, OR 97201 USA. RP Cecere, LM (reprint author), Univ Washington, VA Puget Sound Hlth Care Syst, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM lcecere@u.washington.edu OI Slatore, Christopher/0000-0003-0958-8122 FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [IIR 02-292]; Office of Research and Development Cooperative Studies Program, Department of Veterans Affairs; NIH [2T32HL007287-31]; Veterans Affairs HSRD Fellowship [TPM 61-037]; Veterans Affairs HSR&D Career Development Award; VA Rehabilitation Research and Development Career Development Award [6982]; Giliad Sciences FX This material is based upon work supported by a Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development grant [IIR 02-292]. It is also supported in part by the Office of Research and Development Cooperative Studies Program, Department of Veterans Affairs. Dr. Cecere was previously supported by an NIH institutional training grant [2T32HL007287-31], and is currently supported by a Veterans Affairs HSR&D Fellowship [TPM 61-037]. Dr. Slatore is supported by a Veterans Affairs HSR&D Career Development Award and resources from the Portland VA Medical Center, Portland, OR. Dr. Littman was supported by a VA Rehabilitation Research and Development Career Development Award (#6982). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. An earlier version of this manuscript was presented in abstract format the American Thoracic Society International Conference, May 2009.; Drs. Au and Bryson are co-investigators on a grant from Giliad Sciences for work which is unrelated to this manuscript. Dr. Boyko has consulted for Ely Lily, Inc. and Seventh Sense Biosystems. Dr. Au sits on the medical editorial board for Nexcura and is a research consultant for Bosch LLC. None of the other authors have any potential conflicts of interest to report. NR 38 TC 28 Z9 29 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1541-2555 J9 COPD JI COPD-J. Chronic Obstr. Pulm. Dis. PD AUG PY 2011 VL 8 IS 4 BP 275 EP 284 DI 10.3109/15412555.2011.586660 PG 10 WC Respiratory System SC Respiratory System GA 811BD UT WOS:000294176000006 PM 21809909 ER PT J AU Steffel, J Braunwald, E AF Steffel, Jan Braunwald, Eugene TI Novel oral anticoagulants: focus on stroke prevention and treatment of venous thrombo-embolism SO EUROPEAN HEART JOURNAL LA English DT Review DE Apixaban; Atrial fibrillation; Dabigatran etexilate; Edoxaban; Novel anticoagulants; Rivaroxaban; RE-LY AVERROES; ROCKET AF; ENGAGE-TIMI 48 ID FACTOR-XA INHIBITOR; RE-LY TRIAL; DIRECT THROMBIN INHIBITOR; ACUTE CORONARY SYNDROMES; TOTAL KNEE ARTHROPLASTY; ATRIAL-FIBRILLATION; DABIGATRAN ETEXILATE; DOUBLE-BLIND; RANDOMIZED-TRIAL; MYOCARDIAL-INFARCTION AB Anticoagulation for the long-term treatment and prevention of thrombo-embolic diseases as well as for stroke prevention in atrial fibrillation (AF) has been accomplished by vitamin K antagonists for the last half century. Although effective under optimal conditions, the imminent risk of a recurrent event vs. the risk of bleeding due to the narrow therapeutic window, numerous food-and drug interactions, and the need for regular monitoring complicate the long-term use of these drugs and render treatment with these agents complicated. As a result, novel anticoagulants which selectively block key factors in the coagulation cascade are being developed. The efficacy and safety of the direct thrombin inhibitor dabigatran etexilate, as well as of the selective factor Xa inhibitors rivaroxaban and apixaban, have been demonstrated in Phase III trials for stroke prevention in AF and the treatment and secondary prophylaxis of venous thrombo-embolism. This review summarizes the results from recently published pivotal clinical trials and discusses the opportunities as well as uncertainties in the clinical applications of these novel agents. C1 [Steffel, Jan] Univ Zurich Hosp, Dept Cardiol, CardioVasc Ctr, CH-8091 Zurich, Switzerland. [Steffel, Jan] Univ Zurich, Inst Physiol, Cardiovasc Res, Zurich, Switzerland. [Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. RP Steffel, J (reprint author), Univ Zurich Hosp, Dept Cardiol, CardioVasc Ctr, Ramistr 100, CH-8091 Zurich, Switzerland. EM steffel@access.uzh.ch FU AstraZeneca; Bayer HealthCare; Boehringer Ingelheim; Sanofi-aventis; Johnson and Johnson; Bayer Health Care; Daichi-Sankyo; AstraZeneca Pharmaceuticals LP; Johnson Johnson; Beckman Coulter, Inc.; Eli Lilly; Genentech; Integrated Therapeutics Group; Merck Co., Inc.; Roche Diagnostics Corp.; sanofi aventis; Daiichi Sankyo; Glaxo Smith Kline; Bristol Myers Squibb FX J.S. has received consulting and/or speakers' fees from AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, and Sanofi-aventis. E. B. chairs the ATLAS-2-TIMI 51 trial of rivaroxaban in ACS that is sponsored by Johnson and Johnson as well as by Bayer Health Care; he chairs the ENGAGE-TIMI 48 trial of edoxaban in AF that is sponsored by Daichi-Sankyo; is Founding Chairman of the TIMI Study Group at the Brigham and Women's Hospital-The Brigham and Women's Hospital receives (or has received within the past 24 months) grant support for the TIMI Study Group from the following pharmaceutical companies: AstraZeneca Pharmaceuticals LP, Johnson & Johnson, Beckman Coulter, Inc., Eli Lilly, Genentech, Integrated Therapeutics Group, Merck & Co., Inc., Roche Diagnostics Corp., sanofi aventis, Daiichi Sankyo, Glaxo Smith Kline, and Bristol Myers Squibb. He has also received honoraria and has participated in advisory board meetings and acted as a consultant for Daiichi Sankyo, Eli Lilly, Merck & Co., and Genzyme. NR 68 TC 36 Z9 36 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2011 VL 32 IS 16 BP 1968 EP U34 DI 10.1093/eurheartj/ehr052 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 809PX UT WOS:000294070300010 PM 21421599 ER PT J AU Zhou, JY Dann, GP Liew, CW Smith, RD Kulkarni, RN Qian, WJ AF Zhou, Jian-Ying Dann, Geoffrey P. Liew, Chong Wee Smith, Richard D. Kulkarni, Rohit N. Qian, Wei-Jun TI Unraveling pancreatic islet biology by quantitative proteomics SO EXPERT REVIEW OF PROTEOMICS LA English DT Review DE diabetes; insulin resistance; pancreatic beta cells; pancreatic islets; quantitative proteomics; signaling pathway ID 2-DIMENSIONAL GEL-ELECTROPHORESIS; SPECTROMETRY-BASED PROTEOMICS; BETA-CELL APOPTOSIS; CHROMATOGRAPHY-MASS SPECTROMETRY; DIFFERENTIAL PROTEIN EXPRESSION; IN-VIVO; INSULIN-SECRETION; ELEVATED GLUCOSE; OXIDATIVE STRESS; ACCURATE MASS AB The pancreatic islets of Langerhans play a critical role in maintaining blood glucose homeostasis by secreting insulin and several other important peptide hormones. Impaired insulin secretion due to islet dysfunction is linked to the pathogenesis underlying both Type 1 and Type 2 diabetes. Over the past 5 years, emerging proteomic technologies have been applied to dissect the signaling pathways that regulate islet functions and gain an understanding of the mechanisms of islet dysfunction relevant to diabetes. Herein, we briefly review some of the recent quantitative proteomic studies involving pancreatic islets geared towards gaining a better understanding of islet biology relevant to metabolic diseases. C1 [Zhou, Jian-Ying; Dann, Geoffrey P.; Smith, Richard D.; Qian, Wei-Jun] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Liew, Chong Wee] Harvard Univ, Sch Med, Div Cell & Mol Physiol, Joslin Diabet Ctr,Dept Med, Boston, MA 02215 USA. [Smith, Richard D.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. RP Qian, WJ (reprint author), Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. EM weijun.qian@pnl.gov RI Zhou, Jian-Ying/D-1308-2012; Smith, Richard/J-3664-2012 OI Smith, Richard/0000-0002-2381-2349 FU National Institutes of Health [R01DK074795, RR018522]; DOE [DE-AC05-76RLO1830] FX Portions of this research were supported by National Institutes of Health grants R01DK074795 and RR018522. Experimental work was performed in the Environmental Molecular Sciences Laboratory, a US Department of Energy (DOE) Office of Biological and Environmental Research national scientific user facility on the Pacific Northwest National Laboratory (PNNL) campus. PNNL is a multiprogram national laboratory operated by Battelle for the DOE under Contract No. DE-AC05-76RLO1830. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 87 TC 5 Z9 5 U1 0 U2 6 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-9450 J9 EXPERT REV PROTEOMIC JI Expert Rev. Proteomics PD AUG PY 2011 VL 8 IS 4 BP 495 EP 504 DI 10.1586/EPR.11.39 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 810PX UT WOS:000294139500013 PM 21819304 ER PT J AU Thomas, KA Dichter, ME Matejkowski, J AF Thomas, Kristie A. Dichter, Melissa E. Matejkowski, Jason TI Intimate Versus Nonintimate Partner Murder: A Comparison of Offender and Situational Characteristics SO HOMICIDE STUDIES LA English DT Article DE batterers; domestic violence; intimate partner violence; homicide; murder ID FALSE DISCOVERY RATE; DOMESTIC VIOLENCE; HOMICIDE; CRIME; CHICAGO; FEMALE; POLICY; RATES; WOMEN; LEGAL AB To explore whether homicide of intimate partners is distinct from homicide of nonintimates, we compared sociodemographic, legal, family, clinical, and situational characteristics of men who murdered an intimate partner (n = 71) to those of men who murdered a nonintimate (n = 363). Bivariate findings suggest that intimate murder offenders are more socially bonded and conforming regarding employment and relationship patterns and use fatal violence to meet emotional rather than instrumental needs compared to nonintimate offenders. Multivariate findings indicate marital status, history of severe mental illness, and motive are important factors that differentiate men who murder intimates from those who murder nonintimates. Homicide prevention efforts must be tailored to account for factors that differentiate these two offender types. C1 [Thomas, Kristie A.] Simmons Coll, Sch Social Work, Boston, MA 02115 USA. [Dichter, Melissa E.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Matejkowski, Jason] Treatment Res Inst, Sect Law & Eth, Philadelphia, PA USA. RP Thomas, KA (reprint author), Simmons Coll, Sch Social Work, 300 Fenway, Boston, MA 02115 USA. EM kristie.thomas@simmons.edu OI Matejkowski, Jason/0000-0002-0056-4987 NR 48 TC 12 Z9 12 U1 1 U2 21 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1088-7679 J9 HOMICIDE STUD JI Homicide Stud. PD AUG PY 2011 VL 15 IS 3 BP 291 EP 311 DI 10.1177/1088767911417803 PG 21 WC Criminology & Penology SC Criminology & Penology GA 809OU UT WOS:000294067400005 ER PT J AU Dalal, S Beunza, JJ Volmink, J Adebamowo, C Bajunirwe, F Njelekela, M Mozaffarian, D Fawzi, W Willett, W Adami, HO Holmes, MD AF Dalal, Shona Jose Beunza, Juan Volmink, Jimmy Adebamowo, Clement Bajunirwe, Francis Njelekela, Marina Mozaffarian, Dariush Fawzi, Wafaie Willett, Walter Adami, Hans-Olov Holmes, Michelle D. TI Non-communicable diseases in sub-Saharan Africa: what we know now SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Chronic; cardiovascular; heart; stroke; diabetes; cancer; hypertension; obesity; prevalence; incidence ID CORONARY-HEART-DISEASE; TYPE-2 DIABETES-MELLITUS; MODIFIABLE RISK-FACTORS; RURAL SOUTH-AFRICA; IMPAIRED GLUCOSE-TOLERANCE; GHANAIAN CIVIL-SERVANTS; MIDDLE-INCOME COUNTRIES; BLOOD-PRESSURE; SCHOOL-CHILDREN; CARDIOVASCULAR-DISEASE AB Background Sub-Saharan Africa (SSA) has a disproportionate burden of both infectious and chronic diseases compared with other world regions. Current disease estimates for SSA are based on sparse data, but projections indicate increases in non-communicable diseases (NCDs) caused by demographic and epidemiologic transitions. We review the literature on NCDs in SSA and summarize data from the World Health Organization and International Agency for Research on Cancer on the prevalence and incidence of cardiovascular diseases, diabetes mellitus Type 2, cancer and their risk factors. Methods We searched the PubMed database for studies on each condition, and included those that were community based, conducted in any SSA country and reported on disease or risk factor prevalence, incidence or mortality. Results We found few community-based studies and some countries (such as South Africa) were over-represented. The prevalence of NCDs and risk factors varied considerably between countries, urban/rural location and other sub-populations. The prevalence of stroke ranged from 0.07 to 0.3%, diabetes mellitus from 0 to 16%, hypertension from 6 to 48%, obesity from 0.4 to 43% and current smoking from 0.4 to 71%. Hypertension prevalence was consistently similar among men and women, whereas women were more frequently obese and men were more frequently current smokers. Conclusions The prevalence of NCDs and their risk factors is high in some SSA settings. With the lack of vital statistics systems, epidemiologic studies with a variety of designs (cross-sectional, longitudinal and interventional) capable of in-depth analyses of risk factors could provide a better understanding of NCDs in SSA, and inform health-care policy to mitigate the oncoming NCD epidemic. C1 [Dalal, Shona; Jose Beunza, Juan; Mozaffarian, Dariush; Fawzi, Wafaie; Holmes, Michelle D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Jose Beunza, Juan] Univ Navarra, Dept Prevent Med & Publ Hlth, E-31080 Pamplona, Spain. [Volmink, Jimmy] Univ Stellenbosch, Fac Hlth Sci, ZA-7600 Stellenbosch, South Africa. [Adebamowo, Clement] Inst Human Virol, Abuja, Nigeria. [Adebamowo, Clement] Univ Maryland, Sch Med, Greenbaum Canc Ctr, Baltimore, MD 21201 USA. [Adebamowo, Clement] Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. [Bajunirwe, Francis] Mbarara Univ Sci & Technol, Dept Community Hlth, Mbarara, Uganda. [Njelekela, Marina] Muhimbili Univ Hlth & Allied Sci, Dept Physiol, Dar Es Salaam, Tanzania. [Mozaffarian, Dariush; Holmes, Michelle D.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Fawzi, Wafaie; Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Adami, Hans-Olov] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Holmes, Michelle D.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Dalal, S (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM sdalal@hsph.harvard.edu OI Adebamowo, Clement/0000-0002-6571-2880 FU Dean s Office of the Harvard School of Public Health; La Caixa Fellowship FX This work was supported by the Dean s Office of the Harvard School of Public Health. The funder played no role in the decision to submit the article or in its preparation. Dr. Beunza was supported by a La Caixa Fellowship. NR 165 TC 131 Z9 133 U1 6 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD AUG PY 2011 VL 40 IS 4 BP 885 EP 901 DI 10.1093/ije/dyr050 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 810ER UT WOS:000294108700012 PM 21527446 ER PT J AU Heidel, FH Mar, BG Armstrong, SA AF Heidel, Florian H. Mar, Brenton G. Armstrong, Scott A. TI Self-renewal related signaling in myeloid leukemia stem cells SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE Leukemia stem cell; Self-renewal; Hedgehog; Wnt; Notch; FoxO ID CHRONIC MYELOGENOUS LEUKEMIA; COMPLETE MOLECULAR REMISSION; INHIBITS TUMOR-GROWTH; BETA-CATENIN; IN-VIVO; BCR-ABL; SONIC HEDGEHOG; CANCER; NOTCH; PATHWAY AB A key characteristic of hematopoietic stem cells (HSC) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSC and potentially also in leukemic stem cells. Besides pathways such as Wnt signaling, Hedgehog signaling and Notch signaling, transcription factors (FoxOs) and cell fate determinants may also play a role in stem cells. While some of these pathways seem to be dispensable for maintenance of adult HSC, there may be a distinct requirement in leukemia stem cells for leukemic self-renewal. Here we will focus on self-renewal related signaling in myeloid leukemia stem cells and its therapeutic relevance. C1 [Heidel, Florian H.; Mar, Brenton G.; Armstrong, Scott A.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Heidel, Florian H.; Mar, Brenton G.; Armstrong, Scott A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Heidel, Florian H.] Otto VonGuericke Univ Magdegurg, Dept Hematol Oncol, D-39016 Magdeburg, Germany. [Armstrong, Scott A.] Harvard Univ, Stem Cell Inst, Boston, MA 02115 USA. RP Heidel, FH (reprint author), Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. EM florian.h.heidel@gmail.com OI Mar, Brenton/0000-0002-3857-9324 FU NHLBI NIH HHS [T32 HL007574, T32 HL007574-31] NR 77 TC 18 Z9 20 U1 0 U2 5 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD AUG PY 2011 VL 94 IS 2 BP 109 EP 117 DI 10.1007/s12185-011-0901-0 PG 9 WC Hematology SC Hematology GA 808MM UT WOS:000293981800001 PM 21800073 ER PT J AU Buckley, AW Sassower, K Rodriguez, AJ Jennison, K Wingert, K Buckley, J Thurm, A Sato, S Swedo, S AF Buckley, Ashura Williams Sassower, Kenneth Rodriguez, Alcibiades J. Jennison, Kaitlin Wingert, Katherine Buckley, Jack Thurm, Audrey Sato, Susumu Swedo, Susan TI An Open Label Trial of Donepezil for Enhancement of Rapid Eye Movement Sleep in Young Children with Autism Spectrum Disorders SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID LONG-TERM POTENTIATION; REM-SLEEP; HEALTHY-PERSONS; MEMORY AB Background: Rapid eye movement (REM) sleep is greatest in the developing brain, is driven by acetylcholine, and may represent a protected time for neuroplasticity. Recently published data from our lab observed that children with autism spent significantly less time in this state during a single night recording than did typically developing children and those with developmental delay without autism. The objective of this study was to determine whether or not donepezil can increase the REM % in children with diagnosed autism spectrum disorder (ASD) found to have REM % values of at least two standard deviations below expected for age. Methods: Five subjects found to have an ASD (ages 2.5-6.9 years) and demonstrated deficits in REM sleep compared with within-lab controls were enrolled in a dose finding study of donepezil. Each subject was examined by polysomnography for REM sleep augmentation after drug administration. Results: REM sleep as a percentage of Total Sleep Time was increased significantly and REM latency was decreased significantly after drug administration in all subjects. No other observed sleep parameter was changed significantly. Conclusions: Donepezil can increase the amount of time that children with an ASD spend in the REM sleep state. A double-blind, placebo-controlled trial is needed to assess the association between REM sleep augmentation and learning, cognition, and behavior in such children. C1 [Buckley, Ashura Williams; Jennison, Kaitlin; Wingert, Katherine; Thurm, Audrey; Swedo, Susan] NIMH, Dept Pediat & Dev Neurosci, Bethesda, MD 20892 USA. [Sassower, Kenneth] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Rodriguez, Alcibiades J.] NYU, Dept Neurol, New York, NY 10016 USA. [Sato, Susumu] Natl Inst Neurol Disorders & Stroke, Dept Electrophysiol, Bethesda, MD USA. RP Buckley, AW (reprint author), NIMH, Dept Pediat & Dev Neurosci, Bethesda, MD 20892 USA. EM shu.buckley@nih.gov FU NIH; National Institute of Mental Health [T32MH067763] FX All research was funded by intramural NIH and by Award Number T32MH067763 from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health. NR 26 TC 19 Z9 19 U1 0 U2 8 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD AUG PY 2011 VL 21 IS 4 BP 353 EP 357 DI 10.1089/cap.2010.0121 PG 5 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 809MH UT WOS:000294060000007 PM 21851192 ER PT J AU Ilgen, JS Takayesu, JK Bhatia, K Marsh, RH Shah, S Wilcox, SR Krauss, WH Nadel, ES AF Ilgen, Jonathan S. Takayesu, James K. Bhatia, Kriti Marsh, Regan H. Shah, Sachita Wilcox, Susan R. Krauss, William H. Nadel, Eric S. TI BACK TO THE BEDSIDE: THE 8-YEAR EVOLUTION OF A RESIDENT-AS-TEACHER ROTATION SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE resident-as-teacher; medical education; residency; curriculum; teaching; emergency medicine ID EMERGENCY-MEDICINE; RANDOMIZED-TRIAL; TRAINING-PROGRAM; FOCUS-GROUP; SKILLS; PERCEPTIONS; ATTITUDES; EDUCATION; CURRICULUM; WORKSHOP AB Background: Teaching our residents to teach is a vital responsibility of Emergency Medicine (EM) residency programs. As emergency department (ED) overcrowding may limit the ability of attending physicians to provide bedside instruction, senior residents are increasingly asked to assume this role for more junior trainees. Unfortunately, a recent survey suggests that only 55% of all residencies provide instruction in effective teaching methods. Without modeling from attending physicians, many residents struggle with this responsibility. Objectives: We introduced a "Resident-as-Teacher" curriculum in 2002 as a means to address a decline in bedside instruction and provide our senior residents with a background in effective teaching methods. Discussion: Here, we describe the evolution of this resident-as-teacher rotation, outline its current structure, cite potential pitfalls and solutions, and discuss the unique addition of a teach-the-teacher curriculum. Conclusion: A resident-as-teacher rotation has evolved into a meaningful addition to our senior residents' training, fostering their growth as educators and addressing our need for bedside instruction. (C) 2011 Elsevier Inc. C1 [Ilgen, Jonathan S.] Univ Washington, Harborview Med Ctr, Div Emergency Med, Seattle, WA 98104 USA. [Takayesu, James K.; Marsh, Regan H.; Wilcox, Susan R.; Krauss, William H.; Nadel, Eric S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Bhatia, Kriti; Marsh, Regan H.; Krauss, William H.; Nadel, Eric S.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Shah, Sachita] Brown Univ, Rhode Isl Hosp, Dept Emergency Med, Providence, RI 02903 USA. RP Ilgen, JS (reprint author), Univ Washington, Harborview Med Ctr, Div Emergency Med, 325 9th Ave,Box 359702, Seattle, WA 98104 USA. OI Wilcox, Susan/0000-0001-7477-7531 NR 33 TC 3 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD AUG PY 2011 VL 41 IS 2 BP 190 EP 195 DI 10.1016/j.jemermed.2010.05.020 PG 6 WC Emergency Medicine SC Emergency Medicine GA 811GZ UT WOS:000294195900018 PM 20619571 ER PT J AU Susarla, SM Black, R Dodson, TB AF Susarla, Srinivas M. Black, Rachel Dodson, Thomas B. TI After Dentoalveolar Surgery, Most Patients Are Satisfied With Telephone Follow-Up SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID 3RD MOLAR SURGERY; RISK-FACTORS; COMPLICATIONS; 3RD-MOLAR; EXTRACTION; AGE AB Purpose: To estimate patient satisfaction with telephone follow-up and compare the frequencies of postoperative complications between patients undergoing telephone and those undergoing clinical follow-up after ambulatory office-based dentoalveolar procedures. Materials and Methods: Using a retrospective study design, the investigators enrolled a cohort of subjects who had had at least 1 tooth extracted during a 2-year period. The primary study variable was subject self-report of satisfaction with the telephone follow-up. For additional analyses, the predictor variable was follow-up type grouped as telephone versus clinical. The outcome variable was postoperative complications. To measure the relationships between the follow-up type and postoperative complications, bivariate and multiple logistic regression statistics were computed. P <= .05 was considered significant. Results: The sample was composed of 364 subjects, of whom 155 (42.6%) had received telephone follow-up. The sample's mean age was 28.6 +/- 11.7 years, included 220 females (60.4%), and had had an average of 3.4 +/- 2.1 teeth removed. The self-reported patient satisfaction rate with telephone follow-up was 95.9%. The subjects who experienced postoperative complications were 90% less likely to be satisfied relative to those without complications (P = .04). The overall complication frequency was 19.2%, with telephone follow-up subjects having a lower complication frequency (12.9%) than the clinical follow-up subjects (23.4%) (P < .01). After adjusting for differences between the 2 samples, no significant difference was found in the complication frequencies according to the method of follow-up (P = .7). Conclusion: Patient satisfaction with telephone follow-up was high. The subjects scheduled for telephone follow-up had a complication rate that was similar to that of the clinical follow-up subjects. (C) 2011 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 69: 2099-2105, 2011 C1 [Susarla, Srinivas M.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Black, Rachel] Harvard Univ, Cambridge, MA USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Susarla, SM (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, WACC230, Boston, MA 02114 USA. EM ssusarla1@partners.org OI Susarla, Srinivas/0000-0003-0155-8260 FU Oral and Maxillofacial Surgery Foundation; Massachusetts General Hospital Department of Oral; Maxillofacial Surgery Education and Research Fund; Center for Clinical Investigation; Massachusetts General Hospital Physicians' Organization FX The present study was supported by the Oral and Maxillofacial Surgery Foundation Fellowship in Clinical Investigation (to S. M. S.), the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund (to S. M. S. and T. B. D.), the Center for Clinical Investigation (S. M. S. and T. B. D.), and the Massachusetts General Hospital Physicians' Organization (T. B. D.). NR 10 TC 4 Z9 4 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2011 VL 69 IS 8 BP 2099 EP 2105 DI 10.1016/j.joms.2010.12.013 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 810WT UT WOS:000294160400012 PM 21680076 ER PT J AU Gordon, PE Lawler, ME Kaban, LB Dodson, TB AF Gordon, Paul E. Lawler, Matthew E. Kaban, Leonard B. Dodson, Thomas B. TI Mandibular Fracture Severity and Patient Health Status Are Associated With Postoperative Inflammatory Complications SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID RIGID INTERNAL-FIXATION; RISK-FACTORS; PLATE FIXATION; INFECTION; OSTEOSYNTHESIS; NONUNION; RATES; SCORE AB Purpose: To identify risk factors associated with postoperative inflammatory complications (POICs) after treatment of mandibular fractures. Patients and Methods: The investigators designed a case-control study and enrolled a sample of patients treated for mandibular fractures at Massachusetts General Hospital between August 2004 and January 2010. Subjects who developed POICs after fracture management were categorized as cases. A POIC was defined as 1) recurrent swelling, fever, increased pain, or trismus; 2) wound dehiscence with purulent drainage; 3) exposed or infected hardware; 4) abscess formation; 5) radiographic evidence of osteomyelitis; and/or 6) presence of a fistula. Controls had no complications. For each case, 2 controls were selected. Predictor variables were categorized into the following sets: demographic, fracture-specific, and perioperative. Bivariate and multiple logistic regression analyses were used to identify factors associated with POICs. Results: During the study interval, 575 subjects with mandible fractures were evaluated and treated. The study sample consisted of 44 cases and 88 controls. In the multiple regression model, an increasing Mandibular Injury Severity Score (odds ratio = 1.4; 95% confidence interval 1.2-1.6) and a positive medical history (odds ratio = 1.4; 95% confidence interval 1.03-1.8) were significantly (P < .05) associated with an increased risk for a POIC. Conclusion: Fracture severity assessed using the Mandibular Injury Severity Score and pre-existing medical problems were associated with increased risk for postoperative inflammatory complications following treatment of mandibular fractures. (C) 2011 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 69: 2191-2197, 2011 C1 [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Dodson, TB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, WACC230, Boston, MA 02114 USA. EM tbdodson@partners.org FU Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education; Center for Applied Clinical Investigation; Massachusetts General Physicians Organization FX This study was supported by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund and Center for Applied Clinical Investigation and the Massachusetts General Physicians Organization. NR 31 TC 10 Z9 10 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2011 VL 69 IS 8 BP 2191 EP 2197 DI 10.1016/j.joms.2011.03.071 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 810WT UT WOS:000294160400025 PM 21783003 ER PT J AU Givens, JL Prigerson, HG Jones, RN Mitchell, SL AF Givens, Jane L. Prigerson, Holly G. Jones, Rich N. Mitchell, Susan L. TI Mental Health and Exposure to Patient Distress Among Families of Nursing Home Residents with Advanced Dementia SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Dementia; caregivers; mental health; nursing home ID ADVANCED ALZHEIMERS-DISEASE; OF-LIFE CARE; HOSPICE ENROLLMENT; DEPRESSION; CAREGIVERS; SCALES; POPULATION; PREVALENCE; LENGTH; DEATH AB Context. The effect of suffering among patients with advanced dementia on their family members' mental health has not been investigated. Objectives. To describe family members' exposure to distressing symptoms among nursing home (NH) residents with advanced dementia and associations between such exposure and family members' mental health. Methods. Data were obtained from an 18-month prospective cohort study of NH residents with advanced dementia and their family member health care proxies (HCPs). Exposure to resident symptoms and associated fear and helplessness was measured quarterly using the Stressful Caregiving Adult Reactions to Experiences of Dying (SCARED) scale (range 0-120). HCP mental health was assessed quarterly using the Composite International Diagnostic Interview Short Form (CIDI-SF) (depression), K6 (psychological distress, range 0-24), and SF-12 (R) mental health subscale. Results. Seven hundred seventy-nine SCARED scale assessments were completed by 225 HCPs. The most frequent distressing symptoms were the following: feeling the resident had had enough (33.2%), choking (21.1%), and pain (18.9%). The symptoms eliciting the greatest fear were thinking the resident was dead and seeing them choke. A sense of helplessness was highest when the resident was observed to be in pain or choking. Family members with SCARED scores >0 were more likely to meet criteria for depression on the CIDI-SF (adjusted odds ratio [AOR] 2.59, 95% confidence interval [CI] 1.14, 5.85), have a K6 score >0 (AOR 2.31, 95% CI 1.55, 3.43), and have lower SF-12 scores (adjusted parameter estimate -1.51, 95% CI -2.56, -0.47). Conclusion. Family member exposure to distressing symptoms experienced by their loved ones with advanced dementia is not uncommon and is associated withworse mental health. J Pain Symptom Manage 2011; 42:183-191. (C) 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 [Givens, Jane L.; Jones, Rich N.; Mitchell, Susan L.] Hebrew SeniorLife Inst Aging Res, Boston, MA 02131 USA. [Givens, Jane L.; Mitchell, Susan L.] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA. [Prigerson, Holly G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Givens, JL (reprint author), Hebrew SeniorLife Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM janegivens@hrca.harvard.edu RI Jones, Richard/J-3488-2013 OI Jones, Richard/0000-0002-1049-218X FU National Institute on Aging at the National Institutes of Health [R01 AG024091, K24AG033640] FX This work was supported by the National Institute on Aging at the National Institutes of Health (R01 AG024091, K24AG033640 to Dr. Mitchell) and was conducted while Dr. Givens was a Hartford Geriatrics Health Outcomes Research Scholar. NR 27 TC 4 Z9 4 U1 4 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2011 VL 42 IS 2 BP 183 EP 191 DI 10.1016/j.jpainsymman.2010.10.259 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 810FU UT WOS:000294111900002 PM 21402461 ER PT J AU Kirwan, JR Boonen, A Harrison, MJ Hewlett, SE Wells, GA Singh, JA Furst, DE Dworkin, RH AF Kirwan, John R. Boonen, Annelies Harrison, Mark J. Hewlett, Sarah E. Wells, George A. Singh, Jasvinder A. Furst, Daniel E. Dworkin, Robert H. TI OMERACT 10 Patient Perspective Virtual Campus: Valuing Health; Measuring Outcomes in Rheumatoid Arthritis Fatigue, RA Sleep, Arthroplasty, and Systemic Sclerosis; and Clinical Significance of Changes in Health SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE OUTCOME MEASURES; FATIGUE; ARTHROPLASTY; RHEUMATIC DISEASES ID QUALITY-OF-LIFE; TOTAL KNEE ARTHROPLASTY; INFLAMMATORY ARTHRITIS; POPULATION PREFERENCES; UTILITY MEASURES; TRIALS; QUESTIONNAIRE; EXPERIENCE; VALIDITY; RESPONSIVENESS AB This workshop reviewed progress in a number of areas related to patient perspective outcomes that were not specifically included within other areas of the program. A substantial review of the work of the valuing health outcomes group (the "QALY" working group) with participation and feedback from the plenary audience resulted in guidance to refocus on the use of patient preferences in the elaboration of more robust outcome measures for patient-reported outcomes and life impact measures. Progress and developments in the areas of fatigue and sleep in rheumatoid arthritis, outcome measures in hip and knee arthroplasty clinical trials, and scleroderma were outlined, and the challenge of truly understanding the nature of clinically important improvement was reviewed. (J Rheumatol 2011;38:1728-34; doi:10.3899/jrheum.110393) C1 [Kirwan, John R.] Univ Bristol, Bristol Royal Infirm, Acad Rheumatol Unit, Bristol, Avon, England. [Boonen, Annelies] Maastricht Univ Med Ctr, Maastricht, Netherlands. [Boonen, Annelies] Caphri Res Inst, Maastricht, Netherlands. [Harrison, Mark J.] Univ Manchester, Hlth Methodol Res Grp, Manchester, Lancs, England. [Hewlett, Sarah E.] Univ W England, Bristol Royal Infirm, Acad Rheumatol Unit, Bristol BS16 1QY, Avon, England. [Wells, George A.] Univ Ottawa, Inst Heart, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama, Birmingham, AL USA. [Furst, Daniel E.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY USA. RP Kirwan, JR (reprint author), Univ Bristol, Bristol Royal Infirm, Acad Rheumatol Unit, Bristol, Avon, England. EM john.kirwan@bristol.ac.uk RI Harrison, Mark/E-5788-2012; Agaliotis, Maria/G-5334-2012; OI singh, jasvinder/0000-0003-3485-0006; Kirwan, John/0000-0002-6617-3217 NR 40 TC 9 Z9 9 U1 1 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2011 VL 38 IS 8 BP 1728 EP 1734 DI 10.3899/jrheum.110393 PG 7 WC Rheumatology SC Rheumatology GA 799VU UT WOS:000293315000034 PM 21807793 ER PT J AU Gossec, L Paternotte, S Bingham, CO Clegg, DO Coste, P Conaghan, PG Davis, AM Giacovelli, G Gunther, KP Hawker, G Hochberg, MC Jordan, JM Katz, JN Kloppenburg, M Lanzarotti, A Lim, K Lohmander, LS Mahomed, NN Maillefert, JF Manno, RL March, LM Mazzuca, SA Pavelka, K Punzi, L Roos, EM Rovati, LC Shi, H Singh, JA Suarez-Almazor, ME Tajana-Messi, E Dougados, M AF Gossec, Laure Paternotte, Simon Bingham, Clifton O., III Clegg, Daniel O. Coste, Philippe Conaghan, Philip G. Davis, Aileen M. Giacovelli, Giampaolo Gunther, Klaus-Peter Hawker, Gillian Hochberg, Marc C. Jordan, Joanne M. Katz, Jeffrey N. Kloppenburg, Margreet Lanzarotti, Arturo Lim, Keith Lohmander, L. Stefan Mahomed, Nizar N. Maillefert, Jean Francis Manno, Rebecca L. March, Lyn M. Mazzuca, Steven A. Pavelka, Karel Punzi, Leonardo Roos, Ewa M. Rovati, Lucio C. Shi, Helen Singh, Jasvinder A. Suarez-Almazor, Maria E. Tajana-Messi, Eleonora Dougados, Maxime CA OARSI-OMERACT Task Force Total Art TI OARSI/OMERACT Initiative to Define States of Severity and Indication for Joint Replacement in Hip and Knee Osteoarthritis. An OMERACT 10 Special Interest Group SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE OSTEOARTHRITIS; SEVERITY; PAIN; FUNCTION; STRUCTURE OUTCOME MEASURE ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; RADIOGRAPHIC FEATURES; GLUCOSAMINE SULFATE; PHYSICAL-FUNCTION; PROGRESSION; PAIN; ASSOCIATION; 3-YEAR; 2-YEAR AB Objective. To define pain and physical function cutpoints that would, coupled with structural severity, define a surrogate measure of "need for joint replacement surgery," for use as an outcome measure for potential structure-modifying interventions for osteoarthritis (OA). Methods. New scores were developed for pain and physical function in knee and hip OA. A cross-sectional international study in 1909 patients was conducted to define data-driven cutpoints corresponding to the orthopedic surgeons' indication for joint replacement. A post hoc analysis of 8 randomized clinical trials (1379 patients) evaluated the prevalence and validity of cutpoints, among patients with symptomatic hip/knee OA. Results. In the international cross-sectional study, there was substantial overlap in symptom levels between patients with and patients without indication for joint replacement; indeed, it was not possible to determine cutpoints for pain and function defining this indication. The post hoc analysis of trial data showed that the prevalence of cases that combined radiological progression, high level of pain, and high degree of function impairment was low (2%-12%). The most discriminatory cutpoint to define an indication for joint replacement was found to be [pain (0-100) + physical function (0-100) > 80]. Conclusion. These results do not support a specific level of pain or function that defines an indication for joint replacement. However, a tentative cutpoint for pain and physical function levels is proposed for further evaluation. Potentially, this symptom level, coupled with radiographic progression, could be used to define "nonresponders" to disease-modifying drugs in OA clinical trials. (J Rheumatol 2011;38:1765-9; doi:10.3899/jrheum.110403) C1 [Gossec, Laure; Paternotte, Simon; Dougados, Maxime] Paris Descartes Univ, Fac Med, Paris, France. [Gossec, Laure; Paternotte, Simon; Dougados, Maxime] Cochin Hosp, AP HP, Rheumatol Dept B, Paris, France. [Bingham, Clifton O., III; Manno, Rebecca L.] Johns Hopkins Univ, Div Rheumatol, Baltimore, MD USA. [Bingham, Clifton O., III] Johns Hopkins Univ, Div Clin Immunol & Allergy, Baltimore, MD USA. [Clegg, Daniel O.] Univ Utah, Sch Med, Dept Internal Med, Div Rheumatol, Salt Lake City, UT USA. [Coste, Philippe] Expansci Labs, Courbevoie, France. [Conaghan, Philip G.] Univ Leeds, Sect Musculoskeletal Dis, Leeds, W Yorkshire, England. [Conaghan, Philip G.] NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England. [Davis, Aileen M.] Univ Toronto, Div Hlth Care & Outcomes Res, Toronto, ON, Canada. [Davis, Aileen M.] Univ Toronto, Toronto Western Res Inst, Arthrit & Community Res & Evaluat Unit, Toronto, ON, Canada. [Davis, Aileen M.] Univ Toronto, Dept Rehabil Sci, Toronto, ON, Canada. [Giacovelli, Giampaolo] Rottapharm Madaus, Dept Clin Pharmacol, Dept Biostat, Monza, Italy. [Gunther, Klaus-Peter] Univ Dresden, Dept Orthopaed Surg, Dresden, Germany. [Hawker, Gillian] Univ Toronto, Womens Coll Hosp, Div Rheumatol, Dept Med, Toronto, ON M5S 1A1, Canada. [Hawker, Gillian] Univ Toronto, Fac Med, Dept Hlth Policy Management & Evaluat, Clin Epidemiol & Hlth Care Res Program, Toronto, ON M5S 1A1, Canada. [Hochberg, Marc C.] Univ Maryland, Sch Med, Dept Med, Div Clin Immunol & Rheumatol, Baltimore, MD 21201 USA. [Hochberg, Marc C.] Univ Maryland, Sch Med, Div Gerontol, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Jordan, Joanne M.] Univ N Carolina, Sch Med, Thurston Arthrit Res Ctr, Div Rheumatol Allergy & Immunol,Dept Med, Chapel Hill, NC USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Sch Med, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Dept Orthoped Surg, Sch Med, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kloppenburg, Margreet] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Dept Rheumatol, Leiden, Netherlands. [Lanzarotti, Arturo; Tajana-Messi, Eleonora] IBSA Inst Biochim SA, R&D Dept, Pambio Noranco, Switzerland. [Lim, Keith] St Vincents Hosp, Dept Rheumatol, Melbourne, Vic, Australia. [Lim, Keith] Western Hosp, Melbourne, Vic, Australia. [Lohmander, L. Stefan] Lund Univ, Dept Orthopaed, Lund, Sweden. [Mahomed, Nizar N.] Univ Toronto, Toronto Western Hosp, Div Orthopaed Surg, Toronto, ON M5T 2S8, Canada. [Maillefert, Jean Francis] Dijon Univ Hosp, Dept Rheumatol, Dijon, France. [Maillefert, Jean Francis] Univ Burgundy, Dijon, France. [Maillefert, Jean Francis] INSERM, U887, Dijon, France. [March, Lyn M.] Univ Sydney, Royal N Shore Hosp, Inst Bone & Joint Res, St Leonards, NSW 2065, Australia. [Mazzuca, Steven A.] Indiana Univ Sch Med, Indianapolis, IN USA. [Pavelka, Karel] Charles Univ Prague, Inst Rheumatol, Prague, Czech Republic. [Punzi, Leonardo] Univ Padua, Dept Clin & Expt Med, Rheumatol Unit, Padua, Italy. [Roos, Ewa M.] Univ So Denmark, Inst Sports & Clin Biomech, Odense, Denmark. [Shi, Helen] VA Cooperat Studies Program Coordinating Ctr, Hines, IL USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama, Birmingham, AL USA. [Suarez-Almazor, Maria E.] Univ Texas MD Anderson Canc Ctr, Rheumatol Sect, Houston, TX 77030 USA. RP Dougados, M (reprint author), Paris Descartes Univ, Fac Med, Paris, France. EM maxime.dougados@cch.aphp.fr RI Roos, Ewa/A-5416-2012; Lohmander, Stefan/I-8326-2012; DOUGADOS, MAXIME/P-5287-2016; Pavelka, Karel/E-6578-2017; OI Roos, Ewa/0000-0001-5425-2199; Pavelka, Karel/0000-0003-1952-8422; PUNZI, LEONARDO/0000-0002-8853-516X; Lohmander, Stefan/0000-0002-5424-9448; singh, jasvinder/0000-0003-3485-0006 FU OARSI; OMERACT; pharmaceutical companies Pfizer; Expansciences; Novartis; Negma Lerads; Rottapharm-Madaus; Fidia; Pierre Fabre Sante Laboratories; KOSTAR; Swedish Research Council; National Institutes of Health (NIH) [1 KL2 RR024151-01, T32 AR48522-06]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Agency for Healthcare Research; Houston Center for Education and Research on Therapeutics (CERT); Allergan; Takeda; Savient; Wyeth and Amgen FX Supported by unrestricted grants from OARSI and OMERACT and pharmaceutical companies Pfizer, Expansciences, Novartis, Negma Lerads, Rottapharm-Madaus, Fidia, and Pierre Fabre Sante Laboratories. Procter and Gamble Pharmaceuticals provided unrestricted access to placebo data from the KOSTAR study and an unrestricted grant to COB. LSL was supported by the Swedish Research Council; JAS was supported by the National Institutes of Health (NIH) Clinical Translational Science Award 1 KL2 RR024151-01 (Mayo Clinic Center for Clinical and Translational Research). MSA holds a K24 award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and is partially supported by the Agency for Healthcare Research and Quality through finding of the Houston Center for Education and Research on Therapeutics (CERT). RLM is supported by NIH Training Grant T32 AR48522-06. P. Caste is an employee of Expanscience; A. Lanzaroni and E. Tajana-Messi are employees of IBSA; L.C. Rovati and G. Giacovelli are employees of Rottapharm-Madaus; COB served as a consultant and investigator for Procter and Gamble Pharmaceuticals, Novartis, and Merck and received an unrestricted grant from P&G Pharmaceuticals; LM has received a speaker honorarium and travel grant from Servier. JAS has received speaker honoraria from Abbott; research and travel grants from Allergan, Takeda, Savient, Wyeth and Amgen; and consultant fees from Savient and URL pharmaceuticals. NR 24 TC 32 Z9 32 U1 1 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2011 VL 38 IS 8 BP 1765 EP 1769 DI 10.3899/jrheum.110403 PG 5 WC Rheumatology SC Rheumatology GA 799VU UT WOS:000293315000040 PM 21807799 ER PT J AU Wen, HY Schumacher, HR Pullman-Mooar, SW Einhorn, E AF Wen, Hongyan Schumacher, H. Ralph Pullman-Mooar, Sally W. Einhorn, Eugene TI Unusual Draining Nodules in a Patient with Rheumatoid Nodulosis and Hepatitis C Virus Infection SO JOURNAL OF RHEUMATOLOGY LA English DT Letter ID ARTHRITIS; CLASSIFICATION; AUTOANTIBODIES; ASSOCIATION; ANTIBODIES; CRITERIA C1 [Wen, Hongyan; Schumacher, H. Ralph; Pullman-Mooar, Sally W.] Univ Penn, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. [Einhorn, Eugene] Philadelphia Vet Affairs Med Ctr, Dept Pathol, Philadelphia, PA USA. [Wen, Hongyan] Shanxi Med Univ, Hosp 2, Taiyuan, Shanxi Province, Peoples R China. RP Schumacher, HR (reprint author), Univ Penn, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. EM schumacr@mail.med.upenn.edu NR 15 TC 0 Z9 0 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD AUG PY 2011 VL 38 IS 8 BP 1806 EP 1808 DI 10.3899/jrheum.110244 PG 3 WC Rheumatology SC Rheumatology GA 799VU UT WOS:000293315000046 PM 21807805 ER PT J AU Wang, GL Wang, J Douglas, G Browning, M Hahn, S Ganesh, J Cox, S Aleck, K Schmitt, ES Zhang, W Wong, LJC AF Wang, Guo-li Wang, Jing Douglas, Ganka Browning, Marsha Hahn, Sihoun Ganesh, Jaya Cox, Sarah Aleck, Kirk Schmitt, Eric S. Zhang, Wei Wong, Lee-Jun C. TI Expanded molecular features of carnitine acyl-carnitine translocase (CACT) deficiency by comprehensive molecular analysis SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE CACT deficiency; SLC25A20 gene mutation; Large deletion; Array CGH ID COMPARATIVE GENOMIC HYBRIDIZATION; ACYLCARNITINE CARRIER DEFICIENCY; FUNCTIONAL-ANALYSIS; DEFECT; IDENTIFICATION; PATIENT; DIAGNOSIS; METABOLISM; MUTATIONS; CHILDREN AB Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disease of fatty acid oxidation, mainly affecting long chain fatty acid utilization. The disease usually presents at neonatal period with severe hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and/or arrhythmia, hepatic dysfunction, skeletal muscle weakness, and encephalopathy. Definitive diagnosis of CACT deficiency by molecular analysis of the SLC25A20 gene has recently become clinically available. In contrast to biochemical analysis, sequence analysis is a more rapid and reliable method for diagnosis of CACT deficiency. In this study, we used Sanger sequencing and target array CGH to identify molecular defects in the SLC25A20 gene of patients with clinical features and an acylcarnitine profile consistent with CACT deficiency. Eight novel mutations, including a large 25.9 kb deletion encompassing exons 5 to 9 of SLC25A20 were found. Review of the published cases revealed that CACT deficiency is a pan-ethnic disorder with a broad mutation spectrum. Mutations are distributed along the entire gene without a hot spot. Two thirds of them are nonsense, frame-shift, or splice site mutations resulting in premature stop codons. This study underscores the importance of comprehensive molecular analysis, including sequencing and targeted array CGH of the SLC25A20 gene when CACT deficiency is suspected. (C) 2011 Elsevier Inc. All rights reserved. C1 [Wang, Guo-li; Wang, Jing; Douglas, Ganka; Schmitt, Eric S.; Zhang, Wei; Wong, Lee-Jun C.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Browning, Marsha] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hahn, Sihoun] Seattle Childrens Hosp, Seattle, WA USA. [Ganesh, Jaya] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Cox, Sarah; Aleck, Kirk] AZ Pediat Hematol Oncol Associates, Phoenix, AZ USA. RP Wong, LJC (reprint author), Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza,NAB2015, Houston, TX 77030 USA. EM ljwong@bcm.edu NR 26 TC 10 Z9 10 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2011 VL 103 IS 4 BP 349 EP 357 DI 10.1016/j.ymgme.2011.05.001 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 809ZY UT WOS:000294096400007 PM 21605995 ER PT J AU Heesters, BA Gonzalez, SF Carroll, MC AF Heesters, B. A. Gonzalez, S. F. Carroll, M. C. TI The role of complement in Streptococcus pneumoniae hand-off to follicular dendritic cells SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 13th European Meeting on Complement in Human Disease CY AUG 21-24, 2011 CL Leiden, NETHERLANDS C1 [Gonzalez, S. F.; Carroll, M. C.] Immune Dis Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2011 VL 48 IS 14 SI SI BP 1672 EP 1672 DI 10.1016/j.molimm.2011.06.240 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 809ZV UT WOS:000294096100029 ER PT J AU La Bonte, LR Pavlov, V Takahashi, K Takahashi, M Fujita, T Stahl, GL AF La Bonte, L. R. Pavlov, V. Takahashi, K. Takahashi, M. Fujita, T. Stahl, G. L. TI The MBL-complex is a significant contributor to thrombogenesis in vivo and in vitro SO MOLECULAR IMMUNOLOGY LA English DT Meeting Abstract CT 13th European Meeting on Complement in Human Disease CY AUG 21-24, 2011 CL Leiden, NETHERLANDS C1 [La Bonte, L. R.; Pavlov, V.; Stahl, G. L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Takahashi, K.] Massachusetts Gen Hosp, Dev Immunol Program, Boston, MA 02114 USA. [Takahashi, M.; Fujita, T.] Fukushima Med Univ, Sch Med, Fukushima, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2011 VL 48 IS 14 SI SI BP 1731 EP 1731 DI 10.1016/j.molimm.2011.06.429 PG 1 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 809ZV UT WOS:000294096100217 ER PT J AU Hunter, DJ Guermazi, A Lo, GH Grainger, AJ Conaghan, PG Boudreau, RM Roemer, FW AF Hunter, D. J. Guermazi, A. Lo, G. H. Grainger, A. J. Conaghan, P. G. Boudreau, R. M. Roemer, F. W. TI Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score) SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE MRI; Knee osteoarthritis; Semi-quantitative score; Reliability ID ANTERIOR CRUCIATE LIGAMENT; BONE-MARROW LESIONS; ARTICULAR-CARTILAGE; DIAGNOSTIC PERFORMANCE; PROTON-DENSITY; TRUE-FISP; 3.0 T; CONVENTIONAL MR; MENISCAL TEARS; RESONANCE AB Objective: In an effort to evolve semi-quantitative scoring methods based upon limitations identified in existing tools, integrating expert readers' experience with all available scoring tools and the published data comparing the different scoring systems, we iteratively developed the magnetic resonance imaging (MRI) Osteoarthritis Knee Score (MOAKS). The purpose of this report is to describe the instrument and its reliability. Methods: The MOAKS instrument refines the scoring of bone marrow lesions (BMLs) (providing regional delineation and scoring across regions), cartilage (sub-regional assessment), and refines the elements of meniscal morphology (adding meniscal hypertrophy, partial maceration and progressive partial maceration) scoring. After a training and calibration session two expert readers read MRIs of 20 knees separately. In addition, one reader re-read the same 20 MRIs 4 weeks later presented in random order to assess intra-rater reliability. The analyses presented here are for both intra- and inter-rater reliability (calculated using the linear weighted kappa and overall percent agreement). Results: With the exception of inter-rater reliability for tibial cartilage area (kappa = 0.36) and tibial osteophytes (kappa = 0.49); and intra-rater reliability for tibial BML number of lesions (kappa = 0.54), Hoffa-synovitis (kappa = 0.42) all measures of reliability using kappa statistics were very good (0.61-0.8) or reached near-perfect agreement (0.81-1.0). Only intra-rater reliability for Hoffa-synovitis, and inter-rater reliability for tibial and patellar osteophytes showed overall percent agreement <75%. Conclusion: MOAKS scoring shows very good to excellent reliability for the large majority of features assessed. Further iterative development and research will include assessment of its validation and responsiveness. (C) 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Hunter, D. J.] Univ Sydney, Dept Rheumatol, No Clin Sch, Royal N Shore Hosp, Sydney, NSW 2065, Australia. [Guermazi, A.; Roemer, F. W.] Boston Univ, Sch Med, Quantitat Imaging Ctr, Dept Radiol, Boston, MA 02118 USA. [Lo, G. H.] Michael E DeBakey Vet Adm Med Ctr, Med Care Line Res Care Line & Houston Hlth Serv R, Ctr Excellence, Houston, TX USA. [Lo, G. H.] Baylor Coll Med, Dept Med, Sect Immunol Allergy & Rheumatol, Houston, TX 77030 USA. [Grainger, A. J.] Leeds Teaching Hosp, Dept Radiol, Leeds, W Yorkshire, England. [Grainger, A. J.; Conaghan, P. G.] NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England. [Conaghan, P. G.] Univ Leeds, Sect Musculoskeletal Dis, Leeds, W Yorkshire, England. [Boudreau, R. M.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Roemer, F. W.] Klinikum Augsburg, Dept Radiol, Augsburg, Germany. RP Hunter, DJ (reprint author), Univ Sydney, Dept Rheumatol, No Clin Sch, Royal N Shore Hosp, Sydney, NSW 2065, Australia. EM David.Hunter@sydney.edu.au RI Hunter, David/A-4622-2010; OI Hunter, David/0000-0003-3197-752X; Boudreau, Robert/0000-0003-0162-5187 FU AstraZeneca; DonJoy; Lilly; Merck; NIH; Pfizer; Stryker; Wyeth; GE Healthcare; Australian Research Council FX David Hunter receives research or institutional support from AstraZeneca, DonJoy, Lilly, Merck, NIH, Pfizer, Stryker and Wyeth. Ali Guermazi receives research or institutional support from NIH and GE Healthcare. He is consultant to MerckSerono, Stryker, Genzyme and Novartis. He is President of BICL (Boston Imaging Core Lab), LLC, a company providing radiologic image assessment services.; Dr Hunter is supported by an Australian Research Council Future Fellowship. We would like to acknowledge the support of Dr Daniel Gale who contributed to BLOKS and the initial development of MOAKS. NR 53 TC 126 Z9 128 U1 0 U2 8 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD AUG PY 2011 VL 19 IS 8 BP 990 EP 1002 DI 10.1016/j.joca.2011.05.004 PG 13 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 811UA UT WOS:000294240400009 PM 21645627 ER PT J AU Pangarkar, S Lee, PC AF Pangarkar, Sanjog Lee, Paul C. TI Conservative Treatment for Neck Pain: Medications, Physical Therapy, and Exercise SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Article DE Neck pain; Medications; Exercise; Physical therapy; Modalities ID RANDOMIZED-CONTROLLED-TRIAL; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; BOTULINUM-TOXIN-A; LOW-BACK-PAIN; ELECTRICAL NERVE-STIMULATION; SKELETAL-MUSCLE RELAXANT; TRIGGER-POINT INJECTION; ACUTE LIVER-FAILURE; DOUBLE-BLIND; NEUROPATHIC PAIN AB This article offers conservative treatment strategies for patients suffering from musculoskeletal causes of neck pain. Basic pharmacology is reviewed, including that of opioids, nonsteroidal anti-inflammatory drugs, adjuvants, and topical analgesics. Moreover, indications for therapeutic exercise, manual therapy, and modalities are reviewed, along with any supporting literature. Treatment considerations with each category of medication and physical therapy are discussed. This article is meant to serve as a resource for physicians to tailor conservative treatment options to their individual patients. C1 [Pangarkar, Sanjog; Lee, Paul C.] VA Greater Los Angeles, Dept Phys Med & Rehabil, Los Angeles, CA 90073 USA. [Pangarkar, Sanjog] Univ Calif Los Angeles, David Geffen Sch Med, Vet Hlth Serv Greater Los Angeles, Inpatient Pain Serv, Los Angeles, CA 90073 USA. [Lee, Paul C.] UCLA VA Greater Los Angeles Multicampus Phys Med, Los Angeles, CA 90073 USA. RP Lee, PC (reprint author), VA Greater Los Angeles, Dept Phys Med & Rehabil, Room 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Lee.Paul.C@gmail.com NR 107 TC 7 Z9 7 U1 3 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1047-9651 EI 1558-1381 J9 PHYS MED REH CLIN N JI Phys. Med. Rehabil. Clin. N. Am. PD AUG PY 2011 VL 22 IS 3 BP 503 EP + DI 10.1016/j.pmr.2011.04.001 PG 19 WC Rehabilitation SC Rehabilitation GA 813NL UT WOS:000294374100012 PM 21824590 ER PT J AU Ouimette, P Vogt, D Wade, M Tirone, V Greenbaum, MA Kimerling, R Laffaye, C Fitt, JE Rosen, CS AF Ouimette, Paige Vogt, Dawne Wade, Michael Tirone, Vanessa Greenbaum, Mark A. Kimerling, Rachel Laffaye, Charlene Fitt, Julie E. Rosen, Craig S. TI Perceived Barriers to Care Among Veterans Health Administration Patients With Posttraumatic Stress Disorder SO PSYCHOLOGICAL SERVICES LA English DT Article DE PTSD; access barriers; Iraq War; veterans; stigma; Longitudinal Veterans Health Survey ID MENTAL-HEALTH; AFRICAN-AMERICAN; SERVICE USE; LOW-INCOME; STIGMA; AFFAIRS; AFGHANISTAN; POPULATION; DEPRESSION; ATTITUDES AB Despite the availability of specialty posttraumatic stress disorder (PTSD) care within Department of Veterans Affairs (VA) facilities, many VA patients with PTSD do not seek needed PTSD treatment. This study examined institutional and stigma-related barriers to care among a large diverse group of Vietnam and Iraq/Afghanistan veterans who had been diagnosed with PTSD by a VA provider. A total of 490 patients who had not received VA treatment for PTSD in the previous 2 years (31% response rate) were asked about psychological symptoms and reasons for not using care. Stigma related barriers (concerns about social consequences and discomfort with help-seeking) were rated as more salient (rated in the "slightly" to "moderately" problematic range) than institutional factors (not "fitting into" VA care, staff skill and sensitivity, and logistic barriers; rated in the "not at all" to "slightly" problematic range). Regression analyses revealed that younger age and White females were associated with higher ratings on not fitting into VA health care, whereas non-White males were associated with higher ratings on logistic barriers. PTSD symptoms were positively associated with perceived barriers to care, with the most consistent results observed for PTSD avoidance symptoms. Magnitude of effects was generally small, suggesting the possibility that other factors not assessed in this study may also contribute to perceptions of barriers to care. Future research should attend to the effects of stigma, as well as institutional barriers to care, on VA mental health treatment seeking. C1 [Ouimette, Paige; Wade, Michael; Tirone, Vanessa] Syracuse Univ, Ctr Integrated Healthcare, Syracuse VA Med Ctr, Syracuse, NY 13210 USA. [Vogt, Dawne] Boston Univ, Womens Hlth Sci Div, Natl Ctr PTSD, VA Boston Healthcare Syst,Div Psychiat, Boston, MA 02215 USA. [Greenbaum, Mark A.] VA Palo Alto Hlth Care Syst, Sierra Pacific Mental Illness Res Educ & Clin Ctr, Palo Alto, CA USA. [Kimerling, Rachel; Laffaye, Charlene; Fitt, Julie E.; Rosen, Craig S.] VA Palo Alto Hlth Care Syst, Disseminat & Training Div, Natl Ctr PTSD, Palo Alto, CA USA. [Rosen, Craig S.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Ouimette, P (reprint author), Syracuse Univ, Ctr Integrated Healthcare, Syracuse VA Med Ctr, 116C,800 Irving Ave, Syracuse, NY 13210 USA. EM ouimettepe@aol.com OI Kimerling, Rachel/0000-0003-0996-4212 NR 40 TC 40 Z9 40 U1 2 U2 15 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1541-1559 J9 PSYCHOL SERV JI Psychol. Serv. PD AUG PY 2011 VL 8 IS 3 BP 212 EP 223 DI 10.1037/a0024360 PG 12 WC Psychology, Clinical SC Psychology GA 810PW UT WOS:000294139400006 ER PT J AU Kleespies, PM AhnAllen, CG Knight, JA Presskreischer, B Barrs, KL Boyd, BL Dennis, JP AF Kleespies, Phillip M. AhnAllen, Christopher G. Knight, Jeffrey A. Presskreischer, Benjamin Barrs, Kathryn L. Boyd, Briana L. Dennis, John P. TI A Study of Self-Injurious and Suicidal Behavior in a Veteran Population SO PSYCHOLOGICAL SERVICES LA English DT Article DE self-injury; suicidal behavior; suicide; veterans and self-injury; self-harm ID TOWER-OF-BABEL; REVISED NOMENCLATURE; VIETNAM VETERANS; US VETERANS; RISK; CAPABILITY; GESTURES; SOLDIERS; IRAQ; CARE AB This patient safety improvement study was conducted (1) to establish a database of intentional patient self-injuries and suicidal behavior among veterans in a large urban VA health care system, and (2) to investigate whether there were demographic and/or clinical characteristics of veterans who self-injure that might predict seriousness of suicidal intent and aid in future efforts at prevention. A total of 175 clinician-administered, post self-injury interviews were completed between 2006 and 2008 in a VA health care system in the Northeast. Findings suggest that self-injuries with high suicidal intent were characterized by male gender, older age, planning of self-injury, no wish to be saved, and a negative feeling about having survived. Additional results indicated that staff ratings of patient intent to die were significantly lower than patient self-rated intent to die, a finding that gives rise to questions of whether staff may tend to underestimate patient suicidal intent. Also, although more than 80% of the veterans in this sample considered their self-injurious actions impulsive, planning of self-injury was significantly associated with higher intent to die. Veterans who completed suicide during the study time period were significantly more likely than those who had nonfatal self-injuries to have experienced combat. The implications of these findings are discussed, including whether combat exposure may lead to an acquired capacity for lethal behaviors such as suicide (Joiner, 2005). C1 [Kleespies, Phillip M.; Barrs, Kathryn L.; Boyd, Briana L.; Dennis, John P.] Boston Univ, Sch Med, VA Boston Healthcare Syst, Dept Psychiat, Boston, MA 02130 USA. [AhnAllen, Christopher G.; Presskreischer, Benjamin] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Cambridge, MA 02138 USA. [AhnAllen, Christopher G.; Presskreischer, Benjamin; Barrs, Kathryn L.; Boyd, Briana L.; Dennis, John P.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. RP Kleespies, PM (reprint author), Boston Univ, Sch Med, VA Boston Healthcare Syst, Dept Psychiat, 116 B,150 S Huntington Ave, Boston, MA 02130 USA. EM phillip.kleespies@va.gov NR 39 TC 10 Z9 10 U1 0 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1541-1559 J9 PSYCHOL SERV JI Psychol. Serv. PD AUG PY 2011 VL 8 IS 3 BP 236 EP 250 DI 10.1037/a0024881 PG 15 WC Psychology, Clinical SC Psychology GA 810PW UT WOS:000294139400008 ER PT J AU Henderson, DC Freudenreich, O Borba, CPC Wang, XY Copeland, PM Macklin, E Fan, XD Cather, C Goff, DC AF Henderson, David C. Freudenreich, Oliver Borba, Christina P. C. Wang, Xingyue Copeland, Paul M. Macklin, Eric Fan, Xiaoduo Cather, Corinne Goff, Donald C. TI Effects of modafinil on weight, glucose and lipid metabolism in clozapine-treated patients with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Clozapine; Modafinil; Obesity; Lipids; Glucose metabolism ID DIABETES-MELLITUS; DOUBLE-BLIND; DAYTIME SLEEPINESS; NARCOLEPSY; AMPHETAMINE; DOPAMINE AB Rationale: Sedation is a common side effect of clozapine treatment and may exacerbate metabolic consequences of poor diet and exercise habits that are common in patients with schizophrenia. Modafinil has been proposed as a treatment for clozapine-induced sedation and metabolic abnormalities. Objective: To estimate the effect sizes and person-to-person variation in anthropometric measures, glucose and lipid metabolism, and diet on modafinil treatment for future randomized control trials. Methods: A double-blind, placebo-controlled, flexible-dosed 8-week pilot trial was conducted, adding modafinil up to 300 mg/day to stabilized schizophrenia outpatients receiving clozapine. Blood pressure, weight, BMI, laboratory assays, and dietary intake were tracked to monitor changes in metabolic markers. Results: Thirty-five participants were randomly assigned to treatment with study drug or placebo and were included in the analysis. Modafinil did not improve blood pressure, weight, BMI, glucose or lipid metabolism compared to placebo. Modafinil was well tolerated and did not worsen psychosis. Conclusions: Results of this pilot trial do not support routine use of modafinil to counteract increased weight and metabolic diseases in patients taking clozapine. However, the effects of modafinil on weight and insulin regulation warrant further investigation with effect sizes of 0.4 to 0.6. (C) 2011 Elsevier B.V. All rights reserved. C1 [Henderson, David C.; Freudenreich, Oliver; Borba, Christina P. C.; Wang, Xingyue; Fan, Xiaoduo; Cather, Corinne; Goff, Donald C.] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Henderson, David C.; Freudenreich, Oliver; Borba, Christina P. C.; Copeland, Paul M.; Macklin, Eric; Fan, Xiaoduo; Cather, Corinne; Goff, Donald C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Copeland, Paul M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Macklin, Eric] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Henderson, DC (reprint author), Freedom Trail Clin, 25 Staniford St, Boston, MA 02114 USA. EM dchenderson@partners.org RI Macklin, Eric/E-2955-2013 OI Macklin, Eric/0000-0003-1618-3502 FU Cephalon FX Funding for this trial was provided by an investigator-initiated grant from Cephalon to Dr. Donald Goff. Cephalon had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 31 TC 7 Z9 7 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2011 VL 130 IS 1-3 BP 53 EP 56 DI 10.1016/j.schres.2011.04.009 PG 4 WC Psychiatry SC Psychiatry GA 811SZ UT WOS:000294237700008 PM 21565464 ER PT J AU Schneiderman, JS Hazlett, EA Chu, KW Zhang, J Goodman, CR Newmark, RE Torosjan, Y Canfield, EL Entis, J Mitropoulou, V Tang, CY Friedman, J Buchsbaum, MS AF Schneiderman, Jason S. Hazlett, Erin A. Chu, King-Wai Zhang, Jane Goodman, Chelain R. Newmark, Randall E. Torosjan, Yuliya Canfield, Emily L. Entis, Jonathan Mitropoulou, Vivian Tang, Cheuk Y. Friedman, Joseph Buchsbaum, Monte S. TI Brodmann area analysis of white matter anisotropy and age in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; White matter; Diffusion Tensor Imaging; Anisotropy; Brodmann areas; Age ID DIFFUSION TENSOR ANISOTROPY; AUDITORY HALLUCINATIONS; METABOLIC-RATE; TRACTOGRAPHY; ABNORMALITIES; DISORDER; CONNECTIONS; SYMPTOMS; DEFICITS; PET AB Diffusion tensor and structural MRI images were acquired on ninety-six patients with schizophrenia (69 men and 27 women) between the ages of 18 and 79 (mean = 39.83, SD = 15.16 DSM-IV diagnosis of schizophrenia according to the Comprehensive Assessment of Symptoms and History). The patients reported a mean age of onset of 23 years (range = 13-38, SD = 6). Patients were divided into an acute subgroup (duration <= 3 years, n = 25), and a chronic subgroup (duration >3 years, n = 64). Ninety-three mentally normal comparison subjects were recruited; 55 men and 38 women between the ages of 18 and 82 (mean = 35.77, SD = 18.12). The MRI images were segmented by Brodmann area, and the fractional anisotropy (FA) for the white matter within each Brodmann area was calculated. The FA in white matter was decreased in patients with schizophrenia broadly across the entire brain, but to a greater extent in white matter underneath frontal, temporal and cingulate cortical areas. Both normals and patients with schizophrenia showed a decrease in anisotropy with age but patients with schizophrenia showed a significantly greater rate of decrease in FA in Brodmann area 10 bilaterally, 11 in the left hemisphere and 34 in the right hemisphere. When the effect of age was removed, patients ill more than three years showed lower anisotropy in frontal motor and cingulate white matter in comparison to acute patients ill three years or less, consistent with an ongoing progression of the illness. (C) 2011 Elsevier B.V. All rights reserved. C1 [Schneiderman, Jason S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Psychiat,Psychiat Neuroimaging Lab, Boston, MA 02215 USA. [Hazlett, Erin A.; Chu, King-Wai; Zhang, Jane; Goodman, Chelain R.; Newmark, Randall E.; Torosjan, Yuliya; Canfield, Emily L.; Entis, Jonathan; Mitropoulou, Vivian; Friedman, Joseph] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Tang, Cheuk Y.] Mt Sinai Sch Med, Dept Radiol, New York, NY 10029 USA. [Hazlett, Erin A.] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. [Hazlett, Erin A.] MIRECC, Bronx, NY 10468 USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA. RP Schneiderman, JS (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Psychiat,Psychiat Neuroimaging Lab, 1249 Boylston St, Boston, MA 02215 USA. EM jason@bwh.harvard.edu RI Schneiderman, Jason/E-1528-2013 OI Schneiderman, Jason/0000-0002-9313-0415 FU NIMH [P50MH06639, T32MH016259] FX Funding was provided by NIMH Grant P50MH06639 and T32MH016259; the NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 43 TC 16 Z9 16 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2011 VL 130 IS 1-3 BP 57 EP 67 DI 10.1016/j.schres.2011.04.027 PG 11 WC Psychiatry SC Psychiatry GA 811SZ UT WOS:000294237700009 PM 21600737 ER PT J AU Choi, H Kubicki, M Whitford, TJ Alvarado, JL Terry, DP Niznikiewicz, M McCarley, RW Kwon, JS Shenton, ME AF Choi, Hongyoon Kubicki, Marek Whitford, Thomas J. Alvarado, Jorge L. Terry, Douglas P. Niznikiewicz, Margaret McCarley, Robert W. Kwon, Jun Soo Shenton, Martha E. TI Diffusion tensor imaging of anterior commissural fibers in patients with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Diffusion tensor imaging; Anterior commissure; White matter tractography; Fractional anisotropy; Trace ID WHITE-MATTER ABNORMALITIES; HUMAN PREFRONTAL CORTEX; IOWA GAMBLING TASK; CORPUS-CALLOSUM; DECISION-MAKING; AUDITORY HALLUCINATIONS; ONSET SCHIZOPHRENIA; TEMPORAL-LOBE; HUMAN BRAIN; DISORDER AB Introduction: Alterations in white matter connections in schizophrenia have been investigated using diffusion tensor imaging (DTI). There is also evidence from post-mortem studies as well as from magnetic resonance imaging morphometry studies that the anterior commissure (AC) might be implicated in schizophrenia, but no studies, to date, have investigated the AC using DTI or tractography. Method: DTI scans were analyzed from 25 patients and 23 controls. Mean fractional anisotropy (FA) and trace were measured from the AC tracts. SANS and SAPS were used to evaluate clinical symptoms, and the Iowa Gambling Task, related to decision making, was also examined. Results: Results revealed a significant decrease in mean FA and a significant increase in mean trace of AC tracts in patients compared with controls. In addition, patients, but not controls, showed a negative correlation between age and AC integrity. Statistically significant positive correlations were also found between AC FA and total positive symptom score. Decision making was negatively correlated with FA in patients on the Iowa Gambling Task, but not in controls. Conclusion: This study provides quantitative evidence for a reduction of interhemispheric connectivity in schizophrenia within the AC. Negative correlation between age and AC FA in the patients is consistent with the idea that schizophrenia may be a disorder of white matter maturation. Positive correlation between FA and positive symptom is discussed in the context of white matter's established role in modulating neural conduction velocity. Published by Elsevier B.V. C1 [Choi, Hongyoon; Kubicki, Marek; Whitford, Thomas J.; Alvarado, Jorge L.; Terry, Douglas P.; Shenton, Martha E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Psychiat Neuroimaging Lab,Dept Psychiat, Boston, MA 02215 USA. [Kwon, Jun Soo] Seoul Natl Univ, Coll Med, Dept Psychiat, Seoul, South Korea. [Kubicki, Marek; Niznikiewicz, Margaret; McCarley, Robert W.; Shenton, Martha E.] VA Boston Healthcare Syst, Neurosci Lab, Clin Neurosci Div, Brockton, MA USA. [Whitford, Thomas J.] Univ Melbourne, Dept Psychiat, Melbourne Neuropsychiat Ctr, Melbourne, Vic, Australia. [Whitford, Thomas J.] Melbourne Hlth, Melbourne, Vic, Australia. [Kwon, Jun Soo] Seoul Natl Univ, Coll Nat Sci, Dept Brain & Cognit Sci, WCU Program, Seoul 151742, South Korea. [Shenton, Martha E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol,MRI Div,Surg Planning Lab, Boston, MA 02215 USA. RP Shenton, ME (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Psychiat Neuroimaging Lab,Dept Psychiat, 1249 Boylston St, Boston, MA 02215 USA. EM Shenton@bwh.harvard.edu RI Kwon, Jun Soo/J-2734-2012; McCarley, Robert/N-5562-2014 OI McCarley, Robert/0000-0001-5705-7495 FU National Institute of Health [K05 MH070047, R01 MH 50740, R01 MN 40799, P50MH 080272]; Department of Veterans Affairs; VA Schizophrenia Center; National Alliance for Medical Image Computing (NA-MIC); National Institutes of Health Roadmap for Medical Research [U54 E8005149]; National Health and Medical Council of Australia through University of Melbourne [NHMRC 520627] FX This study was supported, in part, by grants from the National Institute of Health (K05 MH070047 and R01 MH 50740 to MES, R01 MN 40799 to RWM, P50MH 080272 - CIDAR award - to RWM, MES), the Department of Veterans Affairs Merit Awards (MES, RWM), and the VA Schizophrenia Center Grant (RWM/MES). This work was also supported, in part, by the National Alliance for Medical Image Computing (NA-MIC), the latter a grant supported through the National Institutes of Health Roadmap for Medical Research, Grant U54 E8005149 (MK), and by an Overseas-Based Biomedical Training Fellowship from the National Health and Medical Council of Australia (NHMRC 520627) through the University of Melbourne (TW). NR 77 TC 16 Z9 19 U1 3 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2011 VL 130 IS 1-3 BP 78 EP 85 DI 10.1016/j.schres.2011.04.016 PG 8 WC Psychiatry SC Psychiatry GA 811SZ UT WOS:000294237700011 PM 21561738 ER PT J AU Katsel, P Tan, WL Abazyan, B Davis, KL Ross, C Pletnikov, MV Haroutunian, V AF Katsel, Pavel Tan, Weilun Abazyan, Bagrat Davis, Kenneth L. Ross, Christopher Pletnikov, Mikhail V. Haroutunian, Vahram TI Expression of mutant human DISC1 in mice supports abnormalities in differentiation of oligodendrocytes SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Disrupted-in schizophrenia 1; Gene expression; Oligodendrocyte; Oligodendrogenesis; Myelin; Neuregulin ID MESSENGER-RNA EXPRESSION; MULTIPLE BRAIN-REGIONS; CENTRAL-NERVOUS-SYSTEM; PDGF-ALPHA-RECEPTOR; GENE-EXPRESSION; PREFRONTAL CORTEX; BIPOLAR DISORDER; IN-VIVO; BEHAVIORAL PHENOTYPES; CHROMOSOME 1Q42 AB Abnormalities in oligodendrocyte (OLG) differentiation and OLG gene expression deficit have been described in schizophrenia (SZ). Recent studies revealed a critical requirement for Disrupted-in-Schizophrenia 1 (DISCI) in neural development. Transgenic mice with forebrain restricted expression of mutant human DISC1 (Delta hDISC1) are characterized by neuroanatomical and behavioral abnormalities reminiscent of some features of SZ. We sought to determine whether the expression of Delta hDISC1 may influence the development of OLGs in this mouse model. OLG- and cell cycle-associated gene and protein expression were characterized in the forebrain of Delta hDISC1 mice during different stages of neurodevelopment (E15 and P1 days) and in adulthood. The results suggest that the expression of Delta hDISC1 exerts a significant influence on oligodendrocyte differentiation and function, evidenced by premature OLG differentiation and increased proliferation of their progenitors. Additional findings showed that neuregulin 1 and its receptors may be contributing factors to the observed upregulation of OLG genes. Thus, OLG function may be perturbed by mutant hDISC1 in a model system that provides new avenues for studying aspects of the pathogenesis of SZ. (C) 2011 Elsevier B.V. All rights reserved. C1 [Katsel, Pavel; Tan, Weilun; Davis, Kenneth L.; Haroutunian, Vahram] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Haroutunian, Vahram] James J Peters VA Med Ctr, Dept Psychiat, Bronx, NY 10468 USA. [Abazyan, Bagrat; Ross, Christopher; Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Abazyan, Bagrat; Ross, Christopher; Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Abazyan, Bagrat; Ross, Christopher; Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Parhobiol, Baltimore, MD USA. RP Katsel, P (reprint author), Bronx VA Med Ctr, Room 4F-20,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM pavel.katsel@mssm.edu FU NIH [MH064673, MH66392]; NIMH; Conte VA Merit award; Mental Illness Research and Education Clinical Center (MIRECC) [VISN3] FX This study was supported by NIH Grants MH064673, MH66392, NIMH ARRA grant, Conte VA Merit award and by the VISN3 Mental Illness Research and Education Clinical Center (MIRECC). NR 77 TC 18 Z9 19 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2011 VL 130 IS 1-3 BP 238 EP 249 DI 10.1016/j.schres.2011.04.021 PG 12 WC Psychiatry SC Psychiatry GA 811SZ UT WOS:000294237700035 PM 21605958 ER PT J AU Raemer, D Anderson, M Cheng, A Fanning, R Nadkarni, V Savoldelli, G AF Raemer, Daniel Anderson, Mindi Cheng, Adam Fanning, Ruth Nadkarni, Vinay Savoldelli, Georges TI Research Regarding Debriefing as Part of the Learning Process SO SIMULATION IN HEALTHCARE-JOURNAL OF THE SOCIETY FOR SIMULATION IN HEALTHCARE LA English DT Article DE Debriefing; Research; Learning; Simulation; Education ID MEDICAL-EDUCATION; SIMULATION; PERFORMANCE; FEEDBACK; CRISES; SKILLS AB Introduction: Debriefing is a process involving the active participation of learners, guided by a facilitator or instructor whose primary goal is to identify and close gaps in knowledge and skills. A review of existing research and a process for identifying future opportunities was undertaken. Methods: A selective critical review of the literature on debriefing in simulation-based education was done. An iterative process of analysis, gathering input from audience participants, and consensus-based synthesis was conducted. Results: Research is sparse and limited in presentation for all important topic areas where debriefing is a primary variable. The importance of a format for reporting data on debriefing in a research context was realized and a "who, when, where, what, why" approach was proposed. Also, a graphical representation of the characteristics of debriefing studies was developed (Sim-PICO) to help guide simulation researchers in appropriate experimental design and reporting. Conclusion: A few areas of debriefing practice where obvious gaps that deserve study were identified, such as comparing debriefing techniques, comparing trained versus untrained debriefers, and comparing the effect of different debriefing venues and times. A model for publication of research data was developed and presented which should help researchers clarify methodology in future work. (Sim Healthcare 6:S52-S57, 2011) C1 [Raemer, Daniel] Ctr Med Simulat, Cambridge, MA 02139 USA. [Raemer, Daniel] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Management, Cambridge, MA USA. [Raemer, Daniel] Harvard Univ, Sch Med, Dept Anaesthesia, Cambridge, MA 02138 USA. [Anderson, Mindi] Univ Texas Arlington, Coll Nursing, Arlington, TX 76019 USA. [Cheng, Adam] Univ Calgary, Alberta Childrens Hosp, KidSIM Aspire Simulat Res Program, Calgary, AB, Canada. [Fanning, Ruth] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Nadkarni, Vinay] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Ctr Simulat Adv Educ & Innovat, Philadelphia, PA 19104 USA. [Savoldelli, Georges] Univ Hosp Geneva, Dept Anesthesiol, Geneva, Switzerland. [Savoldelli, Georges] Univ Geneva, Unit Dev & Res Med Educ, Geneva, Switzerland. RP Raemer, D (reprint author), Ctr Med Simulat, 65 Landsdowne St, Cambridge, MA 02139 USA. EM draemer@partners.org FU Laerdal Foundation for Acute Medicine; Association of Standardized Patient Educators; UT System; Heart and Stroke Foundation of Canada; NIH; Laerdal Foundation for Acute Care Medicine FX D.R.: Salaried instructor for simulation-based instructor courses at the Center for Medical Simulation; M. A.: Author for the online course, Debriefing and Guided Reflection, on the Simulation Innovation Resource Center site. Additionally, she teaches a continuing education course on simulation, as well as a simulation course for the Master's program at UT Arlington College of Nursing. She has done some consultation related to simulation and has received grant funding from The Laerdal Foundation for Acute Medicine, The Association of Standardized Patient Educators, and the UT System; A. C.: Instructor for simulation-based instructor courses through KidSIM at Alberta Children's Hospital and receives grant support from the Laerdal Foundation for Acute Medicine and the Heart and Stroke Foundation of Canada; R. F.: Instructor for simulation-based instructor courses at Stanford University; V.N.: Endowed Chair, Anesthesia and Critical Care Medicine, The Children's Hospital of Philadelphia. He has received unrestricted research grants from the NIH (cardiac arrest and resuscitation, glycemic control) and Laerdal Foundation for Acute Care Medicine (education); G. S.: Instructor for simulation-based instructor courses through SimulHUG at the University Hospitals of Geneva, Switzerland and the University of Paris Descartes, France. NR 45 TC 68 Z9 71 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1559-2332 EI 1559-713X J9 SIMUL HEALTHC JI Simul. Healthc. PD AUG PY 2011 VL 6 SU S BP S52 EP S57 DI 10.1097/SIH.0b013e31822724d0 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 811KV UT WOS:000294209700009 PM 21817862 ER PT J AU Fukatsu, K Kudsk, KA AF Fukatsu, Kazuhiko Kudsk, Kenneth A. TI Nutrition and Gut Immunity SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Phospholipase A2; Gut-associated lymphoid tissue; Immunoglobulin A; Glutamine; Mucosal immunity; Enteral nutrition; Parenteral nutrition ID TOTAL PARENTERAL-NUTRITION; UPPER RESPIRATORY-TRACT; IMMUNOGLOBULIN-A LEVELS; LYMPHOTOXIN-BETA-RECEPTOR; KAPPA-B ACTIVATION; ADHESION MOLECULE-1 EXPRESSION; MAJOR ABDOMINAL-TRAUMA; NECROSIS-FACTOR-ALPHA; CHAIN FATTY-ACIDS; LYMPHOID-TISSUE AB The human intestine contains huge amounts of nonpathologic bacteria surviving in an environment that is beneficial to both the host and the bacterial populations. When short pauses in oral intake occur with minimal alterations in the mucosa-microbial interface, critical illness, with its attendant acidosis, prolonged gastrointestinal tract starvation, exogenous antibiotics, and breakdown in mucosal defenses, renders the host vulnerable to bacterial challenge and also threatens the survival of the bacteria. This review examines the altered innate and adaptive immunologic host defenses that occur as a result of altered oral or enteral intake and/or injury. C1 [Kudsk, Kenneth A.] Univ Wisconsin Sch Med & Publ Hlth, Dept Surg, Madison, WI 53792 USA. [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. [Fukatsu, Kazuhiko] Tokyo Univ Hosp, Surg Ctr, Dept Surg, Bunkyo Ku, Tokyo 1138655, Japan. RP Kudsk, KA (reprint author), Univ Wisconsin Sch Med & Publ Hlth, Dept Surg, 600 Highland Ave,G5-341, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu FU National Institute of Health (NIH) [R01 GM53439]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Service FX This research is supported by National Institute of Health (NIH) Grant R01 GM53439. This material is also based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Service. The contents of the article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 77 TC 26 Z9 29 U1 0 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2011 VL 91 IS 4 BP 755 EP + DI 10.1016/j.suc.2011.04.007 PG 17 WC Surgery SC Surgery GA 811FC UT WOS:000294188400005 PM 21787966 ER PT J AU McCutcheon, SR AF McCutcheon, Stephen R. TI The Internship Crisis: An Uncommon Urgency To Build a Common Solution SO TRAINING AND EDUCATION IN PROFESSIONAL PSYCHOLOGY LA English DT Editorial Material DE internship imbalance; predoctoral internship; Common Pool Resource; CCTC ID PROFESSIONAL PSYCHOLOGY AB The internship imbalance is a problem of grave individual and professional concern. As the imbalance continues and deepens, many concerted efforts have been directed toward mitigating the imbalance by addressing factors associated with increased demand and insufficient supply of internship positions. These efforts have required the collaboration of groups and organizations that in the past pursued different aims and agendas. Hatcher (this issue, pp. 126-140) moves these efforts forward greatly, by conceptualizing the internship imbalance as a specific example of a scarce resource shared by a large community (a Common Pool Resource) and by providing a framework for development of a governance structure to manage this common resource. This commentary expands on Hatcher (this issue) by highlighting important structural and attitudinal issues underlying the imbalance problem that are evoked by attempts to address the imbalance, and which must be considered when formulating a comprehensive and integrated solution, particularly one that includes an additional governance structure dependent on interorganizational collaboration. C1 [McCutcheon, Stephen R.] Puget Sound Healthcare Syst, Vet Affairs, Seattle, WA USA. RP McCutcheon, SR (reprint author), VA Puget Sound, Mental Hlth 116 POC,1660 S Columbian Way, Seattle, WA 98108 USA. EM stephen.mccutcheon@va.gov NR 21 TC 12 Z9 12 U1 1 U2 1 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1931-3918 J9 TRAIN EDUC PROF PSYC JI Train. Educ. Prof. Psychol. PD AUG PY 2011 VL 5 IS 3 BP 144 EP 148 DI 10.1037/a0024896 PG 5 WC Psychology, Educational SC Psychology GA 810CF UT WOS:000294102300004 ER PT J AU Inman, AG Schlosser, LZ Ladany, N Howard, EE Boyd, DL Altman, AN Stein, EP AF Inman, Arpana G. Schlosser, Lewis Z. Ladany, Nicholas Howard, Erin E. Boyd, Debra L. Altman, Abby N. Stein, Ellyn P. TI Advisee Nondisclosures in Doctoral-Level Advising Relationships SO TRAINING AND EDUCATION IN PROFESSIONAL PSYCHOLOGY LA English DT Article DE advisee; nondisclosure; advisory working alliance; advisee satisfaction ID WORKING-ALLIANCE; PROFESSIONAL PSYCHOLOGY; QUALITATIVE EXAMINATION; SUPERVISION; PERSPECTIVE; EXTENT AB Using a sample of 109 doctoral-level advisees, we examined the content of and reasons for advisee nondisclosures and the relationships between these variables and advising relationship and satisfaction. Discovery-oriented qualitative analyses revealed several themes related to content of advisee nondisclosures (e.g., self-efficacy) and reasons for these nondisclosures (e.g., fear of damaging advising relationship). Quantitative analyses revealed advisor advisee rapport was related to advisee fears of being perceived as unprofessional, and identification with advisor was related to advisor's availability and dependability. Unclear advisor expectations, lack of support, and unavailability of the advisor were all related to satisfaction with the advising relationship. C1 [Inman, Arpana G.] Lehigh Univ, Counseling Psychol Program, Dept Educ & Human Serv, Bethlehem, PA 18015 USA. [Schlosser, Lewis Z.; Stein, Ellyn P.] Seton Hall Univ, S Orange, NJ USA. [Ladany, Nicholas] Loyola Marymount Univ, Counseling Program, Los Angeles, CA 90045 USA. [Howard, Erin E.] Dept Vet Affairs Med Ctr, Fayetteville, NC USA. [Altman, Abby N.] VA Boston Healthcare Syst, Boston, MA USA. [Altman, Abby N.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Inman, AG (reprint author), Lehigh Univ, Counseling Psychol Program, Dept Educ & Human Serv, 111 Res Dr, Bethlehem, PA 18015 USA. EM agi2@lehigh.edu NR 27 TC 5 Z9 5 U1 1 U2 7 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1931-3918 EI 1931-3926 J9 TRAIN EDUC PROF PSYC JI Train. Educ. Prof. Psychol. PD AUG PY 2011 VL 5 IS 3 BP 149 EP 159 DI 10.1037/a0024022 PG 11 WC Psychology, Educational SC Psychology GA 810CF UT WOS:000294102300005 ER PT J AU Pasquier, E Kieran, MW Sterba, J Shaked, Y Baruchel, S Oberlin, O Kivivuori, MS Peyrl, A Diawarra, M Casanova, M Zacharoulis, S Vassal, G Berthold, F Verschuur, A Andre, N AF Pasquier, Eddy Kieran, Mark W. Sterba, Jaroslav Shaked, Yuval Baruchel, Sylvain Oberlin, Odile Kivivuori, Maria Sanna Peyrl, Andreas Diawarra, Mamouna Casanova, Michaela Zacharoulis, Stergios Vassal, Gilles Berthold, Franck Verschuur, Arnauld Andre, Nicolas TI Moving Forward with Metronomic Chemotherapy: Meeting Report of the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology SO TRANSLATIONAL ONCOLOGY LA English DT Review ID ENDOTHELIAL PROGENITOR CELLS; SOLID TUMORS; ORAL ETOPOSIDE; BRAIN-TUMORS; ANTIANGIOGENIC THERAPY; DOSE CYCLOPHOSPHAMIDE; BREAST-CANCER; CHILDREN; RECURRENT; FUTURE AB Metronomic chemotherapy, which is defined by the frequent, repetitive administration of chemotherapeutic drugs at relatively low doses, and without prolonged drug-free break, is an emerging strategy to fight cancer. Initially thought to act by targeting tumor angiogenesis, additional mechanisms have been recently unveiled, and metronomic chemotherapy is now considered to represent a form of multitargeted therapy. Despite representing a genuine alternative for advanced and/or high-risk cancer therapy, the development of metronomic approaches in pediatric oncology still in the early stage. The few numbers of large-scale state-of-the-art clinical trials, issues regarding terminology and the limited understanding of the complex and intertwined mechanisms of action of metronomic treatments have limited progress in this important field of research. On March 18 and 19, 2010, the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology was held in Marseille, France, and brought together clinicians, basic scientists, physician-scientists, trainees, and students from all around the world. The main aim of this international meeting was to provide a unique forum to 1) reflect on the major advances that have been made in this field of research since its creation, 2) communicate results from the most recent clinical trials and preclinical studies, 3) discuss the current and future challenges of the field, and 4) set forth a solid framework for future collaborative biologic and clinical studies. The present report documents the main preclinical and clinical data that were presented in the keynote and best abstract sessions and delivers the key messages from the meeting. C1 [Pasquier, Eddy] Univ New S Wales, Lowy Canc Res Ctr, Childrens Canc Inst Australia, Randwick, NSW, Australia. [Kieran, Mark W.] Childrens Hosp Boston, Boston, MA USA. [Kieran, Mark W.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sterba, Jaroslav] Univ Hosp Brno, Sch Med Brno, Dept Pediat Oncol, Brno, Czech Republic. [Shaked, Yuval] Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel. [Baruchel, Sylvain] Hosp Sick Children, Dept Paediat, Div Haematol Oncol, New Agent & Innovat Therapy Program, Toronto, ON M5G 1X8, Canada. [Oberlin, Odile] Inst Gustave Roussy, Dept Pediat Oncol, Villejuif, France. [Kivivuori, Maria Sanna] Univ Helsinki, Childrens Hosp, Helsinki Univ Cent Hosp, Div Hematol Oncol & Stem Cell Transplantat, Helsinki, Finland. [Peyrl, Andreas] Med Univ Vienna, Dept Paediat, Vienna, Austria. [Diawarra, Mamouna] Hop Gabriel Toure, Serv Oncol Pediat, Bamako, Mali. [Casanova, Michaela] Fdn IRCCS Ist Nazl Tumori, Pediat Oncol Unit, Milan, Italy. [Zacharoulis, Stergios] Royal Marsden NHS Fdn Trust, Dept Paediat, Sutton, Surrey, England. [Vassal, Gilles] Univ Paris 11, Inst Gustave Roussy, UPRES EA 3535, Villejuif, France. [Berthold, Franck] Univ Childrens Hosp, Dept Paediat Oncol, Cologne, Germany. [Berthold, Franck] Ctr Mol Med Cologne, Cologne, Germany. [Verschuur, Arnauld; Andre, Nicolas] Hop Enfants La Timone, Serv Hematol & Oncol Pediat, F-13885 Marseille 5, France. [Andre, Nicolas] Univ Aix Marseille, INSERM, UMR 911, Ctr Rech Oncol Biol & Oncopharmacol CRO2, Marseille, France. [Andre, Nicolas] Metron Global Hlth Initiat, Marseille, France. RP Andre, N (reprint author), Hop Enfants La Timone, Serv Hematol & Oncol Pediat, Bd Jean Moulin, F-13885 Marseille 5, France. EM nicolas.andre@ap-hm.fr RI Sterba, Jaroslav/N-6156-2016; Casanova, Michela/K-8436-2016; OI Casanova, Michela/0000-0003-0368-7883; Kieran, Mark/0000-0003-2184-7692; Pasquier, Eddy/0000-0003-2824-5002 NR 56 TC 6 Z9 6 U1 0 U2 3 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD AUG PY 2011 VL 4 IS 4 BP 189 EP 197 DI 10.1593/tlo.11124 PG 9 WC Oncology SC Oncology GA 811XX UT WOS:000294253200001 ER PT J AU Zaenker, KS Mihich, E Liu, E AF Zaenker, Kurt S. Mihich, Enrico Liu, Edison TI Personalized Cancer Medicine 2011: Toward Individualized Cancer Treatments. XV International Fritz Bender Symposium Held on February 21 to 23, 2011 at Matrix, Biopolis, Singapore SO TRANSLATIONAL ONCOLOGY LA English DT Article AB At the symposium, approaches to individualized cancer medicine were considered, from basic sciences (genetics, epigenetics, biological tumor signatures) to clinical investigations, including strategies about how best to undertake the clinical development of targeted agents. C1 [Zaenker, Kurt S.] Univ Witten Herdecke, Inst Immunol & Expt Oncol, D-58488 Witten, Germany. [Mihich, Enrico] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Liu, Edison] Genome Inst Singapore, Singapore, Singapore. RP Zaenker, KS (reprint author), Univ Witten Herdecke, Inst Immunol & Expt Oncol, Stockumerstr 10, D-58488 Witten, Germany. EM ksz@uni-wh.de NR 0 TC 1 Z9 1 U1 0 U2 2 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1936-5233 J9 TRANSL ONCOL JI Transl. Oncol. PD AUG PY 2011 VL 4 IS 4 BP 198 EP 201 DI 10.1593/tlo.11142 PG 4 WC Oncology SC Oncology GA 811XX UT WOS:000294253200002 ER PT J AU Manning, AL Dyson, NJ AF Manning, Amity L. Dyson, Nicholas J. TI pRB, a tumor suppressor with a stabilizing presence SO TRENDS IN CELL BIOLOGY LA English DT Review ID PROMOTES GENOMIC INSTABILITY; SQUAMOUS-CELL CARCINOMA; CHROMOSOMAL INSTABILITY; GENE-EXPRESSION; CANCER-CELLS; RETINOBLASTOMA PROTEIN; MITOTIC CHECKPOINT; DNA-DAMAGE; CLONAL EVOLUTION; SIGNALING PATHWAYS AB The product of the retinoblastoma tumor-susceptibility gene (RB1) is a key regulator of cell proliferation and this function is thought to be central to its tumor suppressive activity. Several studies have demonstrated that inactivation of pRB not only allows inappropriate proliferation but also undermines mitotic fidelity, leading to genome instability and ploidy changes. Such properties promote tumor evolution and correlate with increased resistance to therapeutics and tumor relapse. These observations suggest that inactivation of pRB could contribute to both tumor initiation and progression. Further characterization of the role of pRB in chromosome segregation will provide insight into processes that are misregulated in human tumors and could reveal new therapeutic targets to kill or stall these chromosomally unstable lesions. We review the evidence that pRB promotes genome stability and discuss the mechanisms that probably contribute to this effect. C1 [Manning, Amity L.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Manning, AL (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA. EM almanning@partners.org FU American Cancer Society; National Institutes of Health [R01GM81607, R01CA64402]; AstraZeneca FX We thank Drs Pellman and Medema for sharing their unpublished work, Neil Ganem for critical reading of the manuscript, and apologize to our colleagues whose work is not cited due to space constraints. A.L.M. is supported by a post-doctoral fellowship from the American Cancer Society. N.J.D. is the Massachusetts General Hospital Cancer Center Saltonstall Foundation Scholar and is supported by funding from the National Institutes of Health (R01GM81607 and R01CA64402) and AstraZeneca. NR 110 TC 38 Z9 41 U1 0 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD AUG PY 2011 VL 21 IS 8 BP 433 EP 441 DI 10.1016/j.tcb.2011.05.003 PG 9 WC Cell Biology SC Cell Biology GA 810BY UT WOS:000294101600001 PM 21664133 ER PT J AU Ewers, M Sperling, RA Klunk, WE Weiner, MW Hampel, H AF Ewers, Michael Sperling, Reisa A. Klunk, William E. Weiner, Michael W. Hampel, Harald TI Neuroimaging markers for the prediction and early diagnosis of Alzheimer's disease dementia SO TRENDS IN NEUROSCIENCES LA English DT Review ID MILD COGNITIVE IMPAIRMENT; POSITRON-EMISSION-TOMOGRAPHY; PITTSBURGH COMPOUND-B; A-BETA-DEPOSITION; APOLIPOPROTEIN-E; AMYLOID DEPOSITION; CEREBROSPINAL-FLUID; APOE GENOTYPE; ASSOCIATION WORKGROUPS; NATIONAL INSTITUTE AB Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. At the time of clinical manifestation of dementia, significant irreversible brain damage is already present, rendering the diagnosis of AD at early stages of the disease an urgent prerequisite for therapeutic treatment to halt, or at least slow, disease progression. In this review, we discuss various neuroimaging measures that are proving to have potential value as biomarkers of AD pathology for the detection and prediction of AD before the onset of dementia. Recent studies that have identified AD-like structural and functional brain changes in elderly people who are cognitively within the normal range or who have mild cognitive impairment (MCI) are discussed. A dynamic sequence model of changes that occur in neuroimaging markers during the different disease stages is presented and the predictive value of multimodal neuroimaging for AD dementia is considered. C1 [Ewers, Michael; Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Ewers, Michael; Weiner, Michael W.] VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Sperling, Reisa A.] Harvard Univ, Brigham & Womens Hosp, Massachusetts Gen Hosp, Ctr Alzheimer Res & Treatment,Dept Neurol,Med Sch, Boston, MA 02115 USA. [Sperling, Reisa A.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Klunk, William E.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Klunk, William E.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Hampel, Harald] Goethe Univ Frankfurt, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany. RP Ewers, M (reprint author), Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. EM michael.ewers@ucsf.edu OI Klunk, William/0000-0001-5512-0251; Hampel, Harald/0000-0003-0894-8982 FU National Institutes of Health (NIH) [R01AG10897, P41RR023953, U01AG024904, P50 AG005133, R37 AG025516, P01 AG025204]; NIA [P01 AG036694, R01AG027435]; Science Foundation Ireland (SFI) [08/IN.1/B1846]; Landesoffensive zur Entwicklung wissenschaftlich-okonomischer Exzellenz (LOEWE) FX This work was supported by National Institutes of Health (NIH) grants R01AG10897, P41RR023953 and U01AG024904 (to MW.), which were administered by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs (VA) Medical Center, San Francisco, California. Additional support came from NIH grants P50 AG005133, R37 AG025516, P01 AG025204 (to BK.), NIA: P01 AG036694, R01AG027435 (to R.S.), the Science Foundation Ireland (SFI) investigator neuroimaging program award 08/IN.1/B1846 (to H.H.), the Landesoffensive zur Entwicklung wissenschaftlich-okonomischer Exzellenz (LOEWE) neuroimaging-neurophysiology research program grant, Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF), and the Neuronal Coordination, Neurodegeneration and Alzheimer's disease project (to H.H.). NR 123 TC 106 Z9 109 U1 2 U2 36 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2011 VL 34 IS 8 BP 430 EP 442 DI 10.1016/j.tins.2011.05.005 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 811SX UT WOS:000294237500005 PM 21696834 ER PT J AU Wen, LS Geduld, HI Nagurney, JT Wallis, LA AF Wen, Leana S. Geduld, Heike I. Nagurney, J. Tobias Wallis, Lee A. TI Africa's First Emergency Medicine Training Program at the University of Cape Town/Stellenbosch University: History, Progress, and Lessons Learned SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID SOUTH-AFRICA AB Africa's first residency training program in emergency medicine (EM) was established at the University of Cape Town (UCT)/Stellenbosch University (SUN) in 2004. There have since been four classes for a total of 29 graduates from this program who are practicing, teaching, and leading EM. This article describes the structure of the program and discusses the history and major drivers behind its founding. We report major changes, cite ongoing challenges, and discuss lessons learned from the program's first 7 years that may help advise other nascent training programs in developing countries. ACADEMIC EMERGENCY MEDICINE 2011; 18:868-871 (C) 2011 by the Society for Academic Emergency Medicine C1 [Wen, Leana S.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Wen, Leana S.; Nagurney, J. Tobias] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Geduld, Heike I.; Wallis, Lee A.] Univ Cape Town, Div Emergency Med, ZA-7925 Cape Town, South Africa. [Geduld, Heike I.; Wallis, Lee A.] Univ Stellenbosch, Div Emergency Med, ZA-7600 Stellenbosch, South Africa. RP Wen, LS (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. EM wen.leana@gmail.com OI Wen, Leana/0000-0003-0259-0537 FU Partners Healthcare FX Dr. Wen received a travel grant from Partners Healthcare. There are no other disclosures and no conflicts of interest. NR 9 TC 11 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD AUG PY 2011 VL 18 IS 8 SI SI BP 868 EP 871 DI 10.1111/j.1553-2712.2011.01131.x PG 4 WC Emergency Medicine SC Emergency Medicine GA 807AJ UT WOS:000293860400012 PM 21843223 ER PT J AU Chen, D Restrepo, MI Fine, MJ Pugh, MJV Anzueto, A Metersky, ML Nakashima, B Good, C Mortensen, EM AF Chen, Dennis Restrepo, Marcos I. Fine, Michael J. Pugh, Mary Jo V. Anzueto, Antonio Metersky, Mark L. Nakashima, Brandy Good, Chester Mortensen, Eric M. TI Observational Study of Inhaled Corticosteroids on Outcomes for COPD Patients with Pneumonia SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE inhaled corticosteroids; pneumonia; chronic obstructive pulmonary disease; mortality ID OBSTRUCTIVE PULMONARY-DISEASE; COMMUNITY-ACQUIRED PNEUMONIA; SALMETEROL/FLUTICASONE PROPIONATE; FLUTICASONE PROPIONATE; RISK-FACTORS; ADMINISTRATIVE DATA; COMORBIDITY INDEX; SALMETEROL; MORTALITY; EXACERBATIONS AB Rationale: Treatment with inhaled corticosteroids (ICS) for those with chronic obstructive pulmonary disease (COPD) has been shown to be associated with an increased incidence of pneumonia. However, it is unclear if this is associated with increased mortality. Objectives: The aim of this study was to examine the effects of prior use of ICS on clinical outcomes for patients with COPD hospitalized with pneumonia. Methods: We conducted a retrospective cohort study using the national administrative databases of the Department of Veterans Affairs. Eligible patients had a preexisting diagnosis of COPD, had a discharge diagnosis of pneumonia, and received treatment with one or more appropriate pulmonary medications before hospitalization. Outcomes included mortality, use of invasive mechanical ventilation, and vasopressor use. Measurements and Main Results: There were 15,768 patients (8,271 with use of ICS and 7,497 with no use of ICS) with COPD who were hospitalized for pneumonia. There was also a significant difference for 90-day mortality (ICS 17.3% vs. no ICS 22.8%; P < 0.001). Multilevel regression analyses demonstrated that prior receipt of ICS was associated with decreased mortality at 30 days (odds ratio [OR] 0.80; 95% confidence interval [CI], 0.72-0.89) and 90 days (OR 0.78; 95% CI, 0.72-0.85), and decreased use of mechanical ventilation (OR 0.83; 95% CI, 0.72-0.94). There was no significant association between receipt of ICS and vasopressor use (OR 0.88; 95% CI, 0.74-1.04). Conclusions: For patients with COPD, prior use of ICS is independently associated with decreased risk of short-term mortality and use of mechanical ventilation after hospitalization for pneumonia. C1 [Chen, Dennis; Restrepo, Marcos I.; Pugh, Mary Jo V.; Anzueto, Antonio; Nakashima, Brandy; Mortensen, Eric M.] VERDICT S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Mortensen, Eric M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Hosp Med, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm & Crit Care Med, San Antonio, TX 78229 USA. [Pugh, Mary Jo V.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol, San Antonio, TX 78229 USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Biostat, San Antonio, TX 78229 USA. [Metersky, Mark L.] Univ Connecticut, Sch Med, Div Pulm & Crit Care Med, Farmington, CT USA. [Fine, Michael J.; Good, Chester] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Fine, Michael J.; Good, Chester] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. RP Mortensen, EM (reprint author), STVHCS UTHSCSA, VERDICT Res Program 11C6, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM mortensene@uthscsa.edu RI Restrepo, Marcos/H-4442-2014; OI Pugh, Mary Jo/0000-0003-4196-7763; Mortensen, Eric/0000-0002-3880-5563 FU National Institute of Nursing Research [R01NR010828]; Department of Veteran Affairs Veterans Integrated Service Network [17]; National Health Institute [KL2 RR025766]; Veterans Health Administration [MRP-05-145] FX Supported by Grant Number R01NR010828 from the National Institute of Nursing Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Nursing Research or the National Institutes of Health. This material is the result of work supported with resources and the use of facilities at the South Texas Veterans Health Care System. Dr. Restrepo is supported by a Department of Veteran Affairs Veterans Integrated Service Network 17 new faculty grant and National Health Institute Grant KL2 RR025766. Dr. Copeland is supported by Veterans Health Administration Grant MRP-05-145. The funding agencies had no role in conducting the study, or role in the preparation, review, or approval of the manuscript. NR 36 TC 44 Z9 44 U1 0 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 1 PY 2011 VL 184 IS 3 BP 312 EP 316 DI 10.1164/rccm.201012-2070OC PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 808EE UT WOS:000293958800009 PM 21512168 ER PT J AU Farabaugh, AH Locascio, JJ Yap, L Fava, M Bitran, S Sousa, JL Growdon, JH AF Farabaugh, Amy H. Locascio, Joseph J. Yap, Liang Fava, Maurizio Bitran, Stella Sousa, Jessica L. Growdon, John H. TI Assessing depression and factors possibly associated with depression during the course of Parkinson's disease SO ANNALS OF CLINICAL PSYCHIATRY LA English DT Article DE age; depression; Parkinson's disease; prevalence; rating scales; severity of illness index ID PREVALENCE; DIAGNOSIS; SYMPTOMS AB BACKGROUND: Although research suggests depression is common among individuals with Parkinson's disease (PD), it is unclear how to best assess depression in PD (dPD). We wanted to examine the prevalence of dPD using different definitions of depression, as well as examine factors associated with dPD. METHODS: One hundred fifty-eight individuals (68% male; age 66.8 +/- 9.6 SD) with a primary diagnosis of PD were assessed for depression using the Harvard Department of Psychiatry/National Depression Screening Day Scale (HANDS) in an outpatient setting at the Movement Disorders Clinic at Massachusetts General Hospital. We defined depression using 4 thresholds based on the HANDS and whether or not an individual was ever on an antidepressant regimen. We also examined potential predictors of the presence of dPD. RESULTS: The prevalence of depression among study participants ranged from 11% to 57%, depending on which of the 4 definitions of depression was applied. Younger age and longer duration of PD predicted a relatively higher prevalence of depression. Having a history of depression prior to onset of PD also was predictive of dPD. CONCLUSIONS: Depression appears to be relatively common among individuals with PD, and history of depression, younger age, and longer PD duration may be factors associated with dPD. C1 [Farabaugh, Amy H.; Fava, Maurizio; Bitran, Stella; Sousa, Jessica L.] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Locascio, Joseph J.; Growdon, John H.] Massachusetts Gen Hosp, Memory Disorders Unit, Movement Disorders Unit, Boston, MA 02114 USA. RP Farabaugh, AH (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM afarabaugh@partners.org FU Harvard Medical School; National Institute for Mental Health; NARSAD; Abbott Laboratories; Alkermes, Inc.; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; Cephalon, Inc.; CeNeRx BioPharma; Clinical Trials Solutions, LLC; Clintara, LLC; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Icon Clinical Research; i3 Innovus/Ingenix; Johnson and Johnson Pharmaceutical Research and Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Mental Health (NIMH); Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; PharmaviteRegistered Trademark LLC; Photothera; Roche; RCT Logic, LLC; sanofi-aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo; Wyeth-Ayerst Laboratories FX This research was supported by the Harvard Medical School Kaplen Fellowship. Data were collected from NINDS/NIH P50 NS038372.; Dr. Farabaugh has received grant/research support from the National Institute for Mental Health, Harvard Medical School, and NARSAD. She also has been a speaker for Massachusetts General Hospital Academy and the American Psychiatric Association. Dr. Fava has received lifetime research support from Abbott Laboratories; Alkermes, Inc.; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; Cephalon, Inc.; CeNeRx BioPharma; Clinical Trials Solutions, LLC; Clintara, LLC; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Icon Clinical Research; i3 Innovus/Ingenix; Johnson and Johnson Pharmaceutical Research and Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; National Alliance for Research on Schizophrenia and Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmavite (R) LLC; Photothera; Roche; RCT Logic, LLC; sanofi-aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo; Wyeth-Ayerst Laboratories. He also has advised/consulted for Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Clinical Trials Solutions, LLC; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Danippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson and Johnson Pharmaceutical Research and Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck, Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; Puretech Ventures; Psycho-Genics; Psylin Neurosciences, Inc.; Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; RCT Logic, LLC; sanofi-aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc. Dr. Fava has spoken for/been published in Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer, Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; ; Eli Lilly and Company; Forest Pharmaceticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource,Corp.; Wyeth-Ayerst Laboratories. Dr Fava has had equity holdings in Compellis. He also has received royalties/other income from Patent for Sequential Parallel Comparison Design (SPCD) and patent application for a combination of azapirones and bupropion in major depressive disorder, copyright royalties for the MGH Cognitive and Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs and Symptoms (DESS), and SAFER. Patent for research and licensing of SPCD with RCT Logic; Lippincott, Williams and Wilkins; World Scientific Publishing Co. Pte. Ltd. Drs. Locascio, Yap, Bitran, and Growdon and Ms. Sousa report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. NR 18 TC 3 Z9 4 U1 0 U2 1 PU QUADRANT HEALTHCOM INC PI PARSIPPANY PA 7 CENTURY DRIVE, STE 302, PARSIPPANY, NJ 07054-4603 USA SN 1040-1237 J9 ANN CLIN PSYCHIATRY JI Ann. Clin. Psychiatry PD AUG PY 2011 VL 23 IS 3 BP 171 EP 177 PG 7 WC Psychiatry SC Psychiatry GA 807YY UT WOS:000293940100003 PM 21808748 ER PT J AU Goldhirsch, A Wood, WC Coates, AS Gelber, RD Thurlimann, B Senn, HJ AF Goldhirsch, A. Wood, W. C. Coates, A. S. Gelber, R. D. Thuerlimann, B. Senn, H. -J. CA Panel Members TI Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011 SO ANNALS OF ONCOLOGY LA English DT Article DE adjuvant therapies; early breast cancer; St Gallen Consensus; subtypes ID PATHOLOGISTS GUIDELINE RECOMMENDATIONS; RANDOMIZED CLINICAL-TRIAL; ADJUVANT CHEMOTHERAPY; ESTROGEN-RECEPTOR; PREDICTIVE-VALUE; GENE-EXPRESSION; NEOADJUVANT CHEMOTHERAPY; POSTMENOPAUSAL WOMEN; AXILLARY DISSECTION; MOLECULAR SUBTYPES AB The 12th St Gallen International Breast Cancer Conference (2011) Expert Panel adopted a new approach to the classification of patients for therapeutic purposes based on the recognition of intrinsic biological subtypes within the breast cancer spectrum. For practical purposes, these subtypes may be approximated using clinicopathological rather than gene expression array criteria. In general, systemic therapy recommendations follow the subtype classification. Thus, 'Luminal A' disease generally requires only endocrine therapy, which also forms part of the treatment of the 'Luminal B' subtype. Chemotherapy is considered indicated for most patients with 'Luminal B', 'Human Epidermal growth factor Receptor 2 (HER2) positive', and 'Triple negative (ductal)' disease, with the addition of trastuzumab in 'HER2 positive' disease. Progress was also noted in defining better tolerated local therapies in selected cases without loss of efficacy, such as accelerated radiation therapy and the omission of axillary dissection under defined circumstances. Broad treatment recommendations are presented, recognizing that detailed treatment decisions need to consider disease extent, host factors, patient preferences, and social and economic constraints. C1 [Goldhirsch, A.] European Inst Oncol, Dept Med, Int Breast Canc Study Grp, I-20141 Milan, Italy. [Wood, W. C.] Emory Univ, Sch Med, Dept Surg, Atlanta, GA 30322 USA. [Coates, A. S.] Univ Sydney, Sydney, NSW 2006, Australia. [Gelber, R. D.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Stat Ctr, Int Breast Canc Study Grp,Dept Biostat & Computat, Boston, MA 02115 USA. [Thuerlimann, B.] Kantonsspital St Gallen, Breast Ctr, St Gallen, Switzerland. [Senn, H. -J.] Tumor & Breast Ctr ZeTuP, St Gallen, Switzerland. [Coates, A. S.] Int Breast Canc Study Grp, Sydney, NSW, Australia. RP Goldhirsch, A (reprint author), European Inst Oncol, Dept Med, Int Breast Canc Study Grp, I-20141 Milan, Italy. EM aron.goldhirsch@ibcsg.org RI Goodwin, Pamela/K-1477-2013 FU SONK; United States National Cancer Institute [CA75362] FX Support for the conference was provided by SONK from registration fees paid by the conference attendees and by Grant No. CA75362 from the United States National Cancer Institute. NR 90 TC 1212 Z9 1349 U1 21 U2 119 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 2011 VL 22 IS 8 BP 1736 EP 1747 DI 10.1093/annonc/mdr304 PG 12 WC Oncology SC Oncology GA 799QH UT WOS:000293300700008 PM 21709140 ER PT J AU Barnes, JA LaCasce, AS Feng, Y Toomey, CE Neuberg, D Michaelson, JS Hochberg, EP Abramson, JS AF Barnes, J. A. LaCasce, A. S. Feng, Y. Toomey, C. E. Neuberg, D. Michaelson, J. S. Hochberg, E. P. Abramson, J. S. TI Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis SO ANNALS OF ONCOLOGY LA English DT Article DE AIDS; Burkitt's lymphoma; HIV; Magrath regimen; non-Hodgkin's lymphoma; rituximab ID CHEMOTHERAPY PLUS RITUXIMAB; B-CELL LYMPHOMA; RANDOMIZED CONTROLLED-TRIAL; ELDERLY-PATIENTS; ADULT BURKITT; HYPER-CVAD; CHOP; CYCLOPHOSPHAMIDE; DOXORUBICIN AB Background: Burkitt's lymphoma (BL) is a highly aggressive B-cell non-Hodgkin's lymphoma (NHL) that may be cured with intensive chemotherapy. The addition of the CD20-directed monoclonal antibody rituximab to CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, alternating with ifosfamide, etoposide, and cytarabine) has not been studied despite efficacy in other aggressive CD20-positive NHLs. Patients and methods: Eighty adult BL patients treated with or without rituximab were identified at our institutions. Response rate, overall survival (OS), and progression-free survival (PFS) are calculated. Results: There were fewer relapses in rituximab-treated patients (3 of 40 versus 13 of 40, P = 0.01). There was a trend for improvement in outcome favoring rituximab-containing therapy, with 3-year PFS (74% versus 61%) and 3-year OS (77% versus 66%), although these did not reach statistical significance. Advanced age and central nervous system involvement were associated with poorer OS on multivariable Cox regression analysis, adjusting for treatment, human immunodeficiency virus (HIV) involvement, and risk group. Conclusions: CODOX-M/IVAC, with or without rituximab, is a highly effective regimen for the treatment of adult BL. Rituximab decreased the recurrence rate and showed a trend in favor of improvement in PFS and OS. HIV-infected patients achieved outcomes comparable with those of their non-HIV-infected counterparts. C1 [Barnes, J. A.; Toomey, C. E.; Hochberg, E. P.; Abramson, J. S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA 02114 USA. [Barnes, J. A.; LaCasce, A. S.; Hochberg, E. P.; Abramson, J. S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [LaCasce, A. S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Feng, Y.; Neuberg, D.] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Neuberg, D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Michaelson, J. S.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Michaelson, J. S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Abramson, JS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, 55 Fruit St, Boston, MA 02114 USA. EM jabramson@partners.org FU Genentech FX EPH reports consulting and speaking fees from Genentech. There are no other conflicts of interest. NR 19 TC 49 Z9 53 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 2011 VL 22 IS 8 BP 1859 EP 1864 DI 10.1093/annonc/mdq677 PG 6 WC Oncology SC Oncology GA 799QH UT WOS:000293300700024 PM 21339382 ER PT J AU Lee, LN Hasserjian, RP Faquin, WC Takvorian, RW Rocco, JW AF Lee, Linda N. Hasserjian, Robert P. Faquin, William C. Takvorian, Ronald W. Rocco, James W. TI Pathology Quiz Case 1: Diffuse large B-cell lymphoma (DLBCL) of the thyroid SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Editorial Material ID DIAGNOSIS C1 [Lee, Linda N.; Rocco, James W.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Takvorian, Ronald W.; Rocco, James W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Lee, Linda N.; Rocco, James W.] Harvard Univ, Sch Med, Boston, MA USA. RP Lee, LN (reprint author), Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD AUG PY 2011 VL 137 IS 8 BP 829 EP + PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 806ZK UT WOS:000293857000018 PM 21844421 ER PT J AU Agnihotri, AK Sundt, TM AF Agnihotri, Arvind K. Sundt, Thoralf M. TI Enzyme Elevation After Coronary Bypass Surgery Cause or Effect? SO ARCHIVES OF SURGERY LA English DT Editorial Material C1 [Agnihotri, Arvind K.; Sundt, Thoralf M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Cardiac Surg, Boston, MA 02114 USA. RP Agnihotri, AK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Cardiac Surg, 55 Fruit St, Boston, MA 02114 USA. EM aagnihotri@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD AUG PY 2011 VL 146 IS 8 BP 983 EP 984 PG 2 WC Surgery SC Surgery GA 806ZP UT WOS:000293857600025 PM 21844442 ER PT J AU Li, X McHugh, GA Damle, N Sikand, VK Glickstein, L Steere, AC AF Li, Xin McHugh, Gail A. Damle, Nitin Sikand, Vijay K. Glickstein, Lisa Steere, Allen C. TI Burden and Viability of Borrelia burgdorferi in Skin and Joints of Patients With Erythema Migrans or Lyme Arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID POLYMERASE-CHAIN-REACTION; REVERSE TRANSCRIPTION-PCR; ESCHERICHIA-COLI O157-H7; ANTIBIOTIC-TREATMENT; MESSENGER-RNA; PULMONARY TUBERCULOSIS; QUANTITATIVE DETECTION; STRESS TREATMENTS; SYNOVIAL-FLUID; RIBOSOMAL-RNA AB Objective. To determine the burden and viability of Borrelia burgdorferi in the skin and joints of patients with Lyme disease. Methods. Standard and quantitative polymerase chain reaction (PCR) techniques were used to detect B burgdorferi DNA in skin samples from 90 patients with erythema migrans (EM) and in synovial fluid (SF) from 63 patients with Lyme arthritis (LA) and in synovial tissue from 9 patients. Quantitative PCR determinations of B burgdorferi DNA, messenger RNA (mRNA), and ribosomal RNA (rRNA) were made in 10 skin samples from EM patients and 11 SF samples from LA patients. Results. Skin lesions in most patients with EM had positive PCR results for B burgdorferi DNA. In the majority of patients with LA, a late disease manifestation, PCR results in pretreatment SF samples were positive. In patients with antibiotic-refractory arthritis, positive PCR results persisted for as long as 11 months, but positive results in samples taken during the post-antibiotic period did not correlate with relapse or with the subsequent duration of arthritis, and at synovectomy, all results of PCR of synovial tissue were negative. B burgdorferi mRNA, a marker of spirochetal viability, was detected in 8 of 10 skin samples from EM patients, but in none of 11 SF samples from LA patients, even when obtained prior to antibiotic administration. Moreover, the median ratio of spirochetal rRNA to DNA, a measure of ribosomal activity, was 160 in the 10 EM skin samples, but only 0.15 in the 3 LA SF samples with positive results. Conclusion. B burgdorferi in the skin lesions of EM patients were active and viable, whereas those in the SF of LA patients were moribund or dead at any time point. Thus, detection of B burgdorferi DNA in SF is not a reliable test of active joint infection in Lyme disease. C1 [Li, Xin; McHugh, Gail A.; Glickstein, Lisa; Steere, Allen C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Li, Xin; McHugh, Gail A.; Glickstein, Lisa; Steere, Allen C.] Harvard Univ, Sch Med, Boston, MA USA. [Damle, Nitin] S Cty Internal Med, Wakefield, RI USA. [Sikand, Vijay K.] Lawrence Mem Hosp, New London, CT USA. RP Steere, AC (reprint author), Massachusetts Gen Hosp, CNY 149-8301,55 Fruit St, Boston, MA 02114 USA. EM asteere@partners.org RI Li, Xin/E-3505-2011 FU NIH [AR-20358]; CDC [CCU110 291]; English, Bonter, Mitchell Foundation; Massachusetts General Hospital; Eshe Fund; Arthritis Foundation FX Supported by the NIH (grant AR-20358), the CDC (grant CCU110 291), the English, Bonter, Mitchell Foundation, the Lyme/Arthritis Research Fund at Massachusetts General Hospital, and the Eshe Fund. Dr. Li's work was supported by the Arthritis Foundation and Massachusetts General Hospital (Claflin award). NR 49 TC 39 Z9 39 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD AUG PY 2011 VL 63 IS 8 BP 2238 EP 2247 DI 10.1002/art.30384 PG 10 WC Rheumatology SC Rheumatology GA 806US UT WOS:000293840200013 PM 21590753 ER PT J AU Silva, F Seo, P Schroeder, DR Stone, JH Merkel, PA Hoffman, GS Spiera, R Sebastian, JK Davis, JC St Clair, EW Allen, NB McCune, WJ Ytterberg, SR Specks, U AF Silva, Francisco Seo, Philip Schroeder, Darrell R. Stone, John H. Merkel, Peter A. Hoffman, Gary S. Spiera, Robert Sebastian, Jodi K. Davis, John C., Jr. St Clair, E. William Allen, Nancy B. McCune, W. Joseph Ytterberg, Steven R. Specks, Ulrich CA Wegener's Granulomatosis TI Solid Malignancies Among Etanercept-Treated Patients With Granulomatosis With Polyangiitis (Wegener's) Long-Term Followup of a Multicenter Longitudinal Cohort SO ARTHRITIS AND RHEUMATISM LA English DT Article ID TUMOR-NECROSIS-FACTOR; SQUAMOUS-CELL CARCINOMA; POPULATION-BASED COHORT; RHEUMATOID-ARTHRITIS; FACTOR-ALPHA; CANCER MORBIDITY; INCREASED RISK; THERAPY; LYMPHOMA; DISEASE AB Objective. An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy. Methods. The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End- Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies. Results. Post-trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69-7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94-6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial followup. Conclusion. The incidence of solid malignancy remained increased during long-term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients. C1 [Silva, Francisco; Schroeder, Darrell R.; Ytterberg, Steven R.; Specks, Ulrich] Mayo Clin, Rochester, MN USA. [Silva, Francisco] Pontificia Univ Catolica Chile, Santiago, Chile. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Merkel, Peter A.; Sebastian, Jodi K.] Boston Univ, Boston, MA 02215 USA. [Hoffman, Gary S.] Cleveland Clin, Cleveland, OH 44106 USA. [Spiera, Robert] Hosp Special Surg, New York, NY 10021 USA. [Davis, John C., Jr.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [St Clair, E. William; Allen, Nancy B.] Duke Univ, Med Ctr, Durham, NC USA. [McCune, W. Joseph] Univ Michigan, Ann Arbor, MI 48109 USA. RP Specks, U (reprint author), Mayo Clin & Mayo Fdn, Div Pulm & Crit Care Med, Thorac Dis Res Unit, Stabile Bldg 8-56,200 1st St SW, Rochester, MN 55905 USA. EM specks.ulrich@mayo.edu FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [N01-AR-92240]; FDA (Office of Orphan Products Development) [FD-R-001652]; Vasculitis Clinical Research Consortium through the NIH (National Center for Research Resources and National Institute of Arthritis and Musculoskeletal and Skin Diseases) [1-U54-RR-019497, 7-U01-AR-1874]; Mayo Foundation for Medical Education and Research; Vasculitis Clinical Research Consortium FX The Wegener's Granulomatosis Etanercept Trial was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant N01-AR-92240) and the FDA (Office of Orphan Products Development grant FD-R-001652). Additional support for the present study was provided by the Vasculitis Clinical Research Consortium through the NIH (National Center for Research Resources and National Institute of Arthritis and Musculoskeletal and Skin Diseases grants 1-U54-RR-019497 and 7-U01-AR-1874). Dr. Silva's work was supported by the Mayo Foundation for Medical Education and Research; he is recipient of a Vasculitis Fellowship from the Vasculitis Clinical Research Consortium. NR 47 TC 32 Z9 35 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD AUG PY 2011 VL 63 IS 8 BP 2495 EP 2503 DI 10.1002/art.30394 PG 9 WC Rheumatology SC Rheumatology GA 806US UT WOS:000293840200039 PM 21484770 ER PT J AU Singh, JA Kwoh, CK Boudreau, RM Lee, GC Ibrahim, SA AF Singh, Jasvinder A. Kwoh, C. Kent Boudreau, Robert M. Lee, Gwo-Chin Ibrahim, Said A. TI Hospital Volume and Surgical Outcomes After Elective Hip/Knee Arthroplasty A Risk-Adjusted Analysis of a Large Regional Database SO ARTHRITIS AND RHEUMATISM LA English DT Article ID TOTAL KNEE ARTHROPLASTY; MYOCARDIAL-INFARCTION MORTALITY; SURGEON PROCEDURE VOLUME; TOTAL HIP-REPLACEMENT; REVISION TOTAL HIP; UNITED-STATES; PROVIDER VOLUME; RIGHT TOOL; APR-DRGS; ASSOCIATION AB Objective. To examine the relationship between hospital procedure volume and surgical outcomes following elective primary total hip arthroplasty/total knee arthroplasty (THA/TKA). Methods. Using the Pennsylvania Health Care Cost Containment Council database, we identified all patients who underwent elective primary THA/TKA in Pennsylvania. Hospitals were categorized according to the annual volume of THA/TKA procedures, as follows: <= 25, 26-100, 101-200, and >200. The 30-day complication rate and 30-day and 1-year mortality rates were assessed by logistic regression models, adjusted for age, sex, race, insurance type, hospital region, 3M All Patient Refined Diagnosis Related Group risk of mortality score, hospital teaching status, and bed count. Results. In the THA and TKA cohorts, the mean age of the patients was 69 years, and 42.8% and 35%, respectively, were men. Compared with patients whose surgeries were performed at very-high-volume hospitals (> 200 procedures/year), patients who underwent elective primary THA procedures at hospitals with a very low volume (<= 25 procedures/year), a low volume (26100 procedures/year), or a high volume (101-200 procedures/year) had higher multivariable-adjusted odds ratios (ORs) for venous thromboembolism (OR 2.0, 95% confidence interval [95% CI] 0.2-16.0), OR 3.4 [95% CI 1.4-8.0], and OR 1.1 [95% CI 0.3-3.7], respectively) and 1-year mortality (OR 2.1 [95% CI 1.2-3.6], OR 2.0 [95% CI 1.4-2.9], and OR 1.0 [95% CI 0.7-1.5], respectively). Among patients ages >= 65 years who underwent elective primary TKA at very-low-volume, low-volume, and high-volume hospitals, the ORs for 1-year mortality were significantly higher (OR 0.6 [95% CI 0.2-2.1], OR 1.6 [95% CI 1.0-2.4], and OR 0.9 [95% CI 0.6-1.3], respectively), compared with very-high-volume hospitals. Conclusion. Performance of elective primary THA and TKA surgeries in low-volume hospitals was associated with a higher risk of venous thromboembolism and mortality. Confounding due to unmeasured variables is possible. Modifiable system-based factors/processes should be targeted to reduce the number of complications associated with THA/TKA procedures. C1 [Singh, Jasvinder A.] Univ Alabama, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] VA Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Mayo Clin, Rochester, MN USA. [Kwoh, C. Kent; Boudreau, Robert M.; Ibrahim, Said A.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Lee, Gwo-Chin; Ibrahim, Said A.] Univ Penn, Philadelphia, PA 19104 USA. [Ibrahim, Said A.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Singh, JA (reprint author), Univ Alabama, Fac Off Tower 805B,510 20th St S, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com OI Boudreau, Robert/0000-0003-0162-5187; singh, jasvinder/0000-0003-3485-0006 FU Western Pennsylvania Chapter of the Arthritis Foundation; NIH [1-KL2-RR-024151-01]; NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [K24-AR-055259] FX Supported by a pilot grant from the Western Pennsylvania Chapter of the Arthritis Foundation. Dr. Singh's work was supported by the NIH (Clinical Translational Science Award 1-KL2-RR-024151-01 to the Mayo Clinic Center for Clinical and Translational Research). Dr. Ibrahim's work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K24-AR-055259). NR 29 TC 28 Z9 28 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD AUG PY 2011 VL 63 IS 8 BP 2531 EP 2539 DI 10.1002/art.30390 PG 9 WC Rheumatology SC Rheumatology GA 806US UT WOS:000293840200044 PM 21656509 ER PT J AU Chan, AT Sima, CS Zauber, AG Ridker, PM Hawk, ET Bertagnolli, MM AF Chan, Andrew T. Sima, Camelia S. Zauber, Ann G. Ridker, Paul M. Hawk, Ernest T. Bertagnolli, Monica M. TI C-reactive Protein and Risk of Colorectal Adenoma According to Celecoxib Treatment SO CANCER PREVENTION RESEARCH LA English DT Article ID CANCER-RISK; CARDIOVASCULAR-DISEASE; INFLAMMATORY MARKERS; ENDOTHELIAL FUNCTION; CIRCULATING LEVELS; SAFETY ANALYSIS; PREVENTION; ASPIRIN; HEALTH; TRIAL AB Inflammation, as measured by the circulating inflammatory marker high-sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data about CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial showed that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined whether serum hsCRP modified these results. We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive 3 years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at years 1 and 3. Among 1,680 patients, the estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP <1 mg/L, compared with 43% [relative risk (RR) = 1.02; 95% CI = 0.85-1.22] for hsCRP 1-3 mg/L, and 41% (RR = 1.10; 95% CI = 0.90-1.34) for hsCRP >3 mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3 mg/L) compared with low (<= 3 mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72-7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (95% CI = 1.09-9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53-1.83) and 1.11 (95% CI = 0.61-2.02). hsCRP may predict risk of celecoxib-associated cardiovascular toxicity but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention. Cancer Prev Res; 4(8); 1172-80. (C) 2011 AACR. C1 [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chan, Andrew T.; Bertagnolli, Monica M.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ridker, Paul M.] Ctr Cardiovasc Dis Prevent, Dept Med, Boston, MA USA. [Bertagnolli, Monica M.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Sima, Camelia S.; Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Hawk, Ernest T.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,GRJ-728A, Boston, MA 02114 USA. EM achan@partners.org FU National Cancer Institute at the NIH [R01 CA137178, N01 CN95015] FX This work was supported by the National Cancer Institute at the NIH (grant number R01 CA137178 to A. T. Chan and N01 CN95015 to M. M. Bertagnolli). NR 40 TC 18 Z9 18 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD AUG PY 2011 VL 4 IS 8 BP 1172 EP 1180 DI 10.1158/1940-6207.CAPR-10-0403 PG 9 WC Oncology SC Oncology GA 802JJ UT WOS:000293505700004 PM 21816845 ER PT J AU Hermiller, J Choy, JS Svendsen, M Bigelow, B Fouts, A Hall, J Parr, K Ball, M Sinha, A Bhatt, DL Kassab, GS AF Hermiller, James Choy, Jenny S. Svendsen, Mark Bigelow, Brian Fouts, A. Hall, Jack Parr, Kirk Ball, Michael Sinha, Anjan Bhatt, Deepak L. Kassab, Ghassan S. TI A Nonimaging Catheter for Measurement of Coronary Artery Lumen Area: A First in Man Pilot Study SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE sizing; electrical conductance; IVUS; QCA; percutaneous coronary intervention ID SUBACUTE STENT THROMBOSIS; INTRAVASCULAR ULTRASOUND; RECONSTRUCTION; VARIABILITY; VALIDATION; TRIAL; RISK AB Objectives: The objective of this human pilot study was to determine the safety and the level of agreement between a novel nonimaging 2.7 Fr. catheter-based system (LumenRECON, LR) that uses electrical conductance for measurement of lumen cross-sectional area (CSA) with intravascular ultrasound (IVUS) and quantitative coronary angiography (QCA). Based on previous animal studies, we hypothesized the level of agreement between LR and IVUS to be 13%. Background: Accurate and reproducible vessel sizing is essential for optimal percutaneous coronary intervention (PCI). Methods: A total of 12 patients were studied to evaluate the safety, accuracy, and reproducibility of the system in comparison with IVUS and QCA. The CSA of coronary arteries was determined by IVUS, QCA, and LR in the distal, proximal, and center of a lesion during standard PCI. Results: A Bland-Altman plot of the LR versus IVUS and QCA show a nonsignificant mean difference between the two measurements of 0.04 and 0.07 mm in diameter, respectively. The root mean square error of LR versus IVUS and QCA was 14.3 and 25.8% of the mean IVUS or QCA diameter, respectively. The mean of the difference between two LR duplicate measurements was nearly zero (0.03 mm) and the repeatability coefficient was within 8.7% of the mean of the two measurements. There were no procedural complications nor were any device-related MACE reported within 30 days of the procedure. Conclusions: This proof of concept pilot study establishes the safety and accuracy of the conductance technology for a pivotal trial of coronary sizing. (C) 2011 Wiley-Liss, Inc. C1 [Choy, Jenny S.; Kassab, Ghassan S.] Indiana Univ Purdue Univ, Dept Biomed Engn, Indianapolis, IN 46202 USA. [Hermiller, James; Bigelow, Brian; Fouts, A.; Hall, Jack; Parr, Kirk; Ball, Michael] Heart Ctr IN, Indianapolis, IN USA. [Svendsen, Mark] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. [Sinha, Anjan] Indiana Univ Purdue Univ, Dept Cardiol, Indianapolis, IN 46202 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Kassab, Ghassan S.] Indiana Univ Purdue Univ, Dept Surg, Indianapolis, IN 46202 USA. [Kassab, Ghassan S.] Indiana Univ Purdue Univ, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. RP Kassab, GS (reprint author), Indiana Univ Purdue Univ, Dept Biomed Engn, Indianapolis, IN 46202 USA. EM gkassab@iupui.edu FU Flowco Inc FX Grant sponsor: Flowco Inc NR 17 TC 8 Z9 8 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD AUG 1 PY 2011 VL 78 IS 2 BP 202 EP 210 DI 10.1002/ccd.22842 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 801PD UT WOS:000293451600010 PM 20939042 ER PT J AU Kostis, WJ Suh, WM Palacios, IF AF Kostis, William J. Suh, William M. Palacios, Igor F. TI Acute Myocardial Infarction Caused by Multivessel Coronary Spasm Due to Calcium Channel Blocker Withdrawal SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE acute myocardial infarction; coronary vasospasm; calcium channel antagonist withdrawal ID ISCHEMIC-HEART-DISEASE; INTRAVASCULAR ULTRASOUND; VASOSPASTIC ANGINA; PROPRANOLOL; EXACERBATION; CESSATION; VERAPAMIL AB Calcium channel blockers are a commonly used class of medications for the management of hypertension, angina, and superventricular tachyarrhythmias. Abrupt withdrawal of these agents can precipitate coronary vasospasm, which may result in myocardial infarction. We present the case of a 47-year-old woman who sustained an acute myocardial infarction mediated by multivessel coronary vasospasm secondary to verapamil withdrawal and the associated interventional management.(C) 2011 Wiley-Liss, Inc. C1 [Kostis, William J.; Suh, William M.; Palacios, Igor F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. RP Kostis, WJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, 55 Fruit St,GRB800, Boston, MA 02114 USA. EM wkostis@partners.org NR 14 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD AUG 1 PY 2011 VL 78 IS 2 BP 229 EP 233 DI 10.1002/ccd.22937 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 801PD UT WOS:000293451600015 PM 21234921 ER PT J AU Mavros, MN Velmahos, GC Falagas, ME AF Mavros, Michael N. Velmahos, George C. Falagas, Matthew E. TI Atelectasis as a Cause of Postoperative Fever Where Is the Clinical Evidence? SO CHEST LA English DT Article ID ARTERY-BYPASS-SURGERY; PULMONARY ATELECTASIS; ABDOMINAL-SURGERY; BODY-TEMPERATURE; CARDIAC-SURGERY; COMPLICATIONS; ASSOCIATION; LUNG; PATHOGENESIS; PREVENTION AB Background: Atelectasis is considered to be the most common cause of early postoperative fever (EPF) but the existing evidence is contradictory. We sought to determine if atelectasis is associated with EPF by analyzing the relevant published evidence. Methods: We performed a systematic search in PubMed and Scopus databases to identify studies examining the association between atelectasis and EPF. Results: A total of eight studies, including 998 cardiac, abdominal, and maxillofacial surgery patients, were eligible for analysis. Only two studies specifically examined our question, and six additional articles reported sufficient data to be included. Only one study reported a significant association between postoperative atelectasis and fever, whereas the remaining studies indicated no such association. The performance of EPF as a diagnostic test for atelectasis was also assessed, and EPF performed poorly (pooled diagnostic OR, 1.40; 95% CI, 0.92-2.12). The significant heterogeneity among the studies precluded a formal metaanalysis. Conclusion: The available evidence regarding the association of atelectasis and fever is scarce. We found no clinical evidence supporting the concept that atelectasis is associated with EPF. More so, there is no clear evidence that atelectasis causes fever at all. Large studies are needed to precisely evaluate the contribution of atelectasis in EPF. CHEST 2011; 140(2):418-424 C1 [Mavros, Michael N.; Falagas, Matthew E.] Alfa Inst Biomed Sci, Athens 15123, Greece. [Velmahos, George C.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Falagas, Matthew E.] Henry Dunant Hosp, Dept Med, Athens, Greece. [Falagas, Matthew E.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. RP Falagas, ME (reprint author), Alfa Inst Biomed Sci, 9 Neapoleos St, Athens 15123, Greece. EM m.falagas@aibs.gr FU Alfa Institute of Biomedical Sciences FX This study was supported by internal funding from the Alfa Institute of Biomedical Sciences. NR 48 TC 15 Z9 15 U1 0 U2 7 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2011 VL 140 IS 2 BP 418 EP 424 DI 10.1378/chest.11-0127 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 808QS UT WOS:000293994100026 PM 21527508 ER PT J AU Noseworthy, PA Weiner, R Kim, J Keelara, V Wang, F Berkstresser, B Wood, MJ Wang, TJ Picard, MH Hutter, AM Newton-Cheh, C Baggish, AL AF Noseworthy, Peter A. Weiner, Rory Kim, Jonathan Keelara, Varsha Wang, Francis Berkstresser, Brant Wood, Malissa J. Wang, Thomas J. Picard, Michael H. Hutter, Adolph M., Jr. Newton-Cheh, Christopher Baggish, Aaron L. TI Early Repolarization Pattern in Competitive Athletes Clinical Correlates and the Effects of Exercise Training SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE exercise; electrocardiography; electrophysiology ID VENTRICULAR-FIBRILLATION; ELECTROCARDIOGRAMS; ELEVATION; VARIANTS AB Background-Inferior lead early repolarization pattern (ERP) recently has been associated with sudden cardiac death. Although ERP is common among athletes, prevalence, ECG lead distribution, clinical characteristics, and effects of physical training remain uncertain. We sought to examine the nonanterior ERP in competitive athletes. Methods and Results-ERP was assessed in a cross-sectional cohort of collegiate athletes (n = 879). The relationship between ERP and cardiac structure were then examined in a longitudinal subgroup (n = 146) before and after a 90-day period of exercise training. ERP was defined as J-point elevation >= 0.1 mV in at least 2 leads within a nonanterior territory (inferior [II, III, aVF] or lateral territory [I, aVL, V4-V6]). Nonanterior ERP was present in 25.1% (221/879) of athletes, including the inferior subtype in 3.8% (33/879). Exercise training led to significant increases in the prevalence of ERP and the inferior subtype, but there were no associations between ERP and echocardiographic measures of left ventricular remodeling. In a multivariable model, ERP was associated with black race (odds ratio [OR], 5.84; 95% CI, 3.54 to 9.61; P < 0.001), increased QRS voltage (OR, 2.08; 95% CI, 1.71 to 2.52; P < 0.001), and slower heart rate (OR, 1.54; 95% CI, 1.26 to 1.87; P < 0.001). Conclusions-Nonanterior ERP, including the inferior subtype, is common and has strong clinical associations among competitive athletes. The finding of increased ERP prevalence after intense physical training establishes a strong association between exercise and ERP. (Circ Arrhythm Electrophysiol. 2011; 4: 432-440.) C1 [Baggish, Aaron L.] Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Performance Program, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Wang, Francis; Berkstresser, Brant; Baggish, Aaron L.] Harvard Univ, Hlth Serv, Cambridge, MA 02138 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Performance Program, Cardiovasc Res Ctr, Yawkey Suite 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org OI Picard, Michael/0000-0002-9264-3243 FU Max Schaldach Fellowship in Cardiac Pacing and Electrophysiology; National Institutes of Health, National Heart, Lung, and Blood Institute [HL080025]; Doris Duke Charitable Foundation; Burroughs Wellcome Fund; American Heart Association [09FTF2220328] FX This work was supported by the Max Schaldach Fellowship in Cardiac Pacing and Electrophysiology (to Dr Noseworthy); the National Institutes of Health, National Heart, Lung, and Blood Institute (HL080025 to Dr Newton-Cheh); the Doris Duke Charitable Foundation (to Dr Newton-Cheh); the Burroughs Wellcome Fund (to Dr Newton-Cheh); and the American Heart Association (09FTF2220328 to Dr Baggish). NR 29 TC 56 Z9 59 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD AUG PY 2011 VL 4 IS 4 BP 432 EP 440 DI 10.1161/CIRCEP.111.962852 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807LG UT WOS:000293898900013 PM 21543642 ER PT J AU Elayi, CS Whitbeck, MG Charnigo, R Shah, J Macaulay, TE Morales, G Gurley, JC Kakavand, B Thal, S Ching, CK Khaykin, Y Verma, A Barrett, C Bai, R Di Biase, L Patwardhan, A Moliterno, DJ Natale, A AF Elayi, Claude S. Whitbeck, Matthew G. Charnigo, Richard Shah, Jignesh Macaulay, Tracy E. Morales, Gustavo Gurley, John C. Kakavand, Bahram Thal, Sergio Ching, Chi Keong Khaykin, Yaariv Verma, Atul Barrett, Conor Bai, Rong Di Biase, Luigi Patwardhan, Abhijit Moliterno, David J. Natale, Andrea CA AFFIRM Study Investigators TI Is There an Association Between External Cardioversions and Long-Term Mortality and Morbidity? Insights From the Atrial Fibrillation Follow-Up Investigation of Rhythm Management Study SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE death; arrhythmia; atrial fibrillation; cardioversion; heart failure ID ACUTE PULMONARY-EDEMA; DEFIBRILLATOR SHOCKS; HEART-FAILURE; TRANSTHORACIC DEFIBRILLATION; MYOCARDIAL DYSFUNCTION; ARRHYTHMIAS; DIGOXIN; AFFIRM; IMPLANTATION; INFARCTION AB Background-Cardiac electric therapies effectively terminate tachyarrhythmias. Recent data suggest a possible increase in long-term mortality associated with implantable cardioverter-defibrillator shocks. Little is known about the association between external cardioversion episodes (ECVe) and long-term mortality. We sought to assess the safety of repeated ECVe with regard to cardiovascular mortality and morbidity. Methods and Results-We analyzed the data of the 4060 patients from the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial. In particular, associations of ECVe with all-cause mortality, cardiovascular mortality, and hospitalizations after ECVe were studied. Over an average follow-up of 3.5 years, 660 (16.3%) patients died, 331 (8.2%) from cardiovascular causes. A total of 207 (5.1%) and 1697 (41.8%) patients had low ejection fraction and nonparoxysmal atrial fibrillation, respectively; 2460 patients received no ECVe, whereas 1600 experienced >= 1 ECVe. Death occurred in 412 (16.7%), 196 (16.5%), 39 (13.5%), and 13 (10.4%) of patients with 0, 1, 2, and >= 3 ECVe, respectively. There was no significant association between ECVe and mortality within any of the 4 subgroups defined by ejection fraction and atrial fibrillation type, although myocardial infarction, coronary artery bypass graft, and digoxin were significantly associated with death (estimated hazard ratios, 1.65, 1.59, and 1.62, respectively; P<0.0001). ECVe were associated with increased cardiac hospitalization reported at the next follow-up visit (39.3% versus 5.8%; estimated odds ratio, 1.39; P<0.0001). Conclusions-In the AFFIRM study, there was no significant association between ECVe and long-term mortality, even though ECVe were associated with increased hospitalizations from cardiac causes. Digoxin, myocardial infarction, and coronary artery bypass graft were significantly associated with mortality. (Circ Arrhythm Electrophysiol. 2011; 4: 465-469.) C1 [Elayi, Claude S.; Whitbeck, Matthew G.; Charnigo, Richard; Shah, Jignesh; Macaulay, Tracy E.; Morales, Gustavo; Gurley, John C.; Kakavand, Bahram; Patwardhan, Abhijit; Moliterno, David J.] Univ Kentucky, Lexington, KY USA. [Thal, Sergio] Vet Adm Med Ctr, Tucson, AZ 85723 USA. [Ching, Chi Keong] Natl Heart Ctr Singapore, Singapore, Singapore. [Khaykin, Yaariv; Verma, Atul] Southlake Reg Hlth Ctr, Newmarket, ON, Canada. [Barrett, Conor] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Barrett, Conor] Harvard Univ, Sch Med, Boston, MA USA. [Bai, Rong; Di Biase, Luigi; Natale, Andrea] St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, Austin, TX USA. RP Elayi, CS (reprint author), Gill Heart Inst, 900 S Limestone St, Lexington, KY 40536 USA. EM samy-claude.elayi@uky.edu OI Di Biase, Luigi/0000-0001-6508-4047 NR 36 TC 11 Z9 12 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD AUG PY 2011 VL 4 IS 4 BP 465 EP 469 DI 10.1161/CIRCEP.110.960591 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807LG UT WOS:000293898900017 PM 21511994 ER PT J AU Wu, EQ Bensimon, AG Marynchenko, M Namjoshi, M Guo, A Yu, AP Ericson, SG Raje, N AF Wu, Eric Q. Bensimon, Arielle G. Marynchenko, Maryna Namjoshi, Madhav Guo, Amy Yu, Andrew P. Ericson, Solveig G. Raje, Noopur TI Comparison of Skeletal Complications and Treatment Patterns Associated With Early vs. Delayed Zoledronic Acid Therapy in Multiple Myeloma SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Article DE Medical chart review; Skeletal-related events; Treatment discontinuation ID PLACEBO-CONTROLLED TRIAL; LONG-TERM EFFICACY; DOUBLE-BLIND; BREAST-CANCER; PHASE-III; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; SOLID TUMORS; FOLLOW-UP; PAMIDRONATE AB Background: This study retrospectively compared the risks of skeletal-related events (SREs) and zoledronic acid (ZOL) treatment discontinuation associated with early vs. delayed ZOL therapy for patients with symptomatic multiple myeloma (MM). Patients and Methods: Data were collected from a physician-administered medical chart review among US patients with a confirmed diagnosis of symptomatic MM treated after 01/01/2002. Early and delayed ZOL therapy were defined, respectively, as initiating ZOL <= 60 days (N = 126) vs. <= 60 days (N = 186) after the first symptomatic MM diagnosis. Kaplan-Meier analysis with a log-rank test was performed to compare the risk of SREs between the cohorts. Cox proportional hazard modeling compared the risk of SREs associated with early vs. delayed ZOL treatment, controlling for demographic factors, stage of MM, bone health status, and presence of major comorbidities at diagnosis. Time to ZOL discontinuation was evaluated using the Kaplan-Meier method, following patients from the date of ZOL initiation. Results: Time to the first SRE was significantly longer for patients who received early treatment with ZOL (P = .005). At 2 years after diagnosis, the SRE-free rate was 74.6% vs. 56.5% in the early vs. delayed treatment group, respectively. Early ZOL therapy was associated with a significantly lower risk of any SRE (hazard rate [HR] = .625 vs. delayed ZOL therapy; P = .029). At 2 years from ZOL therapy initiation, rates of ZOL discontinuation were 9.6% vs. 16.4% among patients with early vs. delayed therapy, respectively (P < .05). Conclusion: Early treatment with ZOL was associated with significantly reduced risks of SREs and with better treatment persistence compared with delayed treatment. C1 [Wu, Eric Q.; Bensimon, Arielle G.; Marynchenko, Maryna; Yu, Andrew P.] Anal Grp Inc, Boston, MA 02199 USA. [Namjoshi, Madhav; Guo, Amy; Ericson, Solveig G.] Novartis Pharmaceut, Hlth Econ & Outcomes Res, E Hanover, NJ USA. [Raje, Noopur] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Marynchenko, M (reprint author), Anal Grp Inc, 111 Huntington Ave,10th Floor, Boston, MA 02199 USA. EM mmarynchenko@analysisgroup.com FU Novartis Pharmaceuticals Corporation FX Novartis Pharmaceuticals Corporation provided an unrestricted grant to Analysis Group, Inc to conduct this study. NR 27 TC 0 Z9 0 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD AUG PY 2011 VL 11 IS 4 BP 326 EP 335 DI 10.1016/j.clml.2011.04.004 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 805BA UT WOS:000293699900004 PM 21700528 ER PT J AU Alsan, MM Issa, NC Hammond, SP Milner, DA DeAngelo, DJ Baden, LR AF Alsan, Marcella M. Issa, Nicolas C. Hammond, Sarah P. Milner, Danny A., Jr. DeAngelo, Daniel J. Baden, Lindsey R. TI Candida albicans Cervical Lymphadenitis in Patients Who Have Acute Myeloid Leukemia SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Article DE Acute myeloid leukemia; Disseminated candidiasis; Lymphadenitis ID DIAGNOSIS AB We describe two patients with acute myelogenous leukemia who developed cervical lymphadenitis and chronic disseminated infection due to Candida albicans. Candida albicans infection should be considered in leukemic patients with acute lymphadenitis. Evaluation for visceral dissemination is warranted even in the absence of fungemia. C1 [Alsan, Marcella M.; Issa, Nicolas C.; Hammond, Sarah P.; Baden, Lindsey R.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Alsan, Marcella M.; Issa, Nicolas C.; Hammond, Sarah P.; Milner, Danny A., Jr.; DeAngelo, Daniel J.; Baden, Lindsey R.] Harvard Univ, Sch Med, Boston, MA USA. [DeAngelo, Daniel J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Milner, Danny A., Jr.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Issa, NC (reprint author), 75 Francis St, Boston, MA 02114 USA. EM nissa@partners.org FU NIAID NIH HHS [T32 AI007433] NR 10 TC 0 Z9 0 U1 0 U2 1 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD AUG PY 2011 VL 11 IS 4 BP 375 EP 377 DI 10.1016/j.clml.2011.06.002 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 805BA UT WOS:000293699900012 PM 21816377 ER PT J AU White, MB Lankarani-Fard, A AF White, Mary B. Lankarani-Fard, Azadeh TI What Is Your Diagnosis? SO CUTIS LA English DT Editorial Material ID CHRONIC ULCERS; DRUG-USERS C1 [White, Mary B.; Lankarani-Fard, Azadeh] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP White, MB (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 8 TC 0 Z9 0 U1 0 U2 1 PU QUADRANT HEALTHCOM INC PI PARSIPPANY PA 7 CENTURY DRIVE, STE 302, PARSIPPANY, NJ 07054-4603 USA SN 0011-4162 J9 CUTIS JI Cutis PD AUG PY 2011 VL 88 IS 2 BP 61 EP + PG 3 WC Dermatology SC Dermatology GA 810BI UT WOS:000294100000002 PM 21916270 ER PT J AU Vassy, JL Shrader, P Jonsson, A Fox, CS Lyssenko, V Isomaa, B Groop, L Meigs, JB Franks, PW AF Vassy, Jason L. Shrader, Peter Jonsson, Anna Fox, Caroline S. Lyssenko, Valeriya Isomaa, Bo Groop, Leif Meigs, James B. Franks, Paul W. TI Association between parental history of diabetes and type 2 diabetes genetic risk scores in the PPP-Botnia and Framingham Offspring Studies SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Type 2 diabetes mellitus; Genetic risk score; Family history ID SUSCEPTIBILITY LOCI; HEART-DISEASE; MELLITUS; PREDICTION AB Objective: Parental history of diabetes and specific gene variants are risk factors for type 2 diabetes, but the extent to which these factors are associated is unknown. Methods: We examined the association between parental history of diabetes and a type 2 diabetes genetic risk score (GRS) in two cohort studies from Finland (population-based PPP-Botnia study) and the US (family-based Framingham Offspring Study). Results: Mean (95% CI) GRS increased from 16.8 (16.8-16.9) to 16.9 (16.8-17.1) to 17.1 (16.8-17.4) among PPP-Botnia participants with 0, 1, and 2 parents with diabetes, respectively (p(trend) = 0.03). The trend was similar among Framingham Offspring but was not statistically significant (p = 0.07). The meta-analyzed p value for trend from the two studies was 0.005. Conclusions: The very modest associations reported above suggest that the increased risk of diabetes in offspring of parents with diabetes is largely the result of shared environmental/lifestyle factors and/or hitherto unknown genetic factors. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Vassy, Jason L.; Shrader, Peter; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Vassy, Jason L.; Fox, Caroline S.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Vassy, Jason L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Jonsson, Anna; Lyssenko, Valeriya; Groop, Leif] Lund Univ, Diabet & Endocrinol Unit, Dept Clin Sci, S-20502 Malmo, Sweden. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Isomaa, Bo] Folkhalsan Res Ctr, Pietarsaari 68660, Finland. [Isomaa, Bo] Dept Social Serv & Hlth Care, Pietarsaari 68601, Finland. [Groop, Leif] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Franks, Paul W.] Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, S-20502 Malmo, Sweden. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Franks, PW (reprint author), Lund Univ, Skane Univ Hosp UMAS, Dept Clin Sci, Genet & Mol Epidemiol Unit,Clin Res Ctr, Bldg 60,Entrance 72,Level 12, S-20502 Malmo, Sweden. EM Paul.Franks@med.lu.se OI Franks, Paul/0000-0002-0520-7604 FU Swedish Diabetes Association; Swedish Heart Lung-Foundation; Novo Nordisk; Knut and Alice Wallenberg Foundation; Pahlsson Foundation; Sigrid Juselius Foundation; Folkhalsan Research Foundation; Nordic Center of Excellence in Disease Genetics; EU; Signe and Ane Gyllenberg Foundation; Swedish Cultural Foundation in Finland; Finnish Diabetes Research Foundation; Foundation for Life and Health in Finland; Finnish Medical Society; Paavo Nurmi Foundation; Helsinki University Central Hospital Research Foundation; Perklen Foundation; Ollqvist Foundation; Narpes Health Care Foundation; Swedish Research Council; National Heart, Lung and Blood Institute's Framingham Heart Study [N01 HC 25195]; Affymetrix, Inc. [N02 HL 6 4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616, NIDDK K24 DK080140]; National Research Service [T32 HP12706] FX The PPP-Botnia study: we thank the study participants and the Botnia Study Group. We are also grateful for the technical assistance of the staff of the CRC in Malmo. This work was funded in part by grants from the Swedish Diabetes Association, Swedish Heart Lung-Foundation, Novo Nordisk, the Knut and Alice Wallenberg Foundation, the Pahlsson Foundation, the Sigrid Juselius Foundation, the Folkhalsan Research Foundation, the Nordic Center of Excellence in Disease Genetics, an EU grant (EXGENESIS), the Signe and Ane Gyllenberg Foundation, the Swedish Cultural Foundation in Finland, the Finnish Diabetes Research Foundation, the Foundation for Life and Health in Finland, the Finnish Medical Society, the Paavo Nurmi Foundation, Helsinki University Central Hospital Research Foundation, the Perklen Foundation, the Ollqvist Foundation and the Narpes Health Care Foundation. P.W.F. was supported in part by grants from the Swedish Research Council, Swedish Heart Lung-Foundation, Novo Nordisk, and the Swedish Diabetes Association.; Framingham Offspring Study: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract no. N01 HC 25195) and its contract with Affymetrix, Inc. for genotyping services (Contract no. N02 HL 6 4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Also supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616, NIDDK K24 DK080140 (J.B.M.) and a National Research Service Award grant T32 HP12706 (J.L.V.). NR 14 TC 8 Z9 8 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD AUG PY 2011 VL 93 IS 2 BP E76 EP E79 DI 10.1016/j.diabres.2011.04.013 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 806QQ UT WOS:000293825400007 PM 21570145 ER PT J AU Haase, A Rigosi, E Anfora, G Vinegoni, C Vallortigara, G Antolini, R AF Haase, Albrecht Rigosi, Elisa Anfora, Gianfranco Vinegoni, Claudio Vallortigara, Giorgio Antolini, Renzo TI In-vivo two-photon imaging of the honeybee antennal lobe SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Meeting Abstract CT 8th EBSA European Biophysics Congress CY AUG 23-27, 2011 CL Budapest, HUNGARY SP Hungarian Biophys Soc, European Biophys Soc Assoc C1 [Haase, Albrecht; Antolini, Renzo] Univ Trent, BIOtech Res Ctr, Mattarello, Italy. [Haase, Albrecht; Antolini, Renzo] Univ Trent, Dept Phys, Mattarello, Italy. [Rigosi, Elisa; Vallortigara, Giorgio] Univ Trent, CIMeC, Ctr Mind Brain Sci, Rovereto, TN, Italy. [Rigosi, Elisa; Anfora, Gianfranco] Fdn E Mach, IASMA Res & Innovat Ctr, San Michele All Adige, Italy. [Vallortigara, Giorgio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA USA. [Vallortigara, Giorgio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0175-7571 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD AUG PY 2011 VL 40 SU 1 BP 126 EP 126 PG 1 WC Biophysics SC Biophysics GA 804EO UT WOS:000293637300303 ER PT J AU Wood, KB AF Wood, Kirkham B. TI Expert's comment concerning Grand Rounds case entitled "Anterior, thoracoscopic-assisted reduction and stabilization of a thoracic burst fracture (T8) in a pregnant woman" (by Klaus John Schnake, Matti Scholz, Andreas Marx, Reinhard Hoffmann, Frank Kandziora) SO EUROPEAN SPINE JOURNAL LA English DT Article ID LUMBAR FRACTURES; FIXATION; SPINE; CLASSIFICATION; MANAGEMENT; PATIENT; INJURY; TRAUMA C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Wood, KB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St Yawkey OCC 3800, Boston, MA 02114 USA. EM kbwood@partners.org NR 14 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0940-6719 J9 EUR SPINE J JI Eur. Spine J. PD AUG PY 2011 VL 20 IS 8 BP 1222 EP 1224 DI 10.1007/s00586-011-1713-x PG 3 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 806BC UT WOS:000293774900002 PM 21404037 ER PT J AU Ananthakrishnan, AN Chan, AT AF Ananthakrishnan, Ashwin N. Chan, Andrew T. TI Missed polyps, missed opportunities SO GASTROINTESTINAL ENDOSCOPY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; COLORECTAL-CANCER; COLONOSCOPY; ADENOMAS; RETROFLEXION; CHROMOSCOPY; PROTECTION; RECURRENCE; MORTALITY; NEOPLASMS C1 [Ananthakrishnan, Ashwin N.; Chan, Andrew T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02215 USA. RP Ananthakrishnan, AN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02215 USA. FU NCI NIH HHS [R01 CA137178] NR 28 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD AUG PY 2011 VL 74 IS 2 BP 262 EP 265 DI 10.1016/j.gie.2011.05.019 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 808DB UT WOS:000293954600004 PM 21802584 ER PT J AU Choueiri, TK AF Choueiri, Toni K. TI Renal Cell Carcinoma Preface SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Editorial Material C1 [Choueiri, Toni K.] Brigham & Womens Hosp, Kidney Canc Ctr, Dana Farber Canc Inst, Boston, MA 02215 USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Choueiri, TK (reprint author), Brigham & Womens Hosp, Kidney Canc Ctr, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Toni_Choueiri@dfci.harvard.edu NR 0 TC 6 Z9 6 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD AUG PY 2011 VL 25 IS 4 BP XIII EP XIV DI 10.1016/j.hoc.2011.06.001 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 804NX UT WOS:000293661700001 PM 21763960 ER PT J AU Li, LJ Kaelin, WG AF Li, Lianjie Kaelin, William G., Jr. TI New Insights into the Biology of Renal Cell Carcinoma SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Renal cell carcinoma; Clear-cell renal carcinoma; Hypoxia-inducible factor; HIF-responsive gene products ID LINDAU TUMOR-SUPPRESSOR; HYPOXIA-INDUCIBLE FACTOR; GROWTH-FACTOR RECEPTOR; PHASE-III TRIAL; CANCER-CELLS; HEPATOCYTE GROWTH; PRIMARY CILIUM; MET PROTOONCOGENE; KIDNEY CANCER; UP-REGULATION AB Ninety percent or more of kidney cancers are believed to be of epithelial cell origin, and are referred to as renal cell carcinoma (RCC), which are further subdivided based on histology into clear-cell RCC (75%), papillary RCC (15%), chromophobe tumor (5%), and oncocytoma (5%). Some genes confer an increased risk of these various histologic RCC subtypes. In practice, there is some overlap among the histologic subtypes, and there are some shared molecular features among these tumor types. This review focuses primarily on the most common form of RCC, clear-cell renal carcinoma, noting some recent advances in the other histologic subtypes. C1 [Li, Lianjie; Kaelin, William G., Jr.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Li, Lianjie; Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Li, Lianjie; Kaelin, William G., Jr.] Brigham & Womens Hosp, Boston, MA 02215 USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Mayer Bldg,Room 457, Boston, MA 02215 USA. EM William_kaelin@dfci.harvard.edu FU Howard Hughes Medical Institute; NCI NIH HHS [R01 CA068490, P50 CA101942, R01 CA068490-16] NR 159 TC 33 Z9 34 U1 0 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD AUG PY 2011 VL 25 IS 4 BP 667 EP + DI 10.1016/j.hoc.2011.04.004 PG 21 WC Oncology; Hematology SC Oncology; Hematology GA 804NX UT WOS:000293661700003 PM 21763962 ER PT J AU Krajewski, KM Giardino, AA Zukotynski, K Van den Abbeele, AD Pedrosa, I AF Krajewski, Katherine M. Giardino, Angela A. Zukotynski, Katherine Van den Abbeele, Annick D. Pedrosa, Ivan TI Imaging in Renal Cell Carcinoma SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Imaging; Renal cell carcinoma; Management; Diagnosis ID POSITRON-EMISSION-TOMOGRAPHY; CONTRAST-ENHANCED CT; PROGRESSION-FREE SURVIVAL; PATHOLOGICAL CORRELATION; COMPUTED-TOMOGRAPHY; ANTIANGIOGENIC THERAPY; TARGETED THERAPIES; INTERFERON-ALPHA; RADIOFREQUENCY ABLATION; PERCUTANEOUS ABLATION AB Imaging plays a central role in the detection, diagnosis, staging, and follow-up of renal cell carcinoma (RCC). Most renal masses are incidentally detected with modern, high-resolution imaging techniques and a variety of management options exist for the renal masses encountered today. This article discusses the role of multiple imaging modalities in the diagnosis of RCC and the imaging features of specific pathologic subtypes and staging techniques. Future directions in RCC imaging are presented, including dynamic contrast-enhanced and unenhanced techniques, as well as the development of novel tracers for positron emission tomography. C1 [Krajewski, Katherine M.; Giardino, Angela A.; Zukotynski, Katherine; Van den Abbeele, Annick D.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA. [Krajewski, Katherine M.; Giardino, Angela A.; Zukotynski, Katherine; Van den Abbeele, Annick D.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. [Krajewski, Katherine M.; Giardino, Angela A.; Zukotynski, Katherine; Van den Abbeele, Annick D.; Pedrosa, Ivan] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Pedrosa, Ivan] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Krajewski, KM (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. EM kmkrajewski@partners.org NR 115 TC 11 Z9 11 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD AUG PY 2011 VL 25 IS 4 BP 687 EP + DI 10.1016/j.hoc.2011.04.005 PG 30 WC Oncology; Hematology SC Oncology; Hematology GA 804NX UT WOS:000293661700004 PM 21763963 ER PT J AU Chowdhury, S Matrana, MR Tsang, C Atkinson, B Choueiri, TK Tannir, NM AF Chowdhury, Simon Matrana, Marc R. Tsang, Christopher Atkinson, Bradley Choueiri, Toni K. Tannir, Nizar M. TI Systemic Therapy for Metastatic Non-Clear-Cell Renal Cell Carcinoma: Recent Progress and Future Directions SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Non-clear-cell renal cell carcinoma; Targeted therapy; Papillary; Chromophobe; Unclassified; Renal medullary carcinoma; Collecting duct carcinoma; Sarcomatoid dedifferentiation ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; COLLECTING DUCT CARCINOMA; FACTOR-TARGETED THERAPY; OF-THE-LITERATURE; PHASE-II TRIAL; MEDULLARY CARCINOMA; INTERFERON-ALPHA; ANTITUMOR-ACTIVITY; TRANSLOCATION CARCINOMAS AB Insights into the biology of clear-cell renal cell carcinoma (CCRCC) have identified multiple pathways associated with the pathogenesis and progression of this cancer. This progress has led to the development of multiple agents targeting these pathways, including the tyrosine kinase inhibitors sorafenib, sunitinib, and pazopanib, the monoclonal antibody bevacizumab, and the mTOR inhibitors temsirolimus and everolimus. With the exception of temsirolimus, phase 3 trials tested these agents in patients with clear-cell histology; therefore, their efficacy in non-CCRCC is unclear. To date, there is no established effective therapy for patients with advanced non-CCRCC. This article focuses on treatment options for metastatic non-CCRCC. C1 [Matrana, Marc R.; Atkinson, Bradley; Tannir, Nizar M.] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA. [Chowdhury, Simon; Tsang, Christopher] Guys Hosp, Dept Med Oncol, London SE1 9RT, England. [Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Tannir, NM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, 1515 Holcombe Blvd,Unit 1374, Houston, TX 77030 USA. EM ntannir@mdanderson.org FU NCI NIH HHS [P30 CA016672] NR 94 TC 15 Z9 15 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 EI 1558-1977 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD AUG PY 2011 VL 25 IS 4 BP 853 EP + DI 10.1016/j.hoc.2011.05.003 PG 19 WC Oncology; Hematology SC Oncology; Hematology GA 804NX UT WOS:000293661700012 PM 21763971 ER PT J AU Appleby, L Morrissey, S Bellmunt, J Rosenberg, J AF Appleby, Laurie Morrissey, Stephanie Bellmunt, Joaquim Rosenberg, Jonathan TI Management of Treatment-Related Toxicity with Targeted Therapies for Renal Cell Carcinoma: Evidence-Based Practice and Best Practices SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Renal cell carcinoma; Treatment-related toxicity; Evidence-based practice; Tyrosine kinase inhibitor; mTOR inhibitor ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE-KINASE INHIBITORS; JOINT NATIONAL COMMITTEE; CANCER-RELATED FATIGUE; HIGH BLOOD-PRESSURE; FOOT SKIN REACTION; PHASE-III TRIAL; INTERFERON-ALPHA; FACTOR RECEPTOR; INTRACEREBRAL HEMORRHAGE AB The advent of targeted agents for the treatment of advanced renal cell carcinoma has led to dramatic improvements in therapy. However, the chronic use of these medications has also led to the identification of new toxicities that require long-term management. Effective management of toxicity is needed to maximize the benefits of treatment and improve patients' quality of life. In addition, toxicity from these agents may affect treatment compliance, particularly with daily oral agents. This review delineates the toxicities that require monitoring, the underlying pathophysiology (when known), and treatments that may have benefits in relieving symptoms and side effects. C1 [Appleby, Laurie; Morrissey, Stephanie; Rosenberg, Jonathan] Harvard Univ, Lank Ctr Genitourinary Oncol, Dana Farber Canc Inst, Sch Med, Boston, MA 02215 USA. [Bellmunt, Joaquim] Hosp del Mar, Barcelona 08003, Spain. RP Rosenberg, J (reprint author), Harvard Univ, Lank Ctr Genitourinary Oncol, Dana Farber Canc Inst, Sch Med, 450 Brookline Ave,D1230, Boston, MA 02215 USA. EM jonathan_rosenberg@dfci.harvard.edu NR 96 TC 13 Z9 14 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD AUG PY 2011 VL 25 IS 4 BP 893 EP + DI 10.1016/j.hoc.2011.05.004 PG 24 WC Oncology; Hematology SC Oncology; Hematology GA 804NX UT WOS:000293661700014 PM 21763973 ER PT J AU Cho, DC Atkins, MB AF Cho, Daniel C. Atkins, Michael B. TI Future Directions in Renal Cell Carcinoma: 2011 and Beyond SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Renal cell carcinoma; Future directions; Therapeutic outcomes ID RANDOMIZED PHASE-II; HYPOXIA-INDUCIBLE FACTORS; CARBONIC-ANHYDRASE-IX; TUMOR-SUPPRESSOR GENE; INTERFERON-ALPHA; DOSE INTERLEUKIN-2; MAMMALIAN TARGET; HIF-ALPHA; VHL GENE; CANCER AB Emerging from a largely cytokine-based era, the last several years have witnessed a dramatic change in the therapeutic landscape of renal cancer. Molecularly targeted and antiangiogenic agents now form the backbone of most therapeutic strategies for patients with advanced renal cell carcinoma (RCC). Although the next few years may not see such broad paradigm shifts, there remains significant room for improvement in the care of patients with RCC. This review discusses challenges that face physicians and researchers as well as innovations that may contribute to improving the therapeutic outcomes for patients with RCC. C1 [Cho, Daniel C.; Atkins, Michael B.] Harvard Univ, Div Hematol Oncol, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Cho, Daniel C.; Atkins, Michael B.] Dana Farber Harvard Canc Ctr, Kidney Canc Program, Boston, MA 02215 USA. RP Cho, DC (reprint author), Harvard Univ, Div Hematol Oncol, Beth Israel Deaconess Med Ctr, Sch Med, 330 Brookline Ave, Boston, MA 02215 USA. EM dcho1@bidmc.harvard.edu FU National Cancer Institute [P50 CA101942] FX This work was partially supported by grant P50 CA101942 from the National Cancer Institute. Disclosures: DC has served as a consultant to Novartis and Genentech MBA- has served as a consultant to Pfizer, Genentech, BMS, Aveo, Bayer, Novartis and Prometheus. NR 92 TC 12 Z9 12 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD AUG PY 2011 VL 25 IS 4 BP 917 EP + DI 10.1016/j.hoc.2011.05.001 PG 20 WC Oncology; Hematology SC Oncology; Hematology GA 804NX UT WOS:000293661700015 PM 21763974 ER PT J AU Rahman, SH Maeder, ML Joung, JK Cathomen, T AF Rahman, Shamim H. Maeder, Morgan L. Joung, J. Keith Cathomen, Toni TI Zinc-Finger Nucleases for Somatic Gene Therapy: The Next Frontier SO HUMAN GENE THERAPY LA English DT Article ID DOUBLE-STRAND BREAKS; SEVERE COMBINED IMMUNODEFICIENCY; DEFICIENT LENTIVIRAL VECTORS; POOL ENGINEERING OPEN; HOMOLOGOUS RECOMBINATION; HOMING ENDONUCLEASE; IN-VIVO; ADENOASSOCIATED VIRUS; MAJOR DETERMINANT; MAMMALIAN-CELLS AB Zinc-finger nucleases (ZFNs) are a powerful tool that can be used to edit the human genome ad libitum. The technology has experienced remarkable development in the last few years with regard to both the target site specificity and the engineering platforms used to generate zinc-finger proteins. As a result, two phase I clinical trials aimed at knocking out the CCR5 receptor in T cells isolated from HIV patients to protect these lymphocytes from infection with the virus have been initiated. Moreover, ZFNs have been successfully employed to knockout or correct disease-related genes in human stem cells, including hematopoietic precursor cells and induced pluripotent stem cells. Targeted genome engineering approaches in multipotent and pluripotent stem cells hold great promise for future strategies geared toward correcting inborn mutations for personalized cell replacement therapies. This review describes how ZFNs have been applied to models of gene therapy, discusses the opportunities and the risks associated with this novel technology, and suggests future directions for their safe application in therapeutic genome engineering. C1 [Rahman, Shamim H.; Cathomen, Toni] Hannover Med Sch, Dept Expt Hematol, D-30625 Hannover, Germany. [Maeder, Morgan L.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Mol Pathol Unit, Charlestown, MA 02129 USA. [Maeder, Morgan L.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA. [Maeder, Morgan L.; Joung, J. Keith] Harvard Univ, Sch Med, Biol & Biomed Sci Program, Boston, MA 02115 USA. [Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cathomen, T (reprint author), Hannover Med Sch, Dept Expt Hematol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM cathomen.toni@mh-hannover.de OI Cathomen, Toni/0000-0002-7757-4630 FU German Research Foundation [SPP1230-Ca311/2, SFB/TR19-TP C5]; Federal Ministry of Education and Research [InTherGD-01GU0834, ReGene-01GN1003B]; European Commission [PERSIST-222878, HeMiBio-266777]; Mukoviszidose Institut gGmbH; National Institutes of Health (NIH) [DP1 OD006862, GM069906]; National Science Foundation FX We thank Celeste Pallant, Claudio Mussolino, Heimo Riedel, and Sylwia Bobis-Wozowicz for helpful discussions. T.C. is supported by the German Research Foundation (SPP1230-Ca311/2 and SFB/TR19-TP C5), the Federal Ministry of Education and Research (InTherGD-01GU0834 and ReGene-01GN1003B), the European Commission's 7th Framework Programme (PERSIST-222878 and HeMiBio-266777), and the Mukoviszidose Institut gGmbH. J.K.J. is supported by a National Institutes of Health (NIH) Director's Pioneer Award (DP1 OD006862) and by NIH R01 GM069906. M.L.M. is supported by a National Science Foundation Graduate Research Fellowship. NR 74 TC 36 Z9 36 U1 0 U2 19 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD AUG PY 2011 VL 22 IS 8 BP 925 EP 933 DI 10.1089/hum.2011.087 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 810GZ UT WOS:000294115100004 PM 21631241 ER PT J AU Park, JS Mehta, P Cooper, AA Veivers, D Heimbach, A Stiller, B Kubisch, C Fung, VS Krainc, D Mackay-Sim, A Sue, CM AF Park, Jin-Sung Mehta, Prachi Cooper, Antony A. Veivers, David Heimbach, Andre Stiller, Barbara Kubisch, Christian Fung, Victor S. Krainc, Dimitri Mackay-Sim, Alan Sue, Carolyn M. TI Pathogenic Effects of Novel Mutations in the P-Type ATPase ATP13A2 (PARK9) Causing Kufor-Rakeb Syndrome, a Form of Early-Onset Parkinsonism SO HUMAN MUTATION LA English DT Article DE Kufor-Rakeb syndrome; KRS; early-onset parkinsonism; ATP13A2; PARK9; proteasomal pathway; nonsense-mediated mRNA decay ID ALPHA-SYNUCLEIN; JUVENILE PARKINSONISM; ENDOPLASMIC-RETICULUM; OLFACTORY MUCOSA; DISEASE; CELLS; STRESS; NEURODEGENERATION; AUTOPHAGOSOMES; LYSOSOMES AB Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS. Hum Mutat 32:956-964, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Park, Jin-Sung; Mehta, Prachi; Veivers, David; Sue, Carolyn M.] Royal N Shore Hosp, Kolling Inst Med Res, Dept Neurogenet, St Leonards, NSW 2065, Australia. [Sue, Carolyn M.] Univ Sydney, Kolling Inst Med Res, St Leonards, NSW 2065, Australia. [Cooper, Antony A.] St Vincents Hosp, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia. [Cooper, Antony A.] Univ New S Wales, Darlinghurst, NSW, Australia. [Heimbach, Andre; Stiller, Barbara; Kubisch, Christian] Univ Cologne, Inst Human Genet, Ctr Mol Med Cologne, Cologne, Germany. [Kubisch, Christian] Univ Ulm, Inst Human Genet, Ulm, Germany. [Fung, Victor S.] Westmead Hosp, Dept Neurol, Westmead, NSW 2145, Australia. [Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,MassGen Inst Neurodegenerat, Charlestown, MA USA. [Mackay-Sim, Alan] Griffith Univ, Natl Adult Stem Cell Res Ctr, Eskitis Inst Cell & Mol Therapies, Sch Biomol & Phys Sci, Nathan, Qld 4111, Australia. RP Sue, CM (reprint author), Royal N Shore Hosp, Dept Neurol, St Leonards, NSW 2065, Australia. EM c.sue@usyd.edu.au RI Park, Jin-Sung/F-9867-2011; Kubisch, Christian/F-1893-2011; Mackay-Sim, Alan/C-3431-2008 OI Kubisch, Christian/0000-0003-4220-0978; Mackay-Sim, Alan/0000-0003-4446-5371 FU Australian Brain Foundation; Parkinsons NSW Association; Australian Department of Health and Aging; National Health and Medical Research Council of Australia [1010839]; Deutsche Forschungsgemeinschaft FX Contract grant sponsors: The Australian Brain Foundation; The Parkinsons NSW Association (to C. M. S.); The Australian Department of Health and Aging (to C. M. S. and A. M.); The National Health and Medical Research Council of Australia; Contract grant number: 1010839 (to C. M. S. and A. A. C.); Contract grant sponsor: The Deutsche Forschungsgemeinschaft (to C. K.). NR 33 TC 63 Z9 65 U1 2 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD AUG PY 2011 VL 32 IS 8 BP 956 EP 964 DI 10.1002/humu.21527 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 808EW UT WOS:000293961000013 PM 21542062 ER PT J AU Robinson, CM Seto, D Jones, MS Dyer, DW Chodosh, J AF Robinson, Christopher M. Seto, Donald Jones, Morris S. Dyer, David W. Chodosh, James TI Molecular evolution of human species D adenoviruses SO INFECTION GENETICS AND EVOLUTION LA English DT Review DE Human adenovirus; HAdV-D; Recombination ID ACUTE RESPIRATORY-DISEASE; TEMPERATURE-SENSITIVE MUTATIONS; USES SIALIC-ACID; EPIDEMIC KERATOCONJUNCTIVITIS; GENE-THERAPY; INTERMEDIATE STRAIN; CELLULAR RECEPTOR; MESSENGER-RNA; SUBGENUS-D; SUBGROUP-D AB Adenoviruses are medium-sized double stranded DNA viruses that infect vertebrates. Human adenoviruses cause an array of diseases. Currently there are 56 human adenovirus types recognized and characterized within seven species (A-G). Of those types, a majority belongs to species D. In this review, the genomic conservation and diversity are examined among human adenoviruses within species D, particularly in contrast to other human adenovirus species. Specifically, homologous recombination is presented as a driving force for the molecular evolution of human adenoviruses and the emergence of new adenovirus pathogens. (C) 2011 Elsevier B.V. All rights reserved. C1 [Robinson, Christopher M.; Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Seto, Donald] George Mason Univ, Dept Bioinformat & Computat Biol, Sch Syst Biol, Manassas, VA 20110 USA. [Jones, Morris S.] Calif Dept Publ Hlth, Viral & Rickettsial Dis Lab, Richmond, CA 94804 USA. [Robinson, Christopher M.; Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. RP Chodosh, J (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Lab,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu FU National Eye Institute [R01 EY01324, P30 EY014104]; Research to Prevent Blindness, Inc., NY, NY FX This work was supported by grants R01 EY01324 and P30 EY014104 from National Eye Institute, and an unrestricted grant to the Department of Ophthalmology, Harvard Medical School from Research to Prevent Blindness, Inc., NY, NY. NR 127 TC 36 Z9 40 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD AUG PY 2011 VL 11 IS 6 BP 1208 EP 1217 DI 10.1016/j.meegid.2011.04.031 PG 10 WC Infectious Diseases SC Infectious Diseases GA 806JV UT WOS:000293804600007 PM 21570490 ER PT J AU Gangaputra, S Almukhtar, T Glassman, AR Aiello, LP Bressler, N Bressler, SB Danis, RP Davis, MD AF Gangaputra, Sapna Almukhtar, Talat Glassman, Adam R. Aiello, Lloyd Paul Bressler, Neil Bressler, Susan B. Danis, Ronald P. Davis, Matthew D. CA Diabetic Retinopathy Clinical Res TI Comparison of Film and Digital Fundus Photographs in Eyes of Individuals with Diabetes Mellitus SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID MACULAR EDEMA; RETINOPATHY SEVERITY AB PURPOSE. To compare grading of diabetic retinopathy (DR) and diabetic macular edema (DME) from stereoscopic film versus stereoscopic digital photographs obtained from a subset of Diabetic Retinopathy Clinical Research Network (DRCR.net) participants. METHODS. In this photographic media comparison study, digital and film images were obtained at a single study visit from some of the subjects enrolled in active DRCR.net clinical study protocols. Digital camera systems and digital and film photographers were certified to obtain images according to standard procedures. Images were graded for DR severity and DME in a masked fashion by Fundus Photograph Reading Center (Madison, WI) graders. Agreement between gradings was assessed by calculating the percentage of agreement and kappa statistics. RESULTS. Images obtained with both film and digital media were submitted for 155 eyes of 96 study participants. On a nine-step Early Treatment Diabetic Retinopathy study DR severity scale, grading agreed exactly in 74%, and was within one step of agreement in 93%, with a weighted kappa statistic of 0.82 (95% confidence interval [CI], 0.71-0.92). On a nine-step DME severity scale and three-step clinically significant macular edema (CSME) scale, grading agreed exactly in 39% and 88%, respectively, and within one step in 70% and 92% (weighted kappa statistic, 0.44 [95% Cl, 0.34-0.54] and 0.72 [95% Cl, 0.55-0.90], respectively). CONCLUSIONS. Among clinical sites participating in the DRCR. net, agreement between film and digital images was substantial to almost perfect for DR severity level and moderate to substantial for DME and CSME severity levels, respectively. Replacement of film fundus images with digital images for DR severity level should not adversely affect clinical trial quality. (ClinicalTrials.gov numbers, NCT00367133, NCT00369486, NCT00444600, NCT00445003, NCT00709319.) (Invest Ophthalmol Vis Sci. 2011; 52: 6168-6173) DOI:10.1167/iovs.11-7321 C1 [Almukhtar, Talat; Glassman, Adam R.] Jaeb Ctr Hlth Res Inc, Tampa, FL 33647 USA. [Gangaputra, Sapna; Danis, Ronald P.; Davis, Matthew D.] Univ Wisconsin, Fundus Photograph Reading Ctr, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Aiello, Lloyd Paul] Harvard Univ, Sch Med, Joslin Diabet Ctr, Eye Res Sect,Dept Ophthalmol, Boston, MA 02115 USA. [Aiello, Lloyd Paul] Harvard Univ, Sch Med, Beetham Eye Inst, Boston, MA USA. [Bressler, Neil; Bressler, Susan B.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. RP Almukhtar, T (reprint author), Jaeb Ctr Hlth Res Inc, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM drcrstat6@jaeb.org RI Symons, Robert/C-2040-2017 OI Symons, Robert/0000-0002-8104-881X FU National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services [EY14231, EY018817, EY14229] FX Supported by a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services Grants EY14231, EY018817, and EY14229. NR 16 TC 13 Z9 13 U1 0 U2 6 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2011 VL 52 IS 9 BP 6168 EP 6173 DI 10.1167/iovs.11-7321 PG 6 WC Ophthalmology SC Ophthalmology GA 806XC UT WOS:000293849400016 PM 21571677 ER PT J AU Ciolino, JB Hudson, SP Mobbs, AN Hoare, TR Iwata, NG Fink, GR Kohane, DS AF Ciolino, Joseph B. Hudson, Sarah P. Mobbs, Ashley N. Hoare, Todd R. Iwata, Naomi G. Fink, Gerald R. Kohane, Daniel S. TI A Prototype Antifungal Contact Lens SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID FUNGAL KERATITIS; DRUG-DELIVERY; MANAGEMENT; FUSARIUM; SUSCEPTIBILITY; GANCICLOVIR; TEMPERATURE; ECONAZOLE; OUTBREAK AB PURPOSE. To design a contact lens to treat and prevent fungal ocular infections. METHODS. Curved contact lenses were created by encapsulating econazole-impregnated poly(lactic-co-glycolic) acid (PLGA) films in poly(hydroxyethyl methacrylate) (pHEMA) by ultraviolet photopolymerization. Release studies were conducted in phosphate-buffered saline at 37 degrees C with continuous shaking. The contact lenses and their release media were tested in an antifungal assay against Candida albicans. Cross sections of the pre- and postrelease contact lenses were characterized by scanning electron microscopy and by Raman spectroscopy. RESULTS. Econazole-eluting contact lenses provided extended antifungal activity against Candida albicans fungi. Fungicidal activity varied in duration and effectiveness depending on the mass of the econazole-PLGA film encapsulated in the contact lens. CONCLUSIONS. An econazole-eluting contact lens could be used as a treatment for fungal ocular infections. (Invest Ophthalmol Vis Sci. 2011;52:6286-6291) DOI:10.1167/iovs.10-6935 C1 [Ciolino, Joseph B.; Kohane, Daniel S.] Harvard Univ, Lab Biomat & Drug Delivery, Dept Anesthesiol, Div Crit Care Med,Childrens Hosp,Sch Med, Boston, MA 02115 USA. [Ciolino, Joseph B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Childrens Hosp,Sch Med, Boston, MA 02115 USA. [Hudson, Sarah P.; Mobbs, Ashley N.; Hoare, Todd R.; Iwata, Naomi G.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Fink, Gerald R.] MIT, Whitehead Inst, Cambridge, MA 02139 USA. [Hudson, Sarah P.] Univ Limerick, Mat & Surface Sci Inst, Limerick, Ireland. [Hoare, Todd R.] McMaster Univ, Dept Chem Engn, Hamilton, ON L8S 4L7, Canada. [Iwata, Naomi G.] Wellesley Coll, Wellesley, MA 02181 USA. RP Kohane, DS (reprint author), Harvard Univ, Lab Biomat & Drug Delivery, Dept Anesthesiol, Div Crit Care Med,Childrens Hosp,Sch Med, Boston, MA 02115 USA. EM daniel.kohane@childrens.harvard.edu FU National Eye Institute (NEI) [1K08EY019686-01]; NIGMS [GM073626, MCOIF-CT2007-040150]; NSERC (National Sciences and Engineering Research Council) [EB-00351, GM035010, GM40266]; CIMIT/J&J Young Investigator Award FX Supported by National Eye Institute (NEI) Grant 1K08EY019686-01 (JBC), NIGMS GM073626 (DSK), MCOIF-CT2007-040150 (SPH), an NSERC (National Sciences and Engineering Research Council) PDF Fellowship (TRH), EB-00351 (RL), GM035010 (GRF), GM40266 (GRF), and a CIMIT/J&J Young Investigator Award (DSK). NR 38 TC 20 Z9 22 U1 3 U2 20 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2011 VL 52 IS 9 BP 6286 EP 6291 DI 10.1167/iovs.10-6935 PG 6 WC Ophthalmology SC Ophthalmology GA 806XC UT WOS:000293849400032 PM 21527380 ER PT J AU Johri, AM Picard, MH Newell, J Marshall, JE King, MEE Hung, J AF Johri, Amer M. Picard, Michael H. Newell, John Marshall, Jane E. King, Mary Etta E. Hung, Judy TI Can a Teaching Intervention Reduce Interobserver Variability in LVEF Assessment A Quality Control Exercise in the Echocardiography Lab SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE 2-dimensional transthoracic echocardiography; quality control; teaching ID SOCIETY-OF-ECHOCARDIOGRAPHY; STANDARDS COMMITTEE; RECOMMENDATIONS; GUIDELINES AB OBJECTIVES This study sought to determine whether a formalized teaching intervention could reduce the interobserver variability (IOV) in visual estimation of left ventricular ejection fraction (LVEF) within a group of sonographers and physicians with a spectrum of experience. BACKGROUND Precise and reliable echocardiographic assessment of LVEF is necessary for clinical decision-making and minimizing duplicative testing. Skill in the visual estimation of LVEF varies depending on experience and is critical for corroborating EF quantification. IOV may also lead to inconsistency if multiple readers are assessing the EF on serial exams. METHODS Fourteen cases of 2-dimensional echocardiograms were shown to 25 participants who estimated the EF based on a complete assessment of LV wall motion including parasternal, short-axis, apical, and subcostal views. The cases represented a spectrum of EF range, image quality, and clinical context. Following the initial interpretations, participants underwent a teaching intervention involving tutorial review of reference cases and group discussion of each case with determination of the EF guided by quantitative measure (biplane Simpson method). Three months after the teaching intervention, 14 new cases were shown to the 25 participants following the same methodology. RESULTS IOV was quantified before and after the teaching intervention with the use of a 3-factor, nested analysis of variance. The factors were: observer, patient, and pre- and post-intervention (time). The analysis of variance showed that the intervention reduced the IOV for the 25 readers between the pre- and post-intervention assessments (F = 2.8, p = 0.007). The IOV decreased from +/- 14% EF prior to intervention to +/- 8.4% EF following intervention (a 40% reduction in IOV). CONCLUSIONS In a large echocardiography laboratory with a wide range of training levels and experience, a simple, formalized teaching intervention can successfully diminish IOV of LVEF assessment. This intervention provides not only discrete quality measures, but also serves as a practical tool to document and improve quality of reporting, potentially reducing clinical inefficiencies and repeat testing. (J Am Coll Cardiol Img 2011;4:821-9) (C) 2011 by the American College of Cardiology Foundation C1 [Johri, Amer M.; Picard, Michael H.; Newell, John; Marshall, Jane E.; King, Mary Etta E.; Hung, Judy] Harvard Univ, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Cardiol Div,Med Sch, Boston, MA 02114 USA. RP Hung, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Cardiol Div,Med Sch, Blake 256,55 Fruit St, Boston, MA 02114 USA. EM jhung@partners.org OI Picard, Michael/0000-0002-9264-3243 NR 9 TC 30 Z9 31 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD AUG PY 2011 VL 4 IS 8 BP 821 EP 829 DI 10.1016/j.jcmg.2011.06.004 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 808CG UT WOS:000293951100001 PM 21835373 ER PT J AU Techasith, T Cury, RC AF Techasith, Tust Cury, Ricardo C. TI Stress Myocardial CT Perfusion An Update and Future Perspective SO JACC-CARDIOVASCULAR IMAGING LA English DT Review DE cardiac CT; myocardial perfusion; pharmacologic stress ID CORONARY-ARTERY-DISEASE; MULTIDETECTOR COMPUTED-TOMOGRAPHY; OPTIMAL MEDICAL THERAPY; IN-STENT RESTENOSIS; DUAL-SOURCE CT; ADENOSINE STRESS; COMPREHENSIVE ASSESSMENT; DIAGNOSTIC PERFORMANCE; NONINVASIVE ASSESSMENT; DIPYRIDAMOLE STRESS AB Coronary computed tomography angiography (CTA) has been shown by several multicenter trials to have excellent diagnostic accuracy in the detection and exclusion of significant coronary stenosis. However, a major limitation of coronary CTA is that the physiological significance of stenotic lesions identified is often unknown. Stress myocardial computed tomography perfusion (CTP) is a novel examination that provides both anatomic and physiological information (i.e., myocardial perfusion). Multiple single-center studies have established the feasibility of stress myocardial CTP. Furthermore, it has been illustrated that a combined CTA/CTP protocol improves the diagnostic accuracy to detect hemodynamic significant stenosis as compared with CTA alone; this combined protocol can also be accomplished at a radiation dose comparable to nuclear myocardial perfusion imaging exams. Although initial results hold some promise, stress myocardial CTP is a modality in its infancy. Further research is required to define, validate, and optimize this new technique. However, it is a modality with significant potential, particularly in the evaluation of chest pain patients, given the advantages of short exam time and comprehensive data acquisition. This review highlights how to perform and interpret stress myocardial CTP, summarizes the current literature, and discusses some future directions. (J Am Coll Cardiol Img 2011;4:905-16) (C) 2011 by the American College of Cardiology Foundation C1 [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Miami, FL 33176 USA. [Cury, Ricardo C.] Baptist Hosp Miami, Miami, FL USA. [Techasith, Tust] Harvard Univ, Sch Med, Boston, MA USA. [Techasith, Tust] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. RP Cury, RC (reprint author), Baptist Cardiac & Vasc Inst, 8900 N Kendall Dr, Miami, FL 33176 USA. EM rcury@baptisthealth.net FU Astellas Pharma; GE Healthcare FX Mr. Techasith has reported that he has no relationships relevant to the contents of this paper to disclose. Dr. Cury receives research grants from Astellas Pharma, and GE Healthcare. NR 47 TC 51 Z9 51 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD AUG PY 2011 VL 4 IS 8 BP 905 EP 916 DI 10.1016/j.jcmg.2011.04.017 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 808CG UT WOS:000293951100012 PM 21835384 ER PT J AU Januzzi, JL AF Januzzi, James L., Jr. TI Use of Biomarkers to "Guide" Care in Chronic Heart Failure: What Have We Learned (So Far)? SO JOURNAL OF CARDIAC FAILURE LA English DT Editorial Material ID THERAPY; BNP; MANAGEMENT; IMPROVE; PROBNP; HF C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5984, Boston, MA 02114 USA. EM JJanuzzi@partners.org NR 14 TC 9 Z9 9 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 BP 622 EP 625 DI 10.1016/j.cardfail.2011.06.373 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YJ UT WOS:000293938600002 PM 21807322 ER PT J AU Deswal, A Richardson, P Bozkurt, B Mann, DL AF Deswal, Anita Richardson, Peter Bozkurt, Biykem Mann, Douglas L. TI Results of the Randomized Aldosterone Antagonism in Heart Failure With Preserved Ejection Fraction Trial (RAAM-PEF) SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Diastolic heart failure; diastolic function; exercise testing; treatment ID LEFT-VENTRICULAR DYSFUNCTION; 6-MINUTE WALK TEST; MYOCARDIAL FIBROSIS; DIASTOLIC FUNCTION; ESSENTIAL-HYPERTENSION; SERUM CONCENTRATIONS; COLLAGEN TURNOVER; SYSTOLIC FUNCTION; EPLERENONE; DISEASE AB Background: Cardiac fibrosis is a major determinant of myocardial stiffness, diastolic dysfunction, and heart failure (HF). By reducing cardiac fibrosis, aldosterone antagonists have the potential to be beneficial in heart failure with preserved ejection fraction (HFpEF). Methods and Results: In a randomized, double-blind, placebo-controlled trial of 44 patients with HFpEF, we examined the effects of eplerenone, an aldosterone antagonist, on changes in 6-minute walk distance (primary end point), diastolic function, and biomarkers of collagen turnover (secondary end points). All patients had a history of hypertension, 61% were diabetic, and 52% had prior HF hospitalization. After 6 months of treatment, similar improvements in 6 minute walk distance were noted in the eplerenone and placebo groups (P = .91). However, compared with placebo, eplerenone was associated with a significant reduction in serum markers of collagen turnover (procollagen type I aminoterminal peptide, P = .009 and carboxy-terminal telopeptide of collagen type I, P = .026) and improvement in echocardiographic measures of diastolic function (E/E', P = .01). Conclusions: Although eplerenone was not associated with an improvement in exercise capacity compared to placebo, it was associated with significant reduction in markers of collagen turnover and improvement in diastolic function. Whether these favorable effects will translate into morbidity and mortality benefit in HFpEF remains to be determined. (J Cardiac Fail 2011;17:634-642) C1 [Deswal, Anita; Bozkurt, Biykem] Michael E DeBakey VA Med Ctr, Winters Ctr Heart Failure Res, Cardiol Sect, Houston, TX USA. [Deswal, Anita; Richardson, Peter] Michael E DeBakey VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. [Mann, Douglas L.] Washington Univ, Sch Med, Div Cardiol, St Louis, MO USA. RP Deswal, A (reprint author), Michael E DeBakey VA Med Ctr 111B, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM adeswal@bcm.tmc.edu OI Mann, Douglas /0000-0002-2516-0145 FU VA Clinical Research Service [CLIN-010-03S] FX Supported by a VA Clinical Research Service grant # CLIN-010-03S (to Dr. Deswal). NR 34 TC 63 Z9 64 U1 0 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 BP 634 EP 642 DI 10.1016/j.cardfail.2011.04.007 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YJ UT WOS:000293938600004 PM 21807324 ER PT J AU Whellan, DJ Zhao, X Hernandez, AF Liang, L Peterson, ED Bhatt, DL Heidenreich, PA Schwamm, LH Fonarow, GC AF Whellan, David J. Zhao, Xin Hernandez, Adrian F. Liang, Li Peterson, Eric D. Bhatt, Deepak L. Heidenreich, Paul A. Schwamm, Lee H. Fonarow, Gregg C. TI Predictors of Hospital Length of Stay in Heart Failure: Findings from Get With the Guidelines SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Heart failure; risk factors; length of stay; morbidity; registries ID MEDICARE BENEFICIARIES; PHYSICIAN SPECIALTY; RISK SCORE; OUTCOMES; CARE; ASSOCIATION; MORTALITY; PROGRAM; READMISSION; ADMISSION AB Background: This study was undertaken to identify predictors of hospital length of stay (LOS) for heart failure (HF) patients using clinical variables available at the time of admission and hospital characteristics. Methods and Results: A cohort of 70,094 HF patients discharged to home from 246 hospitals participating in the Get With The Guidelines Heart Failure was analyzed for admission predictors for LOS. The analysis incorporated patient characteristics (PC) first, then added hospital characteristics (HC) followed by standard laboratory evaluations (SL), including troponin and brain natriuretic peptide (BNP). There were 31,995 patients (45.6%) with LOS < 4 days, 26,750 (38.2%) with LOS 4 to 7 days, and 11,349 (16.2%) with LOS > 7 days. Patients with longer LOS had more comorbidities and a higher severity of disease on admission. Overall models explained a modest amount of LOS variation, with an r(2) of 4.8%, with PC responsible for 1.3% of variation and together with SL explained 2.2% of variation. HC did not change the variation. Conclusions: Based on admission vital signs and BNP levels, patients with longer LOS have more comorbidities and a higher disease seventy. The ability to risk stratify for LOS based on patient admission and hospital characteristics is limited. (J Cardiac Fail 2011;17:649-656) C1 [Whellan, David J.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Zhao, Xin; Hernandez, Adrian F.; Liang, Li; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Heidenreich, Paul A.] VA Palo Alto Healthcare Syst, Palo Alto, CA USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Los Angeles, CA USA. RP Whellan, DJ (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Chestnut St,Suite 317, Philadelphia, PA 19107 USA. EM david.whellan@jefferson.edu RI Hernandez, Adrian F./A-7818-2016 OI Heidenreich, Paul/0000-0001-7730-8490; Schwamm, Lee/0000-0003-0592-9145; Hernandez, Adrian F./0000-0003-3387-9616 FU Medtronic; Ortho-McNeil; American Heart Association Pharmaceutical Roundtable; GlaxoSmithKline; Merck; Abbott Laboratories; Johnson Johnson; Forrest Research; NHLBI; Proventys; Astra Zeneca; Bristol-Myers Squibb; Eisai; Ethicon; Heartscape; Sanofi Aventis; Medicines Company FX The Get With The Guidelines Heart Failure (GWTG-HF) program is provided by the American Heart Association. The GWTG-HF program is currently supported in part by Medtronic, Ortho-McNeil, and the American Heart Association Pharmaceutical Roundtable. GWTG-HF has been funded in the past through support from GlaxoSmithKline.; Dr. Whellan receives research grants from Merck, Abbott Laboratories, Johnson & Johnson, Forrest Research, Medtronic, and NHLBI; consulting for Medtronic, Affymax. Dr. Hernandez receives research funding from Johnson & Johnson and Proventys. Dr. Peterson is the AHA GWTG Data Analysis Co-PI. Dr. Bhatt receives research grants from Astra Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, The Medicines Company. Dr. Fonarow received research funding from the NHLBI, consulting for Novartis and Scios, and honorarium from Medtronic. NR 26 TC 18 Z9 18 U1 0 U2 5 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 BP 649 EP 656 DI 10.1016/j.cardfail.2011.04.005 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YJ UT WOS:000293938600006 PM 21807326 ER PT J AU Fitzgerald, AA Powers, JD Ho, PM Maddox, TM Peterson, PN Allen, LA Masoudi, FA Magid, DJ Havranek, EP AF Fitzgerald, Ashley A. Powers, J. David Ho, P. Michael Maddox, Thomas M. Peterson, Pamela N. Allen, Larry A. Masoudi, Frederick A. Magid, David J. Havranek, Edward P. TI Impact of Medication Nonadherence on Hospitalizations and Mortality in Heart Failure SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Heart failure; medication nonadherence; outcomes ID EVIDENCE-BASED PHARMACOTHERAPY; MYOCARDIAL-INFARCTION; PHARMACY RECORDS; OLDER PATIENTS; ADHERENCE; OUTCOMES; THERAPY; HYPERTENSION; PREDICTORS; SURVIVAL AB Background: Limited literature exists on the association between medication adherence and outcomes among patients with heart failure. Methods and Results: We conducted a retrospective longitudinal cohort study of 557 patients with heart failure with reduced ejection fraction (HFrEF) (defined by EF <50%) in a large health maintenance organization. We used multivariable Cox proportional hazards models to assess the relationship between adherence (with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and aldosterone antagonists) and the primary outcome of all-cause mortality plus cardiovascular hospitalizations. Mean follow-up time was 1.1 years. Nonadherence (defined as <80% adherence) was associated with a statistically significant increase in the primary outcome in the cohort overall (hazard ratio 2.07, 95% confidence interval 1.62-2.64; P < .0001). This association remained significant when all 3 classes of heart failure medications and the components of the composite end point were considered separately and when the adherence threshold was varied to 70% or 90%. Conclusions: Medication nonadherence was associated with an increased risk of all-cause mortality and cardiovascular hospitalizations in a community heart failure population. Further research is needed to define systems of care that optimize adherence among patients with heart failure. (J Cardiac Fail 2011; 17:664-669) C1 [Fitzgerald, Ashley A.; Ho, P. Michael; Maddox, Thomas M.] Denver VA Med Ctr, Div Cardiol, Denver, CO USA. [Fitzgerald, Ashley A.; Ho, P. Michael; Maddox, Thomas M.; Peterson, Pamela N.; Allen, Larry A.; Masoudi, Frederick A.; Havranek, Edward P.] Univ Colorado Denver, Sch Med, Div Cardiol, Denver, CO USA. [Powers, J. David; Ho, P. Michael; Peterson, Pamela N.; Masoudi, Frederick A.; Magid, David J.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Peterson, Pamela N.; Masoudi, Frederick A.; Havranek, Edward P.] Denver Hlth Med Ctr, Div Cardiol, Denver, CO USA. RP Fitzgerald, AA (reprint author), Univ Colorado Denver, Div Cardiol, 12631 E 17th Ave,Campus Box B-130, Aurora, CO 80045 USA. EM ashley.fitzgerald@ucdenver.edu NR 33 TC 57 Z9 57 U1 0 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 BP 664 EP 669 DI 10.1016/j.cardfail.2011.04.011 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YJ UT WOS:000293938600008 PM 21807328 ER PT J AU Allsup, K Zavin, A Joseph, J Arena, R Vokonas, P Lecker, S Lazzari, L Schulze, PC Forman, DE AF Allsup, K. Zavin, A. Joseph, J. Arena, R. Vokonas, P. Lecker, S. Lazzari, L. Schulze, P. C. Forman, D. E. TI Strength and Aerobic Capacities Both Contribute to Functional Decline in Heart Failure SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract C1 [Allsup, K.; Zavin, A.; Joseph, J.; Vokonas, P.; Lecker, S.; Lazzari, L.; Forman, D. E.] VA Boston Healthcare Syst, Boston, MA USA. [Joseph, J.; Lecker, S.; Forman, D. E.] Harvard Univ, Sch Med, Boston, MA USA. [Vokonas, P.; Lazzari, L.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Arena, R.] Univ New Mexico, Albuquerque, NM 87131 USA. [Schulze, P. C.] Columbia Univ, Med Ctr, New York, NY USA. RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 NR 0 TC 0 Z9 0 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 SU 1 BP S17 EP S17 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YK UT WOS:000293938700055 ER PT J AU Bhardwaj, A Rehman, SU Mohammed, AA Kim, HN Barajas, L Barajas, J Moore, SA Sullivan, D Januzzi, JL AF Bhardwaj, Anju Rehman, Shafiq U. Mohammed, Asim A. Kim, Han-na Barajas, Linda Barajas, Justine Moore, Stephanie A. Sullivan, Dorothy Januzzi, James L. TI NT-proBNP Guided Therapy Improves the Quality of Life in Patients with Chronic Heart Failure. Results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy Study SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract C1 [Bhardwaj, Anju; Rehman, Shafiq U.; Mohammed, Asim A.; Kim, Han-na; Barajas, Linda; Barajas, Justine; Moore, Stephanie A.; Sullivan, Dorothy; Januzzi, James L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 SU 1 BP S94 EP S95 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YK UT WOS:000293938700302 ER PT J AU de Boer, RA van Veldhuisen, DJ DeFilippi, C Muntendam, P Adourian, AS Guo, Y Januzzi, JL AF de Boer, Rudolf A. van Veldhuisen, Dirk J. deFilippi, Christopher Muntendam, Pieter Adourian, Aram S. Guo, Yu Januzzi, James L. TI Plasma Galectin-3 Is Associated with Near-Term Rehospitalization in Heart Failure: A Meta-Analysis SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 15th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 18-21, 2011 CL Boston, MA SP Heart Failure Soc Amer C1 [de Boer, Rudolf A.; van Veldhuisen, Dirk J.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [deFilippi, Christopher] Univ Maryland, Div Cardiol, Baltimore, MD 21201 USA. [Muntendam, Pieter; Adourian, Aram S.; Guo, Yu] BG Med Inc, Waltham, MA USA. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RI van Veldhuisen, Dirk Jan/E-8967-2014 NR 0 TC 5 Z9 5 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 SU 1 BP S93 EP S93 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YK UT WOS:000293938700296 ER PT J AU Jones, ML Chokshi, A Collado, JE Layton, A Armstrong, HF Forman, DE Bartels, M Mancini, D Schulze, PC AF Jones, Meaghan L. Chokshi, Aalap Collado, J. Elias Layton, Aimee Armstrong, Hilary F. Forman, Daniel E. Bartels, Matthew Mancini, Donna Schulze, P. Christian TI Impairment of Muscle Fiber Recruitment and Decreased Total Muscle Work Capacity during Isokinetic Exercise in Patients with Advanced Heart Failure SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract C1 [Jones, Meaghan L.; Chokshi, Aalap; Collado, J. Elias; Layton, Aimee; Armstrong, Hilary F.; Bartels, Matthew; Mancini, Donna; Schulze, P. Christian] Columbia Univ, New York, NY USA. [Forman, Daniel E.] VA Boston Hlth Care Syst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 SU 1 BP S60 EP S60 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YK UT WOS:000293938700194 ER PT J AU Rasmusson, K Horne, B Brunisholz, K Januzzi, J Alharethi, R Budge, D Galenko, O Stehlik, J Carlquist, J Connollly, J Frampton, S Moore, S Kfoury, A AF Rasmusson, Kismet Horne, Benjamin Brunisholz, Kim Januzzi, James Alharethi, Rami Budge, Deborah Galenko, Oxana Stehlik, Josef Carlquist, John Connollly, Jenny Frampton, Stacey Moore, Stephanie Kfoury, Abdallah TI Association of Soluble ST2, an Emerging Biomarker of Heart Failure, with Peripartum Cardiomyopathy SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract C1 [Rasmusson, Kismet; Horne, Benjamin; Brunisholz, Kim; Alharethi, Rami; Budge, Deborah; Galenko, Oxana; Carlquist, John; Connollly, Jenny; Frampton, Stacey; Kfoury, Abdallah] Intermt Med Ctr, Heart Failure Prevent & Treatment Program, Salt Lake City, UT USA. [Januzzi, James; Moore, Stephanie] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stehlik, Josef] Univ Utah, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 SU 1 BP S85 EP S85 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YK UT WOS:000293938700273 ER PT J AU Zavin, A Allsup, K Gagnon, DR Arena, R Joseph, J Lazzari, A Schulze, PC Lecker, S Davis, S Forman, DE AF Zavin, A. Allsup, K. Gagnon, D. R. Arena, R. Joseph, J. Lazzari, A. Schulze, P. C. Lecker, S. Davis, S. Forman, D. E. TI Lean Mass as an Indicator of Muscle Strength in Patients with Heart Failure SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract C1 [Zavin, A.; Allsup, K.; Joseph, J.; Lazzari, A.; Davis, S.; Forman, D. E.] VA Boston Healthcare Syst, Boston, MA USA. [Joseph, J.; Lecker, S.; Forman, D. E.] Harvard Univ, Sch Med, Boston, MA USA. [Lazzari, A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Arena, R.] Univ New Mexico, Albuquerque, NM 87131 USA. [Schulze, P. C.] Columbia Univ, Med Ctr, New York, NY USA. [Gagnon, D. R.] Boston Univ, SPH, Boston, MA 02215 USA. [Gagnon, D. R.] VA Cooperat Studies Program, Boston, MA USA. RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 SU 1 BP S14 EP S15 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YK UT WOS:000293938700046 ER PT J AU Zavin, A Allsup, K Gagnon, DR Arena, R Davis, S Joseph, J Lecker, S Lazzari, A Schulze, PC Forman, DE AF Zavin, A. Allsup, K. Gagnon, D. R. Arena, R. Davis, S. Joseph, J. Lecker, S. Lazzari, A. Schulze, P. C. Forman, D. E. TI Fat Measurement and Functional Characteristics in Heart Failure Patients SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract C1 [Zavin, A.; Allsup, K.; Davis, S.; Joseph, J.; Lazzari, A.; Forman, D. E.] VA Boston Healthcare Syst, Boston, MA USA. [Joseph, J.; Lecker, S.; Forman, D. E.] Harvard Univ, Sch Med, Boston, MA USA. [Lazzari, A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Arena, R.] Univ New Mexico, Albuquerque, NM 87131 USA. [Schulze, P. C.] Columbia Univ, Med Ctr, New York, NY USA. [Gagnon, D. R.] Boston Univ, SPH, Boston, MA 02215 USA. [Gagnon, D. R.] VA Cooperat Studies Program, Boston, MA USA. RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2011 VL 17 IS 8 SU 1 BP S9 EP S9 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 807YK UT WOS:000293938700025 ER PT J AU Diaz-Gomez, JL Seigel, T Schmidt, U Pino, RM Bittner, EA AF Diaz-Gomez, Jose L. Seigel, Todd Schmidt, Ulrich Pino, Richard M. Bittner, Edward A. TI Acute hypopituitarism in a pregnant patient after cardiac gunshot injury SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Editorial Material DE Antepartum pituitary infarction; Hypopituitarism; Sheehan's syndrome ID ADRENAL INSUFFICIENCY; DIABETES-MELLITUS; SHEEHANS-SYNDROME; DISEASE; COCAINE; HORMONE; HEART AB Sheehan's syndrome is a well described entity that refers to hypopituitarism with pituitary infarction secondary to postpartum shock or hemorrhage. Antepartum pituitary infarction is a very rare condition that has been reported only in patients with longstanding type 1 diabetes mellitus or uncontrolled gestational diabetes. A case of severe, acute hypopituitarism in the setting of hemorrhagic shock from a gunshot wound is presented. Our case report highlights the importance of including hypopituitarism in the differential diagnosis of a critically ill parturient. (C) 2011 Elsevier Inc. All rights reserved. C1 [Diaz-Gomez, Jose L.; Seigel, Todd; Schmidt, Ulrich; Pino, Richard M.; Bittner, Edward A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Schmidt, Ulrich; Pino, Richard M.; Bittner, Edward A.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. RP Bittner, EA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, White 434A, Boston, MA 02114 USA. EM ebittner@partners.org NR 26 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 J9 J CLIN ANESTH JI J. Clin. Anesth. PD AUG PY 2011 VL 23 IS 5 BP 414 EP 417 DI 10.1016/j.jclinane.2010.09.009 PG 4 WC Anesthesiology SC Anesthesiology GA 807YX UT WOS:000293940000013 PM 21741812 ER PT J AU Goldfarb, JW Bittner, EA George, E Welch, C Schmidt, U AF Goldfarb, Jeremy W. Bittner, Edward A. George, Edward Welch, Charles Schmidt, Ulrich TI Successful management of a morbidly obese patient for electroconvulsive therapy with elective tracheostomy (vol 23, pg 241, 2011) SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Correction C1 [Goldfarb, Jeremy W.; Bittner, Edward A.; George, Edward; Welch, Charles; Schmidt, Ulrich] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goldfarb, Jeremy W.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Goldfarb, JW (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 J9 J CLIN ANESTH JI J. Clin. Anesth. PD AUG PY 2011 VL 23 IS 5 BP 433 EP 433 DI 10.1016/j.jclinane.2011.06.001 PG 1 WC Anesthesiology SC Anesthesiology GA 807YX UT WOS:000293940000020 ER PT J AU Reusch, JEB Wang, CCL AF Reusch, Jane E. B. Wang, Cecilia C. Low TI Cardiovascular Disease in Diabetes: Where Does Glucose Fit In? SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID CORONARY-HEART-DISEASE; SMOOTH-MUSCLE-CELLS; AORTIC ENDOTHELIAL-CELLS; RISK-FACTOR; MYOCARDIAL-INFARCTION; SEVERE HYPOGLYCEMIA; ARTERY-DISEASE; FOLLOW-UP; EPIDEMIOLOGIC ANALYSIS; GLYCATED HEMOGLOBIN AB Context: Recent prospective clinical trials have failed to confirm a unique benefit from normalization of glycemia on cardiovascular disease outcomes, despite evidence from basic vascular biology, epidemiological, and cohort studies. Evidence Acquisition: The literature was searched using the http://www.ncbi.nlm.nih.gov search engine including over 20 million citations on MEDLINE (1970 to present). Keyword searches included: atherosclerosis, cardiovascular, and glucose. Epidemiological, cohort, and interventional data on cardiovascular disease outcomes and glycemic control were reviewed along with analysis of recent reviews on this topic. Evidence Synthesis: High glucose activates a proatherogenic phenotype in all cell types in the vessel wall including endothelial cells, vascular smooth muscle cells, inflammatory cells, fibroblasts, and platelets, leading to a feedforward atherogenic response. Epidemiological and Cohort Studies: Epidemiological and cohort evidence indicates a clear and consistent correlation of glycemia with cardiovascular disease. A recent report of over 25,000 subjects with diabetes in the Swedish National Diabetes Registry verifies this relationship in contemporary practice. Interventional Studies: Prospective randomized interventions targeting a hemoglobin A1c of 6-6.5% for cardiovascular disease prevention failed to consistently decrease cardiovascular events or all-cause mortality. Conclusions: Basic vascular biology data plus epidemiological and cohort evidence would predict that glucose control should impact cardiovascular events. Prospective clinical trials demonstrate that current strategies that improve blood glucose do not achieve this goal but suggest that a period of optimal control may confer long-term cardiovascular disease benefit. Clinicians should target a hemoglobin A1c of 7% for the prevention of microvascular complications, individualized to avoid hypoglycemia. (J Clin Endocrinol Metab 96: 2367-2376, 2011) C1 [Reusch, Jane E. B.] Denver VA Med Ctr, Denver, CO 80220 USA. Univ Colorado, Aurora, CO 80045 USA. RP Reusch, JEB (reprint author), Denver VA Med Ctr, Room 9C120B,Mailstop 111-H,1055 Clermont St, Denver, CO 80220 USA. EM jane.reusch@ucdenver.edu FU Veterans Administration Office of Research and Development; Career Development Award-2; National Institutes of Health [DK64741, HL56481, UL1 RR025780] FX This work was supported by Veterans Administration Office of Research and Development in the form of a Merit Award (to J.E.B.R.), by a Career Development Award-2 (to C.C.L.W.), and by the National Institutes of Health (Grants DK64741, HL56481, and UL1 RR025780 to J.E.B.R. and Grant UL1 RR025780 to C.C.L.W.). NR 69 TC 28 Z9 29 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2011 VL 96 IS 8 BP 2367 EP 2376 DI 10.1210/jc.2010-3011 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 802MT UT WOS:000293516400034 PM 21593112 ER PT J AU Shaw, ND Gill, S Lavoie, HB Marsh, EE Hall, JE AF Shaw, Natalie D. Gill, Sabrina Lavoie, Helene B. Marsh, Erica E. Hall, Janet E. TI Persistence of Sleep-Associated Decrease in GnRH Pulse Frequency in the Absence of Gonadal Steroids SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; EARLY FOLLICULAR PHASE; HYPOTHALAMIC-PITUITARY AXIS; LUTEINIZING-HORMONE; MENSTRUAL-CYCLE; POSTMENOPAUSAL WOMEN; ENERGY AVAILABILITY; LH PULSATILITY; SECRETION; PROGESTERONE AB Context: There is dramatic slowing of GnRH pulse frequency during sleep in the early follicular phase of the menstrual cycle, but it is unknown whether this represents a primary effect of sleep or is dependent upon the sex steroid environment. Objectives: Our objective was to determine 1) whether sleep affects GnRH pulse frequency in postmenopausal women (PMW) in whom gonadal hormones are low and 2) whether this relationship changes with aging. Design and Setting: Studies were performed in the Clinical Research Center of an academic medical center. Subjects: Subjects included healthy PMW, 45-55 (n = 8) and 70-80 (n = 6) years old. Interventions: Subjects were studied during one night of polysomnographic-recorded sleep and one night of monitored wake during which blood was sampled every 5 min for 8 h. Main Outcome Measures: Pulsatile secretion of free alpha-subunit (FAS), a marker of GnRH secretion, was assessed. Results: There were no differences in sleep macroarchitecture or sleep efficiency [75 +/- 12% (mean +/- SD)] between older and younger PMW. The FAS interpulse interval was longer during sleep than nighttime wake in all women (60.5 +/- 4.3 vs. 52.0 +/- 2.8 min, P = 0.03) with a similar effect in the two groups. FAS pulse amplitude did not differ between sleep and wake periods (474.8 +/- 36.7 vs. 478.2 +/- 36.5 ng/liter, P = 0.9). Conclusions: Sleep is associated with a significant decline in GnRH pulse frequency in both older and younger PMW. Its persistence in PMW reinforces the important connection between sleep and GnRH secretion. (J Clin Endocrinol Metab 96: 2590-2595, 2011) C1 [Shaw, Natalie D.; Gill, Sabrina; Lavoie, Helene B.; Marsh, Erica E.; Hall, Janet E.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Shaw, Natalie D.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Hall, JE (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, BHX-5,55 Fruit St, Boston, MA 02114 USA. EM jehall@partners.org OI Shaw, Natalie/0000-0002-0847-9170 FU National Institutes of Health (NIH) [R01 AG13241, M01 RR1066, 5T32 HD007396]; British Columbia Endocrine Research Foundation; Parke-Davis (currently Pfizer); Samuel R. McLaughlin Foundation; Royal College of Physicians of Canada; Ferring Pharmaceuticals; Harvard Clinical and Translational Science Center [UL1 RR025758]; Harvard University, academic health care centers FX This work was supported by National Institutes of Health (NIH) Grants R01 AG13241 and M01 RR1066. S. G. received fellowship support from the British Columbia Endocrine Research Foundation and Parke-Davis (currently Pfizer). H. B. L. received fellowship support from the Samuel R. McLaughlin Foundation, the Royal College of Physicians of Canada (Detweiler Award), and Ferring Pharmaceuticals. N.D.S. received fellowship support from the NIH (5T32 HD007396) and from the Scholars in Clinical Science program of Harvard Catalyst [The Harvard Clinical and Translational Science Center (Award UL1 RR025758) and financial contributions from Harvard University and its affiliated academic health care centers]. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the NIH. NR 39 TC 2 Z9 2 U1 0 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2011 VL 96 IS 8 BP 2590 EP 2595 DI 10.1210/jc.2011-1188 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 802MT UT WOS:000293516400062 PM 21646369 ER PT J AU Chaponis, D Barnes, JW Dellagatta, JL Kesari, S Fast, E Sauvageot, C Panagrahy, D Greene, ER Ramakrishna, N Wen, PY Kung, AL Stiles, C Kieran, MW AF Chaponis, Deviney Barnes, Jessica W. Dellagatta, Jamie L. Kesari, Santosh Fast, Eva Sauvageot, Claire Panagrahy, Dipak Greene, Emily R. Ramakrishna, Naren Wen, Patrick Y. Kung, Andrew L. Stiles, Charles Kieran, Mark W. TI Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Ras; Farnesyltransferase inhibitor; Radiation therapy; Orthotopic glioma; Temozolomide; Stem cell ID ACTIVATED PROTEIN-KINASE; GROWTH-FACTOR RECEPTOR; FARNESYLTRANSFERASE INHIBITOR SCH-66336; TUMOR-CELL LINES; PHASE-I TRIAL; HUMAN GLIOBLASTOMA; BRAIN-TUMORS; STEM-CELLS; TRANSFERASE INHIBITORS; GUANOSINE TRIPHOSPHATE AB Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors. We now report the in vitro and orthotopic in vivo results of combination therapy using radiation, temozolomide and lonafarnib (SCH66336), an oral farnesyl transferase inhibitor, in a murine model of glioblastoma. We examined the viability, proliferation, farnesylation of H-Ras, and activation of downstream signaling of combination-treated U87 cells in vitro. Lonafarnib alone or in combination with radiation and temozolomide had limited tumor cell cytotoxicity in vitro although it did demonstrate significant inhibition in tumor cell proliferation. In vivo, lonafarnib alone had a modest ability to inhibit orthotopic U87 tumors, radiation and temozolomide demonstrated better inhibition, while significant anti-tumor activity was found with concurrent lonafarnib, radiation, and temozolomide, with the majority of animals demonstrating a decrease in tumor volume. The use of tumor neurospheres derived from freshly resected adult human glioblastoma tissue was relatively resistant to both temozolomide and radiation therapy. Lonafarnib had a significant inhibitory activity against these neurospheres and could potentate the activity of temozolomide and radiation. These data support the continued research of high grade glioma treatment combinations of farnesyl transferase inhibitors, temozolomide, and radiation therapy. C1 [Chaponis, Deviney; Barnes, Jessica W.; Dellagatta, Jamie L.; Panagrahy, Dipak; Greene, Emily R.; Kung, Andrew L.; Kieran, Mark W.] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Chaponis, Deviney; Barnes, Jessica W.; Dellagatta, Jamie L.; Panagrahy, Dipak; Greene, Emily R.; Kung, Andrew L.; Kieran, Mark W.] Dana Farber Canc Inst, Childrens Hosp Boston, Boston, MA 02115 USA. [Ramakrishna, Naren] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Kesari, Santosh; Fast, Eva; Wen, Patrick Y.] Dana Farber Canc Inst, Dept Adult Neurooncol, Boston, MA 02115 USA. [Sauvageot, Claire; Stiles, Charles] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Chaponis, Deviney; Barnes, Jessica W.; Panagrahy, Dipak; Greene, Emily R.; Kieran, Mark W.] Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Ramakrishna, Naren] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Kieran, MW (reprint author), Dana Farber Canc Inst, Dept Pediat Hematol Oncol, 44 Binney St,Room SW 331, Boston, MA 02115 USA. EM mark_kieran@dfci.harvard.edu RI Kesari, Santosh/E-8461-2013; OI Kieran, Mark/0000-0003-2184-7692; Kung, Andrew/0000-0002-9091-488X FU Stop & Shop Family Pediatric Brain Tumor Fund; C.J. Buckley Fund; Kyle Johnson Fund; Pediatric Low-Grade Astrocytoma Foundation; Solomon and Marlene Finvarb Brain Tumor Research Fund; Brudnick Foundation; NIH [K08 (SK: K08CA124804)]; Sontag Foundation FX Funding was provided by the Stop & Shop Family Pediatric Brain Tumor Fund, the C.J. Buckley Fund (J.W.B., D.C., D.P., E.R.G., M.W.K.), the Kyle Johnson Fund (J.W.B., M. W. K.), the Pediatric Low-Grade Astrocytoma Foundation (C.S., M.W.K.), the Solomon and Marlene Finvarb Brain Tumor Research Fund (P.Y.W., C.S.), the Brudnick Foundation (N.R.), by NIH K08 (SK: K08CA124804) and by Sontag Foundation Distinguished Scientist Award (SK). NR 53 TC 9 Z9 10 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG PY 2011 VL 104 IS 1 BP 179 EP 189 DI 10.1007/s11060-010-0502-4 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 804IS UT WOS:000293648100017 PM 21246394 ER PT J AU Young, GS Macklin, EA Setayesh, K Lawson, JD Wen, PY Norden, AD Drappatz, J Kesari, S AF Young, Geoffrey S. Macklin, Eric A. Setayesh, Kian Lawson, Joshua D. Wen, Patrick Y. Norden, Andrew D. Drappatz, Jan Kesari, Santosh TI Longitudinal MRI evidence for decreased survival among periventricular glioblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE SVZ; Glioblastoma; Stem cell; Outcome; MRI ID PROGNOSTIC-SIGNIFICANCE; MALIGNANT GLIOMAS; MULTIFORME; RESECTION; REGIONS; ORIGIN; ADULTS AB While the prognosis of patients with glioblastoma (GBM) remains poor despite recent therapeutic advances, variable survival times suggest wide variation in tumor biology and an opportunity for stratified intervention. We used volumetric analysis and morphometrics to measure the spatial relationship between subventricular zone (SVZ) proximity and survival in a cohort of 39 newly diagnosed GBM patients. We collected T2-weighted and gadolinium-enhanced T1-weighted magnetic resonance images (MRI) at pre-operative, post-operative, pre-radiation therapy, and post-radiation therapy time points, measured tumor volumes and distances to the SVZ, and collected clinical data. Univariate and multivariate Cox regression showed that tumors involving the SVZ and tumor growth rate during radiation therapy were independent predictors of shorter progression-free and overall survival. These results suggest that GBMs in close proximity to the ependymal surface of the ventricles convey a worse prognosis-an observation that may be useful for stratifying treatment. C1 [Young, Geoffrey S.; Setayesh, Kian] Brigham & Womens Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02115 USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Wen, Patrick Y.; Norden, Andrew D.; Drappatz, Jan] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Wen, Patrick Y.; Norden, Andrew D.; Drappatz, Jan] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Young, Geoffrey S.; Macklin, Eric A.; Wen, Patrick Y.; Norden, Andrew D.; Drappatz, Jan] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Lawson, Joshua D.; Kesari, Santosh] Univ Calif San Diego, Moores UCSD Canc Ctr, Dept Neurosci, La Jolla, CA 92093 USA. RP Young, GS (reprint author), Brigham & Womens Hosp, Dept Radiol, Div Neuroradiol, 75 Francis St, Boston, MA 02115 USA. EM gsyoung@partners.org; skesari@ucsd.edu RI Macklin, Eric/E-2955-2013; Kesari, Santosh/E-8461-2013 OI Macklin, Eric/0000-0003-1618-3502; NR 17 TC 18 Z9 18 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG PY 2011 VL 104 IS 1 BP 261 EP 269 DI 10.1007/s11060-010-0477-1 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 804IS UT WOS:000293648100027 PM 21132516 ER PT J AU Lu-Emerson, C Norden, AD Drappatz, J Quant, EC Beroukhim, R Ciampa, AS Doherty, LM LaFrankie, DC Ruland, S Wen, PY AF Lu-Emerson, C. Norden, A. D. Drappatz, J. Quant, E. C. Beroukhim, R. Ciampa, A. S. Doherty, L. M. LaFrankie, D. C. Ruland, S. Wen, P. Y. TI Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE High grade glioma; Glioblastoma; Bevacizumab failure; Dasatinib; PDGFR beta inhibitor; SRC inhibitor ID PROGRESSION-FREE SURVIVAL; BLOOD-BRAIN-BARRIER; PHASE-II; ANTIANGIOGENIC THERAPY; MALIGNANT GLIOMAS; PDGF-B; ANAPLASTIC ASTROCYTOMA; PERICYTE RECRUITMENT; TUMOR VASCULATURE; RESISTANCE AB There is no effective treatment for recurrent glioblastoma (GBM) after bevacizumab failure. Putative mechanisms of resistance to bevacizumab include increased pericyte coverage, mediated partly by platelet-derived growth factor receptor (PDGFR) signaling, and an infiltrative tumor growth pattern potentially dependent on SRC. We explored the efficacy of dasatinib, a SRC, BCR-ABL, c-KIT, EPHA2, and PDGFR beta inhibitor, in patients with recurrent GBM after bevacizumab failure. Adult patients with histologically confirmed GBM who failed bevacizumab therapy were treated with dasatinib 70-100 mg twice daily in combination with bevacizumab (n = 14), until tumor progression or unacceptable toxicity. Fourteen patients were treated. Median age was 55 years (range 32-66) and median KPS was 80 (range 50-90). All patients (100%) had glioblastomas. The median number of prior regimens was 4 (range from 2 to 6). Of the thirteen evaluable patients, none had a complete or partial response. Only one patient had stable disease after an 8 week interval. Median progression-free survival (PFS) was 28 days (95% confidence interval [CI] 26-35 days). Six month progression-free survival (PFS6) was 0%. Median overall survival (OS) was 78 days (95% CI 41-137 days). Treatment was moderately well-tolerated, although one patient sustained a grade 4 intracerebral hemorrhage. Dasatinib in conjunction with bevacizumab does not appear to have activity in patients with recurrent, heavily pretreated GBM. C1 [Lu-Emerson, C.; Norden, A. D.; Drappatz, J.; Quant, E. C.; Beroukhim, R.; Ciampa, A. S.; Doherty, L. M.; LaFrankie, D. C.; Ruland, S.; Wen, P. Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [Lu-Emerson, C.; Norden, A. D.; Drappatz, J.; Quant, E. C.; Wen, P. Y.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Neurooncol,Dept Neurol, Boston, MA 02115 USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, 44 Binney St,SW 430, Boston, MA 02115 USA. EM pwen@partners.org NR 47 TC 36 Z9 37 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG PY 2011 VL 104 IS 1 BP 287 EP 291 DI 10.1007/s11060-010-0489-x PG 5 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 804IS UT WOS:000293648100030 PM 21153679 ER PT J AU Chou, R Atlas, SJ Loeser, JD Rosenquist, RW Stanos, SP AF Chou, Roger Atlas, Steven J. Loeser, John D. Rosenquist, Richard W. Stanos, Steven P. TI Guideline Warfare Over Interventional Therapies for Low Back Pain: Can We Raise the Level of Discourse? SO JOURNAL OF PAIN LA English DT Article DE Guidelines; evidence-based medicine; systematic reviews; low back pain; interventional therapies ID RANDOMIZED CONTROLLED-TRIALS; CAUDAL EPIDURAL INJECTIONS; CLINICAL-PRACTICE GUIDELINES; FACET JOINT DENERVATION; DOUBLE-BLIND TRIAL; RADIOFREQUENCY DENERVATION; SYSTEMATIC REVIEWS; OF-INTEREST; QUALITY; MANAGEMENT AB As guidelines proliferate and are used to inform efforts to improve the quality and efficiency of care, disputes over guideline recommendations are likely to become more common and contentious. It is appropriate for guidelines to come under close scrutiny, given their important clinical and policy implications, and critiques that point out missing evidence, improper methods, or errors in interpretation can be valuable. But for critiques to be valid, they should be based on accurate information and a sound scientific basis. A 2009 guideline sponsored by the American Pain Society (APS) on the use of invasive tests and interventional procedures found insufficient evidence to make recommendations for most interventional procedures. It was subsequently the subject of lengthy critiques by the American Society of Interventional Pain Physicians (ASIPP) that sought to challenge the methods used to develop the APS guideline, point out alleged errors in the evidence review commissioned to inform the guideline, and question the integrity of the APS guideline process. We show that the ASIPP critiques contain numerous errors and fail to adhere to scientific standards for reviewing evidence, and provide suggestions on how future disputes regarding guidelines might be addressed in a more constructive manner. Perspective: In order to best serve patients and clinicians, debates over guidelines should be based on accurate information, adhere to current methodological standards, acknowledge important deficiencies in the evidence when they are present, and handle conflicts of interest in a vigorous and transparent manner. (C) 2011 by the American Pain Society C1 [Chou, Roger] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Chou, Roger] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97201 USA. [Atlas, Steven J.] Massachusetts Gen Hosp, Med Serv, Div Gen Med, Boston, MA USA. [Atlas, Steven J.] Harvard Univ, Sch Med, Boston, MA USA. [Loeser, John D.] Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA 98195 USA. [Rosenquist, Richard W.] Univ Iowa, Sch Med, Dept Anesthesiol, Iowa City, IA 52242 USA. [Stanos, Steven P.] Northwestern Univ, Sch Med, Dept Phys Med & Rehabil, Chicago, IL USA. RP Chou, R (reprint author), 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM chour@ohsu.edu FU Medtronic FX John Loeser has received research funding from Medtronic. The other authors have no conflict of interests to report. NR 53 TC 50 Z9 51 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD AUG PY 2011 VL 12 IS 8 BP 833 EP 839 DI 10.1016/j.jpain.2011.04.012 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 807YN UT WOS:000293939000001 PM 21742563 ER PT J AU Wang, WX Gaurav, D Wen, L Ye, MF Sun, QR Liu, WJ Zhang, D AF Wang, Wen-xian Gaurav, Desai Wen, Li Ye, Ming-fu Sun, Qing-rong Liu, Wei-jin Zhang, Dong TI Pediatric esophageal leiomyosarcoma: a case report SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE Leiomyosarcoma; Esophageal; Computed tomography, Pediatric ID METASTASIS AB Esophageal leiomyosarcoma accounts for only 0.5% of all esophageal tumors. This rare tumor has been reported in middle-aged or elderly patients. In contrast, pediatric esophageal leiomyosarcomas have never been reported. The case described herein is the first report of an esophageal leiomyosarcoma in a pediatric patient with its own characteristics. The patient had symptoms of mild cough without dysphagia. The lesion grew rapidly and reached dimensions of 7.0 cm x 5.0 cm x 6.0 cm in a 3-month period. On computed tomography scan of the chest, the mass exhibited mild enhancement after injection of a contrast agent. More evident enhancement was found on the 3-minute delayed enhanced computed tomography scan. A Phemister operation (transthoracic esophagectomy and esophagogastrostomy) was performed on the patient. The patient did not receive adjuvant postoperative radiotherapy or chemotherapy. He has been followed for 3 years and is free of disease. (C) 2011 Elsevier Inc. All rights reserved. C1 [Wang, Wen-xian; Wen, Li; Sun, Qing-rong; Liu, Wei-jin; Zhang, Dong] Third Mil Med Univ, XinQiao Hosp, Dept Radiol, Chongqing 400037, Peoples R China. [Gaurav, Desai] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Ye, Ming-fu] Third Mil Med Univ, XinQiao Hosp, Dept Pathol, Chongqing 400037, Peoples R China. RP Zhang, D (reprint author), Third Mil Med Univ, XinQiao Hosp, Dept Radiol, Chongqing 400037, Peoples R China. EM hszhangd@163.com NR 14 TC 2 Z9 2 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD AUG PY 2011 VL 46 IS 8 BP 1646 EP 1650 DI 10.1016/j.jpedsurg.2011.04.003 PG 5 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 808BZ UT WOS:000293950100037 PM 21843737 ER PT J AU McLean, CP Asnaani, A Litz, BT Hofmann, SG AF McLean, Carmen P. Asnaani, Anu Litz, Brett T. Hofmann, Stefan G. TI Gender differences in anxiety disorders: Prevalence, course of illness, comorbidity and burden of illness SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Sex; Gender; Anxiety; Prevalence; Comorbidity ID POSTTRAUMATIC-STRESS-DISORDER; OBSESSIVE-COMPULSIVE DISORDER; COLLABORATIVE PSYCHIATRIC EPIDEMIOLOGY; NATIONALLY REPRESENTATIVE SAMPLE; PANIC DISORDER; SURVEY REPLICATION; MENTAL-HEALTH; UNITED-STATES; SEX-DIFFERENCES; SOCIAL PHOBIA AB Women have consistently higher prevalence rates of anxiety disorders, but less is known about how gender affects age of onset, chronicity, comorbidity, and burden of illness. Gender differences in DSM-IV anxiety disorders were examined in a large sample of adults (N = 20,013) in the United States using data from the Collaborative Psychiatric Epidemiology Studies (CPES). The lifetime and 12-month male:female prevalence ratios of any anxiety disorder were 1:1.7 and 1:1.79, respectively. Women had higher rates of lifetime diagnosis for each of the anxiety disorders examined, except for social anxiety disorder which showed no gender difference in prevalence. No gender differences were observed in the age of onset and chronicity of the illness. However, women with a lifetime diagnosis of an anxiety disorder were more likely than men to also be diagnosed with another anxiety disorder, bulimia nervosa, and major depressive disorder. Furthermore, anxiety disorders were associated with a greater illness burden in women than in men, particularly among European American women and to some extend also among Hispanic women. These results suggest that anxiety disorders are not only more prevalent but also more disabling in women than in men. (C) 2011 Elsevier Ltd. All rights reserved. C1 [McLean, Carmen P.; Litz, Brett T.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Asnaani, Anu; Litz, Brett T.; Hofmann, Stefan G.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. RP McLean, CP (reprint author), Univ Penn, Ctr Treatment & Study Anxiety, 3535 Market St,6th Floor, Philadelphia, PA 19104 USA. EM mcleanca@mail.med.upenn.edu RI Hofmann, Stefan/B-8769-2014 OI Hofmann, Stefan/0000-0002-3548-9681 FU NIMH NIH HHS [R01 MH078308, R01 MH078308-04] NR 83 TC 200 Z9 203 U1 14 U2 71 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD AUG PY 2011 VL 45 IS 8 BP 1027 EP 1035 DI 10.1016/j.jpsychires.2011.03.006 PG 9 WC Psychiatry SC Psychiatry GA 807YM UT WOS:000293938900005 PM 21439576 ER PT J AU Liu, HY Potter, MP Woodworth, KY Yorks, DM Petty, CR Wozniak, JR Faraone, SV Biederman, J AF Liu, Howard Y. Potter, Mona P. Woodworth, K. Yvonne Yorks, Dayna M. Petty, Carter R. Wozniak, Janet R. Faraone, Stephen V. Biederman, Joseph TI Pharmacologic Treatments for Pediatric Bipolar Disorder: A Review and Meta-Analysis SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE pediatric bipolar disorder; psychopharmacology; mania; depression; attention-deficit/hyperactivity disorder ID OPEN-LABEL TRIAL; PLACEBO-CONTROLLED TRIAL; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; OPEN-CLINICAL-TRIAL; CARE DYSFUNCTION DISORDER; DOUBLE-BLIND; DIVALPROEX SODIUM; ACUTE MANIA; EXTENDED-RELEASE; I DISORDER AB Objective: A growing body of literature has documented pediatric bipolar disorder to be a severely impairing form of psychopathology. However, concerns remain as to the inadequacy of the extant literature on its pharmacotherapy. Furthermore, treatment studies have not been systematically reviewed for treatment effects on core and associated symptoms. Thus, a systematic evaluation and synthesis of the available literature on the efficacy of antimanic pharmacotherapy for pediatric bipolar disorder on symptoms of mania, depression, and attention-deficit/hyperactivity disorder was undertaken. Method: A systematic search was conducted through Pub Med from 1989 through 2010 for open-label and randomized controlled trials published in English on the pharmacotherapy of pediatric mania. Results: There have been 46 open-label (n = 29) and randomized (n = 17) clinical trials of antimanic agents in pediatric bipolar disorder encompassing 2,666 subjects that evaluated a range of therapeutic agents, including traditional mood stabilizers, other anticonvulsants, second-generation antipsychotics, and naturopathic compounds. This literature has documented that the available armamentarium has different levels of efficacy in the treatment of pediatric mania. Because all psychotropic classes are associated with important adverse effects, a careful risk-benefit analysis is warranted when initiating pharmacologic treatment with any of these compounds. In the limited data available, the effects of antimanic agents on depression and symptoms of attention-deficit/hyperactivity disorder have been, in general, modest. Few studies have evaluated the effects of antimanic agents in children younger than 10 years. Conclusions: A substantial body of scientific literature has evaluated the safety and efficacy of various medicines and drug classes in the treatment of mania in pediatric bipolar disorder. More work is needed to assess the safety and efficacy of psychotropic drugs in children younger than 10 years, to further evaluate the efficacy of naturopathic compounds, and to further evaluate the effects of antimanic treatments for the management of depression and attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(8):749-762. C1 [Woodworth, K. Yvonne; Yorks, Dayna M.; Petty, Carter R.; Wozniak, Janet R.; Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Woodworth, K. Yvonne; Yorks, Dayna M.; Petty, Carter R.; Wozniak, Janet R.; Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Adult Attent Deficit Hyperact, Boston, MA 02114 USA. [Liu, Howard Y.] Univ Nebraska Med Ctr, Omaha, NE USA. [Potter, Mona P.] McLean Hosp, Belmont, MA 02178 USA. [Wozniak, Janet R.; Biederman, Joseph] Harvard Univ, Sch Med, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, 55 Fruit St,YAW 6A, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU Pediatric Psychopharmacology Council; Bantam Books; National Institute of Mental Health (NIMH), McNeil, Shire; Eli Lilly and Co.; Pfizer; Shire; National Institutes of Health (NIH); Janssen; McNeil; Novartis; Guilford Press; Elmindo; Next Wave Pharmaceuticals; MGH Psychiatry Academy; AstraZeneca; Abbott; Alza; Bristol Myers Squibb; Celltech; Cephalon; Esai; Forest; Glaxo; Gliatech; Merck; National Alliance for Research on Schizophrenia and Depression (NARSAD); National Institute on Drug Abuse (NIDA); New River; National Institute of Child Health and Human Development (NICHD); NIMH; Noven; Neurosearch; Organon; Otsuka; Pharmacia; Prechter Foundation; The Stanley Foundation; UCB Pharma; Wyeth FX This work was supported in part by the Pediatric Psychopharmacology Council Fund.; Dr. Liu is a secondary investigator for a clinical trial by Eli Lilly and Co. and participation personnel for a clinical trial by Shire. Dr. Wozniak receives royalties from Bantam Books. She has served on the speakers' bureau for McNeil and Primedia/Massachuseits General Hospital (MGH) Psychiatry Academy. She has served on the advisory board for Pfizer and Shire. She has received research support from the National Institute of Mental Health (NIMH), McNeil, Shire, and Eli Lilly and Co. Dr. Faraone, has, this year, received consulting fees from and has served on the advisory board for Shire Development. He has received research support from Pfizer, Shire, and the National Institutes of Health (NIH). In previous years, Dr. Faraone has received consulting fees from, has served on the advisory boards for, or has participated in continuing medical education programs sponsored by Shire, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly and Co. In previous years he has received research support from Eli Lilly and Co., Shire, Pfizer, and NIH. Dr. Faraone receives royalties from Guilford Press. Dr. Biederman is currently receiving research support from Elmindo, Janssen, McNeil, Next Wave Pharmaceuticals, and Shire. This year, he gave a single unpaid talk for Juste Pharmaceutical Spain and received honoraria from the MGH Psychiatry Academy for a tuition-funded continuing medical education (CME) course. He also received an honorarium from Cambridge University Press for a chapter publication. He has received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Eli Lilly and Co., Shire, and AstraZeneca; these royalties are paid to the Department of Psychiatry at MGH. In previous years, he received a speaker's fee from a single talk given at Fundacion Dr. Manuel Camelo A.C. in Monterrey, Mexico and served on the speaker's bureau for Fundacion Areces (Spain), Medice Pharmaceuticals (Germany), and the Spanish Child Psychiatry Association. He served as a consultant for Shionogi Pharma and Cipher Pharmaceuticals. The honoraria for these consultations were paid to the Department of Psychiatry at MGH. He received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course. He has received research support, consultation fees, or speaker's fees for/from Abbott, Alza, AstraZeneca, Bristol Myers Squibb, Celltech, Cephalon, Eli Lilly and Co., Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, Merck, the National Alliance for Research on Schizophrenia and Depression (NARSAD), the National Institute on Drug Abuse (NIDA), New River, the National Institute of Child Health and Human Development (NICHD), NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, and Wyeth. Dr. Potter, Ms. Woodworth, Ms. Yorks, and Mr. Petty report no biomedical financial interests or potential conflicts of interest. NR 74 TC 40 Z9 40 U1 3 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2011 VL 50 IS 8 BP 749 EP 762 DI 10.1016/j.jaac.2011.05.011 PG 14 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 801GY UT WOS:000293427800006 PM 21784295 ER PT J AU Mick, E McGough, J Loo, S Doyle, AE Wozniak, J Wilens, TE Smalley, S McCracken, J Biederman, J Faraone, SV AF Mick, Eric McGough, James Loo, Sandra Doyle, Alysa E. Wozniak, Janet Wilens, Timothy E. Smalley, Susan McCracken, James Biederman, Joseph Faraone, Stephen V. TI Genome-Wide Association Study of the Child Behavior Checklist Dysregulation Profile SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; emotional dysregulation; CBCL; GWAS ID DEFICIT HYPERACTIVITY DISORDER; PEDIATRIC BIPOLAR DISORDER; AUTISM SPECTRUM DISORDERS; FAMILY-BASED ASSOCIATION; QUANTITATIVE TRAITS; SIGNALING PATHWAYS; GROWTH CONES; HUMAN BRAIN; LINKAGE; PHENOTYPE AB Objective: : A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behavior. We have conducted a genome-wide association study of the CBCL-DP in children with attention-deficit/hyperactivity disorder (ADHD). Method: Families were ascertained at Massachusetts General Hospital and University of California, Los Angeles. Genotyping was conducted with the Illumina Human1M or Human1M-Duo Bead Chip platforms. Genome-wide association analyses were conducted with the MQFAM multivariate extension of PLINK. Results: CBCL data were available for 341 ADHD offspring from 339 ADHD affected trio families from the UCLA (N = 128) and the MGH (N = 213) sites. We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p < 5E-05: TMEM132D, LRRC7, SEMA3A, ALK, and STIP1. Conclusions: We found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(8): 807-817. C1 [Mick, Eric] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [McGough, James; McCracken, James] Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [McGough, James; Loo, Sandra; Smalley, Susan; McCracken, James] David Geffen Sch Med, Los Angeles, CA USA. [Loo, Sandra; Smalley, Susan] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA. [Doyle, Alysa E.; Wozniak, Janet; Wilens, Timothy E.; Biederman, Joseph] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Doyle, Alysa E.; Wozniak, Janet; Wilens, Timothy E.; Biederman, Joseph] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY USA. RP Mick, E (reprint author), Univ Massachusetts, Sch Med, 55 Lake Ave N AC7-041, Worcester, MA 01655 USA. EM eric.mick@umassmed.edu OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU Pfizer Inc.; National Institute of Health (NIH) [R13MH059126, R01MH62873, U0IMH085518, R01MH081803]; National Institute of Neurological Disorders and Stroke (NINDS) [NS054124]; National Institute of Mental Health (NIMH) [MH01966, MH01805, MH63706, K08MH001503, R01MH066237]; National Institute on Drug Abuse (NIDA) [K24 DA016264]; Ortho-Mcneil Janssen Scientific Affairs; Pfizer; Shire Pharmaceuticals; Elminda; Janssen; McNeil; Shire; Abbott; Alza; AstraZeneca; Bristol Myers Squibb; Celltech; Cephalon; Eli Lilly and Co.; Esai; Forest; Glaxo; Gliatech; Merck; National Alliance for Research on Schizophrenia and Depression (NARSAD); National Institute on Drug Abuse (NIDA); New River; National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); Novartis; Noven; Neurosearch; Organon; Otsuka; Pharmacia; Prechter Foundation; Stanley Foundation; UCB Pharma, Inc.; Wyeth; Bristol-Myers Squibb; Aspect; Seaside Pharmaceuticals; National Institutes of Health (NIH) - NIDA; Guilford Press; Bantam Books; NIH FX Genotyping was supported with funding from Pfizer Inc. Subject ascertainment and assessment was supported by the following sources: National Institute of Health (NIH) Grants R13MH059126, R01MH62873, U0IMH085518 and R01MH081803 (S.V.F.); National Institute of Neurological Disorders and Stroke (NINDS) grant NS054124 (S. L.); National Institute of Mental Health (NIMH) grant MH01966 (J. McGough); NIMH grant MH01805 (J. McCracken); National Institute on Drug Abuse (NIDA) grant K24 DA016264 (T. W.); NIMH grant MH63706 (S.S.); and NIMH grants K08MH001503 and R01MH066237) (J.W.).; Dr. Mick has received research support from Ortho-Mcneil Janssen Scientific Affairs, Pfizer, and Shire Pharmaceuticals, and has served on the advisory board for Shire Pharmaceuticals. Dr. Biederman receives research support from Elminda, Janssen, McNeil, and Shire. He serves on the speakers' bureau for Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. He has received research support, served as a consultant, or served on the speakers' bureau for/from Abbott, Alza, AstraZeneca, Bristol Myers Squibb, Celltech, Cephalon, Eli Lilly and Co., Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, Merck, the National Alliance for Research on Schizophrenia and Depression (NARSAD), the National Institute on Drug Abuse (NIDA), New River, the National Institute of Child Health and Human Development (NICHD), the National Institute of Mental Health (NIMH), Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, the Prechter Foundation, Shire, the Stanley Foundation, UCB Pharma, Inc. and Wyeth. Dr. McCracken has received research support from Bristol-Myers Squibb, Aspect, and Seaside Pharmaceuticals. He has served as a consultant for Novopharm and BioMarin, and has served on the speakers' bureau for the Tourette Syndrome Association, Veritas, and CME Outfitters. Dr. McGough has served as a consultant for Eli Lilly and Co. and Shire Pharmaceuticals. He has received research support from Eli Lilly and Co. Dr. Wilens receives or has received grant support from Abbott, McNeil, Eli Lilly and Co., the National Institutes of Health (NIH) - NIDA, Merck, and Shire. He has served on the speakers' buearu for Eli Lilly and Co., McNeil, Novartis, and Shire. He has served as a consultant for Abbott, Astra-Zeneca, McNeil, Eli Lilly and Co., NIH, Novartis, Merck, and Shire. He receives royalties from Guilford Press. Dr. Wozniak receives royalties from Bantam Books. She has served on the speakers' bureau for McNeil, Primedia/Massachusetts General Hospital Psychiatry Academy, and Eli Lilly and Co. She has served on the advisory board or as a consultant for Pfizer and Shire. She receives research support from McNeil, Shire, and Eli Lilly and Co. Dr. Faraone has served on the advisory board, served on the speakers' bureau, or served as a consultant for Eli Lilly and Co., Janssen, McNeil, Novartis, Ortho-McNeil, Pfizer, and Shire. He has received research support from Eli Lilly and Co., Pfizer, Shire, and NIH. Drs. Loo, Doyle, and Smalley report no biomedical financial interests or potential conflicts of interest. NR 61 TC 23 Z9 24 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2011 VL 50 IS 8 BP 807 EP 817 DI 10.1016/j.jaac.2011.05.001 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 801GY UT WOS:000293427800011 PM 21784300 ER PT J AU Dublin, S Anderson, ML Haneuse, SJ Heckbert, SR Crane, PK Breitner, JCS McCormick, W Bowen, JD Teri, L McCurry, SM Larson, EB AF Dublin, Sascha Anderson, Melissa L. Haneuse, Sebastien J. Heckbert, Susan R. Crane, Paul K. Breitner, John C. S. McCormick, Wayne Bowen, James D. Teri, Linda McCurry, Susan M. Larson, Eric B. TI Atrial Fibrillation and Risk of Dementia: A Prospective Cohort Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Scientific Meeting on the American-Geriatrics-Society CY MAY 13, 2010 CL Orlando, FL SP Amer Geriatr Soc DE atrial fibrillation; cardiac arrhythmia; dementia; Alzheimer disease; epidemiology ID CEREBRAL BLOOD-FLOW; OLDER PERSONS; COGNITIVE FUNCTION; APOLIPOPROTEIN-E; SELF-REPORT; STROKE; HYPERTENSION; PREVALENCE; INFARCTION; DECLINE AB OBJECTIVES: To determine whether atrial fibrillation (AF) is associated with risk of incident dementia or Alzheimer's disease (AD), beyond its effect on stroke. DESIGN: Prospective cohort study. SETTING: An integrated healthcare delivery system. PARTICIPANTS: A population-based sample of 3,045 community-dwelling adults aged 65 and older without dementia or clinical stroke followed from 1994 to 2008. MEASUREMENTS: AF was identified from health plan electronic data using International Classification of Diseases, Ninth Revision, codes from inpatient and outpatient encounters. Covariates came from self-report, study measures, and health plan data. Participants were screened every 2 years using the Cognitive Abilities Screening Instrument (range 0-100), with detailed neuropsychological and clinical assessment of those scoring less than 86. A multidisciplinary consensus committee determined diagnoses of all-cause dementia and possible or probable AD using standard research criteria. RESULTS: AF was present in 132 (4.3%) participants at baseline and was diagnosed in 370 (12.2%) more over a mean of 6.8 years of follow-up; 572 participants (18.8%) developed dementia (449 with AD). The adjusted hazard ratio associated with AF was 1.38 (95% confidence interval (CI) 51.10-1.73) for all-cause dementia and 1.50 (95% CI51.16-1.94) for possible or probable AD. Results were similar for participants with and without clinically recognized stroke during follow-up and in sensitivity analyses examining only probable AD. CONCLUSION: AF is associated with higher risk of developing AD and dementia. Future studies should examine whether specific treatments, including optimal anticoagulation, can decrease this risk. J Am Geriatr Soc 59: 1369-1375, 2011. C1 [Dublin, Sascha; Anderson, Melissa L.; Haneuse, Sebastien J.; Heckbert, Susan R.; McCurry, Susan M.; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Crane, Paul K.; Larson, Eric B.] Univ Washington, Div Gen Internal Med, Seattle, WA 98195 USA. [Breitner, John C. S.; McCormick, Wayne] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA. [Dublin, Sascha; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Haneuse, Sebastien J.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Larson, Eric B.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Bowen, James D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Teri, Linda; McCurry, Susan M.] Univ Washington, Dept Psychosocial & Community Hlth, Seattle, WA 98195 USA. [Breitner, John C. S.; Teri, Linda; McCurry, Susan M.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Teri, Linda] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Breitner, John C. S.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Bowen, James D.] Swedish Neurosci Inst, Seattle, WA USA. RP Dublin, S (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM dub-lin.s@ghc.org RI Crane, Paul/C-8623-2014; OI Crane, Paul/0000-0003-4278-7465 FU NHLBI NIH HHS [R01 HL068986, 2R01HL068986, R01 HL068986-03]; NIA NIH HHS [2U01AG006781-22A1, K23 AG028954, K23 AG028954-03, K23AG028954, U01 AG006781, U01 AG006781-22A1] NR 37 TC 48 Z9 50 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2011 VL 59 IS 8 BP 1369 EP 1375 DI 10.1111/j.1532-5415.2011.03508.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 808MA UT WOS:000293980600001 PM 21806558 ER PT J AU Jefferson, AL Gibbons, LE Rentz, DM Carvalho, JO Manly, J Bennett, DA Jones, RN AF Jefferson, Angela L. Gibbons, Laura E. Rentz, Dorene M. Carvalho, Janessa O. Manly, Jennifer Bennett, David A. Jones, Richard N. TI A Life Course Model of Cognitive Activities, Socioeconomic Status, Education, Reading Ability, and Cognition SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE education; cognition; reading ability; cognitive reserve ID ETHNICALLY DIVERSE ELDERS; ALZHEIMERS-DISEASE; OLD-AGE; RESERVE HYPOTHESIS; DECLINE; ASSOCIATION; DEMENTIA; RISK; PATHOLOGY; OCCUPATION AB OBJECTIVES: To cross-sectionally quantify the contribution of proxy measures of cognitive reserve reflective of the lifespan, such as education, socioeconomic status (SES), reading ability, and cognitive activities, in explaining late-life cognition. DESIGN: Prospective observational cohort study of aging. SETTING: Retirement communities across the Chicago metropolitan area. PARTICIPANTS: Nine hundred fifty-one older adults free of clinical dementia in the Rush Memory and Aging Project (aged 79 +/- 8, 74% female). MEASUREMENTS: Baseline data on multiple life course factors included early-, mid-, and late-life participation in cognitive activities; early-life and adult SES; education; and reading ability (National Adult Reading Test; NART). Path analysis quantified direct and indirect standardized effects of life course factors on global cognition and five cognitive domains (episodic memory, semantic memory, working memory, visuospatial ability, perceptual speed). RESULTS: Adjusting for age, sex, and race, education had the strongest association with global cognition, episodic memory, semantic memory, and visuospatial ability, whereas NART (followed by education) had the strongest association with working memory. Late-life cognitive activities had the strongest association with perceptual speed, followed by education. CONCLUSIONS: These cross-sectional findings suggest that education and reading ability are the most-robust proxy measures of cognitive reserve in relation to late-life cognition. Additional research leveraging path analysis is warranted to better understand how these life course factors, reflecting the latent construct of cognitive reserve, affect abnormal cognitive aging. J AmGeriatr Soc 59: 1403-1411, 2011. C1 [Jefferson, Angela L.] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Jefferson, Angela L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Gibbons, Laura E.] Univ Washington, Sch Med, Seattle, WA USA. [Rentz, Dorene M.] Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Rentz, Dorene M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Carvalho, Janessa O.] Univ Massachusetts, Amherst, MA 01003 USA. [Manly, Jennifer] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Bennett, David A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Jones, Richard N.] Harvard Univ, Sch Med, Inst Aging Res, Boston, MA USA. RP Jefferson, AL (reprint author), Boston Univ, Sch Med, Alzheimers Dis Ctr, Robinson Complex,Suite 7800,72 E Concord St, Boston, MA 02118 USA. EM angelaj@bu.edu RI Jones, Richard/J-3488-2013 OI Jones, Richard/0000-0002-1049-218X FU ALJ [K23-AG030962]; Boston University Alzheimer's Disease Core Center [P30-AG013846]; Conference on Advanced Psychometric Methods in Cognitive Aging Research [R13-AG030995]; Rush Memory and Aging Project [R01-AG017917]; University of Washington Alzheimer's Disease Research Center [P50-AG05136] FX This research was supported by K23-AG030962 (Paul B. Beeson Career Development Award in Aging; ALJ), P30-AG013846 (Boston University Alzheimer's Disease Core Center), R13-AG030995 (Conference on Advanced Psychometric Methods in Cognitive Aging Research), R01-AG017917 (Rush Memory and Aging Project), and P50-AG05136 (University of Washington Alzheimer's Disease Research Center). NR 49 TC 55 Z9 61 U1 8 U2 40 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2011 VL 59 IS 8 BP 1403 EP 1411 DI 10.1111/j.1532-5415.2011.03499.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 808MA UT WOS:000293980600005 PM 21797830 ER PT J AU Hanlon, JT Wang, XQ Castle, NG Stone, RA Handler, SM Semla, TP Pugh, MJ Berlowitz, DR Dysken, MW AF Hanlon, Joseph T. Wang, Xiaoqiang Castle, Nicholas G. Stone, Roslyn A. Handler, Steven M. Semla, Todd P. Pugh, Mary Jo Berlowitz, Dan R. Dysken, Maurice W. TI Potential Underuse, Overuse, and Inappropriate Use of Antidepressants in Older Veteran Nursing Home Residents SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the Gerontological-Society-of-America CY NOV 19-20, 2009 CL Atlanta, GA SP Gerontol Soc Amer DE aged; nursing homes; depression; pharmacoepidemiology ID MINIMUM DATA SET; LONG-TERM-CARE; COGNITIVE PERFORMANCE; RECOGNIZED DEPRESSION; MEDICATION; PREVALENCE; INTERVENTIONS; VALIDATION; MANAGEMENT; QUALITY AB OBJECTIVES: To examine prevalence and resident-and site-level factors associated with potential underuse, overuse, and inappropriate use of antidepressants in older Veterans Affairs (VA) Community Living Center (CLC) residents. DESIGN: Longitudinal study. SETTING: One hundred thirty-three VA CLCs. PARTICIPANTS: Three thousand six hundred ninety-two veterans aged 65 and older admitted between January 1, 2004, and June 3, 2005, with long stays (>= 90 days). MEASUREMENTS: Prevalence of potential underuse, inappropriate use, and overuse of antidepressants in residents with and without depression (as documented according to International Classification of Diseases, Ninth Revision, Clinical Modification, codes or Depression Rating Scale). RESULTS: Selective serotonin reuptake inhibitors were the most commonly prescribed antidepressant. Of the 877 residents with depression, 25.4% did not receive an antidepressant, suggesting potential underuse. Of residents with depression who received antidepressants, 57.5% had potential inappropriate use due primarily to problems seen with drug-drug and drug-disease interactions. Of the 2,815 residents who did not have depression, 1,190 (42.3%) were prescribed one or more antidepressants; only 48 (4.0%) of these had a Food and Drug Administration-approved labeled indication, suggesting potential overuse. Overall, only 17.6% of antidepressant use was appropriate (324/1,844). The only consistent resident factor associated with potential underuse and overuse use was taking an antipsychotic without evidence of schizophrenia (underuse: adjusted relative risk ratio (ARRR) = 0.56, 95% confidence interval (CI) = 0.33-0.94; overuse: adjusted odds ratio = 1.52, 95% CI = 1.21-1.91). Having moderate to severe pain (ARRR = 1.54, 95% CI = 1.08-2.20) and the prescribing of an anxiolytic or hypnotic (ARRR = 1.33, 95% CI = 1.02-1.74) increased the risk of potential inappropriate antidepressant use. CONCLUSION: Potential problems with the use of antidepressants were frequently observed in older U. S. veteran CLC residents. Future studies are needed to examine the true risks and benefits of antidepressant use in CLC and non-VA nursing homes. J Am Geriatr Soc 59: 1412-1420, 2011. C1 [Hanlon, Joseph T.; Handler, Steven M.] Vet Affairs Pittsburgh Hlth Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Hanlon, Joseph T.; Wang, Xiaoqiang; Stone, Roslyn A.; Handler, Steven M.] Vet Affairs Pittsburgh Hlth Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Hanlon, Joseph T.; Handler, Steven M.] Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.; Handler, Steven M.] Univ Pittsburgh, Sch Med, Dept Biomed Informat, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Castle, Nicholas G.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15213 USA. [Stone, Roslyn A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15213 USA. [Semla, Todd P.] Dept Vet Affairs, Pharm Benefits Management Serv, Hines, IL USA. [Semla, Todd P.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Semla, Todd P.] Northwestern Univ, Dept Psychiat & Behav Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Pugh, Mary Jo] S Texas Vet Affairs Hlth Syst, Vet Evidence Based Res Disseminat & Implementat C, San Antonio, TX USA. [Berlowitz, Dan R.] Ctr Hlth Qual Outcomes & Econ Res, Dept Vet Affairs, Bedford, MA USA. [Dysken, Maurice W.] Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, Minneapolis, MN USA. RP Hanlon, JT (reprint author), Univ Pittsburgh, Dept Geriatr Med, Kaufman Med Bldg Suite 514,3471 5th Ave, Pittsburgh, PA 15213 USA. EM jth14@pitt.edu OI Handler, Steven/0000-0002-3940-3224; Pugh, Mary Jo/0000-0003-4196-7763 FU AHRQ HHS [K12 HS019461, R01 HS017695, R01 HS018721]; NIA NIH HHS [K07AG033174, 3U01 AG012553, K07 AG033174, K07 AG033174-01A1, K07 AG033174-02, K07 AG033174-03, P30 AG024827, P30AG024827, R01 AG034056, R01 AG034056-01, R01 AG034056-02, R01AG034056, R56 AG027017, R56 AG027017-04, R56AG027017, T32 AG021885, U01 AG012553]; NIMH NIH HHS [R34 MH082682]; NINR NIH HHS [R01 NR010135] NR 41 TC 27 Z9 30 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2011 VL 59 IS 8 BP 1412 EP 1420 DI 10.1111/j.1532-5415.2011.03522.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 808MA UT WOS:000293980600006 PM 21824120 ER PT J AU Min, LC Reuben, DB Adams, J Shekelle, PG Ganz, DA Roth, CP Wenger, NS AF Min, Lillian C. Reuben, David B. Adams, John Shekelle, Paul G. Ganz, David A. Roth, Carol P. Wenger, Neil S. TI Does Better Quality of Care for Falls and Urinary Incontinence Result in Better Participant-Reported Outcomes? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE quality of care; urinary incontinence; falls ID NUTRITION EXAMINATION SURVEY; RANDOMIZED CONTROLLED-TRIAL; ELDERLY-PEOPLE; OLDER-ADULTS; URGE INCONTINENCE; NATIONAL-HEALTH; COMMUNITY; WOMEN; INTERVENTIONS; PROGRAM AB OBJECTIVES: To determine whether delivery of better quality of care for urinary incontinence (UI) and falls is associated with better participant-reported outcomes. DESIGN: Retrospective cohort study. SETTING: Assessing Care of Vulnerable Elders Study 2 (ACOVE-2). PARTICIPANTS: Older (>= 75) ambulatory care participants in ACOVE-2 who screened positive for UI (n = 133) or falls or fear of falling (n = 328). MEASUREMENTS: Composite quality scores (percentage of quality indicators (QIs) passed per participant) and change in Incontinence Quality of Life (IQOL, range 0-100) or Falls Efficacy Scale (FES, range 10-40) scores were measured before and after care was delivered (mean 10months). Because the treatment-related falls QIs were measured only on patients who received a physical examination, an alternative Common Pathway QI (CPQI) score was developed that assigned a failing score for falls treatment to unexamined participants. RESULTS: Each 10% increment in receipt of recommended care for UI was associated with a 1.4-point improvement in IQOL score (P = .01). The original falls composite quality-of-care score was unrelated to FES, but the new CPQI scoring method for falls quality of care was related to FES outcomes (10.4 points per 10% increment in falls quality, P = .01). CONCLUSION: Better quality of care for falls and UI was associated with measurable improvement in participant-reported outcomes in less than 1 year. The connection between process and outcome required consideration of the interdependence between diagnosis and treatment in the falls QIs. The link between process and outcome demonstrated for UI and falls underscores the importance of improving care in these areas. J Am Geriatr Soc 59:1435-1443, 2011. C1 [Min, Lillian C.] Univ Michigan, Sch Med, Div Geriatr, Ann Arbor, MI USA. [Min, Lillian C.] Ann Arbor Vet Affairs Healthcare Syst, Geriatr Res Educ & Clin Care Ctr, Ann Arbor, MI USA. [Min, Lillian C.; Adams, John; Shekelle, Paul G.; Roth, Carol P.; Wenger, Neil S.] RAND Hlth, Santa Monica, CA USA. [Reuben, David B.; Shekelle, Paul G.; Ganz, David A.; Wenger, Neil S.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Shekelle, Paul G.; Ganz, David A.] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. RP Min, LC (reprint author), 300 N Ingalls Bldg,Wing E Room 966, Ann Arbor, MI 48109 USA. EM lmin@med.umich.edu FU Agency for Healthcare Research and Quality [R21 HS017621]; University of Michigan Claude Pepper Older Americans Independence Center; Geriatric Research, Education, and Clinical Care Center at the Veterans Administration Healthcare System in Ann Arbor; UCLA Claude Pepper Older Americans Independence Center (NIA-UCLA) [K12 AG001004]; U.S. Department of Veterans Affairs (VA), Veterans Health Administration, VA Health Services Research and Development (HSR&D) Service through the VA Greater Los Angeles HSR&D Center of Excellence [VA CD2 08-012-1]; Pfizer Inc FX Dr. Min is supported by the Agency for Healthcare Research and Quality (R21 HS017621); a Research Career Development Core award from the University of Michigan Claude Pepper Older Americans Independence Center; and the Geriatric Research, Education, and Clinical Care Center at the Veterans Administration Healthcare System in Ann Arbor. Dr. Min was on the University of California at Los Angeles (UCLA) faculty during the writing of this manuscript, supported by the UCLA Claude Pepper Older Americans Independence Center (NIA-UCLA K12 AG001004). Dr. Ganz is funded by the U.S. Department of Veterans Affairs (VA), Veterans Health Administration, VA Health Services Research and Development (HSR&D) Service through the VA Greater Los Angeles HSR&D Center of Excellence (Project VA CD2 08-012-1).; The original ACOVE-2 study was supported by a contract from Pfizer Inc to RAND. Pfizer did not serve a role in the design, analysis, or preparation of this retrospective analysis. NR 35 TC 13 Z9 13 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2011 VL 59 IS 8 BP 1435 EP 1443 DI 10.1111/j.1532-5415.2011.03517.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 808MA UT WOS:000293980600009 PM 21806560 ER PT J AU Huang, AJ Brown, JS Boyko, EJ Moore, EE Scholes, D Walter, LC Lin, F Vittinghoff, E Fihn, SD AF Huang, Alison J. Brown, Jeanette S. Boyko, Edward J. Moore, Elya E. Scholes, Delia Walter, Louise C. Lin, Feng Vittinghoff, Eric Fihn, Stephan D. TI Clinical Significance of Postvoid Residual Volume in Older Ambulatory Women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE postvoid residual; urinary incontinence; urinary tract infection; nocturia ID SELF-RATED HEALTH; URINARY-INCONTINENCE; POSTMENOPAUSAL WOMEN; POPULATION; PREVALENCE; MANAGEMENT; ULTRASOUND; COMMUNITY; BLADDER; PERIMENOPAUSAL AB OBJECTIVES: To examine the prevalence, natural history, and clinical significance of high postvoid residual (PVR) volume in ambulatory older women. DESIGN: Prospective cohort study. SETTING: Group health plan in Washington state. PARTICIPANTS: Nine hundred eighty-seven ambulatory women aged 55 to 75. MEASUREMENTS: PVR was measured using bladder ultrasonography at baseline, 1 year, and 2 years. Participants completed questionnaires about urinary symptoms and provided urine samples for microbiological evaluation. RESULTS: Of the 987 participants, 79% had a PVR less than 50 mL, 10% of 50 to 99 mL, 6% of 100 to 199 mL, and 5% of 200 mL or greater at baseline. Of women with a PVR less than 50 mL, 66% reported at least one urinary symptom at baseline. Of women with a PVR of 200 mL or greater, 27% reported no significant symptoms at baseline. In adjusted analyses using data from all study visits, women with a PVR of 100 mL or greater were more likely to report urinating more than eight times during the day (odds ratio (OR) = 1.42, 95% confidence interval (CI) 51.07-1.87), and women with a PVR of 200 mL or greater were more likely to report weekly urgency incontinence (OR = 1.50, 95% CI = 1.03-2.18) than those with a PVR less than 50 mL. High PVR was not associated with greater risk of stress incontinence, nocturnal frequency, or urinary tract infection in adjusted analyses. Forty-six percent of those with a PVR of 200 mL or greater and 63% of those with a PVR of 100 to 199 mL at baseline had a PVR less than 50 mL at 2 years. CONCLUSION: More than 10% of ambulatory older women may have a PVR of 100 mL or greater, which is associated with greater risk of some urinary symptoms, but many with high PVR are asymptomatic, and high PVR frequently resolves within 2 years. Symptom-guided management of urinary symptoms may be more appropriate than PVR-guided management in this population. J Am Geriatr Soc 59:1452-1458, 2011. C1 [Huang, Alison J.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Brown, Jeanette S.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Lin, Feng; Vittinghoff, Eric] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Boyko, Edward J.] Univ Washington, Dept Med, Seattle, WA USA. [Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Moore, Elya E.] Royal Hosp Women, Dept Microbiol & Infect Dis, Melbourne, Vic, Australia. [Scholes, Delia] Grp Hlth Ctr Hlth Studies, Grp Hlth Cooperat, Seattle, WA USA. [Walter, Louise C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Fihn, Stephan D.] Dept Vet Affairs, Washington, DC USA. RP Huang, AJ (reprint author), 1635 Divisadero St,Suite 600, San Francisco, CA 94115 USA. EM ahuang@ucsfmed.org FU Pfizer, Inc., through University of California at San Francisco; National Institutes of Health (NIH) [RR024130, T32AI07140, RO1 DK43134]; Veterans Affairs Puget Sound Health Care System, Seattle, Washington FX Drs. Huang and Brown have received support for research related to urinary incontinence from Pfizer, Inc., through contracts with the University of California at San Francisco. No other authors have any potential conflicts of interest with regard to this research.; This research was supported by National Institutes of Health (NIH) Grants RR024130, T32AI07140, and RO1 DK43134 and by the resources and facilities at the Veterans Affairs Puget Sound Health Care System, Seattle, Washington. NR 38 TC 12 Z9 12 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2011 VL 59 IS 8 BP 1452 EP 1458 DI 10.1111/j.1532-5415.2011.03511.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 808MA UT WOS:000293980600011 PM 21806559 ER PT J AU Min, L Ubhayakar, N Saliba, D Kelley-Quon, L Morley, E Hiatt, J Cryer, H Tillou, A AF Min, Lillian Ubhayakar, Nitin Saliba, Debra Kelley-Quon, Lorraine Morley, Eric Hiatt, Jonathan Cryer, Henry Tillou, Areti TI The Vulnerable Elders Survey-13 Predicts Hospital Complications and Mortality in Older Adults with Traumatic Injury: A Pilot Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE trauma; acute surgical care; functional status ID MAJOR TRAUMA; FUNCTIONAL DECLINE; GERIATRIC-PATIENTS; CARE; OUTCOMES; PEOPLE; VALIDATION; COMMUNITY; EMERGENCY; SEVERITY AB OBJECTIVES: To determine whether the Vulnerable Elders Survey (VES)-13, a survey based on functional status that has been validated in uninjured older populations, will predict complications and mortality in injured older adults. DESIGN: Prospective observational pilot study. SETTING: Level 1 trauma center. PARTICIPANTS: Sixty-three older adults (>= 65) with a traumatic injury who survived and required inpatient care for at least 24 hours. MEASUREMENTS: Predictor: preinjury VES-13 score (0-10 points, higher = greater risk) obtained by interviewing participants or proxies. Outcomes: composite outcome of one or more medical complications (e. g., aspiration pneumonia, respiratory failure) or death, discharge destination (home, nursing home, death), length of stay, hospital charges. Covariates: Charlson Comorbidity Index (CCI), Injury Severity Score (ISS), and sex. RESULTS: Of the 63 participants, 30 (48%) were discharged to home and 28 (44%) to a nursing facility, 21 (33%) developed one or more complications, and four (6%) died. In a model that also controlled for ISS and comorbidity, each additional VES-13 point was associated with greater risk of complication or death (odds ratio = 1.53 per point, 95% confidence interval = 1.12-2.07). CONCLUSION: The VES-13, in combination with injury severity, may be useful early in the hospital course to predict complications and death in older adults with traumatic C1 [Min, Lillian] Univ Michigan, Sch Med, Div Geriatr, Ann Arbor, MI 48109 USA. [Min, Lillian] Geriatr Res Educ & Clin Care Ctr, Dept Vet Affairs, Ann Arbor, MI USA. [Ubhayakar, Nitin] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Saliba, Debra] Greater Los Angeles Vet Affairs Healthcare Syst, Geriatr Res Educ & Clin Care Ctr, Los Angeles, CA USA. [Saliba, Debra; Kelley-Quon, Lorraine; Hiatt, Jonathan; Cryer, Henry; Tillou, Areti] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Saliba, Debra; Kelley-Quon, Lorraine; Hiatt, Jonathan; Cryer, Henry; Tillou, Areti] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Saliba, Debra] Univ Calif Los Angeles Jewish Homes, Borun Ctr Gerontol Res, Los Angeles, CA USA. [Morley, Eric] Univ Calif Davis, Sch Med, Davis, CA 95616 USA. RP Min, L (reprint author), Univ Michigan, Sch Med, Div Geriatr, 300 N Ingalls Bldg, Ann Arbor, MI 48109 USA. EM lmin@med.umich.edu FU UCLA Claude D. Pepper Older American Independence Center; University of Michigan Pepper Center; American Geriatrics Society FX Drs. Min and Tillou were each supported by the Mentored Clinical Scientist Development Program in Geriatrics Awards sponsored by the UCLA Claude D. Pepper Older American Independence Center. Dr. Min is now supported by a Research Career Development Core Career Development Award from the University of Michigan Pepper Center. Dr. Tillou is supported by an American Geriatrics Society Dennis W. Jahnigen Career Development Award. Dr. Kelley-Quon is a Robert Wood Johnson Foundation Clinical Scholar at UCLA. Mr. Ubhayakar was a 2009 Medical Student Training in Aging Research Scholar at UCLA. NR 31 TC 19 Z9 19 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2011 VL 59 IS 8 BP 1471 EP 1476 DI 10.1111/j.1532-5415.2011.03493.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 808MA UT WOS:000293980600014 PM 21718276 ER PT J AU Steinman, MA Handler, SM Gurwitz, JH Schiff, GD Covinsky, KE AF Steinman, Michael A. Handler, Steven M. Gurwitz, Jerry H. Schiff, Gordon D. Covinsky, Kenneth E. TI Beyond the Prescription: Medication Monitoring and Adverse Drug Events in Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE adverse drug events; drug monitoring; aged ID EMERGENCY-DEPARTMENT VISITS; PATIENTS AFTER-DISCHARGE; AMBULATORY-CARE; RANDOMIZED-TRIAL; MANAGEMENT; THERAPY; INFORMATION; OUTPATIENTS; INITIATION; POTASSIUM AB Whether a person will suffer harm from a medication or how severe that harm will be is difficult to predict precisely. As a result, many adverse drug events (ADEs) occur in patients in whom it was reasonable to believe that the drug's benefits exceeded its risks. Improving safety and reducing the burden of ADEs in older adults requires addressing this uncertainty by not only focusing on the appropriateness of the initial prescribing decision, but also by detecting and mitigating adverse events once they have started to occur. Such enhanced monitoring of signs, symptoms, and laboratory parameters can determine whether an adverse event has only mild and short-term consequences or major long-term effects on morbidity and mortality. Although current medication monitoring practices are often suboptimal, several strategies can be leveraged to improve the quality and outcomes of monitoring. These strategies include using health information technology to link pharmacy and laboratory data, prospective delineation of risk, and patient outreach and activation, all within a framework of team-based approaches to patient management. Although many of these strategies are theoretically possible now, they are poorly used and will be difficult to implement without a significant restructuring of medical practice. An enhanced focus on medication monitoring will also require a new conceptual framework to re-engineer the prescribing process. With this approach, prescribing quality does not hinge on static attributes of the initial prescribing decision but entails a dynamic process in which the benefits and harms of drugs are actively monitored, managed, and reassessed over time. J Am Geriatr Soc 59:1513-1520, 2011. C1 [Steinman, Michael A.; Covinsky, Kenneth E.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Steinman, Michael A.; Covinsky, Kenneth E.] San Francisco VA Med Ctr, San Francisco, CA USA. [Handler, Steven M.] Univ Pittsburgh, Dept Biomed Informat, Div Geriatr Med, Pittsburgh, PA 15260 USA. [Handler, Steven M.] Vet Affairs Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Gurwitz, Jerry H.] Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA USA. [Gurwitz, Jerry H.] Meyers Primary Care Inst, Worcester, MA USA. [Schiff, Gordon D.] Harvard Univ, Sch Med, Div Gen Internal Med, Boston, MA USA. [Schiff, Gordon D.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Steinman, MA (reprint author), 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. EM mike.steinman@ucsf.edu OI Handler, Steven/0000-0002-3940-3224 FU National Institute on Aging (NIA) [1K24AG029812-02]; American Federation for Aging Research [1K23AG030999]; National Institutes of Health [5KL2RR024151]; Agency for Healthcare Research and Quality (AHRQ) [1R01HS018721-01]; [U18HS016973] FX Funding for this work was provided by a Beeson Career Development Award from the National Institute on Aging (NIA) and the American Federation for Aging Research (1K23AG030999, Dr. Steinman), a National Institutes of Health Roadmap Multidisciplinary Clinical Research Career Development Award (5KL2RR024151, Dr. Handler), a grant from the Agency for Healthcare Research and Quality (AHRQ) (1R01HS018721-01; Dr. Handler), a grant to the University of Illinois at Chicago Center for Education and Research in Therapeutics (U18HS016973, Dr. Schiff), and an award from the NIA (1K24AG029812-02, Dr. Covinsky). NR 50 TC 51 Z9 53 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2011 VL 59 IS 8 BP 1513 EP 1520 DI 10.1111/j.1532-5415.2011.03500.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 808MA UT WOS:000293980600021 PM 21797831 ER PT J AU Chatzinasiou, F Lill, CM Kypreou, K Stefanaki, I Nicolaou, V Spyrou, G Evangelou, E Roehr, JT Kodela, E Katsambas, A Tsao, HS Ioannidis, JPA Bertram, L Stratigos, AJ AF Chatzinasiou, Foteini Lill, Christina M. Kypreou, Katerina Stefanaki, Irene Nicolaou, Vasiliki Spyrou, George Evangelou, Evangelos Roehr, Johannes T. Kodela, Elizabeth Katsambas, Andreas Tsao, Hensin Ioannidis, John P. A. Bertram, Lars Stratigos, Alexander J. TI Comprehensive Field Synopsis and Systematic Meta-analyses of Genetic Association Studies in Cutaneous Melanoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID GENOME-WIDE ASSOCIATION; BASAL-CELL CARCINOMA; RECEPTOR MC1R GENE; HUMAN PIGMENTATION; SKIN-CANCER; DNA-REPAIR; MALIGNANT-MELANOMA; FAMILIAL MELANOMA; SEQUENCE VARIANTS; KNOWLEDGE-BASE AB Background Although genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies published in the field and systematic meta-analysis for all eligible polymorphisms have not been reported. Methods We systematically annotated data from all genetic association studies published in the CM field (n = 145), including data from genome-wide association studies (GWAS), and performed random-effects meta-analyses across all eligible polymorphisms on the basis of four or more independent case-control datasets in the main analyses. Supplementary analyses of three available datasets derived from GWAS and GWAS-replication studies were also done. Nominally statistically significant associations between polymorphisms and CM were graded for the strength of epidemiological evidence on the basis of the Human Genome Epidemiology Network Venice criteria. All statistical tests were two-sided. Results Forty-two polymorphisms across 18 independent loci evaluated in four or more datasets including candidate gene studies and available GWAS data were subjected to meta-analysis. Eight loci were identified in the main meta-analyses as being associated with a risk of CM (P < .05) of which four loci showed a genome-wide statistically significant association (P < 1 x 10(-7)), including 16q24.3 (MC1R), 20q11.22 (MYH7B/PIGU/ASIP), 11q14.3 (TYR), and 5p13.2 (SLC45A2). Grading of the cumulative evidence by the Venice criteria suggested strong epidemiological credibility for all four loci with genome-wide statistical significance and one additional gene at 9p23 (TYRP1). In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility. Conclusions To the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis to identify genes associated with an increased susceptibility to CM. C1 [Stratigos, Alexander J.] Univ Athens, Sch Med, Dept Dermatol, Andreas Sygros Hosp, Athens 16121, Greece. [Lill, Christina M.; Roehr, Johannes T.; Bertram, Lars] Max Planck Inst Mol Genet, Dept Vertebrate Genom, Neuropsychiat Genet Grp, Berlin, Germany. [Lill, Christina M.] Johannes Gutenberg Univ Mainz, Dept Neurol, Mainz, Germany. [Spyrou, George] Acad Athens, Biomed Informat Unit, Biomed Res Fdn, Athens, Greece. [Evangelou, Evangelos; Ioannidis, John P. A.] Univ Ioannina, Sch Med, Clin & Mol Epidemiol Unit, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Roehr, Johannes T.] Free Univ Berlin, Dept Math & Comp Sci, D-1000 Berlin, Germany. [Tsao, Hensin] Massachusetts Gen Hosp, Wellman Labs Photomed, Dept Dermatol, Boston, MA 02114 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Stanford Prevent Res Ctr, Sch Med, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Tufts Med Ctr, Ctr Genet Epidemiol & Modeling, ICRHPS, Dept Med, Boston, MA USA. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Stratigos, AJ (reprint author), Univ Athens, Sch Med, Dept Dermatol, Andreas Sygros Hosp, Dragoumi 5, Athens 16121, Greece. EM alstrat@hol.gr RI Ioannidis, John/G-9836-2011; Evangelou, Evangelos/C-3033-2013; Lill, Christina/J-9449-2015; Bertram, Lars/K-3889-2015; OI Lill, Christina/0000-0002-2805-1307; Bertram, Lars/0000-0002-0108-124X; Evangelou, Evangelos/0000-0002-5488-2999 FU NHLBI NIH HHS [T32 HL007034] NR 66 TC 49 Z9 50 U1 2 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG PY 2011 VL 103 IS 16 BP 1227 EP 1235 DI 10.1093/jnci/djr219 PG 9 WC Oncology SC Oncology GA 809RN UT WOS:000294074500008 PM 21693730 ER PT J AU King, DR Schreiber, MA AF King, David R. Schreiber, Martin A. TI The mRDH Bandage Provides Effective Hemostasis in Trauma and Surgical Hemorrhage SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article DE Trauma; Surgery; mRDH bandage; Hemorrhage; Hemostasis; Battlefield wounds ID N-ACETYL GLUCOSAMINE; ACHIEVING HEMOSTASIS; SPLENIC HEMORRHAGE; DAMAGE CONTROL; COAGULOPATHY; FORMULATION; MORTALITY; INJURIES; SURGERY; MODELS AB Background: Traumatic injury is a major global health problem, accounting for approximately 1 in 10 deaths worldwide. Hemorrhagic shock accounts for 30% to 40% of injury-associated deaths (2/3 of those patients surviving to reach the hospital) and is the leading cause of preventable and early in-hospital mortality. Excessive blood loss is an infrequent but important complication of both elective and emergency surgery, increasing the risk of morbidity and mortality and prolonging the duration of hospital stay. Results: The modified rapid deployment hemostat (mRDH) trauma bandage has been developed and tested during the past several years. The mRDH has a unique mechanism of action involving vasoconstriction, platelet activation, and red blood cell activation and is effective in the absence of clotting factors or platelets. The mRDH bandage has shown hemostatic efficacy in patients with severe visceral injuries and hepatic rupture. Conclusions: The following case studies illustrate the effective use of the mRDH bandage in a variety of settings, as follows: (1) application of the mRDH to control severe hemorrhage from an improvised explosive device-induced lower extremity injury in Iraq and (2) the mRDH terminates bleeding from a penetrating groin wound allowing safe neurosurgical intervention while avoiding a groin exploration. C1 [King, David R.] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Schreiber, Martin A.] Oregon Hlth & Sci Univ, Div Trauma Crit Care & Acute Care Surg, Portland, OR 97201 USA. RP King, DR (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. EM dking3@partners.org OI King, David/0000-0003-1028-1478 NR 38 TC 5 Z9 5 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD AUG PY 2011 VL 71 SU 1 BP S167 EP S170 DI 10.1097/TA.0b013e31822555fe PG 4 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 806WZ UT WOS:000293849000003 PM 21814113 ER PT J AU Itkin, M DeLegge, MH Fang, JC McClave, SA Kundu, S d'Othee, BJ Martinez-Salazar, GM Sacks, D Swan, TL Towbin, RB Walker, TG Wojak, JC Zuckerman, DA Cardella, JF AF Itkin, Maxim DeLegge, Mark H. Fang, John C. McClave, Stephen A. Kundu, Sanjoy d'Othee, Bertrand Janne Martinez-Salazar, Gloria M. Sacks, David Swan, Timothy L. Towbin, Richard B. Walker, T. Gregory Wojak, Joan C. Zuckerman, Darryl A. Cardella, John F. TI Multidisciplinary Practical Guidelines for Gastrointestinal Access for Enteral Nutrition and Decompression From the Society of Interventional Radiology and American Gastroenterological Association (AGA) Institute, With Endorsement by Canadian Interventional Radiological Association (CIRA) and Cardiovascular and Interventional Radiological Society of Europe (CIRSE) SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; FEEDING-TUBE PLACEMENT; INTENSIVE-CARE-UNIT; CRITICALLY-ILL PATIENTS; NECK-CANCER PATIENTS; RANDOMIZED PROSPECTIVE TRIAL; ANTEGRADE CONTINENCE ENEMA; TOTAL PARENTERAL-NUTRITION; T-FASTENER GASTROPEXY; ANTIBIOTIC-PROPHYLAXIS C1 [Itkin, Maxim] Univ Penn, Med Ctr, Dept Radiol, Div Intervent Radiol,Penn Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Sacks, David] Reading Hosp, Dept Intervent Radiol, Reading, Berks, England. [Sacks, David] Med Ctr, Reading, Berks, England. [Fang, John C.] Geisinger Hlth Syst, Dept Radiol, Danville, PA USA. [DeLegge, Mark H.] Med Univ S Carolina, Ctr Digest Dis, Charleston, SC 29425 USA. [Fang, John C.] Univ Utah, Hlth Sci Ctr, Div Gastroenterol Hepatol & Nutr, Salt Lake City, UT USA. [McClave, Stephen A.] Univ Louisville, Sch Med, Div Gastroenterol Hepatol, Louisville, KY 40292 USA. [Kundu, Sanjoy] Scarborough Gen Hosp, Dept Med Imaging, Toronto, ON, Canada. [d'Othee, Bertrand Janne] Univ Maryland, Sch Med, Dept Radiol, Div Intervent Radiol, Baltimore, MD 21201 USA. [Martinez-Salazar, Gloria M.; Walker, T. Gregory] Massachusetts Gen Hosp, Div Vasc Imaging & Intervent, Boston, MA 02114 USA. [Swan, Timothy L.] Marshfield Clin Fdn Med Res & Educ, Dept Radiol, Marshfield, WI 54449 USA. [Towbin, Richard B.] Phoenix Childrens Hosp, Dept Radiol, Phoenix, AZ USA. [Wojak, Joan C.] Our Lady Lourdes Med Ctr, Dept Radiol, Lafayette, LA USA. [Zuckerman, Darryl A.] Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. RP Itkin, M (reprint author), Care of Katsarelis D, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM maxim.itkin@uphs.upenn.edu RI Janne d'Othee, Bertrand/E-8467-2010 FU Nestle; ACM Technologies FX M.H.D. is a paid consultant for Cook Medical (Bloomington, Indiana). S.A.M. is a consultant for Kimberly Clark, Covidien, Nestle, and Abbott and is a recipient of research funds from Nestle and ACM Technologies. None of the other authors have identified a conflict of interest. NR 239 TC 14 Z9 14 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD AUG PY 2011 VL 22 IS 8 BP 1089 EP 1106 DI 10.1016/j.jvir.2011.04.006 PG 18 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 802AW UT WOS:000293482700005 PM 21782465 ER PT J AU Joseph, CS Yaroslavsky, AN Neel, VA Goyette, TM Giles, RH AF Joseph, Cecil S. Yaroslavsky, Anna N. Neel, Victor A. Goyette, Thomas M. Giles, Robert H. TI Continuous Wave Terahertz Transmission Imaging of Nonmelanoma Skin Cancers SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE continuous-wave terahertz imaging; skin-cancer imaging ID BASAL-CELL CARCINOMA; IN-VIVO; RADIATION; TISSUE; SPECTROSCOPY; TUMORS; WATER AB Background and Objective: Continuous wave terahertz imaging has the potential to offer a safe, noninvasive medical imaging modality for delineating human skin cancers. Terahertz pulse imaging (TPI) has already shown that there is contrast between basal cell carcinoma and normal skin. Continuous-wave imaging offers a simpler, lower cost alternative to TPI. The goal of this study was to investigate the feasibility of continuous wave terahertz imaging for delineating skin cancers by demonstrating contrast between cancerous and normal tissue in transmission mode. Materials and Methods: Two CO(2) optically pumped far-infrared molecular gas lasers were used for illuminating the tissue at two frequencies, 1.39 and 1.63 THz. The transmitted signals were detected using a liquid Helium cooled Silicon bolometer. Fresh skin cancer specimens were obtained from Mohs surgeries. The samples were processed and imaged within 24 hours after surgery. During the imaging experiment the samples were kept in pH-balanced saline to prevent tissue dehydration. At both THz frequencies two-dimensional THz transmission images of nonmelanoma skin cancers were acquired with spatial resolution of 0.39 mm at 1.4 THz and 0.49 mm at 1.6 THz. For evaluation purposes, hematoxylin and eosin (H&E) histology was processed from the imaged tissue. Results: A total of 10 specimens were imaged and it was determined that for both frequencies, the areas of decreased transmission in the THz image correlated well with cancerous areas in the histopathology. Two negative controls were also imaged. The difference in transmission between normal and cancerous tissue was found to be approximately 60% at both frequencies, which suggests that contrast between normal and cancerous tissue at these frequencies is dominated by differences in water content. Conclusions: Our results suggest that intraoperative delineation of nonmelanoma skin cancers using continuous-wave terahertz imaging is feasible. Lasers Surg. Med. 43:457-462, 2011. (c) 2011 Wiley-Liss, Inc. C1 [Joseph, Cecil S.; Goyette, Thomas M.; Giles, Robert H.] Univ Massachusetts, Submillimeter Wave Technol Lab, Lowell, MA 01854 USA. [Yaroslavsky, Anna N.] Univ Massachusetts, Adv Biophoton Lab, Lowell, MA 01854 USA. [Yaroslavsky, Anna N.; Neel, Victor A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Joseph, CS (reprint author), Univ Massachusetts, Submillimeter Wave Technol Lab, 175 Cabot St, Lowell, MA 01854 USA. EM cecil_joseph@uml.edu NR 24 TC 28 Z9 30 U1 4 U2 32 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD AUG PY 2011 VL 43 IS 6 BP 457 EP 462 DI 10.1002/lsm.21078 PG 6 WC Dermatology; Surgery SC Dermatology; Surgery GA 799DE UT WOS:000293262900002 PM 21761415 ER PT J AU Wang, Y Kochevar, IE Redmond, RW Yao, M AF Wang, Ying Kochevar, Irene E. Redmond, Robert W. Yao, Min TI A Light-Activated Method for Repair of Corneal Surface Defects SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE amniotic membrane transplantation; corneal injury; lasers; photochemical tissue bonding; wound healing ID AMNIOTIC MEMBRANE TRANSPLANTATION; FIBRIN GLUE; RABBIT CORNEA; CROSS-LINKING; INCISIONS; RECONSTRUCTION; OPHTHALMOLOGY; MANAGEMENT; ADHESIVE; SURGERY AB Background and Objective: Amniotic membrane transplantation (AMT) sealed with sutures has been routinely used to treat ocular surface defects (OSD). However, the sutures used to secure the graft on the cornea cause additional injury, infection, and scarring. A new light-activated technique, called photochemical tissue bonding (PTB), has been developed for securing amniotic membrane (AM) over the corneal surface. The purpose of this study was to compare PTB versus traditional sutures in AMT for repair of OSD. Materials and Methods: An OSD was created in the left eye of 40 rabbits. The eyes were randomized into two repair groups: AMT using sutures and AMT using PTB with 0.1% Rose Bengal (RB) and 532 nm laser at 0.4 W/cm(2) for 200 seconds. Eyes were examined for re-epithelialization, inflammation, neovascularization, and scarring histologically and biochemically on postoperative days 1, 3, 14, and 28. Results: PTB strongly bonded AM over corneal defects. Corneal re-epithelialization did not differ significantly between the suture and PTB groups. Histology, immunohistology and Western blotting revealed that the numbers of inflammatory cells and the level of tumor necrosis factor-alpha in the PTB group were dramatically lower than those in the suture group on postoperative day 3. Many fewer neo-vessels were present in the PTB group (2.91 +/- 1.00) compared to the suture group (4.33 +/- 1.15) at day 28 (P < 0.05). The collagen fibers in the PTB group were well organized and orientated as assessed by second harmonic generation microscopy, suggesting that,PTB treatment led to less corneal scarring. Conclusions: PTB is a superior method for securing AM over OSD with improved wound healing compared to sutures. Lasers Surg. Med. 43:481-489, 2011. (c) 2011 Wiley-Liss, Inc. C1 [Wang, Ying; Kochevar, Irene E.; Redmond, Robert W.; Yao, Min] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Wang, Ying; Yao, Min] Shanghai Jiao Tong Univ, Sch Med, Shanghai 201900, Peoples R China. RP Yao, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. EM myao2@partners.org FU American Society for Laser Medicine and Surgery; WangKuanCheng Foundation of the School of Medicine; Shanghai Jiao Tong University; American Society for Laser Medicine and Surgery for Min Yao; WangKuanCheng Foundation of the School of Medicine, Shanghai Jiao Tong University FX Contract grant sponsor: American Society for Laser Medicine and Surgery; Contract grant sponsor: WangKuanCheng Foundation of the School of Medicine; Contract grant sponsor: Shanghai Jiao Tong University.; We are grateful to Dr. Jenny Zhao and Dr. Conor Evans for technical support. This study was partially supported by a grant from the American Society for Laser Medicine and Surgery for Min Yao (2008) and the WangKuanCheng Foundation of the School of Medicine, Shanghai Jiao Tong University (2008 and 2010). NR 26 TC 11 Z9 12 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD AUG PY 2011 VL 43 IS 6 BP 481 EP 489 DI 10.1002/lsm.21083 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 799DE UT WOS:000293262900005 PM 21761418 ER PT J AU Sander, JD Cade, L Khayter, C Reyon, D Peterson, RT Joung, JK Yeh, JRJ AF Sander, Jeffry D. Cade, Lindsay Khayter, Cyd Reyon, Deepak Peterson, Randall T. Joung, J. Keith Yeh, Jing-Ruey J. TI Targeted gene disruption in somatic zebrafish cells using engineered TALENs SO NATURE BIOTECHNOLOGY LA English DT Letter ID ZINC-FINGER NUCLEASES; EFFECTORS C1 [Sander, Jeffry D.; Khayter, Cyd; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA USA. [Sander, Jeffry D.; Khayter, Cyd; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA. [Sander, Jeffry D.; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Cade, Lindsay; Peterson, Randall T.; Yeh, Jing-Ruey J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Cade, Lindsay; Peterson, Randall T.; Yeh, Jing-Ruey J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Reyon, Deepak] Iowa State Univ, Dept Genet Dev & Cell Biol, Interdept Grad Program Bioinformat & Computat Bio, Ames, IA USA. [Peterson, Randall T.] Broad Inst, Cambridge, MA USA. RP Sander, JD (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA USA. EM jjoung@partners.org; jyeh1@partners.org FU NCI NIH HHS [R01 CA140188, T32 CA009216]; NIA NIH HHS [K01 AG031300, K01 AG031300-04]; NIGMS NIH HHS [DP1 GM105378, R01 GM088040]; NIH HHS [DP1 OD006862] NR 11 TC 302 Z9 340 U1 3 U2 79 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2011 VL 29 IS 8 BP 697 EP 698 DI 10.1038/nbt.1934 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 804ZV UT WOS:000293696500016 PM 21822241 ER PT J AU Zhao, WA Schafer, S Choi, J Yamanaka, YJ Lombardi, ML Bose, S Carlson, AL Phillips, JA Teo, WS Droujinine, IA Cui, CH Jain, RK Lammerding, J Love, JC Lin, CP Sarkar, D Karnik, R Karp, JM AF Zhao, Weian Schafer, Sebastian Choi, Jonghoon Yamanaka, Yvonne J. Lombardi, Maria L. Bose, Suman Carlson, Alicia L. Phillips, Joseph A. Teo, Weisuong Droujinine, Ilia A. Cui, Cheryl H. Jain, Rakesh K. Lammerding, Jan Love, J. Christopher Lin, Charles P. Sarkar, Debanjan Karnik, Rohit Karp, Jeffrey M. TI Cell-surface sensors for real-time probing of cellular environments SO NATURE NANOTECHNOLOGY LA English DT Article ID MESENCHYMAL STEM-CELLS; FACTOR-B-CHAIN; IN-VIVO; LIVING CELLS; BONE-MARROW; SELECTION; APTAMERS; LIGANDS; PROTEIN; FRET AB The ability to explore cell signalling and cell-to-cell communication is essential for understanding cell biology and developing effective therapeutics. However, it is not yet possible to monitor the interaction of cells with their environments in real time. Here, we show that a fluorescent sensor attached to a cell membrane can detect signalling molecules in the cellular environment. The sensor is an aptamer (a short length of single-stranded DNA) that binds to platelet-derived growth factor (PDGF) and contains a pair of fluorescent dyes. When bound to PDGF, the aptamer changes conformation and the dyes come closer to each other, producing a signal. The sensor, which is covalently attached to the membranes of mesenchymal stem cells, can quantitatively detect with high spatial and temporal resolution PDGF that is added in cell culture medium or secreted by neighbouring cells. The engineered stem cells retain their ability to find their way to the bone marrow and can be monitored in vivo at the single-cell level using intravital microscopy. C1 [Zhao, Weian; Schafer, Sebastian; Phillips, Joseph A.; Teo, Weisuong; Droujinine, Ilia A.; Cui, Cheryl H.; Sarkar, Debanjan; Karp, Jeffrey M.] Brigham & Womens Hosp, Ctr Regenerat Therapeut, Cambridge, MA 02139 USA. [Zhao, Weian; Schafer, Sebastian; Carlson, Alicia L.; Phillips, Joseph A.; Teo, Weisuong; Droujinine, Ilia A.; Cui, Cheryl H.; Lin, Charles P.; Sarkar, Debanjan; Karp, Jeffrey M.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Zhao, Weian; Schafer, Sebastian; Phillips, Joseph A.; Teo, Weisuong; Droujinine, Ilia A.; Cui, Cheryl H.; Lin, Charles P.; Sarkar, Debanjan; Karp, Jeffrey M.] Harvard Stem Cell Inst, Cambridge, MA 02139 USA. [Zhao, Weian; Schafer, Sebastian; Phillips, Joseph A.; Teo, Weisuong; Droujinine, Ilia A.; Cui, Cheryl H.; Sarkar, Debanjan; Karp, Jeffrey M.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Choi, Jonghoon; Yamanaka, Yvonne J.; Love, J. Christopher] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Yamanaka, Yvonne J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Lombardi, Maria L.; Lammerding, Jan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Cambridge, MA 02139 USA. [Bose, Suman; Karnik, Rohit] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Carlson, Alicia L.; Lin, Charles P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Carlson, Alicia L.; Lin, Charles P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Jain, Rakesh K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,Edwin L Steele Lab, Boston, MA 02114 USA. RP Zhao, WA (reprint author), Brigham & Womens Hosp, Ctr Regenerat Therapeut, 65 Landsdowne St, Cambridge, MA 02139 USA. EM jkarp@rics.bwh.harvard.edu RI Bose, Suman/A-1794-2009; Lammerding, Jan/A-9498-2016; Sarkar, Debanjan/C-6093-2017; OI Lammerding, Jan/0000-0003-4335-8611; Sarkar, Debanjan/0000-0002-6666-3152; Schafer, Sebastian/0000-0002-6909-8275 FU National Institutes of Health (NIH) [HL097172, HL095722, DE019191, HL082792, NS059348, NIAID 5RC1AI086152]; Charles A. Dana Foundation; American Heart Association [0970178N]; International Human Frontier Science Program Organization; National Science Foundation FX The authors thank Lei Xu and Dannie Wang for the preparation of PDGF-producing MDA-MB-231 cells. This work was supported by the National Institutes of Health (NIH; grants nos. HL097172, HL095722 and DE019191 to J.M.K., grants nos. HL082792 and NS059348 to J.L., and grant no. NIAID 5RC1AI086152 to J.C.L.), by the Charles A. Dana Foundation (J.C.L.) and by the American Heart Association (grant no. 0970178N to J.M.K.). W.Z. is supported by an International Human Frontier Science Program Organization postdoctoral fellowship. Y.J.Y. holds a National Science Foundation Graduate Fellowship. NR 49 TC 73 Z9 73 U1 7 U2 111 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD AUG PY 2011 VL 6 IS 8 BP 524 EP 531 DI 10.1038/NNANO.2011.101 PG 8 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 802HH UT WOS:000293499400014 PM 21765401 ER PT J AU De, S Michor, F AF De, Subhajyoti Michor, Franziska TI DNA secondary structures and epigenetic determinants of cancer genome evolution SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID G-QUADRUPLEX; G4 DNA; METHYLATION CHANGES; FORMING SEQUENCES; MAMMALIAN-CELLS; GENE-EXPRESSION; TELOMERIC DNA; COPY-NUMBER; INSTABILITY; BREAST AB An unstable genome is a hallmark of many cancers. It is unclear, however, whether some mutagenic features driving somatic alterations in cancer are encoded in the genome sequence and whether they can operate in a tissue-specific manner. We performed a genome-wide analysis of 663,446 DNA breakpoints associated with somatic copy-number alterations (SCNAs) from 2,792 cancer samples classified into 26 cancer types. Many SCNA breakpoints are spatially clustered in cancer genomes. We observed a significant enrichment for G-quadruplex sequences (G4s) in the vicinity of SCNA breakpoints and established that SCNAs show a strand bias consistent with G4-mediated structural alterations. Notably, abnormal hypomethylation near G4s-rich regions is a common signature for many SCNA breakpoint hotspots. We propose a mechanistic hypothesis that abnormal hypomethylation in genomic regions enriched for G4s acts as a mutagenic factor driving tissue-specific mutational landscapes in cancer. C1 [De, Subhajyoti; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [De, Subhajyoti; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Michor, F (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM michor@jimmy.harvard.edu FU Human Frontier Science Program; US National Cancer Institute's initiative to found Physical Science-Oncology Centers [U54CA143798] FX We would like to thank G. Parmigiani, J. Widom, N. Maizels, G.-Ch. Yuan, R. Beroukhim and D. Patel for discussions and comments. S. D. is a recipient of Human Frontier Science Program long-term fellowship and is a Research Fellow at King's College, Cambridge. This work was funded by the US National Cancer Institute's initiative to found Physical Science-Oncology Centers (U54CA143798). NR 50 TC 83 Z9 84 U1 3 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2011 VL 18 IS 8 BP 950 EP U115 DI 10.1038/nsmb.2089 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 801RD UT WOS:000293457200017 PM 21725294 ER PT J AU Wray, SH Martinez-Hernandez, E Dalmau, J Maheshwari, A Chen, A King, S Pitman, MB Leigh, RJ AF Wray, S. H. Martinez-Hernandez, E. Dalmau, J. Maheshwari, A. Chen, A. King, S. Pitman, M. Bishop Leigh, R. J. TI PARANEOPLASTIC UPBEAT NYSTAGMUS SO NEUROLOGY LA English DT Editorial Material C1 [Wray, S. H.; Dalmau, J.; Maheshwari, A.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Sch Med, Boston, MA 02114 USA. [Pitman, M. Bishop] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Martinez-Hernandez, E.; Dalmau, J.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Chen, A.; King, S.; Leigh, R. J.] Case Western Reserve Univ, Vet Affairs Med Ctr, Neurol Serv, Cleveland, OH 44106 USA. [Chen, A.; King, S.; Leigh, R. J.] Case Western Reserve Univ, Vet Affairs Med Ctr, Daroff DellOsso Lab, Cleveland, OH 44106 USA. RP Wray, SH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Sch Med, 55 Fruit St,Wang 705, Boston, MA 02114 USA. EM wray@helix.mgh.harvard.edu RI Martinez-Hernandez, Eugenia/L-3310-2014; OI Martinez-Hernandez, Eugenia/0000-0002-8317-7068; Dalmau, Josep/0000-0001-5856-2813 FU NEI NIH HHS [EY06717] NR 7 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 2011 VL 77 IS 7 BP 691 EP 693 DI 10.1212/WNL.0b013e318229e6a5 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 807FL UT WOS:000293881600021 PM 21813784 ER PT J AU Pham, CB Kratz, JR Jelin, AC Gelfand, AA AF Pham, Christina B. Kratz, Johannes R. Jelin, Angie C. Gelfand, Amy A. TI Child Neurology: Brachial plexus birth injury What every neurologist needs to know SO NEUROLOGY LA English DT Article ID SHOULDER DYSTOCIA; PALSY; MANAGEMENT AB While most often transient, brachial plexus birth injury can cause permanent neurologic injury. The major risk factors for brachial plexus birth injury are fetal macrosomia and shoulder dystocia. The degree of injury to the brachial plexus should be determined in the neonatal nursery, as those infants with the most severe injury-root avulsion-should be referred early for surgical evaluation so that microsurgical repair of the plexus can occur by 3 months of life. Microsurgical repair options include nerve grafts and nerve transfers. All children with brachial plexus birth injury require ongoing physical and occupational therapy and close follow-up to monitor progress. Neurology (R) 2011;77:695-697 C1 [Gelfand, Amy A.] Univ Calif San Francisco, Dept Neurol, Div Child Neurol, San Francisco, CA 94143 USA. [Pham, Christina B.] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Jelin, Angie C.] Univ Calif San Francisco, Dept Obstet & Gynecol, San Francisco, CA 94143 USA. [Jelin, Angie C.] Univ Calif San Francisco, Dept Genet, San Francisco, CA 94143 USA. [Kratz, Johannes R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Gelfand, AA (reprint author), Univ Calif San Francisco, Dept Neurol, Div Child Neurol, Box 0114,505 Parnassus Ave,M-798, San Francisco, CA 94143 USA. EM GelfandA@neuropeds.ucsf.edu FU American College of Surgeons FX Dr. Pham reports no disclosures. Dr. Kratz serves on the editorial board of the Journal of Thoracic Disease and has received researched fellowship support from the American College of Surgeons. Dr. Jelin reports no disclosures. Dr. Gelfand is a member of the editorial team for the Resident & Fellow section of Neurology (R). NR 15 TC 7 Z9 7 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 2011 VL 77 IS 7 BP 695 EP 697 DI 10.1212/WNL.0b013e31822a6874 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 807FL UT WOS:000293881600023 PM 21844527 ER PT J AU Jadhav, AP Venna, N AF Jadhav, Ashutosh Prabhakar Venna, Nagagopal TI Teaching NeuroImages: Gravity reverses paradoxical herniation in the sinking brain syndrome SO NEUROLOGY LA English DT Editorial Material C1 Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jadhav, AP (reprint author), Kaufmann Med Bldg,Suite 811,3471 5th Ave, Pittsburgh, PA 15213 USA. EM ashu@post.harvard.edu OI Jadhav, Ashutosh/0000-0002-9454-0678 NR 2 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG PY 2011 VL 77 IS 7 BP E42 EP E42 DI 10.1212/WNL.0b013e3182299e25 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 807FL UT WOS:000293881600002 PM 21844521 ER PT J AU Hobson, DTG Imudia, AN Soto, E Awonuga, AO AF Hobson, Deslyn T. G. Imudia, Anthony N. Soto, Eleazar Awonuga, Awoniyi O. TI Pregnancy Complicated by Recurrent Brain Abscess After Extraction of an Infected Tooth SO OBSTETRICS AND GYNECOLOGY LA English DT Article AB BACKGROUND: Odontogenic infections are quite common and, in unusual cases, can extend beyond the oral cavity with potentially life-threatening complications. CASE: A 35-year-old woman, G3P0020, underwent extraction of an infected left maxillary third molar tooth at 19 3/7 weeks of gestation and later presented with mental status changes. Computed tomography revealed left pterygoid muscle abscess, which progressed to brain abscess. She underwent multiple partial lobectomies to drain her recurrent brain abscess. The pregnancy continued until term, and she underwent a cesarean delivery. CONCLUSION: Brain abscess is a rare but life-threatening complication of pregnancy. This case illustrates the potential complications after extraction of an infected tooth in pregnancy. (Obstet Gynecol 2011;118:467-70) DOI: 10.1097/AOG.0b013e31822468d6 C1 [Hobson, Deslyn T. G.] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Div Maternal Fetal Med,Detroit Med Ctr, Detroit, MI 48201 USA. Wayne State Univ, Detroit Med Ctr, Sch Med, Div Reprod Endocrinol & Infertil, Detroit, MI 48201 USA. Massachusetts Gen Hosp, Div Reprod Med & IVF, Boston, MA 02114 USA. RP Hobson, DTG (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Div Maternal Fetal Med,Detroit Med Ctr, 3990 John R St,7 Brush N, Detroit, MI 48201 USA. EM dhobson@med.wayne.edu NR 8 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2011 VL 118 IS 2 BP 467 EP 470 DI 10.1097/AOG.0b013e31822468d6 PN 2 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 797HL UT WOS:000293115000021 PM 21768856 ER PT J AU Pal, J Bertheau, R Buon, L Qazi, A Batchu, RB Bandyopadhyay, S Ali-Fehmi, R Beer, DG Weaver, DW Reis, RJS Goyal, RK Huang, Q Munshi, NC Shammas, MA AF Pal, J. Bertheau, R. Buon, L. Qazi, A. Batchu, R. B. Bandyopadhyay, S. Ali-Fehmi, R. Beer, D. G. Weaver, D. W. Reis, R. J. Shmookler Goyal, R. K. Huang, Q. Munshi, N. C. Shammas, M. A. TI Genomic evolution in Barrett's adenocarcinoma cells: critical roles of elevated hsRAD51, homologous recombination and Alu sequences in the genome SO ONCOGENE LA English DT Article DE Barrett's adenocarcinoma; recombination; evolution; alu; hsRad51 ID ESOPHAGEAL ADENOCARCINOMA; TELOMERASE INHIBITION; DNA-REPAIR; MULTIPLE-MYELOMA; CHROMOSOMAL INSTABILITY; CANCER DEVELOPMENT; GENETIC-CONTROL; GASTRIC-CANCER; BREAST-CANCER; GROWTH ARREST AB A prominent feature of most cancers including Barrett's adenocarcinoma (BAC) is genetic instability, which is associated with development and progression of disease. In this study, we investigated the role of recombinase (hsRAD51), a key component of homologous recombination (HR)/repair, in evolving genomic changes and growth of BAC cells. We show that the expression of RAD51 is elevated in BAC cell lines and tissue specimens, relative to normal cells. HR activity is also elevated and significantly correlates with RAD51 expression in BAC cells. The suppression of RAD51 expression, by short hairpin RNA (shRNA) specifically targeting this gene, significantly prevented BAC cells from acquiring genomic changes to either copy number or heterozygosity (P<0.02) in several independent experiments employing single-nucleotide polymorphism arrays. The reduction in copy-number changes, following shRNA treatment, was confirmed by Comparative Genome Hybridization analyses of the same DNA samples. Moreover, the chromosomal distributions of mutations correlated strongly with frequencies and locations of Alu interspersed repetitive elements on individual chromosomes. We conclude that the hsRAD51 protein level is systematically elevated in BAC, contributes significantly to genomic evolution during serial propagation of these cells and correlates with disease progression. Alu sequences may serve as substrates for elevated HR during cell proliferation in vitro, as they have been reported to do during the evolution of species, and thus may provide additional targets for prevention or treatment of this disease. Oncogene (2011) 30, 3585-3598; doi:10.1038/onc.2011.83; published online 21 March 2011 C1 [Pal, J.; Bertheau, R.; Buon, L.; Munshi, N. C.; Shammas, M. A.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Pal, J.; Bertheau, R.; Goyal, R. K.; Huang, Q.; Munshi, N. C.; Shammas, M. A.] VA Hlth Care Syst, Dept Med Pathol, Boston, MA USA. [Qazi, A.; Batchu, R. B.; Bandyopadhyay, S.; Ali-Fehmi, R.; Weaver, D. W.] Wayne State Univ, Dept Surg Pathol, Detroit, MI USA. [Qazi, A.; Batchu, R. B.; Bandyopadhyay, S.; Ali-Fehmi, R.; Weaver, D. W.] Karmanos Canc Inst, Detroit, MI USA. [Beer, D. G.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Reis, R. J. Shmookler] Univ Arkansas Med Sci, Dept Geriatr, Little Rock, AR 72205 USA. [Reis, R. J. Shmookler] Univ Arkansas Med Sci, Dept Biochem & Mol Biol, Little Rock, AR 72205 USA. [Reis, R. J. Shmookler] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. [Goyal, R. K.; Munshi, N. C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Shammas, MA (reprint author), Dana Farber Canc Inst, 1400 VFW Pkwy,Bldg 3,Room 2A111, W Roxbury, MA 02132 USA. EM Masood_Shammas@DFCI.Harvard.Edu FU National Cancer Institute [R01CA125711]; Department of Veterans Affairs; National Institutes of Health [RO1-1375555, P50-100007, PO1-78378] FX We are grateful to Dr Cheng Li, Department of Bioinformatics and Dr Samir Amin, Departments of Medical Oncology and Bioinformatics, Dana Farber Cancer Institute, Boston, MA, USA, for their critical review of paper and guidance in data analyses. This work was supported in part by grants from National Cancer Institute (R01CA125711 to MAS), from the Department of Veterans Affairs (Merit Review Awards to NCM and RJSR and a Research Career Scientist Award to RJSR) and from the National Institutes of Health (RO1-1375555, P50-100007 and PO1-78378 to NCM). NR 79 TC 14 Z9 14 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG PY 2011 VL 30 IS 33 BP 3585 EP 3598 DI 10.1038/onc.2011.83 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 808UL UT WOS:000294005100003 PM 21423218 ER PT J AU Phillips, GS Bhargava, P Stanescu, L Dick, AA Parnell, SE AF Phillips, Grace S. Bhargava, Puneet Stanescu, Luana Dick, Andre A. Parnell, Shawn E. TI Pediatric intestinal transplantation: normal radiographic appearance and complications SO PEDIATRIC RADIOLOGY LA English DT Article DE Intestinal transplantation; Intestinal failure; Short gut syndrome; Transplant complications; Children ID HEPATIC-ARTERY THROMBOSIS; SMALL-BOWEL TRANSPLANTS; LIVER-TRANSPLANTATION; ENDOVASCULAR TREATMENT; MULTIVISCERAL TRANSPLANTATION; IMAGING FINDINGS; PORTAL-VEIN; CHILDREN; STENOSIS; SPECTRUM AB We present a pictorial essay on pediatric intestinal transplantation that describes the indications for pediatric intestinal transplantation, surgical technique, and the role of imaging in the pre-transplant work-up and detection of post-transplant complications. We illustrate the normal post-transplant imaging appearance and common complications, including rejection, infection, post-transplant lymphoproliferative disease (PTLD), mechanical dysfunction and vascular complications. We conclude with an imaging algorithm for suspected post-transplant complications based on clinical scenarios. C1 [Phillips, Grace S.; Stanescu, Luana; Parnell, Shawn E.] Univ Washington, Dept Radiol, Seattle Childrens Hosp, Seattle, WA 98105 USA. [Bhargava, Puneet] Univ Washington, Dept Radiol, VA Puget Sound Hlth Care Syst, Seattle, WA 98105 USA. [Dick, Andre A.] Univ Washington, Dept Surg, Seattle Childrens Hosp, Seattle, WA 98105 USA. RP Phillips, GS (reprint author), Univ Washington, Dept Radiol, Seattle Childrens Hosp, 4800 Sandpoint Way NE, Seattle, WA 98105 USA. EM grace.phillips@seattlechildrens.org RI Bhargava, Puneet /F-1330-2011; OI Bhargava, Puneet/0000-0002-3849-9666 NR 32 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD AUG PY 2011 VL 41 IS 8 BP 1028 EP 1039 DI 10.1007/s00247-011-2094-3 PG 12 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 806CD UT WOS:000293779400013 PM 21607597 ER PT J AU Fisher, DE AF Fisher, David E. TI UV-tanning behavior: a problem that doesn't go away SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Letter ID MELANOMA C1 Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Fisher, DE (reprint author), Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM dfisher3@partners.org NR 4 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD AUG PY 2011 VL 24 IS 4 BP 724 EP 724 DI 10.1111/j.1755-148X.2011.00865.x PG 1 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 808YZ UT WOS:000294019200020 PM 21535480 ER PT J AU Reddy, SK May, JW AF Reddy, Sashank K. May, James W., Jr. TI Hoofbeats SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Letter ID MANAGEMENT C1 [May, James W., Jr.] Harvard Univ, Massachusetts Gen Hosp, Div Plast Surg, Sch Med, Boston, MA 02114 USA. RP May, JW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Plast Surg, Sch Med, 15 Parkman St,Suite 435, Boston, MA 02114 USA. EM jwmay@partners.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD AUG PY 2011 VL 128 IS 2 BP 94E EP 95E DI 10.1097/PRS.0b013e31821ef358 PG 2 WC Surgery SC Surgery GA 801TV UT WOS:000293464400016 PM 21788813 ER PT J AU Tranulis, C Goff, D Henderson, DC Freudenreich, O AF Tranulis, Constantin Goff, Donald Henderson, David C. Freudenreich, Oliver TI Becoming Adherent to Antipsychotics: A Qualitative Study of Treatment-Experienced Schizophrenia Patients SO PSYCHIATRIC SERVICES LA English DT Article ID MEDICATION ADHERENCE; PSYCHOSIS; INSIGHT; SCALE AB Objective: Discontinuation of antipsychotic medication is a pervasive clinical problem in the treatment of patients suffering from psychosis. The aim of this study was to complement a largely quantitative body of research by focusing on patients' perspectives on the topic. Methods: In-depth semistructured interviews were conducted with 20 persons who have schizophrenia spectrum disorders. Narratives were elicited on illness and medication use and emphasized key turning points, such as periods of nonadherence and illness relapses. Results: Respondents had extensive experience with antipsychotic treatment (15 +/- 12 years of treatment). Nineteen (95%) reported at least one extended period of nonadherence. A complex picture of medication use or refusal emerged from patients' descriptions. An array of external factors influenced initiation of medication and treatment maintenance: pressure from family or clinicians, secondary benefits from initiating and maintaining treatment, and a variety of coercive measures. Moreover, personal factors transcended rational models in deciding whether to take medication; patients' responses stressed the importance of trust, emotional reactions, and subjective experiences with medication and stigma. Conclusions: These findings call into question the validity of a purely voluntaristic model of the use of antipsychotic medication. Its use was part of a long and painful fight with a debilitating disorder, and off-medication periods were essential parts of a learning process. (Psychiatric Services 62:888-892, 2011) C1 [Tranulis, Constantin] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. [Tranulis, Constantin; Goff, Donald; Henderson, David C.; Freudenreich, Oliver] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Tranulis, Constantin; Goff, Donald; Henderson, David C.; Freudenreich, Oliver] Harvard Univ, Sch Med, Boston, MA USA. RP Tranulis, C (reprint author), Univ Montreal, Dept Psychiat, CP 6128 Succursale Ctr Ville, Montreal, PQ H3C 3J7, Canada. EM con-stantin.tranulis@gmail.com FU Eli Lilly; University of Montreal; Louis H. Lafontaine Hospital, Montreal; Johnson Johnson; Pfizer FX Dr. Tranulis was supported by a fellowship grant from the Eli Lilly Schizophrenia Chair, University of Montreal, and from the Louis H. Lafontaine Hospital, Montreal. Dr. Henderson reports receiving research grant support from Johnson & Johnson and an honorarium from Reed Medical Education, and he has been a consultant for both Pfizer and Merck. Dr. Freudenreich reports receiving research grant support from Pfizer and an honorarium from Reed Medical Education, and he has been a consultant for Transcept and for Beacon Health Strategies. The other authors report no competing interests. NR 23 TC 16 Z9 17 U1 5 U2 15 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD AUG PY 2011 VL 62 IS 8 BP 888 EP 892 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 800CP UT WOS:000293336900009 PM 21807827 ER PT J AU Kilbourne, AM Pirraglia, PA Lai, ZS Bauer, MS Charns, MP Greenwald, D Welsh, DE McCarthy, JF Yano, EM AF Kilbourne, Amy M. Pirraglia, Paul A. Lai, Zongshan Bauer, Mark S. Charns, Martin P. Greenwald, Devra Welsh, Deborah E. McCarthy, John F. Yano, Elizabeth M. TI Quality of General Medical Care Among Patients With Serious Mental Illness: Does Colocation of Services Matter? SO PSYCHIATRIC SERVICES LA English DT Article ID HEALTH-CARE; CARDIOVASCULAR-DISEASE; NATIONAL-SURVEY; DISORDERS; VETERANS; INDIVIDUALS; ADULTS AB Objective: This study was conducted to determine whether patients with serious mental illness receiving care in Veterans Affairs (VA) mental health programs with colocated general medical clinics were more likely to receive adequate medical care than patients in programs without colocated clinics based on a nationally representative sample. Methods: The study included all VA patients with diagnoses of serious mental illness in fiscal year (FY) 2006-2007 who were also part of the VA's External Peer Review Program (EPRP) FY 2007 random sample and who received care from VA facilities (N=107 facilities) with organizational data from the VA Mental Health Program Survey (N=7,514).EPRP included patient-level chart review quality indicators for common processes of care (foot and retinal examinations for diabetes complications; screens for colorectal health, breast cancer, and alcohol misuse; and tobacco counseling) and outcomes (hypertension, diabetes blood sugar, and lipid control). Results: Ten out of 107 (10%) mental health programs had colocated medical clinics. After adjustment for organizational and patient-level factors, analyses showed that patients from colocated clinics compared with those without colocation were more likely to receive foot exams (OR=1.87, p<.05), colorectal cancer screenings (OR=1.54, p<.01), and alcohol misuse screenings (OR=2.92, p<.01). They were also more likely to have good blood pressure control (<140/90 mmHg; OR=1.32, p<.05) but less likely to have glycosylated hemoglobin <9% (OR=.69, p<.05). Conclusions: Colocation of medical care was associated with better quality of care for four of nine indicators. Additional strategies, particularly those focused on improving diabetes control and other chronic medical outcomes, might be warranted for patients with serious mental illness. (Psychiatric Services 62:922-928, 2011) C1 [Kilbourne, Amy M.; Lai, Zongshan; Welsh, Deborah E.; McCarthy, John F.] Dept Vet Affairs VA Ann Arbor, Serious Mental Illness Treatment Resource & Evalu, Ann Arbor, MI 48105 USA. [Pirraglia, Paul A.] Providence VA Med Ctr, Providence, RI USA. [Bauer, Mark S.; Charns, Martin P.] VA Boston Ctr Org Management & Leadership Res, Boston, MA USA. [Greenwald, Devra] VA Pittsburgh, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Yano, Elizabeth M.] VA Greater Los Angeles, HSR&D Ctr Excellence, Los Angeles, CA USA. RP Kilbourne, AM (reprint author), Dept Vet Affairs VA Ann Arbor, Serious Mental Illness Treatment Resource & Evalu, 11H,2215 Fuller Rd, Ann Arbor, MI 48105 USA. EM amykilbo@umich.edu FU VA Health Services Research and Development Service [07-115]; National Institute of Mental Health [R34 MH74509] FX This work was supported by grant 07-115 from the VA Health Services Research and Development Service and by grant R34 MH74509 from the National Institute of Mental Health. The authors acknowledge the VA Office of Quality and Performance for providing access to the VA EPRP data. The views expressed in this article are those of the authors and do not necessarily represent the views of the VA. NR 29 TC 17 Z9 17 U1 2 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD AUG PY 2011 VL 62 IS 8 BP 922 EP 928 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 800CP UT WOS:000293336900014 PM 21807832 ER PT J AU Lu, MW Duckart, JP O'Malley, JP Dobscha, SK AF Lu, Mary W. Duckart, Jonathan P. O'Malley, Jean P. Dobscha, Steven K. TI Correlates of Utilization of PTSD Specialty Treatment Among Recently Diagnosed Veterans at the VA SO PSYCHIATRIC SERVICES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; COMORBIDITY SURVEY REPLICATION; COGNITIVE PROCESSING THERAPY; MENTAL-HEALTH TREATMENT; UNITED-STATES; ADMINISTRATIVE DATA; TREATMENT-SEEKING; CARE; EPIDEMIOLOGY; AFGHANISTAN AB Objectives: This study described utilization of specialty treatment for posttraumatic stress disorder (PTSD) at U.S. Department of Veterans Affairs (VA) facilities among veterans of Operation Enduring Freedom (OEF), in Afghanistan, or of Operation Iraqi Freedom (OIF), in Iraq, and non-OEF-OIF veterans recently diagnosed as having PTSD. It also identified predictors of receiving minimally adequate specialty treatment, defined as attending at least nine clinic visits within 365 days of screening positive for PTSD. Methods: VA administrative data were obtained for 869 veterans who screened positive for PTSD between November 7, 2006, and September 30, 2008, received a diagnosis of PTSD, and visited a PTSD specialty clinic operated by the VA in the Pacific Northwest at least once within a year of screening positive. Results: A total of 286 (33%) of the 852 veterans for whom complete data were available received minimally adequate specialty treatment; OEF-OIF veterans were less likely than non-OEF-OIF veterans to receive minimally adequate specialty treatment (29% versus 36%, p=.021) and attended fewer mean +/- SD visits to a PTSD clinic (8.2 +/- 11.4 versus 9.9 +/- 13.5, p=.045). Predictors of receiving minimally adequate specialty treatment included attending a PTSD clinic visit within 30 days of a positive screen, living in an urban location, and having psychiatric comorbidities. Conclusions: Most veterans with new PTSD diagnoses who initiated VA PTSD specialty care did not receive minimally adequate specialty treatment. Future studies should examine factors that lead to premature discontinuation of PTSD treatment and to what extent specialty treatment for PTSD is necessary. (Psychiatric Services 62:943-949, 2011) C1 [Lu, Mary W.] Portland VA Med Ctr, Mental Hlth & Neurosci Div, Portland, OR 97239 USA. [Duckart, Jonathan P.; Dobscha, Steven K.] Portland VA Med Ctr, Portland Ctr Study Chron Comorbid Mental & Phys D, Portland, OR 97239 USA. [Lu, Mary W.; Dobscha, Steven K.] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Dept Psychiat, Portland, OR USA. [O'Malley, Jean P.] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Biostat & Design Program, Portland, OR USA. RP Lu, MW (reprint author), Portland VA Med Ctr, Mental Hlth & Neurosci Div, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM mary.lu@va.gov RI Schueter, nicos/A-3625-2014 FU VA Health Services Research and Development Service [REA 06-174]; Pacific Northwest Mental Illness Research and Education and Clinical Center FX This work was supported by VA Health Services Research and Development Service projects REA 06-174 and the Pacific Northwest Mental Illness Research and Education and Clinical Center. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. The authors acknowledge James M. Sardo, Ph.D., Miles E. McFall, Ph.D., Larry Dewey, M.D., William Minium, and Sara Smucker-Barnwell, Ph.D., for assistance in gathering information about facility PTSD services; Michael C. Leo, Ph.D., for statistical consultation; and Lauren M. Denneson, Ph.D., for editorial assistance. NR 31 TC 35 Z9 35 U1 0 U2 5 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD AUG PY 2011 VL 62 IS 8 BP 943 EP 949 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 800CP UT WOS:000293336900017 PM 21807835 ER PT J AU Miller, MW McKinney, AE Kanter, FS Korte, KJ Lovallo, WR AF Miller, Mark W. McKinney, Ann E. Kanter, Fredrick S. Korte, Kristina J. Lovallo, William R. TI Hydrocortisone suppression of the fear-potentiated startle response and posttraumatic stress disorder SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Hydrocortisone; Startle; PTSD; Cortisol; Fear-potentiated ID CORTICOTROPIN-RELEASING-FACTOR; URINARY CORTISOL EXCRETION; ADMINISTERED PTSD SCALE; ACOUSTIC STARTLE; VIETNAM VETERANS; PLASMA-CORTISOL; COMBAT VETERANS; GLUCOCORTICOID FEEDBACK; NEGATIVE AFFECT; HPA-AXIS AB This study examined the effects of oral administration of 20 mg hydrocortisone on baseline and fear-potentiated startle in 63 male veterans with or without PTSD. The procedure was based on a two-session, within-subject design in which acoustic startle eyeblink responses were recorded during intervals of threat or no threat of electric shock. Results showed that the magnitude of the difference between startle responses recorded during anticipation of imminent shock compared to "safe" periods was reduced after hydrocortisone administration relative to placebo. This effect did not vary as a function of PTSD group nor were there were any significant group differences in other indices startle amplitude. Findings suggest that the acute elevations in systemic cortisol produced by hydrocortisone administration may have fear-inhibiting effects. This finding may have implications for understanding the role of hypothalamic pituitary adrenal (HPA)-axis function in vulnerability and resilience to traumatic stress. Published by Elsevier Ltd. C1 [Miller, Mark W.; McKinney, Ann E.; Kanter, Fredrick S.; Korte, Kristina J.] Natl Ctr PTSD, VA Boston Healthcare Syst, Boston, MA 02130 USA. [Miller, Mark W.; Kanter, Fredrick S.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Lovallo, William R.] Vet Affairs Med Ctr, Behav Sci Labs, Oklahoma City, OK 73104 USA. RP Miller, MW (reprint author), Natl Ctr PTSD, VA Boston Healthcare Syst, 150 S Huntington Ave,116B-2, Boston, MA 02130 USA. EM mark.miller5@va.gov RI Schueter, nicos/A-3625-2014; Miller, Mark/G-7322-2011 OI Miller, Mark/0000-0001-6393-8563 FU NIMH [MH66324] FX Funding for this study was provided by NIMH grant MH66324; the NIMH had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 93 TC 12 Z9 14 U1 6 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD AUG PY 2011 VL 36 IS 7 BP 970 EP 980 DI 10.1016/j.psyneuen.2010.12.009 PG 11 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 807VQ UT WOS:000293931500004 PM 21269779 ER PT J AU Kacmarek, RM AF Kacmarek, Robert M. TI 37th Donald F Egan Scientific Memorial Lecture SO RESPIRATORY CARE LA English DT Article; Proceedings Paper CT 56th International Respiratory Congress of the American-Association-for-Respiratory-Care CY DEC 06-09, 2010 CL Las Vegas, NV SP Amer Assoc Resp Care DE mechanical ventilation; ventilators; negative-pressure ventilation; closed-loop; control; decision; support ID RESPIRATORY-DISTRESS-SYNDROME; ADAPTIVE SUPPORT VENTILATION; PROPORTIONAL ASSIST VENTILATION; POSITIVE-PRESSURE VENTILATION; END-EXPIRATORY PRESSURE; ADJUSTABLE GAIN FACTORS; MECHANICAL VENTILATION; NONINVASIVE VENTILATION; CONTROLLED-TRIAL; ICU VENTILATORS AB The use of ventilatory assistance can be traced back to biblical times. However, mechanical ventilators, in the form of negative-pressure ventilation, first appeared in the early 1800s. Positive-pressure devices started to become available around 1900 and today's typical intensive care unit (ICU) ventilator did not begin to be developed until the 1940s. From the original 1940s ventilators until today, 4 distinct generations of ICU ventilators have existed, each with features different from that of the previous generation. All of the advancements in ICU ventilator design over these generations provide the basis for speculation on the future. ICU ventilators of the future will be able to integrate electronically with other bedside technology; they will be able to effectively ventilate all patients in all settings, invasively and noninvasively; ventilator management protocols will be incorporated into the basic operation of the ventilator; organized information will be presented instead of rows of unrelated data; alarm systems will be smart; closed-loop control will be present on most aspects of ventilatory support; and decision support will be available. The key term that will be used to identify these future ventilators will be smart! C1 Harvard Univ, Sch Med, Resp Care Serv, Massachusetts Gen Hosp, Boston, MA 01460 USA. RP Kacmarek, RM (reprint author), Harvard Univ, Sch Med, Resp Care Serv, Massachusetts Gen Hosp, Warren 1225,55 Fruit St, Boston, MA 01460 USA. EM rkacmarek@partners.org NR 59 TC 14 Z9 14 U1 0 U2 1 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD AUG PY 2011 VL 56 IS 8 BP 1170 EP 1180 DI 10.4187/respcare.01420 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 807BO UT WOS:000293868500014 PM 21801579 ER PT J AU Fisher, DF AF Fisher, Daniel F. TI Novel Endotracheal Tube Cuffs: Improving the Seal as a Barrier to Leakage SO RESPIRATORY CARE LA English DT Editorial Material ID VENTILATOR-ASSOCIATED PNEUMONIA; EXPIRATORY PRESSURE; ASPIRATION; SHAPE C1 Massachusetts Gen Hosp, Resp Care Serv, Boston, MA 02114 USA. RP Fisher, DF (reprint author), Massachusetts Gen Hosp, Resp Care Serv, 55 Fruit St,Blake 652, Boston, MA 02114 USA. EM dfisher2@partners.org NR 17 TC 0 Z9 0 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 J9 RESP CARE JI Respir. Care PD AUG PY 2011 VL 56 IS 8 BP 1213 EP 1214 DI 10.4187/respcare.01460 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 807BO UT WOS:000293868500022 PM 21801582 ER PT J AU Frelinger, AL Michelson, AD Wiviott, SD Trenk, D Neumann, FJ Miller, DL Jakubowski, JA Costigan, TM McCabe, CH Antman, EM Braunwald, E AF Frelinger, Andrew L., III Michelson, Alan D. Wiviott, Stephen D. Trenk, Dietmar Neumann, Franz-Josef Miller, Debra L. Jakubowski, Joseph A. Costigan, Timothy M. McCabe, Carolyn H. Antman, Elliott M. Braunwald, Eugene TI Intrinsic platelet reactivity before P2Y(12) blockade contributes to residual platelet reactivity despite high-level P2Y(12) blockade by prasugrel or high-dose clopidogrel Results from PRINCIPLE-TIMI 44 SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Antiplatelet agents; cardiology; clinical trials; antiplatelet drugs; platelet pharmacology ID PERCUTANEOUS CORONARY INTERVENTION; ADENOSINE-DIPHOSPHATE; RESISTANCE; ACTIVATION; AGGREGATION; ADP; RESPONSIVENESS; METAANALYSIS; VARIABILITY; INHIBITION AB It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y(12) blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y(12) inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned per, cutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y(12) blockade with high-dose. clopidogrel or even higher level P2Y(12) blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies. C1 [Frelinger, Andrew L., III; Michelson, Alan D.] Harvard Univ, Ctr Platelet Res Studies, Div Hematol Oncol, Childrens Hosp Boston,Dana Farber Canc Inst,Med S, Boston, MA 02115 USA. [Frelinger, Andrew L., III; Michelson, Alan D.] Univ Massachusetts, Sch Med, Dept Pediat, Ctr Platelet Funct Studies, Worcester, MA USA. [Wiviott, Stephen D.; McCabe, Carolyn H.; Antman, Elliott M.; Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, TIMI Study Grp, Cardiovasc Div,Med Sch, Boston, MA 02115 USA. [Trenk, Dietmar; Neumann, Franz-Josef] Herz Zentrum Bad Krozingen, Bad Krozingen, Germany. [Miller, Debra L.; Jakubowski, Joseph A.; Costigan, Timothy M.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Michelson, AD (reprint author), Harvard Univ, Ctr Platelet Res Studies, Div Hematol Oncol, Childrens Hosp Boston,Dana Farber Canc Inst,Med S, Karp 08213,300 Longwood Ave, Boston, MA 02115 USA. EM alan.michelson@childrens.harvard.edu FU Daiichi Sankyo Company Limited (Tokyo, Japan); Eli Lilly and Company (Indianapolis, IN); GLSynthesis; Lilly/Daiichi Sankyo; Sanofi Aventis/Bristol-Myers Squibb; Schering Plough; Eli Lilly; Astra Zeneca FX Daiichi Sankyo Company Limited (Tokyo, Japan) and Eli Lilly and Company (Indianapolis, IN) sponsored the PRINCIPLE-TIMI 44 trial. The present analysis had no funding.; Dr. Frelinger: research grants from GLSynthesis, Lilly/Daiichi Sankyo and Sanofi Aventis/Bristol-Myers Squibb; consultant to Eli Lilly. Dr. Michelson: research grants from Lilly/Daiichi Sankyo and Sanofi Aventis/Bristol-Myers Squibb; member of the Data Safety Monitoring Board of Clopidogrel to Lower Arterial Thrombotic Risk in Neonates and Infants Trial (CLARINET) (a clinical trial sponsored by Sanofi Aventis/Bristol-Myers Squibb); consultant to Lilly/Daiichi Sankyo. Dr. Wiviott: research grants from Lilly/Daiichi Sankyo and Schering Plough; CME honoraria from Astra Zeneca, Lilly/Daiichi Sankyo and Schering Plough; consultant to AstraZeneca and Bristol-Myers Squibb/Sanofi Aventis. Dr. Trenk: research grant from Eli Lilly; speakers bureau for Lilly/Daiichi Sankyo; consultant to Astra Zeneca and Lilly/Daiichi Sankyo. Ms Miller and Drs. Jakubowski and Costigan are employees of Eli Lilly. Dr. Antman: research grants from Astra Zeneca, Lilly/Daiichi Sankyo and Sanofi Aventis/Bristol-Myers Squibb. Dr. Braunwald: research grants from Lilly/Daiichi Sankyo; honoraria from Eli Idly; Daiichi Sankyo advisory board; consultant to worldwide clinical trials. Dr. Neumann and Ms. McCabe report no disclosures. NR 28 TC 31 Z9 31 U1 0 U2 0 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 2011 VL 106 IS 2 BP 219 EP 226 DI 10.1160/TH11-03-0185 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 808RM UT WOS:000293996100007 PM 21713327 ER PT J AU Gu, AH Ji, GX Long, Y Zhou, Y Shi, XG Song, L Wang, XR AF Gu, Aihua Ji, Guixiang Long, Yan Zhou, Yong Shi, Xiangguo Song, Ling Wang, Xinru TI Assessment of an Association between an Aryl Hydrocarbon Receptor Gene (AHR) Polymorphism and Risk of Male Infertility SO TOXICOLOGICAL SCIENCES LA English DT Article DE AHR; polymorphisms; PAHs; DNA fragmentation; DNA adduct; male infertility ID POLYCYCLIC AROMATIC-HYDROCARBONS; HUMAN SEMEN QUALITY; CHINESE POPULATION; URINARY METABOLITES; REPRODUCTIVE HEALTH; FUNCTIONAL-ANALYSIS; DNA FRAGMENTATION; HUMAN SPERM; EXPOSURE; MICE AB The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxicity of a variety of environmental chemicals, such as polycyclic aromatic hydrocarbons (PAHs) and dioxins. We hypothesized that polymorphisms of AHR may result in significant differences in sensitivity to toxic effects of PAHs or dioxins and contribute to susceptibility to male infertility. To address this possibility, we conducted a study including 580 idiopathic infertile subjects and 580 fertile controls to assess associations between the male infertility risk and six tagging single nucleotide polymorphisms of AHR gene. Additionally, correlations between AHR polymorphisms and sperm concentration, levels of DNA fragmentation, and benzo(a)pyrene diolepoxide (BPDE)-DNA adducts in sperm were determined in 420 patients. Genotypes were determined using the ABI OpenArray platform. Sperm DNA fragmentation was evaluated by terminal deoxyribonucleotidyl transferase (TdT)-mediated dUDP nick-end labelling (TUNEL) assay, and sperm BPDE-DNA adducts were measured by immunofluorescent assay using flow cytometry. We found that the G variant of rs2158041 was associated with significantly increased risk of male infertility (adjusted odds ratio 1.53, 95% confidence interval 1.21-1.93; p = 6.0 x 10(-6); GA/AA vs. GG genotypes). Furthermore, patients with rs2158041 AA genotype showed a reduced sperm concentration. In addition, a gradual increase of sperm DNA fragmentation and sperm BPDE-DNA adducts was found among the three rs2158041 subgroups (GG -> GA -> AA), though the differences were not statistically significant. These results suggested that the AHR polymorphism might be associated with individual risk of male infertility in the Chinese population study. C1 [Gu, Aihua; Ji, Guixiang; Long, Yan; Shi, Xiangguo; Song, Ling; Wang, Xinru] Nanjing Med Univ, State Key Lab Reprod Med, Inst Toxicol, Nanjing 210029, Peoples R China. [Gu, Aihua; Ji, Guixiang; Long, Yan; Shi, Xiangguo; Song, Ling; Wang, Xinru] Nanjing Med Univ, Sch Publ Hlth, Key Lab Modern Toxicol, Minist Educ, Nanjing 210029, Peoples R China. [Zhou, Yong] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wang, XR (reprint author), Nanjing Med Univ, State Key Lab Reprod Med, Inst Toxicol, 140 Hanzhong Rd, Nanjing 210029, Peoples R China. EM xrwang@njmu.edu.cn FU National Basic Research Program of China (973 Program) [2009CB941703]; National Science Foundation of China [30901210]; National Natural Science Foundation of China [30930079]; Priority Academic Program Development of Jiangsu Higher Education Institutions FX National Basic Research Program of China (973 Program, 2009CB941703); the National Science Foundation of China (30901210); Key Project of National Natural Science Foundation of China (30930079); and Priority Academic Program Development of Jiangsu Higher Education Institutions. NR 43 TC 12 Z9 13 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2011 VL 122 IS 2 BP 415 EP 421 DI 10.1093/toxsci/kfr137 PG 7 WC Toxicology SC Toxicology GA 807QJ UT WOS:000293914500017 PM 21613234 ER PT J AU Rosow, L Jiang, JX Deuel, T Lechpammer, M Zamani, AA Milner, DA Folkerth, R Marty, FM Kesari, S AF Rosow, L. Jiang, J. X. Deuel, T. Lechpammer, M. Zamani, A. A. Milner, D. A. Folkerth, R. Marty, F. M. Kesari, S. TI Cerebral phaeohyphomycosis caused by Bipolaris spicifera after heart transplantation SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE brain abscess; phaeohyphomycosis; heart transplantation; Bipolaris spicifera; immunosuppression ID CENTRAL-NERVOUS-SYSTEM; DEMATIACEOUS FUNGI; INFECTIONS; PATIENT AB Phaeohyphomycosis is an increasingly recognized cause of brain abscess in both immunocompetent and immunocompromised hosts. We report a case of cerebral phaeohyphomycosis in a 55-year-old male heart transplant recipient caused by Bipolaris spicifera. We review the literature regarding the pathogenesis, epidemiology, diagnosis, and management of infections with dematiaceous fungi. C1 [Rosow, L.; Deuel, T.; Lechpammer, M.; Zamani, A. A.; Milner, D. A.; Folkerth, R.; Marty, F. M.; Kesari, S.] Harvard Univ, Sch Med, Boston, MA USA. [Jiang, J. X.] Nanjing Med Univ, Affiliated Hosp 1, Nanjing, Peoples R China. [Jiang, J. X.; Kesari, S.] Univ Calif San Diego, Dept Neurosci, Moores Canc Ctr, La Jolla, CA 92093 USA. [Deuel, T.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Lechpammer, M.; Milner, D. A.; Folkerth, R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Zamani, A. A.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Marty, F. M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Kesari, S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Kesari, S (reprint author), Moores UCSD Canc Ctr, Dept Neurosci, 3855 Hlth Sci Dr, La Jolla, CA 92093 USA. EM skesari@ucsd.edu RI Kesari, Santosh/E-8461-2013 NR 16 TC 13 Z9 13 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-2273 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD AUG PY 2011 VL 13 IS 4 BP 419 EP 423 DI 10.1111/j.1399-3062.2011.00610.x PG 5 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA 804MN UT WOS:000293658000015 PM 21323827 ER PT J AU Ayanbule, F Belaguli, NS Berger, DH AF Ayanbule, Funmi Belaguli, Narasimhaswamy S. Berger, David H. TI GATA Factors in Gastrointestinal Malignancy SO WORLD JOURNAL OF SURGERY LA English DT Article ID MUCIN GENE-EXPRESSION; TRANSCRIPTION FACTORS GATA-4; DNA-BINDING PROTEIN; SPASMOLYTIC POLYPEPTIDE PSP; IN-SITU HYBRIDIZATION; HEART TUBE FORMATION; CANCER CELL-LINE; PLASMINOGEN-ACTIVATOR; COLORECTAL-CANCER; BARRETTS-ESOPHAGUS AB GATA factors are unique transcription factors with conserved DNA-binding domains. They serve diverse roles in embryogenesis, cell differentiation, regulation of tissue-specific genes, and carcinogenesis. The subfamily GATA-4, -5, and -6 are highly expressed in endoderm-derived organs and regulate multiple gut-specific genes. Multiple studies have analyzed the role of GATA factors in gastrointestinal (GI) malignancy, such as those of the stomach, pancreas, and colon, and premalignant lesions such as Barrett's esophagus. The GATA factors appear to have distinct roles in regulating key genes involved in GI malignancy. Understanding the precise role of GATA factors in malignancy may lead to the development of effective molecular targets for cancer therapy. C1 [Ayanbule, Funmi; Belaguli, Narasimhaswamy S.; Berger, David H.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. RP Berger, DH (reprint author), Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Michael E DeBakey Dept Surg, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM dhb@bcm.edu NR 120 TC 14 Z9 14 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD AUG PY 2011 VL 35 IS 8 BP 1757 EP 1765 DI 10.1007/s00268-010-0950-1 PG 9 WC Surgery SC Surgery GA 805CZ UT WOS:000293705300009 PM 21210118 ER PT J AU Fayad, ZA Mani, V Woodward, M Kallend, D Bansilal, S Pozza, J Burgess, T Fuster, V Rudd, JHF Tawakol, A Farkouh, ME AF Fayad, Zahi A. Mani, Venkatesh Woodward, Mark Kallend, David Bansilal, Sameer Pozza, Joseph Burgess, Tracy Fuster, Valentin Rudd, James H. F. Tawakol, Ahmed Farkouh, Michael E. TI Rationale and design of dal-PLAQUE: A study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography SO AMERICAN HEART JOURNAL LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; RAPID EXTENDED COVERAGE; INTIMA-MEDIA THICKNESS; HIGH-RESOLUTION; CAROTID PLAQUE; VASCULAR INFLAMMATION; CETP INHIBITION; CORONARY ATHEROSCLEROSIS; BLOOD-PRESSURE; HIGH-RISK AB dal-PLAQUE is a placebo-controlled multicenter study designed to assess the effect of dalcetrapib on imaging measures of plaque inflammation and plaque burden. dal-PLAQUE is a multimodality imaging study in the context of the large dal-HEART Program. Decreased high-density lipoprotein cholesterol is linked to increased risk of coronary heart disease (CHD). Dalcetrapib, a compound that increases high-density lipoprotein cholesterol by modulating cholesteryl ester transfer protein, is being studied to assess if it can reduce the progression of atherosclerotic disease and thereby decrease cardiovascular morbidity and mortality. Patients with CHD or CHD-risk equivalents were randomized to receive 600 mg dalcetrapib or placebo daily for 24 months, in addition to conventional lipid-lowering medication and other medications for cardiovascular risk factors. The primary outcomes are the effect of dalcetrapib on 18F-fluorodeoxyglucose positron emission tomography target-to-background ratio after 6 months and magnetic resonance imaging (MRI) plaque burden (wall area, wall thickness, total vessel area, and wall area/total vessel area ratio) after 12 months. Secondary objectives include positron emission tomography target-to-background ratio at 3 months and MRI plaque burden at 6 and 24 months; plaque composition at 6, 12, and 24 months; and aortic compliance at 6 months. A tertiary objective is to examine the dynamic contrast-enhanced MRI parameters of plaque neovascularization. In total, 189 subjects entered screening, and 130 were randomized. dal-PLAQUE will provide important information on the effects of dalcetrapib on markers of inflammation and atherosclerotic plaque burden and, thereby, on the safety of cholesteryl ester transfer protein modulation with dalcetrapib. Results are expected in 2011. (Am Heart J 2011;162:214-221.e2.) C1 [Fayad, Zahi A.] Mt Sinai Sch Med, Dept Radiol, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Fayad, Zahi A.; Bansilal, Sameer; Fuster, Valentin; Farkouh, Michael E.] Mt Sinai Sch Med, Cardiovasc Inst, New York, NY 10029 USA. [Woodward, Mark] Univ Sydney, George Inst, Sydney, NSW 2006, Australia. [Pozza, Joseph; Burgess, Tracy] F Hoffmann La Roche Inc, Nutley, NJ USA. [Kallend, David] F Hoffmann La Roche Ltd, Basel, Switzerland. [Fuster, Valentin] Ctr Nacl Invest Cardiovasc, Madrid, Spain. [Rudd, James H. F.] Univ Cambridge, Div Cardiovasc Med, Cambridge CB2 1TN, England. [Tawakol, Ahmed] Harvard Univ, Sch Med, Boston, MA USA. [Tawakol, Ahmed] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Farkouh, Michael E.] Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Farkouh, Michael E.] Li Ki Shing Knowledge Inst, Toronto, ON, Canada. RP Fayad, ZA (reprint author), Mt Sinai Sch Med, Dept Radiol, Translat & Mol Imaging Inst, 1 Gustave L Levy Pl,Box 1234, New York, NY 10029 USA. EM zahi.fayad@mssm.edu RI Mani, Venkatesh/B-8939-2011; Woodward, Mark/D-8492-2015; Fuster, Valentin/H-4319-2015; OI Fuster, Valentin/0000-0002-9043-9986; Rudd, James/0000-0003-2243-3117; Mani, Venkatesh/0000-0002-0432-2918 FU Hoffmann-La Roche Inc.; F. Hoffmann-La Roche Ltd.; Roche; GlaxoSmithKline; Merck; VBL Therapeutics; Novartis; Bristol-Myers Squibb; Via Pharmaceuticals; National Institute for Health Research Cambridge Biomedical Research Centre FX This study was supported by Hoffmann-La Roche Inc.; This study was funded by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Prime Healthcare during the preparation of this report and funded by F. Hoffmann-La Roche Ltd. Z.A.F. discloses that he has received research grants from Roche, GlaxoSmithKline, Merck, VBL Therapeutics, Novartis, Bristol-Myers Squibb, and Via Pharmaceuticals and honoraria from Roche. M. E. F., J.H.F.R., A. T., and M. W. disclose that they have received honoraria from Roche. J.H.F.R. is part-supported by the National Institute for Health Research Cambridge Biomedical Research Centre. T. B. and J.P. disclose that they are employees of Hoffmann-La Roche Inc, and D. K. is an employee of F. Hoffmann-La Roche Ltd. V. M., S. B., and V. F. indicate that they have nothing to disclose. NR 55 TC 25 Z9 25 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2011 VL 162 IS 2 BP 214 EP U29 DI 10.1016/j.ahj.2011.05.006 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 805MB UT WOS:000293729400002 PM 21835280 ER PT J AU Rodriguez, F Joynt, KE Lopez, L Saldana, F Jha, AK AF Rodriguez, Fatima Joynt, Karen E. Lopez, Lenny Saldana, Fidencio Jha, Ashish K. TI Readmission rates for Hispanic Medicare beneficiaries with heart failure and acute myocardial infarction SO AMERICAN HEART JOURNAL LA English DT Article ID QUALITY-OF-CARE; LIMITED ENGLISH PROFICIENCY; DUTY HOUR REFORM; ETHNIC-DIFFERENCES; LANGUAGE BARRIERS; HEALTH-CARE; SOCIOECONOMIC-STATUS; ADMINISTRATIVE DATA; 30-DAY READMISSION; RISK ADJUSTMENT AB Background Hispanics are the fastest growing segment of the US population and have a higher prevalence of cardiovascular risk factors than non-Hispanic whites. However, little is known about whether elderly Hispanics have higher readmission rates for heart failure (HF) and acute myocardial infarction (AMI) than whites and whether this is due to site of care. Methods We examined hospitalizations for Medicare patients with a primary discharge diagnosis of HF and AMI in 2006 to 2008. We categorized hospitals in the top decile of proportion of Hispanic patients as "Hispanic serving" and used logistic regression to examine the relationship between patient ethnicity, hospital Hispanic-serving status, and readmissions. Results Hispanic patients had higher risk-adjusted readmission rates than whites for both HF (27.9% vs 25.9%, odds ratio [OR] 1.11, 95% CI 1.07-1.14, P < .001) and AMI (23.0% vs 21.0%, OR 1.12, 95% CI 1.07-1.18, P < .001). Similarly, Hispanic-serving hospitals had higher readmission rates than non-Hispanic-serving hospitals for both HF (27.4% vs 25.8%, OR 1.09, 95% CI 1.06-1.12, P < .001) and AMI (23.0% vs 20.8%, OR 1.13, 95% CI 1.09-1.18, P < .001). In analyses considering ethnicity and site of care simultaneously, both Hispanics and whites had higher readmission rates at Hispanic-serving hospitals. Conclusions Elderly Hispanic patients are more likely to be readmitted for HF and AMI than whites, partly due to the hospitals where they receive care. Our findings suggest that targeting the site of care and these high-risk patients themselves will be necessary to reduce disparities in readmissions for this growing group of patients. (Am Heart J 2011;162:254-261.e3.) C1 [Joynt, Karen E.; Saldana, Fidencio] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Rodriguez, Fatima] Harvard Univ, Sch Med, Boston, MA USA. [Joynt, Karen E.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Lopez, Lenny; Jha, Ashish K.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Lopez, Lenny] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Lopez, Lenny] Massachusetts Gen Hosp, Dispar Solut Ctr, Boston, MA 02114 USA. [Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. RP Joynt, KE (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. EM kjoynt@partners.org FU NHLBI NIH HHS [T32HL007604-24] NR 43 TC 16 Z9 16 U1 1 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2011 VL 162 IS 2 BP 254 EP U73 DI 10.1016/j.ahj.2011.05.009 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 805MB UT WOS:000293729400007 PM 21835285 ER PT J AU Bhardwaj, A Truong, QA Peacock, WF Yeo, KTJ Storrow, A Thomas, S Curtis, KM Foote, RS Lee, HK Miller, KF Januzzi, JL AF Bhardwaj, Anju Truong, Quynh A. Peacock, W. Frank Yeo, Kiang-Teck J. Storrow, Alan Thomas, Stephen Curtis, Kevin M. Foote, Robert S. Lee, Hong K. Miller, Karen F. Januzzi, James L., Jr. TI A multicenter comparison of established and emerging cardiac biomarkers for the diagnostic evaluation of chest pain in the emergency department SO AMERICAN HEART JOURNAL LA English DT Article ID ISCHEMIA-MODIFIED ALBUMIN; ACUTE CORONARY SYNDROME; ACUTE MYOCARDIAL-INFARCTION; BRAIN NATRIURETIC PEPTIDE; ACID-BINDING PROTEIN; TROPONIN-I ASSAY; MISSED DIAGNOSES; PROGNOSTIC VALUE; ARTERY-DISEASE; MARKER AB Background The aim of this study is to assess the role of novel biomarkers for the diagnostic evaluation of acute coronary syndrome (ACS). Methods Among 318 patients presenting to an emergency department with acute chest discomfort, we evaluated the diagnostic value of 5 candidate biomarkers (amino terminal pro-B-type natriuretic peptide [NT-proBNP], ischemia modified albumin, heart fatty acid binding protein, high-sensitivity troponin I [hsTnI], and unbound free fatty acids [FFAu]) for detecting ACS, comparing their results with that of conventional troponin T (cTnT). Results Sixty-two subjects (19.5%) had ACS. The sensitivity and negative predictive values of NT-proBNP (73%, 90%) and hsTnI (57%, 89%) were higher than that of cTnT (22%, 84%). Unbound free fatty acids had the highest overall combination of sensitivity (75%), specificity (72%), and negative predictive values (92%) of all the markers examined. A significant increase in the C-statistic for cTnT resulted from the addition of results for NT-proBNP (change 0.09, P = .001), hsTnI (change 0.13, P < .001), and FFAu (change 0.15, P < .001). In integrated discrimination improvement and net reclassification improvement analyses, NT-proBNP, hsTnI, and FFAu added significant diagnostic information to cTnT; when changing the diagnostic criterion standard for ACS to hsTnI, FFAu still added significant reclassification for both events and nonevents. In serial sampling (n = 180), FFAu added important reclassification information to hsTnI. Conclusion Among emergency department patients with symptoms suggestive of ACS, neither ischemia modified albumin nor heart fatty acid binding protein detected or excluded ACS, whereas NT-proBNP, hsTnI, or FFAu added diagnostic information to cTnT. In the context of hsTnI results, FFAu measurement significantly reclassified both false negatives and false positives at baseline and in serial samples. (Am Heart J 2011;162:276-282.e1.) C1 [Bhardwaj, Anju; Truong, Quynh A.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Thomas, Stephen] Massachusetts Gen Hosp, Div Emergency Med, Boston, MA 02114 USA. [Peacock, W. Frank] Cleveland Clin Fdn, Dept Emergency Med, Cleveland, OH 44195 USA. [Yeo, Kiang-Teck J.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Storrow, Alan; Miller, Karen F.] Vanderbilt Univ Sch Med, Dept Emergency Med, Nashville, TN USA. [Lee, Hong K.] Dartmouth Hitchcock Med Ctr, Dept Pathol, Lebanon, VT USA. [Curtis, Kevin M.] Dartmouth Hitchcock Med Ctr, Dept Emergency Med, Lebanon, VT USA. [Foote, Robert S.] Dartmouth Hitchcock Med Ctr, Dept Cardiol, Lebanon, VT USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5984,32 Fruit St, Boston, MA 02114 USA. EM JJanuzzi@partners.org NR 28 TC 14 Z9 14 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2011 VL 162 IS 2 BP 276 EP U98 DI 10.1016/j.ahj.2011.05.022 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 805MB UT WOS:000293729400010 PM 21835288 ER PT J AU Medina, HM Cannon, CP Zhao, X Hernandez, AF Bhatt, DL Peterson, ED Liang, L Fonarow, GC AF Medina, Hector M. Cannon, Christopher P. Zhao, Xin Hernandez, Adrian F. Bhatt, Deepak L. Peterson, Eric D. Liang, Li Fonarow, Gregg C. TI Quality of acute myocardial infarction care and outcomes in 33,997 patients aged 80 years or older: Findings from Get With The Guidelines-Coronary Artery Disease (GWTG-CAD) SO AMERICAN HEART JOURNAL LA English DT Article ID PLATELET GLYCOPROTEIN IIB/IIIA; HEART-ASSOCIATION COUNCIL; RANDOMIZED-TRIAL; FIBRINOLYTIC THERAPY; SCIENTIFIC STATEMENT; GERIATRIC-CARDIOLOGY; CLINICAL CARDIOLOGY; HOSPITAL MORTALITY; HEPARIN; TRENDS AB Objectives To determine the adherence to national guidelines and in-hospital mortality of older patients with acute myocardial infarction (AMI) using a national database. Background Prior studies have demonstrated that older patients are less likely to receive evidence-based therapies. Methods Using data from the GWTG-CAD, we examined care and in-hospital outcomes among AMI patients treated at 416 US centers from 2000 to 2009. Evidence-based medical therapy, other quality measures, and in-hospital post-AMI mortality were analyzed. Results A total of 156,677 patients were included in the study; 21.7% (n = 33,997) were aged = 80 years, 33.0% (n = 51,773) 65 to 79 years, and 45.3% (n = 70,907) 18 to 64 years. Older patients had higher prevalence of comorbidities compared to younger patients. Overall, compliance with evidence-based medical treatment upon admission and discharge was high, but age-related differences in care were seen for most measures. After multivariate adjustment, the mortality of the patients aged = 80 years was substantially higher compared to the youngest cohort (adjusted OR 3.4, 95% CI 3.2-3.8, P < .0001). There were substantial improvements in AMI quality measures over time in each age group. Conclusions Among AMI patients aged >= 80 years, the use of evidence-based therapies was high and significant improvements over time have been observed in a national quality improvement program. Nevertheless, there remain important age-related gaps in care and outcomes, suggesting opportunities exist to improve prognosis in this high-risk population. (Am Heart J 2011;162:283-290.e2.) C1 [Fonarow, Gregg C.] Ronald Reagan Univ Calif Los Angeles Med Ctr, Los Angeles, CA USA. [Medina, Hector M.] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR, PET,CT Program, Boston, MA 02114 USA. [Medina, Hector M.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Medina, Hector M.] Harvard Univ, Sch Med, Boston, MA USA. [Cannon, Christopher P.] TIMI Grp, Boston, MA USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Durham, NC USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Durham, NC USA. [Zhao, Xin; Hernandez, Adrian F.; Peterson, Eric D.; Liang, Li] Duke Clin Res Inst, Durham, NC USA. [Zhao, Xin; Hernandez, Adrian F.; Peterson, Eric D.; Liang, Li] Duke Univ, Med Ctr, Durham, NC USA. RP Fonarow, GC (reprint author), Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, 10833 LeConte Ave,Room A2-237 CHSLos Angeles, Los Angeles, CA 90095 USA. EM gfonarow@mednet.ucla.edu RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU American Heart Association; Merck/Schering-Plough Pharmaceutical; Pfizer; National Institutes of Health [1T32 HL076136]; Johnson Johnson; Accumetrics; AstraZeneca; GlaxoSmithKline; Intekrin Therapeutics; Merck; Takeda; GSK; Medtronic; Novartis; Bristol Myers Squibb; Eisai; Sanofi Aventis; Medicines Company FX GWTG-CAD is a program of the American Heart Association and is supported in part by an unrestricted educational grant from Merck/Schering-Plough Pharmaceutical and Pfizer. The analysis of registry data was performed at Duke Clinical Research Institute (Durham, NC), which receives funding from the American Heart Association. The sponsors were not involved in the design, analysis, preparation, review, or approval of this manuscript.; Hector M. Medina, MD: National Institutes of Health grant 1T32 HL076136.; Eric D. Peterson, MD: Schering Plough/Merck, research >$10,000; BMS/Sanofi, research >$10,000; Johnson & Johnson, research grant >$10,000.; Christopher P. Cannon, MD: Research grants/support: Accumetrics, AstraZeneca, GlaxoSmithKline, Intekrin Therapeutics, Merck, Takeda; Advisory Board: Bristol-Myers Squibb/Sanofi, Novartis, Alnylam; Honorarium for development of independent educational symposia: Pfizer, AstraZeneca; Clinical Advisor, equity in Automedics Medical Systems.; Adrian F. Hernandez, MD: Johnson & Johnson/Scios, research grant >$10,000; GSK, research grant <$10,000; Medtronic, research grant <$10,000, honoraria <$10,000; Novartis, research grant <$10,000, honoraria >$10,000; AstraZeneca, honoraria <$10,000.; Deepak L. Bhatt, MD: Bristol Myers Squibb, research grant >$10,000; Eisai, research grant >$10,000; Sanofi Aventis, research grant >$10,000; The Medicines Company, research grant >$10,000; Astra Zeneca, research grant >$10,000.; Gregg C. Fonarow, MD: NIH, research grant >$10,000; Novartis, consultant >$10,000. NR 33 TC 11 Z9 12 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2011 VL 162 IS 2 BP 283 EP U108 DI 10.1016/j.ahj.2011.04.017 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 805MB UT WOS:000293729400011 PM 21835289 ER PT J AU Byrd, JB Zeng, C Tavel, HM Magid, DJ O'Connor, PJ Margolis, KL Selby, JV Ho, PM AF Byrd, James B. Zeng, Chan Tavel, Heather M. Magid, David J. O'Connor, Patrick J. Margolis, Karen L. Selby, Joe V. Ho, P. Michael TI Combination therapy as initial treatment for newly diagnosed hypertension SO AMERICAN HEART JOURNAL LA English DT Article ID JOINT NATIONAL COMMITTEE; HIGH BLOOD-PRESSURE; UNCOMPLICATED HYPERTENSION; 7TH REPORT; TRIAL; PRESCRIPTIONS; PREVENTION; VISITS AB Background The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that clinicians consider the use of multidrug therapy to increase likelihood of achieving blood pressure goal. Little is known about recent patterns of combination antihypertensive therapy use in patients being initiated on hypertension treatment. Methods We investigated combination antihypertensive therapy use in newly diagnosed hypertensive patients from the Cardiovascular Research Network Hypertension Registry. Multivariable logistic regression was used to assess the relationship between combination antihypertensive therapy and 12-month blood pressure control. Results Between 2002 and 2007, a total of 161,585 patients met criteria for incident hypertension and were initiated on treatment. During the study period, an increasing proportion of patients were treated initially with combination rather than with single-agent therapy (20.7% in 2002 compared with 35.8% in 2007, P < .001). This increase in combination therapy use was more pronounced in patients with stage 2 hypertension, whose combination therapy use increased from 21.6% in 2002 to 44.5% in 2007. Nearly 90% of initial combination therapy was accounted for by 2 combinations, a thiazide and a potassium-sparing diuretic (47.6%) and a thiazide and an angiotensin-converting enzyme inhibitor (41.4%). After controlling for relevant clinical factors, including subsequent intensification of treatment and medication adherence, combination therapy was associated with increased odds of blood pressure control at 12 months (odds ratio compared with single-drug initial therapy 1.20; 95% CI 1.15-1.24, P < .001). Conclusions Initial treatment of hypertension with combination therapy is increasingly common and is associated with better long-term blood pressure control. (Am Heart J 2011;162:340-6.) C1 [Byrd, James B.] Univ Colorado, Sch Med, Dept Med, Aurora, CO USA. [Zeng, Chan; Tavel, Heather M.; Magid, David J.] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [O'Connor, Patrick J.; Margolis, Karen L.] HealthPartners Res Fdn, Minneapolis, MN USA. [Selby, Joe V.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Ho, P. Michael] Denver VA Med Ctr, Med Serv, Denver, CO USA. [Ho, P. Michael] Wellpoint Inc, Indianapolis, IN USA. RP Byrd, JB (reprint author), 12631 E 17th Ave B130, Aurora, CO 80045 USA. EM brian.byrd@ucdenver.edu OI Byrd, J. Brian/0000-0002-0509-3520 FU National Heart, Lung, and Blood Institute as part of the Cardiovascular Research Network [U19HL091179]; Veterans Affairs Research & Development Career Development Award [05-026-2]; Department of Veterans Affairs FX This study was funded by grant U19HL091179 from the National Heart, Lung, and Blood Institute as part of the Cardiovascular Research Network. Dr Ho is supported by a Veterans Affairs Research & Development Career Development Award (05-026-2). Dr Byrd was supported by a Department of Veterans Affairs Cardiology Research Fellowship. NR 14 TC 18 Z9 20 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2011 VL 162 IS 2 BP 340 EP 346 DI 10.1016/j.ahj.2011.05.010 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 805MB UT WOS:000293729400018 PM 21835296 ER PT J AU Hage, FG Dean, P Bhatia, V Iqbal, F Heo, J Iskandrian, AE AF Hage, Fadi G. Dean, Phillip Bhatia, Vikas Iqbal, Fahad Heo, Jaekyeong Iskandrian, Ami E. TI The prognostic value of the heart rate response to adenosine in relation to diabetes mellitus and chronic kidney disease SO AMERICAN HEART JOURNAL LA English DT Article ID EMISSION COMPUTED-TOMOGRAPHY; STAGE RENAL-DISEASE; CARDIOVASCULAR AUTONOMIC NEUROPATHY; STRESS MYOCARDIAL-PERFUSION; CORONARY-ARTERY DISEASE; SUDDEN CARDIAC DEATH; RISK; MORTALITY; IMPACT; ASSOCIATION AB Background Myocardial perfusion imaging (MPI) is a useful method for risk assessment in patients with diabetes mellitus (DM) and chronic kidney disease (CKD), but these patients have a residual risk that is not accounted for by MPI. The objective of this study is to determine whether the heart rate response (HRR) to adenosine has an incremental prognostic value to MPI in high-risk patients. Methods The study group included 879 (age 61 +/- 13 years, 48% women, 58% white, 40% DM, 49% CKD) consecutive patients who underwent adenosine MPI. Chronic kidney disease was defined as an estimated glomerular filtration rate b60 mL/min per 1.73 m(2) or dialysis replacement therapy. An HRR <10% (change from baseline) was considered blunted. The outcome of interest was overall mortality. Results During a follow-up period of 40 +/- 14 months, 212 patients (24%) died. Patients with DM (23.4% +/- 16.3% vs 29.4% +/- 21.4%, P < .0001) and CKD (22.7% +/- 17.6% vs 30.5% +/- 20.4%, P < .0001) had lower HRR as compared with patients without DM and CKD, respectively. A blunted HRR was associated with increased mortality in the overall population and in those with DM and CKD and helped in risk stratification when added to traditional MPI findings. In a Cox regression model, a blunted HRR was the strongest predictor of mortality (hazard ratio 2.8, P < .0001) and provided additional prognostic data to MPI (hazard ratio 1.9, P < .0001) after controlling for age, gender, race, history of myocardial infarction, DM, CKD, beta-blocker use, and presence of chest pain. Conclusions A blunted HRR to adenosine is an independent predictor of poor outcome, adds incremental value to MPI, and helps in better risk stratification in high-risk patient groups. (Am Heart J 2011;162:356-62.) C1 [Hage, Fadi G.; Iqbal, Fahad; Heo, Jaekyeong; Iskandrian, Ami E.] Univ Alabama, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Div Cardiol, Birmingham, AL USA. [Dean, Phillip; Bhatia, Vikas] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. RP Hage, FG (reprint author), Zeigler Res Bldg 1024,1530 3rd AVE S, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 26 TC 18 Z9 18 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2011 VL 162 IS 2 BP 356 EP 362 DI 10.1016/j.ahj.2011.05.014 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 805MB UT WOS:000293729400020 PM 21835298 ER PT J AU Uthamalingam, S Gurm, GS Daley, M Flynn, J Capodilupo, R AF Uthamalingam, Shanmugam Gurm, Gagandeep S. Daley, Marilyn Flynn, James Capodilupo, Robert TI Usefulness of Acute Delirium as a Predictor of Adverse Outcomes in Patients > 65 Years of Age With Acute Decompensated Heart Failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID OLDER PATIENTS; FUNCTIONAL OUTCOMES; MULTICENTER SURVEY; ILLNESS AB Delirium is an acute confusional state that is very prevalent in older patients hospitalized with acute decompensated heart failure (ADHF). The association between delirium and ADHF outcome has not been well described. We analyzed 883 consecutive patients >65 years of age admitted with ADHF. Acute delirium was diagnosed based on the Confusion Assessment Method. Delirious patients (total n = 151) had an increased in-hospital all-cause death compared to nondelirious patients (n = 17, 11%, vs n = 45, 6%; adjusted odds ratio [OR] 1.93, 95% confidence interval [CI] 1.07 to 3.48, p = 0.02). Of those surviving to discharge (n = 821), on multivariable logistic regression analysis, delirium was independently associated with increased risk of 30-day (adjusted OR 4.24, 95% CI 2.77 to 6.47, p <0.001) and 90-day (adjusted OR 3.72, 95% CI 2.51 to 5.54, p <0.001) rehospitalizations for ADHF and higher nursing home placement (adjusted OR 2.70, 95% CI 1.59 to 5.30, p <0.001) after adjusting for age, gender, cardiac risk factors, dementia, activities of daily living, instrumental activities of daily living, coronary artery disease, atrial fibrillation, left ventricular ejection fraction, angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker, beta blockers, Charlson co-morbidity index, and other potential confounders. Furthermore, delirium was strongly associated with 90-day all-cause mortality in patients discharged from the hospital (adjusted hazard ratio 2.10, CI 1.53 to 2.88, p <0.0001). In conclusion, acute delirium serves as an important prognostic determinant of in-hospital and posthospital discharge outcomes including increased ADHF readmission risk in older hospitalized patients with ADHF. Thus, delirium plays an important role in the risk stratification and prognosis of patients with ADHF. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:402-408) C1 [Uthamalingam, Shanmugam; Gurm, Gagandeep S.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Uthamalingam, Shanmugam; Daley, Marilyn; Flynn, James; Capodilupo, Robert] New England Heart Inst, Div Cardiol, Manchester, NH USA. RP Uthamalingam, S (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM suthamalingam@partners.org NR 22 TC 25 Z9 25 U1 2 U2 10 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 1 PY 2011 VL 108 IS 3 BP 402 EP 408 DI 10.1016/j.amjcard.2011.03.059 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 805YQ UT WOS:000293767400012 PM 21757045 ER PT J AU McCurdy, SM Dai, QX Zhang, JH Zamilpa, R Ramirez, TA Dayah, T Nguyen, N Jin, YF Bradshaw, AD Lindsey, ML AF McCurdy, Sarah M. Dai, Qiuxia Zhang, Jianhua Zamilpa, Rogelio Ramirez, Trevi A. Dayah, Tariq Nguyen Nguyen Jin, Yu-Fang Bradshaw, Amy D. Lindsey, Merry L. TI SPARC mediates early extracellular matrix remodeling following myocardial infarction SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE cardiac fibroblasts; left ventricular remodeling; mice; secreted protein, acidic, and rich in cysteine ID CYSTEINE SPARC; PROTEIN; HEART; MATRIX-METALLOPROTEINASE-9; FIBROBLASTS; MODEL; RICH AB McCurdy SM, Dai Q, Zhang J, Zamilpa R, Ramirez TA, Dayah T, Nguyen N, Jin YF, Bradshaw AD, Lindsey ML. SPARC mediates early extracellular matrix remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol 301: H497-H505, 2011. First published May 20, 2011; doi:10.1152/ajpheart.01070.2010.-Secreted protein, acidic, and rich in cysteine (SPARC) is a matricellular protein that functions in the extracellular processing of newly synthesized collagen. Collagen deposition to form a scar is a key event following a myocardial infarction (MI). Because the roles of SPARC in the early post-MI setting have not been defined, we examined age-matched wild-type (WT; n = 22) and SPARC-deficient (null; n = 25) mice at day 3 post-MI. Day 0 WT (n = 28) and null (n = 20) mice served as controls. Infarct size was 52 +/- 2% for WT and 47 +/- 2% for SPARC null (P = NS), indicating that the MI injury was comparable in the two groups. By echocardiography, WT mice increased end-diastolic volumes from 45 +/- 2 to 83 +/- 5 mu l (P < 0.05). SPARC null mice also increased end-diastolic volumes but to a lesser extent than WT (39 +/- 3 to 63 +/- 5 mu l; P < 0.05 vs. day 0 controls and vs. WT day 3 MI). Ejection fraction fell post-MI in WT mice from 57 +/- 2 to 19 +/- 1%. The decrease in ejection fraction was attenuated in the absence of SPARC (65 +/- 2 to 28 +/- 2%). Fibroblasts isolated from SPARC null left ventricle (LV) showed differences in the expression of 22 genes encoding extracellular matrix and adhesion molecule genes, including fibronectin, connective tissue growth factor (CTGF; CCN2), matrix metalloproteinase-3 (MMP-3), and tissue inhibitor of metalloproteinase-2 (TIMP-2). The change in fibroblast gene expression levels was mirrored in tissue protein extracts for fibronectin, CTGF, and MMP-3 but not TIMP-2. Combined, the results of this study indicate that SPARC deletion preserves LV function at day 3 post-MI but may be detrimental for the long-term response due to impaired fibroblast activation. C1 [McCurdy, Sarah M.; Dai, Qiuxia; Zhang, Jianhua; Zamilpa, Rogelio; Ramirez, Trevi A.; Dayah, Tariq; Lindsey, Merry L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Cardiol, San Antonio, TX 78229 USA. [Nguyen Nguyen; Jin, Yu-Fang] Univ Texas San Antonio, Dept Elect & Comp Engn, San Antonio, TX USA. [Bradshaw, Amy D.] Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Div Cardiol, Charleston, SC 29425 USA. [Bradshaw, Amy D.] Ralph H Johnson Vet Adm, Charleston, SC USA. RP Lindsey, ML (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Cardiol, 7703 Floyd Curl Dr,Mail Code 7872, San Antonio, TX 78229 USA. EM lindseym@uthscsa.edu RI Lindsey, Merry/B-2650-2012 FU National Institute of Biomedical Imaging and Bioengineering [1R03-EB-009496]; National Heart, Lung, and Blood Institute [SC2-HL-101430, 2P01-HL-48788, HL-094517, R01-HL-75360]; Veteran's Administration; American Heart Association [AHA 0855119F]; Max and Minnie Tomerlin Voelcker Fund; American Physiological Society FX Support for this study was provided by National Institute of Biomedical Imaging and Bioengineering Grant 1R03-EB-009496 and National Heart, Lung, and Blood Institute Grant SC2-HL-101430 (to Y. Jin); National Heart, Lung, and Blood Institute Grants 2P01-HL-48788 and HL-094517 and a Veteran's Administration Merit Award (to A. D. Bradshaw); and National Heart, Lung, and Blood Institute Grant R01-HL-75360, the American Heart Association AHA 0855119F, and the Max and Minnie Tomerlin Voelcker Fund (to M. L. Lindsey). S. M. McCurdy was supported in 2008 by the American Physiological Society Summer Undergraduate Research Fellowship. NR 21 TC 28 Z9 30 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG PY 2011 VL 301 IS 2 BP H497 EP H505 DI 10.1152/ajpheart.01070.2010 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 801MQ UT WOS:000293443800026 PM 21602472 ER PT J AU Li, W Zhang, Y Bouley, R Chen, Y Matsuzaki, T Nunes, P Hasler, U Brown, D Lu, HAJ AF Li, Wei Zhang, Yan Bouley, Richard Chen, Ying Matsuzaki, Toshiyuki Nunes, Paula Hasler, Udo Brown, Dennis Lu, Hua A. Jenny TI Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aquaporin 2; simvastatin; vasopressin; endocytosis; Brattleboro rats ID RENAL EPITHELIAL-CELLS; CHOLESTEROL DEPLETION; WATER CHANNEL; MEMBRANE INSERTION; APICAL MEMBRANE; COLLECTING DUCT; NITRIC-OXIDE; TRAFFICKING; PHOSPHORYLATION; AQP2 AB Li W, Zhang Y, Bouley R, Chen Y, Matsuzaki T, Nunes P, Hasler U, Brown D, Lu HA. Simvastatin enhances aquaporin 2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase. Am J Physiol Renal Physiol 301: F309-F318, 2011. First published April 20, 2011; doi: 10.1152/ajprenal.00001.2011.-Statins are 3-hydroxyl-3-methy-glutaryl-CoA reductase inhibitors that are commonly used to inhibit cholesterol biosynthesis. Emerging data have suggested that they also have "pleotropic effects," including modulating actin cytoskeleton reorganization. Here, we report an effect of simvastatin on the trafficking of aquaporin-2 (AQP2). Specifically, simvastatin induced the membrane accumulation of AQP2 in cell cultures and kidneys in situ. The effect of simvastatin was independent of protein kinase A activation and phosphorylation at AQP2-Ser(256), a critical event involved in vasopressin (VP)-regulated AQP2 trafficking. Further investigation showed that simvastatin inhibited endocytosis in parallel with downregulation of RhoA activity. Overexpression of active RhoA attenuated simvastatin's effect, suggesting the involvement of this small GTPase in simvastatin-mediated AQP2 trafficking. Finally, the effect of simvastatin on urinary concentration was investigated in VP-deficient Brattleboro rats. Simvastatin acutely (3-6 h) increased urinary concentration and decreased urine output in these animals. In summary, simvastatin regulates AQP2 trafficking in vitro and urinary concentration in vivo via events involving downregulation of Rho GTPase activity and inhibition of endocytosis. Our study provides an alternative mechanism to regulate AQP2 trafficking, bypassing the VP-vasopressin receptor signaling pathway. C1 [Lu, Hua A. Jenny] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol,Div Nephrol,Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lu, HAJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol,Div Nephrol,Dept Med, CPZN 8150,185 Cambridge St, Boston, MA 02114 USA. EM Halu@partners.org RI Nunes-Hasler, Paula/N-4337-2015 OI Nunes-Hasler, Paula/0000-0002-4598-685X FU NIH [DK-075940, DK-38452]; American Society of Nephrology; National Kidney Foundation; Swiss Fondation Suisee de Bourse en Medicine et Biologie; Massachusetts General Hospital; Boston Area Diabetes and Endocrinology Research Center (NIH) [DK-57521]; Center for the Study of Inflammatory Bowel Disease (NIH) [DK-43351] FX We thank Dr. Silvio Gutkind [National Institutes of Health (NIH)/National Institute of Dental and Craniofacial Research] and Emily Lecuona (Northwestern University) for providing important reagents. Dr. H. A. J. Lu is supported by an NIH KO8 Grant DK-075940 and a Gottschalk research grant from the American Society of Nephrology. Additional support was from NIH Grant DK-38452 (D. Brown). R. Bouley received a Young Investigator Award from the National Kidney Foundation. U. Hasler was supported by a Swiss Fondation Suisee de Bourse en Medicine et Biologie Fellowship and an Executive Committee on Research Fellowship from Massachusetts General Hospital. The Microscopy Core Facility of the Program in Membrane Biology receives additional support from the Boston Area Diabetes and Endocrinology Research Center (NIH DK-57521) and from the Center for the Study of Inflammatory Bowel Disease (NIH DK-43351). NR 57 TC 34 Z9 36 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD AUG PY 2011 VL 301 IS 2 BP F309 EP F318 DI 10.1152/ajprenal.00001.2011 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 801WV UT WOS:000293472200011 PM 21511701 ER PT J AU Kossman, S Hsieh, Y Peace, J Valdez, R Severtson, L Burke, L Brennan, PF AF Kossman, Susan Hsieh, Yichuan Peace, Jane Valdez, Rupa Severtson, Lori Burke, Laura Brennan, Patricia Flatley TI A theory-based problem-solving approach to recruitment challenges in a large randomized field trial SO APPLIED NURSING RESEARCH LA English DT Article ID INFORMED-CONSENT; PATIENT SAFETY; CARE; TELEMEDICINE; BARRIERS; DESIGN; SYSTEM AB Despite best-laid plans, recruitment problems arise in large field trials. Research teams must work hard on problem solving and push comfort zones to sustain recruitment and accrual levels. A systematic theory-based problem-solving approach helped us look deeply for challenges and implement strategies continuously to sustain accrual to our target enrollment. (C) 2011 Elsevier Inc. All rights reserved. C1 [Kossman, Susan] Illinois State Univ, Mennonite Coll Nursing, Normal, IL 61790 USA. [Severtson, Lori; Brennan, Patricia Flatley] Univ Wisconsin, Sch Nursing, Madison, WI 53792 USA. [Valdez, Rupa; Brennan, Patricia Flatley] Univ Wisconsin, Dept Ind & Syst Engn, Madison, WI 53706 USA. [Burke, Laura] Aurora Hlth Care Syst, Nursing Res, Milwaukee, WI 53233 USA. [Hsieh, Yichuan] Massachusetts Gen Hosp, Harvard Mit Hlth Sci & Technol, Comp Sci Lab, Boston, MA 02114 USA. [Peace, Jane] Univ N Carolina, Sch Nursing, Chapel Hill, NC 27599 USA. RP Kossman, S (reprint author), Illinois State Univ, Mennonite Coll Nursing, Campus Box 5810, Normal, IL 61790 USA. EM skossm@ilstu.edu; yhsieh1@partners.org; peace@wisc.edu; rsvaldez@students.wisc.edu; djsevert@wisc.edu; laura.burke@aurora.org; pbrennan@engr.wisc.edu FU National Library of Medicine [LM009063]; Yichuan Hsieh and Delores Severtson [5T15LM007359]; National Science Foundation; [LM008638]; [LM06249] FX Supported by the National Library of Medicine LM009063 (Susan Kossman), 5T15LM007359 (Yichuan Hsieh and Delores Severtson), LM008638 (Jane Peace), and LM06249 (Patricia Flatley Brennan) and the National Science Foundation Graduate Research Fellowship Program (Rupa Valdez). NR 18 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0897-1897 J9 APPL NURS RES JI Appl. Nurs. Res. PD AUG PY 2011 VL 24 IS 3 BP 179 EP 187 DI 10.1016/j.apnr.2009.06.006 PG 9 WC Nursing SC Nursing GA 804QW UT WOS:000293670100007 PM 20974068 ER PT J AU Singhal, AB Hajj-Ali, RA Topcuoglu, MA Fok, J Bena, J Yang, DS Calabrese, LH AF Singhal, Aneesh B. Hajj-Ali, Rula A. Topcuoglu, Mehmet A. Fok, Joshua Bena, James Yang, Donsheng Calabrese, Leonard H. TI Reversible Cerebral Vasoconstriction Syndromes Analysis of 139 Cases SO ARCHIVES OF NEUROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; SUBARACHNOID HEMORRHAGE; THUNDERCLAP HEADACHE; SEROTONERGIC DRUGS; BENIGN ANGIOPATHY; PRIMARY ANGIITIS; CLINICAL-COURSE; STROKE; ANGIOGRAPHY; DIAGNOSIS AB Objectives: To compare the clinical, laboratory, and imaging features of patients with reversible cerebral vasoconstriction syndromes evaluated at 2 academic centers, compare subgroups, and investigate treatment effects. Design: Retrospective analysis. Setting: Massachusetts General Hospital (n = 84) or Cleveland Clinic (n = 55). Patients: One hundred thirty-nine patients with reversible cerebral vasoconstriction syndromes. Main Outcome Measures: Clinical, laboratory, and imaging features; treatment; and outcomes. Results: The mean age was 42.5 years, and 81% were women. Onset with thunderclap headache was documented in 85% and 43% developed neurological deficits. Prior migraine was documented in 40%, vasoconstrictive drug exposure in 42%, and recent pregnancy in 9%. Admission computed tomography or magnetic resonance imaging was normal in 55%; however, 81% ultimately developed brain lesions including infarcts (39%), convexity subarachnoid hemorrhage (34%), lobar hemorrhage (20%), and brain edema (38%). Cerebral angiographic abnormalities typically normalized within 2 months. Nearly 90% had good clinical outcome; 9% developed severe deficits; and 2% died. In the combined cohort, calcium channel blocker therapy and symptomatic therapy alone showed no significant effect on outcome; however, glucocorticoid therapy showed a trend for poor outcome (P = .08). Subgroup comparisons based on prior headache status and identified triggers (vasoconstrictive drugs, pregnancy, other) showed no major differences. Conclusion: Patients with reversible cerebral vasoconstriction syndromes have a unique set of clinical imaging features, with no significant differences between subgroups. Prospective studies are warranted to determine the effects of empirical treatment with calcium channel blockers and glucocorticoids. C1 [Singhal, Aneesh B.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hajj-Ali, Rula A.; Calabrese, Leonard H.] Cleveland Clin, Dept Rheumatol, Cleveland, OH 44106 USA. [Bena, James; Yang, Donsheng] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Topcuoglu, Mehmet A.] Hacettepe Univ, Dept Neurol, Ankara, Turkey. [Fok, Joshua] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. RP Singhal, AB (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, ACC 729C, Boston, MA 02114 USA. EM asinghal@partners.org FU National Institutes of Health National Institute of Neurological Disorders and Stroke [R01NS051412, 5R01NS38477, R21NS061119, R01NS059775, P01 NS035611, P50NS051343] FX Dr Singhal has served as a medical expert witness in cases of RCVS. Over the last 2 years, Dr Singhal has received salary support from National Institutes of Health National Institute of Neurological Disorders and Stroke grants R01NS051412, 5R01NS38477, R21NS061119, R01NS059775, P01 NS035611, and P50NS051343. NR 33 TC 138 Z9 142 U1 2 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 2011 VL 68 IS 8 BP 1005 EP 1012 DI 10.1001/archneurol.2011.68 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 804IM UT WOS:000293647500006 PM 21482916 ER PT J AU Sabuncu, MR Desikan, RS Sepulcre, J Yeo, BTT Liu, HS Schmansky, NJ Reuter, M Weiner, MW Buckner, RL Sperling, RA Fischl, B AF Sabuncu, Mert R. Desikan, Rahul S. Sepulcre, Jorge Yeo, Boon Thye T. Liu, Hesheng Schmansky, Nicholas J. Reuter, Martin Weiner, Michael W. Buckner, Randy L. Sperling, Reisa A. Fischl, Bruce CA Alzheimers Dis Neuroimaging Initia TI The Dynamics of Cortical and Hippocampal Atrophy in Alzheimer Disease SO ARCHIVES OF NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; REGISTERED SERIAL MRI; HUMAN CEREBRAL-CORTEX; BRAIN ATROPHY; COORDINATE SYSTEM; LONGITUDINAL MRI; OLDER-ADULTS; PROGRESSION; RATES; DEMENTIA AB Objective: To characterize rates of regional Alzheimer disease (AD)-specific brain atrophy across the presymptomatic, mild cognitive impairment, and dementia stages. Design: Multicenter case-control study of neuroimaging, cerebrospinal fluid, and cognitive test score data from the Alzheimer's Disease Neuroimaging Initiative. Setting: Research centers across the United States and Canada. Patients: We examined a total of 317 participants with baseline cerebrospinal fluid biomarker measurements and 3T1-weighted magnetic resonance images obtained within 1 year. Main Outcome Measures: We used automated tools to compute annual longitudinal atrophy in the hippocampus and cortical regions targeted in AD. We used Mini-Mental State Examination scores as a measure of cognitive performance. We performed a cross-subject analysis of atrophy rates and acceleration on individuals with an AD-like cerebrospinal fluid molecular profile. Results: In presymptomatic individuals harboring indicators of AD, baseline thickness in AD-vulnerable cortical regions was significantly reduced compared with that of healthy control individuals, but baseline hippocampal volume was not. Across the clinical spectrum, rates of AD-specific cortical thinning increased with decreasing cognitive performance before peaking at approximately the Mini-Mental State Examination score of 21, beyond which rates of thinning started to decline. Annual rates of hippocampal volume loss showed a continuously increasing pattern with decreasing cognitive performance as low as the Mini-Mental State Examination score of 15. Analysis of the second derivative of imaging measurements revealed that AD-specific cortical thinning exhibited early acceleration followed by deceleration. Conversely, hippocampal volume loss exhibited positive acceleration across all study participants. Conclusions: Alzheimer disease-specific cortical thinning and hippocampal volume loss are consistent with a sigmoidal pattern, with an acceleration phase during the early stages of the disease. Clinical trials should carefully consider the nonlinear behavior of these AD biomarkers. C1 [Sabuncu, Mert R.; Desikan, Rahul S.; Sepulcre, Jorge; Yeo, Boon Thye T.; Liu, Hesheng; Schmansky, Nicholas J.; Reuter, Martin; Buckner, Randy L.; Sperling, Reisa A.; Fischl, Bruce] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Desikan, Rahul S.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Sabuncu, Mert R.; Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Sepulcre, Jorge; Yeo, Boon Thye T.; Buckner, Randy L.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Sepulcre, Jorge; Yeo, Boon Thye T.; Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Sepulcre, Jorge; Buckner, Randy L.] Howard Hughes Med Inst, Cambridge, MA USA. [Sperling, Reisa A.] Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol, Boston, MA 02115 USA. [Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Weiner, Michael W.] Dept Vet Affairs, San Francisco, CA USA. RP Sabuncu, MR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,13th St,Room 2301, Charlestown, MA 02129 USA. EM ms-abuncu@csail.mit.edu RI Reuter, Martin/B-3456-2010; OI Reuter, Martin/0000-0002-2665-9693; Liu, Hesheng/0000-0002-7233-1509; Yeo, B.T. Thomas/0000-0002-0119-3276 FU Foundation for the National Institutes of Health (NIH); Avid Radiopharmaceuticals Inc; GE Healthcare Japan; Research Association for Biotechnology; Pfizer Global Research Development; Forest Laboratories Inc; Alliance Medicale et Scientifique; National Multiple Sclerosis Society; Bayer Healthcare; Johns Hopkins University; Alzheimer's Association; Telemedicine & Advanced Technology Research Center; University of Pittsburgh; Neuroscience Early Stage Research Training Program; Rotman Research Institute; Wien Center for Alzheimer's Disease and Memory Disorders; Mount Sinai Medical Center; Society of Photographic Instrumentation Engineers; Montreal Neurological Institute and Hospital of McGill University; Michael J. Fox Foundation for Parkinson's Research; Elan and Wyeth Alzheimer's Immunotherapy Program (North America); University of California; Tel Aviv University Medical School; Colloquium Paris; Ipsen Group; Wenner-Gren Foundation; US Social Security Administration; Korean Neurological Association; NIH [U01 AG024904]; Washington University; Banner Alzheimer's Institute; Clinical Trials on Alzheimer's Disease; Veterans Affairs Central Office; Beijing Institute of Geriatrics; Innogenetics NV; New York University; NeuroVigil Inc; Centre Hospitalier Regional Universitaire-Hopital Roger Salengro; Siemens AG; AstraZeneca AB; Geneva University Hospitals; Eli Lilly and Company; Hopital Pitie-Salpetriere (Assistance Publique-Hopitaux de Paris); Institut Catala de Neurocisncies Aplicades; University of New Mexico School of Medicine; Merck Co Inc; US Department of Defense; US Department of Veterans Affairs; ADNI; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; National Center for Research Resources [P41-RR14075]; National Institute for Biomedical Imaging and Bioengineering [R01EB006758]; National Institute on Aging [AG022381]; National Institute for Neurological Disorders and Stroke [R01 NS052585-01]; National Center for Research Resources Biomedical Informatics Research Network [BIRN002, U24 RR021382]; National Center for Alternative Medicine [RC1 AT005728-01]; Shared Instrumentation Grants [1S10RR023401, 1S10RR019, 1S10RR023043]; Ellison Medical Foundation; Harvard Clinical and Translational Science Center [1KL2RR025757-01]; Harvard University and its affiliated academic health care centers FX Dr Weiner has served on scientific advisory boards for CoMentis Inc, Neurochem International Limited, Elan and Wyeth Alzheimer's Immunotherapy Program (North America), Novartis International AG, Banner Alzheimer's Institute Alzheimer's Prevention Initiative, Eli Lilly and Company, Araclon Biotech, Institut Catala de Neurociencies Aplicades, Research Advisory Committee on Gulf War Veterans' Illnesses, Biogen Idec, Pfizer Global Research & Development, Forest Laboratories Inc, Medivation Inc, Bayer Schering-Plough Corporation, Elan Pharmaceuticals Inc, Ipsen Group, Daiichi Sankyo Inc, AstraZeneca AB, TauRx Therapeutics Ltd, Bayer Healthcare, Exonhit Therapeutics SA, Servier Laboratories, and SYNARC Inc. He has received funding for travel from the Foundation for the National Institutes of Health (NIH); Avid Radiopharmaceuticals Inc; GE Healthcare Japan; the Research Association for Biotechnology; Pfizer Global Research & Development; Forest Laboratories Inc; Alliance Medicale et Scientifique; the National Multiple Sclerosis Society; Bayer Healthcare; The Johns Hopkins University; the Alzheimer's Association; the Telemedicine & Advanced Technology Research Center; the University of Pittsburgh; the Neuroscience Early Stage Research Training Program; the Rotman Research Institute; the Wien Center for Alzheimer's Disease and Memory Disorders; Mount Sinai Medical Center; the Society of Photographic Instrumentation Engineers; the Montreal Neurological Institute and Hospital of McGill University; the Michael J. Fox Foundation for Parkinson's Research; Elan and Wyeth Alzheimer's Immunotherapy Program (North America); Forest Laboratories Inc; the University of California, Davis; Tel Aviv University Medical School; Colloquium Paris; Ipsen Group; the Wenner-Gren Foundation; the US Social Security Administration; the Korean Neurological Association; the NIH; Washington University in St Louis; Banner Alzheimer's Institute; Clinical Trials on Alzheimer's Disease; the Veterans Affairs Central Office; the Beijing Institute of Geriatrics; Innogenetics NV; New York University; NeuroVigil Inc; Centre Hospitalier Regional Universitaire-Hopital Roger Salengro; Siemens AG; AstraZeneca AB; Geneva University Hospitals; Eli Lilly and Company; Hopital Pitie-Salpetriere (Assistance Publique-Hopitaux de Paris); Institut Catala de Neurocisncies Aplicades; the University of New Mexico School of Medicine; and Clinical Trials on Alzheimer's Disease. He has served on the editorial board for Alzheimer's & Dementia, has received honoraria from GEHealth-care Japan, Research Association for Biotechnology, The Johns Hopkins University, the Rotman Research Institute, the American Academy of Neurology, Ipsen Group, NeuroVigil Inc, and Institut Catala de Neurociencies Aplicades; has received commercial entities research support from Merck & Co Inc and Avid Radiopharmaceuticals Inc; has received government entities research support from the NIH, the US Department of Defense, and the US Department of Veterans Affairs; and has stock options in SYNARC Inc and Elan Pharmaceuticals Inc.; Data collection and sharing for this project was funded by the ADNI and NIH grant U01 AG024904 (principal investigator [PI], Dr Weiner). The ADNI is funded by the National Institute on Aging, by the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from Abbott Laboratories, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation plc, Genentech Inc, GEHealthcare, GlaxoSmithKline plc, Innogenetics NV, Johnson & Johnson Services Inc, Eli Lilly and Company, Medpace Inc, Merck & Co Inc, Novartis International AG, Pfizer Inc, F. Hoffman-La Roche Ltd, Schering-Plough Corporation, SYNARC Inc, and Wyeth Pharmaceuticals, as well as nonprofit partners the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to the ADNI are facilitated by the Foundation for the NIH. The grantee organization is the Northern California Institute for Research and Education Inc, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. The ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. Further support for this research was provided in part by grant P41-RR14075 from the National Center for Research Resources (Dr Fischl [PI, Bruce Rosen, MD, PhD]), grant R01EB006758 from the National Institute for Biomedical Imaging and Bioengineering (PI, Dr Fischl), grant AG022381 from the National Institute on Aging (Dr Fischl [PI, William S. Kremen, PhD]), grant R01 NS052585-01 from the National Institute for Neurological Disorders and Stroke (PI, Dr Fischl), grant P41-RR14075 from the National Center for Research Resources (Dr Fischl [PI, Dr Rosen]), grants BIRN002 and U24 RR021382 from the National Center for Research Resources Biomedical Informatics Research Network Morphometric Project (Dr Fischl [PI, Dr Rosen]), grant RC1 AT005728-01 from the National Center for Alternative Medicine (Dr Fischl [PI, Dr Rosen]), grant R01EB006758 from the National Institute for Biomedical Imaging and Bioengineering (PI, Dr Fischl), and grant R01 NS052585-01 from the National Institute for Neurological Disorders and Stroke (PI, Dr Fischl); from Shared Instrumentation Grants 1S10RR023401, 1S10RR019, and 1S10RR023043; and The Autism & Dyslexia Project funded by the Ellison Medical Foundation. Dr Sabuncu receives support from a KL2 Medical Research Investigator Training grant awarded via Harvard Catalyst, The Harvard Clinical and Translational Science Center (NIH grant 1KL2RR025757-01 and financial contributions from Harvard University and its affiliated academic health care centers). NR 42 TC 92 Z9 95 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 2011 VL 68 IS 8 BP 1040 EP 1048 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 804IM UT WOS:000293647500012 PM 21825241 ER PT J AU Hyman, BT AF Hyman, Bradley T. TI Amyloid-Dependent and Amyloid-Independent Stages of Alzheimer Disease SO ARCHIVES OF NEUROLOGY LA English DT Editorial Material ID SENILE PLAQUES; NEUROFIBRILLARY TANGLES; MOUSE MODEL; TAU; ACTIVATION; DEPOSITION; ACCUMULATION; IMMUNIZATION; DYSFUNCTION; NEURONS C1 Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, 114 16th St, Charlestown, MA 02129 USA. EM bhyman@partners.org FU NIA NIH HHS [P50AG05134, AG08487, P50 AG005134, R01 AG008487] NR 28 TC 85 Z9 86 U1 3 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD AUG PY 2011 VL 68 IS 8 BP 1062 EP 1064 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 804IM UT WOS:000293647500015 PM 21482918 ER PT J AU Stein, JD Pasquale, LR Talwar, N Kim, DS Reed, DM Nan, B Kang, JH Wiggs, JL Richards, JE AF Stein, Joshua D. Pasquale, Louis R. Talwar, Nidhi Kim, Denise S. Reed, David M. Nan, Bin Kang, Jae Hee Wiggs, Janey L. Richards, Julia E. TI Geographic and Climatic Factors Associated With Exfoliation Syndrome SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID SENSORINEURAL HEARING-LOSS; OPEN-ANGLE GLAUCOMA; RETINAL VEIN OCCLUSION; PSEUDOEXFOLIATION SYNDROME; DROPLET KERATOPATHY; LENS CAPSULE; PREVALENCE; HOMOCYSTEINE; PLASMA; CATARACT AB Objective: To identify geographic and climatic risk factors associated with exfoliation syndrome (ES). Methods: A retrospective study of 626 901 eye care recipients, dating from 2001 to 2007 from 47 US states in a managed care network. Incident ES cases-patients (N = 3367) were identified by using billing codes. We assessed the risk of ES by geographic latitude tier in the continental United States and assigned state-level climatic data (eg, ambient temperature, elevation, and sun exposure) according to patients' residential location. The hazard of ES was calculated by using multivariable-adjusted Cox proportional hazards regression models. Results: Compared with middle-tier residence, northerntier residence (above 42 N) was associated with an increased hazard of ES (adjusted hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.94-2.35). Southern-tier (below 37 N) was associated with a reduced hazard of ES (HR, 0.83; 95% CI, 0.75-0.93). Excluding whites did not change these associations. After adjustment for joint environmental effects, for every 1 increase in July high temperature, the hazard of ES decreased by 9% (HR, 0.91; 95% CI, 0.89-0.93); for every 1 increase in January low temperature, the hazard decreased 3% (0.97; 0.96-0.98). For each additional sunny day annually, the hazard increased by 1.5% (HR, 1.02; 95% CI, 1.01-1.02) in locations with average levels of other climatic factors. Conclusion: Ambient temperature and sun exposure may be important environmental triggers of ES. C1 [Stein, Joshua D.; Talwar, Nidhi; Kim, Denise S.; Reed, David M.; Richards, Julia E.] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Kang, Jae Hee] Harvard Univ, Brigham & Womens Hosp, Dept Med, Channing Lab,Sch Med, Boston, MA 02115 USA. [Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Sch Med, Boston, MA 02115 USA. [Nan, Bin] Univ Michigan, Dept Biostat, Sch Publ Hlth, Ann Arbor, MI 48105 USA. [Richards, Julia E.] Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48105 USA. RP Stein, JD (reprint author), Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. EM jdstein@med.umich.edu OI Reed, David/0000-0002-4772-6138 FU National Eye Institute [1K23EY019511-01, R01 EY011671, R01 EY015473]; American Glaucoma Society; Blue Cross Blue Shield of Michigan Foundation; Research to Prevent Blindness; Core Center for Vision Research, National Institutes of Health [EY007003] FX This study was supported by National Eye Institute K23 Mentored Clinician Scientist Award 1K23EY019511-01 and grants R01 EY011671 and R01 EY015473; an American Glaucoma Society Clinician Scientist Award; the Blue Cross Blue Shield of Michigan Foundation; unrestricted grants from Research to Prevent Blindness (Dr Pasquale); and the Core Center for Vision Research, National Institutes of Health grant EY007003 (Dr Reed). NR 67 TC 33 Z9 33 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD AUG PY 2011 VL 129 IS 8 BP 1053 EP 1060 PG 8 WC Ophthalmology SC Ophthalmology GA 804IZ UT WOS:000293648800011 PM 21825188 ER PT J AU Field, AE Gordon, CM Pierce, LM Ramappa, A Kocher, MS AF Field, Alison E. Gordon, Catherine M. Pierce, Laura M. Ramappa, Arun Kocher, Mininder S. TI Prospective Study of Physical Activity and Risk of Developing a Stress Fracture Among Preadolescent and Adolescent Girls SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID BONE MASS ACCUMULATION; MINERAL DENSITY; FEMALE RECRUITS; RUNNERS; AGE; EXERCISE; WEIGHT; TRACK; WOMEN; EPIDEMIOLOGY AB Objective: To identify predictors of developing a stress fracture among adolescent girls during a 7-year period. Design: Prospective cohort study. Setting: Adolescent girls living throughout the United States. Participants: A total of 6831 girls aged 9 to 15 years at baseline in the Growing Up Today Study, an ongoing prospective cohort study. Main Exposures: Exposures were assessed by self-report questionnaires completed by adolescent girls in 1996, 1997, 1998, 1999, 2000, 2001, and 2003. The adolescent girls' history of stress fracture, including age when fracture occurred and site, were reported by their mothers, who are registered nurses, in 2004. Cox proportional hazards models were used in the analysis. Main Outcome Measure: Incident stress fracture that occurred between 1997 and 2004. Results: During 7 years of follow-up, 267 girls (3.9%) developed a stress fracture. Independent of age, age at menarche, family history of fracture, and hours per week of low-and moderate-impact activity, hours per week of running (hazard ratio = 1.13; 95% confidence interval, 1.04-1.23), basketball (hazard ratio = 1.12; 95% confidence interval, 1.03-1.23), and cheerleading/gymnastics (hazard ratio = 1.12; 95% confidence interval, 1.02-1.22) were significant predictors of developing a stress fracture. No other type of high-impact activity was associated with an increased risk. Conclusion: Girls who engage in running, basketball, cheerleading, or gymnastics should be encouraged to include varied training in lower-impact activities to decrease the cumulative amount of impact in order to minimize their risk of stress fractures. C1 [Field, Alison E.; Gordon, Catherine M.; Pierce, Laura M.] Childrens Hosp, Div Adolescent Young Adult Med, Dept Med, Boston, MA 02115 USA. [Gordon, Catherine M.] Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Kocher, Mininder S.] Childrens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Field, Alison E.] Harvard Univ, Sch Med, Boston, MA USA. [Ramappa, Arun] Beth Israel Deaconness Med Ctr, Div Sports Med, Dept Orthopaed Surg, Boston, MA USA. [Field, Alison E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Field, Alison E.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Field, AE (reprint author), Childrens Hosp, Div Adolescent Young Adult Med, Dept Med, 300 Longwood Ave,AU-506, Boston, MA 02115 USA. EM alison.field@childrens.harvard.edu FU Pfizer/Merck; Harvard/Massachusetts Institute of Technology; Department of Orthopedics; Children's Hospital Boston; National Institutes of Health [DK-59570] FX Dr Gordon receives some salary support from Pfizer/Merck for her role as the codirector of a clinical investigator training program, which is funded by Harvard/Massachusetts Institute of Technology and Pfizer/Merck. Dr Kocher consults for Smith and Nephew Endoscopy, Biomet, OrthoPediatrics, Pivot Medical, and ConMed Linvatec.; This work was supported by the Department of Orthopedics, Children's Hospital Boston, and by research grant DK-59570 from the National Institutes of Health. NR 45 TC 23 Z9 26 U1 3 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD AUG PY 2011 VL 165 IS 8 BP 723 EP 728 DI 10.1001/archpediatrics.2011.34 PG 6 WC Pediatrics SC Pediatrics GA 800EP UT WOS:000293342900006 PM 21464375 ER PT J AU Mahajan, H Spaeth, DM Dicianno, BE Collins, DM Boninger, ML Cooper, RA AF Mahajan, Harshal Spaeth, Donald M. Dicianno, Brad E. Collins, Diane M. Boninger, Michael L. Cooper, Rory A. TI Comparison of Virtual Wheelchair Driving Performance of People With Traumatic Brain Injury Using an Isometric and a Conventional Joystick SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Assistive technology; Brain injuries, traumatic; Rehabilitation; User-computer interface; Wheelchairs, computer simulation ID ELECTRIC-POWERED WHEELCHAIRS; TARGET ACQUISITION; TECHNOLOGY; DISABILITIES; INDIVIDUALS; WORLDS AB Mahajan H, Spaeth DM, Dicianno BE, Collins DM, Boninger ML, Cooper RA. Comparison of virtual wheelchair driving performance of people with traumatic brain injury using an isometric and a conventional joystick. Arch Phys Med Rehabil 2011;92:1298-304. Objective: To compare wheelchair driving performance in a driving simulator using a conventional joystick and an isometric joystick. Design: Randomized, cohort study. Setting: A research facility based in a hospital or in an independent living center. Participants: Participants (N=20; 12 men, 8 women; mean age +/- SD, 30.62 +/- 10.91y) who were at least 1 year post-TBI. Interventions: Driving performance using an isometric joystick compared with a conventional movement joystick. Main Outcome Measures: Average trial completion time, and trajectory-specific measures measured orthogonal to the center of driving tasks: root mean squared error, movement offset, movement error, and number of significant changes in heading. Results: After statistically controlling for driving speed, participants were able to complete the driving tasks faster with an isometric joystick than while using a conventional movement joystick. Compared with the conventional joystick, an isometric joystick used for driving forward demonstrated fewer driving errors. During reverse driving the conventional joystick performed better. Conclusions: The customizable isometric joystick seems to be a promising interface for driving a powered wheelchair for individuals with TBI. C1 [Mahajan, Harshal; Spaeth, Donald M.; Dicianno, Brad E.; Boninger, Michael L.; Cooper, Rory A.] VA Pittsburgh HealthCare Syst, Human Engn Res Lab, Pittsburgh, PA 15206 USA. [Mahajan, Harshal; Spaeth, Donald M.; Dicianno, Brad E.; Boninger, Michael L.; Cooper, Rory A.] VA Pittsburgh HealthCare Syst, Ctr Excellence Wheelchairs & Related Technol, Pittsburgh, PA 15206 USA. [Dicianno, Brad E.; Boninger, Michael L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Mahajan, Harshal; Spaeth, Donald M.; Dicianno, Brad E.; Collins, Diane M.; Boninger, Michael L.; Cooper, Rory A.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Dicianno, Brad E.; Boninger, Michael L.; Cooper, Rory A.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. RP Cooper, RA (reprint author), VA Pittsburgh HealthCare Syst, Human Engn Res Lab, 7180 Highland Dr,Bldg 4,2nd Fl E,151R1-H, Pittsburgh, PA 15206 USA. EM rcooper@pitt.edu OI Boninger, Michael/0000-0001-6966-919X; Dicianno, Brad/0000-0003-0738-0192 FU National Institute on Disability and Rehabilitation Research; U.S. Department of Education [H133A020502]; Human Engineering Research Laboratories, VA Pittsburgh HealthCare System FX Supported by the National Institute on Disability and Rehabilitation Research, U.S. Department of Education (grant no. H133A020502), and with resources and facilities by the Human Engineering Research Laboratories, VA Pittsburgh HealthCare System. The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government. NR 25 TC 8 Z9 8 U1 4 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD AUG PY 2011 VL 92 IS 8 BP 1298 EP 1304 DI 10.1016/j.apmr.2011.03.011 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 803WL UT WOS:000293612800016 PM 21807150 ER PT J AU Palmer, CD Guinan, EC Levy, O AF Palmer, Christine D. Guinan, Eva C. Levy, Ofer TI Deficient expression of bactericidal/permeability-increasing protein in immunocompromised hosts: translational potential of replacement therapy SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article DE antibody (Ab); bactericidal/permeability-increasing protein (BPI); cystic fibrosis (CF); host defence; lipoxin (LX) ID AMINO-TERMINAL FRAGMENT; GRAM-NEGATIVE BACTERIA; SEVERE MENINGOCOCCAL SEPSIS; HUMAN MUCOSAL EPITHELIA; CYSTIC-FIBROSIS; BINDING PROTEIN; INNATE IMMUNITY; POLYMORPHONUCLEAR LEUKOCYTES; MICROBIAL TRANSLOCATION; ANTIMICROBIAL PROTEINS AB BPI (bactericidal/permeability-increasing protein) is a 55 kDa anti-infective molecule expressed in neutrophil and eosinophil granules and on some epithelial cells. BPI's high affinity for the lipid A region of endotoxin targets its opsonizing, microbicidal and endotoxin-neutralizing activities towards Gram-negative bacteria. Several immunocompromised patient populations demonstrate BPI deficiency, including newborns, those with anti-neutrophil cytoplasmic antibodies (as in cystic fibrosis and HIV infection) and those exposed to radiochemotherapy. BPI may be replenished by administering agents that induce its expression or by administration of recombinant BPI congeners, potentially shielding BPI-deficient individuals against Gram-negative bacterial infection, endotoxemia and its toxic sequelae. C1 [Palmer, Christine D.; Guinan, Eva C.; Levy, Ofer] Childrens Hosp, Boston, MA 02115 USA. [Palmer, Christine D.; Guinan, Eva C.; Levy, Ofer] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Guinan, Eva C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Levy, O (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM ofer.levy@childrens.harvard.edu FU Dana Foundation; DARPA (Defense Advanced Research Projects Agency); NIH [R21 1R21HL089659-01A1, R01 AI067353-01A1]; Greene Family Fund; Dartmouth Center for Medical Countermeasures against Radiation FX Work by E.C.G. and O.L. has been supported by a Human Immunology Grant from The Dana Foundation, The DARPA (Defense Advanced Research Projects Agency), NIH R21 1R21HL089659-01A1. C.D.P. is in part supported by Greene Family Fund. O.L's laboratory is also supported by NIH R01 AI067353-01A1 and a pilot grant award from the Dartmouth Center for Medical Countermeasures against Radiation. The Levy and Guinan laboratories have received reagent support in the form of rPBI21 from XOMA (US) LLC. NR 69 TC 9 Z9 11 U1 1 U2 6 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2011 VL 39 BP 994 EP 999 DI 10.1042/BST0390994 PN 4 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 806NL UT WOS:000293814800026 PM 21787336 ER PT J AU Neuhausen, SL Brummel, S Ding, YC Steele, L Nathanson, KL Domchek, S Rebbeck, TR Singer, CF Pfeiler, G Lynch, HT Garber, JE Couch, F Weitzel, JN Godwin, A Narod, SA Ganz, PA Daly, MB Isaacs, C Olopade, OI Tomlinson, GE Rubinstein, WS Tung, N Blum, JL Gillen, DL AF Neuhausen, Susan L. Brummel, Sean Ding, Yuan Chun Steele, Linda Nathanson, Katherine L. Domchek, Susan Rebbeck, Timothy R. Singer, Christian F. Pfeiler, Georg Lynch, Henry T. Garber, Judy E. Couch, Fergus Weitzel, Jeffrey N. Godwin, Andrew Narod, Steven A. Ganz, Patricia A. Daly, Mary B. Isaacs, Claudine Olopade, Olufunmilayo I. Tomlinson, Gail E. Rubinstein, Wendy S. Tung, Nadine Blum, Joanne L. Gillen, Daniel L. TI Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; MUTATION CARRIERS; OVARIAN-CANCER; FAMILIES; PENETRANCE; INFERENCE; AXIS; ASSOCIATION; POPULATION; EXPRESSION AB Background: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made. Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 20(8); 1690-702. (C)2011 AACR. C1 [Brummel, Sean] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Garber, Judy E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Nathanson, Katherine L.; Domchek, Susan; Rebbeck, Timothy R.] Univ Penn, Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Nathanson, Katherine L.; Domchek, Susan] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Singer, Christian F.; Pfeiler, Georg] Med Univ Vienna, Div Special Gynecol, Dept Obstet & Gynaecol, Vienna, Austria. [Lynch, Henry T.] Creighton Univ, Dept Med, Omaha, NE 68178 USA. [Lynch, Henry T.] Creighton Univ, Dept Prevent Med & Publ Hlth, Omaha, NE 68178 USA. [Couch, Fergus] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Godwin, Andrew] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Narod, Steven A.] Womens Coll Hosp, Toronto, ON M5S 1B2, Canada. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Isaacs, Claudine] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. [Olopade, Olufunmilayo I.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Olopade, Olufunmilayo I.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Tomlinson, Gail E.] Univ Texas Hlth Sci Ctr San Antonio, Div Pediat Hematol Oncol, San Antonio, TX 78229 USA. [Tomlinson, Gail E.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Rubinstein, Wendy S.] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA. [Rubinstein, Wendy S.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Blum, Joanne L.] Baylor Charles A Sammons Canc Ctr, Dallas, TX USA. [Gillen, Daniel L.] Univ Calif Irvine, Dept Stat, Irvine, CA USA. [Gillen, Daniel L.] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Neuhausen, Susan L.; Ding, Yuan Chun; Steele, Linda; Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, Duarte, CA 91010 USA. RP Neuhausen, SL (reprint author), City Hope Natl Med Ctr, Dept Populat Sci, Beckman Res Inst, 1500 E Duarte, Duarte, CA 91010 USA. EM sneuhausen@coh.org RI Tomlinson, George/L-5432-2016; OI Tomlinson, George/0000-0002-9328-6399; Nathanson, Katherine/0000-0002-6740-0901 FU NIH [5UO1 CA86389, R01-CA083855, R01-CA74415, R03-CA135691, R01-CA102776, RC4-CA153828, R01CA140323, 5U01CA113916, R01-CA128978, R01-CA116167, U01CA69631]; Breast Cancer Research Foundation; Nebraska Department of Health and Human Services; Morris and Horowitz Families Endowment FX Support was received from NIH grants 5UO1 CA86389 (to H.T. Lynch), R01-CA083855 and R01-CA74415 (to S.L. Neuhausen), R03-CA135691 (to D.L. Gillen), R01-CA102776 and R01-CA083855 (to T.R. Rebbeck), RC4-CA153828 (to J.N. Weitzel), R01CA140323 and 5U01CA113916 (to A. Godwin), R01-CA128978 and R01-CA116167 (to F. Couch), and U01CA69631 (to M.B. Daly) and a grant from the Breast Cancer Research Foundation (to F. Couch). This publication was supported in part by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. S.L. Neuhausen is partially supported by the Morris and Horowitz Families Endowment. NR 45 TC 11 Z9 11 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2011 VL 20 IS 8 BP 1690 EP 1702 DI 10.1158/1055-9965.EPI-10-1336 PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 804AK UT WOS:000293625600014 PM 21708937 ER PT J AU Permuth-Wey, J Chen, ZH Tsai, YY Lin, HY Chen, YA Barnholtz-Sloan, J Birrer, MJ Chanock, SJ Cramer, DW Cunningham, JM Fenstermacher, D Fridley, BL Garcia-Closas, M Gayther, SA Gentry-Maharaj, A Gonzalez-Bosquet, J Iversen, E Jim, H McLaughlin, J Menon, U Narod, SA Phelan, CM Ramus, SJ Risch, H Song, HL Sutphen, R Terry, KL Tyrer, J Vierkant, RA Wentzensen, N Lancaster, JM Cheng, JQ Berchuck, A Pharoah, PDP Schildkraut, JM Goode, EL Sellers, TA AF Permuth-Wey, Jennifer Chen, Zhihua Tsai, Ya-Yu Lin, Hui-Yi Chen, Y. Ann Barnholtz-Sloan, Jill Birrer, Michael J. Chanock, Stephen J. Cramer, Daniel W. Cunningham, Julie M. Fenstermacher, David Fridley, Brooke L. Garcia-Closas, Montserrat Gayther, Simon A. Gentry-Maharaj, Aleksandra Gonzalez-Bosquet, Jesus Iversen, Edwin Jim, Heather McLaughlin, John Menon, Usha Narod, Steven A. Phelan, Catherine M. Ramus, Susan J. Risch, Harvey Song, Honglin Sutphen, Rebecca Terry, Kathryn L. Tyrer, Jonathan Vierkant, Robert A. Wentzensen, Nicolas Lancaster, Johnathan M. Cheng, Jin Q. Berchuck, Andrew Pharoah, Paul D. P. Schildkraut, Joellen M. Goode, Ellen L. Sellers, Thomas A. CA OCAC TI MicroRNA Processing and Binding Site Polymorphisms Are Not Replicated in the Ovarian Cancer Association Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY; RISK AB Background: Single nucleotide polymorphisms (SNP) in microRNA-related genes have been associated with epithelial ovarian cancer (EOC) risk in two reports, yet associated alleles may be inconsistent across studies. Methods: We conducted a pooled analysis of previously identified SNPs by combining genotype data from 3,973 invasive EOC cases and 3,276 controls from the Ovarian Cancer Association Consortium. We also conducted imputation to obtain dense coverage of genes and comparable genotype data for all studies. In total, 226 SNPs within 15 kb of 4 miRNA biogenesis genes (DDX20, DROSHA, GEMIN4, and XPO5) and 23 SNPs located within putative miRNA binding sites of 6 genes (CAV1, COL18A1, E2F2, IL1R1, KRAS, and UGT2A3) were genotyped or imputed and analyzed in the entire dataset. Results: After adjustment for European ancestry, no overall association was observed between any of the analyzed SNPs and EOC risk. Conclusions: Common variants in these evaluated genes do not seem to be strongly associated with EOC risk. Impact: This analysis suggests earlier associations between EOC risk and SNPs in these genes may have been chance findings, possibly confounded by population admixture. To more adequately evaluate the relationship between genetic variants and cancer risk, large sample sizes are needed, adjustment for population stratification should be carried out, and use of imputed SNP data should be considered. Cancer Epidemiol Biomarkers Prev; 20(8); 1793-7. (C)2011 AACR. C1 [Permuth-Wey, Jennifer; Tsai, Ya-Yu] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Chen, Zhihua; Fenstermacher, David] H Lee Moffitt Canc Ctr & Res Inst, Dept Biomed Informat, Tampa, FL 33612 USA. [Lin, Hui-Yi; Chen, Y. Ann] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat, Tampa, FL 33612 USA. [Gonzalez-Bosquet, Jesus; Lancaster, Johnathan M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Womens Oncol, Tampa, FL 33612 USA. [Jim, Heather] H Lee Moffitt Canc Ctr & Res Inst, Dept Hlth Outcomes & Behav, Tampa, FL 33612 USA. [Phelan, Catherine M.; Cheng, Jin Q.] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL 33612 USA. [Sutphen, Rebecca] Univ S Florida, Coll Med, Pediat Epidemiol Ctr, Tampa, FL USA. [Barnholtz-Sloan, Jill] Case Sch Med, Case Comprehens Canc Ctr, Cleveland, OH USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02114 USA. [Chanock, Stephen J.; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Cunningham, Julie M.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Fridley, Brooke L.; Vierkant, Robert A.; Goode, Ellen L.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. [Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Iversen, Edwin] Duke Univ, Dept Stat Sci, Durham, NC USA. [Risch, Harvey] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Gayther, Simon A.; Ramus, Susan J.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [McLaughlin, John] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Narod, Steven A.] Ctr Res Womens Hlth, Toronto, ON, Canada. [Song, Honglin; Tyrer, Jonathan; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge CB2 1TN, England. [Garcia-Closas, Montserrat] Inst Canc Res, Epidemiol Sect, London SW3 6JB, England. [Garcia-Closas, Montserrat] Inst Canc Res, Genet Sect, London SW3 6JB, England. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, London, England. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, EGA Inst Womens Hlth, Dept Gynaecol Oncol, London, England. RP Sellers, TA (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Epidemiol, MRC CANCONT, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM Thomas.Sellers@Moffitt.org RI McLaughlin, John/E-4577-2013; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; OI Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Vierkant, Robert/0000-0001-6242-5221; Ramus, Susan/0000-0003-0005-7798 FU Mayo Foundation; American Cancer Society [CRTG-00-196-01-CCE]; Advanced Cancer Detection Center; Department of Defense [DAMD-17-98-1-8659]; Canadian Cancer Society; NIH [R01-CA-63682, R01-CA-63678]; National Cancer Institute [P30-CA-15083]; NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Center for Cancer Research; Cancer Research UK; Eve Appeal; OAK Foundation; Department of Health; [R01-CA-114343]; [R01-CA114343-S1]; [R01-CA-122443]; [P50-CA-136393]; [R01-CA-76016]; [R01-CA-106414]; [CA-54419]; [P50 CA105009] FX The genotyping, bioinformatic, and biostatistical data analysis for MAY, NCO, and TOR was supported by R01-CA-114343 and R01-CA114343-S1. The MAY study is supported by R01-CA-122443 and P50-CA-136393 and funding from the Mayo Foundation. The NCO study is supported by R01-CA-76016. The TBO study is supported by R01-CA-106414, the American Cancer Society (CRTG-00-196-01-CCE), and the Advanced Cancer Detection Center Grant, Department of Defense (DAMD-17-98-1-8659). The TOR study is supported by grants from the Canadian Cancer Society and the NIH (R01-CA-63682 and R01-CA-63678). The Mayo Clinic Genotyping Shared Resource is supported by the National Cancer Institute (P30-CA-15083). The NEC study is supported by grants CA-54419 and P50 CA105009. The POL study was supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research. The SEA study is funded by a program grant from Cancer Research UK. The UKO study is supported by funding from Cancer Research UK, the Eve Appeal, and the OAK Foundation; some of this work was undertaken at UCLH/UCL who received some funding from the Department of Health's NIHR Biomedical Research Centre funding scheme. UK genotyping and data analysis were supported by a project grant from Cancer Research UK. UK studies also make use of data generated by the Wellcome Trust Case-Control consortium. A list of investigators who contributed to the generation of data is available at www.wtccc.org.uk. NR 12 TC 14 Z9 14 U1 0 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2011 VL 20 IS 8 BP 1793 EP 1797 DI 10.1158/1055-9965.EPI-11-0397 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 804AK UT WOS:000293625600026 PM 21636674 ER PT J AU Ter-Minassian, M Wang, ZX Asomaning, K Wu, MC Liu, CY Paulus, JK Liu, G Bradbury, PA Zhai, RH Su, L Frauenhoffer, CS Hooshmand, SM De Vivo, I Lin, XH Christiani, DC Kulke, MH AF Ter-Minassian, Monica Wang, Zhaoxi Asomaning, Kofi Wu, Michael C. Liu, Chen-Yu Paulus, Jessica K. Liu, Geoffrey Bradbury, Penelope A. Zhai, Rihong Su, Li Frauenhoffer, Christine S. Hooshmand, Susanne M. De Vivo, Immaculata Lin, Xihong Christiani, David C. Kulke, Matthew H. TI Genetic associations with sporadic neuroendocrine tumor risk SO CARCINOGENESIS LA English DT Article ID LUNG-CANCER RISK; CARCINOID-TUMORS; CANDIDATE GENES; GEP-NETS; POLYMORPHISMS; EPIDEMIOLOGY; PATHWAY; INTERLEUKIN-12; VARIANTS; LYMPHOMA AB Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non-cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value < 0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value < 0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET. C1 [Ter-Minassian, Monica; Wang, Zhaoxi; Asomaning, Kofi; Liu, Chen-Yu; Zhai, Rihong; Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Ter-Minassian, Monica; Frauenhoffer, Christine S.; Hooshmand, Susanne M.; Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wu, Michael C.; Lin, Xihong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Paulus, Jessica K.; De Vivo, Immaculata; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liu, Geoffrey; Bradbury, Penelope A.] Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON M5G 2C4, Canada. [Christiani, David C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. RP Ter-Minassian, M (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, 677 Huntington Ave, Boston, MA 02115 USA. EM mtermina@hsph.harvard.edu RI Liu, Geoffrey/N-4421-2016; OI LIU, CHEN-YU/0000-0002-4693-5667; Wu, Michael C./0000-0002-3357-6570 FU Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health [T42-OH008416]; National Research Service Award [T32 ES 007069]; National Institutes of Health [CA074386, CA119650]; Gitta Kurlat and the Dana-Farber/Harvard Cancer Center SPORE in Gastrointestinal Cancer [P50 CA127003]; Novartis Pharmaceuticals; Broad Institute Center for Genotyping and Analysis [U54 RR020278]; National Center for Research Resources; John F. and Virginia B. Taplin Scholarship Fund FX Centers for Disease Control and Prevention, The National Institute for Occupational Safety and Health [(T42-OH008416) to D. C. C., M. T.], National Research Service Award [(T32 ES 007069) to M. T.]; John F. and Virginia B. Taplin Scholarship Fund to M. T. and National Institutes of Health [(CA074386, CA119650) to D. C. C.]; this work was also supported by a gift from Saul and Gitta Kurlat and the Dana-Farber/Harvard Cancer Center SPORE in Gastrointestinal Cancer [(P50 CA127003) to M. H. K. and a grant from Novartis Pharmaceuticals to M. H. K.]. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. NR 42 TC 11 Z9 13 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2011 VL 32 IS 8 BP 1216 EP 1222 DI 10.1093/carcin/bgr095 PG 7 WC Oncology SC Oncology GA 804EI UT WOS:000293636700014 PM 21606320 ER PT J AU Miceli, TS Colson, K Faiman, BM Miller, K Tariman, JD AF Miceli, Teresa S. Colson, Kathleen Faiman, Beth M. Miller, Kena Tariman, Joseph D. CA Int Myeloma Fdn Nurse Leadership TI Maintaining Bone Health in Patients With Multiple Myeloma: Survivorship Care Plan of the International Myeloma Foundation Nurse Leadership Board SO CLINICAL JOURNAL OF ONCOLOGY NURSING LA English DT Article ID MARROW-TRANSPLANTATION; CLINICAL-FEATURES; STAGING SYSTEM; PROTEASOME INHIBITOR; CONSENSUS STATEMENT; ZOLEDRONIC ACID; MINERAL DENSITY; FRACTURE RISK; DISEASE; MANAGEMENT AB About 90% of individuals with multiple myeloma will develop osteolytic bone lesions from increased osteoclastic and decreased osteoblastic activity. Severe morbidities from pathologic fractures and other skeletal events can lead to poor circulation, blood clots, muscle wasting, compromised performance status, and overall poor survival. Supportive care targeting bone disease is an essential adjunct to antimyeloma therapy. In addition, the maintenance of bone health in patients with multiple myeloma can significantly improve quality of life. Oncology nurses and other healthcare providers play a central role in the management of bone disease and maintenance throughout the course of treatment. Safe administration of bisphosphonates, promotion of exercise, maintenance of adequate nutrition, vitamin and mineral supplementation, scheduled radiographic examinations, and monitoring of bone complications are among the important functions that oncology nurses and healthcare providers perform in clinical practice. C1 [Miceli, Teresa S.] Mayo Clin, Bone Marrow Transplant RN Coordinator, Rochester, MN 55905 USA. [Colson, Kathleen] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Faiman, Beth M.] Cleveland Clin, Hematol & Med Oncol Dept, Cleveland, OH USA. [Miller, Kena] Roswell Pk Canc Inst, Dept Med, Lymphoma Myeloma Div, Buffalo, NY 14263 USA. [Tariman, Joseph D.] Northwestern Univ, Myeloma Program, Chicago, IL 60611 USA. RP Miceli, TS (reprint author), Mayo Clin, Bone Marrow Transplant RN Coordinator, Rochester, MN 55905 USA. EM miceli.teresa@mayo.edu FU Celgene Corp.; Millennium: Takeda Oncology Company FX Teresa S. Miceli, RN, BSN, OCN (R), is the bone marrow transplant RN coordinator at the Mayo Clinic in Rochester, MN; Kathleen Colson, RN, BSN, BS, is a clinical research nurse in the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, MA; Beth M. Faiman, MSN, APRN-BC, AOCN (R), is a nurse practitioner in the Hematology and Medical Oncology Department at the Cleveland Clinic in Ohio; Kena Miller, RN, MSN, FNP, is a nurse practitioner in the Department of Medicine, Lymphoma/Myeloma Division, at Roswell Park Cancer Institute in Buffalo, NY; and Joseph D. Tariman, PhD, APRN, BC, is an advanced practice nurse in the myeloma program at Northwestern University in Chicago, IL. The authors take full responsibility for the content of this article. Publication of this supplement was made possible through an unrestricted educational grant to the International Myeloma Foundation from Celgene Corp. and Millennium: The Takeda Oncology Company. Colson is a consultant with Merck & Co., Inc., and Millennium: The Takeda Oncology Company; Faiman is a consultant and on the speakers bureau at Celgene Corp. and Millennium: The Takeda Oncology Company; Miller is on the advisory board and speakers bureau at Celgene Corp. and Millennium: The Takeda Oncology Company; and Tariman is a consultant with Millennium: The Takeda Oncology Company. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by independent peer reviewers or editorial staff. (First submission February 2011. Revision submitted March 30, 2011. Accepted for publication April 5, 2011.) NR 78 TC 8 Z9 8 U1 2 U2 5 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD AUG PY 2011 VL 15 IS 4 SU S BP 9 EP 23 DI 10.1188/11.S1.CJON.9-23 PG 15 WC Oncology; Nursing SC Oncology; Nursing GA 805KF UT WOS:000293724600003 PM 21816707 ER PT J AU Richards, TA Bertolotti, PA Doss, D McCullagh, EJ AF Richards, Tiffany A. Bertolotti, Page A. Doss, Deborah McCullagh, Emily J. CA Int Myeloma Fdn Nurse Leadership TI Sexual Dysfunction in Multiple Myeloma: Survivorship Care Plan of the International Myeloma Foundation Nurse Leadership Board SO CLINICAL JOURNAL OF ONCOLOGY NURSING LA English DT Article ID QUALITY-OF-LIFE; ERECTILE DYSFUNCTION; CONSENSUS STATEMENT; CANCER-PATIENTS; FERTILITY PRESERVATION; ENDOCRINE DISORDERS; MENTAL-ILLNESS; TESTOSTERONE; WOMEN; IMPACT AB The World Health Organization describes sexuality as a "central aspect of being human throughout life and encompasses sex, gender identities and roles, sexual orientation, eroticism, pleasure, intimacy, and reproduction. Sexuality is influenced by the interaction of biological, psychological, social, economic, political, cultural, ethical, legal, historical, religious, and spiritual factors." Currently, no research has been conducted regarding sexual dysfunction in patients with multiple myeloma; therefore, information related to the assessment and evaluation of sexual dysfunction is gleaned from other malignancies and diseases. In this article, members of the International Myeloma Foundation's Nurse Leadership Board discuss the definition, presentation, and causes of sexual dysfunction; provide recommendations for sexual assessment practices; and promote discussion among patients with multiple myeloma, their healthcare providers, and their partners. C1 [Richards, Tiffany A.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. [Bertolotti, Page A.] Samuel Oschin Comprehens Canc Inst, Cedars Sinai Outpatient Canc Ctr, Los Angeles, CA USA. [Doss, Deborah] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [McCullagh, Emily J.] Mem Sloan Kettering Canc Ctr, Adult Bone Marrow Transplant Serv, New York, NY 10021 USA. RP Richards, TA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA. EM tarichards@uwalumni.com FU Celgene Corp.; Millennium: The Takeda Oncology Company FX Tiffany A. Richards, MS, ANP-BC, is a nurse practitioner in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center in Houston; Page A. Bertolotti, RN, BSN, OCN (R), is an oncology practice nurse in the Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute in Los Angeles, CA; Deborah Doss, RN, OCN (R), is a clinical research nurse in the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, MA; and Emily J. McCullagh, RN, NP-C, OCN (R), is the clinical coordinator in the Adult Bone Marrow Transplant Service at Memorial Sloan-Kettering Cancer Center in New York, NY. The authors take full responsibility for the content of this article. Publication of this supplement was made possible through an unrestricted educational grant to the International Myeloma Foundation from Celgene Corp. and Millennium: The Takeda Oncology Company. Richards is a consultant and advisory board member for Millennium: The Takeda Oncology Company, and Bertolotti and Doss are on the speakers bureaus for Celgene Corp. and Millennium: The Takeda Oncology Company. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers or editorial staff. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Clinical Journal of Oncology Nursing or the Oncology Nursing Society. (Submitted March 2011. Accepted for publication April 5, 2011.) NR 86 TC 5 Z9 6 U1 1 U2 5 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD AUG PY 2011 VL 15 IS 4 SU S BP 53 EP 65 DI 10.1188/11.CJON.S1.53-65 PG 13 WC Oncology; Nursing SC Oncology; Nursing GA 805KF UT WOS:000293724600006 PM 21816710 ER PT J AU Grubaugh, AL Zinzow, HM Paul, L Egede, LE Frueh, BC AF Grubaugh, Anouk L. Zinzow, Heidi M. Paul, Lisa Egede, Leonard E. Frueh, B. Christopher TI Trauma exposure and posttraumatic stress disorder in adults with severe mental illness: A critical review SO CLINICAL PSYCHOLOGY REVIEW LA English DT Review DE Posttraumatic stress disorder (PTSD); Severe mental illness (SMI); Trauma; Victimization; Psychotic; Bipolar ID NATIONAL COMORBIDITY SURVEY; SCHIZOPHRENIA SPECTRUM DISORDERS; SUBSTANCE USE DISORDERS; PSYCHIATRIC INPATIENT POPULATION; COGNITIVE-BEHAVIORAL TREATMENT; RANDOMIZED CONTROLLED-TRIAL; CHILDHOOD SEXUAL-ABUSE; QUALITY-OF-LIFE; CYCLING BIPOLAR DISORDER; ADMINISTERED PTSD SCALE AB There is a great deal of research on the prevalence, correlates, and treatment of PTSD in the general population. However, we know very little about the manifestation and consequences of PTSD in more complicated patient populations. The purpose of the current paper is to provide a comprehensive review of PTSD within the context of severe mental illness (SMI; i.e., schizophrenia spectrum disorders, mood disorders). Extant data suggest that trauma and PTSD are highly prevalent among individuals with SMI relative to the general population, and both are associated with adverse clinical functioning and increased healthcare burden. However, trauma and PTSD remain overlooked in this population, with low recognition rates in public-sector settings. Additionally, there are few data on the clinical course and treatment of PTSD among individuals with SMI. Particularly lacking are longitudinal studies, randomized controlled treatment trials, and studies using ethno-racially diverse samples. Furthermore, there is a need to better understand the interplay between trauma. PTSD, and severe forms of mental illness and to further develop and disseminate evidence-based PTSD treatments in this population. The current state of the literature and future directions for practice are discussed. Published by Elsevier Ltd. C1 [Grubaugh, Anouk L.; Paul, Lisa] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Grubaugh, Anouk L.; Egede, Leonard E.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Zinzow, Heidi M.] Clemson Univ, Dept Psychol, Clemson, SC 29634 USA. [Egede, Leonard E.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Frueh, B. Christopher] Univ Hawaii, Dept Psychol, Hilo, HI 96720 USA. [Frueh, B. Christopher] Menninger Clin, Houston, TX USA. RP Grubaugh, AL (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, POB 250861, Charleston, SC 29425 USA. EM grubaugh@musc.edu FU NIDDK NIH HHS [K24 DK093699]; NIMH NIH HHS [K24 MH074468, K24 MH074468-03, K24 MH074468-04, K24 MH074468-05, MH074468] NR 210 TC 60 Z9 62 U1 16 U2 46 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0272-7358 J9 CLIN PSYCHOL REV JI Clin. Psychol. Rev. PD AUG PY 2011 VL 31 IS 6 BP 883 EP 899 DI 10.1016/j.cpr.2011.04.003 PG 17 WC Psychology, Clinical SC Psychology GA 804TL UT WOS:000293676800001 PM 21596012 ER PT J AU Weir, GC Bonner-Weir, S AF Weir, Gordon C. Bonner-Weir, Susan TI Sleeping Islets and the Relationship Between beta-Cell Mass and Function SO DIABETES LA English DT Editorial Material ID DIABETES-MELLITUS; OBESE SUBJECTS; TURNOVER C1 [Weir, Gordon C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell Biol & Regenerat Med,Res Div, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Weir, GC (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell Biol & Regenerat Med,Res Div, Boston, MA 02115 USA. EM gordon.weir@joslin.harvard.edu NR 15 TC 6 Z9 6 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD AUG PY 2011 VL 60 IS 8 BP 2018 EP 2019 DI 10.2337/db10-1808 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 802CY UT WOS:000293488100002 PM 21788579 ER PT J AU Ackerman, MJ Priori, SG Willems, S Berul, C Brugada, R Calkins, H Camm, AJ Ellinor, PT Gollob, M Hamilton, R Hershberger, RE Judge, DP Le Marec, H McKenna, WJ Schulze-Bahr, E Semsarian, C Towbin, JA Watkins, H Wilde, A Wolpert, C Zipes, DP AF Ackerman, Michael J. Priori, Silvia G. Willems, Stephan Berul, Charles Brugada, Ramon Calkins, Hugh Camm, A. John Ellinor, Patrick T. Gollob, Michael Hamilton, Robert Hershberger, Ray E. Judge, Daniel P. Le Marec, Herve McKenna, William J. Schulze-Bahr, Eric Semsarian, Chris Towbin, Jeffrey A. Watkins, Hugh Wilde, Arthur Wolpert, Christian Zipes, Douglas P. TI HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies SO EUROPACE LA English DT Article DE Genetics; Cardiomyopathies; Channelopathies ID LONG-QT SYNDROME; RIGHT-VENTRICULAR CARDIOMYOPATHY; INFANT-DEATH-SYNDROME; SUDDEN CARDIAC DEATH; FAMILIAL ATRIAL-FIBRILLATION; OF-FUNCTION MUTATION; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; GENOTYPE-PHENOTYPE CORRELATION; CAUSE HYPERTROPHIC CARDIOMYOPATHY; RYANODINE RECEPTOR GENE C1 [Ackerman, Michael J.] Mayo Clin, Rochester, MN USA. [Priori, Silvia G.] Univ Pavia, Fdn Salvatore Maugeri, I-27100 Pavia, Italy. [Priori, Silvia G.] NYU, New York, NY USA. [Willems, Stephan] Univ Hosp Hamburg Eppendorf, Hamburg, Germany. [Berul, Charles] Childrens Natl Med Ctr, Washington, DC USA. [Berul, Charles] George Washington Sch Med, Washington, DC USA. [Brugada, Ramon] Girona Inst Biomed Res, Girona, Spain. [Brugada, Ramon] Univ Girona, Sch Med, Girona, Spain. [Calkins, Hugh; Judge, Daniel P.] Johns Hopkins Univ, Baltimore, MD USA. [Camm, A. John] St Georges Univ London, London, England. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Gollob, Michael] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. [Hamilton, Robert] Hosp Sick Children, Toronto, ON, Canada. [Hershberger, Ray E.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Judge, Daniel P.] Univ Paris 05, Paris, France. [Le Marec, Herve] Inst Thorax, Nantes, France. [McKenna, William J.] UCL, Inst Cardiovasc Sci, London, England. [Schulze-Bahr, Eric] Univ Hosp Muenster, Munster, Germany. [Semsarian, Chris] Univ Sydney, Sydney, NSW 2006, Australia. [Towbin, Jeffrey A.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Oxford OX3 9DU, England. [Wilde, Arthur] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Wolpert, Christian] Ludwigsburg Clin, Ludwigsburg, Germany. [Zipes, Douglas P.] Indiana Univ, Sch Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA. RP Ackerman, MJ (reprint author), Care of Olson S, Heart Rhythm Soc, 1400 K St NW, Washington, DC 20005 USA. EM solson@hrsonline.org RI Le Marec, Herve/D-2718-2015; McKenna, William/C-3243-2008; Schwartz, Peter/J-4267-2016; OI Le Marec, Herve/0000-0002-8288-8693; McKenna, William/0000-0001-7994-2460; Schwartz, Peter/0000-0003-0367-1048; Zipes, Douglas/0000-0001-7141-6829 FU Wellcome Trust [090532] NR 271 TC 177 Z9 189 U1 2 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1099-5129 J9 EUROPACE JI Europace PD AUG PY 2011 VL 13 IS 8 BP 1077 EP 1109 DI 10.1093/europace/eur245 PG 33 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 804BZ UT WOS:000293630200005 PM 21810866 ER PT J AU Margey, R Browne, L Murphy, E O'Reilly, M Mahon, N Blake, G McCann, H Sugrue, D Galvin, J AF Margey, Ronan Browne, Lisa Murphy, Eamonn O'Reilly, Martin Mahon, Niall Blake, Gavin McCann, Hugh Sugrue, Declan Galvin, Joseph TI The Dublin cardiac arrest registry: temporal improvement in survival from out-of-hospital cardiac arrest reflects improved pre-hospital emergency care SO EUROPACE LA English DT Article DE Out-of-hospital cardiac arrest Sudden cardiac death; Pre-hospital emergency care; Resuscitation; Ventricular fibrillation; Automated-external defibrillators; Cardiopulmonary resuscitation ID CORONARY-HEART-DISEASE; MULTIPLE SOURCE SURVEILLANCE; CARDIOPULMONARY-RESUSCITATION; VENTRICULAR-FIBRILLATION; EUROPEAN-SOCIETY; UNITED-STATES; TASK-FORCE; SUDDEN; DEATH; TRENDS AB Aims Out-of-hospital cardiac arrest (OOHCA) survival remains poor, estimated at 3-7%. We aim to describe the incidence of OOHCA, survival from OOHCA, and the impact of improved pre-hospital care on survival from OOHCA. Methods and results A retrospective registry was established using multi-source information to assess survival from cardiac arrest following the introduction of several improvements in pre-hospital emergency medical care from 2003. Survival from OOHCA, from asystole/pulseless electrical activity, and from ventricular tachycardia/ventricular fibrillation was estimated. Adjusted per 100 000 population annual incidence rates from national population census data were calculated. Mean and median emergency medical services (EMS) response times to OOHCA calls were assessed. A total of 962 OOHCAs occurred from 1 January 2003 until 31 December 2008. Sixty-nine per cent (69%, n = 664) were male. Seventy-two per cent (72%, n = 693) occurred at home with 28% occurring in a public venue. Of these public venues, 33.9% (91 of 268) had an automated external defibrillator available. Bystander cardiopulmonary resuscitation CPR) was in progress when emergency services arrived in 11% (n = 106) of the cases. Nineteen per cent (19.4%, n = 187) had a known prior cardiac history or chest pain prior to circulatory collapse. Overall survival to hospital discharge improved significantly from 2.6 to 11.3%, P = 0.001. Survival from ventricular fibrillation (VF) to hospital admission, rose from 28.6 to 86.3%, P = 0.001. Survival to hospital discharge from VF improved from 21.4 to 33%, P = 0.007. Mean EMS response times to the scene of arrest decreased from 9.18 to 8.34 min. Emergency medical services scene time, reflecting acute pre-hospital medical care, rose from 14.46 to 18.12 min. The adjusted incidence of OOHCA for our catchment population declined from 109.4 to 88.2 per 100 000 population between 2003 and 2008. Conclusions The incidence of OOHCA has declined but importantly, survival to hospital discharge has improved dramatically. Reduction in ambulance response time, resulting in earlier initiation of basic and advanced life support and earlier defibrillation, was associated with an increase in the proportion of victims found in VF rather than asystole and likely accounted for most of the improvement. Further improvements in response times and public education to improve bystander CPR rates should remain a priority. C1 [Browne, Lisa; Murphy, Eamonn; Mahon, Niall; Blake, Gavin; McCann, Hugh; Sugrue, Declan; Galvin, Joseph] Mater Misericordiae Univ Hosp, Dept Cardiol, Dublin 7, Ireland. [Margey, Ronan] Massachusetts Gen Hosp, Div Internal Med, Dept Cardiol, Boston, MA 02114 USA. [Margey, Ronan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [O'Reilly, Martin] Dublin Fire Brigade, Emergency Med Serv Support, Dublin, Ireland. RP Galvin, J (reprint author), Mater Misericordiae Univ Hosp, Dept Cardiol, Eccles St, Dublin 7, Ireland. OI Mahon, Niall/0000-0002-2872-2297 FU Health Services Executive of Ireland; Irish Heart Foundation; Medtronic Corporation, Ireland FX R.J.M. research position was funded through unrestricted educational grants from the Health Services Executive of Ireland, the Irish Heart Foundation, and Medtronic Corporation, Ireland. NR 38 TC 12 Z9 12 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1099-5129 EI 1532-2092 J9 EUROPACE JI Europace PD AUG PY 2011 VL 13 IS 8 BP 1157 EP 1165 DI 10.1093/europace/eur092 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 804BZ UT WOS:000293630200012 PM 21474456 ER PT J AU Ferraro, F Lymperi, S Spencer, JA Lin, CP Scadden, DT AF Ferraro, F. Lymperi, S. Spencer, J. A. Lin, C. P. Scadden, D. T. TI ISOLATION OF A COMMON MESENCHYMAL PROGENITOR FROM BONE, HEART AND LUNG SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 [Ferraro, F.; Scadden, D. T.] Harvard Univ, Sch Med, MGH, Ctr Regenerat Med, Boston, MA USA. [Lymperi, S.; Spencer, J. A.; Lin, C. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Adv Microscopy Program,Wellman Ctr Photomed, Boston, MA USA. RI Spencer, Joel/A-4590-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2011 VL 39 IS 8 SU 1 BP S26 EP S27 PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 806IS UT WOS:000293801700052 ER PT J AU Montel-Hagen, A Van Handel, B Ferrari, R Sasidharan, R Nakano, H Org, T Zhou, J Li, X Pellegrini, M Orkin, SH Nakano, A Kurdistani, SK Mikkola, HK AF Montel-Hagen, A. Van Handel, B. Ferrari, R. Sasidharan, R. Nakano, H. Org, T. Zhou, J. Li, X. Pellegrini, M. Orkin, S. H. Nakano, A. Kurdistani, S. K. Mikkola, H. K. TI CONVERSION OF PROSPECTIVE HEMOGENIC ENDOTHELIUM TO CARDIOGENIC FATE IN THE ABSENCE OF SCL/TAL1 SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 [Montel-Hagen, A.; Van Handel, B.; Ferrari, R.; Sasidharan, R.; Nakano, H.; Org, T.; Zhou, J.; Li, X.; Pellegrini, M.; Nakano, A.; Kurdistani, S. K.; Mikkola, H. K.] Univ Calif Los Angeles, Los Angeles, CA USA. [Orkin, S. H.] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp, Boston, MA USA. [Orkin, S. H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2011 VL 39 IS 8 SU 1 BP S55 EP S55 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 806IS UT WOS:000293801700093 ER PT J AU North, TE Harris, JM Harris, LJ Cox, AG Garnaas, MK Cortes, M Cutting, CC Dovey, MC Pawa, BH Heiden, MGV Goessling, W AF North, T. E. Harris, J. M. Harris, L. J. Cox, A. G. Garnaas, M. K. Cortes, M. Cutting, C. C. Dovey, M. C. Pawa, B. H. Heiden, M. G. Vander Goessling, W. TI METABOLISM-INDUCED REACTIVE OXYGEN SPECIES (ROS) AND HIF1A STIMULATION CONTROL THE INDUCTION AND EXPANSION OF HEMATOPOIETIC STEM CELLS SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 [North, T. E.; Goessling, W.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. [North, T. E.; Harris, J. M.; Harris, L. J.; Cortes, M.; Dovey, M. C.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Cox, A. G.; Garnaas, M. K.; Cutting, C. C.; Goessling, W.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Pawa, B. H.; Goessling, W.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Heiden, M. G. Vander] MIT, Robert Koch Inst, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2011 VL 39 IS 8 SU 1 BP S49 EP S50 PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 806IS UT WOS:000293801700086 ER PT J AU Sykes, DB Szekely, BA Doench, J Brown, A Scadden, DT AF Sykes, D. B. Szekely, B. A. Doench, J. Brown, A. Scadden, D. T. TI UNDERSTANDING AND TARGETING THE MECHANISM OF HOXA9 DIFFERENTIATION ARREST IN ACUTE MYELOID LEUKEMIA SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 [Sykes, D. B.; Szekely, B. A.; Scadden, D. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Doench, J.; Brown, A.] Broad Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2011 VL 39 IS 8 SU 1 BP S21 EP S22 PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 806IS UT WOS:000293801700044 ER PT J AU Sykes, SM Lane, SW Bullinger, L Demetrios, K Yusuf, R Saez, B Ferraro, F Mercier, F Singh, H Brumme, KM Acharya, S Scholl, C Tothova, Z Attar, E Frohling, S DePinho, RA Gilliland, DG Armstrong, SA Sca, DT AF Sykes, S. M. Lane, S. W. Bullinger, L. Demetrios, K. Yusuf, R. Saez, B. Ferraro, F. Mercier, F. Singh, H. Brumme, K. M. Acharya, S. Scholl, C. Tothova, Z. Attar, E. Froehling, S. DePinho, R. A. Gilliland, D. G. Armstrong, S. A. Sca, D. T. TI AKT/FOXO SIGNALING PATHWAY ENFORCES THE DIFFERENTIATION BLOCKADE IN MYELOID LEUKEMIAS SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 [Sykes, S. M.; Yusuf, R.; Saez, B.; Ferraro, F.; Mercier, F.; Singh, H.; Acharya, S.; Tothova, Z.; Attar, E.] Massachusetts Gen Hosp, Harvard Stem Cell Inst, Ctr Regenerat Med Stem Cell & Regenerat Biol, Boston, MA 02114 USA. [Lane, S. W.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Bullinger, L.; Scholl, C.; Froehling, S.] Univ Hosp Ulm, Ulm, Baden Wurttembe, Germany. [Demetrios, K.; Brumme, K. M.; Armstrong, S. A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [DePinho, R. A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Gilliland, D. G.] Merck Res Labs, N Wales, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2011 VL 39 IS 8 SU 1 BP S26 EP S26 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 806IS UT WOS:000293801700051 ER PT J AU Yu, VWC Raaijmakers, MHGP Lotinun, S Saez, B Cook, C Wu, JY Kronenberg, HM Baron, R Scadden, DT AF Yu, Vionnie W. C. Raaijmakers, Marc H. G. P. Lotinun, Sutada Saez, Borja Cook, Colleen Wu, Joy Y. Kronenberg, Henry M. Baron, Roland Scadden, David T. TI DIFFERENTIAL REGULATION OF B AND T LYMPHOPOIESIS BY IMMATURE AND MATURE OSTEOLINEAGE CELLS SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 [Yu, Vionnie W. C.; Saez, Borja; Cook, Colleen; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Yu, Vionnie W. C.; Saez, Borja; Scadden, David T.] Harvard Stem Cell Inst, Boston, MA USA. [Yu, Vionnie W. C.; Saez, Borja; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Lotinun, Sutada; Wu, Joy Y.; Kronenberg, Henry M.; Baron, Roland] Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Lotinun, Sutada; Wu, Joy Y.; Kronenberg, Henry M.; Baron, Roland] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2011 VL 39 IS 8 SU 1 BP S107 EP S108 PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 806IS UT WOS:000293801700178 ER PT J AU Shaheen, NJ Overholt, BF Sampliner, RE Wolfsen, HC Wang, KK Fleischer, DE Sharma, VK Eisen, GM Fennerty, MB Hunter, JG Bronner, MP Goldblum, JR Bennett, AE Mashimo, H Rothstein, RI Gordon, SR Edmundowicz, SA Madanick, RD Peery, AF Muthusamy, VR Chang, KJ Kimmey, MB Spechler, SJ Siddiqui, AA Souza, RF Infantolino, A Dumot, JA Falk, GW Galanko, JA Jobe, BA Hawes, RH Hoffman, BJ Sharma, P Chak, A Lightdale, CJ AF Shaheen, Nicholas J. Overholt, Bergein F. Sampliner, Richard E. Wolfsen, Herbert C. Wang, Kenneth K. Fleischer, David E. Sharma, Virender K. Eisen, Glenn M. Fennerty, M. Brian Hunter, John G. Bronner, Mary P. Goldblum, John R. Bennett, Ana E. Mashimo, Hiroshi Rothstein, Richard I. Gordon, Stuart R. Edmundowicz, Steven A. Madanick, Ryan D. Peery, Anne F. Muthusamy, V. Raman Chang, Kenneth J. Kimmey, Michael B. Spechler, Stuart J. Siddiqui, Ali A. Souza, Rhonda F. Infantolino, Anthony Dumot, John A. Falk, Gary W. Galanko, Joseph A. Jobe, Blair A. Hawes, Robert H. Hoffman, Brenda J. Sharma, Prateek Chak, Amitabh Lightdale, Charles J. TI Durability of Radiofrequency Ablation in Barrett's Esophagus With Dysplasia SO GASTROENTEROLOGY LA English DT Article DE Esophagus; Cancer; Prevention; Endoscopic Therapy ID HIGH-GRADE DYSPLASIA; PUMP INHIBITOR USE; FOCAL ABLATION; ACQUIRED PNEUMONIA; RISK; NEOPLASIA; OUTCOMES; THERAPY; DIAGNOSIS; REGISTRY AB BACKGROUND & AIMS: Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS: We performed a randomized trial of 127 subjects with dysplastic BE; after crossover subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS: After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS: In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years. C1 [Shaheen, Nicholas J.; Madanick, Ryan D.; Peery, Anne F.; Galanko, Joseph A.] Univ N Carolina, Sch Med, Ctr Esophageal Dis & Swallowing, Chapel Hill, NC 27599 USA. [Overholt, Bergein F.] Gastrointestinal Associates, Knoxville, TN USA. [Sampliner, Richard E.] Univ Arizona, Ctr Canc, Tucson, AZ USA. [Wolfsen, Herbert C.] Mayo Clin Florida, Jacksonville, FL USA. [Wang, Kenneth K.] Mayo Clin Rochester, Rochester, MN USA. [Fleischer, David E.] Mayo Clin Arizona, Scottsdale, AZ USA. [Sharma, Virender K.] Arizona Ctr Digest Hlth, Gilbert, AZ USA. [Eisen, Glenn M.; Fennerty, M. Brian; Hunter, John G.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Bronner, Mary P.] Univ Utah, Salt Lake City, UT USA. [Goldblum, John R.; Bennett, Ana E.] Cleveland Clin, Cleveland, OH 44106 USA. [Mashimo, Hiroshi] VA Boston Healthcare Syst, W Roxbury, MA USA. [Rothstein, Richard I.; Gordon, Stuart R.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Edmundowicz, Steven A.] Washington Univ, Med Ctr, St Louis, MO USA. [Muthusamy, V. Raman; Chang, Kenneth J.] Univ Calif Irvine, Orange, CA 92668 USA. [Kimmey, Michael B.] Tacoma Digest Dis Res Ctr LLC, Tacoma, WA USA. [Spechler, Stuart J.; Souza, Rhonda F.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Siddiqui, Ali A.; Infantolino, Anthony] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Dumot, John A.; Chak, Amitabh] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Falk, Gary W.] Univ Penn, Philadelphia, PA 19104 USA. [Jobe, Blair A.] Univ Pittsburgh, Pittsburgh, PA USA. [Hawes, Robert H.; Hoffman, Brenda J.] Med Univ S Carolina, Charleston, SC 29425 USA. [Sharma, Prateek] VA Med Ctr, Kansas City, MO USA. [Sharma, Prateek] Univ Kansas, Sch Med, Kansas City, MO USA. [Lightdale, Charles J.] Columbia Univ, Med Ctr, New York, NY USA. RP Shaheen, NJ (reprint author), Univ N Carolina, Sch Med, Ctr Esophageal Dis & Swallowing, CB 7080, Chapel Hill, NC 27599 USA. EM nshaheen@med.unc.edu RI Shaheen, Nicholas/A-1898-2013; OI Falk, Gary/0000-0002-7143-1436; Edmundowicz, Steven/0000-0002-6541-3485 FU BARRX Medical; AstraZeneca; Boston Scientific; Pfizer; Takeda; Olympus; Given Imaging; Nycomed; Ethicon Endosurgery; Novartis; Merck; Bristol Myers Squibb; Salix; Lantheus Medical Imaging; Otsuka Medical Research; Santarus; Abbott; UCB; Centocor; CSA Medical; NeoGenomics; TAP/Takeda; EndoGastric Solutions; NIH [P30 DK034987] FX The authors disclose the following: Drs Chang and Lightdale received additional grant support from BARRX Medical. Drs Chang, Infantolino, and Lightdale received consulting fees from BARRX Medical. Drs Chang, Edmundowicz, Infantolino, Madanick, Muthasamy, and Overholt received lecture fees from BARRX Medical. Dr Chang has equity ownership in BARRX Medical and received consulting fees from BARRX Medical and royalties from the BARRX Medical Halo 90 device. Drs Eisen, Falk, Hoffman, Shaheen, Spechler, and Souza received grant support from AstraZeneca. Drs Eisen, Falk, Fennerty, Infantolino, Lightdale, Shaheen, Sharma, Souza, and Spechler received consulting fees from AstraZeneca. Drs Eisen, Falk, Infantolino, Madanick, and Shaheen received lecture fees from AstraZeneca. Dr Edmundowicz received consulting fees from Boston Scientific. Dr Eisen received consulting fees from Pfizer and lecture fees from Takeda. Drs Eisen, Shaheen, and Spechler received grant support from Takeda. Drs Edmundowicz and Falk received consulting fees from Olympus. Drs Eisen and Hoffman received lecture fees from Given Imaging. Dr Falk received consulting fees from Nycomed and Ethicon Endosurgery. Drs Falk and Sharma report receiving grant support from Given Imaging. Dr Fennerty received consulting fees from Novartis and Merck. Dr Hoffman received grant support from Bristol Myers Squibb, Salix, Lantheus Medical Imaging, and Otsuka Medical Research. Drs Fennerty, Infantolino, and Sharma received consulting fees from Santarus. Dr Infantolino received lecture fees from Santarus, Abbott, UCB, Centocor, and CSA Medical. Dr Infantolino also received consulting fees from Abbott, UCB, and Centocor. Drs Infantolino and Shaheen received consulting fees from CSA Medical. Dr Shaheen received consulting fees from NeoGenomics. Dr Lightdale received grant support from Boston Scientific. Drs Sampliner, Shaheen, Sharma, Souza, and Spechler received consulting fees from TAP/Takeda. Dr Shaheen received grant support from CSA Medical and NeoGenomics. Dr Sharma received grant support from Olympus. Dr Jobe received grant support from EndoGastric Solutions. The remaining authors disclose no conflicts.; This study was supported by funding from BARRX Medical, Inc. Study medication was provided through the investigator-sponsored study program of AstraZeneca. Statistical analysis and data management were supported by NIH P30 DK034987. NR 25 TC 186 Z9 188 U1 2 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2011 VL 141 IS 2 BP 460 EP 468 DI 10.1053/j.gastro.2011.04.061 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 802PK UT WOS:000293523300025 PM 21679712 ER PT J AU Itkin, M DeLegge, MH Fang, JC McClave, SA Kundu, S d'Othee, BJ Martinez-Salazar, GM Sacks, D Swan, TL Towbin, RB Walker, TG Wojak, JC Zuckerman, DA Cardella, JF AF Itkin, Maxim DeLegge, Mark H. Fang, John C. McClave, Stephen A. Kundu, Sanjoy d'Othee, Bertrand Janne Martinez-Salazar, Gloria M. Sacks, David Swan, Timothy L. Towbin, Richard B. Walker, T. Gregory Wojak, Joan C. Zuckerman, Darryl A. Cardella, John F. TI Multidisciplinary Practical Guidelines for Gastrointestinal Access for Enteral Nutrition and Decompression From the Society of Interventional Radiology and American Gastroenterological Association (AGA) Institute, With Endorsement by Canadian Interventional Radiological Association (CIRA) and Cardiovascular and Interventional Radiological Society of Europe (CIRSE) SO GASTROENTEROLOGY LA English DT Article ID PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; FEEDING-TUBE PLACEMENT; INTENSIVE-CARE-UNIT; CRITICALLY-ILL PATIENTS; NECK-CANCER PATIENTS; RANDOMIZED PROSPECTIVE TRIAL; ANTEGRADE CONTINENCE ENEMA; TOTAL PARENTERAL-NUTRITION; T-FASTENER GASTROPEXY; ANTIBIOTIC-PROPHYLAXIS C1 [Itkin, Maxim] Univ Penn, Med Ctr, Dept Radiol, Div Intervent Radiol,Penn Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Sacks, David] Reading Hosp Med Ctr, Dept Intervent Radiol, Reading, PA USA. [Cardella, John F.] Geisinger Hlth Syst, Dept Radiol, Danville, PA USA. [DeLegge, Mark H.] Med Univ S Carolina, Digest Dis Ctr, Charleston, SC 29425 USA. [Fang, John C.] Univ Utah, Hlth Sci Ctr, Div Gastroenterol Hepatol & Nutr, Salt Lake City, UT USA. [McClave, Stephen A.] Univ Louisville, Sch Med, Div Gastroenterol Hepatol, Louisville, KY 40292 USA. [Kundu, Sanjoy] Scarborough Gen Hosp, Dept Med Imaging, Toronto, ON, Canada. [d'Othee, Bertrand Janne] Univ Maryland, Sch Med, Div Intervent Radiol, Dept Radiol, Baltimore, MD 21201 USA. [Martinez-Salazar, Gloria M.; Walker, T. Gregory] Massachusetts Gen Hosp, Div Vasc Imaging & Intervent, Boston, MA 02114 USA. [Swan, Timothy L.] Marshfield Clin Fdn Med Res & Educ, Dept Radiol, Marshfield, WI USA. [Towbin, Richard B.] Phoenix Childrens Hosp, Dept Radiol, Phoenix, AZ USA. [Wojak, Joan C.] Our Lady Lourdes Med Ctr, Dept Radiol, Lafayette, LA USA. [Zuckerman, Darryl A.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. RP Itkin, M (reprint author), 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM maxim.itkin@uphs.upenn.edu FU Nestle; ACM Technologies FX M.H.D. is a paid consultant for Cook Medical (Bloomington, Indiana). S. A. M. is a consultant for Kimberly Clark, Covidien, Nestle, and Abbott and is a recipient of research funds from Nestle and ACM Technologies. None of the other authors have identified a conflict of interest. NR 240 TC 31 Z9 31 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2011 VL 141 IS 2 BP 742 EP 765 DI 10.1053/j.gastro.2011.06.001 PG 24 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 802PK UT WOS:000293523300052 PM 21820533 ER PT J AU Fuchsluger, TA Jurkunas, U Kazlauskas, A Dana, R AF Fuchsluger, T. A. Jurkunas, U. Kazlauskas, A. Dana, R. TI Anti-apoptotic gene therapy prolongs survival of corneal endothelial cells during storage SO GENE THERAPY LA English DT Article DE apoptosis; cornea; transplantation; storage ID MESENCHYMAL STEM-CELLS; CULTURED CORNEAS; GRAFT-REJECTION; FOLLOW-UP; IN-VITRO; VECTORS; TRANSPLANTATION; COMPLEX; PROTEIN; DEATH AB Corneal transplantation is the most common form of grafting performed worldwide. Corneal endothelial cells (EC) form a monolayer in the posterior portion of the cornea and are essential for corneal transparency. EC loss during storage before transplantation is a principal reason for rendering donor tissue unsuitable for transplantation, and apoptosis has been shown to be the major contributor to EC loss during storage and after transplantation. Therefore, the potential use of anti-apoptotic gene therapy to promote both graft storage and graft survival is of major interest. The goal of this study was to transduce human donor corneas in vitro to enhance EC survival during storage conditions used in eye banking. We utilized a lentiviral vector to perform gene transfer of baculoviral p35 or mammalian Bcl-xL to corneal endothelium in different storage conditions utilizing a lentiviral vector. Our results show significantly enhanced survival and prolonged retention of physiological EC morphology in cells expressing either p35 or Bcl-xL. The clinical application of this technology could lead to a higher availability of donor tissue for transplantation, extend storage periods and reduce graft failure after transplantation. Gene Therapy (2011) 18, 778-787; doi:10.1038/gt.2011.20; published online 17 March 2011 C1 [Fuchsluger, T. A.; Jurkunas, U.; Kazlauskas, A.; Dana, R.] Harvard Univ, Sch Med, Schepens Eye Res Inst, Dept Ophthalmol, Boston, MA 02114 USA. [Fuchsluger, T. A.] Univ Duisburg Essen, Essen Univ Hosp, Ctr Ophthalmol, Essen, Germany. [Dana, R.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Dana, R (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, Dept Ophthalmol, 20 Staniford St, Boston, MA 02114 USA. EM reza.dana@schepens.harvard.edu FU NIH [R01EY012963, K24EY019098]; Research to Prevent Blindness; German Research Foundation [DFG/FU 726/1-1]; Eye Bank Association of America FX This work was supported by NIH R01EY012963 (RD), K24EY019098 (RD), Research to Prevent Blindness Lew R. Wasserman Merit Award (RD), the German Research Foundation (DFG/FU 726/1-1, TF) and the Eye Bank Association of America (TF). We thank Tissue Banks International and the Lions Eye Institute for Transplant and Research (Tampa, Florida) for providing corneas for research purposes. We thank Kim Fechtel, PhD, for the critical review of the manuscript. NR 42 TC 19 Z9 19 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD AUG PY 2011 VL 18 IS 8 BP 778 EP 787 DI 10.1038/gt.2011.20 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 806CE UT WOS:000293779500004 PM 21412281 ER PT J AU Li, G Biju, KC Xu, X Zhou, Q Chen, C Valente, AJ He, W Reddick, RL Freeman, GL Ahuja, SS Clark, RA Li, S AF Li, G. Biju, K. C. Xu, X. Zhou, Q. Chen, C. Valente, A. J. He, W. Reddick, R. L. Freeman, G. L. Ahuja, S. S. Clark, R. A. Li, S. TI Macrophage LXR alpha gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR-/- mice SO GENE THERAPY LA English DT Article DE LXR alpha; stem cell gene therapy; macrophage; atherosclerosis; triglyceride ID LIVER-X-RECEPTORS; DENSITY-LIPOPROTEIN RECEPTOR; APOLIPOPROTEIN-E; DEFICIENT MICE; LESION FORMATION; METABOLISM; EXPRESSION; DISEASE; ATHEROGENESIS; CHOLESTEROL AB Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR-/-)mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXR alpha (Lenti-SP-LXR alpha) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXR alpha mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXR alpha gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR-/- mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis. Gene Therapy (2011) 18, 835-841; doi:10.1038/gt.2011.29; published online 10 March 2011 C1 [Li, G.; Biju, K. C.; Xu, X.; Zhou, Q.; Chen, C.; Valente, A. J.; He, W.; Freeman, G. L.; Ahuja, S. S.; Clark, R. A.; Li, S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Li, G.; Biju, K. C.; Xu, X.; Zhou, Q.; Chen, C.; Valente, A. J.; He, W.; Freeman, G. L.; Ahuja, S. S.; Clark, R. A.; Li, S.] S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. [Reddick, R. L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Reddick, R. L.] S TexasVet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. [Li, S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. RP Li, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM lis1@uthscsa.edu FU Research Division of the Department of Veterans Affairs; Texas Affiliate of the American Heart Association FX We are grateful to Ronald M Evans (The Salk Institute for Biological Studies, San Diego, CA, USA) for providing mouse LXR alpha cDNA (pCMX-mLXR alpha) and Jessica Han for her technical assistance. This study was supported by a research grant from the Research Division of the Department of Veterans Affairs and a Grant-in-Aid from the Texas Affiliate of the American Heart Association. NR 35 TC 10 Z9 11 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD AUG PY 2011 VL 18 IS 8 BP 835 EP 841 DI 10.1038/gt.2011.29 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 806CE UT WOS:000293779500010 PM 21390069 ER PT J AU Garg, HG Mrabat, H Yu, LY Hales, C Li, BYZ Moore, CN Zhang, FM Linhardt, RJ AF Garg, Hari G. Mrabat, Hicham Yu, Lunyin Hales, Charles A. Li, Boyangzi Moore, Casey N. Zhang, Fuming Linhardt, Robert J. TI Anti-proliferative effects of O-acyl-low-molecular-weight heparin derivatives on bovine pulmonary artery smooth muscle cells SO GLYCOCONJUGATE JOURNAL LA English DT Article DE Heparin; Low molecular weight heparin; O-acylated; Smooth muscle cells; Surface plasmon resonance ID FIBROBLAST-GROWTH-FACTOR; TERMINALLY ALKYLATED HEPARIN; VASCULAR INJURY; PROLIFERATION; SULFATE; INHIBITION; HYPERTENSION; INCREASE; INVIVO AB Heparin (HP) inhibits the growth of several cell types in vitro including bovine pulmonary artery (BPA) smooth muscle cells (SMCs). In initial studies we discovered that an O-hexanoylated low-molecular-weight (LMW) HP derivative having acyl groups with 6-carbon chain length was more potent inhibitor of BPA-SMCs than the starting HP. We prepared several O-acylated LMWHP derivatives having 4-, 6-, 8-, 10-, 12-, and 18- carbon acyl chain lengths to determine the optimal acyl chain length for maximum anti-proliferative properties of BPA-SMCs. The starting LMWHP was prepared from unfractionated HP by sodium periodate treatment followed by sodium borohydride reduction. The tri-n-butylammonium salt of this LMWHP was O-acylated with butanoic, hexanoic, octanoic, decanoic, dodecanoic, and stearyl anhydrides separately to give respective O-acylated LMWHP derivatives. Gradient polyacrylamide gel electrophoresis (PAGE) was used to examine the average molecular weights of those O-acylated LMWHP derivatives. NMR analysis indicated the presence of one O-acyl group per disaccharide residue. Measurement of the inhibition of BPA-SMCS as a function of O-acyl chain length shows two optima, at a carbon chain length of 6 (O-hexanoylated LMWHP) and at a carbon chain length 12-18 (O-dodecanoyl and O-stearyl LMWHPs). A solution competition SPR study was performed to test the ability of different O-acylated LMWHP derivatives to inhibit fibroblast growth factor (FGF) 1 and FGF2 binding to surface-immobilized heparin. All the LMWHP derivatives bound to FGF1 and FGF2 but each exhibited slightly different binding affinity. C1 [Li, Boyangzi; Moore, Casey N.; Zhang, Fuming; Linhardt, Robert J.] Rensselaer Polytech Inst, Dept Chem, Ctr Biotechnol & Interdisciplinary Studies, Troy, NY 12180 USA. [Li, Boyangzi; Moore, Casey N.; Zhang, Fuming; Linhardt, Robert J.] Rensselaer Polytech Inst, Dept Biol Chem, Ctr Biotechnol & Interdisciplinary Studies, Troy, NY 12180 USA. [Garg, Hari G.; Mrabat, Hicham; Yu, Lunyin; Hales, Charles A.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Pulm Crit Care Unit, Boston, MA 02114 USA. RP Linhardt, RJ (reprint author), Rensselaer Polytech Inst, Dept Chem, Ctr Biotechnol & Interdisciplinary Studies, Troy, NY 12180 USA. EM linhar@rpi.edu RI Li, Boyangzi/B-4813-2012 FU National Institute of Health [HL 039150, HL 62244, GM 38060] FX This work was supported by National Institute of Health Grant HL 039150 to Charles A. Hales and HL 62244 and GM 38060 to Robert J. Linhardt. NR 34 TC 5 Z9 7 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0282-0080 J9 GLYCOCONJUGATE J JI Glycoconjugate J. PD AUG PY 2011 VL 28 IS 6 BP 419 EP 426 DI 10.1007/s10719-011-9341-6 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 804GG UT WOS:000293641700005 PM 21773727 ER PT J AU Bech, P Fava, M Trivedi, MH Wisniewski, SR Rush, AJ AF Bech, P. Fava, M. Trivedi, M. H. Wisniewski, S. R. Rush, A. J. TI Factor structure and dimensionality of the two depression scales in STAR*D using level 1 datasets SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Hamilton depression scale; Inventory of Depressive Symptomatology; Principal component analysis; Item response theory analysis ID SEQUENCED TREATMENT ALTERNATIVES; RATIONALE; DISORDER; ILLNESS AB Background: The factor structure and dimensionality of the HAM-D(17) and the IDS-C(30) are as yet uncertain, because psychometric analyses of these scales have been performed without a clear separation between factor structure profile and dimensionality (total scores being a sufficient statistic). Methods: The first treatment step (Level 1) in the STAR*D study provided a dataset of 4041 outpatients with DSM-IV nonpsychotic major depression. The HAM-D(17) and IDS-C(30) were evaluated by principal component analysis (PCA) without rotation. Mokken analysis tested the unidimensionality of the IDS-C(6), which corresponds to the unidimensional HAM-D(6). Results: For both the HAM-D(17) and IDS-C(30), PCA identified a bi-directional factor contrasting the depressive symptoms versus the neurovegetative symptoms. The HAM-D(6) and the corresponding IDS-C(6) symptoms all emerged in the depression factor. Both the HAM-D(6) and IDS-C(6) were found to be unidimensional scales, i.e., their total scores are each a sufficient statistic for the measurement of depressive states. Limitations: STAR*D used only one medication in Level 1. Conclusions: The unidimensional HAM-D(6) and IDS-C(6) should be used when evaluating the pure clinical effect of antidepressive treatment, whereas the multidimensional HAM-D(17) and IDS-C(30) should be considered when selecting antidepressant treatment. (C) 2011 Elsevier B.V. All rights reserved. C1 [Bech, P.] Univ Copenhagen, Psychiat Res Unit, Frederiksborg Gen Hosp, DK-3400 Hillerod, Denmark. [Fava, M.] Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. [Trivedi, M. H.] Univ Texas, SW Med Sch, Dallas, TX USA. [Wisniewski, S. R.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Rush, A. J.] Duke NUS, Singapore, Singapore. RP Bech, P (reprint author), Univ Copenhagen, Psychiat Res Unit, Frederiksborg Gen Hosp, Dyrehavevej 48, DK-3400 Hillerod, Denmark. EM Per.bech@regionh.dk OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382 FU Astra-Zeneca; Lilly; H Lundbeck A/S; Organon; Abbott Laboratories; Alkermes, Inc.; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; Cephalon, Inc.; Clinical Trials Solutions, LLC; Covidien; Eli Lilly and Company; En Vivo Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmavite(R) LLC; Roche; RTC Logic, LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Solvay Pharmaceuticals, Inc.; Synthelabo; Wyeth-Ayerst Laboratories; Agency for Healthcare Research and Quality (AHRQ); Corcept Therapeutics, Inc.; Cyberonics, Inc.; Merck; National Alliance for Research in Schizophrenia and Depression; National Institute of Mental Health; National Institute on Drug Abuse; Novartis; Pharmacia Upjohn; Predix Pharmaceuticals (Epix); Targacept; Abbott Laboratories, Inc.; Abdi Ibrahim; Akzo (Organon Pharmaceuticals Inc.); Bristol-Myers Squibb Company; Evotec; Fabre Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals; Janssen Pharmaceutica Products; LP; Johnson Johnson PRD; Eli Lilly Company; Meade Johnson; Medtronic; Neuronetics; Otsuka Pharmaceuticals; Parke-Davis Pharmaceuticals, Inc.; Sepracor; SHIRE Development; VantagePoint; National Alliance for Research on Schizophrenia and Depression (NARSAD); National Institutes of Health FX Until August 2008, Per Bech occasionally received funding from and was a speaker or member of advisory boards for pharmaceutical companies with an interest in the drug treatment of affective disorders (Astra-Zeneca, Lilly, H Lundbeck A/S, and Organon).; Research support: Abbott Laboratories; Alkermes, Inc.; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; Cephalon, Inc.; Clinical Trials Solutions, LLC; Covidien; Eli Lilly and Company; En Vivo Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmavite (R) LLC; Roche; RTC Logic, LLC: Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo; and Wyeth-Ayerst Laboratories.; Dr. Trivedi reports that he has received research support from the Agency for Healthcare Research and Quality (AHRQ), Corcept Therapeutics, Inc., Cyberonics, Inc., Merck, National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health, National Institute on Drug Abuse, Novartis, Pharmacia & Upjohn, Predix Pharmaceuticals (Epix), Solvay Pharmaceuticals, Inc., and Targacept. He has received consulting and speaker fees from Abbott Laboratories, Inc., Abdi Ibrahim, Akzo (Organon Pharmaceuticals Inc.), AstraZeneca, Bristol-Myers Squibb Company, Cephalon, Inc., Evotec, Fabre Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica Products, LP, Johnson & Johnson PRD, Eli Lilly & Company, Meade Johnson, Medtronic, Neuronetics, Otsuka Pharmaceuticals, Parke-Davis Pharmaceuticals, Inc., Pfizer Inc., Sepracor, SHIRE Development, VantagePoint, and Wyeth-Ayerst Laboratories. Dr. Greer has received grant support from a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award and National Institutes of Health. NR 29 TC 25 Z9 25 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD AUG PY 2011 VL 132 IS 3 BP 396 EP 400 DI 10.1016/j.jad.2011.03.011 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 805JE UT WOS:000293721900013 PM 21440308 ER PT J AU Ta, NN Schuyler, CA Li, YC Lopes-Virella, MF Huang, Y AF Ta, Nga N. Schuyler, Corinne A. Li, Yanchun Lopes-Virella, Maria F. Huang, Yan TI DPP-4 (CD26) Inhibitor Alogliptin Inhibits Atherosclerosis in Diabetic Apolipoprotein E-Deficient Mice SO JOURNAL OF CARDIOVASCULAR PHARMACOLOGY LA English DT Article DE dipeptidyl peptidase-4; CD26; atherosclerosis; diabetes; inflammation ID DIPEPTIDYL-PEPTIDASE-IV; U937 MONONUCLEAR-CELLS; E-KNOCKOUT MICE; DP-IV; EXPRESSION; ACTIVATION; GLUCOSE; LIPOPOLYSACCHARIDE; 17-BETA-ESTRADIOL; INTERLEUKIN-6 AB Dipeptidyl peptidase-4 (DPP-4 or CD26) inhibitors, a new class of antidiabetic compounds, are effective in the treatment of hyperglycemia. Because atherosclerosis-related cardiovascular diseases are the major complications of diabetes, it is important to determine the effect of DPP-4 inhibitors on atherosclerosis. In this study, nondiabetic and diabetic apolipoprotein E-deficient mice were treated with DPP-4 inhibitor alogliptin for 24 weeks, and atherosclerotic lesions in aortic origins were examined. Results showed that diabetes significantly increased atherosclerotic lesions, but alogliptin treatment reduced atherosclerotic lesions in diabetic mice. Metabolic studies showed that diabetes increased plasma glucose and that alogliptin treatment reduced glucose. Furthermore, immunohistochemistry study showed that diabetes increased interleukin-6 (IL-6) and IL-1b protein expression in atherosclerotic plaques, but alogliptin treatment attenuated diabetes-augmented IL-6 and IL-1b expression. In consistence with the observations from the mouse models, our in vitro studies showed that alogliptin-inhibited toll-like receptor 4 (TLR-4)-mediated upregulation of IL-6, IL-1b, and other proinflammatory cytokines by mononuclear cells. Taken together, our findings showed that alogliptin-inhibited atherosclerosis in diabetic apolipoprotein E-deficient mice and that the actions of alogliptin on both glucose and inflammation may contribute to the inhibition. C1 [Schuyler, Corinne A.; Lopes-Virella, Maria F.; Huang, Yan] Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Dept Res & Dev, Charleston, SC 29403 USA. [Ta, Nga N.; Li, Yanchun; Lopes-Virella, Maria F.; Huang, Yan] Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. RP Huang, Y (reprint author), Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Dept Res & Dev, 114 Doughty St, Charleston, SC 29403 USA. EM huangyan@musc.edu FU Takeda Pharmaceuticals North America, Inc; Department of Veterans Affairs; NIH [DE016353]; Takeda Pharmaceuticals North America, Inc. FX Supported by a preclinical grant from Takeda Pharmaceuticals North America, Inc, a Merit Review grant from Department of Veterans Affairs and NIH grant DE016353 (to Y.H.).; This study was partially funded by a preclinical grant from Takeda Pharmaceuticals North America, Inc. NR 41 TC 71 Z9 77 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-2446 J9 J CARDIOVASC PHARM JI J. Cardiovasc. Pharmacol. PD AUG PY 2011 VL 58 IS 2 BP 157 EP 166 DI 10.1097/FJC.0b013e31821e5626 PG 10 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 806AS UT WOS:000293773900007 PM 21558879 ER PT J AU Pistilli, EE Bogdanovich, S Garton, F Yang, N Gulbin, JP Conner, JD Anderson, BG Quinn, LS North, K Ahima, RS Khurana, TS AF Pistilli, Emidio E. Bogdanovich, Sasha Garton, Fleur Yang, Nan Gulbin, Jason P. Conner, Jennifer D. Anderson, Barbara G. Quinn, LeBris S. North, Kathryn Ahima, Rexford S. Khurana, Tejvir S. TI Loss of IL-15 receptor alpha alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; RETRACTED ARTICLE. SEE; TUMOR-BEARING RATS; INTERLEUKIN-15 RECEPTOR; TRANSCRIPTIONAL COACTIVATOR; CONTRACTILE PROPERTIES; EXTRAOCULAR-MUSCLE; MOTOR UNITS; BETA-CHAIN; IN-VIVO AB IL-15 receptor alpha (IL-15R alpha) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15R alpha is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15R alpha have unique phenotypes. IL-15 and IL-15R alpha have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15R alpha. induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15R alpha-knockout (IL-15R alpha-KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15R alpha has a role in defining the phenotype of fast skeletal muscles in vivo. C1 [Khurana, Tejvir S.] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. [Pistilli, Emidio E.; Bogdanovich, Sasha; Khurana, Tejvir S.] Univ Penn, Penn Muscle Inst, Philadelphia, PA 19104 USA. [Garton, Fleur; Yang, Nan; North, Kathryn] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW, Australia. [Gulbin, Jason P.] AIS, Canberra, ACT, Australia. [Conner, Jennifer D.; Anderson, Barbara G.; Quinn, LeBris S.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Anderson, Barbara G.; Quinn, LeBris S.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA. [Ahima, Rexford S.] Univ Penn, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. RP Khurana, TS (reprint author), Univ Penn, Sch Med, Dept Physiol, 3700 Hamilton Walk,A601 Richards Bldg, Philadelphia, PA 19104 USA. EM tsk@mail.med.upenn.edu RI Garton, Fleur/H-7713-2016; North, Kathryn/K-6476-2012 OI Garton, Fleur/0000-0002-1490-5930; North, Kathryn/0000-0003-0841-8009 FU NIH under Ruth L. Kirschstein National Research Service from National Institute of Arthritis and Musculoskeletal and Skin Diseases [5T32AR053461, EY013862, AR48871]; [R01AG024136] FX This research was supported by the NIH under Ruth L. Kirschstein National Research Service Award 5T32AR053461 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (to E.E. Pistilli), EY013862 and AR48871 to T.S. Khurana, and R01AG024136 to L.S. Quinn, with resources from the VA Puget Sound Health Care System. The authors acknowledge Ravindra Dhir for collection and analysis of body composition and ambulatory activity data. NR 67 TC 29 Z9 30 U1 0 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2011 VL 121 IS 8 BP 3120 EP 3132 DI 10.1172/JCI44945 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 802FU UT WOS:000293495500023 PM 21765213 ER PT J AU Buijze, GA Mudgal, CS AF Buijze, Geert A. Mudgal, Chaitanya S. TI Nondisplaced Fractures of the Proximal Carpal Row: Case Report SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Greater arc; lesser arc; translunate arc; translunate fracture; perilunate injury ID PERILUNATE; WRIST; DISLOCATIONS; INJURY AB We present a 24-year-old woman who sustained isolated nondisplaced fractures of the proximal carpal row after a low-energy injury. The radiographic features are most consistent with the recently described translunate arc injury and appear to be a transitional injury between an inferior arc injury as well as the greater and lesser arc injuries. The injury was successfully treated with below-elbow thumb-spica cast immobilization for 10 weeks. (J Hand Surg 2011;36A:1310-1312. Copyright (C) 2011 by the American Society for Surgery of the Hand. All rights reserved.) C1 [Buijze, Geert A.; Mudgal, Chaitanya S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Orthopaed Hand Serv, Boston, MA USA. RP Buijze, GA (reprint author), Massachusetts Gen Hosp, Hand & Upper Extrem Serv, 55 Fruit St,YAW 2, Boston, MA 02114 USA. EM gbuijze@partners.org FU Netherlands Organisation for Scientific Research (NWO) FX G.A.B. would like to thank the Netherlands Organisation for Scientific Research (NWO) for support. NR 10 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD AUG PY 2011 VL 36A IS 8 BP 1310 EP 1312 DI 10.1016/j.jhsa.2011.05.032 PG 3 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 804QP UT WOS:000293669400008 PM 21741779 ER PT J AU Kim, JS Werth, VP AF Kim, Jessica S. Werth, Victoria P. TI Identification of Specific Chondroitin Sulfate Species in Cutaneous Autoimmune Disease SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE chondroitin sulfate; glycosaminoglycans; lupus erythematosus; dermatomyositis; cutaneous autoimmune disease ID TRABECULAR MESHWORK CELLS; HUMAN SKIN FIBROBLASTS; CD44 SPLICE VARIANTS; ENDOTHELIAL-CELLS; SOLUBLE CD44; TNF-ALPHA; INFLAMMATORY MYOPATHIES; DIFFERENTIAL REGULATION; EXTRACELLULAR-MATRIX; LUPUS-ERYTHEMATOSUS AB Cutaneous lupus erythematosus and dermatomyositis (DM) are chronic inflammatory diseases of the skin with accumulated dermal mucin. Earlier work has shown chondroitin sulfate (CS) accumulation within the dermis of discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and DM lesions compared with control skin. Immunohistochemistry for C4S revealed a greater density in DLE and DM lesions, whereas SCLE lesions did not differ from controls. Scleredema and scleromyxedema are attributed to increased hyaluronic acid, and lesional samples from these diseases also demonstrated accumulated dermal C4S. Interferon-gamma and interleukin-1 alpha, but not interferon-alpha, treatment of cultured dermal fibroblasts induced mRNA expression of CHST-11, which attaches sulfates to the 4-position of unsulfated chondroitin. These studies on possible CS core proteins revealed that serglycin, known to have C6S side chains in endothelial cells, had greater density within DM dermal endothelia but not in DLE or SCLE, following the pattern of C6S overexpression reported previously. CD44 variants expand the CS binding repertoire of the glycoprotein; CD44v7 co-localized to the distribution of C4S in DLE lesions, a finding not observed in DM, SCLE lesions, or controls. Because C4S and C6S have immunologic effects, their dysregulation in cutaneous mucinoses may contribute to the pathogenesis of these disorders. (J Histochem Cytochem 59:780-790, 2011) C1 [Werth, Victoria P.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Kim, Jessica S.] NYU, Sch Med, New York, NY USA. [Kim, Jessica S.; Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Werth, VP (reprint author), Univ Penn, Dept Dermatol, 2 Rhoads Pavil,36th & Spruce St, Philadelphia, PA 19104 USA. EM werth@mail.med.upenn.edu FU Lupus Foundation of America; Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development) FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This material is based on work supported by the Lupus Foundation of America and in part by a Merit Review Grant from the Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development). NR 66 TC 7 Z9 7 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD AUG PY 2011 VL 59 IS 8 BP 780 EP 790 DI 10.1369/0022155411411304 PG 11 WC Cell Biology SC Cell Biology GA 805DI UT WOS:000293706200006 PM 21804080 ER PT J AU Stoddard, FJ Gold, J Henderson, SW Merlino, JP Norwood, A Post, JM Shanfield, S Weine, S Katz, CL AF Stoddard, Frederick J., Jr. Gold, Joel Henderson, Schuyler W. Merlino, Joseph P. Norwood, Ann Post, Jerrold M. Shanfield, Stephen Weine, Stevan Katz, Craig L. TI Psychiatry and Terrorism SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Review DE 9/11; terrorism; disasters; PTSD; mental health services ID POSTTRAUMATIC-STRESS-DISORDER; NEW-YORK-CITY; MENTAL-HEALTH; HUMAN-RIGHTS; WORKERS; INTERVENTION; POSITION; ATTACKS; TRAUMA; SARS AB Terrorism has dominated the domestic and international landscape since 9/11. Like other fields, psychiatry was not well prepared. With the 10th anniversary of the 9/11 attack approaching, it is timely to consider what can be done to prepare before the next event. Much has been learned to provide knowledge and resources. The roles of psychiatrists are challenged by what is known of the causes of, consequences of, and responses to terrorism. Reflecting on knowledge from before and since 9/11 introduces concepts, how individuals become terrorists, how to evaluate the psychiatric and behavioral effects of terrorism, and how to expand treatments, behavioral health interventions, public policy initiatives, and other responses for its victims. New research, clinical approaches, and policy perspectives inform strategies to reduce fear and cope with the aftermath. This article identifies the psychiatric training, skills and services, and ethical considerations necessary to prevent or reduce terrorism and its tragic consequences and to enhance resilience. C1 [Stoddard, Frederick J., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Henderson, Schuyler W.] New York Presbyterian Columbia Univ, New York, NY USA. [Gold, Joel] NYU, New York, NY USA. [Merlino, Joseph P.] Kings Cty Hosp Ctr, Dept Psychiat, New York, NY USA. [Merlino, Joseph P.] SUNY Downstate Med Coll, Dept Clin Psychiat, New York, NY USA. [Norwood, Ann] Univ Pittsburgh, Med Ctr, Ctr Biosecur, Baltimore, MD USA. [Post, Jerrold M.] George Washington Univ, Washington, DC USA. [Shanfield, Stephen] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Weine, Stevan] Univ Illinois, Chicago, IL USA. [Katz, Craig L.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Katz, Craig L.] Mt Sinai Sch Med, Dept Med Educ, New York, NY USA. RP Stoddard, FJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, SHC 610,55 Fruit St, Boston, MA 02114 USA. EM FStoddard@partners.org NR 70 TC 6 Z9 6 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 2011 VL 199 IS 8 BP 537 EP 543 DI 10.1097/NMD.0b013e318225ee90 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 802IE UT WOS:000293502000005 PM 21814075 ER PT J AU Eth, S Leong, GB AF Eth, Spencer Leong, Gregory B. TI Psychiatric Ethics Foundational and Evolutionary SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Psychiatric ethics; research ethics; post-9/11 ethics; ethics education ID CLINICAL-RESEARCH; INFORMED-CONSENT; TUSKEGEE; MEDICINE; LESSONS; ISSUES; DUTY AB As with the basic and clinical sciences, the field of medical ethics, in particular, that of psychiatric ethics, has grown and developed during the last four decades, the time when Dr. Eugene Brody edited the Journal of Nervous and Mental Disease. In this paper, the authors will consider a series of ethical problems that psychiatrists have identified in their clinical practice and suggest paths to resolution that may artfully balance conflicts in core moral beliefs. C1 [Eth, Spencer] VA Med Ctr, Psychiat Serv, Miami, FL USA. [Eth, Spencer] Univ Miami, Miller Sch Med, Dept Psychiat, Miami, FL 33136 USA. [Leong, Gregory B.] VA Puget Sound Hlth Care Syst, Amer Lake Div, Mental Hlth Serv, Tacoma, WA USA. [Leong, Gregory B.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Eth, S (reprint author), VA Med Ctr, Psychiat Serv, Miami, FL USA. NR 33 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 2011 VL 199 IS 8 BP 562 EP 566 DI 10.1097/NMD.0b013e318225f0fe PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 802IE UT WOS:000293502000009 PM 21814079 ER PT J AU Freeman, DK Jeng, JS Kelly, SK Hartveit, E Fried, SI AF Freeman, Daniel K. Jeng, Jed S. Kelly, Shawn K. Hartveit, Espen Fried, Shelley I. TI Calcium channel dynamics limit synaptic release in response to prosthetic stimulation with sinusoidal waveforms SO JOURNAL OF NEURAL ENGINEERING LA English DT Article; Proceedings Paper CT 39th Neural Interfaces Conference (NIC2010) CY JUN, 2010 CL Long Beach, CA ID RETINAL GANGLION-CELLS; ROD BIPOLAR CELLS; VOLTAGE-DEPENDENT NA+; ELECTRICAL-STIMULATION; DIFFERENTIAL EXPRESSION; MAMMALIAN RETINA; AXON TERMINALS; RAT RETINA; NEUROTRANSMITTER RELEASE; MEMBRANE-PROPERTIES AB Extracellular electric stimulation with sinusoidal waveforms has been shown to allow preferential activation of individual types of retinal neurons by varying stimulus frequency. It is important to understand the mechanisms underlying this frequency dependence as a step toward improving methods of preferential activation. In order to elucidate these mechanisms, we implemented a morphologically realistic model of a retinal bipolar cell and measured the response to extracellular stimulation with sinusoidal waveforms. We compared the frequency response of a passive membrane model to the kinetics of voltage-gated calcium channels that mediate synaptic release. The passive electrical properties of the membrane exhibited lowpass filtering with a relatively high cutoff frequency (nominal value = 717 Hz). This cutoff frequency was dependent on intra-axonal resistance, with shorter and wider axons yielding higher cutoff frequencies. However, we found that the cutoff frequency of bipolar cell synaptic release was primarily limited by the relatively slow opening kinetics of L- and T-type calcium channels. The cutoff frequency of calcium currents depended nonlinearly on stimulus amplitude, but remained lower than the cutoff frequency of the passive membrane model for a large range of membrane potential fluctuations. These results suggest that while it may be possible to modulate the membrane potential of bipolar cells over a wide range of stimulus frequencies, synaptic release will only be initiated at the lower end of this range. C1 [Freeman, Daniel K.; Jeng, Jed S.; Kelly, Shawn K.; Fried, Shelley I.] Boston VA Healthcare Syst, Ctr Innovat Visual Rehabil, Boston, MA 02130 USA. [Freeman, Daniel K.; Jeng, Jed S.; Fried, Shelley I.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Freeman, Daniel K.; Jeng, Jed S.; Fried, Shelley I.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kelly, Shawn K.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Hartveit, Espen] Univ Bergen, Dept Biomed, N-5009 Bergen, Norway. RP Freeman, DK (reprint author), Boston VA Healthcare Syst, Ctr Innovat Visual Rehabil, 150 S Huntington Ave, Boston, MA 02130 USA. EM fried.shelley@mgh.harvard.edu OI Kelly, Shawn/0000-0003-3533-5268 FU NEI NIH HHS [R01 EY019967, R01 EY-019967-01, R01 EY019967-01] NR 69 TC 11 Z9 11 U1 1 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 J9 J NEURAL ENG JI J. Neural Eng. PD AUG PY 2011 VL 8 IS 4 SI SI AR 046005 DI 10.1088/1741-2560/8/4/046005 PG 19 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA 795GR UT WOS:000292962800015 PM 21628768 ER PT J AU Wilker, E Korrick, S Nie, LH Sparrow, D Vokonas, P Coull, B Wright, RO Schwartz, J Hu, H AF Wilker, Elissa Korrick, Susan Nie, Linda H. Sparrow, David Vokonas, Pantel Coull, Brent Wright, Robert O. Schwartz, Joel Hu, Howard TI Longitudinal Changes in Bone Lead Levels The VA Normative Aging Study SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID X-RAY-FLUORESCENCE; BLOOD LEAD; ELDERLY-MEN; KINETIC-MODEL; METABOLISM; TOXICITY; EXPOSURE; ADULTS; AGE; NUTRITION AB Objective: Bone lead is a cumulative measure of lead exposure that can also be remobilized. We examined repeated measures of bone lead over 11 years to characterize long-term changes and identify predictors of tibia and patella lead stores in an elderly male population. Methods: Lead was measured every 3 to 5 years by k-x-ray fluorescence and mixed-effect models with random effects were used to evaluate change over time. Results: A total of 554 participants provided up to four bone lead measurements. Final models predicted a -1.4% annual decline (95% CI: -2.2 to -0.7) for tibia lead and piecewise linear model for patella with an initial decline of 5.1% per year (95% CI: -6.2 to -3.9) during the first 4.6 years but no significant change thereafter (-0.4% [95% CI: -2.4 to 1.7]). Conclusions: These results suggest that bone lead half-life may be longer than previously reported. C1 [Wilker, Elissa] Beth Israel Deaconess Med Ctr, Cardiovasc Epidemiol Res Unit, Boston, MA 02215 USA. [Wilker, Elissa; Korrick, Susan; Coull, Brent; Wright, Robert O.; Schwartz, Joel] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Korrick, Susan; Wright, Robert O.; Schwartz, Joel] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Nie, Linda H.] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Sparrow, David; Vokonas, Pantel] Boston Univ, Sch Med, VA Normat Aging Study, VA Boston Healthcare Syst, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Hu, Howard] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. RP Wilker, E (reprint author), Beth Israel Deaconess Med Ctr, Cardiovasc Epidemiol Res Unit, 375 Longwood Ave, Boston, MA 02215 USA. EM ewilker@bidmc.harvard.edu OI Hu, Howard/0000-0002-3676-2707 FU NIEHS [R01- ES005257, R01- ES007821, 000002, T32-ES07069, T32-HL007374]; NIH [SBIR 2R44 ES03918-02]; US Department of Veterans Affairs FX NIEHS R01-ES005257, R01ES007821, and 000002, T32-ES07069 and T32-HL007374.; Test subjects were evaluated for measurement of bone lead levels in the outpatient Clinical Research Center of the Brigham and Women's Hospital. The K-XRF instrument used in some of this work was developed by ABIOMED, Inc., of Danvers, Massachusetts, with support from NIH grant no. SBIR 2R44 ES03918-02. The Normative Aging Study is supported by the Research Services and the Cooperative Studies Program/ERIC of the US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). NR 26 TC 23 Z9 24 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 2011 VL 53 IS 8 BP 850 EP 855 DI 10.1097/JOM.0b013e31822589a9 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 804XE UT WOS:000293687400005 PM 21788910 ER PT J AU Soteriades, ES Targino, MC Talias, MA Hauser, R Kawachi, I Christiani, DC Kales, SN AF Soteriades, Elpidoforos S. Targino, Marcelo C. Talias, Michael A. Hauser, Russ Kawachi, Ichiro Christiani, David C. Kales, Stefanos N. TI Obesity and Risk of LVH and ECG Abnormalities in US Firefighters SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; BODY-MASS INDEX; HYPERTENSIVE PATIENTS; BLOOD-PRESSURE; ELECTROCARDIOGRAPHIC DIAGNOSIS; MILD HYPERTENSION; HEART-DISEASE; UNITED-STATES; FAT-FREE; MORTALITY AB Objective: To evaluate the association between obesity and electrocardiographic (ECG) abnormalities. Methods: We conducted a secondary analysis examining the association between body mass index and ECG abnormalities among Massachusetts' firefighters. Results: Overall, 276 firefighters had undergone ECG testing at baseline (1996/97) and follow-up (2000). The incidence of left ventricular hypertrophy (LVH) was 15 per 1000 person-years of follow-up. After adjusting for age, systolic and diastolic blood pressure, obese firefighters were about two times more likely to develop ECG-LVH (OR = 2.0; 95% CI, 0.6 to 6.6) and were 1.5 times more likely to develop ECG abnormalities (OR = 1.5; 95% CI, 0.6 to 3.9) at follow-up. Conclusions: Obese firefighters appear to have a higher risk of LVH and ECG abnormalities than normal-weight individuals. Our findings need further evaluation and may have important implications for occupational health policies and periodic medical evaluations. C1 [Soteriades, Elpidoforos S.; Hauser, Russ; Christiani, David C.; Kales, Stefanos N.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth Environm & Occupat Med & Epide, Boston, MA 02115 USA. [Kawachi, Ichiro] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kawachi, Ichiro] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Christiani, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm Crit Care Unit, Boston, MA USA. [Soteriades, Elpidoforos S.] Cyprus Inst Biomed Sci, Dept Occupat & Environm Med, Nicosia, Cyprus. [Talias, Michael A.] Open Univ Cyprus, Healthcare Management Program, Nicosia, Cyprus. [Targino, Marcelo C.] Exeter Hlth Resources, Exeter, NH USA. [Kales, Stefanos N.] Cambridge Hlth Alliance Employee & Ind Med, Cambridge, MA USA. RP Soteriades, ES (reprint author), Cyprus Inst Biomed Sci, 2 Antigonis St, CY-2035 Strovolos, Cyprus. EM esoteria@hsph.harvard.edu FU Respironics FX SNK has consulted with Novartis Pharmaceuticals and received research funding from Respironics. The other authors declare that they have no financial and/or other relationship that may lead to a conflict of interest. NR 47 TC 5 Z9 5 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 2011 VL 53 IS 8 BP 867 EP 871 DI 10.1097/JOM.0b013e318221c6fe PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 804XE UT WOS:000293687400007 PM 21775903 ER PT J AU Sorensen, G Stoddard, AM Stoffel, S Buxton, O Sembajwe, G Hashimoto, D Dennerlein, JT Hopcia, K AF Sorensen, Glorian Stoddard, Anne M. Stoffel, Sonja Buxton, Orfeu Sembajwe, Grace Hashimoto, Dean Dennerlein, Jack T. Hopcia, Karen TI The Role of the Work Context in Multiple Wellness Outcomes for Hospital Patient Care Workers SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID LOW-BACK-PAIN; TIME PHYSICAL-ACTIVITY; REPORTED MUSCULOSKELETAL DISORDERS; ALL-CAUSE MORTALITY; HEALTH-CARE; LEISURE-TIME; REGISTERED NURSES; LIFE-STYLE; SLEEP DURATION; UNITED-STATES AB Objective: To examine the relationships among low back pain (LBP), inadequate physical activity, and sleep deficiency among patient care workers, and of these outcomes to work context. Methods: A cross-sectional survey of patient care workers (N = 1572, response rate = 79%). Results: A total of 53% reported LBP, 46%, inadequate physical activity, and 59%, sleep deficiency. Inadequate physical activity and sleep deficiency were associated (P = 0.02), but LBP was not significantly related to either. Increased risk of LBP was significantly related to job demands, harassment at work, decreased supervisor support, and job title. Inadequate physical activity was significantly associated with low decision latitude. Sleep deficiency was significantly related to low supervisor support, harassment at work, low ergonomic practices, people-oriented culture, and job title. Conclusions: These findings point to shared pathways in the work environment that jointly influence multiple health and well-being outcomes. C1 [Sorensen, Glorian; Stoffel, Sonja] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sorensen, Glorian; Stoffel, Sonja; Sembajwe, Grace; Hashimoto, Dean; Dennerlein, Jack T.; Hopcia, Karen] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Buxton, Orfeu] Harvard Univ, Sch Med, Boston, MA USA. [Hashimoto, Dean; Hopcia, Karen] Partners HealthCare Inc, Boston, MA USA. [Buxton, Orfeu] Brigham & Womens Hosp, Boston, MA 02115 USA. [Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. RP Sorensen, G (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM glorian_sorensen@dfci.harvard.edu OI Dennerlein, Jack/0000-0001-7703-643X FU Sepracor Inc. (now Sunovion); National Institute for Occupational Safety and Health for the Harvard School of Public Health Center for Work, Health and Well-being [U19 OH008861] FX During the past three years, Dr. Buxton received an investigator-initiated research grant from Sepracor Inc. (now Sunovion) and consults for Disnmore LLC as an expert witness. All other authors have no conflicts of interest to report.; This work was supported by a grant from the National Institute for Occupational Safety and Health (U19 OH008861) for the Harvard School of Public Health Center for Work, Health and Well-being. This study would not have been accomplished without the participation of Partners HealthCare System and leadership from Dennis Colling and Kurt Westerman. The authors would like to thank Partners Occupational Health Services including Marlene Freeley for her guidance and Terry Orechia for programming support. We also thank individuals at each of the hospitals including Jeanette Ives Erickson, Mairead Hickey and Trish Gibbons in Patient Care Services leadership, and Jeff Davis and Lisa Pontin in Human Resources. We also thank Chris Kenwood of NERI for his statistical and programming support and Linnea Benson-Whelan for her assistance with the production of this manuscript. NR 97 TC 28 Z9 28 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 2011 VL 53 IS 8 BP 899 EP 910 DI 10.1097/JOM.0b013e318226a74a PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 804XE UT WOS:000293687400012 PM 21775897 ER PT J AU Lai, JS Butt, Z Zelko, F Cella, D Krull, KR Kieran, MW Goldman, S AF Lai, Jin-Shei Butt, Zeeshan Zelko, Frank Cella, David Krull, Kevin R. Kieran, Mark W. Goldman, Stewart TI Development of a Parent-Report Cognitive Function Item Bank Using Item Response Theory and Exploration of its Clinical Utility in Computerized Adaptive Testing SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE assessment; cancer and oncology; cognitive assessment; computer applications/eHealth; neuropsychology; quality of life ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDRENS CANCER GROUP; QUALITY-OF-LIFE; RADIATION-THERAPY; ADULT SURVIVORS; WORKING-MEMORY; THEORY MODELS; BRAIN-TUMOR; PERFORMANCE; MEDULLOBLASTOMA AB Objective The purpose of this study is to report the reliability, validity, and clinical utility of a parent-report perceived cognitive function (pedsPCF) item bank. Methods From the U. S. general population, 1,409 parents of children aged 7-17 years completed 45 pedsPCF items. Their psychometric properties were evaluated using Item Response Theory (IRT) approaches. Receiver operating characteristic (ROC) curves and discriminant function analysis were used to predict clinical problems on child behavior checklist (CBCL) scales. A computerized adaptive testing (CAT) simulation was used to evaluate clinical utility. Results The final 43-item pedsPCF item bank demonstrates no item bias, has acceptable IRT parameters, and provides good prediction of related clinical problems. CAT simulation resulted in correlations of 0.98 between CAT and the full-length pedsPCF. Conclusions The pedsPCF has sound psychometric properties, U. S. general population norms, and a brief-yet-precise CAT version is available. Future work will evaluate pedsPCF in other clinical populations in which cognitive function is important. C1 [Lai, Jin-Shei] Northwestern Univ, Dept Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Butt, Zeeshan] Northwestern Univ, Comprehens Transplant Ctr, Transplant Outcomes Res Collaborat NUTORC, Chicago, IL 60611 USA. [Butt, Zeeshan] Northwestern Univ, Inst Healthcare Studies, Chicago, IL 60611 USA. [Zelko, Frank; Goldman, Stewart] Northwestern Univ, Childrens Mem Hosp, Feinberg Sch Med, Chicago, IL 60611 USA. [Krull, Kevin R.] Harvard Univ, Sch Med, St Jude Childrens Res Hosp, Cambridge, MA 02138 USA. [Kieran, Mark W.] Harvard Univ, Sch Med, Childrens Hosp Boston, Cambridge, MA 02138 USA. [Kieran, Mark W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. RP Lai, JS (reprint author), Northwestern Univ, Dept Med Social Sci, Feinberg Sch Med, 710 N Lake Shore Dr,724, Chicago, IL 60611 USA. EM js-lai@northwestern.edu OI Kieran, Mark/0000-0003-2184-7692 FU NCI NIH HHS [R01CA125671]; NCRR NIH HHS [UL1RR025741] NR 44 TC 13 Z9 13 U1 2 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 EI 1465-735X J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD AUG PY 2011 VL 36 IS 7 BP 766 EP 779 DI 10.1093/jpepsy/jsr005 PG 14 WC Psychology, Developmental SC Psychology GA 804CB UT WOS:000293630400004 PM 21378106 ER PT J AU Picard, MH AF Picard, Michael H. TI Re: "American Society of Echocardiography Recommendations for Quality Echocardiography Laboratory Operations" Reply SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Letter C1 Massachusetts Gen Hosp, Lab Qual Task Force, Boston, MA 02114 USA. RP Picard, MH (reprint author), Massachusetts Gen Hosp, Lab Qual Task Force, Boston, MA 02114 USA. OI Picard, Michael/0000-0002-9264-3243 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD AUG PY 2011 VL 24 IS 8 BP 930 EP 930 DI 10.1016/j.echo.2011.05.005 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 796RZ UT WOS:000293070900017 ER PT J AU Kerlikowske, K Phipps, AI AF Kerlikowske, Karla Phipps, Amanda I. TI Breast Density Influences Tumor Subtypes and Tumor Aggressiveness SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ESTROGEN-RECEPTOR STATUS; AFRICAN-AMERICAN WOMEN; MAMMOGRAPHIC DENSITY; CANCER RISK; POSTMENOPAUSAL WOMEN; HORMONE-RECEPTOR; ASSOCIATION; SURVIVAL; FEATURES; DIFFERENCE C1 [Kerlikowske, Karla] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Gen Internal Med Sect, Dept Vet Affairs, San Francisco, CA 94121 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol & Biostat, Dept Med, San Francisco, CA 94121 USA. [Phipps, Amanda I.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Phipps, Amanda I.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Kerlikowske, K (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Gen Internal Med Sect, Dept Vet Affairs, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM karla.kerlikowske@ucsf.edu FU NCI NIH HHS [R25 CA94880, P01 CA107584]; PHS HHS [P50 C A58207] NR 41 TC 6 Z9 6 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG PY 2011 VL 103 IS 15 BP 1143 EP 1145 DI 10.1093/jnci/djr263 PG 3 WC Oncology SC Oncology GA 804BH UT WOS:000293628200003 PM 21795663 ER PT J AU Norvell, DC Turner, AP Williams, RM Hakimi, KN Czerniecki, JM AF Norvell, Daniel C. Turner, Aaron P. Williams, Rhonda M. Hakimi, Kevin N. Czerniecki, Joseph M. TI Defining successful mobility after lower extremity amputation for complications of peripheral vascular disease and diabetes SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID LOWER-LIMB AMPUTATION; QUALITY-OF-LIFE; WALKING ABILITY; UNITED-STATES; AMPUTEES; REHABILITATION; SATISFACTION; CAPABILITIES; POPULATION; VALIDATION AB Background: Information about longer-term functional outcomes following lower extremity amputation for peripheral vascular disease and diabetes remains limited. This study examined factors associated with mobility success during the first year following amputation. Methods: Prospective cohort study of 87 amputees experiencing a first major unilateral amputation surgery. Seventy-five (86%) participants completed 12-month follow-up interview. Results: Twenty-eight subjects (37%) achieved mobility success, defined as returning to or exceeding a baseline level of mobility on the locomotor capability index (LCI-5). Forty-three subjects (57%) were satisfied with their mobility. Individuals who were 65 years of age and older (risk difference [RD] = -0.52; 95% confidence interval [CI]: -0.75, -0.29), reported a current alcohol use disorder (RI) = -0.37; 95% CI: -0.48, -0.26), had a history of hypertension (RD = -0.23; 95% CI: -0.43, -0.03) or treatment for anxiety or depression (RD = -0.39; 95% CI: -0.50, -0.28) were less likely to achieve mobility success. Mobility success was associated with mobility satisfaction (RD = 0.36; 95% CI: 0.20, 0.53) and satisfaction with life (RD = 0.28; 95% CI: 0.06, 0.50). Although higher absolute mobility at 12 months was also associated with mobility satisfaction and overall life satisfaction, 50% of individuals who achieved success with low to moderate 12-month mobility function reported they were satisfied with their mobility. Conclusion: Defining success after amputation in relation to an individual's specific mobility prior to the development of limb impairment which led to amputation provides a useful, patient-centered measure that takes other aspects of health, function, and impairment into account. (J Vase Surg 2011;54:412-9.) C1 [Turner, Aaron P.] VA Puget Sound Hlth Care Syst, Dept Rehabil Med, Seattle, WA 98108 USA. [Norvell, Daniel C.] Spectrum Res Inc, Tacoma, WA USA. [Turner, Aaron P.; Williams, Rhonda M.; Hakimi, Kevin N.; Czerniecki, Joseph M.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. RP Turner, AP (reprint author), VA Puget Sound Hlth Care Syst, Dept Rehabil Med, S-117-RCS,1660 S Columbian Way, Seattle, WA 98108 USA. EM aaron.Turner@va.gov OI Turner, Aaron/0000-0001-6897-8003 FU US Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development [A41241, B4927W] FX Supported by the US Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development (Merit Review A41241 Joseph Czerniecki, PI, and Career Development Award B4927W Aaron Turner, PI). NR 29 TC 24 Z9 24 U1 1 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD AUG PY 2011 VL 54 IS 2 BP 412 EP 419 DI 10.1016/j.jvs.2011.01.046 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 806NH UT WOS:000293814400023 PM 21531528 ER PT J AU Chen, HT Kougias, P Lin, PH Bechara, CF AF Chen, Huiting Kougias, Panagiotis Lin, Peter H. Bechara, Carlos F. TI Jaw claudication in the era of carotid stenting SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID INTERMITTENT CLAUDICATION; ARTERY; ENDARTERECTOMY; OCCLUSION; DISEASE; PAIN AB Jaw claudication could result from external carotid artery (ECA) occlusive disease. Carotid artery stenting (CAS) has been shown to worsen the disease in the ECA. This could potentially worsen the symptoms in patients with pre-existing jaw claudication undergoing CAS. Meanwhile, ECA endarterectomy is routinely done during internal carotid artery endarterectomy (CEA). This has been shown to alleviate jaw claudication symptoms. We report a case of a high-risk patient for CEA who presented with symptomatic carotid disease as well as bilateral jaw claudication. Both symptoms resolved after CEA. We also present the case of another patient treated for recurrent high-grade carotid disease with CAS resulting in acute ECA occlusion and jaw claudication. High-risk patients with symptomatic carotid disease and jaw claudication should be considered for CEA and not only CAS. (J Vase Surg 2011;54:526-8.) C1 [Chen, Huiting; Kougias, Panagiotis; Lin, Peter H.; Bechara, Carlos F.] Baylor Coll Med, Michael E DeBakey Dept Surg, Michael E DeBakey Vet Adm Med Ctr, Div Vasc & Endovasc Therapy, Houston, TX 77030 USA. RP Bechara, CF (reprint author), Baylor Coll Med, Michael E DeBakey Dept Surg, Michael E DeBakey VA Med Ctr, Div Vasc Surg & Endovasc Therapy, 2002 Holcombe Blvd 112, Houston, TX 77030 USA. EM bechara@bcm.edu NR 14 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD AUG PY 2011 VL 54 IS 2 BP 526 EP 528 DI 10.1016/j.jvs.2010.12.057 PG 3 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 806NH UT WOS:000293814400044 PM 21397442 ER PT J AU Biffi, A Anderson, CD Jagiella, JM Schmidt, H Kissela, B Hansen, BM Jimenez-Conde, J Pires, CR Ayres, AM Schwab, K Cortellini, L Pera, J Urbanik, A Romero, JM Rost, NS Goldstein, JN Viswanathan, A Pichler, A Enzinger, C Rabionet, R Norrving, B Tirschwell, DL Selim, M Brown, DL Silliman, SL Worrall, BB Meschia, JF Kidwell, CS Broderick, JP Greenberg, SM Roquer, J Lindgren, A Slowik, A Schmidt, R Woo, D Rosand, J AF Biffi, Alessandro Anderson, Christopher D. Jagiella, Jeremiasz M. Schmidt, Helena Kissela, Brett Hansen, Bjorn M. Jimenez-Conde, Jordi Pires, Caroline R. Ayres, Alison M. Schwab, Kristin Cortellini, Lynelle Pera, Joanna Urbanik, Andrzej Romero, Javier M. Rost, Natalia S. Goldstein, Joshua N. Viswanathan, Anand Pichler, Alexander Enzinger, Christian Rabionet, Raquel Norrving, Bo Tirschwell, David L. Selim, Magdy Brown, Devin L. Silliman, Scott L. Worrall, Bradford B. Meschia, James F. Kidwell, Chelsea S. Broderick, Joseph P. Greenberg, Steven M. Roquer, Jaume Lindgren, Arne Slowik, Agnieszka Schmidt, Reinhold Woo, Daniel Rosand, Jonathan CA Int Stroke Genetics Consortium TI APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study SO LANCET NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; APOLIPOPROTEIN-E GENOTYPE; E EPSILON-2; POLYMORPHISM; POPULATION; MORTALITY; SURVIVAL; HEMATOMA; WARFARIN; DISEASE AB Background Carriers of APOE epsilon 2 and epsilon 4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome. Methods We investigated the association of APOE epsilon 2 and epsilon 4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE epsilon 4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH. Findings For patients with lobar ICH, carriers of the APOE epsilon 2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2. 5x10(-5)), in both replication phases (p=0.008 in Europeans and p=0.016 in African-Americans), and in the meta-analysis (p=3.2x10(-8)). In the meta-analysis, each copy of APOE epsilon 2 increased haematoma size by a mean of 5.3 mL (95% CI 4.7-5.9; p=0.004). Carriers of APOE epsilon 2 had increased mortality (odds ratio [OR] 1.50, 95% CI 1.23-1.82; p=2.45x10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1-52, 1.25-1.85; p=1.74x10(-5)) compared with non-carriers after lobar ICH. APOE epsilon 4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1.08,0.86-1.36; p=0.52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality. Interpretation Vasculopathic changes associated with the APOE epsilon 2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the epsilon 2 variant might allow identification of those at increased risk of mortality and poor functional outcomes. C1 [Biffi, Alessandro; Anderson, Christopher D.; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Biffi, Alessandro; Anderson, Christopher D.; Pires, Caroline R.; Ayres, Alison M.; Schwab, Kristin; Cortellini, Lynelle; Rost, Natalia S.; Viswanathan, Anand; Greenberg, Steven M.; Rosand, Jonathan] Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. [Biffi, Alessandro; Anderson, Christopher D.; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Dept Neurol, Boston, MA 02114 USA. [Romero, Javier M.] Massachusetts Gen Hosp, Serv Neuroradiol, Dept Radiol, Boston, MA 02114 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Biffi, Alessandro; Anderson, Christopher D.; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Jagiella, Jeremiasz M.; Pera, Joanna; Urbanik, Andrzej; Slowik, Agnieszka] Jagiellonian Univ, Dept Neurol, Coll Med, Krakow, Poland. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Med Biochem, Graz, Austria. [Pichler, Alexander; Enzinger, Christian; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Enzinger, Christian] Med Univ Graz, Neuroradiol Sect, Dept Radiol, Graz, Austria. [Kissela, Brett; Broderick, Joseph P.; Woo, Daniel] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA. [Hansen, Bjorn M.; Norrving, Bo; Lindgren, Arne] Lund Univ, Dept Clin Sci Lund, Lund, Sweden. [Hansen, Bjorn M.; Norrving, Bo; Lindgren, Arne] Skane Univ Hosp, Dept Neurol, Lund, Sweden. [Jimenez-Conde, Jordi; Roquer, Jaume] Univ Autonoma Barcelona, Neurovasc Res Unit, Dept Neurol, Inst Municipal Invest Med,Hosp Mar, E-08193 Barcelona, Spain. [Jimenez-Conde, Jordi; Roquer, Jaume] Univ Autonoma Barcelona, Inst Municipal Invest Med, Hosp Mar, Program Inflammat & Cardiovasc Disorders, E-08193 Barcelona, Spain. [Rabionet, Raquel] CIBERESP, Genes & Dis Program, CRG, Natl Genotyping Ctr CeGen, Barcelona, Spain. [Rabionet, Raquel] Pompeu Fabra Univ, Barcelona, Spain. [Tirschwell, David L.] Univ Washington, Harborview Med Ctr, Stroke Ctr, Seattle, WA 98104 USA. [Selim, Magdy] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Brown, Devin L.] Univ Michigan Hlth Syst, Stroke Program, Dept Neurol, Ann Arbor, MI USA. [Silliman, Scott L.] Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Neurol & Publ Hlth Sci, Charlottesville, VA USA. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Kidwell, Chelsea S.] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. RP Rosand, J (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN-6818, Boston, MA 02114 USA. EM jrosand@partners.org RI rabionet, raquel/C-8379-2009; rabionet, raquel/A-7407-2009; JIMENEZ-CONDE, JORDI/C-1941-2012; Goldstein, Joshua/H-8953-2016; OI rabionet, raquel/0000-0001-5006-8140; rabionet, raquel/0000-0001-5006-8140; Hansen, Bjorn/0000-0001-8661-9063; Brown, Devin/0000-0002-9815-3421; Norrving, Bo/0000-0002-8024-5096; Ayres, Alison/0000-0002-5492-1695; Anderson, Christopher/0000-0002-0053-2002; Kissela, Brett/0000-0002-9773-4013 FU Sygnis Pharma; Sender; Bayer; PhotoThera; Boehringer-Ingelheim; Allergan; Pfizer; Sanofi; Bristol-Myers Squibb; W L Gore and Associates; AstraZeneca; Novartis; Merz Austria; Lundbeck; LCC; Takeda; Hoffman LaRoche; Medtronic; Janssen Alzheimer Immunotherapy; US National Institutes of Health-National Institute of Neurological Disorders and Stroke; Keane Stroke Genetics Research Fund; Edward and Maybeth Sonn Research Fund; US National Center for Research Resources; National Institute of Neurological Disorders And Stroke (NINDS) [U54NS057405]; National Institute on Minority Health and Health Disparities (NIMHD) [U54NS057405]; NIH [NS36695, NS30678]; Greater Cincinnati Foundation; NIH-NINDS [K23NS042695, 5K23NS059774, R01NS059727, 5R01NS042147]; University of Michigan General Clinical Research Center [M01 RR000042]; National Center for Research Resources; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]; Ministerio de Sanidad y Consumo de Espana; Instituto de Salud Carlos III [PI051737, CM06100067, RD06/0009]; Polish Ministry of Education [N N402 083934]; Lund University; Region Skane; Swedish Medical Research Council [K2007-61X-20378-01-3]; Austrian Science Fond [P20545-P05, P13180]; Medical University of Graz FX BN has received financial compensation from Sygnis Pharma, Sender, Bayer, PhotoThera, Boehringer-Ingelheim, and Allergan. AL has received financial compensation and grant support from Boehringer-Ingelheim, Pfizer, Sanofi, Bristol-Myers Squibb, W L Gore and Associates, and AstraZeneca. RS serves on the advisory boards of Pzifer and Novartis and has received financial compensation for lectures from Pfizer, Novartis, Merz Austria, Lundbeck, LCC, and Takeda. SMG has received consultancy fees from Hoffman LaRoche, Pfizer, Medtronic, Bristol-Myers Squibb, and Janssen Alzheimer Immunotherapy. BK received consultancy fees and payment for lectures from Allergan. We certify that all our affiliations with or financial involvement, within the past 5 years and foreseeable future (eg, employment, consultancies, honoraria, speakers bureau, stock ownership or options, expert testimony, grants or patents received or pending, royalties, or donation of medical equipment) with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript are fully disclosed.; US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.; We thank Tammy Gillis and Marcy MacDonald for technical assistance in genotyping of APOE samples in the Genetics of Cerebral Hemorrhage on Anticoagulation (GOCHA) study.9 The Differences in the Imaging of Primary Hemorrhage based on Ethnicity or Race (DECIPHER) project was supported by Award Number U54NS057405 from the National Institute of Neurological Disorders And Stroke (NINDS) and National Institute on Minority Health and Health Disparities (NIMHD) (U54NS057405). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health (DECIPHER). The Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study was supported by NIH grants NS36695 (Genetic and Environmental Risk Factors for Hemorrhagic Stroke) and NS30678 (Hemorrhagic and Ischemic Stroke among Blacks and Whites), and by the Greater Cincinnati Foundation Grant (Cincinnati Control Cohort). The GOCHA study was funded by NIH-NINDS grants K23NS042695, 5K23NS059774, R01NS059727, and 5R01NS042147, the Keane Stroke Genetics Research Fund, the Edward and Maybeth Sonn Research Fund, by the University of Michigan General Clinical Research Center (M01 RR000042), and by a grant from the National Center for Research Resources. AB and CDA were supported in part by the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (0775010N). The Hospital del Mar ICH (HM-ICH) study was funded by the Ministerio de Sanidad y Consumo de Espana, Instituto de Salud Carlos III with the grants "Registro BASICMAR" Funding for Research in Health (PI051737), Contract for Research Training for Professionals with Specialty (CM06100067), "Ramon y Cajal" Postdoctoral Contract, and Spanish Research Networks "Red HERACLES" (RD06/0009). The Jagiellonian University Hemorrhagic Stroke Study (JUHSS) was supported by a grant funded by the Polish Ministry of Education (N N402 083934). The Lund Stroke Register (LSR) was funded by Lund University, Region Skane and the Swedish Medical Research Council (K2007-61X-20378-01-3). Biobank services and genotyping were done at Region Skane Competence Centre (RSKC Malmo), Skane University Hospital, Malmo, Sweden. Controls from the Medical University of Gratz ICH (MUG-ICH) study were from the Austrian Stroke Prevention Study, which is a population-based study funded by the Austrian Science Fond grant numbers P20545-P05 and P13180; The Medical University of Graz supports the databank of the Austrian Stroke Prevention Study. NR 29 TC 63 Z9 67 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD AUG PY 2011 VL 10 IS 8 BP 702 EP 709 DI 10.1016/S1474-4422(11)70148-X PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 803WJ UT WOS:000293612600012 PM 21741316 ER PT J AU Holbrook, EH Wu, EM Curry, WT Lin, DT Schwob, JE AF Holbrook, Eric H. Wu, Enming Curry, William T. Lin, Derrick T. Schwob, James E. TI Immunohistochemical Characterization of Human Olfactory Tissue SO LARYNGOSCOPE LA English DT Article DE Esthesioneuroblastoma; cytoskeletal proteins; cell division; transcription factors; autopsy ID GLOBOSE BASAL-CELLS; EXPRESSION PATTERNS; PROGENITOR CELLS; SINONASAL TRACT; STEM-CELLS; EPITHELIUM; MUCOSA; REGENERATION; ESTHESIONEUROBLASTOMA; NEUROEPITHELIUM AB Objectives/Hypothesis: The pathophysiology underlying human olfactory disorders is poorly understood because biopsying the olfactory epithelium (OE) can be unrepresentative and extensive immunohistochemical analysis is lacking. Autopsy tissue enriches our grasp of normal and abnormal olfactory immunohistology and guides the sampling of the OE by biopsy. Furthermore, a comparison of the molecular phenotype of olfactory epithelial cells between rodents and humans will improve our ability to correlate human histopathology with olfactory dysfunction. Study Design: An immunohistochemical analysis of human olfactory tissue using a comprehensive battery of proven antibodies. Methods: Human olfactory mucosa obtained from 21 autopsy specimens was analyzed with immunohistochemistry. The position and extent of olfactory mucosa was assayed by staining whole mounts (WMs) with neuronal markers. Sections of the OE were analyzed with an extensive group of antibodies directed against cytoskeletal proteins and transcription factors, as were surgical specimens from an esthesioneuroblastoma. Results: Neuron-rich epithelium is always found inferior to the cribriform plate, even at advanced age, despite the interruptions in the neuroepithelial sheet caused by patchy respiratory metaplasia. The pattern of immunostaining with our antibody panel identifies two distinct types of basal cell progenitors in human OE similar to rodents. The panel also clarifies the complex composition of esthesioneuroblastoma. Conclusions: The extent of human olfactory mucosa at autopsy can easily be delineated as a function of age and neurologic disease. The similarities in human versus rodent OE will enable us to translate knowledge from experimental animals to humans and will extend our understanding of human olfactory pathophysiology. C1 [Holbrook, Eric H.; Lin, Derrick T.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Wu, Enming; Schwob, James E.] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. [Curry, William T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg Neurosurg, Boston, MA 02114 USA. RP Holbrook, EH (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM eric_holbrook@meei.harvard.edu FU NIH/NIDCD [R01DC010242] FX All financial and material support for this research was provided through a generous donation from Mr. David Clem and a grant from NIH/NIDCD (R01DC010242). None of the authors have any financial interest in companies or other entities that may have an interest in this work. NR 34 TC 17 Z9 19 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2011 VL 121 IS 8 BP 1687 EP 1701 DI 10.1002/lary.21856 PG 15 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 806JJ UT WOS:000293803400017 PM 21792956 ER EF