FN Thomson Reuters Web of Science™ VR 1.0 PT J AU McMillan, PJ Kraemer, BC Robinson, L Leverenz, JB Raskind, M Schellenberg, G AF McMillan, Pamela J. Kraemer, Brian C. Robinson, Linda Leverenz, James B. Raskind, Murray Schellenberg, Gerard TI Truncation of tau at E391 Promotes Early Pathologic Changes in Transgenic Mice SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Aggregation; Alzheimer disease; Tau; Transgenic mice; Truncation ID PAIRED HELICAL FILAMENTS; INDUCIBLE MOUSE MODELS; RAT DENTATE GYRUS; ALZHEIMERS-DISEASE; PROTEIN-TAU; NEURODEGENERATIVE DISORDERS; NEUROFIBRILLARY PATHOLOGY; DETERMINES AGGREGATION; NERVOUS-SYSTEM; TAUOPATHY AB Proteolytic cleavage of tau at glutamic acid 391 (E391) is linked to the pathogenesis of Alzheimer disease (AD). This C-terminal-truncated tau species exists in neurofibrillary tangles and abnormal neurites in the brains of AD patients and may potentiate tau polymerization. We generated a mouse model that expresses human tau truncated at E391 to begin to elucidate the role of this C-terminal-truncated tau species in the development of tau pathology. Our results show that truncated but otherwise wild-type human tau is sufficient to drive pretangle pathologic changes in tau, including accumulation of insoluble tau, somatodendritic redistribution, formation of pathologic conformations, and dual phosphorylation of tau at sites associated with AD pathology. In addition, these mice exhibit atypical neuritic tau immunoreactivity, including abnormal neuritic processes and dystrophic neurites. These results suggest that changes in tau proteolysis can initiate tauopathy. C1 [McMillan, Pamela J.; Leverenz, James B.; Raskind, Murray] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Kraemer, Brian C.; Robinson, Linda] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Leverenz, James B.] Vet Affairs Puget Sound Hlth Care Syst, Parkinsons Dis Res Educ & Clin Ctr, Seattle, WA USA. [McMillan, Pamela J.; Leverenz, James B.; Raskind, Murray] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Kraemer, Brian C.] Univ Washington, Div Gerontol & Geriatr Med, Dept Med, Seattle, WA 98195 USA. [Leverenz, James B.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Schellenberg, Gerard] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP McMillan, PJ (reprint author), Seattle Vet Affairs Puget Sound Hlth Care Syst, Box 358280,S182 GRECC,1660 S Columbian Way, Seattle, WA 98108 USA. EM pammcm@u.washington.edu FU National Institute on Aging [AG17586, 2P50AG005136-27]; Department of Veterans Affairs; Veterans Affairs National Institute of Neurological Disorders and Stroke [5P50NS062684-02] FX This work was supported by National Institute on Aging Grant AG17586 to G.D.S., Department of Veterans Affairs Merit Review Grant to B.C.K., and Veterans Affairs National Institute of Neurological Disorders and Stroke 5P50NS062684-02 and National Institute on Aging 2P50AG005136-27 to J.B.L. NR 53 TC 14 Z9 15 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD NOV PY 2011 VL 70 IS 11 BP 1006 EP 1019 DI 10.1097/NEN.0b013e31823557fb PG 14 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 842DB UT WOS:000296567800006 PM 22002427 ER PT J AU Patenaude, AF AF Patenaude, Andrea Farkas TI Commentary: Save the Children: Direct-to-Consumer Testing of Children is Premature, Even for Research SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Editorial Material ID CANCER SUSCEPTIBILITY; MUTATION; MOTHERS; UPDATE; LEGAL C1 [Patenaude, Andrea Farkas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genet,Psychol Serv,Dept Psychosocial Onc, Boston, MA 02215 USA. [Patenaude, Andrea Farkas] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Patenaude, AF (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genet,Psychol Serv,Dept Psychosocial Onc, 450 Brookline Ave, Boston, MA 02215 USA. EM andrea_patenaude@dfci.harvard.edu NR 25 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 0146-8693 J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD NOV-DEC PY 2011 VL 36 IS 10 BP 1122 EP 1127 DI 10.1093/jpepsy/jsr068 PG 6 WC Psychology, Developmental SC Psychology GA 839AE UT WOS:000296335600007 PM 21994422 ER PT J AU Spector, J AF Spector, J. TI The evolution of neonatal resuscitation training SO JOURNAL OF PERINATOLOGY LA English DT Letter C1 Massachusetts Gen Hosp, Div Newborn Serv, Boston, MA 02114 USA. RP Spector, J (reprint author), Massachusetts Gen Hosp, Div Newborn Serv, Boston, MA 02114 USA. EM jmspector@partners.org NR 1 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD NOV PY 2011 VL 31 IS 11 BP 744 EP 744 DI 10.1038/jp.2011.35 PG 1 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 842IH UT WOS:000296590600010 PM 22037158 ER PT J AU Stark, S Snetselaar, L Piraino, B Stone, RA Kim, S Hall, B Burke, LE Sevick, MA AF Stark, Susan Snetselaar, Linda Piraino, Beth Stone, Roslyn A. Kim, Sunghee Hall, Beth Burke, Lora E. Sevick, Mary Ann TI Personal Digital Assistant-Based Self-Monitoring Adherence Rates in 2 Dialysis Dietary Intervention Pilot Studies: BalanceWise-HD and BalanceWise-PD SO JOURNAL OF RENAL NUTRITION LA English DT Article ID HOME-BASED WALKING; WEIGHT-LOSS; PROGRAM AB Objective: The dialysis dietary regimen is complicated, and computer-based dietary self-monitoring may be useful for helping dialysis patients manage their dietary regimen. In this report, we describe dietary self-monitoring rates among study participants randomized to the intervention arms of 2 pilot studies. Methods: Both studies tested similar interventions involving dietary counseling paired with personal digital assistant-based self-monitoring. One study was performed in hemodialysis (HD) and one in peritoneal dialysis (PD) patients. Results: HD intervention participants entered an average of 244.9 meals (median = 288; interquartile range [IQR]: 186 to 342) over the 16-week intervention, 2.2 meals per day (median = 2.6; IQR: 1.7 to 3.1), and 73% of expected meals (median = 86; IQR: 55 to 102), assuming intake of 3 meals per day. At least some meals were entered in 87% of the observed weeks (median = 100%; IQR: 81 to 100). PD intervention participants entered an average of 212.1 meals (median = 203; IQR: 110 to 312) over the 16-week intervention, 1.9 meals per day (median = 1.8; IQR: 1 to 2.8), and 63% of expected meals (median = 60; IQR: 33 to 93), assuming 3 meals per day. At least some meals were entered in 80% of the observed weeks (median = 94; IQR: 50 to 100). Conclusion: These HD and PD patients demonstrated excellent rates of self-monitoring. Additional research with a larger sample is required to confirm these findings. (C) 2011 by the National Kidney Foundation, Inc. All rights reserved. C1 [Stark, Susan] Univ Pittsburgh, Sch Med, Dept Med, Ctr Res Hlth Care, Pittsburgh, PA 15213 USA. [Snetselaar, Linda] Univ Iowa, Coll Publ Hlth, Dept Endocrinol, Iowa City, IA USA. [Stone, Roslyn A.; Kim, Sunghee; Burke, Lora E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Stone, Roslyn A.; Kim, Sunghee; Sevick, Mary Ann] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Burke, Lora E.] Univ Pittsburgh, Sch Nursing, Dept Hlth & Community Syst, Pittsburgh, PA 15261 USA. [Piraino, Beth] Univ Pittsburgh, Dept Med, Renal Electrolyte Div, Pittsburgh, PA USA. [Burke, Lora E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Sevick, Mary Ann] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, Pittsburgh, PA USA. [Sevick, Mary Ann] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Stark, S (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Ctr Res Hlth Care, 3520 Forbes Ave,1st Floor, Pittsburgh, PA 15213 USA. EM starsa2@upmc.edu OI Piraino, Beth/0000-0001-5061-0841 FU Paul Teschan Research Foundation; [NIH/NIDDK/DK-R21DK067181]; [NIH/NCRR/CTSA-UL1-RR024153]; [NIH/NCRR/GCRC-M01- RR000056] FX The work in this article was supported by the following grants: Paul Teschan Research Foundation, NIH/NIDDK/DK-R21DK067181, NIH/NCRR/CTSA-UL1-RR024153, and NIH/NCRR/GCRC-M01- RR000056. The authors take full responsibility for the contents of this article, which do not represent the views of the Department of Veterans Affairs or the United States Government. The authors acknowledge the individual contributions of: Rita Marsh, RN, MSN; Deborah Klinvex, BA; and Tienna Luster. NR 18 TC 4 Z9 4 U1 1 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 1051-2276 J9 J RENAL NUTR JI J. Renal Nutr. PD NOV PY 2011 VL 21 IS 6 BP 492 EP 498 DI 10.1053/j.jrn.2010.10.026 PG 7 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA 841SJ UT WOS:000296533100009 PM 21420316 ER PT J AU Marshall, CL Balentine, CJ Robinson, CN Wilks, JA Anaya, D Artinyan, A Awad, SS Berger, DH Albo, D AF Marshall, Christy L. Balentine, Courtney J. Robinson, Celia N. Wilks, Jonathan A. Anaya, Daniel Artinyan, Avo Awad, Samir S. Berger, David H. Albo, Daniel TI A Multidisciplinary Cancer Center Maximizes Surgeons' Impact SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE colorectal cancer center; specialty-trained surgeons; prognostic; outcomes; colorectal cancer ID COLORECTAL LIVER METASTASES; HOSPITAL PROCEDURE VOLUME; COLON-CANCER; RECTAL-CANCER; COMBINED RESECTION/ABLATION; RADIOFREQUENCY ABLATION; SURGICAL SPECIALITY; HEPATIC RESECTION; OUTCOMES; RECURRENCE AB Background. Colorectal cancer patients require care across different disciplines. Integration of multidisciplinary care is critical to accomplish excellent oncologic results. We hypothesized that the establishment of a dedicated colorectal cancer center (CRCC) around specialty-trained surgeons will lead to increased multidisciplinary management and improved outcomes in colorectal cancer patients. Methods. We analyzed data from three periods: a baseline group, a period after the recruitment of specialty-trained surgeons, and a period after the creation of a dedicated multidisciplinary cancer center. Data analyzed included surrogate markers of surgical oncologic care, multidisciplinary integration, and oncologic outcomes. Results. Recruitment of specialized surgeons led to improvements in surgical oncologic care; the establishment of the CRCC resulted in further improvements in surgical oncologic care and multidisciplinary integration. Conclusion. Our study suggests that although the recruitment of specialty-trained surgeons in a high volume center leads to improvement in surgical oncologic care, it is the establishment of a multidisciplinary center around the surgeons that leads to integrated care and improvements in oncologic outcomes. (C) 2011 Elsevier Inc. All rights reserved. C1 [Albo, Daniel] Baylor Coll Med, Div Surg Oncol, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. Baylor Coll Med, Dept Surg, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Albo, D (reprint author), Baylor Coll Med, Div Surg Oncol, Michael E DeBakey Dept Surg, 1709 Dryden,Suite 1500, Houston, TX 77030 USA. EM dalbo@bcm.edu NR 29 TC 4 Z9 4 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD NOV PY 2011 VL 171 IS 1 BP 15 EP 22 DI 10.1016/j.jss.2010.12.007 PG 8 WC Surgery SC Surgery GA 839LS UT WOS:000296368000022 PM 21696763 ER PT J AU Nezami, BG Rahimpour, S Sadeghi, M Sianati, S Anaraki, DK Ebrahimi, F Ghasemi, M Dehpour, AR AF Nezami, Behtash Ghazi Rahimpour, Sina Sadeghi, Mahsa Sianati, Setareh Anaraki, Dina Kalbasi Ebrahimi, Farzad Ghasemi, Mehdi Dehpour, Ahmad Reza TI Chronic Lithium Impairs Skin Tolerance to Ischemia in Random-Pattern Skin Flap of Rats SO JOURNAL OF SURGICAL RESEARCH LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3-BETA; NITRIC-OXIDE; CORPUS CAVERNOSUM; SEXUAL FUNCTION; GRANULE CELLS; ANIMAL-MODELS; RELAXATION; PHOSPHORYLATION; INHIBITION; NEURONS AB Background. Despite its apparent anti-apoptotic effect, lithium impairs endothelium-dependent vasorelaxation in various tissues. In this study, we assessed the effect of lithium treatment on ischemic skin flap survival and its interaction with nitric oxide pathway. Materials and Methods. Seventy-six male Sprague-Dawley rats were randomly assigned into 13 groups. For skin flap surgery, dorsal skin flap measuring 8 x 2 cm was elevated on the midline. After local injections (if needed), the cranial pedicle was cut and flap was sutured back. Flap survival was assessed after 7 d. Animals in the chronic lithium group received lithium chloride in tap water for 4 wk preoperatively and 7 d postoperatively. Acute lithium groups received 3 nmol, 10 nmol and 3 mu mol/flap lithium locally. In another experiment, interaction with nitric oxide synthase inhibitor L-NAME as well as nitric oxide precursor L-arginine was studied, and the effect of ischemic preconditioning on skin flap survival in lithium treated rats was investigated. Results. Chronic lithium group had mean flap survival value of 32.6% +/- 5.2% (mean +/- SD), which was significantly lower than normal subjects (52.7% +/- 6.1%, P < 0.001), while acute local lithium treatment had no effect. In chronic lithium group, systemic L-NAME (10 mg/kg, 30 min before flap elevation) failed to significantly decrease the survival, while sub-effective systemic L-arginine (100 mg/kg) and ischemic preconditioning significantly increased flap survival (P < 0.001 and P < 0.01, respectively). Conclusions. We conclude that long-term lithium treatment impairs the skin tolerance to ischemia in rats, which seems to be nitric oxide mediated. This effect is prevented by ischemic preconditioning or L-arginine treatment. The results suggest that skin-involving interventions should be applied more cautiously in patients who are on lithium treatment. (C) 2011 Elsevier Inc. All rights reserved. C1 [Nezami, Behtash Ghazi; Rahimpour, Sina; Sadeghi, Mahsa; Sianati, Setareh; Anaraki, Dina Kalbasi; Ghasemi, Mehdi; Dehpour, Ahmad Reza] Univ Tehran Med Sci, Dept Pharmacol, Sch Med, Tehran, Iran. [Ebrahimi, Farzad] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Dehpour, AR (reprint author), Univ Tehran Med Sci, Dept Pharmacol, Sch Med, POB 13145-784, Tehran, Iran. EM dehpour@yahoo.com OI dehpour, ahmad reza/0000-0002-8001-5565 FU Tehran University of Medical Sciences FX The authors acknowledge support for this work by a research grant provided by the Tehran University of Medical Sciences Vice Chancellor of Research. NR 37 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD NOV PY 2011 VL 171 IS 1 BP 374 EP 378 DI 10.1016/j.jss.2010.03.048 PG 5 WC Surgery SC Surgery GA 839LS UT WOS:000296368000073 PM 20605607 ER PT J AU Bichakjian, CK Halpern, AC Johnson, TM Hood, AF Grichnik, JM Swetter, SM Tsao, H Barbosa, VH Chuang, TY Duvic, M Ho, VC Sober, AJ Beutner, KR Bhushan, R Begolka, WS AF Bichakjian, Christopher K. Halpern, Allan C. Johnson, Timothy M. Hood, Antoinette Foote Grichnik, James M. Swetter, Susan M. Tsao, Hensin Barbosa, Victoria Holloway Chuang, Tsu-Yi Duvic, Madeleine Ho, Vincent C. Sober, Arthur J. Beutner, Karl R. Bhushan, Reva Begolka, Wendy Smith TI Guidelines of care for the management of primary cutaneous melanoma SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE biopsy; follow-up; melanoma; pathology report; sentinel lymph node biopsy; surgical margins ID SENTINEL LYMPH-NODE; LENTIGO MALIGNA MELANOMA; AMERICAN-JOINT-COMMITTEE; MOHS MICROGRAPHIC SURGERY; UNDERGO COMPLETION LYMPHADENECTOMY; PREDICTING 10-YEAR SURVIVAL; COOPERATIVE-ONCOLOGY-GROUP; RANDOMIZED SURGICAL TRIAL; CANCER STAGING SYSTEM; MM PRIMARY MELANOMA AB The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma. (J Am Acad Dermatol 2011;65:1032-47.) C1 [Bhushan, Reva; Begolka, Wendy Smith] Amer Acad Dermatol, Schaumburg, IL 60173 USA. [Bichakjian, Christopher K.; Johnson, Timothy M.] Univ Michigan Hlth Syst, Dept Dermatol, Ann Arbor, MI USA. [Halpern, Allan C.] Mem Sloan Kettering Canc Ctr, Dept Dermatol, New York, NY 10021 USA. [Hood, Antoinette Foote] Eastern Virginia Med Sch, Dept Dermatol, Norfolk, VA USA. [Grichnik, James M.] Univ Miami Hosp & Clin, Univ Miami Hlth Syst, Dept Dermatol, Sylvester Comprehens Canc Ctr,Melanoma Program, Miami, FL USA. [Swetter, Susan M.] Stanford Univ, Dept Dermatol, Med Ctr, Stanford, CA 94305 USA. [Swetter, Susan M.] Dept Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Tsao, Hensin; Sober, Arthur J.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tsao, Hensin; Sober, Arthur J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Barbosa, Victoria Holloway] Rush Univ, Dept Dermatol, Med Ctr, Chicago, IL 60612 USA. [Chuang, Tsu-Yi] Univ So Calif, Los Angeles, CA USA. [Chuang, Tsu-Yi] Desert Oasis Healthcare, Palm Springs, CA USA. [Duvic, Madeleine] Univ Texas MD Anderson Canc Ctr, Dept Dermatol, Houston, TX USA. [Ho, Vincent C.] Univ British Columbia, Div Dermatol, Vancouver, BC V5Z 1M9, Canada. [Beutner, Karl R.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Beutner, Karl R.] Solano Dermatol, Fairfield, CA USA. RP Bhushan, R (reprint author), Amer Acad Dermatol, 930 E Woodfield Rd, Schaumburg, IL 60173 USA. EM rbhushan@aad.org NR 145 TC 121 Z9 125 U1 0 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD NOV PY 2011 VL 65 IS 5 BP 1032 EP 1047 DI 10.1016/j.jaad.2011.04.031 PG 16 WC Dermatology SC Dermatology GA 838DW UT WOS:000296268000014 PM 21868127 ER PT J AU Wiviott, SD Hochholzer, W AF Wiviott, Stephen D. Hochholzer, Willibald TI On-Clopidogrel Platelet Reactivity A Target in Sight? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE platelets; platelet inhibitor; P2Y(12); thienopyridine ID ACUTE CORONARY SYNDROMES; ST-SEGMENT ELEVATION; RANDOMIZED-TRIALS; METAANALYSIS; CHOLESTEROL; ASPIRIN; PARTICIPANTS; EFFICACY; THERAPY; STATINS C1 [Wiviott, Stephen D.; Hochholzer, Willibald] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Dept Med, Boston, MA 02115 USA. [Wiviott, Stephen D.; Hochholzer, Willibald] Harvard Univ, Sch Med, Boston, MA USA. [Hochholzer, Willibald] Herz Zentrum Bad Krozingen, Bad Krozingen, Germany. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Dept Med, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM swiviott@partners.org NR 18 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD NOV 1 PY 2011 VL 58 IS 19 BP 1955 EP 1957 DI 10.1016/j.jacc.2011.08.016 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 841VC UT WOS:000296542300004 PM 22032705 ER PT J AU Nanji, KC Rothschild, JM Salzberg, C Keohane, CA Zigmont, K Devita, J Gandhi, TK Dalal, AK Bates, DW Poon, EG AF Nanji, Karen C. Rothschild, Jeffrey M. Salzberg, Claudia Keohane, Carol A. Zigmont, Katherine Devita, Jim Gandhi, Tejal K. Dalal, Anuj K. Bates, David W. Poon, Eric G. TI Errors associated with outpatient computerized prescribing systems SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID PHYSICIAN ORDER ENTRY; CLINICAL DECISION-SUPPORT; ADVERSE DRUG EVENTS; MEDICATION ERRORS; IMPLEMENTATION; IMPACT; SAFETY AB Objective To report the frequency, types, and causes of errors associated with outpatient computer-generated prescriptions, and to develop a framework to classify these errors to determine which strategies have greatest potential for preventing them. Materials and methods This is a retrospective cohort study of 3850 computer-generated prescriptions received by a commercial outpatient pharmacy chain across three states over 4 weeks in 2008. A clinician panel reviewed the prescriptions using a previously described method to identify and classify medication errors. Primary outcomes were the incidence of medication errors; potential adverse drug events, defined as errors with potential for harm; and rate of prescribing errors by error type and by prescribing system. Results Of 3850 prescriptions, 452 (11.7%) contained 466 total errors, of which 163 (35.0%) were considered potential adverse drug events. Error rates varied by computerized prescribing system, from 5.1% to 37.5%. The most common error was omitted information (60.7% of all errors). Discussion About one in 10 computer-generated prescriptions included at least one error, of which a third had potential for harm. This is consistent with the literature on manual handwritten prescription error rates. The number, type, and severity of errors varied by computerized prescribing system, suggesting that some systems may be better at preventing errors than others. Conclusions Implementing a computerized prescribing system without comprehensive functionality and processes in place to ensure meaningful system use does not decrease medication errors. The authors offer targeted recommendations on improving computerized prescribing systems to prevent errors. C1 [Nanji, Karen C.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Rothschild, Jeffrey M.; Dalal, Anuj K.; Bates, David W.; Poon, Eric G.] Harvard Univ, Sch Med, Boston, MA USA. [Rothschild, Jeffrey M.; Salzberg, Claudia; Keohane, Carol A.; Zigmont, Katherine; Gandhi, Tejal K.; Dalal, Anuj K.; Bates, David W.; Poon, Eric G.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Devita, Jim] CVS Pharm, Woonsocket, RI USA. [Gandhi, Tejal K.; Bates, David W.; Poon, Eric G.] Partners Healthcare, Boston, MA USA. RP Nanji, KC (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM knanji@partners.org FU Agency for Healthcare Research and Quality (Rockville MD) [U18HS016970]; Harvard Risk Management Foundation, Cambridge, Massachusetts FX This project was supported by grant number U18HS016970 from the Agency for Healthcare Research and Quality (Rockville MD) and in part by a grant from the Harvard Risk Management Foundation, Cambridge, Massachusetts. NR 29 TC 51 Z9 52 U1 1 U2 11 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD NOV PY 2011 VL 18 IS 6 BP 767 EP 773 DI 10.1136/amiajnl-2011-000205 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 841DB UT WOS:000296491600008 PM 21715428 ER PT J AU Calboli, FCF Cox, DG Buring, JE Gaziano, JM Ma, J Stampfer, M Willett, WC Tworoger, SS Hunter, DJ Camargo, CA Michaud, DS AF Calboli, Federico C. F. Cox, David G. Buring, Julie E. Gaziano, J. Michael Ma, Jing Stampfer, Meir Willett, Walter C. Tworoger, Shelley S. Hunter, David J. Camargo, Carlos A., Jr. Michaud, Dominique S. TI Prediagnostic Plasma IgE Levels and Risk of Adult Glioma in Four Prospective Cohort Studies SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BRAIN-TUMORS; IMMUNOGLOBULIN-E; ALLERGY; DISEASE AB Background Increased levels of serum immunoglobulin E (IgE) because of allergies have been inversely associated with risk of glioma in observational studies. Despite consistency across studies examining history of allergies and glioma, questions remain as to whether those are causal associations. An inverse association between serum IgE and risk of glioma was reported in a large case-control study, but reverse causality and treatment effects remain potential explanations for those findings. Methods We combined data from four prospective cohort studies and used a nested case-control design to examine the association between allergy and glioma. We included glioma case subjects who were confirmed from medical or pathology records or from death certificates, and with prediagnostic blood available. We matched three control subjects per case subject, and the final numbers for analyses were 169 case subjects and 520 control subjects. Total IgE, food allergen-specific IgE, and respiratory allergen-specific IgE levels were measured using a highly sensitive fluorescent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression analysis. Stratified analyses were conducted by age and birth cohorts. Results Borderline elevated total IgE levels (25-100 kU/L) showed a statistically significant inverse association with glioma (OR = 0.63, 95% CI = 0.42 to 0.93), but no association was noted between elevated IgE (>100 kU/L) and glioma (OR = 0.98, 95% CI = 0.61 to 1.56) compared with clinically normal IgE levels (<25 kU/L). The association between glioma and total IgE was consistent for both men and women. Non-statistically significant inverse associations were noted for elevated IgE levels among individuals born before year 1930 (OR = 0.67, 95% CI = 0.34 to 1.34) and when restricting analyses to highly fatal (deceased within 2 years of diagnosis) glioma case subjects (OR = 0.64, 95% CI = 0.34 to 1.19) compared with individuals with clinically normal IgE levels. No associations were observed for either food allergen-specific or respiratory allergen-specific IgE levels. Conclusions Overall, our prospective findings are consistent with recent retrospective studies and support an association between total IgE levels and glioma. However, this association requires further elucidation. C1 [Michaud, Dominique S.] Brown Univ, Dept Epidemiol, Div Biol & Med, Providence, RI 02912 USA. [Calboli, Federico C. F.; Cox, David G.; Michaud, Dominique S.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. [Cox, David G.] Ctr Leon Berard, INSERM, U1052, Lyon Canc Res Ctr, F-69373 Lyon, France. [Buring, Julie E.; Gaziano, J. Michael] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Ma, Jing; Stampfer, Meir; Willett, Walter C.; Tworoger, Shelley S.; Hunter, David J.; Camargo, Carlos A., Jr.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ma, Jing; Stampfer, Meir; Willett, Walter C.; Tworoger, Shelley S.; Hunter, David J.; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Stampfer, Meir; Willett, Walter C.; Tworoger, Shelley S.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir; Willett, Walter C.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Michaud, DS (reprint author), Brown Univ, Dept Epidemiol, Div Biol & Med, Box G-S121-2,121 S Main St, Providence, RI 02912 USA. EM dominique_michaud@brown.edu RI Cox, David/A-2023-2009; Michaud, Dominique/I-5231-2014; OI Cox, David/0000-0002-2152-9259; Tworoger, Shelley/0000-0002-6986-7046 FU National Institutes of Health [R01 CA114205, R01 CA047988, R01 HL043851, P01 CA097193, P01 CA087969, P01 CA055075] FX This work was supported by the National Institutes of Health (R01 CA114205 to DSM, R01 CA047988 and R01 HL043851 to JEB, P01 CA097193 to JMG, P01 CA087969 to Dr Susan Hankinson, P01 CA055075 to WCW). NR 20 TC 28 Z9 28 U1 0 U2 1 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 NOV PY 2011 VL 103 IS 21 BP 1588 EP 1595 DI 10.1093/jnci/djr361 PG 8 WC Oncology SC Oncology GA 843HK UT WOS:000296662700007 PM 22010181 ER PT J AU McMahon, PM Kong, CY Bouzan, C Weinstein, MC Cipriano, LE Tramontano, AC Johnson, BE Weeks, JC Gazelle, GS AF McMahon, Pamela M. Kong, Chung Yin Bouzan, Colleen Weinstein, Milton C. Cipriano, Lauren E. Tramontano, Angela C. Johnson, Bruce E. Weeks, Jane C. Gazelle, G. Scott TI Cost-Effectiveness of Computed Tomography Screening for Lung Cancer in the United States SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Lung cancer; Screening; Cost-utility analysis; Microsimulation model ID QUALITY-OF-LIFE; SMOKING-CESSATION; MORTALITY REDUCTION; CONTROLLED-TRIAL; NICOTINE PATCH; TASK-FORCE; HEALTH; BUPROPION; OUTCOMES; INTERVENTION AB Introduction: A randomized trial has demonstrated that lung cancer screening reduces mortality. Identifying participant and program characteristics that influence the cost-effectiveness of screening will help translate trial results into benefits at the population level. Methods: Six U.S. cohorts (men and women aged 50, 60, or 70 years) were simulated in an existing patient-level lung cancer model. Smoking histories reflected observed U.S. patterns. We simulated lifetime histories of 500,000 identical individuals per cohort in each scenario. Costs per quality-adjusted life-year gained ($/QALY) were estimated for each program: computed tomography screening; stand-alone smoking cessation therapies (4-30% 1-year abstinence); and combined programs. Results: Annual screening of current and former smokers aged 50 to 74 years costs between $126,000 and $169,000/QALY (minimum 20 pack-years of smoking) or $110,000 and $166,000/QALY (40 pack-year minimum), when compared with no screening and assuming background quit rates. Screening was beneficial but had a higher cost per QALY when the model included radiation-induced lung cancers. If screen participation doubled background quit rates, the cost of annual screening (at age 50 years, 20 pack-year minimum) was below $75,000/QALY. If screen participation halved background quit rates, benefits from screening were nearly erased. If screening had no effect on quit rates, annual screening costs more but provided fewer QALYs than annual cessation therapies. Annual combined screening/cessation therapy programs at age 50 years costs $130,500 to $159,700/QALY, when compared with annual stand-alone cessation. Conclusions: The cost-effectiveness of computed tomography screening will likely be strongly linked to achievable smoking cessation rates. Trials and further modeling should explore the consequences of relationships between smoking behaviors and screen participation. C1 [McMahon, Pamela M.; Kong, Chung Yin; Bouzan, Colleen; Cipriano, Lauren E.; Tramontano, Angela C.; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [McMahon, Pamela M.; Kong, Chung Yin; Gazelle, G. Scott] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Weinstein, Milton C.; Johnson, Bruce E.; Weeks, Jane C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Weinstein, Milton C.; Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Cipriano, Lauren E.] Stanford Univ, Dept Management Sci & Engn, Stanford, CA 94305 USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Weeks, Jane C.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Weeks, Jane C.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP McMahon, PM (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM pamela@mgh-ita.org RI Cipriano, Lauren/C-3521-2017 OI Cipriano, Lauren/0000-0001-5568-4516 FU National Electrical Manufacturers Association; American Cancer Society [RSG 2008A060554]; National Cancer Institute [R01CA97337, R00CA126147] FX The National Electrical Manufacturers Association funded Tramontano and Gazelle for an unrelated project. Gazelle is a consultant to GE Healthcare. All other authors declare no conflicts of interest.; Supported by American Cancer Society (RSG 2008A060554) and National Cancer Institute (R01CA97337 [to G.S.G.] and R00CA126147 [to P.M.M.]). NR 43 TC 92 Z9 93 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2011 VL 6 IS 11 BP 1841 EP 1848 DI 10.1097/JTO.0b013e31822e59b3 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 843UW UT WOS:000296700400009 PM 21892105 ER PT J AU Caplin, DM Nikolic, B Kalva, SP Ganguli, S Saad, WEA Zuckerman, DA AF Caplin, Drew M. Nikolic, Boris Kalva, Sanjeeva P. Ganguli, Suvranu Saad, Wael E. A. Zuckerman, Darryl A. CA Soc Interventional Radiology Stand TI Quality Improvement Guidelines for the Performance of Inferior Vena Cava Filter Placement for the Prevention of Pulmonary Embolism SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID TITANIUM GREENFIELD FILTER; CLINICAL-EXPERIENCE; VENOUS THROMBOSIS; FOLLOW-UP; COMPLICATIONS; MIGRATION; MULTICENTER; SAFETY; TEMPORARY; INSERTION C1 [Caplin, Drew M.] N Shore Univ Hosp, Dept Radiol, Div Intervent Radiol, Manhasset, NY USA. [Nikolic, Boris] Albert Einstein Med Ctr, Dept Radiol, Philadelphia, PA 19141 USA. [Kalva, Sanjeeva P.; Ganguli, Suvranu] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Saad, Wael E. A.] Univ Virginia Hlth Syst, Dept Radiol, Charlottesville, VA USA. [Zuckerman, Darryl A.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. RP Caplin, DM (reprint author), SIR, 3975 Fair Ridge Dr,Suite 400 N, Fairfax, VA 22033 USA. EM dcaplin@nshs.edu FU Siemens (Forchheim, Germany); Amirsys; Elsevier FX S.P.K. receives royalties from book publishers Amirsys and Elsevier. W.E.A.S. is a paid consultant for Boston Scientific (Natick, Massachusetts), has research funded by Siemens (Forchheim, Germany), and serves on the Speaker's Bureau for Atrium (Hudson, New Hampshire). None of the other authors have identified a conflict of interest NR 74 TC 69 Z9 73 U1 1 U2 8 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 NOV PY 2011 VL 22 IS 11 BP 1499 EP 1506 DI 10.1016/j.jvir.2011.07.012 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 843HB UT WOS:000296661800001 PM 21890380 ER PT J AU Angel, LF Tapson, V Galgon, RE Restrepo, MI Kaufman, J AF Angel, Luis F. Tapson, Victor Galgon, Richard E. Restrepo, Marcos I. Kaufman, John TI Systematic Review of the Use of Retrievable Inferior Vena Cava Filters SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Review ID DEEP-VEIN THROMBOSIS; PULMONARY-EMBOLISM; VENOUS THROMBOEMBOLISM; LONG-TERM; FOLLOW-UP; CLINICAL-EXPERIENCE; TECHNICAL SUCCESS; TRAUMA PATIENTS; OPTEASE FILTER; MULTICENTER AB Purpose: To review the available literature on retrievable inferior vena cava (IVC) filters to examine the effectiveness and risks of these devices. Materials and Methods: Investigators searched MEDLINE for clinical trials evaluating retrievable filters and reviewed the complications reported to the Manufacturer and User Facility Device Experience (MAUDE) database of the U.S. Food and Drug Administration (FDA). Results: Eligibility criteria were met by 37 studies comprising 6,834 patients. All of the trials had limitations, and no studies were randomized. There were 11 prospective clinical trials; the rest were retrospective studies. Despite the limitations of the evidence, the IVC filters seemed to be effective in preventing pulmonary embolism (PE); the rate of PE after IVC placement was 1.7%. The mean retrieval rate was 34%. Most of the filters became permanent devices. Multiple complications associated with the use of IVC filters were described in the reviewed literature or were reported to the MAUDE database; most of these were associated with long-term use (> 30 days). At the present time, the objective comparison data of different filter designs do not support superiority of any particular design. Conclusions: In high-risk patients for whom anticoagulation is not feasible, retrievable IVC filters seem to be effective in preventing PE. Long-term complications are a serious concern with the use of these filters. The evidence of the effectiveness and the risks was limited by the small number of prospective studies. C1 [Angel, Luis F.; Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm & Crit Care Med, San Antonio, TX 78229 USA. [Tapson, Victor] Duke Univ, Med Ctr, Div Pulm Allergy & Crit Care Med, Durham, NC USA. [Galgon, Richard E.] Univ Wisconsin, Dept Anesthesiol, Madison, WI USA. [Restrepo, Marcos I.] S Texas Vet Hlth Care Syst, VERDICT, Audie L Murphy Div, San Antonio, TX USA. [Kaufman, John] Oregon Hlth & Sci Ctr, Dotter Intervent Inst, Portland, OR USA. RP Angel, LF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Pulm & Crit Care Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM angel@uthscsa.edu RI Restrepo, Marcos/H-4442-2014 FU Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Texas Health Science Center at San Antonio; BiO2 Medical FX Funding was provided by the Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Texas Health Science Center at San Antonio.; L.F.A. has a financial relationship with BiO2 Medical. J.K. has received research funding from BiO2 Medical. None of the other authors have identified a conflict of interest. NR 66 TC 104 Z9 106 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD NOV PY 2011 VL 22 IS 11 BP 1522 EP 1530 DI 10.1016/j.jvir.2011.08.024 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 843HB UT WOS:000296661800006 PM 22024114 ER PT J AU Fishman, JA AF Fishman, Jay A. TI Infections in Immunocompromised Hosts and Organ Transplant Recipients: Essentials SO LIVER TRANSPLANTATION LA English DT Article AB Key Points (1) Why do we need to know anything about these patients? Regardless of their specialties, physicians are increasingly confronted with the side effects of therapies that cause varying degrees of immunosuppression: chemotherapy and stem cell transplantation for cancer, solid organ transplantation, and therapies for autoimmune and rheumatological diseases. The management of these patients is increasingly being returned to community-based physicians. The infectious disease clinician is faced with major challenges. (2) The possible etiologies of infections are diverse; they range from common bacterial and viral pathogens that affect the entire community to opportunistic pathogens that are clinically significant only for immunocompromised hosts. (3) Inflammatory responses are impaired by immunosuppressive therapy, and this results in diminished clinical and radiological findings. Thus, an early diagnosis is much more difficult, but it is the key to successful therapy. Invasive diagnostic procedures are often required. (4) Antimicrobial therapies are often more complex in these patients versus other patients because of the urgency of empiric therapy and the frequency of drug toxicity and drug interactions. (5) Drug interactions and drug toxicity are common. The initiation or cessation of antimicrobial therapies may alter the levels of calcineurin inhibitors, antifungal agents, and other drugs. (6) Graft rejection and graft-versus-host disease may be confused with infections. (7) New pathogens and new manifestations of infections in compromised hosts are also problems: a. Pathogens common to individuals with prolonged defects in their cellular immune function (human immunodeficiency virus) and to neutropenic hosts [Rhodococcus, Cryptosporidium, and Penicillium species; Mycobacterium species (eg, Mycobacterium avium complex); and Scedosporium] have been identified in transplant recipients. b. Antimicrobial resistance is a major problem [vancomycin-resistant Enterococcus; methicillin-resistant Staphylococcus aureus; Pseudomonas, Stenotrophomonas, and Burkholderia species; fungi (both yeasts and molds); and ganciclovir-resistant cytomegalovirus]. c. There are few therapies for newer viral pathogens (eg, human herpesvirus 6, human herpesvirus 8, and BK virus) and common respiratory viruses (eg, respiratory syncytial virus, adenoviruses, and Metapneumovirus). d. Patients from endemic regions may have parasites (eg, Chagas disease and Leishmania). C1 Harvard Univ, Transplant Infect Dis & Compromised Host Serv, Div Infect Dis, Massachusetts Gen Hosp,Sch Med,Transplant Ctr, Boston, MA 02114 USA. RP Fishman, JA (reprint author), Harvard Univ, Transplant Infect Dis & Compromised Host Serv, Div Infect Dis, Massachusetts Gen Hosp,Sch Med,Transplant Ctr, 55 Fruit St,GRJ 05, Boston, MA 02114 USA. EM jfishman@partners.org NR 0 TC 43 Z9 43 U1 0 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD NOV PY 2011 VL 17 SU 3 BP S34 EP S37 DI 10.1002/lt.22378 PG 4 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 843VH UT WOS:000296702000007 PM 21748845 ER PT J AU Muir, ER Duong, TQ AF Muir, Eric R. Duong, Timothy Q. TI Layer-Specific Functional and Anatomical MRI of the Retina With Passband Balanced SSFP SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE steady state free precession; SSFP; fMRI; retina; ophthalmology; hypoxia ID MANGANESE-ENHANCED MRI; CHOROIDAL BLOOD-FLOW; RAT RETINA; DEGENERATION; RESOLUTION; BRAIN; TESLA AB The retina consists of multiple cellular and synaptic layers and is nourished by two distinct (retinal and choroidal) circulations bounding the retina, separated by an avascular layer. High spatiotemporal resolution, layer-specific MRI of the retina remains challenging due to magnetic inhomogeneity-induced artifacts. This study reports passband balanced steady-state free-precession (bSSFP) MRI at 45x45x500 mm and 1.6 s temporal resolution to image the mouse retina, overcoming geometric distortion and signal dropout while maintaining rapid acquisition and high signal-to-noise ratio. bSSFP images revealed multiple alternating dark-bright-dark-bright retinal layers. Hypoxic (10% O(2)) inhalation decreased bSSFP signals in the two layers bounding the retina, corresponding to the retinal and choroidal vasculatures. The layer in between showed no substantial response and was assigned the avascular photoreceptor layers. Choroidal responses (-25.9 +/- 6.4%, mean +/- SD, n=6) were significantly (P< 0.05) larger than retinal vascular responses (-11.6 +/- 2.4%). bSSFP offers very high spatiotemporal resolution and could have important applications in imaging layer-specific changes in retinal diseases. Magn Reson Med 66: 1416-1421, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, Dept Ophthalmol, San Antonio, TX 78229 USA. [Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, Dept Radiol, San Antonio, TX 78229 USA. [Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, Dept Physiol, San Antonio, TX 78229 USA. [Muir, Eric R.] Georgia Inst Technol, Dept Biomed Engn, Atlanta, GA 30332 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, Dept Ophthalmol, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu RI Duong, Timothy/B-8525-2008; Muir, Eric/H-8830-2013 FU National Eye Institute/National Institutes of Health [R01 EY018855, R01 EY014211]; Department of Veterans Affairs FX Grant sponsor: National Eye Institute/National Institutes of Health; Grant numbers: R01 EY018855, R01 EY014211; Grant sponsor: Department of Veterans Affairs (VA MERIT Award). NR 27 TC 15 Z9 15 U1 0 U2 0 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 NOV PY 2011 VL 66 IS 5 BP 1416 EP 1421 DI 10.1002/mrm.22935 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 839SP UT WOS:000296389800024 PM 21604296 ER PT J AU Tisdall, MD Lockhart, RA Atkins, MS AF Tisdall, M. Dylan Lockhart, Richard A. Atkins, M. Stella TI The Bias/Variance Trade-Off When Estimating the MR Signal Magnitude From the Complex Average of Repeated Measurements SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE signal-to-noise ratio; image bias; maximum likelihood estimate; denoising; nuisance parameters ID MAGNETIC-RESONANCE IMAGES; MAXIMUM-LIKELIHOOD-ESTIMATION; CONFIDENCE-INTERVALS; RICIAN DISTRIBUTION; LOW SNR; NOISE; PARAMETERS; PERFORMANCE; VARIANCE; ENVELOPE AB The signal-dependent bias of MR images has been considered a hindrance to visual interpretation almost since the beginning of clinical MRI. Over time, a variety of procedures have been suggested to produce less-biased images from the complex average of repeated measurements. In this work, we re-evaluate these approaches using first a survey of previous estimators in the MRI literature, then a survey of the methods statisticians employ for our specific problem. Our conclusions are substantially different from much of the previous work: first, removing bias completely is impossible if we demand the estimator have bounded variance; second, reducing bias may not be beneficial to image quality. Magn Reson Med 66:1456-1467, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Tisdall, M. Dylan] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Tisdall, M. Dylan] Harvard Univ, Dept Radiol, Sch Med, Brookline, MA USA. [Lockhart, Richard A.] Simon Fraser Univ, Dept Stat & Actuarial Sci, Burnaby, BC V5A 1S6, Canada. [Atkins, M. Stella] Simon Fraser Univ, Sch Comp Sci, Burnaby, BC V5A 1S6, Canada. RP Tisdall, MD (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM tisdall@nmr.mgh.harvard.edu FU Natural Sciences and Engineering Research Council of Canada FX Grant sponsor: Natural Sciences and Engineering Research Council of Canada NR 40 TC 1 Z9 1 U1 0 U2 5 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 NOV PY 2011 VL 66 IS 5 BP 1456 EP 1467 DI 10.1002/mrm.22910 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 839SP UT WOS:000296389800028 PM 21469187 ER PT J AU Shifren, JL AF Shifren, Jan L. TI Increasing our understanding of women's sexuality at midlife and beyond SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID POSTMENOPAUSAL WOMEN; UNITED-STATES; HEALTH; NATION; LIFE C1 Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. RP Shifren, JL (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. NR 12 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD NOV PY 2011 VL 18 IS 11 BP 1149 EP 1151 DI 10.1097/gme.0b013e31823161fe PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 842NF UT WOS:000296605500001 PM 21993079 ER PT J AU Chan, K Davis, J Pai, SY Bonilla, FA Puck, JM Apkon, M AF Chan, Kee Davis, Joie Pai, Sung-Yun Bonilla, Francisco A. Puck, Jennifer M. Apkon, Michael TI A Markov model to analyze cost-effectiveness of screening for severe combined immunodeficiency (SCID) SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Severe combined immunodeficiency (SCID); Newborn screening; Cost-effectiveness; Markov models; T-cell receptor excision circle (TREC); Hematopoietic cell transplant ID STEM-CELL TRANSPLANTATION; MEDICAL DECISION-MAKING; QUALITY-OF-LIFE; THYMIC OUTPUT; HEALTH; CHILDREN; DISEASE; DEFICIENCY; UNIVERSAL; BENEFITS AB Objective: To evaluate the cost-effectiveness of universal neonatal screening for T cell lymphocytopenia in enhancing quality of life and life expectancy for children with severe combined immunodeficiency (SCID). Methods: Decision trees were created and analyzed to estimate the cost, life years, and quality adjusted life years (QALYs) across a population when universal screening for lack of T cells is used to detect SCID, as implemented in five states, compared to detection based on recognizing symptoms and signs of disease. Terminal values of each tree limb were derived through Markov models simulating the natural history of three cohorts: unaffected subjects; those diagnosed with SCID as neonates (early diagnosis); and those diagnosed after becoming symptomatic and arousing clinical suspicion (late diagnosis). Models considered the costs of screening and of care including hematopoietic cell transplantation for affected individuals. Key decision variables were derived from the literature and from a survey of families with children affected by SCID, which was used to describe the clinical history and healthcare utilization for affected subjects. Sensitivity analyses were conducted to explore the influence of these decision variables. Results: Over a 70-year time horizon, the average cost per infant was $8.89 without screening and $14.33 with universal screening. The model predicted that universal screening in the U.S. would cost approximately $22.4 million/year with a gain of 880 life years and 802 QALYs. Sensitivity analyses showed that screening test specificity and disease incidence were critical driving forces affecting the incremental cost-effectiveness ratio (ICER). Assuming a SCID incidence of 1/75,000 births and test specificity and sensitivity each at 0.99, screening remained cost-effective up to a maximum cost of $15 per infant screened. Conclusion: At our current estimated screening cost of $4.22/infant, universal screening for SCID would be a cost effective means to improve quality and duration of life for children with SCID. (C) 2011 Elsevier Inc. All rights reserved. C1 [Chan, Kee] Boston Univ, Coll Hlth & Rehabil Sci, Sargent Coll, Dept Hlth Sci, Boston, MA 02215 USA. [Chan, Kee] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Davis, Joie] NIAID, NIH, Bethesda, MD 20892 USA. [Pai, Sung-Yun; Bonilla, Francisco A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Pai, Sung-Yun] Childrens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Pai, Sung-Yun] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bonilla, Francisco A.] Childerns Hosp, Div Immunol, Dept Med, Boston, MA USA. [Puck, Jennifer M.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Puck, Jennifer M.] Univ Calif San Francisco, Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Apkon, Michael] Univ Penn, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Apkon, Michael] Childrens Hosp Philadelphia, Philadelphia, PA USA. [Chan, Kee; Davis, Joie; Puck, Jennifer M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Chan, Kee] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Apkon, Michael] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Apkon, Michael] Yale Univ, Sch Management, New Haven, CT 06510 USA. RP Chan, K (reprint author), Boston Univ, Coll Hlth & Rehabil Sci, Sargent Coll, Dept Hlth Sci, 635 Commonwealth Ave, Boston, MA 02215 USA. EM keechan@bu.edu FU NHGRI; NIH; Division of Intramural Research; USIDNET [NO1-AI-30070]; Jeffrey Modell Foundation FX Funds for this work came from the NHGRI, NIH, Division of Intramural Research, USIDNET grant NO1-AI-30070 to JMP and the Jeffrey Modell Foundation. We are grateful to the Immune Deficiency Foundation SCID Initiative and SCID.net for posting our survey online and to the parents of SCID children who recounted and re-lived their experiences for us in the hope that future SCID children would benefit. NR 38 TC 41 Z9 43 U1 3 U2 7 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 NOV PY 2011 VL 104 IS 3 BP 383 EP 389 DI 10.1016/j.ymgme.2011.07.007 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 843KN UT WOS:000296670800027 PM 21810544 ER PT J AU Rivas, MA Beaudoin, M Gardet, A Stevens, C Sharma, Y Zhang, CK Boucher, G Ripke, S Ellinghaus, D Burtt, N Fennell, T Kirby, A Latiano, A Goyette, P Green, T Halfvarson, J Haritunians, T Korn, JM Kuruvilla, F Lagace, C Neale, B Lo, KS Schumm, P Torkvist, L Dubinsky, MC Brant, SR Silverberg, MS Duerr, RH Altshuler, D Gabriel, S Lettre, G Franke, A D'Amato, M McGovern, DPB Cho, JH Rioux, JD Xavier, RJ Daly, MJ AF Rivas, Manuel A. Beaudoin, Melissa Gardet, Agnes Stevens, Christine Sharma, Yashoda Zhang, Clarence K. Boucher, Gabrielle Ripke, Stephan Ellinghaus, David Burtt, Noel Fennell, Tim Kirby, Andrew Latiano, Anna Goyette, Philippe Green, Todd Halfvarson, Jonas Haritunians, Talin Korn, Joshua M. Kuruvilla, Finny Lagace, Caroline Neale, Benjamin Lo, Ken Sin Schumm, Phil Torkvist, Leif Dubinsky, Marla C. Brant, Steven R. Silverberg, Mark S. Duerr, Richard H. Altshuler, David Gabriel, Stacey Lettre, Guillaume Franke, Andre D'Amato, Mauro McGovern, Dermot P. B. Cho, Judy H. Rioux, John D. Xavier, Ramnik J. Daly, Mark J. CA Natl Inst Diabet Digestive Kidney United Kingdom Inflammatory Bowel Int Inflammatory Bowel Dis TI Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MURAMYL DIPEPTIDE RECOGNITION; SUSCEPTIBILITY LOCI; CROHNS-DISEASE; CARD15 MUTATIONS; RISK LOCI; GENE; NOD2; FREQUENCY; RECRUITMENT AB More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 x 10(-16), odds ratio approximate to 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models. C1 [Rivas, Manuel A.; Ripke, Stephan; Kirby, Andrew; Neale, Benjamin; Altshuler, David; Xavier, Ramnik J.; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Rivas, Manuel A.; Stevens, Christine; Ripke, Stephan; Burtt, Noel; Fennell, Tim; Kirby, Andrew; Green, Todd; Korn, Joshua M.; Kuruvilla, Finny; Neale, Benjamin; Altshuler, David; Gabriel, Stacey; Xavier, Ramnik J.; Daly, Mark J.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Rivas, Manuel A.] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Beaudoin, Melissa; Boucher, Gabrielle; Goyette, Philippe; Lagace, Caroline; Lo, Ken Sin; Lettre, Guillaume; Rioux, John D.] Univ Montreal, Montreal, PQ, Canada. [Beaudoin, Melissa; Boucher, Gabrielle; Goyette, Philippe; Lagace, Caroline; Lo, Ken Sin; Lettre, Guillaume; Rioux, John D.] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Gardet, Agnes; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Ctr Study Inflammatory Bowe, Boston, MA USA. [Gardet, Agnes; Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Sharma, Yashoda; Zhang, Clarence K.; Cho, Judy H.] Yale Univ, Sch Med, New Haven, CT USA. [Ellinghaus, David; Franke, Andre] Inst Clin Mol Biol, Kiel, Germany. [Latiano, Anna] Casa Sollievo Sofferenza Hosp, Ist Ricovero & Cura Carattere Sci, Gastroenterol Unit, San Giovanni Rotondo, Italy. [Halfvarson, Jonas] Univ Orebro, Dept Med, Orebro Univ Hosp, Orebro, Sweden. [Halfvarson, Jonas] Univ Orebro, Sch Hlth & Med Sci, Orebro, Sweden. [Haritunians, Talin; McGovern, Dermot P. B.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Kuruvilla, Finny] Clarus Ventures, Cambridge, MA USA. [Schumm, Phil] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Torkvist, Leif] Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Dubinsky, Marla C.] Cedars Sinai Med Ctr, Pediat Inflammatory Bowel Dis Ctr, Los Angeles, CA 90048 USA. [Brant, Steven R.] Johns Hopkins Univ, Sch Med, Dept Med, Meyerhoff Inflammatory Bowel Dis Ctr, Baltimore, MD 21205 USA. [Brant, Steven R.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Silverberg, Mark S.] Univ Toronto, Mt Sinai Hosp, Inflammatory Bowel Dis Grp, Toronto, ON M5G 1X5, Canada. [Duerr, Richard H.] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Duerr, Richard H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [D'Amato, Mauro] Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden. [McGovern, Dermot P. B.] Cedars Sinai Med Ctr, Inflammatory Bowel & Immunobiol Res Inst, Los Angeles, CA 90048 USA. RP Daly, MJ (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM rivas@broadinstitute.org; mjdaly@atgu.mgh.harvard.edu RI D'Amato, Mauro/F-2450-2010; Ellinghaus, David/G-4467-2012; Anderson, Carl/B-8327-2013; Silverberg, Mark/B-4183-2008; Altshuler, David/A-4476-2009; Schreiber, Stefan/B-6748-2008; Rioux, John/A-9599-2015; Palmieri, Orazio/J-7697-2012; Latiano, Anna/R-1965-2016; Franke, Andre/B-2151-2010 OI Henderson, Paul/0000-0003-3634-6428; Panes, Julian/0000-0002-4971-6902; Barrett, Jeffrey/0000-0002-1152-370X; Gearry, Richard/0000-0002-2298-5141; Halfvarson, Jonas/0000-0003-0122-7234; Newman, William/0000-0002-6382-4678; D'Amato, Mauro/0000-0003-2743-5197; Duerr, Richard/0000-0001-6586-3905; Laukens, Debby/0000-0002-1984-5850; Anderson, Carl/0000-0003-1719-7009; Altshuler, David/0000-0002-7250-4107; Schreiber, Stefan/0000-0003-2254-7771; Rioux, John/0000-0001-7560-8326; Palmieri, Orazio/0000-0002-0019-7929; Latiano, Anna/0000-0003-3719-2061; Franke, Andre/0000-0003-1530-5811 FU US National Human Genome Research Institute [DK83756, AI062773, DK060049, DK086502, HG005923, DK043351]; Helmsley Trust; La Fondation pour la Recherche Medicale; CCFA; Canada Research Chair; US National Institutes of Allergy and Infectious Diseases [AI065687, AI067152]; NIDDK [DK064869, DK062432]; CCFA [SRA512]; La Fondation de l'Institut de Cardiologie de Montreal; Crohn's and Colitis Foundation of Canada (CCFC); Fonds de Recherche en Sante du Quebec [17199]; Canadian Institutes of Health Research [01038]; Italian Ministry for Health [GR-2008-1144485]; Giuliani; NCRR [M01-RR00425, U01-DK062413, P01-DK046763]; Southern California Diabetes Endocrinology Research Center [DK063491, R21-DK84554-01, U01 DK062413]; German Ministry of Education and Research through the National Genome Research Network; Swedish Research Council; Bengt Ihre Foundation; rebro University Hospital Research Foundation; [DK062431]; [DK062422]; [DK062420]; [DK062423]; [DK062413]; [DK062429] FX We thank L. Solomon for designing figures, R. Onofrio for designing PCR primers, K. Ardlie and S. Mahan for assistance in DNA sample preparation, J. Wilkinson and L. Ambrogio for Illumina sequence project management, B. Thomson, G. Crenshaw and A. Taylor for genotyping assistance, E.S. Lander for helpful comments, the Broad Institute Sequencing Platform for sequence data production, J. Flannick and J. Maguire for assistance with pooled sequence analysis, and M. dePristo and the Broad Institute Genome Sequence Analysis Group for sequencing analysis help and useful discussions. The work was supported by US National Human Genome Research Institute sequencing grant DK83756; Funds from the Helmsley Trust to M.J.D. and R.J.X.; and US National Institutes of Health grants AI062773, DK060049, DK086502, HG005923 and DK043351 (to R.J.X.). A. G. was supported by fellowships from La Fondation pour la Recherche Medicale and the CCFA. J.D.R. holds a Canada Research Chair and is funded by grants from the US National Institutes of Allergy and Infectious Diseases (AI065687; AI067152) from the NIDDK (DK064869; DK062432), the CCFA (SRA512), La Fondation de l'Institut de Cardiologie de Montreal, the Crohn's and Colitis Foundation of Canada (CCFC), the Fonds de Recherche en Sante du Quebec (17199) and the Canadian Institutes of Health Research (01038). Genotyping of the Italian samples was supported by the Italian Ministry for Health GR-2008-1144485 and unrestricted research grant of Giuliani, with case collections provided by the Italian Group for IBD. The NIDDK IBDGC is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), DK062423 (M.S.), DK062413 (D.P.B.M.) and DK062429 (J.H.C.). D.P.B.M. is supported by NCRR grant M01-RR00425 to the Cedars-Sinai General Research Center Genotyping Core, U01-DK062413 (IBD Genetics Research Center), P01-DK046763 (IBD Program Project Grant) and Southern California Diabetes Endocrinology Research Center grants DK063491, R21-DK84554-01 and U01 DK062413. Genotyping of the German samples was supported by the German Ministry of Education and Research through the National Genome Research Network with infrastructure support through the Deutsche Forschungsgemeinschaft cluster of excellence Inflammation at Interfaces. Genotyping of the Swedish samples was supported by the Swedish Research Council, the Bengt Ihre Foundation and the rebro University Hospital Research Foundation. NR 46 TC 327 Z9 335 U1 5 U2 40 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD NOV PY 2011 VL 43 IS 11 BP 1066 EP U50 DI 10.1038/ng.952 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 842GS UT WOS:000296584000009 PM 21983784 ER PT J AU Chambers, JC Zhang, WH Sehmi, J Li, XZ Wass, MN Van der Harst, P Holm, H Sanna, S Kavousi, M Baumeister, SE Coin, LJ Deng, GH Gieger, C Heard-Costa, NL Hottenga, JJ Kuhnel, B Kumar, V Lagou, V Liang, LM Luan, JA Vidal, PM Leach, IM O'Reilly, PF Peden, JF Rahmioglu, N Soininen, P Speliotes, EK Yuan, X Thorleifsson, G Alizadeh, BZ Atwood, LD Borecki, IB Brown, MJ Charoen, P Cucca, F Das, D de Geus, EJC Dixon, AL Doering, A Ehret, G Eyjolfsson, GI Farrall, M Forouhi, NG Friedrich, N Goessling, W Gudbjartsson, DF Harris, TB Hartikainen, AL Heath, S Hirschfield, GM Hofman, A Homuth, G Hypponen, E Janssen, HLA Johnson, T Kangas, AJ Kema, IP Kuhn, JP Lai, S Lathrop, M Lerch, MM Li, Y Liang, TJ Lin, JP Loos, RJF Martin, NG Moffatt, MF Montgomery, GW Munroe, PB Musunuru, K Nakamura, Y O'Donnell, CJ Olafsson, I Penninx, BW Pouta, A Prins, BP Prokopenko, I Puls, R Ruokonen, A Savolainen, MJ Schlessinger, D Schouten, JNL Seedorf, U Sen-Chowdhry, S Siminovitch, KA Smit, JH Spector, TD Tan, WT Teslovich, TM Tukiainen, T Uitterlinden, AG Van der Klauw, MM Vasan, RS Wallace, C Wallaschofski, H Wichmann, HE Willemsen, G Wurtz, P Xu, C Yerges-Armstrong, LM Abecasis, GR Ahmadi, KR Boomsma, DI Caulfield, M Cookson, WO van Duijn, CM Froguel, P Matsuda, K McCarthy, MI Meisinger, C Mooser, V Pietilainen, KH Schumann, G Snieder, H Sternberg, MJE Stolk, RP Thomas, HC Thorsteinsdottir, U Uda, M Waeber, G Wareham, NJ Waterworth, DM Watkins, H Whitfield, JB Witteman, JCM Wolffenbuttel, BHR Fox, CS Ala-Korpela, M Stefansson, K Vollenweider, P Volzke, H Schadt, EE Scott, J Jarvelin, MR Elliott, P Kooner, JS AF Chambers, John C. Zhang, Weihua Sehmi, Joban Li, Xinzhong Wass, Mark N. Van der Harst, Pim Holm, Hilma Sanna, Serena Kavousi, Maryam Baumeister, Sebastian E. Coin, Lachlan J. Deng, Guohong Gieger, Christian Heard-Costa, Nancy L. Hottenga, Jouke-Jan Kuehnel, Brigitte Kumar, Vinod Lagou, Vasiliki Liang, Liming Luan, Jian'an Vidal, Pedro Marques Leach, Irene Mateo O'Reilly, Paul F. Peden, John F. Rahmioglu, Nilufer Soininen, Pasi Speliotes, Elizabeth K. Yuan, Xin Thorleifsson, Gudmar Alizadeh, Behrooz Z. Atwood, Larry D. Borecki, Ingrid B. Brown, Morris J. Charoen, Pimphen Cucca, Francesco Das, Debashish de Geus, Eco J. C. Dixon, Anna L. Doering, Angela Ehret, Georg Eyjolfsson, Gudmundur I. Farrall, Martin Forouhi, Nita G. Friedrich, Nele Goessling, Wolfram Gudbjartsson, Daniel F. Harris, Tamara B. Hartikainen, Anna-Liisa Heath, Simon Hirschfield, Gideon M. Hofman, Albert Homuth, Georg Hyppoenen, Elina Janssen, Harry L. A. Johnson, Toby Kangas, Antti J. Kema, Ido P. Kuehn, Jens P. Lai, Sandra Lathrop, Mark Lerch, Markus M. Li, Yun Liang, T. Jake Lin, Jing-Ping Loos, Ruth J. F. Martin, Nicholas G. Moffatt, Miriam F. Montgomery, Grant W. Munroe, Patricia B. Musunuru, Kiran Nakamura, Yusuke O'Donnell, Christopher J. Olafsson, Isleifur Penninx, Brenda W. Pouta, Anneli Prins, Bram P. Prokopenko, Inga Puls, Ralf Ruokonen, Aimo Savolainen, Markku J. Schlessinger, David Schouten, Jeoffrey N. L. Seedorf, Udo Sen-Chowdhry, Srijita Siminovitch, Katherine A. Smit, Johannes H. Spector, Timothy D. Tan, Wenting Teslovich, Tanya M. Tukiainen, Taru Uitterlinden, Andre G. Van der Klauw, Melanie M. Vasan, Ramachandran S. Wallace, Chris Wallaschofski, Henri Wichmann, H-Erich Willemsen, Gonneke Wuertz, Peter Xu, Chun Yerges-Armstrong, Laura M. Abecasis, Goncalo R. Ahmadi, Kourosh R. Boomsma, Dorret I. Caulfield, Mark Cookson, William O. van Duijn, Cornelia M. Froguel, Philippe Matsuda, Koichi McCarthy, Mark I. Meisinger, Christa Mooser, Vincent Pietilainen, Kirsi H. Schumann, Gunter Snieder, Harold Sternberg, Michael J. E. Stolk, Ronald P. Thomas, Howard C. Thorsteinsdottir, Unnur Uda, Manuela Waeber, Gerard Wareham, Nicholas J. Waterworth, Dawn M. Watkins, Hugh Whitfield, John B. Witteman, Jacqueline C. M. Wolffenbuttel, Bruce H. R. Fox, Caroline S. Ala-Korpela, Mika Stefansson, Kari Vollenweider, Peter Voelzke, Henry Schadt, Eric E. Scott, James Jarvelin, Marjo-Riitta Elliott, Paul Kooner, Jaspal S. CA Alcohol Genome-wide Assoc AlcGen Diabet Genetics Replication Genetic Invest Anthropometric Global Lipids Genetics Consortium Genetics Liver Dis GOLD Consortium Int Consortium Blood Pressure ICBP Meta-Anal Glucose Insulin-Related TI Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma SO NATURE GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; SALT EXPORT PUMP; METABOLIC SYNDROME; RISK-FACTORS; HEPATOCELLULAR-CARCINOMA; HEREDITARY CHOLESTASIS; SUSCEPTIBILITY LOCI; GENETIC-VARIANTS; COMMON VARIANTS AB Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function. C1 [Chambers, John C.; Zhang, Weihua; Coin, Lachlan J.; O'Reilly, Paul F.; Charoen, Pimphen; Sen-Chowdhry, Srijita; Tukiainen, Taru; Wuertz, Peter; Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, London, England. [Chambers, John C.; Thomas, Howard C.; Kooner, Jaspal S.] Imperial Coll Healthcare Natl Hlth Serv NHS Trust, London, England. [Chambers, John C.; Zhang, Weihua; Sehmi, Joban; Das, Debashish; Kooner, Jaspal S.] Ealing Hosp NHS Trust, Middlesex, England. [Sehmi, Joban; Scott, James; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England. [Li, Xinzhong] Univ London Imperial Coll Sci Technol & Med, Royal Brompton Hosp, Inst Clin Sci, London, England. [Wass, Mark N.; Sternberg, Michael J. E.] Univ London Imperial Coll Sci Technol & Med, Div Mol Biosci, Struct Bioinformat Grp, London, England. [Van der Harst, Pim; Leach, Irene Mateo] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 AB Groningen, Netherlands. [Holm, Hilma; Thorleifsson, Gudmar; Gudbjartsson, Daniel F.; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Sanna, Serena; Cucca, Francesco; Lai, Sandra; Uda, Manuela] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Kavousi, Maryam; Hofman, Albert; Janssen, Harry L. A.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Kavousi, Maryam; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Netherlands Genom Initiat, Rotterdam, Netherlands. [Baumeister, Sebastian E.; Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17487 Greifswald, Germany. [Deng, Guohong; Tan, Wenting] Third Mil Med Univ, Southwest Hosp, Inst Infect Dis, Chongqing, Peoples R China. [Gieger, Christian; Kuehnel, Brigitte] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Hottenga, Jouke-Jan; de Geus, Eco J. C.; Willemsen, Gonneke; Boomsma, Dorret I.] VU Univ Amsterdam VUA, Dept Biol Psychol, Amsterdam, Netherlands. [Kumar, Vinod; Nakamura, Yusuke; Matsuda, Koichi] Univ Tokyo, Inst Med Sci, Mol Med Lab, Tokyo, Japan. [Lagou, Vasiliki; Alizadeh, Behrooz Z.; Prins, Bram P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Genet Epidemiol & Bioinformat, Groningen, Netherlands. [Lagou, Vasiliki; Rahmioglu, Nilufer; Prokopenko, Inga; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Lagou, Vasiliki; Prokopenko, Inga; McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Luan, Jian'an; Forouhi, Nita G.; Loos, Ruth J. F.; Wareham, Nicholas J.] Addenbrookes Hosp, Med Res Council Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Vidal, Pedro Marques] Univ Lausanne Hosp, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland. [Vidal, Pedro Marques; Ehret, Georg] Univ Lausanne, Lausanne, Switzerland. [Peden, John F.; Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford, England. [Soininen, Pasi; Kangas, Antti J.; Savolainen, Markku J.; Tukiainen, Taru; Wuertz, Peter; Ala-Korpela, Mika] Univ Oulu, Inst Clin Med, Computat Med Res Grp, Oulu, Finland. [Soininen, Pasi; Kangas, Antti J.; Savolainen, Markku J.; Tukiainen, Taru; Wuertz, Peter; Ala-Korpela, Mika] Univ Oulu, Bioctr, Oulu, Finland. [Soininen, Pasi; Ala-Korpela, Mika] Univ Eastern Finland, Dept Biosci, Nucl Magnet Resonance NMR Metabon Lab, Kuopio, Finland. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Yuan, Xin; Mooser, Vincent; Waterworth, Dawn M.] GlaxoSmithKline Inc, Genet, King Of Prussia, PA USA. [Atwood, Larry D.; Musunuru, Kiran] Boston Univ, Sch Med, Boston, MA 02118 USA. [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Brown, Morris J.; Wallace, Chris] Univ Cambridge, Cambridge Inst Med Res, Diabet Inflammat Lab, Cambridge, England. [Charoen, Pimphen] Mahidol Univ, Fac Trop Med, Dept Trop Hyg, Bangkok, Thailand. [de Geus, Eco J. C.] VUA, Amsterdam, Netherlands. [de Geus, Eco J. C.] VUA Med Ctr, Amsterdam, Netherlands. [Dixon, Anna L.; Moffatt, Miriam F.; Cookson, William O.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Doering, Angela; Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Ehret, Georg] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Ehret, Georg] CHU Vaudois, IUMSP, CH-1011 Lausanne, Switzerland. [Ehret, Georg] Univ Hosp Geneva, Dept Med, Geneva, Switzerland. [Eyjolfsson, Gudmundur I.] Lab Mjodd, Reykjavik, Iceland. [Farrall, Martin; Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Friedrich, Nele; Wallaschofski, Henri] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, D-17487 Greifswald, Germany. [Goessling, Wolfram] Brigham & Womens Hosp, Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Div Genet, Boston, MA 02115 USA. [Goessling, Wolfram] Brigham & Womens Hosp, Div Gastroenterol, Gastrointestinal Canc Ctr, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hartikainen, Anna-Liisa; Pouta, Anneli] Univ Oulu, Inst Clin Med, Oulu, Finland. [Heath, Simon; Lathrop, Mark] CEA IG Ctr Natl Genotypage, Evry, France. [Hirschfield, Gideon M.; Siminovitch, Katherine A.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Hirschfield, Gideon M.] Toronto Western Hosp, Ctr Liver, Toronto, ON M5T 2S8, Canada. [Hirschfield, Gideon M.] Univ Birmingham, Liver Res Ctr, Birmingham, W Midlands, England. [Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Hyppoenen, Elina] Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Janssen, Harry L. A.; Schouten, Jeoffrey N. L.] Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands. [Johnson, Toby; Munroe, Patricia B.; Caulfield, Mark] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol & Genome Ctr, London, England. [Kema, Ido P.] Univ Groningen, Univ Med Ctr Groningen, Dept Lab Med, Groningen, Netherlands. [Kuehn, Jens P.; Puls, Ralf] Ernst Moritz Arndt Univ Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany. [Lathrop, Mark] Fdn Jean Dausset Ceph, Paris, France. [Lerch, Markus M.] Univ Med Greifswald, Dept Med A, Greifswald, Germany. [Li, Yun] Univ N Carolina, Dept Biostat, Dept Genet, Chapel Hill, NC USA. [Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Lin, Jing-Ping] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Martin, Nicholas G.; Montgomery, Grant W.; Whitfield, John B.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Musunuru, Kiran] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Musunuru, Kiran] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Musunuru, Kiran] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Musunuru, Kiran] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Olafsson, Isleifur] Landspitali Univ Hosp, Dept Clin Biochem, Reykjavik, Iceland. [Penninx, Brenda W.; Smit, Johannes H.] VUA Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Penninx, Brenda W.; Smit, Johannes H.] VUA Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Pouta, Anneli; Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Lifecourse & Serv, Oulu, Finland. [Ruokonen, Aimo] Univ Oulu, Inst Diagnost, Oulu, Finland. [Savolainen, Markku J.; Ala-Korpela, Mika] Univ Oulu, Clin Res Ctr, Dept Internal Med, Oulu, Finland. [Savolainen, Markku J.; Ala-Korpela, Mika] Univ Oulu, Clin Res Ctr, Bioctr Oulu, Oulu, Finland. [Schlessinger, David] NIA, Genet Lab, Baltimore, MD 21224 USA. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany. [Siminovitch, Katherine A.] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [Siminovitch, Katherine A.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Siminovitch, Katherine A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Siminovitch, Katherine A.] Toronto Gen Res Inst, Toronto, ON, Canada. [Spector, Timothy D.; Ahmadi, Kourosh R.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Teslovich, Tanya M.; Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Van der Klauw, Melanie M.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Van der Klauw, Melanie M.; Sternberg, Michael J. E.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, Groningen, Netherlands. [Van der Klauw, Melanie M.; Sternberg, Michael J. E.; Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Biobank, Groningen, Netherlands. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Willemsen, Gonneke; Boomsma, Dorret I.] VUA Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Xu, Chun] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Xu, Chun] Toronto Gen Res Inst, Toronto, ON, Canada. [Yerges-Armstrong, Laura M.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Rotterdam, Netherlands. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Publ Hlth, London, England. [McCarthy, Mark I.] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England. [Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Pietilainen, Kirsi H.] Helsinki Univ Hosp, Div Internal Med, Dept Med, Obes Res Unit, Helsinki, Finland. [Pietilainen, Kirsi H.] Inst Mol Med FIMM, Helsinki, Finland. [Pietilainen, Kirsi H.] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Schumann, Gunter] Kings Coll London, Inst Psychiat, MRC Social Genet Dev Psychiat SGDP Ctr, London WC2R 2LS, England. [Stolk, Ronald P.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Thomas, Howard C.] Univ London Imperial Coll Sci Technol & Med, Fac Med, London, England. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Waeber, Gerard; Vollenweider, Peter] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA. [Schadt, Eric E.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC, HPA, Ctr Environm Hlth, London, England. RP Chambers, JC (reprint author), Univ London Imperial Coll Sci Technol & Med, Norfolk Pl, London, England. EM john.chambers@ic.ac.uk; p.elliott@ic.ac.uk; j.kooner@ic.ac.uk RI Smith, Albert Vernon/K-5150-2015; Marques-Vidal, Pedro/C-9449-2009; Kronenberg, Florian/B-1736-2008; Lucas, Gavin/D-4346-2012; Ridderstrale, Martin/F-7678-2012; Elliott, Amanda/G-5120-2012; Rudan, Igor/I-1467-2012; Heath, Simon/J-4138-2012; Laan, Maris/A-4100-2011; Singleton, Andrew/C-3010-2009; Stolk, Ronald/B-2341-2013; Wolffenbuttel, Bruce/A-8419-2011; Willems van Dijk, Ko/A-1798-2008; Soininen, Pasi/B-9716-2008; EHRET, Georg/A-9532-2009; Knowles, Josh/C-9241-2013; Marusic, Ana/E-7683-2013; Kuznetsova, Tatiana/I-6882-2013; Colaus, PsyColaus/K-6607-2013; Lagou, Vasiliki/N-8451-2013; van der Klauw, Melanie/A-2138-2014; Hypponen, Elina/B-2596-2014; Hernaez, Ruben/C-4039-2014; Kiemeney, Lambertus/D-3357-2009; Meisinger, Christine/B-5358-2014; Grobbee, Diederick/C-7651-2014; Siminovitch, Katherine/K-1475-2013; Palmer, Lyle/K-3196-2014; Boehm, Bernhard/F-8750-2015; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Mattace- Raso, Francesco/L-2541-2015; Hirschfield, Gideon/M-2143-2015; Polasek, Ozren/B-6002-2011; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Prokopenko, Inga/H-3241-2014; Lerch, Markus M./E-2206-2016; Grarup, Niels/K-2807-2015; Aben, Katja/G-9686-2016; Ejebe, Kenechi/I-9238-2016; Kyvik, Kirsten /K-5680-2016; Matullo, Giuseppe/K-6383-2016; Visvikis-Siest, Sophie/H-2324-2014; Bochud, Murielle/A-3981-2010; Coin, Lachlan/A-9001-2014; Erdmann, Jeanette/A-4417-2009; Naitza, Silvia/D-5620-2017; Feitosa, Mary/K-8044-2012; OI Jorgensen, Torben/0000-0001-9453-2830; Watkins, Hugh/0000-0002-5287-9016; Visscher, Peter/0000-0002-2143-8760; Marmot, Michael/0000-0002-2431-6419; Prabhakaran, Dorairaj/0000-0002-3172-834X; Ouwehand, Willem/0000-0002-7744-1790; Kaprio, Jaakko/0000-0002-3716-2455; Lawlor, Debbie A/0000-0002-6793-2262; Rivolta, Carlo/0000-0002-0733-9950; Johansson, Asa/0000-0002-2915-4498; Arora, Pankaj/0000-0003-2420-3550; Matsuda, Koichi/0000-0001-7292-2686; Kumari, Meena/0000-0001-9716-1035; Melzer, David/0000-0002-0170-3838; Goessling, Wolfram/0000-0001-9972-1569; Forouhi, Nita/0000-0002-5041-248X; Ziad Alizadeh, Behrooz/0000-0002-1415-8007; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Wallace, Chris/0000-0001-9755-1703; Vandenput, Liesbeth/0000-0002-1712-6131; Smith, Albert Vernon/0000-0003-1942-5845; Zgaga, Lina/0000-0003-4089-9703; Zeggini, Eleftheria/0000-0003-4238-659X; Ramachandran, Vasan/0000-0001-7357-5970; Luben, Robert/0000-0002-5088-6343; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Adeyemo, Adebowale/0000-0002-3105-3231; Hide, Winston/0000-0002-8621-3271; Org, Elin/0000-0003-1451-9375; Meisinger, Christa/0000-0002-9026-6544; sanna, serena/0000-0002-3768-1749; Marques-Vidal, Pedro/0000-0002-4548-8500; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Ikram, Mohammad Arfan/0000-0003-0372-8585; Abecasis, Goncalo/0000-0003-1509-1825; Gudbjartsson, Daniel/0000-0002-5222-9857; Wurtz, Peter/0000-0002-5832-0221; Marroni, Fabio/0000-0002-1556-5907; Seshadri, Sudha/0000-0001-6135-2622; Sternberg, Michael/0000-0002-1884-5445; Magi, Reedik/0000-0002-2964-6011; Wass, Mark/0000-0001-5428-6479; Martin, Nicholas/0000-0003-4069-8020; Wain, Louise/0000-0003-4951-1867; Kronenberg, Florian/0000-0003-2229-1120; Rudan, Igor/0000-0001-6993-6884; Laan, Maris/0000-0002-8519-243X; Stolk, Ronald/0000-0002-0518-1205; Wolffenbuttel, Bruce/0000-0001-9262-6921; Willems van Dijk, Ko/0000-0002-2172-7394; EHRET, Georg/0000-0002-5730-0675; Marusic, Ana/0000-0001-6272-0917; Kuznetsova, Tatiana/0000-0003-3564-7405; van der Klauw, Melanie/0000-0001-7178-009X; Hypponen, Elina/0000-0003-3670-9399; Hernaez, Ruben/0000-0002-1518-4020; Kiemeney, Lambertus/0000-0002-2368-1326; Grobbee, Diederick/0000-0003-4472-4468; Palmer, Lyle/0000-0002-1628-3055; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Hirschfield, Gideon/0000-0002-6736-2255; Polasek, Ozren/0000-0002-5765-1862; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Prokopenko, Inga/0000-0003-1624-7457; Lerch, Markus M./0000-0002-9643-8263; Grarup, Niels/0000-0001-5526-1070; Aben, Katja/0000-0002-0214-2147; Ejebe, Kenechi/0000-0002-6090-8657; Kyvik, Kirsten /0000-0003-2981-0245; Visvikis-Siest, Sophie/0000-0001-8104-8425; Bochud, Murielle/0000-0002-5727-0218; Coin, Lachlan/0000-0002-4300-455X; Feitosa, Mary/0000-0002-0933-2410; Seedorf, Udo/0000-0003-4652-5358; Heard-Costa, Nancy/0000-0001-9730-0306 FU European Commission; European Science Foundation; European Science Council; US NIH; US National Institute of Mental Health; US NIDDK; Genetic Association Information Network; US National Institute on Aging; US National Human Genome Research Institute; US NHLBI; UK NIHR; NIHR Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; NIHR Comprehensive Biomedical Research Centre Guy's and St. Thomas' NHS Trust; UK Biotechnology and Biological Sciences Research Council; UK MRC; British Heart Foundation; Wellcome Trust; Swiss National Science Foundation; Academy of Finland; Finnish Cardiovascular Research Foundation; Swedish Research Council; Swedish Heart-Lung Foundation; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; German Federal Ministry of Education and Research; German National Genome Research Network; Netherlands Organization for Scientific Research; Dutch Ministries of Economic Affairs, of Education, Culture and Science, for Health, Welfare and Sports; Netherlands Organization for Health Research and Development; Dutch government; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Dutch Brain Foundation; Dutch Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Canadian Institutes for Health Research; Ontario Research Fund; Barts and the London Charity; University Medical Center Groningen; University of Groningen; University of Oulu, Biocenter Oulu; University Hospital Oulu; Biocentrum Helsinki; Erasmus Medical Center and Erasmus University, Rotterdam; Karolinska Institutet; Stockholm County Council; Municipality of Rotterdam; Federal State of Mecklenburg-West Pomerania; AstraZeneca; GlaxoSmithKline; Siemens Healthcare; Novo Nordisk Foundation; Yrjo Jahnsson Foundation; Biomedicum Helsinki Foundation; Gyllenberg Foundation; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg Foundation; Boston University School of Medicine; Instrumentarium Science Foundation; Jenny and Antti Wihuri Foundation; Canadian Primary Biliary Cirrhosis Society FX We thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of data. We also thank the research participants who took part in these studies. Major support for the work came from European Commission (FP5, FP6 and FP7); European Science Foundation; European Science Council; US NIH; US National Institute of Mental Health; US NIDDK; Genetic Association Information Network; US National Institute on Aging; US National Human Genome Research Institute; US NHLBI; UK NIHR; NIHR Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust; NIHR Comprehensive Biomedical Research Centre Guy's and St. Thomas' NHS Trust; UK Biotechnology and Biological Sciences Research Council; UK MRC; British Heart Foundation; Wellcome Trust; Swiss National Science Foundation; Academy of Finland; Finnish Cardiovascular Research Foundation; Swedish Research Council; Swedish Heart-Lung Foundation; Helmholtz Zentrum Munchen; German Research Center for Environmental Health; German Federal Ministry of Education and Research; German National Genome Research Network; Netherlands Organization for Scientific Research; Dutch Ministries of Economic Affairs, of Education, Culture and Science, for Health, Welfare and Sports; Netherlands Organization for Health Research and Development; Economic Structure Enhancing Fund of the Dutch government; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Dutch Brain Foundation; Dutch Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Canadian Institutes for Health Research; Ontario Research Fund; The Barts and the London Charity; University Medical Center Groningen; University of Groningen; University of Oulu, Biocenter Oulu; University Hospital Oulu; Biocentrum Helsinki; Erasmus Medical Center and Erasmus University, Rotterdam; Karolinska Institutet; Stockholm County Council; Municipality of Rotterdam; Federal State of Mecklenburg-West Pomerania; AstraZeneca; GlaxoSmithKline; Siemens Healthcare; Novo Nordisk Foundation; Yrjo Jahnsson Foundation; Biomedicum Helsinki Foundation; Gyllenberg Foundation; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg Foundation; Robert Dawson Evans Endowment, Boston University School of Medicine; Instrumentarium Science Foundation; Jenny and Antti Wihuri Foundation and the Canadian Primary Biliary Cirrhosis Society. A full list of acknowledgments is provided in the Supplementary Note. NR 72 TC 181 Z9 186 U1 7 U2 76 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD NOV PY 2011 VL 43 IS 11 BP 1131 EP U129 DI 10.1038/ng.970 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 842GS UT WOS:000296584000019 PM 22001757 ER PT J AU Dvir, T Timko, BP Brigham, MD Naik, SR Karajanagi, SS Levy, O Jin, HW Parker, KK Langer, R Kohane, DS AF Dvir, Tal Timko, Brian P. Brigham, Mark D. Naik, Shreesh R. Karajanagi, Sandeep S. Levy, Oren Jin, Hongwei Parker, Kevin K. Langer, Robert Kohane, Daniel S. TI Nanowired three-dimensional cardiac patches SO NATURE NANOTECHNOLOGY LA English DT Article ID MYOCARDIAL-INFARCTION; GOLD NANORODS; DEVICE ARRAYS; TISSUE; SCAFFOLDS; ALGINATE; REGENERATION; DELIVERY; HEARTS; REPAIR AB Engineered cardiac patches for treating damaged heart tissues after a heart attack are normally produced by seeding heart cells within three-dimensional porous biomaterial scaffolds(1-3). These biomaterials, which are usually made of either biological polymers such as alginate(4) or synthetic polymers such as poly(lactic acid) (PLA)(5), help cells organize into functioning tissues, but poor conductivity of these materials limits the ability of the patch to contract strongly as a unit(6). Here, we show that incorporating gold nanowires within alginate scaffolds can bridge the electrically resistant pore walls of alginate and improve electrical communication between adjacent cardiac cells. Tissues grown on these composite matrices were thicker and better aligned than those grown on pristine alginate and when electrically stimulated, the cells in these tissues contracted synchronously. Furthermore, higher levels of the proteins involved in muscle contraction and electrical coupling are detected in the composite matrices. It is expected that the integration of conducting nanowires within three-dimensional scaffolds may improve the therapeutic value of current cardiac patches. C1 [Dvir, Tal; Timko, Brian P.; Naik, Shreesh R.; Karajanagi, Sandeep S.; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Dvir, Tal; Timko, Brian P.; Kohane, Daniel S.] Harvard Univ, Childrens Hosp Boston, Lab Biomat & Drug Delivery, Dept Anesthesiol,Div Crit Care Med,Med Sch, Boston, MA 02115 USA. [Brigham, Mark D.; Jin, Hongwei; Parker, Kevin K.] Harvard Univ, Sch Engn & Appl Sci, Wyss Inst Biol Inspired Engn, Dis Biophys Grp, Cambridge, MA 02138 USA. [Karajanagi, Sandeep S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Levy, Oren] Harvard Massachusetts Inst Technol Div Hlth Sci &, Cambridge, MA 02139 USA. [Levy, Oren] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Cambridge, MA 02139 USA. RP Dvir, T (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM Daniel.Kohane@childrens.harvard.edu FU National Institutes of Health (NIH) [GM073626, DE13023, DE016516]; American Heart Association; NIH Ruth L. Kirschstein National Research Service [F32GM096546] FX This research was funded by the National Institutes of Health (NIH, grants GM073626 to D. S. K. and DE13023 and DE016516 to R. L.). T. D. thanks the American Heart Association for a Postdoctoral Fellowship. B. P. T. acknowledges an NIH Ruth L. Kirschstein National Research Service Award (no. F32GM096546). The authors would like to thank H. Park, B. Tian, D. Liu, A. Argun and L. Bellan for their assistance and discussions. NR 33 TC 196 Z9 199 U1 20 U2 198 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 NOV PY 2011 VL 6 IS 11 BP 720 EP 725 DI 10.1038/NNANO.2011.160 PG 6 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 844HC UT WOS:000296737300010 PM 21946708 ER PT J AU Flaherty, KT Yasothan, U Kirkpatrick, P AF Flaherty, Keith. T. Yasothan, Uma Kirkpatrick, Peter TI Vemurafenib SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID MELANOMA; BRAF; INHIBITION C1 [Flaherty, Keith. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yasothan, Uma] IMS Hlth, London NW1 6JB, England. RP Flaherty, KT (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM kflaherty@partners.org; UYasothan@imscg.com; p.kirkpatrick@nature.com NR 9 TC 76 Z9 78 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD NOV PY 2011 VL 10 IS 11 BP 811 EP 812 DI 10.1038/nrd3579 PG 2 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 842IR UT WOS:000296592100015 PM 22037033 ER PT J AU Ginsburg, ES Partridge, AH AF Ginsburg, Elizabeth S. Partridge, Ann H. TI REPRODUCTIVE ENDOCRINOLOGY Triptorelin ovarian suppression during breast cancer chemotherapy SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Editorial Material ID WOMEN; PREMENOPAUSAL; MENOPAUSE C1 [Ginsburg, Elizabeth S.; Partridge, Ann H.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ginsburg, ES (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 450 Longwood Ave, Boston, MA 02115 USA. EM eginsburg@partners.org NR 10 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD NOV PY 2011 VL 7 IS 11 BP 637 EP 638 DI 10.1038/nrendo.2011.159 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 842CM UT WOS:000296565200004 PM 21931373 ER PT J AU Kim, M Sun, ZYJ Rand, KD Shi, XM Song, LK Cheng, YX Fahmy, AF Majumdar, S Ofek, G Yang, YP Kwong, PD Wang, JH Engen, JR Wagner, G Reinherz, EL AF Kim, Mikyung Sun, Zhen-Yu J. Rand, Kasper D. Shi, Xiaomeng Song, Likai Cheng, Yuxing Fahmy, Amr F. Majumdar, Shreoshi Ofek, Gilad Yang, Yongping Kwong, Peter D. Wang, Jia-Huai Engen, John R. Wagner, Gerhard Reinherz, Ellis L. TI Antibody mechanics on a membrane-bound HIV segment essential for GP41-targeted viral neutralization SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; EXCHANGE-MASS-SPECTROMETRY; COMPLEMENTARITY-DETERMINING REGION; STRUCTURAL BASIS; GP41 ECTODOMAIN; COMBINING SITE; HEAVY-CHAIN; EPITOPE; 2F5; 4E10 AB Broadly neutralizing antibodies such as 2F5 are directed against the membrane-proximal external region (MPER) of HIV-1 GP41 and recognize well-defined linear core sequences. These epitopes can be engrafted onto protein scaffolds to serve as immunogens with high structural fidelity. Although antibodies that bind to this core GP41 epitope can be elicited, they lack neutralizing activity. To understand this paradox, we used biophysical methods to investigate the binding of human 2F5 to the MPER in a membrane environment, where it resides in vivo. Recognition is stepwise, through a paratope more extensive than core binding site contacts alone, and dynamic rearrangement through an apparent scoop-like movement of heavy chain complementarity-determining region 3 (CDRH3) is essential for MPER extraction from the viral membrane. Core-epitope recognition on the virus requires the induction of conformational changes in both the MPER and the paratope. Hence, target neutralization through this lipid-embedded viral segment places stringent requirements on the plasticity of the antibody combining site. C1 [Kim, Mikyung; Cheng, Yuxing; Majumdar, Shreoshi; Wang, Jia-Huai; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Kim, Mikyung; Song, Likai; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sun, Zhen-Yu J.; Fahmy, Amr F.; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Rand, Kasper D.; Shi, Xiaomeng; Engen, John R.] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Rand, Kasper D.; Shi, Xiaomeng; Engen, John R.] Northeastern Univ, Barnett Inst Chem & Biol Anal, Boston, MA 02115 USA. [Song, Likai; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Song, Likai] Natl High Magnet Field Lab, Tallahassee, FL USA. [Cheng, Yuxing] Harvard Univ, Sch Publ Hlth, PhD Program Biol Sci Publ Hlth, Boston, MA 02115 USA. [Ofek, Gilad; Yang, Yongping; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Wang, Jia-Huai] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Immunobiol Lab, 44 Binney St, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu OI Rand, Kasper/0000-0002-6337-5489 FU US National Institutes of Health (NIH) [RO1AI84785, U19AI91693]; Gates Foundation; NIH [RO1-GM086507]; Waters Corporation; The Danish Council for Independent Research in Natural Sciences [09-063876]; US National High Magnetic Field Laboratory (NHMFL); US National Science Foundation [DMR-0654118]; State of Florida; US Department of Energy; The Collaboration for AIDS Vaccine Discovery (CAVD) Program FX This work was supported by US National Institutes of Health (NIH) grants RO1AI84785 and U19AI91693 to E.L.R. and G.W., and a grant from the Gates Foundation, The Collaboration for AIDS Vaccine Discovery (CAVD) Program to E.L.R., G.W. and J.R.E. J.R.E. was also supported by NIH grant RO1-GM086507 and funding through a cooperative research agreement with the Waters Corporation. K.D.R. was supported by The Danish Council for Independent Research in Natural Sciences (FNU grant 09-063876). J.R.E. would like to thank T.E. Wales for expert technical assistance. L.S. was also supported by an US National High Magnetic Field Laboratory (NHMFL) User Collaboration Grants Program award. The NHMFL is funded by the US National Science Foundation through the Cooperative Agreement No. DMR-0654118, the State of Florida, and the US Department of Energy. NR 58 TC 51 Z9 51 U1 1 U2 11 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 NOV PY 2011 VL 18 IS 11 BP 1235 EP U81 DI 10.1038/nsmb.2154 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 844FX UT WOS:000296734200010 PM 22002224 ER PT J AU Middleton, LE Grinberg, LT Miller, B Kawas, C Yaffe, K AF Middleton, L. E. Grinberg, L. T. Miller, B. Kawas, C. Yaffe, K. TI Neuropathologic features associated with Alzheimer disease diagnosis Age matters SO NEUROLOGY LA English DT Article ID CENTER NACC DATABASE; OLDEST-OLD; LEWY BODIES; DEMENTIA; CENTENARIANS; POPULATION; NONAGENARIANS; PREVALENCE; AUTOPSY; COHORT AB Objective: To examine whether the association between clinical Alzheimer disease (AD) diagnosis and neuropathology and the precision by which neuropathology differentiates people with clinical AD from those with normal cognition varies by age. Methods: We conducted a cross-sectional analysis of 2,014 older adults (>= 70 years at death) from the National Alzheimer's Coordinating Center database with clinical diagnosis of normal cognition (made <= 1 year before death, n = 419) or AD (at >= 65 years, n = 1,595) and a postmortem neuropathologic examination evaluating AD pathology (neurofibrillary tangles, neuritic plaques) and non-AD pathology (diffuse plaques, amyloid angiopathy, Lewy bodies, macrovascular disease, microvascular disease). We used adjusted logistic regression to analyze the relationship between clinical AD diagnosis and neuropathologic features, area under the receiver operating characteristic curve (c statistic) to evaluate how precisely neuropathology differentiates between cognitive diagnoses, and an interaction to identify effect modification by age group. Results: In a model controlling for coexisting neuropathologic features, the relationship between clinical AD diagnosis and neurofibrillary tangles was significantly weaker with increasing age (p < 0.001 for interaction). The aggregate of all neuropathologic features more strongly differentiated people with clinical AD from those without in younger age groups (70-74 years: c statistic, 95% confidence interval: 0.93, 0.89-0.96; 75-84 years: 0.95, 0.87-0.95; >= 85 years: 0.83, 0.80-0.87). Non-AD pathology significantly improved precision of differentiation across all age groups (p < 0.004). Conclusion: Clinical AD diagnosis was more weakly associated with neurofibrillary tangles among the oldest old compared to younger age groups, possibly due to less accurate clinical diagnosis, better neurocompensation, or unaccounted pathology among the oldest old. Neurology (R) 2011;77:1737-1744 C1 [Middleton, L. E.] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. [Middleton, L. E.] Sunnybrook Hlth Sci Ctr, Heart & Stroke Fdn, Ctr Stroke Recovery, Toronto, ON M4N 3M5, Canada. [Miller, B.; Yaffe, K.] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Grinberg, L. T.; Miller, B.; Yaffe, K.] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, K.] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, K.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Middleton, LE (reprint author), 200 Univ Ave W,BMH 1114, Waterloo, ON N2L 3G1, Canada. EM laura.middleton@uwaterloo.ca RI Middleton, Laura/C-6024-2009; OI Middleton, Laura/0000-0001-8624-3123; grinberg, lea/0000-0002-6809-0618 FU Canadian Institute of Health Research; Alzheimer's Association; John Douglas French Alzheimer's Foundation; publication of Behavioral Neurology of Dementia (Cambridge); Handbook of Neurology (Elsevier); Human Frontal Lobes (Guilford); Novartis; NIH/NIA; State of California Alzheimer's Center; NIH/ Alzheimer's Disease Research Centre; NIH (NIA, NIDDK, NIMH); Department of Defense; American Health Assistance Foundation; Anonymous Foundation; Alzheimer Association; NIH [U01 AG016976] FX Dr. Middleton serves on the editorial board of the Journal of Alzheimer's Disease and receives fellowship support from the Canadian Institute of Health Research fellowship. Dr. Grinberg serves as an Associate Editor for Frontiers in Dementia and Cell and Tissue Banking; and receives research support from the Alzheimer's Association and the John Douglas French Alzheimer's Foundation. Dr. Miller serves on a scientific advisory board for the Alzheimer's Disease Clinical Study; serves as an Editor for Neurocase and as an Associate Editor of ADAD; receives royalties from the publication of Behavioral Neurology of Dementia (Cambridge, 2009), Handbook of Neurology (Elsevier, 2009), and The Human Frontal Lobes (Guilford, 2008); serves as a consultant for Lundbeck Inc., Elan Corporation, and Allon Therapeutics, Inc.; serves on speakers' bureaus for Novartis and Pfizer Inc.; and receives research support from Novartis and the NIH/NIA and the State of California Alzheimer's Center. Dr. Kawas serves on a scientific advisory board for Quintiles and receives research support from the NIH/ Alzheimer's Disease Research Centre. Dr. Yaffe has served on data safety monitoring boards for Pfizer Inc, Medivation, Inc., and the NIH (NIMH and NIA trials); and has received research support from the NIH (NIA, NIDDK, NIMH), the Department of Defense, American Health Assistance Foundation, Anonymous Foundation, and the Alzheimer Association.; The National Alzheimer's Coordinating Centre is funded by NIH U01 AG016976. The NIA approved the final manuscript but did not influence the analysis, results, or interpretation. NR 31 TC 24 Z9 24 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD NOV PY 2011 VL 77 IS 19 BP 1737 EP 1744 DI 10.1212/WNL.0b013e318236f0cf PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 844SO UT WOS:000296767800010 PM 22031532 ER PT J AU Seddon, JM Reynolds, R Yu, Y Daly, MJ Rosner, B AF Seddon, Johanna M. Reynolds, Robyn Yu, Yi Daly, Mark J. Rosner, Bernard TI Risk Models for Progression to Advanced Age-Related Macular Degeneration Using Demographic, Environmental, Genetic, and Ocular Factors SO OPHTHALMOLOGY LA English DT Article ID COMPLEMENT FACTOR-H; BODY-MASS INDEX; DIETARY-FAT; VITAMIN-C; VARIANT; ASSOCIATION; SUSCEPTIBILITY; POLYMORPHISM; MACULOPATHY; HTRA1 AB Purpose: To expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status. Design: Prospective, longitudinal study. Participants: We included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up. Methods: Cox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables. Main Outcome Measures: Progression to advanced AMD, including geographic atrophy and neovascular disease. Results: In multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered. Conclusions: Factors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011;118:2203-2211 (C) 2011 by the American Academy of Ophthalmology. C1 [Seddon, Johanna M.] New England Eye Ctr, Tufts Med Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA 02111 USA. [Seddon, Johanna M.; Reynolds, Robyn; Yu, Yi] Tufts Univ, Sch Med, Ophthalm Epidemiol & Genet Serv, Boston, MA 02111 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rosner, Bernard] Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. RP Seddon, JM (reprint author), New England Eye Ctr, Tufts Med Ctr, Ophthalm Epidemiol & Genet Serv, 800 Washington St 450, Boston, MA 02111 USA. EM jseddon@tuftsmedicalcenter.org FU National Institutes of Health [RO1-EY11309]; Massachusetts Lions Eye Research Fund Inc., New Bedford, MA; Research to Prevent Blindness Inc., New York, NY; American Macular Degeneration Foundation, Northampton, MA; Tufts Medical Center; Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Tufts University School of Medicine FX Supported by grant RO1-EY11309 from the National Institutes of Health; the Massachusetts Lions Eye Research Fund Inc., New Bedford, MA; unrestricted grants from Research to Prevent Blindness Inc., New York, NY; the American Macular Degeneration Foundation, Northampton, MA; Virginia B Smith Fund, Tufts Medical Center; and the Age-Related Macular Degeneration Research Fund, Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Tufts University School of Medicine. NR 34 TC 86 Z9 88 U1 3 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2011 VL 118 IS 11 BP 2203 EP 2211 DI 10.1016/j.ophtha.2011.04.029 PG 9 WC Ophthalmology SC Ophthalmology GA 842EG UT WOS:000296573500016 PM 21959373 ER PT J AU Lee, J Ferrucci, S AF Lee, Jimin Ferrucci, Steven TI Peripapillary subretinal neovascular membranes: A review SO OPTOMETRY-JOURNAL OF THE AMERICAN OPTOMETRIC ASSOCIATION LA English DT Review DE Peripapillary subretinal neovascularization; Juxtapapillary subretinal neovascularization; Age-related macular degeneration; Choroidal neovascular membrane ID POLYPOIDAL CHOROIDAL VASCULOPATHY; INTRAVITREAL BEVACIZUMAB; LASER PHOTOCOAGULATION; OCULAR HISTOPLASMOSIS; PHOTODYNAMIC THERAPY; SURGICAL-TREATMENT; NATURAL-HISTORY; VERTEPORFIN; SURGERY; REMOVAL AB Peripapillary subretinal neovascular membranes (PSRNVM) are most commonly associated with age-related macular degeneration and idiopathic causes in older patients. In younger patients, the condition has been linked to a wide variety of other conditions. As with the more commonly occurring macular form of choroidal neovascular membranes, PSRNVM can also lead to severe vision loss. Therefore, clinicians must take care to avoid overlooking this event to provide appropriate management and treatment. Current knowledge of PSRNVM suggests the importance of regular examinations of the affected eye in both treated and untreated cases to watch for progression and recurrence, which are unpredictable, and also of the fellow eye because there is a high risk of bilateral involvement. Optometry 2011;82:681-688 C1 [Lee, Jimin; Ferrucci, Steven] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Lee, Jimin; Ferrucci, Steven] Sepulveda Vet Affairs Ambulatory Care Ctr Nursing, Sepulveda, CA USA. [Ferrucci, Steven] So Calif Coll Optometry, Fullerton, CA USA. RP Ferrucci, S (reprint author), Sepulveda Vet Affairs Ambulatory Care Ctr, Dept Optometry, 16111 Plummer St 112E, Sepulveda, CA 91343 USA. EM steven.ferrucci@va.gov NR 32 TC 1 Z9 1 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-1839 J9 OPTOMETRY JI Optometry PD NOV PY 2011 VL 82 IS 11 BP 681 EP 688 DI 10.1016/j.optm.2011.04.104 PG 8 WC Ophthalmology SC Ophthalmology GA 843QL UT WOS:000296687200006 PM 21873121 ER PT J AU Zhang, LZ Chari, S Smyrk, TC Deshpande, V Kloppel, G Kojima, M Liu, XL Longnecker, DS Mino-Kenudson, M Notohara, K Rodriguez-Justo, M Srivastava, A Zamboni, G Zen, Y AF Zhang, Lizhi Chari, Suresh Smyrk, Thomas C. Deshpande, Vikram Kloeppel, Guenter Kojima, Motohiro Liu, Xiuli Longnecker, Daniel S. Mino-Kenudson, Mari Notohara, Kenji Rodriguez-Justo, Manuel Srivastava, Amitabh Zamboni, Giuseppe Zen, Yoh TI Autoimmune Pancreatitis (AIP) Type 1 and Type 2 An International Consensus Study on Histopathologic Diagnostic Criteria SO PANCREAS LA English DT Article DE autoimmune pancreatitis; chronic pancreatitis; granulocytic epithelial lesion; IgG4 ID LYMPHOPLASMACYTIC SCLEROSING PANCREATITIS; DISEASE; INFILTRATION; CARCINOMA; FEATURES; CELL AB Objectives: To develop and validate histologic diagnostic criteria for autoimmune pancreatitis (AIP) and its types. Methods: Thirteen pathologists participated in this 2-phase study to develop diagnostic criteria for AIP types 1 and 2 (phase 1) and validate them (phase 2). A virtual library of 40 resected pancreata with AIP and other forms of chronic pancreatitis (CP) was constructed. Readers reviewed the slides online and filled out a questionnaire for histopathologic findings and diagnosis. Results: Diagnostic criteria for AIP and its types were proposed according to the results from the top 5 reviewers in phase 1. The interobserver agreement was significantly improved in phase 2 by applying the proposed diagnostic criteria. Features distinguishing AIP from alcoholic and obstructive forms of CP were periductal lymphoplasmacytic infiltrate, inflamed cellular stroma with storiform fibrosis, obliterative phlebitis, and granulocytic epithelial lesions. Although there was overlap, 2 types of AIP were recognized. Type 1 had dense lymphoplasmacytic infiltrate with storiform fibrosis and obliterative phlebitis, whereas type 2 was distinguished from type 1 by the presence of granulocytic epithelial lesions. Conclusions: Autoimmune pancreatitis can be distinguished from other forms of CP with substantial interobserver agreement. The 2 types of AIP can be distinguished by the proposed consensus histopathologic diagnostic criteria. C1 [Zhang, Lizhi; Smyrk, Thomas C.] Mayo Clin, Dept Lab & Anat Pathol, Rochester, MN 55905 USA. [Chari, Suresh] Mayo Clin, Div Gastroenterol, Rochester, MN 55905 USA. [Chari, Suresh] Mayo Clin, Div Hepatol, Rochester, MN 55905 USA. [Deshpande, Vikram; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kloeppel, Guenter] Univ Kiel, Dept Pathol, D-2300 Kiel, Germany. [Kojima, Motohiro] Natl Canc Ctr Hosp E, Div Clin Pathol, Chiba, Japan. [Liu, Xiuli] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 USA. [Longnecker, Daniel S.] Dartmouth Med Sch, Dept Pathol, Lebanon, NH USA. [Longnecker, Daniel S.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Notohara, Kenji] Kurashiki Cent Hosp, Dept Pathol, Kurashiki, Okayama, Japan. [Rodriguez-Justo, Manuel] UCL, Dept Pathol, London, England. [Srivastava, Amitabh] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zamboni, Giuseppe] Univ Verona, Dept Pathol, I-37100 Verona, Italy. [Zen, Yoh] Kings Coll Hosp London, Inst Liver Studies, London SE5 8RX, England. RP Zhang, LZ (reprint author), Mayo Clin, Dept Lab & Anat Pathol, 200 1st St SW, Rochester, MN 55905 USA. EM zhang.lizhi@mayo.edu; chari.suresh@mayo.edu; smyrk.thomas@mayo.edu RI Giuseppe, Zamboni/A-5991-2016; OI Giuseppe, Zamboni/0000-0001-7428-4673; Kloppel, Gunter/0000-0002-6688-086X; Rodriguez-Justo, Manuel/0000-0001-5007-1761 NR 29 TC 47 Z9 49 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1172 EP 1179 DI 10.1097/MPA.0b013e318233bec5 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000003 PM 21975436 ER PT J AU Mareninova, OA Yakubov, I Gukovsky, I Gukovskaya, AS AF Mareninova, O. A. Yakubov, I. Gukovsky, I. Gukovskaya, A. S. TI Lysosomal Dysfunction in Pancreatitis SO PANCREAS LA English DT Meeting Abstract C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Los Angeles, CA USA. So Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1337 EP 1337 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000155 ER PT J AU Michailidou, M Chiou, G Warshaw, A Fernandez-del Castillo, C Fagenholz, P AF Michailidou, M. Chiou, G. Warshaw, A. Fernandez-del Castillo, C. Fagenholz, P. TI Contemporary Retrospective Review of Open Pancreatic Debridements - How Are We Doing? SO PANCREAS LA English DT Meeting Abstract C1 [Michailidou, M.; Chiou, G.; Warshaw, A.; Fernandez-del Castillo, C.; Fagenholz, P.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1339 EP 1339 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000163 ER PT J AU Morales-Oyarvide, V Mino-Kenudson, M Thayer, SP Wargo, JA Ferrone, CR Lillemoe, KD Warshaw, AL Fernandez-del Castillo, C AF Morales-Oyarvide, V. Mino-Kenudson, M. Thayer, S. P. Wargo, J. A. Ferrone, C. R. Lillemoe, K. D. Warshaw, A. L. Fernandez-del Castillo, C. TI IPMNs Presenting with Acute Pancreatitis are Associated with an Intestinal Phenotype SO PANCREAS LA English DT Meeting Abstract C1 [Morales-Oyarvide, V.; Thayer, S. P.; Wargo, J. A.; Ferrone, C. R.; Lillemoe, K. D.; Warshaw, A. L.; Fernandez-del Castillo, C.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Mino-Kenudson, M.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1340 EP 1340 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000169 ER PT J AU Morales-Oyarvide, V Ingkakul, T Deshpande, V Forcione, DG Brugge, WR Fernandez-del Castillo, C Pitman, MB AF Morales-Oyarvide, V. Ingkakul, T. Deshpande, V. Forcione, D. G. Brugge, W. R. Fernandez-del Castillo, C. Pitman, M. B. TI Utility of EUS-FNAB in the Diagnosis of Cystic Pancreatic Endocrine Neoplasms SO PANCREAS LA English DT Meeting Abstract C1 [Morales-Oyarvide, V.; Ingkakul, T.; Fernandez-del Castillo, C.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Deshpande, V.; Pitman, M. B.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Forcione, D. G.; Brugge, W. R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastroenterol Unit, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1340 EP 1340 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000168 ER PT J AU Morales-Oyarvide, V Fernandez-del Castillo, C Valsangkar, NP Sahani, DV Pitman, MB Thayer, SP Mino-Kenudson, M AF Morales-Oyarvide, V. Fernandez-del Castillo, C. Valsangkar, N. P. Sahani, D. V. Pitman, M. B. Thayer, S. P. Mino-Kenudson, M. TI PDAC with Tumor-Related Retention Cysts, a Mimicker of Invasive IPMN, May Be Associated with Poor Prognosis SO PANCREAS LA English DT Meeting Abstract C1 [Morales-Oyarvide, V.; Fernandez-del Castillo, C.; Valsangkar, N. P.; Thayer, S. P.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Sahani, D. V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Pitman, M. B.; Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1341 EP 1341 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000170 ER PT J AU Spofford, I Conwell, D Wu, B Mortele, K Khorasani, R Yu, S Banks, P Thompson, C AF Spofford, I. Conwell, D. Wu, B. Mortele, K. Khorasani, R. Yu, S. Banks, P. Thompson, C. TI Endoscopic Versus Surgical Necrosectomy for Patients with Symptomatic Pancreatic Necrotic Collections: A Retrospective Cohort Study SO PANCREAS LA English DT Meeting Abstract C1 [Spofford, I.] Massachusetts Gen Hosp, Div Pediat Gastroenterol, Boston, MA 02114 USA. [Spofford, I.; Conwell, D.; Wu, B.; Yu, S.; Banks, P.; Thompson, C.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Mortele, K.; Khorasani, R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1355 EP 1355 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000229 ER PT J AU Valsangkar, NP Ingkakul, T Correa-Gallego, C Warshaw, AL Fernandez-del Castillo, C Liss, AS Thayer, SP AF Valsangkar, N. P. Ingkakul, T. Correa-Gallego, C. Warshaw, A. L. Fernandez-del Castillo, C. Liss, A. S. Thayer, S. P. TI The G12D Mutation of KRAS Predicts Early Recurrence and Poor Overall Survival in Ampullary Adenocarcinoma SO PANCREAS LA English DT Meeting Abstract C1 [Valsangkar, N. P.; Ingkakul, T.; Correa-Gallego, C.; Warshaw, A. L.; Fernandez-del Castillo, C.; Liss, A. S.; Thayer, S. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Warshaw Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1360 EP 1361 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000252 ER PT J AU Yamaguchi, J Mino-Kenudson, M Liss, AS Fernandez-del Castillo, C Warshaw, AL Thayer, SP AF Yamaguchi, J. Mino-Kenudson, M. Liss, A. S. Fernandez-del Castillo, C. Warshaw, A. L. Thayer, S. P. TI Pancreatic Duct Glands (PDG) Are the Origin of Gastric-Type IPMN SO PANCREAS LA English DT Meeting Abstract C1 [Yamaguchi, J.; Liss, A. S.; Fernandez-del Castillo, C.; Warshaw, A. L.; Thayer, S. P.] Massachusetts Gen Hosp, Warshaw Inst, Boston, MA 02114 USA. [Yamaguchi, J.; Liss, A. S.; Fernandez-del Castillo, C.; Warshaw, A. L.; Thayer, S. P.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mino-Kenudson, M.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1364 EP 1364 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000267 ER PT J AU Yamaguchi, J Mino-Kenudson, M Liss, AS Fernandez-del Castillo, C Warshaw, AL Thayer, SP AF Yamaguchi, J. Mino-Kenudson, M. Liss, A. S. Fernandez-del Castillo, C. Warshaw, A. L. Thayer, S. P. TI Pancreatic Duct Glands (PDG), a Progenitor Stem Cell Niche Responsible For Pancreatic Epithelial Renewal and Repair in Response To Inflammatory Injury SO PANCREAS LA English DT Meeting Abstract C1 [Yamaguchi, J.; Liss, A. S.; Fernandez-del Castillo, C.; Warshaw, A. L.; Thayer, S. P.] Massachusetts Gen Hosp, Warshaw Inst, Boston, MA 02114 USA. [Yamaguchi, J.; Liss, A. S.; Fernandez-del Castillo, C.; Warshaw, A. L.; Thayer, S. P.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mino-Kenudson, M.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2011 VL 40 IS 8 BP 1364 EP 1364 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 839VQ UT WOS:000296398000268 ER PT J AU Gordon, CR Susarla, SM Peacock, ZS Cetrulo, CL Zins, JE Papay, F Kaban, LB Yaremchuk, MJ AF Gordon, Chad R. Susarla, Srinivas M. Peacock, Zachary S. Cetrulo, Curtis L. Zins, James E. Papay, Frank Kaban, Leonard B. Yaremchuk, Michael J. TI Osteocutaneous Maxillofacial Allotransplantation: Lessons Learned from a Novel Cadaver Study Applying Orthognathic Principles and Practice SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID FACIAL ALLOGRAFT TRANSPLANTATION; TOTAL HUMAN FACE; MICROVASCULAR RECONSTRUCTION; CLASSIFICATION-SYSTEM; SKELETAL; DEFECTS; MIDFACE; APPEARANCE; PROGRESS; SURGERY AB Background: Osteocutaneous maxillofacial allotransplantation is an encouraging technique for reconstruction of complex midfacial injuries (i.e., Gordon type III composite tissue allotransplantation). Although clinical results have been promising, there are no published guidelines, to date, on how to establish a functional occlusion and class I skeletal relation between the donor maxilla and recipient mandible. The purpose of this study was to use orthognathic principles and practice to improve occlusal and facial skeletal outcomes in osteocutaneous maxillofacial allotransplantation. Methods: Three Le Fort III-based maxillofacial allotransplantations were performed, using six fresh cadavers. Each recipient was prepared bluntly simulating a massive, bilateral orbitozygomatic maxillofacial defect. The first transplant was completed according to published protocol. The second was planned using dental cast models, cephalometric analyses, model surgery, and occlusal splint fabrication. The third involved an edentulous scenario, with the donor alloflap fixated to the recipient's mandible using a mimic Gunning splint to establish the vertical dimension of occlusion. Results: All three operations resulted in facial aesthetics comparable to those seen with autologous methods. Operative times ranged from 3.5 to 5.3 hours. The first allotransplant resulted in a class II malocclusion (overjet, 5 mm). The second recipient, with a preexisting class II skeleton, displayed a small anterior open bite of -1.7 mm, 1 mm of overjet, and a class I skeletal relationship (A-point-nasion-B-point angle, 2.3 degrees) following transplantation. The final transplant, consisting of an edentulous alloflap to an edentulous recipient, demonstrated an orthognathic profile. Conclusion: Use of orthognathic principles and practice in osteocutaneous maxillofacial allotransplantation resulted in improved occlusion, skeletal projection, and facial harmony relative to standard technique. (Plast. Reconstr. Surg. 128: 465e, 2011.) C1 Johns Hopkins Univ, Sch Med, Dept Plast Surg, Johns Hopkins Hosp, Baltimore, MD 21287 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Cambridge, MA 02138 USA. Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Cambridge, MA 02138 USA. Cleveland Clin, Inst Dermatol & Plast Surg, Dept Plast Surg, Cleveland, OH USA. RP Gordon, CR (reprint author), Johns Hopkins Univ, Sch Med, Dept Plast & Reconstruct Surg, Johns Hopkins Hosp,JHOC, Suite 8161,601 N Caroline St, Baltimore, MD 21287 USA. EM cgordon@jhmi.edu OI Susarla, Srinivas/0000-0003-0155-8260 NR 46 TC 13 Z9 13 U1 0 U2 5 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 NOV PY 2011 VL 128 IS 5 BP 465E EP 479E DI 10.1097/PRS.0b013e31822b6949 PG 15 WC Surgery SC Surgery GA 842GQ UT WOS:000296583600010 PM 22030506 ER PT J AU Nyame, TT Lemon, KP Kolter, R Liao, EC AF Nyame, Theodore T. Lemon, Katherine P. Kolter, Roberto Liao, Eric C. TI High-Throughput Assay for Bacterial Adhesion on Acellular Dermal Matrices and Synthetic Surgical Materials SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID ABDOMINAL-WALL RECONSTRUCTION; INGUINAL-HERNIA REPAIR; STAPHYLOCOCCUS-AUREUS; BREAST RECONSTRUCTION; BIOFILM FORMATION; MESH REPAIR; INFECTION; ALLODERM; BIOMATERIALS; PATHOGENESIS AB Background: There has been increasing use of synthetic and acellular dermal matrix materials in surgery, ranging from breast reconstruction to hernia repairs. There is a paucity of data on how acellular dermal matrix compares with other surgical materials as a substrate for bacterial adhesion, the first step in formation biofilm, which occurs in prosthetic wound infections. The authors have designed a high-throughput assay to evaluate Staphylococcus aureus adherence on various synthetic and biologically derived materials. Methods: Clinical isolates of S. aureus (strains SC-1 and UAMS-1) were cultured with different materials, and bacterial adherence was measured using a resazurin cell vitality assay. Four materials that are commonly used in surgery were evaluated: Prolene mesh, Vicryl mesh, and two different acellular dermal matrix preparations (AlloDerm and FlexHD). The authors were able to develop a high-throughput and reliable assay for quantifying bacterial adhesion on synthetic and biologically derived materials. Results: The resazurin vitality assay can be reliably used to quantify bacterial adherence to acellular dermal matrix material and synthetic material. S. aureus strains SC-1 and UAMS-1 both adhered better to acellular dermal matrix materials (AlloDerm versus FlexHD) than to the synthetic material Prolene. S. aureus also adhered better to Vicryl than to Prolene. Strain UAMS-1 adhered better to Vicryl and acellular dermal matrix materials than did strain SC-1. Conclusions: The results show that S. aureus adheres more readily to acellular dermal matrix material than to synthetic material. The resazurin assay provides a standard method for evaluating surgical materials with regard to bacterial adherence and potential propensity for biofilm development. (Plast. Reconstr. Surg. 128: 1061, 2011.) C1 [Liao, Eric C.] Harvard Univ, Ctr Regenerat Med, Div Plast & Reconstruct Surg, Massachusetts Gen Hosp,Sch Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Ctr Regenerat Med, Div Infect Dis,Harvard Stem Cell Inst,Childrens H, Cambridge, MA 02138 USA. Harvard Univ, Dept Microbiol & Mol Genet, Cambridge, MA 02138 USA. RP Liao, EC (reprint author), Harvard Univ, Ctr Regenerat Med, Div Plast & Reconstruct Surg, Massachusetts Gen Hosp,Sch Med, WACC 435,15 Parkman St, Boston, MA 02114 USA. EM cliao@partners.org FU Mentored Clinical Scientist Development Award [K08 AI070561]; American Surgical Association; March of Dimes Basil O'Connor Starter Scholar Research Award; Shriners Hospitals for Children; [GM58213] FX This work was generously supported by the Plastic Surgery Foundation. This work was also supported in part by Mentored Clinical Scientist Development Award K08 AI070561 (to K.P.L.) and by grant GM58213 (to R.K.). Strains of S. aureus were graciously donated by Dr. Mark S. Smeltzer and his laboratory. Eric C. Liao, M.D., Ph.D., received funding support from the American Surgical Association Research Fellowship, the March of Dimes Basil O'Connor Starter Scholar Research Award, and the Shriners Hospitals for Children. NR 46 TC 13 Z9 13 U1 0 U2 6 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 NOV PY 2011 VL 128 IS 5 BP 1061 EP 1068 DI 10.1097/PRS.0b013e31822b65af PG 8 WC Surgery SC Surgery GA 842GQ UT WOS:000296583600045 PM 22030489 ER PT J AU Carpenter, LL Tyrka, AR Lee, JK Tracy, AP Wilkinson, CW Price, LH AF Carpenter, Linda L. Tyrka, Audrey R. Lee, Janet K. Tracy, Aaron P. Wilkinson, Charles W. Price, Lawrence H. TI A placebo-controlled study of sertraline's effect on cortisol response to the dexamethasone/corticotropin-releasing hormone test in healthy adults SO PSYCHOPHARMACOLOGY LA English DT Article DE Sertraline; Dex/CRH test; Cortisol; HPA axis ID PITUITARY-ADRENAL-SYSTEM; MAJOR DEPRESSIVE EPISODE; HPA-AXIS REACTIVITY; CHILDHOOD TRAUMA; DEX/CRH TEST; ANTIDEPRESSANT TREATMENT; LITHIUM AUGMENTATION; UNIPOLAR DEPRESSION; AFFECTIVE-DISORDERS; ACTH RESPONSES AB Rationale The dexamethasone/corticotropin-releasing hormone (Dex/CRH) test is a neuroendocrine probe involving serial blood sampling of cortisol during a standardized pharmacological challenge without inducing psychological distress in humans. Some past studies in depressed patients have shown a "normalization" or decrease in cortisol response to the Dex/CRH test following successful treatment with an antidepressant. Studies in nondepressed healthy adult samples have also shown aberrant cortisol reactivity to be associated with depression risk factors. These findings prompted research into the use of the Dex/CRH test as a tool for developing antidepressant drugs. Objectives In this study, the Dex/CRH test was evaluated with regard to its potential utility for drug development in nonclinical samples. Methods The Dex/CRH test was administered before and after 6 weeks of blinded treatment with either sertraline 100 mg/day or matching placebo in 22 healthy adults ( 13 women, nine men). Results Cortisol response to the Dex/CRH test increased following treatment with standard doses of sertraline, compared to placebo, after controlling for age and sex. Conclusions The observed pattern of change contrasts with results from published studies in depressed patients and with our initial hypothesis. C1 [Carpenter, Linda L.; Tyrka, Audrey R.; Lee, Janet K.; Tracy, Aaron P.; Price, Lawrence H.] Butler Hosp, Mood Disorders Res Program, Providence, RI 02906 USA. [Carpenter, Linda L.; Tyrka, Audrey R.; Lee, Janet K.; Tracy, Aaron P.; Price, Lawrence H.] Butler Hosp, Lab Clin Neurosci, Brown Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Wilkinson, Charles W.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Wilkinson, Charles W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA. RP Carpenter, LL (reprint author), Butler Hosp, Mood Disorders Res Program, 345 Blackstone Blvd, Providence, RI 02906 USA. EM Linda_Carpenter_MD@brown.edu RI Tyrka, Audrey/L-2504-2014 FU Pfizer Inc.; Department of Veterans Affairs FX The authors thank Kelly Colombo, B. A. for her assistance with data management, Ashley Clement for her research assistant support in manuscript preparation, and Daniel Gonzalez for performance of the cortisol assays. This work was supported by an investigator-initiated grant from Pfizer Inc. (LLC) and by the Department of Veterans Affairs (CWW). NR 63 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2011 VL 218 IS 2 BP 371 EP 379 DI 10.1007/s00213-011-2336-y PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 844EL UT WOS:000296730400007 PM 21617914 ER PT J AU Geller, AC Brooks, DR Woodring, B Oppenheimer, S McCabe, M Rogers, J Timm, A Resnick, EA Winickoff, JP AF Geller, Alan C. Brooks, Daniel R. Woodring, Barbara Oppenheimer, Sarah McCabe, Margaret Rogers, Jayne Timm, Alison Resnick, Elissa A. Winickoff, Jonathan P. TI Smoking Cessation Counseling for Parents During Child Hospitalization: A National Survey of Pediatric Nurses SO PUBLIC HEALTH NURSING LA English DT Article DE nursing education; patient education; smoking ID RESPIRATORY ILLNESS; PREVENTIVE CARE; QUIT SMOKING; TOBACCO; INTERVENTION; ATTITUDES AB Objectives: Given the central role played by pediatric nurses in intake assessment, discharge planning, and education for families of hospitalized pediatric patients, a child's hospitalization may provide a unique opportunity for counseling parents about smoking. We sought to determine if hospital policies can support nurses in effectively counseling parents about smoking. Design and Sample: We conducted a national survey of pediatric staff nurses and administrators/educators who were members of the Society of Pediatric Nurses in 2008 (n = 5888) to explore counseling practices for tobacco control. Measures: Questionnaires included data on demographics, personal and work environment characteristics, hospital policy characteristics, work attitudes and barriers and the main outcome-5As for smoking cessation counseling-Ask, Advise, Assess, Assist, and Arrange. Results: Overall, routine screening for household smokers was most common (43%), followed by advice to quit (25%), assessing willingness to quit (19%), assisting with a quit plan (6%), and arranging follow-up contact (3%). Nurses working in hospitals with admission assessments specifically asking about household members who smoke were 7 times more likely than those without such assessments to routinely ask about smoking (OR: 7.2, 95% CI: 4.9-10.5). Conclusion: Future research should test the efficacy of developing comprehensive hospital-wide policies to deliver smoking cessation for parents during a child's hospitalization. C1 [Geller, Alan C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Brooks, Daniel R.; Timm, Alison] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Woodring, Barbara] Georgia State Univ, Dept Nursing, Atlanta, GA 30303 USA. [Oppenheimer, Sarah] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [McCabe, Margaret; Rogers, Jayne] Childrens Hosp, Boston, MA 02115 USA. [Resnick, Elissa A.] Univ Chicago, Inst Hlth Res & Policy, Chicago, IL 60637 USA. [Winickoff, Jonathan P.] MGH Ctr Child & Adolescent Hlth Policy, Boston, MA USA. [Winickoff, Jonathan P.] Amer Acad Pediat Julius, B Richmond Ctr, Tobacco Consortium, Elk Grove Village, IL USA. RP Geller, AC (reprint author), Kresge Bldg,677 Huntington Ave, Boston, MA 02215 USA. EM ageller@hsph.harvard.edu OI Brooks, Daniel/0000-0001-6220-6889 NR 23 TC 8 Z9 8 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0737-1209 J9 PUBLIC HEALTH NURS JI Public Health Nurs. PD NOV-DEC PY 2011 VL 28 IS 6 BP 475 EP 484 DI 10.1111/j.1525-1446.2011.00954.x PG 10 WC Public, Environmental & Occupational Health; Nursing SC Public, Environmental & Occupational Health; Nursing GA 839DN UT WOS:000296345300002 PM 22092457 ER PT J AU Venkatesan, AM Wood, BJ Gervais, DA AF Venkatesan, Aradhana M. Wood, Bradford J. Gervais, Debra A. TI Percutaneous Ablation in the Kidney SO RADIOLOGY LA English DT Editorial Material ID RENAL-CELL CARCINOMA; RADIO-FREQUENCY ABLATION; GUIDED RADIOFREQUENCY ABLATION; INTENSITY FOCUSED ULTRASOUND; TERM-FOLLOW-UP; THERMAL ABLATION; TUMOR ABLATION; LAPAROSCOPIC CRYOABLATION; HEPATOCELLULAR-CARCINOMA; HEPATIC CRYOSURGERY C1 [Venkatesan, Aradhana M.; Wood, Bradford J.] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Gervais, Debra A.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal & Intervent Radiol, Boston, MA 02114 USA. RP Venkatesan, AM (reprint author), NIH, Ctr Clin, Dept Radiol & Imaging Sci, 10 Ctr Dr,Bldg 10,Room 1C369,MSC 1182, Bethesda, MD 20892 USA. EM VenkatesanA@cc.nih.gov NR 112 TC 32 Z9 33 U1 0 U2 4 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2011 VL 261 IS 2 BP 375 EP 391 DI 10.1148/radiol.11091207 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 841PL UT WOS:000296524600007 PM 22012904 ER PT J AU Vanness, DJ Knudsen, AB Lansdorp-Vogelaar, I Rutter, CM Gareen, IF Herman, BA Kuntz, KM Zauber, AG van Ballegooijen, M Feuer, EJ Chen, MH Johnson, CD AF Vanness, David J. Knudsen, Amy B. Lansdorp-Vogelaar, Iris Rutter, Carolyn M. Gareen, Ilana F. Herman, Benjamin A. Kuntz, Karen M. Zauber, Ann G. van Ballegooijen, Marjolein Feuer, Eric J. Chen, Mei-Hsiu Johnson, C. Daniel TI Comparative Economic Evaluation of Data from the ACRIN National CT Colonography Trial with Three Cancer Intervention and Surveillance Modeling Network Microsimulations SO RADIOLOGY LA English DT Article ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; SERVICES TASK-FORCE; FECAL-OCCULT-BLOOD; COST-EFFECTIVENESS ANALYSIS; COLORECTAL-CANCER; VIRTUAL COLONOSCOPY; LARGE-INTESTINE; LARGE-BOWEL; CONVENTIONAL COLONOSCOPY; EXTRACOLONIC FINDINGS AB Purpose: To estimate the cost-effectiveness of computed tomographic (CT) colonography for colorectal cancer (CRC) screening in average-risk asymptomatic subjects in the United States aged 50 years. Materials and Methods: Enrollees in the American College of Radiology Imaging Network National CT Colonography Trial provided informed consent, and approval was obtained from the institutional review board at each site. CT colonography performance estimates from the trial were incorporated into three Cancer Intervention and Surveillance Modeling Network CRC microsimulations. Simulated survival and lifetime costs for screening 50-year-old subjects in the United States with CT colonography every 5 or 10 years were compared with those for guideline-concordant screening with colonoscopy, flexible sigmoidoscopy plus either sensitive unrehydrated fecal occult blood testing (FOBT) or fecal immunochemical testing (FIT), and no screening. Perfect and reduced screening adherence scenarios were considered. Incremental cost-effectiveness and net health benefits were estimated from the U. S. health care sector perspective, assuming a 3% discount rate. Results: CT colonography at 5- and 10-year screening intervals was more costly and less effective than FOBT plus flexible sigmoidoscopy in all three models in both 100% and 50% adherence scenarios. Colonoscopy also was more costly and less effective than FOBT plus flexible sigmoidoscopy, except in the CRC-SPIN model assuming 100% adherence (incremental cost-effectiveness ratio: $26300 per life-year gained). CT colonography at 5- and 10-year screening intervals and colonoscopy were net beneficial compared with no screening in all model scenarios. The 5-year screening interval was net beneficial over the 10-year interval except in the MISCAN model when assuming 100% adherence and willingness to pay $50000 per life-year gained. Conclusion: All three models predict CT colonography to be more costly and less effective than non-CT colonographic screening but net beneficial compared with no screening given model assumptions. (C) RSNA, 2011 C1 [Vanness, David J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53726 USA. [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Lansdorp-Vogelaar, Iris; van Ballegooijen, Marjolein] Erasmus MC Univ Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands. [Rutter, Carolyn M.] Grp Hlth Seattle, Ctr Hlth Studies, Seattle, WA USA. [Gareen, Ilana F.; Herman, Benjamin A.; Chen, Mei-Hsiu] Brown Univ, Ctr Stat Sci, Providence, RI 02912 USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Johnson, C. Daniel] Mayo Clin, Dept Radiol, Scottsdale, AZ USA. RP Vanness, DJ (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, 610 Walnut St, Madison, WI 53726 USA. EM dvanness@wisc.edu RI Gareen, Ilana/I-2816-2014; OI Gareen, Ilana/0000-0002-0457-5595; Herman, Benjamin/0000-0001-6649-0354 FU United BioSource FX D.J.V. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received money for a consultancy from United BioSource; was employed by United BioSource. Other relationships: none to disclose. A. B. K. No potential conflicts of interest to disclose. I. L. V. No potential conflicts of interest to disclose. C. M. R. No potential conflicts of interest to disclose. I. F. G. No potential conflicts of interest to disclose. B. A. H. No potential conflicts of interest to disclose. K. M. K. No potential conflicts of interest to disclose. A.G.Z. No potential conflicts of interest to disclose. M. v. B. No potential conflicts of interest to disclose. E.J.F. No potential conflicts of interest to disclose. M. H. C. No potential conflicts of interest to disclose. C.D.J. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution received money for a software license/patent; receives royalties from GE Medical Systems; institution receives royalties from GE Medical Systems. Other relationships: none to disclose. NR 73 TC 11 Z9 11 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2011 VL 261 IS 2 BP 487 EP 498 DI 10.1148/radiol.11102411 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 841PL UT WOS:000296524600018 PM 21813740 ER PT J AU Pan, JD Pialat, JB Joseph, T Kuo, D Joseph, GB Nevitt, MC Link, TM AF Pan, Judong Pialat, Jean-Baptiste Joseph, Tom Kuo, Daniel Joseph, Gabby B. Nevitt, Michael C. Link, Thomas M. TI Knee Cartilage T2 Characteristics and Evolution in Relation to Morphologic Abnormalities Detected at 3-T MR Imaging: A Longitudinal Study of the Normal Control Cohort from the Osteoarthritis Initiative SO RADIOLOGY LA English DT Article ID HUMAN ARTICULAR-CARTILAGE; PHYSICAL-ACTIVITY; RELAXATION-TIMES; VALIDATION; JOINT; PREVALENCE; PRECISION; ARTHRITIS; DISEASE; VALUES AB Purpose: To determine the frequency of degenerative knee morphologic abnormalities in asymptomatic individuals by using 3-T magnetic resonance (MR) imaging and to investigate the characteristics and evolution of cartilage T2 values in relation to morphologic abnormalities with a longitudinal study. Materials and Methods: The study was approved by the institutional review board and was compliant with HIPAA. Ninety-five asymptomatic subjects aged 45-78 years who were free of risk factors for osteoarthritis (OA) were selected from the Osteoarthritis Initiative normal control cohort and examined with radiography and 3-T MR imaging. Data obtained at both baseline and 2-year follow-up were analyzed. OA-related knee abnormalities were analyzed by using the whole-organ MR imaging score (WORMS). Cartilage T2 maps were generated by using sagittal two-dimensional multi-echo spin-echo images of the right knee. Statistical significance was determined with the Student t test, the paired t test, a mixed random effects model, one-way analysis of variance, and a multiple linear regression model. Results: Knee abnormalities were identified with a high frequency (90% at baseline and 92 % at 2-year follow-up). The prevalence of hyaline cartilage lesions was particularly high (86% at baseline and 84% at follow-up). A significant longitudinal increase in T2 was detected in the tibiofemoral cartilage but not the patellofemoral cartilage (P = .0072). The longitudinal change in T2 was significantly associated with worsening of the cartilage WORMS (P = .038). Conclusion: Asymptomatic subjects have a high frequency of OA-related morphologic abnormalities. A significant increase in tibiofemoral cartilage T2 was detected over the 2-year period. A greater increase in T2 was associated with increased progression of cartilage morphologic abnormalities. (C) RSNA, 2011 C1 [Joseph, Tom] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Pan, Judong; Pialat, Jean-Baptiste; Kuo, Daniel; Joseph, Gabby B.; Link, Thomas M.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Nevitt, Michael C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Pialat, Jean-Baptiste] INSERM, U831, F-69008 Lyon, France. [Pialat, Jean-Baptiste] Univ Lyon, Lyon, France. RP Pan, JD (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,YAW 6E, Boston, MA 02114 USA. EM jpan4@partners.org OI Kuo, Daniel/0000-0002-3505-0169 FU Merck Research Laboratories; Novartis Pharmaceuticals; GlaxoSmithKline; Pfizer; Foundation for the National Institutes of Health; National Institutes of Health, a branch of the Department of Health and Human Services [N01-AR-2-2258, N01-AR-2-2259, N01-AR-2-2260, N01-AR-2-2261, N01-AR-2-2262] FX Supported in part by Merck Research Laboratories, Novartis Pharmaceuticals, GlaxoSmithKline, and Pfizer. Private-sector Osteoarthritis Initiative funding is managed by the Foundation for the National Institutes of Health.; The OAI is a public-private partnership comprised of five contracts (N01-AR-2-2258, N01-AR-2-2259, N01-AR-2-2260, N01-AR-2-2261, N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Pfizer, Novartis Pharmaceuticals, Merck Research Laboratories, and GlaxoSmithKline. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript has received the approval of the OAI Publications Committee based on a review of its scientific content and data interpretation. NR 35 TC 33 Z9 34 U1 0 U2 7 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2011 VL 261 IS 2 BP 507 EP 515 DI 10.1148/radiol.11102234 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 841PL UT WOS:000296524600020 PM 21900614 ER PT J AU Chen, L Miller, JW Vavvas, D Kim, IK AF Chen, Ling Miller, Joan W. Vavvas, Demetrios Kim, Ivana K. TI ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR MONOTHERAPY VERSUS COMBINATION TREATMENT WITH PHOTODYNAMIC THERAPY FOR SUBFOVEAL CHOROIDAL NEOVASCULARIZATION SECONDARY TO CAUSES OTHER THAN AGE-RELATED MACULAR DEGENERATION SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE choroidal neovascularization; anti-VEGF; photodynamic therapy; non-AMD ID RANDOMIZED CLINICAL-TRIAL; INTRAVITREAL BEVACIZUMAB; ANGIOID STREAKS; PATHOLOGICAL MYOPIA; MULTIFOCAL CHOROIDITIS; VERTEPORFIN AB Purpose: To compare the visual outcomes and retreatment rates of monotherapy with intravitreal bevacizumab versus combination with photodynamic therapy for choroidal neovascularization secondary to causes other than age-related macular degeneration. Methods: Seventeen patients received intravitreal bevacizumab, and 6 patients underwent intravitreal bevacizumab combined with verteporfin photodynamic therapy within 3 days. Additional bevacizumab was administrated if there was persistent fluorescein leakage or subretinal fluid on optical coherence tomography. Results: The mean change in visual acuity was vision gain of 1.7 lines in the monotherapy group compared with 2.8 lines in the combination therapy group at 12-month follow-up (P = 0.45). At 12 months, 93% in the monotherapy group and 100% in the combination group lost <2 lines of vision (P = 1.0); 36% gained >3 lines of vision in the monotherapy compared with 60% in the combination therapy group (P = 0.60). The monotherapy group received a mean of 4.8 reinjections, while the combination group received 2.6 reinjections over 12 months (P = 0.11). Subgroup analysis of cases of choroidal neovascularization caused by pathologic myopia demonstrated a mean change in visual acuity of vision gain of +2.0 lines in the monotherapy group versus +2.3 lines in the combination therapy group (P = 0.82) and a mean of 7.2 reinjections versus 2 in monotherapy and combination group, respectively (P = 0.0498) at 12 months. Conclusion: The majority of patients had stabilization or improvement in vision in both treatment groups. Combination therapy with bevacizumab plus photodynamic therapy showed lower retreatment rates in patients with myopia. Randomized clinical trials are necessary to confirm these findings. RETINA 31:2078-2083, 2011 C1 [Chen, Ling; Miller, Joan W.; Vavvas, Demetrios; Kim, Ivana K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, Boston, MA 02114 USA. [Chen, Ling] Fudan Univ, Shanghai Med Sch, Dept Ophthalmol & Vis Sci, Eye & ENT Hosp, Shanghai 200433, Peoples R China. RP Kim, IK (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM ivana_kim@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 FU Research to Prevent Blindness; Pujiang Talent Fund [10PJ1401900] FX Supported in part by Research to Prevent Blindness Physician-Scientist Award (I.K. Kim) and Pujiang Talent Fund (10PJ1401900, L. Chen). NR 27 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD NOV PY 2011 VL 31 IS 10 BP 2078 EP 2083 DI 10.1097/IAE.0b013e3182109074 PG 6 WC Ophthalmology SC Ophthalmology GA 842AS UT WOS:000296558500017 PM 21691258 ER PT J AU Aiello, LP Vignati, L Sheetz, MJ Zhi, X Girach, A Davis, MD Wolka, AM Shahri, N Milton, RC AF Aiello, Lloyd Paul Vignati, Louis Sheetz, Matthew J. Zhi, Xin Girach, Aniz Davis, Matthew D. Wolka, Anne M. Shahri, Nazila Milton, Roy C. CA PKC-DRS Study Grp PKC-DRS2 Study Grp TI ORAL PROTEIN KINASE C beta INHIBITION USING RUBOXISTAURIN Efficacy, Safety, and Causes of Vision Loss Among 813 Patients (1,392 Eyes) with Diabetic Retinopathy in the Protein Kinase C beta Inhibitor-Diabetic Retinopathy Study and the Protein kinase C beta Inhibitor-Diabetic Retinopathy Study 2 SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE clinical trial; diabetes; diabetic retinopathy; PKC-DRS; PKC-DRS2; protein kinase C beta; ruboxistaurin; vision loss ID PKC-BETA; CLINICAL-TRIAL; MACULAR EDEMA; GROWTH-FACTOR; VISUAL-LOSS; COMPLICATIONS; LY333531; RATS AB Purpose: To evaluate efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with moderately severe to very severe nonproliferative diabetic retinopathy from the Protein Kinase C beta Inhibitor-Diabetic Retinopathy Study and Protein Kinase C beta Inhibitor-Diabetic Retinopathy Study 2 ruboxistaurin (RBX) protein kinase C beta inhibitor trials. Methods: Patients in these 3-year, randomized, placebo-controlled, double-masked, Phase 3 trials had best-corrected Early Treatment Diabetic Retinopathy Study visual acuity >= 45 letters (similar to 20/125 Snellen), Early Treatment Diabetic Retinopathy Study retinopathy level 47A/B-53E, and no previous panretinal photocoagulation in >= 1 eye. Patients received placebo (N = 401) or RBX 32 mg/day (N = 412). Data from the 2 studies were combined and masked evaluation of retinal photographs was performed for cause of visual decline in all patients experiencing sustained moderate visual loss (>= 15-letter loss sustained for the last 6 months of study). Results: In the studies combined, sustained moderate visual loss occurred in 10.2% of placebo-treated patients versus 6.1% of RBX-treated patients (P = 0.011). A >= 15-letter gain occurred in 2.4% of placebo versus 4.7% of RBX eyes (P = 0.021) and a >= 15-letter loss occurred in 11.4% versus 7.4%, respectively (P = 0.012). Diabetic macular edema was the probable primary cause of vision loss. Among eyes without focal/grid photocoagulation at baseline, fewer RBX group eyes (26.7%) required initial focal/grid photocoagulation versus placebo (35.6%; P = 0.008). No safety concerns were identified. Conclusion: Analysis of data combined from two similar studies adds further statistical significance to RBX's beneficial effects on visual loss, need for focal laser, and vision gain, most likely through effects on macular edema. RETINA 31:2084-2094, 2011 C1 [Aiello, Lloyd Paul] Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst,Dept Ophthalmol, Boston, MA 02215 USA. [Vignati, Louis; Sheetz, Matthew J.; Zhi, Xin; Wolka, Anne M.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Girach, Aniz] Eli Lilly & Co, Windlesham, Surrey, England. [Davis, Matthew D.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Shahri, Nazila] i3 Corp, San Diego, CA USA. [Milton, Roy C.] EMMES Corp, Rockville, MD USA. RP Aiello, LP (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst,Dept Ophthalmol, 1 Joslin Pl, Boston, MA 02215 USA. EM lpaiello@joslin.harvard.edu FU Eli Lilly and Company (Indianapolis, IN) FX Supported by Eli Lilly and Company (Indianapolis, IN). Drs. L. P. Aiello, M. D. Davis, and R. C. Milton are consultants for Eli Lilly and Company. Drs. M. J. Sheetz, X. Zhi, A. Girach, and A. M. Wolka are or were full-time employees and shareholders of Eli Lilly and Company. NR 20 TC 41 Z9 45 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD NOV PY 2011 VL 31 IS 10 BP 2084 EP 2094 DI 10.1097/IAE.0b013e3182111669 PG 11 WC Ophthalmology SC Ophthalmology GA 842AS UT WOS:000296558500018 PM 21862954 ER PT J AU Krueger, PM Saint Onge, JM Chang, VW AF Krueger, Patrick M. Saint Onge, Jarron M. Chang, Virginia W. TI Race/ethnic differences in adult mortality: The role of perceived stress and health behaviors SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Race; Ethnicity; Mortality; Health behaviors; Stress; USA ID UNITED-STATES; SOCIOECONOMIC-STATUS; RACIAL DISPARITIES; ALCOHOL-CONSUMPTION; CIGARETTE-SMOKING; PHYSICAL-ACTIVITY; SLEEP DURATION; BLACK; WHITE; RISK AB We examine the role of perceived stress and health behaviors (i.e., cigarette smoking, alcohol consumption, physical inactivity, sleep duration) in shaping differential mortality among whites, blacks, and Hispanics. We use data from the 1990 National Health Interview Survey (N = 38,891), a nationally representative sample of United States adults, to model prospective mortality through 2006. Our first aim examines whether unhealthy behaviors and perceived stress mediate race/ethnic disparities in mortality. The black disadvantage in mortality, relative to whites, closes after adjusting for socioeconomic status (SES), but re-emerges after adjusting for the lower smoking levels among blacks. After adjusting for SES. Hispanics have slightly lower mortality than whites; that advantage increases after adjusting for the greater physical inactivity among Hispanics, but closes after adjusting for their lower smoking levels. Perceived stress, sleep duration, and alcohol consumption do not mediate race/ethnic disparities in mortality. Our second aim tests competing hypotheses about race/ethnic differences in the relationships among unhealthy behaviors, perceived stress, and mortality. The social vulnerability hypothesis predicts that unhealthy behaviors and high stress levels will be more harmful for race/ethnic minorities. In contrast, the Blaxter (1990) hypothesis predicts that unhealthy lifestyles will be less harmful for disadvantaged groups. Consistent with the social vulnerability perspective, smoking is more harmful for blacks than for whites. But consistent with the Blaxter hypothesis, compared to whites, current smoking has a weaker relationship with mortality for Hispanics, and low or high levels of alcohol consumption, high levels of physical inactivity, and short or long sleep hours have weaker relationships with mortality for blacks. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Krueger, Patrick M.] Univ Colorado Denver, Denver, CO USA. [Krueger, Patrick M.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Saint Onge, Jarron M.] Univ Houston, Dept Sociol, Houston, TX USA. [Chang, Virginia W.] Philadelphia VAMC, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Chang, Virginia W.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Chang, Virginia W.] Univ Penn, Dept Sociol, Philadelphia, PA 19104 USA. RP Krueger, PM (reprint author), Univ Colorado Denver, Denver, CO USA. EM Patrick.Krueger@ucdenver.edu OI Saint Onge, Jarron/0000-0002-0914-4882 FU University of Colorado [NICHD R21 HD51146]; University of Houston [NIDA R24 DA019798]; National Institutes of Health [NICHD K12-HD043459] FX This paper has benefited from presentation at the 2008 meetings of the American Sociological Association in Boston, MA. We acknowledge administrative support from the University of Colorado Population Program (NICHD R21 HD51146), the University of Houston (NIDA R24 DA019798), and the Leonard Davis Institute of Health Economics at the University of Pennsylvania, and research support from the National Institutes of Health (NICHD K12-HD043459). NR 52 TC 18 Z9 18 U1 2 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2011 VL 73 IS 9 BP 1312 EP 1322 DI 10.1016/j.socscimed.2011.08.007 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 843OF UT WOS:000296680800005 PM 21920655 ER PT J AU Liu, L Cohen, S Schulz, MS Waldinger, RJ AF Liu, Liang Cohen, Shiri Schulz, Marc S. Waldinger, Robert J. TI Sources of somatization: Exploring the roles of insecurity in relationships and styles of anger experience and expression SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE USA; Gender; Attachment; Somatization; Anger proneness; Anger expression; Emotion regulation ID HEALTH-CARE-UTILIZATION; ADULT ATTACHMENT; TRANSIENT HYPOCHONDRIASIS; SOMATIC SYMPTOMS; PARTNER VIOLENCE; MODEL; SELF; PERSONALITY; DEPRESSION; COMPLAINTS AB Research in the U.S. has shown strong connections between insecure attachment in close relationships and somatization. In addition, studies have demonstrated connections between somatic symptoms and anger experience and expression. In this study, we integrate perspectives from these two literatures by testing the hypothesis that proneness to anger and suppression of anger mediate the link between insecurity in relationships and somatization. Between 2000 and 2003, a community-based sample of 101 couples in a large U.S. city completed self-report measures, including the Somatic Symptom Inventory, the Relationship Scales Questionnaire, the Multidimensional Anger Inventory, the Revised Conflict Tactics Scale, and the Beck Depression Inventory. Controlling for age, income, and recent intimate partner violence, analyses showed that the link between insecure attachment and somatization was partially mediated by anger proneness for men and by anger suppression for women. Findings are consistent with the hypothesis that men who are insecurely attached are more prone to experience anger that in turn fosters somatization. For women, findings suggest that insecure attachment may influence adult levels of somatization by fostering suppression of anger expression. Specific clinical interventions that help patients manage and express angry feelings more adaptively may reduce insecurely attached individuals' vulnerability to medically unexplained somatic symptoms. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Waldinger, Robert J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Liu, Liang] Tongji Univ, Sch Med, Shanghai 200092, Peoples R China. [Liu, Liang] Tongji Univ, Shanghai E Hosp, Dept Psychosomat Med, Shanghai 200092, Peoples R China. [Cohen, Shiri; Waldinger, Robert J.] Harvard Univ, Sch Med, Boston, MA USA. [Schulz, Marc S.] Bryn Mawr Coll, 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 of Mental Health [K08 MH01555]; National Institute on Aging [R01 AG034554] FX Supported by grants from the National Institute of Mental Health (K08 MH01555, Waldinger, PI) and the National Institute on Aging (R01 AG034554, Waldinger, PI). The funding sources had no involvement in the design, data collection or analysis of the research, nor were the sponsors involved in the preparation and submission of the manuscript. NR 49 TC 12 Z9 13 U1 4 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2011 VL 73 IS 9 BP 1436 EP 1443 DI 10.1016/j.socscimed.2011.07.034 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 843OF UT WOS:000296680800021 PM 21907475 ER PT J AU Fidalgo, M Shekar, PC Ang, YS Fujiwara, Y Orkin, SH Wang, JL AF Fidalgo, Miguel Shekar, P. Chandra Ang, Yen-Sin Fujiwara, Yuko Orkin, Stuart H. Wang, Jianlong TI Zfp281 Functions as a Transcriptional Repressor for Pluripotency of Mouse Embryonic Stem Cells SO STEM CELLS LA English DT Article DE Zfp281; Nanog; Embryonic stem cells; Transcriptional repressor; Self-renewal; Pluripotency ID PROTEIN-INTERACTION NETWORK; SELF-RENEWAL; SIGNALING NETWORKS; RNA INTERFERENCE; ES CELLS; NANOG; OCT4; MYC; DIFFERENTIATION; IDENTIFICATION AB Embryonic stem cells (ESCs) derived from preimplantation blastocysts have unique self-renewal and multilineage differentiation properties that are controlled by key components of a core regulatory network including Oct4, Sox2, and Nanog. Understanding molecular underpinnings of these properties requires identification and characterization of additional factors that act in conjunction with these key factors in ESCs. We have previously identified Zfp281, a Kruppel-like zinc finger transcription factor, as an interaction partner of Nanog. We now present detailed functional analyses of Zfp281 using a genetically ablated null allele in mouse ESCs. Our data show that while Zfp281 is dispensable for establishment and maintenance of ESCs, it is required for their proper differentiation in vitro. We performed microarray profiling in combination with previously published datasets of Zfp281 global target gene occupancy and found that Zfp281 mainly functions as a repressor to restrict expression of many stem cell pluripotency genes. In particular, we demonstrated that deletion of Zfp281 resulted in upregulation of Nanog at both the transcript and protein levels with concomitant compromised differentiation of ESCs during embryoid body culture. Chromatin immunoprecipitation experiments demonstrated that Zfp281 is required for Nanog binding to its own promoter, suggesting that Nanog-associated repressive complex(es) involving Zfp281 may fine-tune Nanog expression for pluripotency of ESCs. STEM CELLS 2011;29:1705-1716 C1 [Fidalgo, Miguel; Shekar, P. Chandra; Ang, Yen-Sin; Wang, Jianlong] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, Black Family Stem Cell Inst, New York, NY 10029 USA. [Fujiwara, Yuko; Orkin, Stuart H.] Childrens Hosp, Boston, MA 02115 USA. [Fujiwara, Yuko; Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Fujiwara, Yuko; Orkin, Stuart H.] Harvard Stem Cell Inst, Cambridge, MA USA. [Fujiwara, Yuko; Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Wang, JL (reprint author), Mt Sinai Sch Med, Dept Dev & Regenerat Biol, Black Family Stem Cell Inst, Atran Bldg,AB7-10D,1428 Madison Ave, New York, NY 10029 USA. EM jianlong.wang@mssm.edu OI Fidalgo, Miguel/0000-0003-1134-2674 FU Black Family Stem Cell Institute at Mount Sinai School of Medicine; New York State Department of Health [N09G315]; NIH [1R01-GM095942-01A1] FX We thank Francesco Faiola and Arven Saunders of the Wang laboratory for critically reading the manuscript. Research in the Wang laboratory is supported by the seed fund from Black Family Stem Cell Institute at Mount Sinai School of Medicine, a New York State Stem Cell Science (NYSTEM) grant through New York State Department of Health (N09G315), and a grant from the NIH (1R01-GM095942-01A1). NR 38 TC 18 Z9 20 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD NOV PY 2011 VL 29 IS 11 BP 1705 EP 1716 DI 10.1002/stem.736 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 842CN UT WOS:000296565500008 PM 21915945 ER PT J AU Sebastiano, V Maeder, ML Angstman, JF Haddad, B Khayter, C Yeo, DT Goodwin, MJ Hawkins, JS Ramirez, CL Batista, LFZ Artandi, SE Wernig, M Joung, JK AF Sebastiano, Vittorio Maeder, Morgan L. Angstman, James F. Haddad, Bahareh Khayter, Cyd Yeo, Dana T. Goodwin, Mathew J. Hawkins, John S. Ramirez, Cherie L. Batista, Luis F. Z. Artandi, Steven E. Wernig, Marius Joung, J. Keith TI In Situ Genetic Correction of the Sickle Cell Anemia Mutation in Human Induced Pluripotent Stem Cells Using Engineered Zinc Finger Nucleases SO STEM CELLS LA English DT Article DE Induced pluripotency; Gene therapy; Gene targeting; Anemia; Zinc finger nucleases ID HUMAN SOMATIC-CELLS; HOMOLOGOUS RECOMBINATION; TRANSCRIPTION FACTORS; DEFINED FACTORS; HUMAN ESCS; GENERATION; GENOME; DISEASE; PATIENT; CONSTRUCTION AB The combination of induced pluripotent stem cell (iPSC) technology and targeted gene modification by homologous recombination (HR) represents a promising new approach to generate genetically corrected, patient-derived cells that could be used for autologous transplantation therapies. This strategy has several potential advantages over conventional gene therapy including eliminating the need for immunosuppression, avoiding the risk of insertional mutagenesis by therapeutic vectors, and maintaining expression of the corrected gene by endogenous control elements rather than a constitutive promoter. However, gene targeting in human pluripotent cells has remained challenging and inefficient. Recently, engineered zinc finger nucleases (ZFNs) have been shown to substantially increase HR frequencies in human iPSCs, raising the prospect of using this technology to correct disease causing mutations. Here, we describe the generation of iPSC lines from sickle cell anemia patients and in situ correction of the disease causing mutation using three ZFN pairs made by the publicly available oligomerized pool engineering method (OPEN). Gene-corrected cells retained full pluripotency and a normal karyotype following removal of reprogramming factor and drug-resistance genes. By testing various conditions, we also demonstrated that HR events in human iPSCs can occur as far as 82 bps from a ZFN-induced break. Our approach delineates a roadmap for using ZFNs made by an open-source method to achieve efficient, transgene-free correction of monogenic disease mutations in patient-derived iPSCs. Our results provide an important proof of principle that ZFNs can be used to produce gene-corrected human iPSCs that could be used for therapeutic applications. STEM CELLS 2011;29:1717-1726 C1 [Sebastiano, Vittorio; Haddad, Bahareh; Yeo, Dana T.; Hawkins, John S.; Wernig, Marius] Stanford Univ, Dept Pathol, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Sebastiano, Vittorio] Stanford Univ, Dept Obstet & Gynecol, Sch Med, Stanford, CA 94305 USA. [Batista, Luis F. Z.; Artandi, Steven E.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Maeder, Morgan L.; Angstman, James F.; Khayter, Cyd; Goodwin, Mathew J.; Ramirez, Cherie L.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA USA. [Maeder, Morgan L.; Angstman, James F.; Khayter, Cyd; Goodwin, Mathew J.; Ramirez, Cherie L.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA. [Maeder, Morgan L.; Ramirez, Cherie L.; Joung, J. Keith] Harvard Univ, Sch Med, Biol & Biomed Sci Program, Boston, MA USA. [Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Wernig, M (reprint author), Stanford Univ, Dept Pathol, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. EM wernig@stanford.edu; jjoung@partners.org OI Batista, Luis/0000-0002-7538-3240 FU NIH [R01 GM069906, DP1 OD006862]; National Science Foundation; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine; Donald E. and Delia B. Baxter Foundation; CIRM Training Grant FX We thank the patients who volunteered to donate a skin biopsy for this project, Rob Cho for consenting the patients and collecting the biopsies, Pei Wang for help with the Adeno-Cre infections and fluorescence-activated cell sorting, Stacey Thibodeau-Beganny for help with plasmid construction, Jeffry Sander for help with identification of potential genomic off-target sites, and Gerlinde Wernig for providing critical technical advice. This work was supported by NIH Grant R01 GM069906 and Pioneer Award DP1 OD006862 (to J.K.J.); National Science Foundation Graduate Research Fellowships (to M. L. M. and C. L. R.); Start-up funds of the Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine and the Donald E. and Delia B. Baxter Foundation (to M. W.); and the CIRM Training Grant for postdoctoral fellows (to V. S.). M. W. is a New York Stem Cell Foundation Robertson Investigator. J.K.J. is the Jim and Ann Orr Massachusetts General Hospital Research Scholar. NR 49 TC 156 Z9 163 U1 5 U2 43 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD NOV PY 2011 VL 29 IS 11 BP 1717 EP 1726 DI 10.1002/stem.718 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 842CN UT WOS:000296565500009 PM 21898685 ER PT J AU Nelson, P Young, HN Knobloch, MJ Griesbach, SA AF Nelson, Philip Young, Henry N. Knobloch, Mary Jo Griesbach, Sara A. TI Telephonic Monitoring and Optimization of Inhaler Technique SO TELEMEDICINE AND E-HEALTH LA English DT Article DE asthma; asthma management; telephonic monitoring; inhaler; metered-dose inhalers; MDI; diskus; dry powder inhalers,patient education as topic; telemedicine ID METERED-DOSE INHALER; RANDOMIZED CONTROLLED-TRIAL; INHALATION TECHNIQUE; ASTHMA REVIEWS; CARE; ACCESSIBILITY; INSTRUCTION; MISUSE AB Introduction: Improper inhaler technique is a common problem affecting asthma control and healthcare costs. Telephonic asthma management can increase access to care while reducing costs and hospitalizations. However, no reliable method has been established for telephonically evaluating and correcting inhaler technique. Objective: The purpose of this study was to pilot test a method for assessing and correcting patient inhaler technique via telephone. Methods: Participants (n = 30) were adults with asthma using metered-dose inhalers (MDIs) and diskus inhalers. A pharmacist was located in one room and communicated via telephone with a participant in another room. The pharmacist telephonically assessed and taught inhaler technique. Participants were videorecorded, and videos were later examined by a second pharmacist to visually evaluate inhaler technique. Participants were assigned pre- and posteducation inhaler technique scores for the telephonic and video assessments. Scores were based on summated scales for MDI (0-9) and diskus (0-11) inhalers. Paired samples t-tests were used to compare telephone and video assessments. Results: Findings indicated a significant difference between the telephone and video assessments of MDI technique (p < 0.05); however, no difference was found for the diskus inhaler. Comparing pre-and posteducation inhaler technique for MDI and diskus, mean scores significantly improved from 5.7 to 7.8 (p < 0.05) and from 8.5 to 10.4 (p < 0.05), respectively. Conclusions: The telephonic method was able to improve and detect some deficiencies in patients' inhaler technique. However, modifications and further investigation will more clearly determine the role and value of such a telephonic intervention. C1 [Knobloch, Mary Jo; Griesbach, Sara A.] Marshfield Clin Fdn Med Res & Educ, Div Educ, Marshfield, WI 54449 USA. [Nelson, Philip] S Texas Vet Hlth Care Syst, Ambulatory Care Pharm, San Antonio, TX USA. [Young, Henry N.] Univ Wisconsin, Social & Adm Sci Div, Madison Sch Pharm, Sonderegger Res Ctr, Madison, WI USA. [Knobloch, Mary Jo] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Partnership Program, Madison, WI USA. RP Griesbach, SA (reprint author), Marshfield Clin Fdn Med Res & Educ, Div Educ, 1000 N Oak Ave,GQ4, Marshfield, WI 54449 USA. EM griesbach.sara@marshfieldclinic.org FU Marshfield Clinic's Division of Education; National Center for Research Resources, National Institutes of Health [1UL1RR025011] FX The authors are grateful to Andrea Mahnke, BIRC usability analyst, for the wonderful technical support in utilizing the Marshfield Clinic Research Foundation's BIRC lab. We also thank Nina M. Antoniotti, RN, MBA, PhD; Elizabeth D. Cox, MD, PhD; and Megan A. Moreno, MD, MSEd, MPH, for their review of the article. We further thank Marie Fleisner of the Marshfield Clinic Research Foundation's Office of Scientific Publication for editorial assistance in the preparation of this article. Funding for this study was provided by Marshfield Clinic's Division of Education Resident Research Program and supported by grant 1UL1RR025011 from the Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health. NR 33 TC 6 Z9 6 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 J9 TELEMED E-HEALTH JI Telemed. e-Health PD NOV PY 2011 VL 17 IS 9 BP 734 EP 740 DI 10.1089/tmj.2011.0047 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 842HT UT WOS:000296588400012 PM 21943162 ER PT J AU Reynolds, HN Sheinfeld, G Chang, J Tabatabai, A Simmons, D AF Reynolds, H. Neal Sheinfeld, Geoffrey Chang, James Tabatabai, Ali Simmons, Dell TI The Tele-Intensive Care Unit During a Disaster: Seamless Transition from Routine Operations to Disaster Mode SO TELEMEDICINE AND E-HEALTH LA English DT Article DE disaster medicine; telemedicine; telehealth AB Disaster plans, during the actual disaster, often do not function as conceived and designed. Disaster or emergency situations may not present as anticipated in planning sessions confounding the intent of disaster planners. Systems that are created and shelved awaiting the disaster may be dysfunctional when needed due to problems such as failed batteries, forgotten training, misplaced equipment, the retraining curve, or software that has not been updated. We report here the smooth and seamless transition to disaster mode from a system in daily use and therefore operational when needed. C1 [Reynolds, H. Neal; Chang, James; Tabatabai, Ali; Simmons, Dell] Univ Maryland, R Adams Cowley Shock Trauma Ctr, Sch Med, Baltimore, MD 21201 USA. [Sheinfeld, Geoffrey] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Reynolds, HN (reprint author), Univ Maryland, R Adams Cowley Shock Trauma Ctr, Sch Med, 22 S Greene St, Baltimore, MD 21201 USA. EM hneal.reynolds@gmail.com NR 13 TC 4 Z9 4 U1 1 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 J9 TELEMED E-HEALTH JI Telemed. e-Health PD NOV PY 2011 VL 17 IS 9 BP 746 EP 749 DI 10.1089/tmj.2011.0046 PG 4 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 842HT UT WOS:000296588400014 PM 21943160 ER PT J AU Daniels, GH AF Daniels, Gilbert H. TI Screening for Medullary Thyroid Carcinoma with Serum Calcitonin Measurements in Patients with Thyroid Nodules in the United States and Canada SO THYROID LA English DT Article ID C-CELL HYPERPLASIA; ROUTINE MEASUREMENT; PREOPERATIVE DIAGNOSIS; PLASMA CALCITONIN; PREDICTIVE-VALUE; HIGH PREVALENCE; DISEASE; AUTOPSY; CANCER; MICROCARCINOMA AB Background: Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy with the potential for aggressive behavior. Measurement of serum calcitonin (Ct) in the thyroid nodule population is the most sensitive way to detect occult MTC. An important and controversial question is whether all patients with thyroid nodules should undergo Ct measurements to detect occult MTC. Summary: The prevalence of MTC detected by performing surgery on unselected individuals with thyroid nodules with elevated serum Ct is 0.4%. The central role of pentagastrin (PG) stimulation for triaging patients with minimally elevated serum Ct to prevent unnecessary surgery is reviewed. Data concerning a large reservoir of medullary thyroid microcarcinomas are discussed. Conclusion: Given the unavailability of PG in the United States and Canada, the available data argue against routine Ct measurements in all individuals with thyroid nodules in these countries because of the potential for unnecessary surgery and the uncertain benefit in diagnosing medullary microcarcinoma. C1 [Daniels, Gilbert H.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med,Thyroid Unit, Boston, MA 02114 USA. [Daniels, Gilbert H.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. RP Daniels, GH (reprint author), Massachusetts Gen Hosp ACC 730, Thyroid Unit ACC 730, Ctr Canc, Boston, MA 02114 USA. EM gdaniels@partners.org NR 60 TC 19 Z9 20 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD NOV PY 2011 VL 21 IS 11 BP 1199 EP 1207 DI 10.1089/thy.2010.0297 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 844IU UT WOS:000296741700006 PM 21936671 ER PT J AU Cristini, S Alessandri, G Acerbi, F Ciusani, E Colombo, A Fascio, U Nicosia, RF Invernizzi, RW Gelati, M Parati, EA Invernici, G AF Cristini, Silvia Alessandri, Giulio Acerbi, Francesco Ciusani, Emilio Colombo, Augusto Fascio, Umberto Nicosia, Roberto F. Invernizzi, Roberto W. Gelati, Maurizio Parati, Eugenio A. Invernici, Gloria TI Three-Dimensional Self-Organizing Neural Architectures: A Neural Stem Cells Reservoir and a System for Neurodevelopmental Studies SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; ADULT HUMAN BRAIN; PROGENITOR CELLS; IN-VITRO; NEURONAL PROGENITORS; RECEPTOR ACTIVATION; GENE-EXPRESSION; PRECURSOR CELLS; SPINAL-CORD AB Complex microenvironmental stimuli influence neural cell properties. To study this, we developed a three-dimensional (3-D) neural culture system, composed of different populations including neurons, astrocytes, and neural stem cells (NSCs). In particular, these last-mentioned cells represent a source potentially exploitable to test drugs, to study neurodevelopment and cell-therapies for neuroregenerations. On seeding on matrigel in a medium supplemented with serum and mitogens, cells obtained from human fetal brain tissue formed 3-D self-organizing neural architectures. Immunocytochemical analysis demonstrated the presence of undifferentiated nestin + and CD133+ cells, surrounded by beta-tub-III+ and GFAP + cells, suggesting the formation of niches containing potential human NSCs (hNSCs). The presence of hNSCs was confirmed by both neurosphere assay and RT-PCR, and their multipotentiality was demonstrated by both immunofluorescent staining and RT-PCR. Flow cytometry analysis revealed that neurosphere forming cells originating from at least two different subsets expressing, respectively, CD133 and CD146 markers were endowed with different proliferative and differentiation potential. Our data implicate that the complexity of environment within niches and aggregates of heterogeneous neural cell subsets may represent an innovative platform for neurobiological and neurodevelopmental investigations and a reservoir for a rapid expansion of hNSCs. C1 [Cristini, Silvia; Alessandri, Giulio; Gelati, Maurizio; Parati, Eugenio A.; Invernici, Gloria] Fdn IRCCS Ist Neurol Carlo Besta, Lab Cellular Neurobiol, I-20133 Milan, Italy. [Acerbi, Francesco] Fdn IRCCS Ist Neurol Carlo Besta, Dept Neurosurg, I-20133 Milan, Italy. [Acerbi, Francesco] Univ Milan, Dept Neurol Sci, Milan, Italy. [Ciusani, Emilio] Fdn IRCCS Ist Neurol Carlo Besta, Lab Clin Anal, I-20133 Milan, Italy. [Colombo, Augusto] Fdn IRCCS Osped Maggiore Policlin Mangiagalli & R, Dept Obstet & Gynecol, Milan, Italy. [Fascio, Umberto] Univ Milan, Interdept Ctr Adv Microscopy CIMA, Milan, Italy. [Nicosia, Roberto F.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Nicosia, Roberto F.] Univ Washington, Seattle, WA 98195 USA. [Invernizzi, Roberto W.] Ist Ric Farmacol M Negri, Lab Neurochem & Behav, Milan, Italy. RP Invernici, G (reprint author), Fdn IRCCS Ist Neurol Carlo Besta, Lab Cellular Neurobiol, Via Celoria 11, I-20133 Milan, Italy. EM gloria.invernici@istituto-besta.it RI Parati, Eugenio/G-8765-2011; Gelati, Maurizio/H-2110-2016 OI Gelati, Maurizio/0000-0002-4828-9849 FU Fondazione IRCCS Istituto Neurologico "Carlo Besta" [LR8]; Italian Ministry of Health [RF2008.22]; National Heart, Lung, and Blood Institute [HL52585]; Department of Veterans Affairs Medical Research Service FX The authors thank Dr. Andrea Smith for the English review of the article. We thank Deborah Jones for her excellent technical assistance with the electron microscopy studies. This work was supported by Fondazione IRCCS Istituto Neurologico "Carlo Besta" (LR8); the Italian Ministry of Health (RF2008.22); National Heart, Lung, and Blood Institute (HL52585); and Merit Review Grant, Department of Veterans Affairs Medical Research Service. NR 65 TC 1 Z9 1 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 EI 1937-3392 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD NOV PY 2011 VL 17 IS 11 BP 1109 EP 1120 DI 10.1089/ten.tec.2010.0622 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 844BB UT WOS:000296721200008 PM 21721991 ER PT J AU Lee, DH Chowdhury, D AF Lee, Dong-Hyun Chowdhury, Dipanjan TI What goes on must come off: phosphatases gate-crash the DNA damage response SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID DOUBLE-STRAND BREAK; REPLICATION-PROTEIN-A; CHECKPOINT KINASE RAD53; WIP1 PHOSPHATASE; DEPHOSPHORYLATES GAMMA-H2AX; REGULATORY SUBUNIT; TUMOR-SUPPRESSOR; SACCHAROMYCES-CEREVISIAE; DOCKING MOTIF; FORK RESTART AB DNA-damage-induced phospho-signaling has been studied for decades, with a focus mainly on initiation of the signaling cascade, and the kinases activated by DNA lesions. It is widely accepted that the balance of phosphorylation needs to be restored and/or maintained by phosphatases, yet there have only been sporadic efforts to investigate the impact of phosphatases on DNA repair. Recent advances in phosphoproteomic strategies and implementation of large genetic screens indicate that these enzymes play pivotal roles in these signaling networks. Dephosphorylation of repair proteins is crucial for efficient DNA repair, and the recommencement of cell division post-repair. Here, we focus on serine/threonine phosphatases implicated in dephosphorylation of DNA repair factors, summarizing recent findings and speculating on untested roles of phosphatases in the DNA damage response. C1 [Lee, Dong-Hyun; Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Chowdhury, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM dipanjan_chowdhury@dfci.harvard.edu FU Barr Award; NIH [CA 009078-34] FX DC is by R01CA142698 (NCI), JCRT and a Barr Award. DL was supported by NIH-training grant (CA 009078-34). We apologize to our colleagues whose work we could not discuss due to space constraints. NR 100 TC 15 Z9 15 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD NOV PY 2011 VL 36 IS 11 BP 569 EP 577 DI 10.1016/j.tibs.2011.08.007 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 843MG UT WOS:000296675300002 PM 21930385 ER PT J AU Ix, JH Chonchol, M Laughlin, GA Shlipak, MG Whooley, MA AF Ix, Joachim H. Chonchol, Michel Laughlin, Gail A. Shlipak, Michael G. Whooley, Mary A. TI Relation of Sex and Estrogen Therapy to Serum Fibroblast Growth Factor 23, Serum Phosphorus, and Urine Phosphorus: The Heart and Soul Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Menopause; fibroblast growth factor 23; phosphorus; estradiol; sex hormones ID CORONARY-ARTERY-DISEASE; NUTRITION EXAMINATION SURVEY; CHRONIC KIDNEY-DISEASE; VITAMIN-D METABOLITES; 3RD NATIONAL-HEALTH; POSTMENOPAUSAL WOMEN; MINERAL METABOLISM; OSTEOPOROTIC FRACTURES; PHOSPHATE REABSORPTION; CARDIOVASCULAR-DISEASE AB Background: Menopause is associated with urine phosphorus retention, which is mitigated by estrogen therapy. Fibroblast growth factor 23 (FGF-23) is a hormone originating from bone that regulates urine phosphorus excretion. Whether sex or estrogen therapy is associated with different FGF-23 levels is unknown. Study Design & Setting: Cross-sectional study of ambulatory individuals with prevalent cardiovascular disease. Predictors: Sex and, in women, use or nonuse of estrogen. Outcomes: Serum phosphorus, tubular maximum reabsorption of phosphorus indexed to glomerular filtration rate (TMP/GFR), and plasma FGF-23 concentrations. Results: For 987 participants, mean age was 67 +/- 11 years, 182 (18%) were women, and 46 (25%) were using estrogen. Mean estimated GFR was 71 +/- 23 (SD) mL/min/1.73 m(2). Compared with women who were not using estrogen, both women on estrogen therapy and men had significantly lower serum phosphorus concentrations, lower TMP/GFR values (indicating higher urine phosphorus excretion), and lower FGF-23 concentrations with adjustment for age, demographics, and kidney function (P < 0.001 for each). Mean FGF-23 levels were 68.7 (95% CI, 59.7-79.0) relative units (RU)/mL in non-estrogen-using women, 43.8 (95% CI, 41.2-46.5) RU/mL in men, and 45.1 (95% CI, 35.2-57.4) RU/mL in women using estrogen in adjusted analysis (P < 0.001). Limitations: Most participants were men. Estrogen therapy was not randomly assigned. Conclusions: Older women who are not using estrogen have higher FGF-23 levels than either men or women using estrogen. In the context of prior literature, these data suggest that postmenopausal phosphorus retention may stimulate higher FGF-23 concentrations after menopause. Am J Kidney Dis. 58(5): 737-745. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol & Hypertens, San Diego, CA 92161 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Family & Prevent Med, Div Prevent Med, San Diego, CA 92161 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Chonchol, Michel] Univ Colorado Denver, Dept Med, Div Renal Dis & Hypertens, Aurora, CO USA. [Laughlin, Gail A.] Univ Calif San Diego, Dept Family & Prevent Med, Div Epidemiol, San Diego, CA 92103 USA. [Shlipak, Michael G.; Whooley, Mary A.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA USA. [Shlipak, Michael G.; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shlipak, Michael G.; Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Ix, JH (reprint author), Univ Calif San Diego, Dept Med, Div Nephrol & Hypertens, 3350 La Jolla Village Dr,Mail Code 111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu FU National Heart, Lung and Blood Institute [NHLBI: R01 HL096851, R01 HL079235]; American Heart Association (AHA) [0575021N]; Sandra Daugherty Foundation; Department of Veterans; Department of Veterans Affairs Health Services Research and Development service; American Federation for Aging Research; Robert Wood Johnson Foundation; Ischemia Research and Education Foundation FX This study was supported by grants from the National Heart, Lung and Blood Institute (NHLBI: R01 HL096851), American Heart Association (AHA 0575021N), and the Sandra Daugherty Foundation to Dr Ix. The Heart and Soul Study was supported by the Department of Veterans Epidemiology Merit Review Program, the Department of Veterans Affairs Health Services Research and Development service, the NHLBI (R01 HL079235), the American Federation for Aging Research (Paul Beeson Scholars Program), the Robert Wood Johnson Foundation (Generalist Physician Faculty Scholars Program), and the Ischemia Research and Education Foundation. NR 51 TC 27 Z9 27 U1 0 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2011 VL 58 IS 5 BP 737 EP 745 DI 10.1053/j.ajkd.2011.06.011 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 839RF UT WOS:000296385700011 PM 21855188 ER PT J AU Diaz, MFP Pichler, RH Nicosia, RF Alpers, CE Smith, KD AF Diaz, Miguel F. Palma Pichler, Raimund H. Nicosia, Roberto F. Alpers, Charles E. Smith, Kelly D. TI Collapsing Glomerulopathy Associated With Natural Killer Cell Leukemia: A Case Report and Review of the Literature SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Focal segmental glomerulosclerosis; collapsing glomerulopathy; natural killer (NK) cell leukemia ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; NEPHROTIC SYNDROME; AFRICAN-AMERICANS; HEMOPHAGOCYTIC SYNDROME; PATHOGENESIS; NEPHROPATHY; APOL1; PODOCYTE; DISEASE; MYH9 AB We report a case of collapsing glomerulopathy associated with natural killer cell leukemia in a previously healthy 27-year-old African American man. An initial kidney biopsy showed findings concordant with the cellular variant of focal segmental glomerulosclerosis. A repeated biopsy 3 months later showed collapsing glomerulopathy, likely representing a morphologic evolution from a cellular variant into the collapsing glomerulopathy variant of focal segmental glomerulosclerosis. Collapsing glomerulopathy has been described in connection with a number of disparate disorders in which podocyte injury seems to be the common denominator. The close temporal association between clinical presentation and the development of nephropathy provides support for a direct pathogenic link between the underlying lymphoproliferative disorder and the glomerular lesions. We hypothesize that dysregulated cytokine production by the neoplastic cells led to podocyte alterations and eventually to the development of collapsing glomerulopathy. Am J Kidney Dis. 58(5):855-859. (C) 2011 by the National Kidney Foundation, Inc. C1 [Diaz, Miguel F. Palma; Nicosia, Roberto F.; Alpers, Charles E.; Smith, Kelly D.] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. [Pichler, Raimund H.] Univ Washington, Med Ctr, Div Nephrol, Seattle, WA 98195 USA. [Nicosia, Roberto F.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Diaz, MFP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, 10833 Le Conte Ave,CHS 13-145, Los Angeles, CA 90095 USA. EM fpalmadiaz@mednet.ucla.edu NR 25 TC 3 Z9 3 U1 0 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2011 VL 58 IS 5 BP 855 EP 859 DI 10.1053/j.ajkd.2011.07.011 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 839RF UT WOS:000296385700025 ER PT J AU Rigotti, NA Bitton, A Kelley, JK Hoeppner, BB Levy, DE Mort, E AF Rigotti, Nancy A. Bitton, Asaf Kelley, Jennifer K. Hoeppner, Bettina B. Levy, Douglas E. Mort, Elizabeth TI Offering Population-Based Tobacco Treatment in a Healthcare Setting A Randomized Controlled Trial SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID NICOTINE REPLACEMENT THERAPY; SMOKING-CESSATION; QUITLINE; SMOKERS; SYSTEM; RATES AB Background: The healthcare system is a key channel for delivering treatment to tobacco users. Brief clinic-based interventions are effective but not reliably offered. Population management strategies might improve tobacco treatment delivery in a healthcare system. Purpose: To test the effectiveness of supplementing clinic-based care with a population-based direct-to-smoker (DTS) outreach offering easily accessible free tobacco treatment. Design: Randomized controlled trial, conducted in 2009-2010, comparing usual clinical care to usual care plus DTS outreach. Setting/participants: A total of 590 smokers registered for primary care at a community health center in Revere MA. Interventions: Three monthly letters offering a free telephone consultation with a tobacco coordinator who provided free treatment including up to 8 weeks of nicotine patches (NRT) and proactive referral to the state quitline for multisession counseling. Main outcome measures: Use of any tobacco treatment (primary outcome) and tobacco abstinence at the 3-month follow-up; cost per quit. Results: Of 413 eligible smokers, 43 (10.4%) in the DTS group accepted the treatment offer; 42 (98%) requested NRT and 30 (70%) requested counseling. In intention-to-treat analyses adjusted by logistic regression for age, gender, race, insurance, diabetes, and coronary heart disease, a higher proportion of the DTS group, compared to controls, had used NRT (11.6% vs 3.9%, OR = 3.47; 95% CI = 1.52, 7.92) or any tobacco treatment (14.5% vs 7.3%, OR = 1.95, 95% CI = 1.04, 3.65) and reported being tobacco abstinent for the past 7 days (5.3% vs 1.1%, OR = 5.35, 95% CI = 1.23, 22.32) and past 30 days (4.1% vs 0.6%, OR = 8.25, 95% CI = 1.08, 63.01). The intervention did not increase smokers' use of counseling (1.7% vs 1.1%) or non-NRT medication (3.6% vs 3.9%). Estimated incremental cost per quit was $464. Conclusions: A population-based outreach offering free tobacco treatment to smokers in a health center was a feasible, cost-effective way to increase the reach of treatment (primarily NRT) and to increase short-term quit rates. Trial registration: This study is registered at Clinicaltrials.gov NCT01321944. (Am J Prev Med 2011;41(5):498-503) (C) 2011 American Journal of Preventive Medicine C1 [Rigotti, Nancy A.; Mort, Elizabeth] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. [Rigotti, Nancy A.; Bitton, Asaf; Kelley, Jennifer K.; Hoeppner, Bettina B.; Levy, Douglas E.] Tobacco Res & Treatment Ctr, Boston, MA USA. [Hoeppner, Bettina B.] Massachusetts Gen Hosp, Ctr Addict Med, Dept Psychiat, Boston, MA 02114 USA. [Bitton, Asaf] Brigham & Womens Hosp, Dept Med, Div Gen Med & Primary Care, Boston, MA 02115 USA. [Kelley, Jennifer K.; Mort, Elizabeth] Partners HealthCare, Mongan Inst Hlth Policy, High Performance Med, Boston, MA USA. [Rigotti, Nancy A.; Bitton, Asaf; Hoeppner, Bettina B.; Levy, Douglas E.; Mort, Elizabeth] Harvard Univ, Sch Med, Boston, MA USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM nrigotti@partners.org FU DTS; Health Resources and Services Administration [T32HP10251]; [1K01DA027097-01A1]; [K24-HL08880] FX Partners Health Care, Inc., funded the DTS program, study data collection and data management. Data analysis was conducted by an independently funded investigator (BBH). Study investigators' efforts on the project were supported by grants T32HP10251 from the Health Resources and Services Administration for the Harvard General Medicine Fellowship (AB); 1K01DA027097-01A1 (BBH); and K24-HL08880 (NAR). The funders of these grants had no role in study design or conduct; data collection, analysis, or interpretation; or manuscript preparation, review, or approval. NR 20 TC 13 Z9 13 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD NOV PY 2011 VL 41 IS 5 BP 498 EP 503 DI 10.1016/j.amepre.2011.07.022 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 839UI UT WOS:000296394500007 PM 22011421 ER PT J AU Robertson, WJ Griffith, MH Carroll, K O'Donnell, T Gill, TJ AF Robertson, William J. Griffith, Matthew H. Carroll, Kaitlin O'Donnell, Thomas Gill, Thomas J. TI Arthroscopic Versus Open Distal Clavicle Excision A Comparative Assessment at Intermediate-Term Follow-up SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE acromioclavicular joint; excision; open; arthroscopic ID ACROMIOCLAVICULAR JOINT; BIOMECHANICAL ANALYSIS; RESECTION; DISLOCATION; END AB Background: While few comparative studies exist, it has been suggested that open distal clavicle excisions (DCEs) provide inferior results when compared with the all-arthroscopic technique. Purpose: The purpose of this study was to compare the intermediate-term (5-year follow-up) results of patients undergoing arthroscopic versus open DCE for the treatment of recalcitrant acromioclavicular joint pain. Study Design: Cohort study; Level of evidence, 3. Methods: All patients who underwent an arthroscopic or open DCE between January 1999 and September 2006 were reviewed. Forty-eight patients (49 shoulders; 32 arthroscopic, 17 open) following DCE without significant glenohumeral pathologic changes were included. The mean follow-up for group I (open) and group II (arthroscopic) was 5.3 years and 4.2 years, respectively. The American Shoulder and Elbow Surgeons (ASES) score, visual analog scale (VAS) pain score, surgical time, and minimum radiographic acromioclavicular joint distance were calculated. Each patient completed a questionnaire assessing their scar satisfaction, percentage of normal shoulder function, and willingness to have the surgery again. Risk factors for poor outcomes were analyzed. Results: Arthroscopic patients had significantly less pain (P = .035) by VAS (0.61 +/- 1.02) compared with open (1.59 +/- 2.15) at final follow-up. There was no significant difference between group I and group II with regard to ASES (87.5 +/- 17.6 vs 94.6 +/- 8.6), percentage of normal shoulder function (89.7% +/- 12.5 vs 92.9% +/- 8.6), average operative time (53.1 minutes vs 48 minutes), or radiographic resection distance (12.8 +/- 2.1 mm vs 9.5 +/- 2.9 mm). In the open group, patients with 16 of 17 shoulders were satisfied with their scar and 100% would do it again. In the arthroscopic group, patients with 31 of 32 shoulders (97%) were both satisfied and would have the surgery again. Conclusion: Open and arthroscopic DCE are both effective surgeries to treat recalcitrant acromioclavicular joint pain. At intermediate-term follow-up, they provide similarly good to excellent results with regard to patient satisfaction and shoulder function. Although both are effective treatments, less residual pain was found using the arthroscopic technique. C1 [Robertson, William J.; Griffith, Matthew H.; Carroll, Kaitlin; O'Donnell, Thomas; Gill, Thomas J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Robertson, WJ (reprint author), UT SW Med Ctr Dallas, 1801 Inwood Rd, Dallas, TX 75390 USA. EM robertsonwj@gmail.com NR 18 TC 12 Z9 12 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0363-5465 J9 AM J SPORT MED JI Am. J. Sports Med. PD NOV PY 2011 VL 39 IS 11 BP 2415 EP 2420 DI 10.1177/0363546511419633 PG 6 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 838KG UT WOS:000296287900018 PM 21900626 ER PT J AU Levesque, V Bardwell, PD Shimizu, I Haspot, F Benichou, G Yeap, BY Sykes, M AF Levesque, V. Bardwell, P. D. Shimizu, I. Haspot, F. Benichou, G. Yeap, B. Y. Sykes, M. TI B-Cell-Dependent Memory T Cells Impede Nonmyeloablative Mixed Chimerism Induction in Presensitized Mice SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Alloantibodies; memory; mixed chimerism; presensitization; T-cell memory; tolerance ID BONE-MARROW ENGRAFTMENT; TRANSPLANTATION TOLERANCE; HEMATOPOIETIC CHIMERISM; ALLOGRAFT-REJECTION; DEFICIENT MICE; IN-VIVO; RECIPIENTS; PATHWAY; IMMUNOSUPPRESSION; IRRADIATION AB Presensitization to HLA antigens limits the success of organ transplantation. The achievement of donor-specific tolerance via mixed chimerism could improve outcomes of transplantation in presensitized patients. In presensitized B-cell-deficient mu MT B6 mice, we developed nonmyeloablative bone marrow transplantation (BMT) regimens that successfully tolerized presensitized T cells, achieving long-term(LT) multilineage chimerism and tolerance to donor-type skin. To apply these regimens in wild-type (WT) animals while avoiding antibody-mediated destruction of donor bone marrow cells, presensitized WT B6 mice were rested >2 years to allow alloantibody clearance. However, chimerism and tolerance were not reliably achieved in LT presensitized WT B6 mice in which alloantibody had declined to minimal or undetectable levels before BMT. Strong antidonor memory T-cell responses were detected in LT presensitized WT B6 mice after rejection of donor bone marrow (BM) occurred, whereas levels of alloantibody remained consistently low. In contrast, presensitized mu MT B6 mice had diminished memory T-cell responses compared to WT B6 mice. These data implicate T-cell memory, but not alloantibody, in rejection of donor BM in LT presensitized WT mice. C1 [Levesque, V.; Bardwell, P. D.; Shimizu, I.; Haspot, F.; Sykes, M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02115 USA. [Benichou, G.] Harvard Univ, Sch Med, Dept Surg, Transplantat Ctr,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Yeap, B. Y.] Harvard Univ, Sch Med, Dept Med, Biostat Unit,Massachusetts Gen Hosp, Boston, MA USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02115 USA. EM Megan.Sykes@tbrc.mgh.harvard.edu RI Bardwell, Philip/H-2219-2014 OI Bardwell, Philip/0000-0002-3835-255X FU NHLBI NIH HHS [P01 HL018646, R01 HL049915]; NIAID NIH HHS [R01 AI054976] NR 27 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD NOV PY 2011 VL 11 IS 11 BP 2322 EP 2331 DI 10.1111/j.1600-6143.2011.03683.x PG 10 WC Surgery; Transplantation SC Surgery; Transplantation GA 839AF UT WOS:000296335800011 PM 21831158 ER PT J AU Tulsky, JA Arnold, RM Alexander, SC Olsen, MK Jeffreys, AS Rodriguez, KL Skinner, CS Farrell, D Abernethy, AP Pollak, KI AF Tulsky, James A. Arnold, Robert M. Alexander, Stewart C. Olsen, Maren K. Jeffreys, Amy S. Rodriguez, Keri L. Skinner, Celette Sugg Farrell, David Abernethy, Amy P. Pollak, Kathryn I. TI Enhancing Communication Between Oncologists and Patients With a Computer-Based Training Program A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ADVANCED CANCER; PRIMARY-CARE; SCOPE TRIAL; SKILLS; QUALITY; PHYSICIAN; EFFICACY; MODEL; TRUST; LIFE AB Background: Quality cancer care requires addressing patients' emotions, which oncologists infrequently do. Multiday courses can teach oncologists skills to handle emotion; however, such workshops are long and costly. Objective: To test whether a brief, computerized intervention improves oncologist responses to patient expressions of negative emotion. Design: Randomized, controlled, parallel-group trial stratified by site, sex, and oncologic specialty. Oncologists were randomly assigned to receive a communication lecture or the lecture plus a tailored CD-ROM. (ClinicalTrials. gov registration number: NCT00276627) Setting: Oncology clinics at a comprehensive cancer center and Veterans Affairs Medical Center in Durham, North Carolina, and a comprehensive cancer center in Pittsburgh, Pennsylvania. Participants: 48 medical, gynecologic, and radiation oncologists and 264 patients with advanced cancer. Intervention: Oncologists were randomly assigned in a 1: 1 ratio to receive an interactive CD-ROM about responding to patients' negative emotions. The CD-ROM included tailored feedback on the oncologists' own recorded conversations. Measurements: Postintervention audio recordings were used to identify the number of empathic statements and responses to patients' expressions of negative emotion. Surveys evaluated patients' trust in their oncologists and perceptions of their oncologists' communication skills. Results: Oncologists in the intervention group used more empathic statements (relative risk, 1.9 [95% Cl, 1.1 to 3.3]; P = 0.024) and were more likely to respond to negative emotions empathically (odds ratio, 2.1 [Cl, 1.1 to 4.2]; P = 0.028) than control oncologists. Patients of intervention oncologists reported greater trust in their oncologists than did patients of control oncologists (estimated mean difference, 0.1 [Cl, 0.0 to 0.2]; P = 0.036). There was no significant difference in perceptions of communication skills. Limitations: Long-term effects were not examined. The findings may not be generalizable outside of academic medical centers. Conclusion: A brief computerized intervention improves how oncologists respond to patients' expressions of negative emotions. Primary Funding Source: National Cancer Institute. C1 Duke Univ, Vet Affairs Med Ctr, Durham, NC 27705 USA. People Designs, Durham, NC USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Tulsky, JA (reprint author), Duke Univ, Ctr Palliat Care, Hock Plaza,Suite 1105,2424 Erwin Rd,Box 2720, Durham, NC 27705 USA. EM jtulsky@duke.edu FU National Cancer Institute [R01 CA100387] FX By grant R01 CA100387 from the National Cancer Institute. NR 38 TC 69 Z9 69 U1 4 U2 18 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 NOV 1 PY 2011 VL 155 IS 9 BP 593 EP U64 DI 10.7326/0003-4819-155-9-201111010-00007 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 842PW UT WOS:000296612400004 PM 22041948 ER PT J AU Qaseem, A Chou, R Humphrey, LL Starkey, M Shekelle, P AF Qaseem, Amir Chou, Roger Humphrey, Linda L. Starkey, Melissa Shekelle, Paul CA Amer Coll Phys TI Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline From the American College of Physicians SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID DEEP-VEIN THROMBOSIS; MOLECULAR-WEIGHT HEPARIN; ACUTE ISCHEMIC-STROKE; LOW-DOSE HEPARIN; PLACEBO-CONTROLLED TRIAL; ILL MEDICAL PATIENTS; FATAL PULMONARY-EMBOLISM; DOUBLE-BLIND; UNFRACTIONATED HEPARIN; RANDOMIZED-TRIAL AB Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on prophylaxis of venous thromboembolism for hospitalized nonsurgical patients (medical patients and patients with acute stroke). Methods: This guideline is based on published literature on the topic from 1950 through April 2011 that was identified by using MEDLINE, the Cochrane Library, and reference lists of pertinent randomized trials and systematic reviews to identify additional reports. Searches were limited to randomized trials and English-language publications. The primary outcome for this guideline was total mortality up to 120 days after randomization. Secondary outcomes included symptomatic deep venous thrombosis; all pulmonary embolisms; fatal pulmonary embolism; all bleeding events; major bleeding events; and, for mechanical prophylaxis, effects on skin. This guideline grades the evidence and recommendations by using the ACP's clinical practice guidelines grading system. Recommendation 1: ACP recommends assessment of the risk for thromboembolism and bleeding in medical (including stroke) patients prior to initiation of prophylaxis of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence). Recommendation 2: ACP recommends pharmacologic prophylaxis with heparin or a related drug for venous thromboembolism in medical (including stroke) patients unless the assessed risk for bleeding outweighs the likely benefits (Grade: strong recommendation, moderate-quality evidence). Recommendation 3: ACP recommends against the use of mechanical prophylaxis with graduated compression stockings for prevention of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence). Policy Implication: ACP does not support the application of performance measures in medical (including stroke) patients that promotes universal venous thromboembolism prophylaxis regardless of risk. C1 [Qaseem, Amir] Amer Coll Physicians, Philadelphia, PA 19106 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Qaseem, A (reprint author), Amer Coll Physicians, 190 N Independence Mall W, Philadelphia, PA 19106 USA. EM aqaseem@acponline.org FU ACP FX Financial support for the development of this guideline comes exclusively from the ACP operating budget. NR 50 TC 93 Z9 97 U1 0 U2 7 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 NOV 1 PY 2011 VL 155 IS 9 BP 625 EP U118 DI 10.7326/0003-4819-155-9-201111010-00011 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 842PW UT WOS:000296612400007 PM 22041951 ER PT J AU Cheng, YW Kaimal, AJ Bruckner, TA Hallaron, DR Caughey, AB AF Cheng, Y. W. Kaimal, A. J. Bruckner, T. A. Hallaron, D. R. Caughey, A. B. TI Perinatal morbidity associated with late preterm deliveries compared with deliveries between 37 and 40 weeks of gestation SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article DE Late preterm births; perinatal outcomes ID NEAR-TERM INFANTS; CESAREAN DELIVERY; TEMPORAL TRENDS; UNITED-STATES; OUTCOMES; BIRTH; AGE; RISK; MORTALITY; COHORT AB Objective To estimate the risk of short-term complications in neonates born between 34 and 36 weeks of gestation. Design This is a retrospective cohort study. Setting Deliveries in 2005 in the USA. Population Singleton live births between 34 and 40 weeks of gestation. Methods Gestational age was subgrouped into 34, 35, 36 and 37-40 completed weeks of gestation. Statistical comparisons were performed using chi-square test and multivariable logistic regression models, with 37-40 weeks of gestation designated as referent. Main outcome measures Perinatal morbidities, including 5-minute Apgar scores, hyaline membrane disease, neonatal sepsis/antibiotics use, and admission to the intensive care unit. Results In all, 175 112 neonates were born between 34 and 36 weeks in 2005. Compared with neonates born between 37 and 40 weeks, neonates born at 34 weeks had higher odds of 5-minute Apgar <7 (adjusted odds ratio [aOR] 5.51, 95% CI 5.16-5.88), hyaline membrane disease (aOR 10.2, 95% CI 9.44-10.9), mechanical ventilation use >6 hours (aOR 9.78, 95% CI 8.99-10.6) and antibiotic use (aOR 9.00, 95% CI 8.43-9.60). Neonates born at 35 weeks were similarly at risk of morbidity, with higher odds of 5-minute Apgar <7 (aOR 3.42, 95% CI 3.23-3.63), surfactant use (aOR 3.74, 95% CI 3.21-4.22), ventilation use >6 hours (aOR 5.53, 95% CI 5.11-5.99) and neonatal intensive-care unit admission (aOR 11.3, 95% CI 11.0-11.7). Neonates born at 36 weeks remain at higher risk of morbidity compared with deliveries at 37-40 weeks of gestation. Conclusions Although the risk of undesirable neonatal outcomes decreases with increasing gestational age, the risk of neonatal complications in late preterm births remains higher compared with infants delivered at 37-40 weeks of gestation. C1 [Cheng, Y. W.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Div Maternal Fetal Med, San Francisco, CA 94143 USA. [Kaimal, A. J.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02114 USA. [Bruckner, T. A.] Univ Calif Irvine, Sch Social Ecol, Dept Publ Hlth & Planning Policy & Design, Irvine, CA USA. [Hallaron, D. R.] St Louis Univ, Dept Pediat, St Louis, MO 63103 USA. [Caughey, A. B.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. RP Cheng, YW (reprint author), Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, Div Maternal Fetal Med, 505 Parnassus Ave Box 0132, San Francisco, CA 94143 USA. EM yvecheng@hotmail.com FU UCSF; NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development [K12 HD001262]; Washington University CTSA [KL2RR024994-01] FX YWC is supported by the UCSF Women's Reproductive Health Research Career Development Award, NIH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12 HD001262) and DRH is supported by the Washington University CTSA (KL2RR024994-01). NR 35 TC 29 Z9 29 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1470-0328 J9 BJOG-INT J OBSTET GY JI BJOG PD NOV PY 2011 VL 118 IS 12 BP 1446 EP 1454 DI 10.1111/j.1471-0528.2011.03045.x PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 837LG UT WOS:000296203900005 PM 21883872 ER PT J AU Stockdale, SE Sherin, JE Chan, JA Hermann, RC AF Stockdale, Susan E. Sherin, Jonathan E. Chan, Jeffrey A. Hermann, Richard C. TI Barriers and strategies for improving communication between inpatient and outpatient mental health clinicians SO BMJ QUALITY & SAFETY LA English DT Article ID HOSPITAL DISCHARGE; CARE; TRANSITIONS; CONTINUITY AB Objectives: To explore hospital leaders' perceptions of organisational factors as barriers and/or facilitators in improving inpatient-outpatient (IP-OP) communication. Design: Semistructured in-person interviews. Analysis: Constant comparative method of qualitative data. Setting: Inpatient psychiatry units in 33 general medical/surgical and specialty psychiatric hospitals in California and Massachusetts (USA). Participants: Psychiatry chair/chief, service director or medical director. Variables: Importance to leadership, resources, organisational structure and culture. Results: A majority of hospital leaders rated the IP-OP communication objective as highly or moderately important. Hospitals with good IP-OP communication had structures in place to support communication or had changed/implemented new procedures to enhance communication, and anticipated clinicians would 'buy in' to the goal of improved communication. Hospitals reporting no improvement efforts were less likely to have structures supporting IP-OP communication, anticipated resistance among clinicians and reported a need for technological resources such as electronic health records, integrated IT and secure online communication. Most leaders reported a need for additional staff time and information, knowledge or data. Conclusions: For many hospitals, successfully improving communication will require overcoming organisational barriers such as cultures not conducive to change and lack of resources and infrastructure. Creating a culture that values communication at discharge may help improve outcomes following hospitalisation, but changes in healthcare delivery in the past few decades may necessitate new strategies or changes at the systems level to address barriers to effective communication. C1 [Stockdale, Susan E.] VA Greater Los Angeles Healthcare Syst, HSR&D Ctr Study Healthcare Provider Behav, Sepulveda, CA 91343 USA. [Stockdale, Susan E.] Univ Calif Los Angeles, UCLA Semel Inst Ctr Hlth Serv & Soc, Los Angeles, CA USA. [Sherin, Jonathan E.] Miami VA Healthcare Syst, Miami, FL USA. [Sherin, Jonathan E.] Univ Miami, Miami, FL USA. [Chan, Jeffrey A.; Hermann, Richard C.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Chan, Jeffrey A.; Hermann, Richard C.] VA Boston Healthcare Syst, COLMR, Boston, MA USA. RP Stockdale, SE (reprint author), VA Greater Los Angeles Healthcare Syst, HSR&D Ctr Study Healthcare Provider Behav, 16111 Plummer St,Bldg 25,Room A-103, Sepulveda, CA 91343 USA. EM susan.stockdale@va.gov FU National Institute of Mental Health [R34 MH074788, P30 MH082760, P30 MH068639] FX This research was supported by grants from the National Institute of Mental Health (R34 MH074788, PI: R. Hermann; P30 MH082760, PI: K. Wells; P30 MH068639, PI: K. Wells). NR 33 TC 2 Z9 2 U1 1 U2 13 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD NOV PY 2011 VL 20 IS 11 BP 941 EP 946 DI 10.1136/bmjqs.2010.050450 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 837KQ UT WOS:000296201200005 PM 21606473 ER PT J AU Zhang, Y Moriguchi, H AF Zhang, Yue Moriguchi, Hisashi TI Chromatin remodeling system, cancer stem-like attractors, and cellular reprogramming SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE Caenorhabditis elegans; Drosophila melanogaster; Carcinogenesis; Cell attractors; Chromatin remodeling system; Cellular reprogramming ID GENE-EXPRESSION; EMBRYONIC STEM; C-ELEGANS; EXTRACELLULAR-MATRIX; CELLS; COMPLEX; DIFFERENTIATION; PROTEIN; HSP90; PLURIPOTENCY AB The cancer cell attractors theory provides a next-generation understanding of carcinogenesis and natural explanation of punctuated clonal expansions of tumor progression. The impressive notion of atavism of cancer is now updated but more evidence is awaited. Besides, the mechanisms that the ectopic expression of some germline genes result in somatic tumors such as melanoma and brain tumors are emerging but are not well understood. Cancer could be triggered by cells undergoing abnormal cell attractor transitions, and may be reversible with "cyto-education''. From mammals to model organisms like Caenorhabditis elegans and Drosophila melanogaster, the versatile Mi-2 beta/nucleosome remodeling and histone deacetylation complexes along with their functionally related chromatin remodeling complexes (CRCs), i.e., the dREAM/Myb-MuvB complex and Polycomb group complex are likely master regulators of cell attractors. The trajectory that benign cells switch to cancerous could be the reverse of navigation of embryonic cells converging from a series of intermediate transcriptional states to a final adult state, which is supported by gene expression dynamics inspector assays and some cross-species genetic evidence. The involvement of CRCs in locking cancer attractors may help find the recipes of perturbing genes to achieve successful reprogramming such that the reprogrammed cancer cell function in the same way as the normal cells. C1 [Zhang, Yue] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Radiat Oncol, Boston, MA 02215 USA. [Moriguchi, Hisashi] Univ Tokyo, Sch Med, Dept Plast & Reconstruct Surg, Tokyo 113, Japan. [Moriguchi, Hisashi] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Zhang, Y (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Radiat Oncol, 99 Brookline Ave, Boston, MA 02215 USA. EM yzhang1@bidmc.harvard.edu; hisashi.moriguchi@gmail.com NR 90 TC 5 Z9 7 U1 0 U2 8 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD NOV PY 2011 VL 68 IS 21 BP 3557 EP 3571 DI 10.1007/s00018-011-0808-1 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 840VK UT WOS:000296469200010 PM 21909785 ER PT J AU Upadhyay, GA Singh, JP AF Upadhyay, Gaurav A. Singh, Jagmeet P. TI Making a Splash? - Intrathoracic Impedance and the Prediction of Arrhythmic Events SO CIRCULATION JOURNAL LA English DT Editorial Material ID CARDIAC RESYNCHRONIZATION THERAPY; HEART-FAILURE HOSPITALIZATIONS; DEVICE DIAGNOSTICS; VOLUME OVERLOAD C1 [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv,Heart Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Singh, JP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv,Heart Ctr, 55 Fruit St,Gray Bldg 109, Boston, MA 02114 USA. EM jsingh@partners.org NR 12 TC 0 Z9 1 U1 0 U2 1 PU JAPANESE CIRCULATION SOC PI KYOTO PA KINKI INVENTION CENTER, 14 YOSHIDA KAWAHARACHO, SAKYO-KU, KYOTO, 606-8305, JAPAN SN 1346-9843 J9 CIRC J JI Circ. J. PD NOV PY 2011 VL 75 IS 11 BP 2539 EP 2540 DI 10.1253/circj.CJ-11-1054 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 839XP UT WOS:000296403100006 PM 21963573 ER PT J AU Koontz, AM Kankipati, P Lin, YS Cooper, RA Boninger, ML AF Koontz, Alicia M. Kankipati, Padmaja Lin, Yen-Sheng Cooper, Rory A. Boninger, Michael L. TI Upper limb kinetic analysis of three sitting pivot wheelchair transfer techniques SO CLINICAL BIOMECHANICS LA English DT Article DE Biomechanics; Upper limb pain; Spinal cord injury; Activities of daily living; Wheelchair ID SPINAL-CORD-INJURY; UPPER EXTREMITY; BIOMECHANICAL ANALYSIS; INDIVIDUALS; SHOULDER; USERS; PARAPLEGIA; SYSTEM; KINEMATICS; MANEUVER AB Background: The objective of this study was to investigate differences in shoulder, elbow and hand kinetics while performing three different SPTs that varied in terms of hand and trunk positioning. Methods: Fourteen unimpaired individuals (8 male and 6 female) performed three variations of sitting pivot transfers in a random order from a wheelchair to a level tub bench. Two transfers involved a forward flexed trunk (head-hips technique) and the third with the trunk remaining upright. The two transfers involving a head hips technique were performed with two different leading hand initial positions. Motion analysis equipment recorded upper body movements and force sensors recorded hand reaction forces. Shoulder and elbow joint and hand kinetics were computed for the lift phase of the transfer. Findings: Transferring using either of the head hips techniques compared to the trunk upright style of transferring resulted in reduced superior forces at the shoulder (P<0.002), elbow (P<0.004) and hand (P<0.013). There was a significant increase in the medial forces in the leading elbow (P=0.049) for both head hip transfers and the trailing hand for the head hip technique with the arm further away from the body (P<0.028). The head hip techniques resulted in higher shoulder external rotation, flexion and extension moments compared to the trunk upright technique (P<0.021). Interpretation: Varying the hand placement and trunk positioning during transfers changes the load distribution across all upper limb joints. The results of this study may be useful for determining a technique that helps preserve upper limb function overtime. Published by Elsevier Ltd. C1 [Koontz, Alicia M.; Kankipati, Padmaja; Lin, Yen-Sheng; Cooper, Rory A.; Boninger, Michael L.] Dept Vet Affairs, Human Engn Res Labs, Pittsburgh, PA USA. [Koontz, Alicia M.; Kankipati, Padmaja; Lin, Yen-Sheng; Cooper, Rory A.; Boninger, Michael L.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Cooper, Rory A.; Boninger, Michael L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. RP Koontz, AM (reprint author), VA Pittsburgh Hlth Care Syst, Human Engn Res Labs 151R1 H, 7180 Highland Dr,151R1-H, Pittsburgh, PA 15206 USA. EM akoontz@pitt.edu OI Boninger, Michael/0000-0001-6966-919X FU VA Rehabilitation Research RD Services; National Institute on Disability and Rehabilitation Research; National Institute of Health, Center for Injury Research Control [VA-RRD E3589V, B3079R NIDRR H133A011107, NIH R49/CCR310285-06] FX Funding for this study was provided by the VA Rehabilitation Research R&D Services and the National Institute on Disability and Rehabilitation Research and the National Institute of Health, Center for Injury Research Control (VA-RR&D E3589V and B3079R NIDRR H133A011107, NIH R49/CCR310285-06). The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States Government. NR 27 TC 14 Z9 14 U1 3 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 J9 CLIN BIOMECH JI Clin. Biomech. PD NOV PY 2011 VL 26 IS 9 BP 923 EP 929 DI 10.1016/j.clinbiomech.2011.05.005 PG 7 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 840AK UT WOS:000296410400006 PM 21664733 ER PT J AU Kozanek, M Hosseini, A Van de Velde, SK Moussa, ME Li, JS Gill, TJ Li, GA AF Kozanek, Michal Hosseini, Ali Van de Velde, Samuel K. Moussa, Mohamed E. Li, Jing Sheng Gill, Thomas J. Li, Guoan TI Kinematic evaluation of the step-up exercise in anterior cruciate ligament deficiency SO CLINICAL BIOMECHANICS LA English DT Article DE Anterior cruciate ligament; Injury; Rehabilitation; Kinematics; Knee; Imaging ID KINETIC-CHAIN EXERCISES; TIBIOFEMORAL JOINT FORCES; ELECTROMYOGRAPHIC ACTIVITY; STAIR ASCENT; KNEE; COACTIVATION; TRANSLATION; WALKING; MOTION; REHABILITATION AB Background: Step-up exercise is one of the most commonly utilized exercises during rehabilitation of patients after both anterior cruciate ligament (ACL) injury and reconstruction. Currently, insurance providers increasingly required a trial of intensified rehabilitation before surgical reconstruction is attempted. The purpose of this study was to investigate whether this "safe" rehabilitation exercise in the setting of ACL deficiency can cause altered knee kinematics. Methods: Thirty patients with unilateral ACL rupture were recruited for this study. The mean time from injury was 3.3 months. Tibiofemoral kinematics were determined during a step-up exercise using a combination of magnetic resonance imaging (MRI), dual fluoroscopy and advanced computer modeling. Findings: The ACL-injured knee displayed an average 50 greater external tibial rotation than the uninjured knee (P<0.05), during the last 30% of step-up. The ACL-injured knee also demonstrated on average 2.5 mm greater anterior tibial shift during the last 40% of stance phase (P<0.01). In addition, during the last 30% of stance the tibia of the ACL-deficient knee tended to shift more medially (similar to 1 mm) as the knee approached full extension (P<0.01). Interpretation: The data confirmed the initial hypothesis as it was found that ACL deficient knees demonstrated significantly increased anterior tibial translation, medial tibial translation and external tibial rotation toward the end of the step-up as the knee approached full extension. Intensive rehabilitation utilizing the step-up exercise in the setting of ACL deficiency can potentially introduce repetitive microtrauma by way of altered kinematics. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab,Sch Med,GRJ 1215, Boston, MA 02114 USA. [Kozanek, Michal; Moussa, Mohamed E.; Gill, Thomas J.; Li, Guoan] Massachusetts Gen Hosp, Harvard Combined Orthopaed Residency Program, WHT 535, Boston, MA 02114 USA. [Kozanek, Michal] Comenius Univ, Dept Orthopaed & Traumatol 1, Fac Med, Fac Hosp Ruzinov, Bratislava 82101, Slovakia. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab,Sch Med,GRJ 1215, 55 Fruit St, Boston, MA 02114 USA. EM gli1@partners.org FU National Institutes of Health (NIH) [R-01 AR055612, F-32 AR056451] FX This investigation was made possible through the support of the National Institutes of Health (NIH), grants R-01 AR055612 and F-32 AR056451. NR 29 TC 11 Z9 11 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 J9 CLIN BIOMECH JI Clin. Biomech. PD NOV PY 2011 VL 26 IS 9 BP 950 EP 954 DI 10.1016/j.clinbiomech.2011.05.003 PG 5 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 840AK UT WOS:000296410400010 PM 21652128 ER PT J AU Merchant, RM Yang, L Becker, LB Berg, RA Nadkarni, V Nichol, G Carr, BG Mitra, N Bradley, SM Abella, BS Groeneveld, PW AF Merchant, Raina M. Yang, Lin Becker, Lance B. Berg, Robert A. Nadkarni, Vinay Nichol, Graham Carr, Brendan G. Mitra, Nandita Bradley, Steven M. Abella, Benjamin S. Groeneveld, Peter W. CA American Heart Assoc Get Guideline TI Incidence of treated cardiac arrest in hospitalized patients in the United States SO CRITICAL CARE MEDICINE LA English DT Article DE cardiopulmonary resuscitation; heart arrest; resuscitation ID AMERICAN-HEART-ASSOCIATION; EMERGENCY CARDIOVASCULAR CARE; CARDIOPULMONARY-RESUSCITATION; NATIONAL REGISTRY; SURVIVAL; GUIDELINES; IMPLEMENTATION; DISPARITIES; COUNCIL; ORDERS AB Objective: The incidence and incidence over time of cardiac arrest in hospitalized patients is unknown. We sought to estimate the event rate and temporal trends of adult inhospital cardiac arrest treated with a resuscitation response. Design: Three approaches were used to estimate the inhospital cardiac arrest event rate. First approach: calculate the inhospital cardiac arrest event rate at hospitals (n = 433) in the Get With The Guidelines-Resuscitation registry, years 2003-2007, and multiply this by U. S. annual bed days. Second approach: use the Get With The Guidelines-Resuscitation inhospital cardiac arrest event rate to develop a regression model (including hospital demographic, geographic, and organizational factors), and use the model coefficients to calculate predicted event rates for acute care hospitals (n = 5445) responding to the American Hospital Association survey. Third approach: classify acute care hospitals into groups based on academic, urban, and bed size characteristics, and determine the average event rate for Get With The Guidelines-Resuscitation hospitals in each group, and use weighted averages to calculate the national inhospital cardiac arrest rate. Annual event rates were calculated to estimate temporal trends. Setting: Get With The Guidelines-Resuscitation registry. Patients: Adult inhospital cardiac arrest with a resuscitation response. Measurements and Main Results: The mean adult treated inhospital cardiac arrest event rate at Get With The Guidelines-Resuscitation hospitals was 0.92/1000 bed days (interquartile range 0.58 to 1.2/1000). In hospitals (n = 150) contributing data for all years of the study period, the event rate increased from 2003 to 2007. With 2.09 million annual U. S. bed days, we estimated 192,000 inhospital cardiac arrests throughout the United States annually. Based on the regression model, extrapolating Get With The Guidelines-Resuscitation hospitals to hospitals participating in the American Hospital Association survey projected 211,000 annual inhospital cardiac arrests. Using weighted averages projected 209,000 annual U. S. inhospital cardiac arrests. Conclusions: There are approximately 200,000 treated cardiac arrests among U. S. hospitalized patients annually, and this rate may be increasing. This is important for understanding the burden of inhospital cardiac arrest and developing strategies to improve care for hospitalized patients. (Crit Care Med 2011; 39: 2401-2406) C1 [Merchant, Raina M.; Becker, Lance B.; Carr, Brendan G.; Abella, Benjamin S.] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Berg, Robert A.; Nadkarni, Vinay] Univ Penn, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA. [Mitra, Nandita] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Yang, Lin; Groeneveld, Peter W.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Berg, Robert A.; Nadkarni, Vinay] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Nichol, Graham; Bradley, Steven M.] Univ Washington, Seattle, WA 98195 USA. [Groeneveld, Peter W.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Merchant, RM (reprint author), Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. EM raina.merchant@uphs.upenn.edu OI Abella, Benjamin/0000-0003-2521-0891 FU Robert Wood Johnson Foundation at University of Pennsylvania; Institute for Health Technology Studies (Washington, DC); National Heart, Lung, and Blood Institute [1-R01-HL086919]; Pennsylvania Department of Health; Department of Veterans Affairs' Health Services Research and Development Service [RRP 09-117]; Philips Healthcare, Seattle, WA; Laerdal Medical, Stavanger, Norway; NIH, Bethesda, MD; Cardiac Science, Bothell, Washington; Laerdal Foundation for Acute Care Medicine, Stavanger, Norway; NIH; Asmund S. Laerdal Foundation for Acute Medicine; NHLBI; Medtronic Foundation; AHRQ; Medivance Corporation, Louisville, CO; Philips Healthcare, Andover, MA; Doris Duke Foundation, New York City, NY; American Heart Association, Dallas, TX FX Supported, in part, by funding from the Robert Wood Johnson Foundation Clinical Scholars program at the University of Pennsylvania (Merchant); an unrestricted grant from the Institute for Health Technology Studies (Washington, DC); grant 1-R01-HL086919 from the National Heart, Lung, and Blood Institute; and a grant from the Pennsylvania Department of Health, which specifically disclaims responsibility for any analyses, interpretations, or conclusions. Dr. Groeneveld was additionally supported by a Research Career Development Award (RRP 09-117) from the Department of Veterans Affairs' Health Services Research and Development Service.; Dr. Becker received speaker honoraria/consultant fees from Philips Healthcare, Seattle, WA; institutional grant/research support from Philips Healthcare, Seattle, WA, Laerdal Medical, Stavanger, Norway, NIH, Bethesda, MD, and Cardiac Science, Bothell, Washington. Dr. Nadkarni received institutional grant/research support from the Laerdal Foundation for Acute Care Medicine, Stavanger, Norway, and NIH, Bethesda, MD. Dr. Nichol received institutional grant/research support from NIH, the Asmund S. Laerdal Foundation for Acute Medicine, the NHLBI, the Medtronic Foundation, and has research collaborations with Gambro Renal, Lakewood, CO, Sotera Wireless, San Diego, CA, Lifebridge Medizintechnik AG, Ampfing, Germany. Dr. Carr received institutional grant/research support from NIH, and AHRQ. Dr. Abella received speaker honoraria/consultant fees from Philips Healthcare, Seattle, WA, Medivance Corporation, Louisville, CO; and institutional grant/research support: Philips Healthcare, Andover, MA, Doris Duke Foundation, New York City, NY, American Heart Association, Dallas, TX, NIH, Bethesda, MD. The remaining authors have not disclosed any potential conflict of interests. NR 36 TC 126 Z9 128 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2011 VL 39 IS 11 BP 2401 EP 2406 DI 10.1097/CCM.0b013e3182257459 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 841JV UT WOS:000296509500002 PM 21705896 ER PT J AU Cobb, JP Hayden, DL Schoenfeld, DA AF Cobb, J. Perren Hayden, Douglas L. Schoenfeld, David A. TI Novel diagnostics for sepsis: A decade of promise for gene expression profiling SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE genomics; human; inflammation; microarray ID CRITICAL ILLNESS; INJURY; RIBOLEUKOGRAM; PLASTICITY; DISEASE C1 [Cobb, J. Perren] Massachusetts Gen Hosp, Crit Care Ctr, Boston, MA 02114 USA. [Hayden, Douglas L.; Schoenfeld, David A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Cobb, JP (reprint author), Massachusetts Gen Hosp, Crit Care Ctr, Boston, MA 02114 USA. NR 21 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2011 VL 39 IS 11 BP 2579 EP 2581 DI 10.1097/CCM.0b013e31822a5e36 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 841JV UT WOS:000296509500039 PM 22005238 ER PT J AU Ciuffreda, D Kim, AY AF Ciuffreda, Donatella Kim, Arthur Y. TI Update on hepatitis C virus-specific immunity SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE CD4 T cell; CD8 T cell; HLA; inhibitory markers ID CD8(+) T-CELLS; HUMAN-IMMUNODEFICIENCY-VIRUS; PERSISTENT VIRAL-INFECTION; NATURAL-KILLER-CELLS; ACUTE HCV INFECTION; ANTIGEN CLASS-I; MHC CLASS-I; PD-1 EXPRESSION; DISEASE PROGRESSION; HIV-INFECTION AB Purpose of review The goal of this study is to review key recent findings related to the immunopathogenesis of hepatitis C virus (HCV) infection, especially in regards to T lymphocytes. It aims to complement other reviews in this issue on the roles of host genetics (IL-28B), acute HCV infection (when disease outcome is determined) and other factors that may influence fibrosis progression (microbial translocation). The main focus is on specific immunity and T cells in the context of success and failure to control viral infection. Recent findings This review focuses on two areas of intense interest in the recent literature: the relationship between the human leukocyte antigen (HLA), class I-restricted T-cell responses and the evolution of the virus and the role of inhibitory markers on T cells in the immunopathogenesis of HCV. When appropriate, we compare findings from studies of HIV-specific immunity. Summary From examining the virus and the mutational changes associated with T-cell responses and from analyzing the markers on T cells, there have been numerous advances in the understanding of immune evasion mechanisms employed by HCV. C1 [Kim, Arthur Y.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Ciuffreda, Donatella] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Kim, AY (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,Cox 5, Boston, MA 02114 USA. EM akim1@partners.org FU Swiss National Science Foundation; National Institutes of Health/National Institute of Allergy and Infectious Diseases [AI066345, AI091649] FX D. C. is supported by the Swiss National Science Foundation. A. Y. K. is supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (AI066345 and AI091649). A. Y. K. serves as a speaker for the New England AIDS Treatment and Education Center (nonprofit) and is on an editorial board for FirstConsult.com. NR 105 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD NOV PY 2011 VL 6 IS 6 BP 559 EP 565 DI 10.1097/COH.0b013e32834b879e PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839IX UT WOS:000296360000017 PM 22001897 ER PT J AU Preffer, FI Gratama, JW AF Preffer, Frederic I. Gratama, Jan W. TI Clinical Cytometry on Both Sides of the Atlantic, 2011 Introduction to ICCS and ESCCA/ICyS Abstracts SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Editorial Material C1 [Preffer, Frederic I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gratama, Jan W.] Erasmus MC, Dept Internal Oncol, NL-3075 EA Rotterdam, Netherlands. RP Preffer, FI (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM preffer@helix.mgh.harvard.edu; j.w.gratama@erasmusmc.nl NR 0 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2011 VL 80B IS 6 BP 373 EP 374 DI 10.1002/cyto.b.20626 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 838FT UT WOS:000296273300006 PM 22002905 ER PT J AU Daley, J Smith, R Lazo-Kallanian, S AF Daley, John, II Smith, Robert Lazo-Kallanian, Suzan TI REMOTE FLOW CYTOMETRY: A REVIEW OF OPTIONS AVAILABLE AND SELECTED APPLICATIONS SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 26th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 14-18, 2011 CL Portland, OR SP Int Clin Cytometry Soc C1 [Daley, John, II; Smith, Robert; Lazo-Kallanian, Suzan] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2011 VL 80B IS 6 BP 391 EP 392 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 838FT UT WOS:000296273300051 ER PT J AU Hansen, P Dombkowski, D DeLelys, M Restell, A Sylvia, D Krauledat, P Magnin, O Preffer, F AF Hansen, Peter Dombkowski, David DeLelys, Michelle Restell, Amanda Sylvia, Dorothy Krauledat, Petra Magnin, Olivier Preffer, Frederic TI ENABLING POINT-OF-CARE CD4 T-CELL COUNTING WITH A ONE MINUTE SAMPLE PREPARATION METHOD AND HEAT STABLE ANTIBODY CONJUGATE SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 26th Annual Meeting of the International-Clinical-Cytometry-Society CY OCT 14-18, 2011 CL Portland, OR SP Int Clin Cytometry Soc C1 [Hansen, Peter] Union Biometr Tech, Canaan, NY USA. [Dombkowski, David; DeLelys, Michelle; Preffer, Frederic] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Restell, Amanda; Sylvia, Dorothy; Krauledat, Petra] PointCare Technol, Marlborough, MA USA. [Magnin, Olivier] C2 Diagnost, Montpellier, France. 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 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD NOV PY 2011 VL 80B IS 6 BP 404 EP 404 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 838FT UT WOS:000296273300086 ER PT J AU Ghillebert, R Swinnen, E Wen, J Vandesteene, L Ramon, M Norga, K Rolland, F Winderickx, J AF Ghillebert, Ruben Swinnen, Erwin Wen, Jing Vandesteene, Lies Ramon, Matthew Norga, Koen Rolland, Filip Winderickx, Joris TI The AMPK/SNF1/SnRK1 fuel gauge and energy regulator: structure, function and regulation SO FEBS JOURNAL LA English DT Review DE allosteric regulation; AMP-activated kinase (AMPK); cross-species conservation; energy signaling; function; phosphorylation; Snf1-related kinase1 (SnRK1); stress response; structure; sucrose nonfermenting1 (SNF1) ID ACTIVATED PROTEIN-KINASE; TREHALOSE-PHOSPHATE SYNTHASE; SACCHAROMYCES-CEREVISIAE CELLS; MIG1 GLUCOSE REPRESSOR; ACETYL-COA CARBOXYLASE; SNF1 KINASE; YEAST SNF1; CAENORHABDITIS-ELEGANS; BETA-SUBUNITS; SUBCELLULAR-LOCALIZATION AB All life forms on earth require a continuous input and monitoring of carbon and energy supplies. The AMP-activated kinase (AMPK)/sucrose nonfermenting1 (SNF1)/Snf1-related kinase1 (SnRK1) protein kinases are evolutionarily conserved metabolic sensors found in all eukaryotic organisms from simple unicellular fungi (yeast SNF1) to animals (AMPK) and plants (SnRK1). Activated by starvation and energy-depleting stress conditions, they enable energy homeostasis and survival by up-regulating energy-conserving and energy-producing catabolic processes, and by limiting energy-consuming anabolic metabolism. In addition, they control normal growth and development as well as metabolic homeostasis at the organismal level. As such, the AMPK/SNF1/SnRK1 kinases act in concert with other central signaling components to control carbohydrate uptake and metabolism, fatty acid and lipid biosynthesis and the storage of carbon energy reserves. Moreover, they have a tremendous impact on developmental processes that are triggered by environmental changes such as nutrient depletion or stress. Although intensive research by many groups has partly unveiled the factors that regulate AMPK/SNF1/SnRK1 kinase activity as well as the pathways and substrates they control, several fundamental issues still await to be clarified. In this review, we will highlight these issues and focus on the structure, function and regulation of the AMPK/SNF1/SnRK1 kinases. C1 [Ghillebert, Ruben; Swinnen, Erwin; Wen, Jing; Vandesteene, Lies; Ramon, Matthew; Rolland, Filip; Winderickx, Joris] Katholieke Univ Leuven, Dept Biol, Lab Funct Biol, B-3001 Heverlee, Belgium. [Ramon, Matthew] Harvard Univ, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA USA. [Norga, Koen] Flanders Inst Biotechnol VIB, Lab Dev Genet, Louvain, Belgium. [Norga, Koen] Katholieke Univ Leuven, Dept Woman & Child Pediat Hematol & Oncol, Louvain, Belgium. RP Winderickx, J (reprint author), Katholieke Univ Leuven, Dept Biol, Lab Funct Biol, Kasteelpk Arenberg 31,POB 2433, B-3001 Heverlee, Belgium. EM joris.winderickx@bio.kuleuven.be OI Norga, Koenraad/0000-0002-9231-0350 FU Fonds voor Wetenschappelijk Onderzoek (FWO); Agentschap voor Innovatie door Wetenschap en Technologie in Vlaanderen (IWT); K.U.Leuven (BOF, Bijzonder Onderzoeksfonds); NSF [IOS-0843244] FX Work on AMPK/SNF1/SnRK1 in the K.U.Leuven laboratories is funded by Fonds voor Wetenschappelijk Onderzoek (FWO), Agentschap voor Innovatie door Wetenschap en Technologie in Vlaanderen (IWT) and K.U.Leuven (BOF, Bijzonder Onderzoeksfonds). Work on SnRK1 at MGH is funded by NSF grant IOS-0843244. NR 131 TC 83 Z9 86 U1 3 U2 67 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD NOV PY 2011 VL 278 IS 21 BP 3978 EP 3990 DI 10.1111/j.1742-4658.2011.08315.x PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 837XT UT WOS:000296245400002 PM 21883929 ER PT J AU Bakirtzi, K Hatziapostolou, M Karagiannides, I Polytarchou, C Jaeger, S Iliopoulos, D Pothoulakis, C AF Bakirtzi, Kyriaki Hatziapostolou, Maria Karagiannides, Iordanes Polytarchou, Christos Jaeger, Savina Iliopoulos, Dimitrios Pothoulakis, Charalabos TI Neurotensin Signaling Activates MicroRNAs-21 and-155 and Akt, Promotes Tumor Growth in Mice, and Is Increased in Human Colon Tumors SO GASTROENTEROLOGY LA English DT Article DE Neuropeptide; Colorectal Cancer; Signal Transduction; Tumor Suppressor ID INFLAMMATORY-BOWEL-DISEASE; PROTEIN-KINASE-B; CANCER-CELLS; GASTRIC-CANCER; TARGET GENES; MAP-KINASE; EXPRESSION; IDENTIFICATION; PATHWAY; RAT AB BACKGROUND & AIMS: Neurotensin promotes inflammation and colon cancer via the neurotensin-1 receptor (NTR1). MicroRNAs (miR) regulate protein synthesis by degrading or preventing translation of mRNAs. We analyzed expression of 365 different microRNAs by human colonic epithelial cells (NCM460) after activation of NTR1. METHODS: We performed microarray analysis of mRNA expression by neurotensin-stimulated NCM460 cells that overexpressed NTR1. Nuclear factor-kappa B (NF-kappa B) binding sites were identified and tumorigenesis was assessed using soft agar assays and xenograft analysis of severe combined immunodeficiency mice. Targets of neurotensin-regulated microRNAs were identified via bioinformatic, real-time polymerase chain reaction, and immunoblot analyses. We analyzed RNA samples from human normal colon and tumor samples. RESULTS: Neurotensin stimulated differential expression of 38 microRNAs, including miR-21 and miR-155, which have been associated with tumor growth and contain NF-kappa B binding sites. Neurotensin expression increased colony formation by HCT-116 cells. Blocking miR-21 and/or miR-155 prevented colony formation (P<.001). In mice, intraperitoneal administration of neurotensin increased the growth rate of HCT-116 xenograft tumors; blocking miR-21 and/or miR-155 slowed this tumor growth. Neurotensin activated Akt in HCT-116 cells; this effect was inhibited by blocking miR-21 and/or miR-155 (P<.001). Neurotensin activated AKT through miR-155-mediated suppression of the phosphatase protein phosphatase 2A catalytic subunit alpha (PPP2CA). Levels of phosphatase and tensin homolog (PTEN) and suppressor of cytokine signaling 1 (SOCS1) mRNA, potential targets of miR-21 and miR-155, respectively, were down-regulated by these miRs. Levels of NTR1, miR-21, and miR-155 increased significantly in human colon tumor samples, compared with normal tissues, whereas PPP2CA, SOCS1, and PTEN mRNAs were reduced significantly. CONCLUSIONS: NTR1 activation stimulates expression of miR-21 and miR-155 in colonocytes, via Akt and NF-kappa B, to down-regulate PTEN and SOCS1 and promote growth of tumors in mice. Levels of NTR1, miR-21, and miR-155 increase in human colon tumor samples and correlate with tumor stage. C1 [Bakirtzi, Kyriaki; Karagiannides, Iordanes; Pothoulakis, Charalabos] Univ Calif Los Angeles, Div Digest Dis, Ctr Inflammatory Bowel Dis, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Hatziapostolou, Maria; Iliopoulos, Dimitrios] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Hatziapostolou, Maria; Iliopoulos, Dimitrios] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Polytarchou, Christos] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA USA. [Jaeger, Savina] Novartis Inst Biomed Res, Dept Dev Mol Pathways, Cambridge, MA USA. RP Pothoulakis, C (reprint author), Univ Calif Los Angeles, Div Digest Dis, Ctr Inflammatory Bowel Dis, David Geffen Sch Med, 675 Charles E Young Dr,S MRL Bldg 1240, Los Angeles, CA 90095 USA. EM cpothoulakis@mdenet.ucla.edu RI Hatziapostolou, Maria/N-1820-2015 OI Hatziapostolou, Maria/0000-0003-2493-7028 FU US Public Health Service [RO1 DK60729]; Crohn's and Colitis Foundation of America; Broad Foundation; Blinder Research Foundation for Crohn's Disease; Eli and Edythe Broad Chair FX Supported by US Public Health Service grant RO1 DK60729 (C. P.), a Crohn's and Colitis Foundation of America Research Fellowship (I. K.), a Medical Research Award from the Broad Foundation (I. K.), and by the Blinder Research Foundation for Crohn's Disease and the Eli and Edythe Broad Chair (C.P.). NR 50 TC 53 Z9 59 U1 5 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2011 VL 141 IS 5 BP 1749 EP U311 DI 10.1053/j.gastro.2011.07.038 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 841KW UT WOS:000296512200040 PM 21806946 ER PT J AU Paidassi, H Acharya, M Zhang, AL Mukhopadhyay, S Kwon, M Chow, C Stuart, LM Savill, J Lacy-Hulbert, A AF Paidassi, Helena Acharya, Mridu Zhang, Ailiang Mukhopadhyay, Subhankar Kwon, Manjae Chow, Camille Stuart, Lynda M. Savill, John Lacy-Hulbert, Adam TI Preferential Expression of Integrin alpha v beta 8 Promotes Generation of Regulatory T Cells by Mouse CD103(+) Dendritic Cells SO GASTROENTEROLOGY LA English DT Article DE FoxP3; Signaling; Macrobiota; Immune Regulation ID ALPHA-V INTEGRINS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; RETINOIC-ACID; DIFFERENTIATION; MICE; TH17; COLITIS; T(H)17; ACTIVATION; TOLERANCE AB BACKGROUND & AIMS: Immune responses in the intestine are controlled by regulatory T cells (Tregs), which prevent inflammation in response to commensal bacteria. A specific population of intestinal dendritic cells (DCs), marked by expression of CD103, generate Tregs more efficiently than other DC populations through mechanisms that involve retinoic acid and transforming growth factor (TGF)-beta. However, it is not clear how CD103(+) DCs are specialized for this function. We investigated the ability of CD103(+) DCs to promote Treg generation through activation of TGF-beta and the role of integrins with the alpha v subunit in this process. METHODS: Nave T cells were cultured with purified DCs from mesenteric lymph nodes (MLNs) or intestines of wild-type and alpha v conditional knockout mice to assess generation of Tregs. Antigens were administered orally to mice, and antigen-specific generation of Tregs was measured in intestinal tissues. Expression of the integrin alpha v subunit was measured in purified subpopulations of DCs by quantitative polymerase chain reaction and immunoblot analyses. RESULTS: In vitro, CD103(+) DCs generated more Tregs in the presence of latent TGF-beta than other MLN DCs. Efficient generation of Tregs required expression of the integrin alpha v subunit by DCs; mice that lacked alpha v in immune cells did not convert nave T cells to intestinal Tregs in response to oral antigen. CD103(+) DCs derived from the MLNs selectively expressed high levels of integrin alpha v beta 8 compared with other populations of DCs. CONCLUSIONS: Expression of alpha v beta 8 is required for CD103(+) DCs to become specialized and activate latent TGF-beta and generate Tregs during the induction of tolerance to intestinal antigens in mice. C1 [Paidassi, Helena; Acharya, Mridu; Mukhopadhyay, Subhankar; Kwon, Manjae; Chow, Camille; Stuart, Lynda M.; Lacy-Hulbert, Adam] Harvard Univ, Massachusetts Gen Hosp, Program Dev Immunol, Sch Med,Dept Pediat, Boston, MA 02114 USA. [Paidassi, Helena; Zhang, Ailiang; Savill, John] Univ Edinburgh, Queens Med Res Inst, MRC Ctr Inflammat Res, Edinburgh, Midlothian, Scotland. [Mukhopadhyay, Subhankar] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. RP Lacy-Hulbert, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Program Dev Immunol, Sch Med,Dept Pediat, GRJ1402,55 Fruit St, Boston, MA 02114 USA. EM alacy-hulbert@partners.org RI Paidassi, Helena/M-5739-2014; OI Lacy-Hulbert, Adam/0000-0003-2162-0156 FU Crohn's and Colitis Foundation of America; Hood Pediatric Research Foundation; National Institutes of Health [RO1AI79198]; UK Medical Research Council [G0802069]; Wellcome Trust; Philippe Foundation; Bettencourt-Schueller Foundation FX Supported by grants from the Crohn's and Colitis Foundation of America and the Hood Pediatric Research Foundation (to A. L.-H.), the National Institutes of Health (grant RO1AI79198 to L. M. S.), the UK Medical Research Council (grant G0802069 to J.S.), a Wellcome Trust traveling fellowship (to S. M.), and the Philippe Foundation and the Bettencourt-Schueller Foundation (Young Scientist Award to H.P.). NR 30 TC 39 Z9 40 U1 0 U2 9 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 NOV PY 2011 VL 141 IS 5 BP 1813 EP 1820 DI 10.1053/j.gastro.2011.06.076 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 841KW UT WOS:000296512200046 PM 21745448 ER PT J AU Corradini, E Rozier, M Meynard, D Odhiambo, A Lin, HY Feng, Q Migas, MC Britton, RS Babitt, JL Fleming, RE AF Corradini, Elena Rozier, Molly Meynard, Delphine Odhiambo, Adam Lin, Herbert Y. Feng, Qi Migas, Mary C. Britton, Robert S. Babitt, Jodie L. Fleming, Robert E. TI Iron Regulation of Hepcidin Despite Attenuated Smad1,5,8 Signaling in Mice Without Transferrin Receptor 2 or Hfe SO GASTROENTEROLOGY LA English DT Article DE Bone Morphogenetic Protein 6; Id1 ID HEREDITARY HEMOCHROMATOSIS PROTEIN; MOUSE MODEL; IN-VIVO; JUVENILE HEMOCHROMATOSIS; EXPRESSION; OVERLOAD; HEMOJUVELIN; METABOLISM; LIVER; TFR2 AB BACKGROUND & AIMS: HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes. METHODS: Hepatic iron concentrations and messenger RNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad) 1,5,8 and Id1 messenger RNA levels were measured as markers of Bmp/Smad signaling. RESULTS: Whereas Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also showed attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. CONCLUSIONS: These observations show that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via the Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver Bmp6 messenger RNA or steady-state P-Smad1,5,8 levels. C1 [Rozier, Molly; Feng, Qi; Migas, Mary C.; Fleming, Robert E.] St Louis Univ, Sch Med, Dept Pediat, St Louis, MO 63104 USA. [Britton, Robert S.] St Louis Univ, Sch Med, Dept Internal Med, St Louis, MO 63104 USA. [Fleming, Robert E.] St Louis Univ, Sch Med, Edward A Doisy Dept Biochem & Mol Biol, St Louis, MO 63104 USA. [Corradini, Elena; Meynard, Delphine; Odhiambo, Adam; Lin, Herbert Y.; Babitt, Jodie L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol,Div Nephrol,Program Membrane Biol, Boston, MA USA. RP Fleming, RE (reprint author), St Louis Univ, Sch Med, Dept Pediat, 1465 S Grand Ave, St Louis, MO 63104 USA. EM flemingr@slu.edu RI Corradini, Elena/O-4167-2016; meynard, delphine/B-4236-2014 OI Corradini, Elena/0000-0001-9477-2164; FU National Institutes of Health [R01 DK063016, K08 DK075846, R01 DK069533, R01 DK071837]; Massachusetts General Hospital FX Supported by National Institutes of Health grants (R01 DK063016 to R. E. F., K08 DK075846 to J.L.B., and R01 DK069533 and R01 DK071837 to H.Y.L.) and a Claflin Distinguished Scholar Award from the Massachusetts General Hospital (to J.L.B). NR 54 TC 34 Z9 37 U1 1 U2 5 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 NOV PY 2011 VL 141 IS 5 BP 1907 EP 1914 DI 10.1053/j.gastro.2011.06.077 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 841KW UT WOS:000296512200055 PM 21745449 ER PT J AU Byrd, JB Ho, PM AF Byrd, James Brian Ho, P. Michael TI The possibility of unmeasured confounding variables in observational studies: a forgotten fact? SO HEART LA English DT Editorial Material ID ACUTE MYOCARDIAL-INFARCTION; CLOPIDOGREL; OUTCOMES; DISEASE C1 [Byrd, James Brian] Univ Colorado, Div Cardiol, Denver, CO 80202 USA. [Ho, P. Michael] Denver VA Med Ctr, Cardiol Sect, Denver, CO USA. RP Ho, PM (reprint author), 1055 Clermont St, Denver, CO 80220 USA. EM michael.ho@coloradooutcomes.org OI Byrd, J. Brian/0000-0002-0509-3520 NR 10 TC 3 Z9 3 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD NOV PY 2011 VL 97 IS 22 BP 1815 EP 1816 DI 10.1136/heartjnl-2011-300630 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 837LF UT WOS:000296203800001 PM 21795300 ER PT J AU Murphy, K van Ginneken, B Reinhardt, JM Kabus, S Ding, K Deng, X Cao, KL Du, KF Christensen, GE Garcia, V Vercauteren, T Ayache, N Commowick, O Malandain, G Glocker, B Paragios, N Navab, N Gorbunova, V Sporring, J de Bruijne, M Han, X Heinrich, MP Schnabel, JA Jenkinson, M Lorenz, C Modat, M McClelland, JR Ourselin, S Muenzing, SEA Viergever, MA De Nigris, D Collins, DL Arbel, T Peroni, M Li, R Sharp, GC Schmidt-Richberg, A Ehrhardt, J Werner, R Smeets, D Loeckx, D Song, G Tustison, N Avants, B Gee, JC Staring, M Klein, S Stoel, BC Urschler, M Werlberger, M Vandemeulebroucke, J Rit, S Sarrut, D Pluim, JPW AF Murphy, Keelin van Ginneken, Bram Reinhardt, Joseph M. Kabus, Sven Ding, Kai Deng, Xiang Cao, Kunlin Du, Kaifang Christensen, Gary E. Garcia, Vincent Vercauteren, Tom Ayache, Nicholas Commowick, Olivier Malandain, Gregoire Glocker, Ben Paragios, Nikos Navab, Nassir Gorbunova, Vladlena Sporring, Jon de Bruijne, Marleen Han, Xiao Heinrich, Mattias P. Schnabel, Julia A. Jenkinson, Mark Lorenz, Cristian Modat, Marc McClelland, Jamie R. Ourselin, Sebastien Muenzing, Sascha E. A. Viergever, Max A. De Nigris, Dante Collins, D. Louis Arbel, Tal Peroni, Marta Li, Rui Sharp, Gregory C. Schmidt-Richberg, Alexander Ehrhardt, Jan Werner, Rene Smeets, Dirk Loeckx, Dirk Song, Gang Tustison, Nicholas Avants, Brian Gee, James C. Staring, Marius Klein, Stefan Stoel, Berend C. Urschler, Martin Werlberger, Manuel Vandemeulebroucke, Jef Rit, Simon Sarrut, David Pluim, Josien P. W. TI Evaluation of Registration Methods on Thoracic CT: The EMPIRE10 Challenge SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Chest; computed tomography; evaluation; registration ID DEFORMABLE IMAGE REGISTRATION; LUNG MOTION; MULTI-INSTITUTION; MEDICAL IMAGES; ACCURACY; ALGORITHMS; QUANTIFICATION; SEGMENTATION; VALIDATION; FRAMEWORK AB EMPIRE10 (Evaluation of Methods for Pulmonary Image REgistration 2010) is a public platform for fair and meaningful comparison of registration algorithms which are applied to a database of intrapatient thoracic CT image pairs. Evaluation of nonrigid registration techniques is a nontrivial task. This is compounded by the fact that researchers typically test only on their own data, which varies widely. For this reason, reliable assessment and comparison of different registration algorithms has been virtually impossible in the past. In this work we present the results of the launch phase of EMPIRE10, which comprised the comprehensive evaluation and comparison of 20 individual algorithms from leading academic and industrial research groups. All algorithms are applied to the same set of 30 thoracic CT pairs. Algorithm settings and parameters are chosen by researchers expert in the configuration of their own method and the evaluation is independent, using the same criteria for all participants. All results are published on the EMPIRE10 website (http://empire10.isi.uu.nl). The challenge remains ongoing and open to new participants. Full results from 24 algorithms have been published at the time of writing. This paper details the organization of the challenge, the data and evaluation methods and the outcome of the initial launch with 20 algorithms. The gain in knowledge and future work are discussed. C1 [van Ginneken, Bram] Radboud Univ Nijmegen, Med Ctr, Dept Radiol, NL-6500 HB Nijmegen, Netherlands. [Murphy, Keelin; van Ginneken, Bram; Muenzing, Sascha E. A.; Viergever, Max A.; Pluim, Josien P. W.] Univ Med Ctr, Image Sci Inst, NL-3584 CX Utrecht, Netherlands. [Reinhardt, Joseph M.; Ding, Kai; Du, Kaifang] Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA. [Kabus, Sven; Lorenz, Cristian] Philips Res Labs, D-22335 Hamburg, Germany. [Cao, Kunlin; Christensen, Gary E.] Univ Iowa, Dept Elect & Comp Engn, Iowa City, IA 52242 USA. [Garcia, Vincent; Ayache, Nicholas; Malandain, Gregoire] INRIA Sophia Antipolis Mediterranee, F-06902 Sophia Antipolis, France. [Vercauteren, Tom] Mauna Kea Technol, F-75010 Paris, France. [Commowick, Olivier] INRIA Rennes Bretagne Atlantique, Rennes, France. [Glocker, Ben; Navab, Nassir] Tech Univ Munich, D-85748 Garching, Germany. [Paragios, Nikos] INRIA Saclay Ile de France, F-91893 Orsay, France. [Paragios, Nikos] Ecole Cent Paris, Lab MAS, F-92295 Chatenay Malabry, France. [Gorbunova, Vladlena; Sporring, Jon; de Bruijne, Marleen] Univ Copenhagen, Dept Comp Sci, DK-2100 Copenhagen, Denmark. [de Bruijne, Marleen; Klein, Stefan] Erasmus MC, Biomed Imaging Grp Rotterdam, NL-3000 CA Rotterdam, Netherlands. [Han, Xiao] Elekta Inc, CMS Software, Maryland Hts, MO 63043 USA. [Heinrich, Mattias P.; Schnabel, Julia A.] Univ Oxford, Inst Biomed Engn, Dept Engn Sci, Oxford OX3 7DQ, England. [Heinrich, Mattias P.; Jenkinson, Mark] Univ Oxford, Ctr Funct MRI Brain, Oxford OX3 9DU, England. [Modat, Marc; McClelland, Jamie R.; Ourselin, Sebastien] UCL, Ctr Med Image Comp, London WC1E 6BT, England. [De Nigris, Dante; Arbel, Tal] McGill Univ, Ctr Intelligent Machines, Montreal, PQ H3A 2T5, Canada. [Collins, D. Louis] McGill Univ, Dept Biomed Engn, Montreal, PQ H3A 2T5, Canada. [Peroni, Marta; Li, Rui; Sharp, Gregory C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Peroni, Marta] Politecn Milan, I-20133 Milan, Italy. [Peroni, Marta] MIT, Cambridge, MA 02139 USA. [Schmidt-Richberg, Alexander; Ehrhardt, Jan; Werner, Rene] Univ Lubeck, Inst Med Informat, D-23538 Lubeck, Germany. [Smeets, Dirk; Loeckx, Dirk] Univ Hosp Gasthuisberg, KU Leuven, Fac Engn, ESAT PSI,Med Imaging Res Ctr, B-3000 Louvain, Belgium. [Song, Gang; Avants, Brian; Gee, James C.] Univ Penn, Sch Med, PICSL, Dept Radiol, Philadelphia, PA 19104 USA. [Tustison, Nicholas] Univ Virginia, Dept Radiol & Med Imaging, Charlottesville, VA 22908 USA. [Staring, Marius; Stoel, Berend C.] Leiden Univ, Med Ctr, Div Image Proc, Dept Radiol, NL-2300 RC Leiden, Netherlands. [Urschler, Martin; Werlberger, Manuel] Graz Univ Technol, Inst Comp Graph & Vis, A-8010 Graz, Austria. [Urschler, Martin] Ludwig Boltzmann Inst Clin Forens Imaging, A-8010 Graz, Austria. [Vandemeulebroucke, Jef; Rit, Simon; Sarrut, David] Univ Lyon 1, CREATIS, CNRS UMR5220, Inserm U1044,INSA Lyon,Ctr Leon Berard, F-69000 Lyon, France. RP van Ginneken, B (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Radiol, NL-6500 HB Nijmegen, Netherlands. EM b.vanginneken@rad.umcn.nl RI Staring, Marius/A-9517-2009; Ding, Kai/E-1943-2013; Rit, Simon/H-9410-2014; Viergever, Max/J-1215-2014; Vercauteren, Tom/I-7290-2013; Sarrut, David/F-4849-2010; Schmidt-Richberg, Alexander/G-1597-2015; van Ginneken, Bram/A-3728-2012; Vandemeulebroucke, Jef/F-2596-2016; Malandain, Gregoire/J-8115-2015; Sporring, Jon/L-4499-2016; de Bruijne, Marleen/G-2662-2010; Werner, Rene/B-4989-2017 OI Jenkinson, Mark/0000-0001-6043-0166; avants, brian/0000-0002-4212-3362; TUSTISON, NICHOLAS/0000-0001-9418-5103; Schnabel, Julia/0000-0001-6107-3009; McClelland, Jamie/0000-0002-4922-0093; Urschler, Martin/0000-0001-5792-3971; Glocker, Ben/0000-0002-4897-9356; Vercauteren, Tom/0000-0003-1794-0456; Sarrut, David/0000-0002-4854-4141; Schmidt-Richberg, Alexander/0000-0002-0633-4832; van Ginneken, Bram/0000-0003-2028-8972; Vandemeulebroucke, Jef/0000-0001-5714-3254; Malandain, Gregoire/0000-0002-4559-1575; Sporring, Jon/0000-0003-1261-6702; de Bruijne, Marleen/0000-0002-6328-902X; Werner, Rene/0000-0002-2296-3305 FU Roberto Rocca Foundation FX The work of M. Peroni was supported by the Roberto Rocca Foundation. Asterisk indicates corresponding author. NR 63 TC 146 Z9 147 U1 3 U2 27 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD NOV PY 2011 VL 30 IS 11 BP 1901 EP 1920 DI 10.1109/TMI.2011.2158349 PG 20 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 840QM UT WOS:000296455500003 PM 21632295 ER PT J AU Balamayooran, T Batra, S Balamayooran, G Cai, SS Kobayashi, KS Flavell, RA Jeyaseelan, S AF Balamayooran, Theivanthiran Batra, Sanjay Balamayooran, Gayathriy Cai, Shanshan Kobayashi, Koichi S. Flavell, Richard A. Jeyaseelan, Samithamby TI Receptor-Interacting Protein 2 Controls Pulmonary Host Defense to Escherichia coli Infection via the Regulation of Interleukin-17A SO INFECTION AND IMMUNITY LA English DT Article ID NF-KAPPA-B; CONTAINING ADAPTER PROTEIN; INNATE IMMUNE-RESPONSES; NEUTROPHIL RECRUITMENT; KLEBSIELLA-PNEUMONIAE; INFLAMMATORY RESPONSE; BACTERIAL PNEUMONIA; INHALED ENDOTOXIN; IL-17 PRODUCTION; KINASE-ACTIVITY AB Recognition of microbial patterns by host receptors is the first step in a multistep sequence leading to neutrophil-dependent host resistance. Although the role of membrane-bound sensors in bacterial recognition has been examined in detail, the importance of cytosolic sensors in the lungs is largely unexplored. In this context, there is a major lack of understanding related to the downstream signaling mediators, such as cells and/or molecules, during acute extracellular Gram-negative bacterial pneumonia. In order to determine the role of NOD-like receptors (NLRs), we used an experimental Escherichia coli infection model using mice deficient in the gene coding for the NLR adaptor, receptor-interacting protein 2 (RIP2). RIP2(-/-) mice with E. coli infection displayed higher bacterial burden and reduced neutrophil recruitment and tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), macrophage inflammatory protein 2 (MIP-2), and CXCL5/LIX expression, along with attenuated histopathological changes in the lungs. Decreased IL-17A levels were observed, along with lower numbers of IL-17A-producing T cells, in RIP2(-/-) mice after infection. RIP2(-/-) mice also show reduced IL-6 and IL-23 levels in the lungs, along with decreased activation of STAT3 after infection. Furthermore, activation of NF-kappa B and mitogen-activated protein kinases (MAPKs) and expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the lungs of infected RIP2(-/-) mice were attenuated following infection. Although neutrophil mobilization to the blood was impaired in RIP2(-/-) mice following infection, the expression of CD62P, CD11a/18, CD11b, and CXCR2 on blood and lung neutrophils was not altered between infected wild-type (WT) and RIP2(-/-) mice. Thus, RIP2 contributes to neutrophil-dependent host defense against an extracellular Gram-negative pathogen via (i) IL-17A regulation and (ii) neutrophil mobilization to the blood. C1 [Balamayooran, Theivanthiran; Batra, Sanjay; Balamayooran, Gayathriy; Cai, Shanshan; Jeyaseelan, Samithamby] Louisiana State Univ, Dept Pathobiol Sci, Lab Lung Biol, Baton Rouge, LA 70803 USA. [Balamayooran, Theivanthiran; Batra, Sanjay; Balamayooran, Gayathriy; Cai, Shanshan; Jeyaseelan, Samithamby] Louisiana State Univ, Ctr Expt Infect Dis Res, Baton Rouge, LA 70803 USA. [Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Flavell, Richard A.] Yale Univ, Howard Hughes Med Inst, Dept Immunobiol, Sch Med, New Haven, CT 06520 USA. [Jeyaseelan, Samithamby] LSU Hlth Sci Ctr, Sect Pulm & Crit Care Med, Dept Med, New Orleans, LA 70112 USA. RP Jeyaseelan, S (reprint author), Louisiana State Univ, Dept Pathobiol Sci, Lab Lung Biol, Baton Rouge, LA 70803 USA. EM jey@lsu.edu FU FAMRI [YCSA-062466]; NIH via ARRA [R01 HL-091958, R01 HL-091958S1] FX This work was supported by a Scientist Award from the FAMRI (YCSA-062466); and grants from the NIH (R01 HL-091958 and R01 HL-091958S1 via ARRA) to S.J. NR 60 TC 14 Z9 14 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2011 VL 79 IS 11 BP 4588 EP 4599 DI 10.1128/IAI.05641-11 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 839GB UT WOS:000296352400030 PM 21844230 ER PT J AU Nguyen, DD AF Nguyen, Deanna D. TI Thiopurines and Paternity: Is It Safe? SO INFLAMMATORY BOWEL DISEASES LA English DT Editorial Material ID INFLAMMATORY-BOWEL-DISEASE; POPULATION-BASED COHORT; AZATHIOPRINE; 6-MERCAPTOPURINE; PREGNANCY; OUTCOMES; MERCAPTOPURINE; WOMEN C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Crohns & Colitis Ctr, Boston, MA 02114 USA. RP Nguyen, DD (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Crohns & Colitis Ctr, Boston, MA 02114 USA. NR 13 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD NOV PY 2011 VL 17 IS 11 BP 2402 EP 2403 DI 10.1002/ibd.21718 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 840ED UT WOS:000296420200025 PM 21484969 ER PT J AU Sajatovic, M Al Jurdi, R Gildengers, A Greenberg, RL Tenhave, T Bruce, ML Mulsant, B Young, RC AF Sajatovic, Martha Al Jurdi, Rayan Gildengers, Ariel Greenberg, Rebecca L. Tenhave, Thomas Bruce, Martha L. Mulsant, Benoit Young, Robert C. TI Depression symptom ratings in geriatric patients with bipolar mania SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE bipolar disorder; geriatrics; older; depression; rating scales ID OLDER-ADULTS; MIXED MANIA; CLINICAL-TRIALS; II DISORDERS; SCALE; SENSITIVITY; DIAGNOSIS; SAMPLE; PURE AB Objective: Given the paucity of information available regarding standardized ratings of depression symptoms in bipolar manic states, and in particular those in older adults, we explored depression ratings in symptomatic participants in a multicenter study of treatment of bipolar I disorder in late life. Methods: Baseline data was obtained from the first 100 patients enrolled in an NIMH-funded, 9-week, randomized, double-blind RCT comparing treatment with lithium or valproate in patients of age 60 years and older with Type I Bipolar mania or hypomania. This multi-site study was conducted at six academic medical centers in the United States and enrolled inpatients and outpatients with a total Young Mania Rating Scale (YMRS) score of 18 or greater. Depressive symptoms were evaluated with the Hamilton Depression Rating Scale (HAM-D) and the Montgomery-Asberg Depression Rating Scale (MADRS). The criterion for at least moderate bipolar depressive symptoms was the European College of Neuropsychopharmacology (ECNP) Consensus Meeting definition of HAM-D 17 total score >20. Results: Eleven percent of patients had mixed symptoms defined by depression scale severity according to ECNP criterion. In the overall sample, total scores on the two depression scales were highly correlated. Total YMRS scores of this mixed symptom group were similar to the remainder of the sample. Conclusions: These preliminary findings suggest that moderate to severe depressive symptoms occur in about one in ten bipolar manic elders. Future studies are needed to further evaluate symptom profiles, clinical correlates, and treatments for bipolar older adults with combined manic and depressive symptoms. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Sajatovic, Martha] Case Western Reserve Univ, Sch Med, Dept Psychiat, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Al Jurdi, Rayan] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Dept Psychiat, Menninger Dept Psychiat, Houston, TX 77030 USA. [Gildengers, Ariel] Univ Pittsburgh, Sch Med, Dept Psychiat, Western Psychiat Inst & Clin, Pittsburgh, PA USA. [Greenberg, Rebecca L.; Bruce, Martha L.; Young, Robert C.] Weill Cornell Med Coll, Dept Psychiat, White Plains, NY USA. [Tenhave, Thomas] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Mulsant, Benoit] Univ Toronto, Geriatr Mental Hlth Program, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Mulsant, Benoit] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. RP Sajatovic, M (reprint author), Case Western Reserve Univ, Sch Med, Dept Psychiat, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. EM martha.sajatovic@uhhospitals.org RI Sajatovic, Martha/I-8001-2014; OI Young, Robert/0000-0002-6380-6314 FU National Institute of Mental Health (NIMH) [U01 MH074091-01]; National Center for Research Resources (NCRR), National Institutes of Health (NIH) [M01 RR00080, UL1 RR024989] FX This study was supported by National Institute of Mental Health (NIMH) grant U01 MH074091-01 (all authors); 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.; The project described was supported by Grant Number M01 RR00080 and UL1 RR024989 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. NR 36 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6230 EI 1099-1166 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD NOV PY 2011 VL 26 IS 11 BP 1201 EP 1208 DI 10.1002/gps.2664 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 840NK UT WOS:000296447300013 PM 21360754 ER PT J AU Charlton, BM Corliss, HL Missmer, SA Frazier, AL Rosario, M Kahn, JA Austin, SB AF Charlton, Brittany M. Corliss, Heather L. Missmer, Stacey A. Frazier, A. Lindsay Rosario, Margaret Kahn, Jessica A. Austin, S. Bryn TI Reproductive Health Screening Disparities and Sexual Orientation in a Cohort Study of U.S. Adolescent and Young Adult Females SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Homosexuality; Female; Bisexuality; Heterosexuality; Sexuality; Sexual behavior; Healthcare disparities; Papanicolaou test; Sexually transmitted diseases; Papillomavirus infections ID HUMAN-PAPILLOMAVIRUS INFECTION; GENITAL HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; WOMEN; LESBIANS; CARCINOGENESIS; MANAGEMENT; BEHAVIORS; SERVICES; HISTORY AB Purpose: To examine sexual orientation group disparities in the Papanicolaou (Pap) and sexually transmitted infection (STI)/human papillomavirus (HPV) tests among adolescents and young adult females. Methods: Survey data from 4,224 adolescents and young adults aged 17-25 years who responded to the 2005 wave questionnaire of the Growing Up Today Study were cross-sectionally examined with multivariate generalized estimating equations regression. We examined associations between sexual orientation and reproductive healthcare utilization as well as abnormal results with completely heterosexual as the referent group, controlling for age, race/ethnicity, geographic region, and sexual history. Results: After accounting for sociodemographics and sexual history, mostly heterosexual/bisexual females had 30% lower odds of having a Pap test within the last year and almost 40% higher odds of being diagnosed with an STI, as compared with the completely heterosexual group. Additionally, lesbians had very low odds of having a Pap test in their lifetime (odds ratio = .13, p <= .0001) and having a Pap test within the last year (odds ratio = .25, p = .0002), as compared with completely heterosexuals. Conclusions: Our study demonstrates that sexual minority adolescent and young adult women underutilize routine reproductive health screenings, including Pap smears and STI tests. Providers and health educators should be aware of these disparities so that they can provide appropriate care to young women and their families and ensure that all young women receive reproductive health screening. Further research is needed to explore reasons sexual minority females are not accessing care as recommended because this may suggest opportunities to improve reproductive health screenings as well as broader healthcare access issues. (C) 2011 Society for Adolescent Health and Medicine. All rights reserved. C1 [Charlton, Brittany M.; Missmer, Stacey A.; Frazier, A. Lindsay] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Corliss, Heather L.; Austin, S. Bryn] Childrens Hosp, Div Adolescent & Young Adult Med, Boston, MA 02115 USA. [Corliss, Heather L.; Austin, S. Bryn] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Missmer, Stacey A.; Frazier, A. Lindsay; Austin, S. Bryn] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Missmer, Stacey A.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Frazier, A. Lindsay] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Rosario, Margaret] CUNY City Coll, Dept Psychol, New York, NY USA. [Kahn, Jessica A.] Cincinnati Childrens Hosp, Med Ctr, Div Adolescent Med, Cincinnati, OH USA. [Kahn, Jessica A.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. [Austin, S. Bryn] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Rosario, Margaret] CUNY, Grad Ctr, New York, NY USA. RP Charlton, BM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,9th Floor, Boston, MA 02115 USA. EM bcharlto@hsph.harvard.edu FU National Institutes of Health [R01HD057368]; Maternal and Child Health Bureau [T71 MC 00009-17]; National Institute on Drug Abuse [K01 DA023610] FX This study was supported by research grant R01HD057368 from the National Institutes of Health. HL Corliss and SB Austin are supported by the Leadership Education in Adolescent Health Project grant T71 MC 00009-17 from the Maternal and Child Health Bureau. HL Corliss is also supported by the National Institute on Drug Abuse grant K01 DA023610. NR 34 TC 36 Z9 37 U1 1 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD NOV PY 2011 VL 49 IS 5 BP 505 EP 510 DI 10.1016/j.jadohealth.2011.03.013 PG 6 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 839SR UT WOS:000296390000010 PM 22018565 ER PT J AU Khullar, D Oreskovic, NM Perrin, JM Goodman, E AF Khullar, Dhruv Oreskovic, Nicolas M. Perrin, James M. Goodman, Elizabeth TI Optimism and the Socioeconomic Status Gradient in Adolescent Adiposity SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Socioeconomic status; Disparities; Dispositional optimism; Body mass index; Adiposity ID LIFE; OBESITY AB Purpose: To assess whether dispositional optimism is associated with adiposity and to explore whether dispositional optimism mediates the relationship between parent education and adiposity (body mass index [BMI] z-score). Methods: Multivariate regression analyses of data were collected from 1,298 non-Hispanic black and white adolescents aged 12-19 years from a single Midwestern public school district. Results: Less optimistic adolescents had higher BMI z-scores (r = -.09, p < .001). Addition of dispositional optimism to the regression model caused an approximately 10% attenuation of the parent education and BMI z-score relationship. Sobel tests confirmed that this attenuation indicated partial mediation. Conclusion: Lower dispositional optimism is associated with higher adiposity and this association accounts for some of the influence of parent education on adolescent adiposity. (C) 2011 Society for Adolescent Health and Medicine. All rights reserved. C1 [Oreskovic, Nicolas M.; Perrin, James M.; Goodman, Elizabeth] MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Khullar, Dhruv] Yale Univ, Sch Med, New Haven, CT USA. RP Goodman, E (reprint author), MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM egoodman3@partners.org OI Oreskovic, Nicolas/0000-0001-8702-8636; Goodman, Elizabeth/0000-0002-9640-9884 FU National Institutes of Health [HD041527, T35-HD007446] FX The present study was supported by National Institutes of Health grants HD041527 and T35-HD007446. NR 10 TC 5 Z9 5 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD NOV PY 2011 VL 49 IS 5 BP 553 EP 555 DI 10.1016/j.jadohealth.2011.04.003 PG 3 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 839SR UT WOS:000296390000019 PM 22018574 ER PT J AU Coumans, JVCE Walcott, BP AF Coumans, Jean-Valery C. E. Walcott, Brian P. TI Rapidly progressive lumbar subdural empyema following acromial bursal injection SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Complication; Infection; Spine; Staphylococcus aureus; Subdural empyema ID DERMAL SINUS; ABSCESS AB Spinal subdural empyemas are rare. We describe a 53-year-old male who presented with back pain, mental status changes, and sepsis. Five days prior he had undergone a triamcinolone and lidocaine injection of the acromial bursa. He also had a remote history of epidural steroid injection for thoracic back pain. Two lumbar MRI conducted 62 hours apart revealed a newly developed subdural empyema that was successfully treated with surgical evacuation and post-operative antibiotics. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Walcott, Brian P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,White Bldg Room 502, Boston, MA 02114 USA. EM walcott.brian@mgh.harvard.edu NR 11 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD NOV PY 2011 VL 18 IS 11 BP 1562 EP 1563 DI 10.1016/j.jocn.2011.03.009 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 839XM UT WOS:000296402800036 PM 21868236 ER PT J AU Sonnenberg, A AF Sonnenberg, Amnon TI Birth cohort patterns of gastric cancer and peptic ulcer among non-whites in the USA SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID TIME TRENDS; HELICOBACTER-PYLORI; MORTALITY; SALT; INFECTION; GERMANY; DISEASE; RATES; RISK AB Background The aim of this study was to follow the long-term trends of mortality from gastric cancer, gastric ulcer and duodenal ulcer in the USA. It was hypothesised that the time trends among different ethnic groups would be shaped by similar birth cohort patterns. Methods The US ulcer and cancer data were available from 1923 to 2006 and 1930 to 2006, respectively. Age-specific death rates were calculated for consecutive 10-year periods and 10-year age groups, stratified by sex and race. They were plotted against the period of death as period-age contours and against the period of birth as cohort-age contours. The time trends were also summarised as standardised cohort mortality ratios. Results The occurrence of birth cohort patterns with an initial rise and a subsequent decline was observed in gastric cancer and both ulcer types. It occurred similarly in white and non-white population, as well as men and women. In all ethnic groups alike, the initial rise in mortality from gastric cancer and gastric ulcer preceded the rise of duodenal ulcer by 10-20 years. The two time lags between gastric cancer and gastric ulcer and between gastric and duodenal ulcer were most pronounced in white patients. In non-white patients, the rise of gastric cancer occurred later than in white patients and coincided with that of gastric ulcer. The initial rise in mortality from gastric cancer was more evident in non-white than in white patients. Conclusion The birth cohort pattern has shaped the time trends of Helicobacter pylori-related disease similarly among different ethnic and socioeconomic groups. Its cause remains unknown and warrants further investigation. C1 [Sonnenberg, Amnon] Portland VA Med Ctr, Gastroenterol Sect, Portland, OR 97239 USA. [Sonnenberg, Amnon] Oregon Hlth & Sci Univ, Div Gastroenterol, Portland, OR 97201 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr, Gastroenterol Sect, P3-GI,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 31 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2011 VL 65 IS 11 BP 1059 EP 1064 DI 10.1136/jech.2010.121368 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 836VK UT WOS:000296143300017 PM 21597103 ER PT J AU Joseph, J AF Joseph, Jacob TI Fattening by deprivation: methyl balance and perinatal cardiomyopathy SO JOURNAL OF PATHOLOGY LA English DT Editorial Material DE methylation; homocysteine; folate; B12; cardiomyopathy ID TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; HYPERHOMOCYSTEINEMIA LEADS; HYPERTENSIVE-RATS; HEART; HOMOCYSTEINE; METABOLISM; ACTIVATION; MECHANISMS AB Folate deficiency during pregnancy is associated with reduced birth weight, and a low birth weight is associated with increased cardiometabolic risk in adulthood. In the study by Moreno Garcia, Gueant-Rodriguez and colleagues reported in the current issue of the Journal of Pathology, the effect of methyl group deprivation in pregnancy on the neonatal myocardium was investigated. By utilizing a diet deficient in folate, vitamin B(12) and choline, the authors created a significant deficit of methyl groups in the fetus. During the weaning period and the concomitant shift from the relative hypoxia and glucose dependence of the gestational period to the aerobic, milk-derived high-fat metabolic environment of the weaning phase, the offspring developed a myocardial hypertrophy associated with disordered fatty acid oxidation and mitochondrial dysfunction. The functionality of PGC-1 alpha, a master regulator of metabolic pathways including mitochondrial energetics and fatty acid oxidation, was found to be reduced in the methyl-deprived group, due to an imbalance in the ratio of methylation to acetylation. This study demonstrates that maternal methyl deprivation could 'prime' the fetus by reducing its ability to oxidize fatty acids in the myocardium, thereby causing lipid accumulation and myocardial hypertrophy during exposure to high-fat diet in the weaning phase. This study has important implications for clinical perinatal cardiomyopathy and for the effect of maternal methyl group deprivation on the future risk of cardiovascular disease, and also potentially in enhancing the understanding of the elusive link between hyperhomocysteinaemic states in the adult and cardiovascular disease. Copyright. (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Joseph, Jacob] VA Boston Healthcare Syst, Cardiol Sect 111, W Roxbury, MA 02132 USA. [Joseph, Jacob] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Joseph, J (reprint author), VA Boston Healthcare Syst, Cardiol Sect 111, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM jjoseph16@partners.org FU NHLBI NIH HHS [HL89734] NR 22 TC 7 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3417 J9 J PATHOL JI J. Pathol. PD NOV PY 2011 VL 225 IS 3 BP 315 EP 317 DI 10.1002/path.2942 PG 3 WC Oncology; Pathology SC Oncology; Pathology GA 839ME UT WOS:000296369900001 PM 21735445 ER PT J AU Prager, LM AF Prager, Laura M. TI Bipolar Disorder in the Book Forum SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Prager, LM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM lmprager@partners.org NR 0 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2011 VL 50 IS 11 BP 1186 EP 1186 DI 10.1016/j.jaac.2011.07.023 PG 1 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 838PS UT WOS:000296305300013 PM 22024006 ER PT J AU Wozniak, J McDonnell, MA Brenneman, JF AF Wozniak, Janet McDonnell, Mary Ann Brenneman, Judy Fort TI Bipolar Disorder in the Book Forum SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Letter ID I DISORDER; ONSET; COMORBIDITY; ADOLESCENTS; CHILDREN; FAMILY C1 [Wozniak, Janet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [McDonnell, Mary Ann] STEP Up Kids Inc, Marshfield, MA USA. [Brenneman, Judy Fort] Greenfire Creat LLC, Ft Collins, CO USA. RP Wozniak, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. EM jwozniak@partners.org NR 9 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 50 IS 11 BP 1186 EP 1187 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 838PS UT WOS:000296305300014 PM 22024007 ER PT J AU Okpokwasili, E AF Okpokwasili, Ebele TI Thirteen Reasons Why SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Book Review ID ETHNOCULTURAL ASPECTS; YOUNG-PEOPLE; SUICIDE C1 [Okpokwasili, Ebele] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Okpokwasili, E (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM eokpokwasili@partners.org NR 3 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 50 IS 11 BP 1191 EP 1192 DI 10.1016/j.jaac.2011.09.004 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 838PS UT WOS:000296305300018 ER PT J AU Suri, RM Burkhart, HM Daly, RC Dearani, JA Park, SJ Sundt, TM Li, Z Enriquez-Sarano, M Schaff, HV AF Suri, Rakesh M. Burkhart, Harold M. Daly, Richard C. Dearani, Joseph A. Park, Soon J. Sundt, Thoralf M., III Li, Zhuo Enriquez-Sarano, Maurice Schaff, Hartzell V. TI Robotic mitral valve repair for all prolapse subsets using techniques identical to open valvuloplasty: Establishing the benchmark against which percutaneous interventions should be judged SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 91st Annual Meeting of the American-Association-for-Thoracic-Surgery CY MAY 07-11, 2011 CL Philadelphia, PA SP Amer Assoc Thorac Surg ID CARDIAC-SURGERY DATABASE; LEAFLET PROLAPSE; OPERATIONS TRENDS; OUTCOMES; DURABILITY; REGURGITATION; ANNULOPLASTY; EXPERIENCE; SURVIVAL; SOCIETY AB Objective: Recent reports have shown that robotic mitral valve repair is effective in treating posterior leaflet disease; however, comparison with trans-sternal (open) valvuloplasty for all prolapse categories has not been performed. Moreover, data from the recently published EVEREST II trial infer that adverse event rates after mitral valve repair for degenerative disease are high. We therefore compared early outcomes of robotic versus open mitral valve repair for patients with mitral valve prolapse. Methods: Among 745 consecutive patients undergoing open or robotic mitral repair for degenerative disease, 95 propensity-matched pairs were identified. Leaflet prolapse categories were similar between groups. Complete mitral valve repair was performed using identical techniques. Results: Median crossclamp and bypass times were longer in the robotic group but decreased significantly over time (P <.001). There were no conversions to open sternotomy, repair rate and early survival were 100%, dismissal mitral regurgitation grade was similar (P - 1.00), and all patients in the robotic group had mild or less mitral regurgitation at 1 month after repair. There were no differences in adverse events (5% open vs 4% robotic, P = 1.00). Patients in the robotic group had shorter postoperative ventilation time, intensive care unit stay, and hospital stay. Conclusions: Robotic mitral valve repair allows complete anatomic correction of all categories of leaflet prolapse using techniques identical to open approaches. Robotic repair effectively corrects mitral regurgitation, offers excellent freedom from adverse events, and facilitates rapid weaning from ventilation, translating into earlier hospital dismissal. Safety and efficacy after both open and robotic mitral valve repair are higher than recently reported in the EVEREST II trial and establish a benchmark against which nonsurgical therapies should be evaluated. (J Thorac Cardiovasc Surg 2011;142:970-9) C1 [Suri, Rakesh M.; Burkhart, Harold M.; Daly, Richard C.; Dearani, Joseph A.; Park, Soon J.; Schaff, Hartzell V.] Mayo Clin, Div Cardiovasc Surg, Rochester, MN 55905 USA. [Li, Zhuo] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Enriquez-Sarano, Maurice] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Sundt, Thoralf M., III] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. RP Suri, RM (reprint author), Mayo Clin, Div Cardiovasc Surg, 200 1st St SW, Rochester, MN 55905 USA. EM suri.rakesh@mayo.edu OI Schaff, Hartzell/0000-0003-0994-027X NR 34 TC 50 Z9 50 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD NOV PY 2011 VL 142 IS 5 BP 970 EP 979 DI 10.1016/j.jtcvs.2011.07.027 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 839AT UT WOS:000296337500006 PM 21911231 ER PT J AU Dixon, JA Goodman, AM Gaillard, WF Rivers, WT McKinney, RA Mukherjee, R Baker, NL Ikonomidis, JS Spinale, FG AF Dixon, Jennifer A. Goodman, Amy M. Gaillard, William F., II Rivers, William T. McKinney, Richard A. Mukherjee, Rupak Baker, Nathaniel L. Ikonomidis, John S. Spinale, Francis G. TI Hemodynamics and myocardial blood flow patterns after placement of a cardiac passive restraint device in a model of dilated cardiomyopathy SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID INDUCED HEART-FAILURE; TACHYCARDIA-INDUCED CARDIOMYOPATHY; FUNCTIONAL MITRAL REGURGITATION; CONVERTING ENZYME-INHIBITION; ACORN CLINICAL-TRIAL; SUPPORT DEVICE; COMBINATION THERAPY; INFARCTION; REDUCTION; ADENOSINE AB Background: The present study examined a cardiac passive restraint device which applies epicardial pressure (HeartNet Implant; Paracor Medical, Inc, Sunnyvale, Calif) in a clinically relevant model of dilated cardiomyopathy to determine effects on hemodynamic and myocardial blood flow patterns. Methods: Dilated cardiomyopatht was established in 10 pigs (3 weeks of atrial pacing, 240 beats/min). Hemodynamic parameters and regional left ventricular blood flow were measured under baseline conditions and after acute placement of the HeartNet Implant. Measurements were repeated after adenosine infusion, allowing maximal coronary vasodilation and coronary flow reserve to be determined. Results: Left ventricular dilation and systolic dysfunction occurred relative to baseline as measured by echocardiography. Left ventricular end-diastolic dimension increased and left ventricular fractional shortening decreased (3.8 +/- 0.1 vs 6.1 +/- 0.2 cm and 31.6% +/- 0.5% vs 16.2% +/- 2.1%, both P < .05, respectively), consistent with the dilated cardiomyopathy phenotype. The HeartNet Implant was successfully deployed without arrhythmias and a computed median mid-left ventricular epicardial pressure of 1.4 mm Hg was applied by the HeartNet Implant throughout the cardiac cycle. Acute HeartNet placement did not adversely affect steady state hemodynamics. With the HeartNet Implant in place, coronary reserve was significantly blunted. Conclusions: In a large animal model of dilated cardiomyopathy, the cardiac passive restraint device did not appear to adversely affect basal resting myocardial blood flow. However, after acute HeartNet Implant placement, left ventricular maximal coronary reserve was blunted. These unique results suggest that cardiac passive restraint devices that apply epicardial transmural pressure can alter myocardial blood flow patterns in a model of dilated cardiomyopathy. Whether this blunting of coronary reserve holds clinical relevance with chronic passive restraint device placement remains unestablished. (J Thorac Cardiovasc Surg 2011;142:1038-45) C1 [Dixon, Jennifer A.; Gaillard, William F., II; Rivers, William T.; McKinney, Richard A.; Mukherjee, Rupak; Spinale, Francis G.] Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29425 USA. [Dixon, Jennifer A.; Gaillard, William F., II; Rivers, William T.; McKinney, Richard A.; Mukherjee, Rupak; Spinale, Francis G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Goodman, Amy M.; Ikonomidis, John S.] Paracor Med Inc, Sunnyvale, CA USA. [Baker, Nathaniel L.] Med Univ S Carolina, Dept Biostat & Epidemiol, Charleston, SC 29425 USA. RP Spinale, FG (reprint author), Strom Thurmond Res Ctr, 114 Doughty St,Suite 625, Charleston, SC 29425 USA. EM wilburnm@musc.edu FU Paracor Medical, Inc; National Institutes of Health [HL81692, HL87134]; Veterans' Affairs Health Administration FX This research was supported by a grant from Paracor Medical, Inc, as well as by National Institutes of Health grants HL81692 and HL87134 and a Merit Award from the Veterans' Affairs Health Administration. NR 26 TC 8 Z9 8 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD NOV PY 2011 VL 142 IS 5 BP 1038 EP 1045 DI 10.1016/j.jtcvs.2010.09.065 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 839AT UT WOS:000296337500015 PM 21397269 ER PT J AU Oniangue-Ndza, C Kuntzen, T Kemper, M Berical, A Wang, YYE Neumann-Haefelin, C Foote, PK Hills-Evans, K Reyor, LL Kane, K Gladden, AD Bloom, AK Power, KA Thimme, R Lauer, GM Henn, MR Kim, AY Allen, TM AF Oniangue-Ndza, Cesar Kuntzen, Thomas Kemper, Michael Berical, Andrew Wang, Yaoyu E. Neumann-Haefelin, Christoph Foote, Peter Kristian Hills-Evans, Kelsey Reyor, Laura L. Kane, Katherine Gladden, Adrianne D. Bloom, Allyson K. Power, Karen A. Thimme, Robert Lauer, Georg M. Henn, Matthew R. Kim, Arthur Y. Allen, Todd M. TI Compensatory Mutations Restore the Replication Defects Caused by Cytotoxic T Lymphocyte Escape Mutations in Hepatitis C Virus Polymerase SO JOURNAL OF VIROLOGY LA English DT Article ID RESTRICTED IMMUNE PRESSURE; LONG-TERM NONPROGRESSORS; RESISTANCE MUTATIONS; CLASS-I; REPLICON VARIANTS; TYPE-1 INFECTION; RNA REPLICATION; VIRAL FITNESS; CELL-CULTURE; GAG AB While human leukocyte antigen B57 (HLA-B57) is associated with the spontaneous clearance of hepatitis C virus (HCV), the mechanisms behind this control remain unclear. Immunodominant CD8(+) T cell responses against the B57-restricted epitopes comprised of residues 2629 to 2637 of nonstructural protein 5B (NS5B(2629-2637)) (KSKKTPMGF) and E2(541-549) (NTRPPLGNW) were recently shown to be crucial in the control of HCV infection. Here, we investigated whether the selection of deleterious cytotoxic T lymphocyte (CTL) escape mutations in the NS5B KSKKTPMGF epitope might impair viral replication and contribute to the B57-mediated control of HCV. Common CTL escape mutations in this epitope were identified from a cohort of 374 HCV genotype 1a-infected subjects, and their impact on HCV replication assessed using a transient HCV replicon system. We demonstrate that while escape mutations at residue 2633 (position 5) of the epitope had little or no impact on HCV replication in vitro, mutations at residue 2629 (position 1) substantially impaired replication. Notably, the deleterious mutations at position 2629 were tightly linked in vivo to upstream mutations at residue 2626, which functioned to restore the replicative defects imparted by the deleterious escape mutations. These data suggest that the selection of costly escape mutations within the immunodominant NS5B KSKKTPMGF epitope may contribute in part to the control of HCV replication in B57-positive individuals and that persistence of HCV in B57-positive individuals may involve the development of specific secondary compensatory mutations. These findings are reminiscent of the selection of deleterious CTL escape and compensatory mutations by HLA-B57 in HIV-1 infection and, thus, may suggest a common mechanism by which alleles like HLA-B57 mediate protection against these highly variable pathogens. C1 [Oniangue-Ndza, Cesar; Kuntzen, Thomas; Kemper, Michael; Berical, Andrew; Wang, Yaoyu E.; Neumann-Haefelin, Christoph; Kane, Katherine; Gladden, Adrianne D.; Bloom, Allyson K.; Power, Karen A.; Allen, Todd M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Reyor, Laura L.; Lauer, Georg M.; Kim, Arthur Y.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Foote, Peter Kristian; Hills-Evans, Kelsey; Reyor, Laura L.; Lauer, Georg M.; Kim, Arthur Y.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Neumann-Haefelin, Christoph; Thimme, Robert] Univ Hosp Freiburg, Freiburg, Germany. [Henn, Matthew R.] Broad Inst, Cambridge, MA USA. RP Allen, TM (reprint author), Bldg 149,Rm 6625,13th St, Charlestown, MA 02129 USA. EM tallen2@partners.org RI Neumann-Haefelin, Christoph/E-5550-2011; Allen, Todd/F-5473-2011 FU National Institute of Allergy and Infectious Disease (NIAID) [R01-AI067926, U19-AI066345, U19-AI082630] FX This project was funded in part with federal funds from the National Institute of Allergy and Infectious Disease (NIAID) under grants R01-AI067926 (T. M. A.), U19-AI066345 (T. M. A. and G. M. L.), and U19-AI082630 (T.M.A. and G.M.L.). NR 53 TC 13 Z9 14 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2011 VL 85 IS 22 BP 11883 EP 11890 DI 10.1128/JVI.00779-11 PG 8 WC Virology SC Virology GA 840FB UT WOS:000296422700031 PM 21880756 ER PT J AU Perlis, RH AF Perlis, R. H. TI Translating biomarkers to clinical practice SO MOLECULAR PSYCHIATRY LA English DT Review DE biomarker; test; diagnostic; genetic; cost-effectiveness; utility ID STAR-ASTERISK-D; DEXAMETHASONE SUPPRESSION TEST; COST-EFFECTIVENESS ANALYSIS; SERVICES TASK-FORCE; BREAST-CANCER; ANTIDEPRESSANT RESPONSE; PREDICTION MODELS; BIPOLAR DISORDER; ROC CURVE; STEP-BD AB Biomarkers are the measurable characteristics of an individual that may represent risk factors for a disease or outcome, or that may be indicators of disease progression or of treatment-associated changes. In general, the process by which biomarkers, once identified, might be translated into clinical practice has received scant attention in recent psychiatric literature. A body of work in diagnostic development suggests a framework for evaluating and validating novel biomarkers, but this work may be unfamiliar to clinical and translational researchers in psychiatry. Therefore, this review focuses on the steps that might follow the identification of putative biomarkers. It first addresses standard approaches to characterizing biomarker performance, followed by demonstrations of how a putative biomarker might be shown to have clinical relevance. Finally, it addresses ways in which a biomarker-based test might be validated for clinical application in terms of efficacy and cost-effectiveness. Molecular Psychiatry (2011) 16, 1076-1087; doi:10.1038/mp.2011.63; published online 28 June 2011 C1 [Perlis, R. H.] Massachusetts Gen Hosp, Dept Psychiat, Lab Psychiat Pharmacogen, Boston, MA 02114 USA. [Perlis, R. H.] Harvard Univ, Sch Med, Boston, MA USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Lab Psychiat Pharmacogen, 185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@partners.org FU Stanley Center for Psychiatric Research; [R01 MH086026] FX I thank Shaun Purcell, PhD, and Pamela Sklar, MD, PhD, for helpful discussion. This work was supported by R01 MH086026 and by the Stanley Center for Psychiatric Research. NR 67 TC 42 Z9 42 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD NOV PY 2011 VL 16 IS 11 BP 1076 EP 1087 DI 10.1038/mp.2011.63 PG 12 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 840HD UT WOS:000296429100007 PM 21709685 ER PT J AU Chen, X Lee, G Maher, BS Fanous, AH Chen, J Zhao, Z Guo, A van den Oord, E Sullivan, PF Shi, J Levinson, DF Gejman, PV Sanders, A Duan, J Owen, MJ Craddock, NJ O'Donovan, MC Blackman, J Lewis, D Kirov, GK Qin, W Schwab, S Wildenauer, D Chowdari, K Nimgaonkar, V Straub, RE Weinberger, DR O'Neill, FA Walsh, D Bronstein, M Darvasi, A Lencz, T Malhotra, AK Rujescu, D Giegling, I Werge, T Hansen, T Ingason, A Noethen, MM Rietschel, M Cichon, S Djurovic, S Andreassen, OA Cantor, RM Ophoff, R Corvin, A Morris, DW Gill, M Pato, CN Pato, MT Macedo, A Gurling, HMD McQuillin, A Pimm, J Hultman, C Lichtenstein, P Sklar, P Purcell, SM Scolnick, E St Clair, D Blackwood, DHR Kendler, KS AF Chen, X. Lee, G. Maher, B. S. Fanous, A. H. Chen, J. Zhao, Z. Guo, A. van den Oord, E. Sullivan, P. F. Shi, J. Levinson, D. F. Gejman, P. V. Sanders, A. Duan, J. Owen, M. J. Craddock, N. J. O'Donovan, M. C. Blackman, J. Lewis, D. Kirov, G. K. Qin, W. Schwab, S. Wildenauer, D. Chowdari, K. Nimgaonkar, V. Straub, R. E. Weinberger, D. R. O'Neill, F. A. Walsh, D. Bronstein, M. Darvasi, A. Lencz, T. Malhotra, A. K. Rujescu, D. Giegling, I. Werge, T. Hansen, T. Ingason, A. Noeethen, M. M. Rietschel, M. Cichon, S. Djurovic, S. Andreassen, O. A. Cantor, R. M. Ophoff, R. Corvin, A. Morris, D. W. Gill, M. Pato, C. N. Pato, M. T. Macedo, A. Gurling, H. M. D. McQuillin, A. Pimm, J. Hultman, C. Lichtenstein, P. Sklar, P. Purcell, S. M. Scolnick, E. St Clair, D. Blackwood, D. H. R. Kendler, K. S. CA Int Schizophrenia Consortium TI GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE association study; cardiomyopathy; GWA data mining; meta-analysis; schizophrenia ID GENOME-WIDE ASSOCIATION; SIB-PAIR FAMILIES; COMMON VARIANTS; SUSCEPTIBILITY GENE; SAMPLES PROVIDES; PROTEIN MYOSPRYN; LINKAGE ANALYSES; BINDING PARTNER; DYSBINDIN GENE; LUNG-CANCER AB We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values <= 0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2) = 0.008; rs10043986-rs4704591, r(2) = 0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR) = 1.11, 95% confidence interval (CI) = 1.04-1.18, P = 8.2 x 10(-4) and rs4704591, OR = 1.07, 95% CI = 1.03-1.11, P = 3.0 x 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR = 1.11, 95% CI = 1.03-1.17, P = 0.0026 and rs4704591, OR = 1.07, 95% CI = 1.02-1.11, P = 0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted. Molecular Psychiatry (2011) 16, 1117-1129; doi:10.1038/mp.2010.96; published online 14 September 2010 C1 [Chen, X.; Lee, G.; Maher, B. S.; Fanous, A. H.; Chen, J.; van den Oord, E.; Kendler, K. S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA. [Chen, X.; Kendler, K. S.] Virginia Commonwealth Univ, Dept Mol & Human Genet, Richmond, VA 23298 USA. [Fanous, A. H.] Washington VA Med Ctr, Washington, DC USA. [Fanous, A. H.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Zhao, Z.; Guo, A.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN USA. [van den Oord, E.] Virginia Commonwealth Univ, Dept Pharm, Richmond, VA 23298 USA. [Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Shi, J.; Levinson, D. F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Gejman, P. V.; Sanders, A.; Duan, J.] NorthShore Univ HealthSyst Res Inst, Ctr Psychiat Genet, Evanston, IL USA. [Owen, M. J.; Craddock, N. J.; O'Donovan, M. C.; Blackman, J.; Lewis, D.; Kirov, G. K.] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Dept Psychol Med, Cardiff, S Glam, Wales. [Qin, W.; Schwab, S.; Wildenauer, D.] Univ Western Australia, Sch Psychiat, Perth, WA 6009, Australia. [Qin, W.; Schwab, S.; Wildenauer, D.] Western Australian Inst Med Res, Perth, WA, Australia. [Chowdari, K.; Nimgaonkar, V.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Chowdari, K.; Nimgaonkar, V.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Straub, R. E.; Weinberger, D. R.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [O'Neill, F. A.] Queens Univ Belfast, Dept Psychiat, Belfast, Antrim, North Ireland. [Walsh, D.] Hlth Res Board, Dublin, Ireland. [Bronstein, M.; Darvasi, A.] Hebrew Univ Jerusalem, Dept Genet, IL-91904 Jerusalem, Israel. [Lencz, T.; Malhotra, A. K.] N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Psychiat Res, Glen Oaks, NY USA. [Rujescu, D.; Giegling, I.] Univ Munich, Div Mol & Clin Neurobiol, Munich, Germany. [Werge, T.; Hansen, T.; Ingason, A.] Copenhagen Univ Hosp, Mental Hlth Ctr Sct Hans, Inst Psychiat, Roskilde, Denmark. [Noeethen, M. M.; Cichon, S.] Univ Bonn, Inst Human Genet, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Rietschel, M.] Univ Heidelberg, Dept Genet Epidemiol Psychiat, Cent Inst Mental Hlth Mannheim, D-6800 Mannheim, Germany. [Rietschel, M.] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. [Cichon, S.] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. [Djurovic, S.; Andreassen, O. A.] Oslo Univ Hosp, Oslo, Norway. [Djurovic, S.; Andreassen, O. A.] Univ Oslo, Inst Psychiat, Oslo, Norway. [Cantor, R. M.; Ophoff, R.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Dept Human Genet, Los Angeles, CA USA. [Ophoff, R.] Univ Med Ctr Utrecht, Dept Med Genet, Cg Utrecht, Netherlands. [Corvin, A.; Morris, D. W.; Gill, M.] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland. [Corvin, A.; Morris, D. W.; Gill, M.] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Pato, C. N.; Pato, M. T.] Univ So Calif, Ctr Genom Psychiat, Los Angeles, CA USA. [Macedo, A.] Univ Coimbra, Dept Psychiat, Coimbra, Portugal. [Gurling, H. M. D.; McQuillin, A.; Pimm, J.] UCL, Sch Med, Windeyer Inst Med Sci, Res Dept Mental Hlth Sci,Mol Psychiat Lab, London W1N 8AA, England. [Hultman, C.; Lichtenstein, P.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Sklar, P.; Purcell, S. M.; Scolnick, E.] Psychiat & Neurodev Genet Unit, Boston, MA USA. [Sklar, P.; Purcell, S. M.; Scolnick, E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [St Clair, D.] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Kendler, K. S.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. RP Chen, X (reprint author), Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, 800 E Leigh St,Suite 390, Richmond, VA 23298 USA. EM xchen@vcu.edu RI Ingason, Andres/G-6817-2012; Morley, Christopher P/K-1907-2014; Cahn , Wiepke /B-5743-2013; Gurling, Hugh/A-5029-2010; Maher, Brion/F-9185-2010; macedo santos, antonio/M-5737-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Myin-Germeys, Inez /L-5106-2014; Hansen, Thomas/O-5965-2014; Ruderfer, Douglas/M-5795-2016; Lencz, Todd/J-3418-2014 OI McQuillin, Andrew/0000-0003-1567-2240; Andreassen, Ole A./0000-0002-4461-3568; Visscher, Peter/0000-0002-2143-8760; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Morris, Derek/0000-0002-3413-570X; Myin-Germeys, Inez/0000-0002-3731-4930; Gill, Michael/0000-0003-0206-5337; lichtenstein, paul/0000-0003-3037-5287; Moran, Jennifer/0000-0002-5664-4716; Bruggeman, Richard/0000-0002-3238-8471; O'Neill, Francis Anthony/0000-0002-7531-7657; Morley, Christopher P/0000-0003-0185-7148; de Oliveira Barreto Coimbra Carvalho, Celia Maria/0000-0003-4453-8139; macedo santos, antonio/0000-0003-2180-2718; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Hansen, Thomas/0000-0001-6703-7762; Ruderfer, Douglas/0000-0002-2365-386X; Lencz, Todd/0000-0001-8586-338X FU Stanley Medical Research Institute [07R-1770]; NARSAD; CATIE; GAIN; international schizophrenia consortium; National Institutes of Health [MH41953, MH63480, MH56242, MH078075]; Donald & Barbara Zucker Foundation, USA; Medical Research Council; Wellcome Trust Foundation, UK; Research Council of Norway [163070/V50, 167153/V50]; South-Eastern Norway Health Authority [123/2004]; Science Foundation Ireland; Health Research Board, Ireland; Lundbeck Foundation; Danish National Advanced Technology Foundation, Denmark; National Institute of Mental Health [N01 MH900001, MH074027]; Eli Lilly and Company; National Alliance for Research on Schizophrenia and Depression; National Center for Research Resources FX We thank the volunteers, patients and their family members for participating in this study. This study was supported in part by a research grant (07R-1770) from the Stanley Medical Research Institute and an Independent Investigator Award from NARSAD to XC, and by grants to investigators involved in the collection and analyses of the samples from CATIE, GAIN, the international schizophrenia consortium and other independent samples (National Institutes of Health (MH41953, MH63480, MH56242, MH078075); NARSAD Young Investigator Award; Donald & Barbara Zucker Foundation, USA; the Medical Research Council and the Wellcome Trust Foundation, UK; the Research Council of Norway (Grant No. 163070/V50, 167153/V50); the South-Eastern Norway Health Authority (123/2004); Science Foundation Ireland and Health Research Board, Ireland; the Lundbeck Foundation and Danish National Advanced Technology Foundation, Denmark). The Ashkenazi samples are part of the Hebrew University Genetic Resource (HUGR). The principal investigators of the CATIE trial were Jeffrey A Lieberman, T Scott Stroup and Joseph P McEvoy. The CATIE trialwas funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. The principle investigators for the MGS were Pablo Gejman and Douglas Levinson. MGS study was supported by funding from the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression. Genotyping of part of the sample was supported by GAIN and the Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT with support from the National Center for Research Resources. NR 53 TC 28 Z9 28 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD NOV PY 2011 VL 16 IS 11 BP 1117 EP 1129 DI 10.1038/mp.2010.96 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 840HD UT WOS:000296429100011 PM 20838396 ER PT J AU Lukacs-Kornek, V Malhotra, D Fletcher, AL Acton, SE Elpek, KG Tayalia, P Collier, AR Turley, SJ AF Lukacs-Kornek, Veronika Malhotra, Deepali Fletcher, Anne L. Acton, Sophie E. Elpek, Kutlu G. Tayalia, Prakriti Collier, Ai-ris Turley, Shannon J. TI Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes SO NATURE IMMUNOLOGY LA English DT Article ID MESENCHYMAL STEM-CELLS; FIBROBLASTIC RETICULAR CELLS; INTERFERON-GAMMA; IMMUNE-RESPONSES; ANTIGEN PRESENTATION; IFN-GAMMA; SYNTHASE; TOLERANCE; HOMEOSTASIS; SELF AB Fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) are nonhematopoietic stromal cells of lymphoid organs. They influence the migration and homeostasis of naive T cells; however, their influence on activated T cells remains undescribed. Here we report that FRCs and LECs inhibited T cell proliferation through a tightly regulated mechanism dependent on nitric oxide synthase 2 (NOS2). Expression of NOS2 and production of nitric oxide paralleled the activation of T cells and required a tripartite synergism of interferon-gamma, tumor necrosis factor and direct contact with activated T cells. Notably, in vivo expression of NOS2 by FRCs and LECs regulated the size of the activated T cell pool. Our study elucidates an as-yet-unrecognized role for the lymph node stromal niche in controlling T cell responses. C1 [Lukacs-Kornek, Veronika; Malhotra, Deepali; Fletcher, Anne L.; Acton, Sophie E.; Elpek, Kutlu G.; Collier, Ai-ris; 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. [Tayalia, Prakriti] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. RP Turley, SJ (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM shannon_turley@dfci.harvard.edu RI Acton, Sophie/G-9784-2012; OI Acton, Sophie/0000-0003-2704-716X; Malhotra, Deepali/0000-0002-8215-7639 FU US National Institutes of Health [R01 DK074500, P01 AI045757]; Dana-Farber Cancer Institute FX We thank M. Curry for technical assistance at the Dana-Farber Cancer Institute Flow Cytometry Core Facility; A. Sharpe (Harvard Medical School) for PD-L1-deficient mice; L. Lefrancois (University of Connecticut) for iFABP-tOVA mice; L.-H. Ang, Y. Zheng and S.J. Hagen for technical assistance at the Imaging Microscopy Core of Beth Israel Deaconess Medical Center; and J. Astarita and A. Bellemare-Pelletier for critically reading the manuscript. Supported by the US National Institutes of Health (R01 DK074500 and P01 AI045757 to S.J.T.) and the Dana-Farber Cancer Institute (V.L.-K). NR 50 TC 96 Z9 98 U1 5 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2011 VL 12 IS 11 BP 1096 EP U105 DI 10.1038/ni.2112 PG 10 WC Immunology SC Immunology GA 841GG UT WOS:000296500100015 PM 21926986 ER PT J AU Wesseling-Perry, K Tsai, EW Ettenger, RB Juppner, H Salusky, IB AF Wesseling-Perry, Katherine Tsai, Eileen W. Ettenger, Robert B. Jueppner, Harald Salusky, Isidro B. TI Mineral abnormalities and long-term graft function in pediatric renal transplant recipients: a role for FGF-23? SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE acute rejection; FGF-23; indices of mineral metabolism; pediatric renal transplantation; progression of renal failure ID CHRONIC KIDNEY-DISEASE; VITAMIN-D STATUS; GLOMERULAR-FILTRATION-RATE; GROWTH-HORMONE; CHILDREN; BONE; RATS; DEFICIENCY; FGF23 AB Background. Although current guidelines recommend the evaluation of mineral and bone metabolism in patients with all stages of chronic kidney disease (CKD), the prevalence of altered mineral ion homeostasis in the pediatric post-transplant population is unknown. Moreover, the contribution of abnormal mineral ion metabolism to graft outcomes in this population has not been evaluated. Methods. Serum calcium, phosphorus, 25(OH) vitamin D, 1,25(OH)(2)vitamin D, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) levels were evaluated 4.9 +/- 0.5 years after transplantation in 68 stable pediatric renal allograft recipients. Patients were subsequently followed for 2 years. Results. At baseline, mean estimated glomerular filtration rate (GFR) was 60 +/- 2 mL/min/1.73m(2). Serum calcium and phosphorus values were within the reference interval. PTH values were elevated but did not differ by CKD stage. 25(OH) vitamin D levels were low in nearly half of all subjects. Tubular reabsorption of phosphate and 1,25(OH)(2)vitamin D values were lower, while FGF-23 and PTH values were higher in more advanced stages of CKD. Thirty percent of patients with FGF-23 values >110 RU/mL had a decrease in GFR of >50% (P < 0.05) and FGF-23 values predicted future episodes of rejection. Conclusions. Despite normal serum calcium and phosphorus levels in the majority of prevalent pediatric renal transplant recipients, abnormalities in PTH, 25(OH) vitamin D and FGF-23 are common. FGF-23 levels may be associated with increased risk for deterioration of kidney function and episodes of rejection. C1 [Wesseling-Perry, Katherine; Tsai, Eileen W.; Ettenger, Robert B.; Salusky, Isidro B.] Univ Calif Los Angeles, David Geffen Sch Med, Div Pediat Nephrol, Los Angeles, CA 90095 USA. [Jueppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Jueppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Jueppner, Harald] Harvard Univ, Sch Med, Boston, MA USA. RP Wesseling-Perry, K (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Pediat Nephrol, Los Angeles, CA 90095 USA. EM kwesseling@mednet.ucla.edu FU USPHS [DK-67563, DK-35423, DK-51081, DK-073039, RR-00865]; National Kidney Foundation; Casey Lee Ball Foundation FX This work was supported in part by USPHS grants DK-67563, DK-35423, DK-51081, DK-073039 and RR-00865; the National Kidney Foundation and funds from the Casey Lee Ball Foundation. NR 29 TC 19 Z9 19 U1 0 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD NOV PY 2011 VL 26 IS 11 BP 3779 EP 3784 DI 10.1093/ndt/gfr126 PG 6 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 839FH UT WOS:000296350400057 PM 21441401 ER PT J AU Zuo, YT Lu, HB Vaupel, DB Zhang, Y Chefer, SI Rea, WR Moore, AV Yang, YH Stein, EA AF Zuo, Yantao Lu, Hanbing Vaupel, D. Bruce Zhang, Yi Chefer, Svetlana I. Rea, William R. Moore, Anna V. Yang, Yihong Stein, Elliot A. TI Acute Nicotine-Induced Tachyphylaxis Is Differentially Manifest in the Limbic System SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE phMRI; nicotine; tolerance; relative cerebral blood volume ID CEREBRAL-BLOOD-FLOW; ACETYLCHOLINE-RECEPTORS; RAT-BRAIN; ALPHA-BUNGAROTOXIN; PHARMACOLOGICAL MRI; FUNCTIONAL MRI; CHOLINERGIC MECHANISMS; DOPAMINE ANTAGONISTS; CIGARETTE-SMOKING; NEURONAL-ACTIVITY AB Rapid tolerance develops to many of nicotine's behavioral and autonomic effects, A better understanding of the spatiotemporal patterns in neuronal activity as a consequence of acute nicotine tolerance (tachyphylaxis) may help explain its commonly found inverted 'U'-shaped biphasic dose-effect relationship on various behaviors. To this end, we employed high-resolution functional magnetic resonance imaging and relative cerebral blood volume (rCBV) as a marker of neuronal activity, to characterize the regional development of acute tolerance as a function of nicotine dose in naive, anesthetized rats. A single intravenous nicotine injection at 0.1 and 0.3, but not 0.03 mg/kg, significantly increased neuronal activity in many neocortical areas. In contrast, dose-dependent increases in rCBV were most pronounced in limbic regions, such that responses seen at 0.1 mg/kg nicotine in accumbens, hippocampus, amygdala, and several other limbic areas were not seen following 0.3 mg/kg nicotine. Finally, whereas profound tolerance was observed in many cortical regions after the second of two paired nicotine injections at either 0.1 or 0.3 mg/kg, subcortical limbic structures showed only a weak trend for tolerance. Lack of rCBV changes in animals receiving nicotine methiodide, a quaternary nicotine analog that does not cross the blood-brain barrier, supports a direct neuronal effect of nicotine rather than an action on the vasculature. These data provide pharmacodynamic insight into the regional heterogeneity of nicotine tachyphylaxis development, which may be relevant to behavioral and neurobiological mechanisms associated with repeated tobacco consumption. Neuropsychopharmacology (2011) 36, 2498-2512; doi:10.1038/npp.2011.139; published online 27 July 2011 C1 [Zuo, Yantao; Lu, Hanbing; Vaupel, D. Bruce; Chefer, Svetlana I.; Rea, William R.; Yang, Yihong; Stein, Elliot A.] NIDA, Intramural Res Program, Neuroimaging Res Branch, Baltimore, MD 21224 USA. [Zhang, Yi] NIMH, Bethesda, MD 20892 USA. [Moore, Anna V.] Massachusetts Gen Hosp, Dept Radiol, Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. RP Stein, EA (reprint author), NIDA, Intramural Res Program, Neuroimaging Res Branch, 251 Bayview Blvd,Suite 200,Room 7A71 1A, Baltimore, MD 21224 USA. EM estein@mail.nih.gov FU US National Institutes of Health; National Institute on Drug Abuse; Intramural Research Program FX This research was funded by the US National Institutes of Health, National Institute on Drug Abuse, and Intramural Research Program. We thank Pradeep Kurup, MS and Tom Ross, PhD for their statistical assistance. NR 91 TC 6 Z9 6 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2011 VL 36 IS 12 BP 2498 EP 2512 DI 10.1038/npp.2011.139 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 835XS UT WOS:000296070900014 PM 21796109 ER PT J AU Shen, Q Duong, TQ AF Shen, Qiang Duong, Timothy Q. TI Background suppression in arterial spin labeling MRI with a separate neck labeling coil SO NMR IN BIOMEDICINE LA English DT Article DE arterial spin labeling; rodents; cerebral blood flow; cerebral perfusion; high fields; inversion recovery ID CEREBRAL-BLOOD-FLOW; TRANSIT-TIME; RAT-BRAIN; TISSUE WATER; PERFUSION; DIFFUSION; INVERSION; ISCHEMIA; EXCHANGE; SIGNAL AB In arterial spin labeling (ASL) MRI to measure cerebral blood flow (CBF), pair-wise subtraction of temporally adjacent non-labeled and labeled images often can not completely cancel the background static tissue signal because of temporally fluctuating physiological noise. While background suppression (BS) by inversion nulling improves CBF temporal stability, imperfect pulses compromise CBF contrast. Conventional BS techniques may not be applicable in small animals because the arterial transit time is short. This study presents a novel approach of BS to overcome these drawbacks using a separate 'neck' radiofrequency coil for ASL and a 'brain' radiofrequency coil for BS with the inversion pulse placed before spin labeling. The use of a separate 'neck' coil for ASL should also improve ASL contrast. This approach is referred to as the inversion-recovery BS with the two-coil continuous ASL (IR-cASL) technique. The temporal and spatial contrast-to-noise characteristics of basal CBF and CBF-based fMRI of hypercapnia and forepaw stimulation in rats at 7 Tesla were analyzed. IR-cASL yielded two times better temporal stability and 2.0-2.3 times higher functional contrast-to-noise ratios for hypercapnia and forepaw stimulation compared with cASL without BS in the same animals. The Bloch equations were modified to provide accurate CBF quantification at different levels of BS and for multislice acquisition where different slices have different degree of BS and residual degree of labeling. Improved basal CBF and CBF-based fMRI sensitivity should lead to more accurate CBF quantification and should prove useful for imaging low CBF conditions such as in white matter and stroke. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Shen, Qiang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Shen, Qiang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Shen, Qiang; 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.] Dept Vet Affairs, S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Duong, TQ (reprint author), UTHSCSA, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu RI Shen, Qiang/B-8784-2008; Duong, Timothy/B-8525-2008 OI Shen, Qiang/0000-0002-4287-3403; FU NIH [R01-NS45879, R01EY014211, R01EY018855]; American Heart Association [SDG-0430020N, SDG-0830293N]; VA MERIT award FX This work was supported in part by the NIH (R01-NS45879, R01EY014211 and R01EY018855), the American Heart Association (SDG-0430020N and SDG-0830293N) and a VA MERIT award. NR 33 TC 5 Z9 5 U1 0 U2 4 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 NOV PY 2011 VL 24 IS 9 BP 1111 EP 1118 DI 10.1002/nbm.1666 PG 8 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 840DT UT WOS:000296419200011 PM 21294207 ER PT J AU Al-Safi, Z Imudia, AN Filetti, LC Hobson, DT Bahado-Singh, RO Awonuga, AO AF Al-Safi, Zain Imudia, Anthony N. Filetti, Lusia C. Hobson, Deslyn T. Bahado-Singh, Ray O. Awonuga, Awoniyi O. TI Delayed Postpartum Preeclampsia and Eclampsia Demographics, Clinical Course, and Complications SO OBSTETRICS AND GYNECOLOGY LA English DT Article AB OBJECTIVE: To estimate and evaluate the demographics, clinical course, and complications of delayed postpartum preeclampsia in patients with and without eclampsia. METHODS: We conducted a retrospective cohort study of patients who were discharged and later readmitted with the diagnosis of delayed postpartum preeclampsia more than 2 days to 6 weeks or less after delivery between January 2003 and August 2009. RESULTS: One hundred fifty-two patients met criteria for the diagnosis of delayed postpartum preeclampsia. Of these, 96 (63.2%) patients had no antecedent diagnosis of hypertensive disease in the current pregnancy, whereas seven (4.6%), 14 (9.2%), 28 (18.4%), and seven (4.6%) patients had gestational hypertension, chronic hypertension, preeclampsia, and preeclampsia superimposed on chronic hypertension, respectively, during the peripartum period. Twenty-two patients (14.5%) developed postpartum eclampsia, and more than 90% of these patients presented within 7 days after discharge from the hospital. The most common presenting symptom was headache in 105 (69.1%) patients. Patients who developed eclampsia were significantly younger than those who did not (mean +/- standard deviation, 23.2 +/- 6.2 compared with 28.3 +/- 6.7 years; adjusted odds ratio [OR] 1.13, 95% confidence interval [CI] 1.02-1.26, P=.03), and other demographic variables were no different. A lower readmission hemoglobin was associated with a lower odds of progression to eclampsia (10.7 +/- 1.7 compared with 11.6 +/- 2.2 g/dL, adjusted OR 0.75, 95% CI 0.57-0.98, P=.04). CONCLUSION: One week after discharge appears to be a critical period for the development of postpartum eclampsia. Education about the possibility of delayed postpartum preeclampsia and eclampsia should occur after delivery, whether or not patients develop hypertensive disease before discharge from the hospital. (Obstet Gynecol 2011;118:1102-7) DOI: 10.1097/AOG.0b013e318231934c C1 [Awonuga, Awoniyi O.] Wayne State Univ, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Sch Med,Detroit Med Ctr, Detroit, MI 48201 USA. Massachusetts Gen Hosp, Div Reprod Med & Infertil, Boston, MA 02114 USA. RP Awonuga, AO (reprint author), Wayne State Univ, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Sch Med,Detroit Med Ctr, 60 W Hancock, Detroit, MI 48201 USA. EM aawonuga@med.wayne.edu NR 14 TC 24 Z9 27 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 NOV PY 2011 VL 118 IS 5 BP 1102 EP 1107 DI 10.1097/AOG.0b013e318231934c PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 838LK UT WOS:000296292600019 PM 21979459 ER PT J AU Tracy, EE AF Tracy, Erin E. TI Three Is a Crowd The New Doctor-Patient-Policymaker Relationship SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID GAG RULE; POLITICS; VIOLENCE; SAFETY; FAMILY; WOMEN; RISK; HOME AB A recent increase in legislative initiatives involving specific aspects of the practice of medicine is challenging traditional doctor-patient relationships. A Florida state law prohibiting physicians from asking patients about the presence of guns in the home could potentially result in real harm because of the risk of childhood injuries, domestic violence, suicide, and homicide. A number of states have specific language physicians are supposed to use when obtaining consent for pregnancy terminations. Some of these items required by law to be contained in the informed consent are not based on science, but instead on political beliefs. Other legislative initiatives involve issues as varied as hysterectomy consents, glomerular filtration rates, family planning, and palliative care. Laws that prohibit physicians from asking patients certain questions may be violating doctors' First Amendment rights. Laws mandating what information is contained in procedural consent forms and requiring certain scripts to be utilized may interfere with patients' ability to have accurate, unbiased, objective information to assist in their decision making. Physicians may be caught in the untenable position of balancing their professional and ethical obligations to their patients with their duty to obey the law as citizens. Physicians should be involved in legislative advocacy to try to prevent policy makers from legislating the practice of medicine. The American Congress of Obstetricians and Gynecologists' Committee on Ethics should consider review of this evolving issue. (Obstet Gynecol 2011;118:1164-8) DOI: 10.1097/AOG.0b013e31823188d6 C1 [Tracy, Erin E.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Tracy, EE (reprint author), Gen Hosp, 55 Fruit St,406 Founders House, Boston, MA USA. EM EETracy@partners.org NR 27 TC 3 Z9 3 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD NOV PY 2011 VL 118 IS 5 BP 1164 EP 1167 DI 10.1097/AOG.0b013e31823188d6 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 838LK UT WOS:000296292600028 PM 22015887 ER PT J AU Zimmermann, K Lennerz, JK Hein, A Link, AS Kaczmarek, JS Delling, M Uysal, S Pfeifer, JD Riccio, A Clapham, DE AF Zimmermann, Katharina Lennerz, Jochen K. Hein, Alexander Link, Andrea S. Kaczmarek, J. Stefan Delling, Markus Uysal, Serdar Pfeifer, John D. Riccio, Antonio Clapham, David E. TI Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pain; single-fiber; thermo-transient receptor potential; nociception; temperature sensing ID ROOT GANGLION NEURONS; IN-VITRO; CAPSAICIN-RECEPTOR; NOXIOUS HEAT; TRPM8; MOUSE; TEMPERATURES; MICE; STRAINS; DOMAIN AB Detection and adaptation to cold temperature is crucial to survival. Cold sensing in the innocuous range of cold (> 10-15 degrees C) in the mammalian peripheral nervous system is thought to rely primarily on transient receptor potential (TRP) ion channels, most notably the menthol receptor, TRPM8. Here we report that TRP cation channel, subfamily C member 5 (TRPC5), but not TRPC1/TRPC5 heteromeric channels, are highly cold sensitive in the temperature range 37-25 degrees C. We found that TRPC5 is present in mouse and human sensory neurons of dorsal root ganglia, a substantial number of peripheral nerves including intraepithelial endings, and in the dorsal lamina of the spinal cord that receives sensory input from the skin, consistent with a potential TRPC5 function as an innocuous cold transducer in nociceptive and thermosensory nerve endings. Although deletion of TRPC5 in 129S1/SvImJ mice resulted in no temperature-sensitive behavioral changes, TRPM8 and/or other menthol-sensitive channels appear to underpin a much larger component of noxious cold sensing after TRPC5 deletion and a shift in mechanosensitive C-fiber subtypes. These findings demonstrate that highly cold-sensitive TRPC5 channels are a molecular component for detection and regional adaptation to cold temperatures in the peripheral nervous system that is distinct from noxious cold sensing. C1 [Zimmermann, Katharina; Lennerz, Jochen K.; Hein, Alexander; Kaczmarek, J. Stefan; Delling, Markus; Uysal, Serdar; Riccio, Antonio; Clapham, David E.] Harvard Univ, Sch Med, Dept Cardiol, Manton Ctr Orphan Dis, Boston, MA 02115 USA. [Zimmermann, Katharina; Kaczmarek, J. Stefan; Clapham, David E.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Lennerz, Jochen K.; Pfeifer, John D.] Washington Univ, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Lennerz, Jochen K.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02116 USA. [Link, Andrea S.] Univ Erlangen Nurnberg, Dept Physiol & Pathophysiol, D-91054 Erlangen, Germany. [Clapham, David E.] Harvard Univ, Howard Hughes Med Inst, Sch Med, Childrens Hosp, Boston, MA 02115 USA. RP Clapham, DE (reprint author), Harvard Univ, Sch Med, Dept Cardiol, Manton Ctr Orphan Dis, Boston, MA 02115 USA. EM dclapham@enders.tch.harvard.edu RI Hein, Alexander/F-6999-2010; OI Hein, Alexander/0000-0003-2601-3398; Zimmermann, Katharina/0000-0003-2529-0692 FU National Institutes of Health [R01 MH090293-01, P30-HD18655]; German Research Council [DFG Zi1172/1-1] FX We thank B. Desai, P. Reeh, and J. N. Wood for discussions, D. Julius and J. Siemens for TRPM8-deficient tissue samples, and H. Xu who first noted that TRPC5 current decreases upon warming. We also thank A. Watson, V. Layton, J. Hardges, O. Crisp, B. Henderson, K. Selle, D. Leahart, K. Keith, and R. Brown for histotechnical assistance and G. Krapivinsky, B. Zhou, J. Li, and C. Tyler for assistance with immunohistochemistry. This work was funded by National Institutes of Health Grant R01 MH090293-01. The Mental Retardation and Developmental Disabilities Research Center Molecular Genetics Core Facility at Children's Hospital Boston is supported by National Institutes of Health Grant P30-HD18655. K.Z. was supported by German Research Council Grant DFG Zi1172/1-1. NR 47 TC 63 Z9 65 U1 0 U2 7 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 NOV 1 PY 2011 VL 108 IS 44 BP 18114 EP 18119 DI 10.1073/pnas.1115387108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839NH UT WOS:000296373400051 PM 22025699 ER PT J AU Sher, L AF Sher, L. TI Teaching medical professionals about suicide prevention: what's missing? SO QJM-AN INTERNATIONAL JOURNAL OF MEDICINE LA English DT Article ID PSYCHIATRY RESIDENCY PROGRAMS; INPATIENT SUICIDE; CLINICAL-PSYCHOLOGY; NATIONAL-SURVEY; DEPRESSION; PATIENT; RISK; HOSPITALIZATION; INTERVENTION; ASSESSMENTS C1 [Sher, L.] James J Peters Vet Adm Med Ctr, Bronx, NY 10468 USA. [Sher, L.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Sher, L (reprint author), James J Peters Vet Adm Med Ctr, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM leo.sher@mssm.edu NR 43 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1460-2725 EI 1460-2393 J9 QJM-INT J MED JI QJM-An Int. J. Med. PD NOV PY 2011 VL 104 IS 11 BP 1005 EP 1008 DI 10.1093/qjmed/hcr125 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 839GX UT WOS:000296354600018 PM 21824917 ER PT J AU Capitao, L Sampaio, A Sampaio, C Vasconcelos, C Fernandez, M Garayzabal, E Shenton, ME Goncalves, OF AF Capitao, Liliana Sampaio, Adriana Sampaio, Cassandra Vasconcelos, Cristiana Fernandez, Montse Garayzabal, Elena Shenton, Martha E. Goncalves, Oscar F. TI MRI amygdala volume in Williams Syndrome SO RESEARCH IN DEVELOPMENTAL DISABILITIES LA English DT Article DE Williams Syndrome; Hypersociability; Amygdala; Neurodevelopment ID SOCIAL-BEHAVIOR; NEURAL BASIS; BRAIN; COGNITION; MEMORY; FEAR; HYPERSOCIABILITY; APPROACHABILITY; ABNORMALITIES; HIPPOCAMPAL AB One of the most intriguing characteristics of Williams Syndrome individuals is their hypersociability. The amygdala has been consistently implicated in the etiology of this social profile, particularly given its role in emotional and social behavior. This study examined amygdala volume and symmetry in WS individuals and in age and sex matched controls. Magnetic resonance imaging scans were obtained on a GE 1.5-T magnet with 1.5-mm contiguous slices and were used to measure whole gray matter, white matter and cerebrospinal fluid volumes, as well as amygdala volume (right and left). Results revealed significantly reduced intracranial volume in individuals with WS, compared with controls. There were no differences between groups in absolute amygdalae volume, although there was a relative increase in amygdalae volumes, when adjusted for total intracranial content. There were no inter-hemispheric differences in amygdalae volumes in both groups. These results suggest a relative increase in amygdala volume in WS compared with healthy controls that likely reflects abnormal neurodevelopmental processes of midline brain structures. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Capitao, Liliana; Sampaio, Adriana; Sampaio, Cassandra; Goncalves, Oscar F.] Univ Minho, Sch Psychol, Neuropsychophysiol Lab, CIPsi, P-4710057 Braga, Portugal. [Vasconcelos, Cristiana] Hosp Geral Santo Antonio, Dept Neuroradiol, Oporto, Portugal. [Fernandez, Montse] Univ Santiago de Compostela, Galician Publ Fdn Genom Med, Mol Genet Unit, Santiago De Compostela, Spain. [Garayzabal, Elena] Univ Autonoma Madrid, Dept Linguist, Madrid, Spain. [Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Dept Psychiat,Sch Med, Boston, MA 02115 USA. [Shenton, Martha E.] Harvard Univ, Sch Med, Brockton, MA USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Dept Psychiat, Clin Neurosci Div, Lab Neurosci, Brockton, MA USA. RP Sampaio, A (reprint author), Univ Minho, Sch Psychol, Neuropsychophysiol Lab, CIPsi, P-4710057 Braga, Portugal. EM adriana.sampaio@psi.uminho.pt RI Goncalves, Oscar/G-5278-2010; Sampaio, Adriana/C-8361-2011; OI Goncalves, Oscar/0000-0003-2735-9155; Sampaio, Adriana/0000-0001-7347-1282; , /0000-0002-7893-0289 NR 36 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 0891-4222 J9 RES DEV DISABIL JI Res. Dev. Disabil. PD NOV-DEC PY 2011 VL 32 IS 6 BP 2767 EP 2772 DI 10.1016/j.ridd.2011.05.033 PG 6 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 838PF UT WOS:000296304000086 PM 21752593 ER PT J AU Baker, JF George, M Baker, DG Toedter, G Von Feldt, JM Leonard, MB AF Baker, Joshua F. George, Michael Baker, Daniel G. Toedter, Gary Von Feldt, Joan M. Leonard, Mary B. TI Associations between body mass, radiographic joint damage, adipokines and risk factors for bone loss in rheumatoid arthritis SO RHEUMATOLOGY LA English DT Article DE Rheumatoid arthritis; Body mass index; Erosion; Disease activity; Adipokines; Adiponectin ID SERUM CREATININE; PLASMA-LEVELS; ADIPONECTIN; INDEX; OSTEOPOROSIS; DESTRUCTION; ANTIBODY; OBESITY; LEPTIN; WOMEN AB Objective. To evaluate the association between BMI and radiographic joint damage (RJD) in RA. Methods. van der Heijde-Sharp (vdHS) erosion scores were determined in 499 participants with RA, ages 18-85 years, while enrolled in a clinical trial of golimumab (GO-BEFORE trial). Subjects were MTX and biologic therapy naive. Multivariable logistic regressions determined the odds of prevalent RJD (defined as vdHS score > 10) according to BMI category. Longitudinal analyses evaluated the association between BMI category and progression of vdHS score over 52 weeks. Analyses in a subset of 100 participants examined the association between adipokines and vdHS scores. Results. At enrolment and 52 weeks, 37.6 and 43.6% of participants had RJD. Compared with normal weight, obese subjects had lower odds of RJD [0.40 (95% CI 0.22, 0.74); P = 0.003], and underweight subjects had greater odds [3.86 (95% CI 1.66, 9.00); P = 0.002] at baseline, adjusted for demographic and disease characteristics. The baseline associations between BMI category and RJD were greater among participants with multiple risk factors for bone loss (female > 50 years, smoking, glucocorticoid exposure and vitamin D deficiency); test for interaction P = 0.05. Adjustment for adiponectin levels did not attenuate the association between BMI and vdHS scores. Baseline BMI and change in weight did not independently predict radiographic progression (P > 0.1). Conclusions. Higher BMI was independently associated with less RJD and was greatest in participants with risk factors for bone loss. Future studies are needed to examine the associations between RJD, obesity, weight loss and osteoporosis. C1 [Baker, Joshua F.; George, Michael] Univ Penn, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. [Baker, Daniel G.] Centocor Res & Dev, Clin Immunol, Malvern, PA USA. [Leonard, Mary B.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Toedter, Gary] Centocor Res & Dev, Biomarker, Malvern, PA USA. [Von Feldt, Joan M.] Vet Affairs Med Ctr, Div Rheumatol, Philadelphia, PA USA. [Leonard, Mary B.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. RP Baker, JF (reprint author), Hosp Univ Penn, Dept Med, Div Rheumatol, 8 Penn Tower Bldg,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM bakerjo@uphs.upenn.edu NR 29 TC 20 Z9 20 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 EI 1462-0332 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD NOV PY 2011 VL 50 IS 11 BP 2100 EP 2107 DI 10.1093/rheumatology/ker294 PG 8 WC Rheumatology SC Rheumatology GA 838MH UT WOS:000296295800025 PM 21890621 ER PT J AU Kim, MC Kim, KH Jung, GJ Rattner, DW AF Kim, Min-Chan Kim, Ki-Han Jung, Ghap Joong Rattner, David W. TI Comparative Study of Complete and Partial Omentectomy in Radical Subtotal Gastrectomy for Early Gastric Cancer SO YONSEI MEDICAL JOURNAL LA English DT Article DE Partial omentectomy; gastric cancer; post-operative outcome; comparative study ID LAPAROSCOPY-ASSISTED GASTRECTOMY; DISTAL GASTRECTOMY; MULTICENTER; SURGERY; NODE; LYMPHADENECTOMY; COMPLICATIONS; GUIDELINES; MORBIDITY; MORTALITY AB Purpose: Curative surgery for patients with advanced or even early gastric cancer can be defined as resection of the stomach and dissection of the first and second level lymph nodes, including the greater omentum. The aim of this study was to evaluate the short- and long- term outcomes of partial omentectomy (PO) as compared with complete omentectomy (CO). Materials and Methods: Seventeen consecutive open distal gastrectomies with POs were initially performed between February and July in 2006. The patients' clinicopathologic data and post-operative outcomes were retrospectively compared with 20 patients who underwent open distal gastrectomies with COs for early gastric cancer in 2005. Results: The operation time in PO group was significantly shorter than that in CO group (142.4 minutes vs. 165.0 minutes, p=0.018). The serum albumin concentration on the first post-operative day in PO group was significantly higher than CO group (3.8 g/dL vs. 3.5 g/dL, p=0.018). Three postoperative minor complications were successfully managed with conservative treatment. Median follow-up period between PO and CO was 38.1 and 37.7 months. All patients were alive without recurrence until December 30, 2009. Conclusion: PO during open radical distal gastrectomy can be considered a more useful procedure than CO for treating early gastric cancer. To document the long-term technical and oncologic safety of this procedure, a large-scale prospective randomized trial will be needed. C1 [Kim, Min-Chan; Kim, Ki-Han; Jung, Ghap Joong] Dong A Univ, Coll Med, Dept Surg, Pusan 602715, South Korea. [Rattner, David W.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Kim, MC (reprint author), Dong A Univ, Coll Med, Dept Surg, 1 Dongdaesin Dong 3 Ga, Pusan 602715, South Korea. EM mckim@donga.ac.kr FU Dong-A University FX This work was supported by the Dong-A University Research Fund in 2007. NR 35 TC 10 Z9 12 U1 0 U2 3 PU YONSEI UNIV COLLEGE MEDICINE PI SEOUL PA IN-HONG CHOI, MD, PH D, 250 SEONGSAN-RO, SEODAEMUN-GU, SEOUL 120-752, SOUTH KOREA SN 0513-5796 J9 YONSEI MED J JI Yonsei Med. J. PD NOV 1 PY 2011 VL 52 IS 6 BP 961 EP 966 DI 10.3349/ymj.2011.52.6.961 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 838PQ UT WOS:000296305100012 PM 22028160 ER PT J AU Bartosch, C Lopes, JM Oliva, E AF Bartosch, Carla Lopes, Jose Manuel Oliva, Esther TI Endometrial Carcinomas: A Review Emphasizing Overlapping and Distinctive Morphological and Immunohistochemical Features SO ADVANCES IN ANATOMIC PATHOLOGY LA English DT Review DE uterus; endometrium; endometrial carcinoma; endometrioid; serous; clear cell; dedifferentiated; malignant mixed mullerian; lynch-related ID FEMALE GENITAL-TRACT; OF-THE-LITERATURE; UTERINE SEROUS CARCINOMA; CLEAR-CELL CARCINOMA; GYNECOLOGIC-ONCOLOGY-GROUP; SMOOTH-MUSCLE TUMORS; NONPOLYPOSIS COLORECTAL-CANCER; METASTATIC BREAST-CARCINOMA; MIXED MULLERIAN TUMORS; E-CADHERIN EXPRESSION AB This review focuses on the most common diagnostic pitfalls and helpful morphologic and immunohistochemical markers in the differential diagnosis between the different subtypes of endometrial carcinomas, including: (1) endometrioid versus serous glandular carcinoma, (2) papillary endometrioid (not otherwise specified, villoglandular and nonvillous variants) versus serous carcinoma, (3) endometrioid carcinoma with spindle cells, hyalinization, and heterologous components versus malignant mixed mullerian tumor, (4) high-grade endometrioid versus serous carcinoma, (5) high-grade endometrioid carcinoma versus dedifferentiated or undifferentiated carcinoma, (6) endometrioid carcinoma with clear cells versus clear cell carcinoma, (7) clear cell versus serous carcinoma, (8) undifferentiated versus neuroendocrine carcinoma, (9) carcinoma of mixed cell types versus carcinoma with ambiguous features or variant morphology, (10) Lynch syndrome-related endometrial carcinomas, (11) high-grade or undifferentiated carcinoma versus nonepithelial uterine tumors. As carcinomas in the endometrium are not always primary, this review also discusses the differential diagnosis between endometrial carcinomas and other gynecological malignancies such as endocervical (glandular) and ovarian/peritoneal serous carcinoma, as well as with extra-gynecologic metastases (mainly breast and colon). C1 [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Oliva, Esther] Harvard Univ, Sch Med, Boston, MA USA. [Bartosch, Carla; Lopes, Jose Manuel] Univ Porto IPATIMUP, Ctr Hosp S Joao, Oporto, Portugal. [Lopes, Jose Manuel] Univ Porto IPATIMUP, Fac Med, Oporto, Portugal. [Lopes, Jose Manuel] Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Oporto, Portugal. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 2,55 Fruit St, Boston, MA 02114 USA. EM eoliva@partners.org RI Lopes, Jose Manuel/J-7428-2013; OI Lopes, Jose Manuel/0000-0001-8597-3474; Bartosch, Carla/0000-0003-0646-7667 NR 248 TC 28 Z9 31 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-4109 J9 ADV ANAT PATHOL JI Adv. Anat. Pathol. PD NOV PY 2011 VL 18 IS 6 BP 415 EP 437 DI 10.1097/PAP.0b013e318234ab18 PG 23 WC Pathology SC Pathology GA 836WO UT WOS:000296148200001 PM 21993268 ER PT J AU Barcena, C Oliva, E AF Barcena, Carmen Oliva, Esther TI WT1 Expression in the Female Genital Tract SO ADVANCES IN ANATOMIC PATHOLOGY LA English DT Review DE WT1; female genital tract; differential diagnosis; immunohistochemistry ID WILMS-TUMOR GENE; TRANSITIONAL-CELL-CARCINOMA; CORD-STROMAL TUMORS; SMOOTH-MUSCLE TUMORS; INVASIVE MICROPAPILLARY CARCINOMA; EPITHELIAL MEMBRANE ANTIGEN; OVARIAN SEROUS CARCINOMAS; ENDOMETRIOID GLANDULAR DIFFERENTIATION; PRIMITIVE NEUROECTODERMAL TUMOR; MULLERIAN MIXED TUMORS AB The Wilms tumor gene 1 (WT1) has been reported in normal tissues and many neoplasms of the female genital tract. This review discusses WT1 expression in the female genital tract and its potential utility in the differential diagnosis of neoplasms that occur at this location. WT1 is of value in the differential diagnosis of synchronous serous carcinomas arising in the ovary/fallopian tube/peritoneum and endometrium, as strong WT1 positivity in both tumors points toward an extrauterine origin. In addition, WT1 can be used to distinguish sex cord stromal tumors (WT1 positive) from endometrioid carcinomas (OECs). WT1 expression is not helpful in the differential diagnosis of ovarian serous carcinomas (OSCs) and transitional carcinomas, as both are typically positive and has limited value in the distinction of serous tumors arising in the ovary/fallopian tube/peritoneum from mesotheliomas. WT1 is also not helpful to differentiate small cell carcinoma of hypercalcemic type from juvenile granulosa cell tumor, a common diagnostic problem. Intra-abdominal desmoplastic round cell tumor reacts to WT1 (C-terminal) in contrast to all other tumors discussed which helps to separate this rare tumor from most other small round cell tumors that may involve, primarily or secondarily, the ovary with the exception of small cell carcinoma of hypercalcemic type that typically reacts with the N-terminal of WT1. C1 [Barcena, Carmen; Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 2,55 Fruit St, Boston, MA 02114 USA. EM eoliva@partners.org NR 205 TC 18 Z9 19 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-4109 J9 ADV ANAT PATHOL JI Adv. Anat. Pathol. PD NOV PY 2011 VL 18 IS 6 BP 454 EP 465 DI 10.1097/PAP.0b013e318234aaed PG 12 WC Pathology SC Pathology GA 836WO UT WOS:000296148200005 PM 21993272 ER PT J AU Proeschold-Bell, RJ Hoeppner, B Taylor, B Cohen, S Blouin, R Stringfield, B Muir, AJ AF Proeschold-Bell, Rae Jean Hoeppner, Bettina Taylor, Baishakhi Cohen, Sarah Blouin, Rachel Stringfield, Beth Muir, Andrew J. TI An Interrupted Time Series Evaluation of a Hepatitis C Intervention for Persons with HIV SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Hepatitis C; Intervention research; Prevention; Interrupted Time Series ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; SEXUAL TRANSMISSION; INFECTED PATIENTS; NATURAL-HISTORY; LIVER-DISEASE; UNITED-STATES; KNOWLEDGE; PREVALENCE; MORTALITY AB Accurate HCV knowledge is lacking among high-risk groups, including people with HIV/AIDS (PLWHA). Liver disease primarily due to HCV has emerged as a serious cause of mortality among PLWHA. We used an Interrupted Time Series design to evaluate a social-ecologically based intervention for PLWHA, where an infectious disease clinic serving a six-county intervention area was monitored before (7 months) and after (17 months) intervention onset. The intervention included education of PLWHA and medical providers, HIV/HCV support groups, and adaptation of the patient chart top sheet to include HCV test information. Clinic-level outcomes were assessed prospectively every other week for 2 years by interviewing patients (n = 259) with clinic appointments on assessment days. Abrupt, gradual and delayed intervention effects were tested. Weighted regression analyses showed higher average HCV knowledge and a higher prevalence of patients reporting HCV discussion with their medical providers after intervention onset. A delayed effect was found for HCV awareness, and a gradually increasing effect was found for knowing one's HCV status. Other communities may consider adopting this intervention. Additional HCV interventions for PLWHA with HIV are needed. C1 [Proeschold-Bell, Rae Jean] Duke Univ, Ctr Hlth Policy, Global Hlth Inst, Durham, NC 27708 USA. [Hoeppner, Bettina] Harvard Univ, Massachusetts Gen Hosp, Ctr Addict Med, Boston, MA 02115 USA. [Taylor, Baishakhi] Duke Univ, N Carolina Consortium S Asian Studies, Durham, NC USA. [Cohen, Sarah; Blouin, Rachel] Duke Univ, Duke Hlth Inequal Program, Durham, NC USA. [Stringfield, Beth] Duke Univ, Ctr Hlth Policy, Piedmont HIV Hlth Care Consortium, Durham, NC USA. [Muir, Andrew J.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. RP Proeschold-Bell, RJ (reprint author), Duke Univ, Ctr Hlth Policy, Global Hlth Inst, Box 90392, Durham, NC 27708 USA. EM Rae.jean@duke.edu FU NIDA NIH HHS [L30 DA025511, K01 DA027097] NR 38 TC 5 Z9 5 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2011 VL 15 IS 8 BP 1721 EP 1731 DI 10.1007/s10461-010-9870-1 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 831MN UT WOS:000295735200014 PM 21191643 ER PT J AU Becker, BW Thames, AD Woo, E Castellon, SA Hinkin, CH AF Becker, Brian W. Thames, April D. Woo, Ellen Castellon, Steven A. Hinkin, Charles H. TI Longitudinal Change in Cognitive Function and Medication Adherence in HIV-Infected Adults SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Medication adherence; HAART; Cognitive decline; Memory ID ANTIRETROVIRAL THERAPY; NEUROPSYCHOLOGICAL PERFORMANCE; PROSPECTIVE MEMORY; DRUG-RESISTANCE; VIRAL LOAD; COHORT; HAART; INDIVIDUALS; IMPAIRMENT; PREDICTORS AB Neuropsychological (NP) dysfunction has been linked to poor medication adherence among HIV-infected adults. However, there is a dearth of research examining longitudinal changes in the relationship between NP status and adherence rates. We hypothesized that declines in NP functioning would be associated with a corresponding decline in medication adherence while stable NP functioning would be associated with stable or improving adherence rates. Participants included 215 HIV-infected adults who underwent cognitive testing at study entry and six months later. Compared to the NP stable group, the NP decline group showed a greater drop in adherence rates. Further analysis revealed that, beyond global NP, learning and memory was significantly associated with changes in adherence rates. These findings further support the link between cognitive functioning and medication adherence and illustrates the importance of documenting changes in cognitive abilities for identifying individuals at risk for poor adherence. C1 [Becker, Brian W.; Castellon, Steven A.; Hinkin, Charles H.] VA Greater Angeles Hlth Care Syst, Neuropsychol Lab 256, Los Angeles, CA 90073 USA. [Becker, Brian W.; Thames, April D.; Woo, Ellen; Castellon, Steven A.; Hinkin, Charles H.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Becker, BW (reprint author), VA Greater Angeles Hlth Care Syst, Neuropsychol Lab 256, 11301 Wilshire, Los Angeles, CA 90073 USA. EM brian.becker@va.gov RI Thames, April/K-1964-2014 OI Thames, April/0000-0001-8414-7189 FU NIDA NIH HHS [R01 DA013799, R01 DA13799]; NIMH NIH HHS [R25 MH080663, T32 MH019535, T32 MH19535] NR 27 TC 30 Z9 30 U1 0 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2011 VL 15 IS 8 BP 1888 EP 1894 DI 10.1007/s10461-011-9924-z PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 831MN UT WOS:000295735200030 PM 21437726 ER PT J AU Ix, JH Biggs, ML Kizer, JR Mukamal, KJ Djousse, L Zieman, SJ de Boer, IH Nelson, TL Newman, AB Criqui, MH Siscovick, DS AF Ix, Joachim H. Biggs, Mary L. Kizer, Jorge R. Mukamal, Kenneth J. Djousse, Luc Zieman, Susan J. de Boer, Ian H. Nelson, Tracy L. Newman, Anne B. Criqui, Michael H. Siscovick, David S. TI Association of Body Mass Index With Peripheral Arterial Disease in Older Adults SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE ankle brachial index; body mass index; cardiovascular diseases; peripheral arterial disease ID CARDIOVASCULAR RISK-FACTORS; ANKLE BRACHIAL INDEX; INTERMITTENT CLAUDICATION; ARM INDEX; PREVALENCE; HEALTH; MORTALITY; ATHEROSCLEROSIS; POPULATION; SMOKING AB The authors hypothesized that the absence of cross-sectional associations of body mass index (BMI; weight (kg)/height (m)(2)) with peripheral arterial disease (PAD) in prior studies may reflect lower weight among persons who smoke or have poor health status. They conducted an observational study among 5,419 noninstitutionalized residents of 4 US communities aged >= 65 years at baseline (1989-1990 or 1992-1993). Ankle brachial index was measured, and participants reported their history of PAD procedures. Participants were followed longitudinally for adjudicated incident PAD events. At baseline, mean BMI was 26.6 (standard deviation, 4.6), and 776 participants (14%) had prevalent PAD. During 13.2 (median) years of follow-up through June 30, 2007, 276 incident PAD events occurred. In cross-sectional analysis, each 5-unit increase in BMI was inversely associated with PAD (prevalence ratio (PR) = 0.92, 95% confidence interval (CI): 0.85, 1.00). However, among persons in good health who had never smoked, the direction of association was opposite (PR = 1.20, 95% CI: 0.94, 1.52). Similar results were observed between BMI calculated using weight at age 50 years and PAD prevalence (PR = 1.30, 95% CI: 1.11, 1.51) and between BMI at baseline and incident PAD events occurring during follow-up (hazard ratio = 1.32, 95% CI: 1.00, 1.76) among never smokers in good health. Greater BMI is associated with PAD in older persons who remain healthy and have never smoked. Normal weight maintenance may decrease PAD incidence and associated comorbidity in older age. C1 [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA 92161 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, Dept Med, Sch Med, San Diego, CA 92161 USA. [Ix, Joachim H.; Criqui, Michael H.] Univ Calif San Diego, Div Prevent Med, Dept Family & Prevent Med, Sch Med, San Diego, CA 92161 USA. [Biggs, Mary L.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Sch Publ Hlth, Dept Med, Seattle, WA 98195 USA. [Siscovick, David S.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Kizer, Jorge R.] Cornell Univ, Dept Med, Weill Med Coll, New York, NY 10021 USA. [Kizer, Jorge R.] Cornell Univ, Dept Publ Hlth, Weill Med Coll, New York, NY 10021 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Mukamal, Kenneth J.] Harvard Univ, Sch Med, Boston, MA USA. [Djousse, Luc] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Aging, Boston, MA USA. [Djousse, Luc] Boston VA Healthcare Syst, Boston, MA USA. [Zieman, Susan J.] Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr, Baltimore, MD 21205 USA. [Zieman, Susan J.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [de Boer, Ian H.] Univ Washington, Sch Med, Dept Med, Kidney Res Inst,Div Nephrol, Seattle, WA 98195 USA. [Nelson, Tracy L.] Colorado State Univ, Colorado Sch Publ Hlth, Coll Appl Human Sci, Ft Collins, CO 80523 USA. [Nelson, Tracy L.] Colorado State Univ, Dept Hlth & Exercise Sci, Coll Appl Human Sci, Ft Collins, CO 80523 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Criqui, Michael H.] Univ Calif San Diego, Div Cardiol, Dept Med, Sch Med, San Diego, CA 92161 USA. RP Ix, JH (reprint author), Univ Calif San Diego, Div Nephrol & Hypertens, Dept Med, 3350 La Jolla Village Dr,Mail Code 111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu RI Newman, Anne/C-6408-2013; Djousse, Luc/F-5033-2017 OI Newman, Anne/0000-0002-0106-1150; Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute [R01 HL094555, N01 HC-85079, N01HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01 HC-75150, N01 HC-54133, N01-HC-80007, U01 HL080295]; National Institute of Neurological Disorders and Stroke; VA San Diego Healthcare System FX This publication was supported by grant R01 HL094555 from the National Heart, Lung, and Blood Institute (to Drs. Ix, Kizer, Mukamal, Djousse, and Zieman). The Cardiovascular Health Study was supported by contracts N01 HC-85079 through N01HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01 HC-75150, N01 HC-54133, and N01-HC-80007 and grant U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contributions from the National Institute of Neurological Disorders and Stroke. The current study was partly supported by the VA San Diego Healthcare System. NR 31 TC 14 Z9 14 U1 0 U2 3 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 NOV 1 PY 2011 VL 174 IS 9 BP 1036 EP 1043 DI 10.1093/aje/kwr228 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 836EW UT WOS:000296093800006 PM 21920948 ER PT J AU Toosi, KK Impink, BG Baker, NA Boninger, ML AF Toosi, Kevin K. Impink, Bradley G. Baker, Nancy A. Boninger, Michael L. TI Effects of Computer Keyboarding on Ultrasonographic Measures of the Median Nerve SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE carpal tunnel syndrome; computer keyboarding; median nerve; ultrasonography; ultrasound ID CARPAL-TUNNEL-SYNDROME; CUMULATIVE TRAUMA DISORDERS; MUSCULOSKELETAL DISORDERS; RISK-FACTORS; GENERAL-POPULATION; UPPER EXTREMITY; OFFICE WORKERS; SONOGRAPHY; DIAGNOSIS; WRIST AB Background Keyboarding is a highly repetitive daily task and has been linked to musculoskeletal disorders of the upper extremity. However, the effect of keyboarding on median nerve injuries is not well understood. The purpose of this study was to use ultrasonographic measurements to determine whether continuous keyboarding can cause acute changes in the median nerve. Methods Ultrasound images of the median nerve from 21 volunteers were captured at the levels of the pisiform and distal radius prior to and following a prolonged keyboarding task (i.e., 1 hr of continuous keyboarding). Images were analyzed by a blinded investigator to quantify the median nerve characteristics. Changes in the median nerve ultrasonographic measures as a result of continuous keyboarding task were evaluated. Results Cross-sectional areas at the pisiform level were significantly larger in both dominant (P = 0.004) and non-dominant (P = 0.001) hands following the keyboarding task. Swelling ratio was significantly greater in the dominant hand (P = 0.020) after 60 min of keyboarding when compared to the baseline measures. Flattening ratios were not significantly different in either hand as a result of keyboarding. Conclusion We were able to detect an acute increase in the area of the median nerve following 1 hr of keyboarding with a computer keyboard. This suggests that keyboarding has an impact on the median nerve. Further studies are required to understand this relationship, which would provide insight into the pathophysiology of median neuropathies such as carpal tunnel syndrome. Am. J. Ind. Med. 54:826-833, 2011. (C) 2011 Wiley Periodicals, Inc. C1 [Toosi, Kevin K.; Impink, Bradley G.; Boninger, Michael L.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Dept Vet Affairs, Pittsburgh, PA 15206 USA. [Toosi, Kevin K.; Impink, Bradley G.; Boninger, Michael L.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Toosi, Kevin K.; Boninger, Michael L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Baker, Nancy A.] Univ Pittsburgh, Dept Occupat Therapy, Pittsburgh, PA USA. RP Boninger, ML (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Dept Vet Affairs, 7180 Highland Dr 151R1-H,Bldg 4,2nd Floor,East Wi, Pittsburgh, PA 15206 USA. EM boninger@pitt.edu OI Boninger, Michael/0000-0001-6966-919X FU U.S. Department of Veterans Affairs [B3142C]; National Institutes of Health [T32HD049307] FX This material is the result of work supported with resources and the use of facilities at the Human Engineering Research Laboratories, VA Pittsburgh Healthcare System. This study was supported by the U.S. Department of Veterans Affairs (B3142C) and the National Institutes of Health (T32HD049307). The contents of this paper do not represent the views of the Department of Veterans Affairs or the United States Government. NR 40 TC 12 Z9 12 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD NOV PY 2011 VL 54 IS 11 BP 826 EP 833 DI 10.1002/ajim.20983 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 837YF UT WOS:000296248400003 PM 21739468 ER PT J AU van Blitterswijk, M Gulati, S Smoot, E Jaffa, M Maher, N Hyman, BT Ivinson, AJ Scherzer, CR Schoenfeld, DA Cudkowicz, ME Brown, RH Bosco, DA AF van Blitterswijk, Marka Gulati, Sunita Smoot, Elizabeth Jaffa, Matthew Maher, Nancy Hyman, Bradley T. Ivinson, Adrian J. Scherzer, Clemens R. Schoenfeld, David A. Cudkowicz, Merit E. Brown, Robert H., Jr. Bosco, Daryl A. TI Anti-superoxide dismutase antibodies are associated with survival in patients with sporadic amyotrophic lateral sclerosis SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article DE Sporadic amyotrophic lateral sclerosis; superoxide dismutase; immunotherapy; Parkinson's disease; Alzheimer's disease ID NEISSERIA-GONORRHOEAE; SPINAL-CORD; MUTANT SOD1; WILD-TYPE; MOTOR CORTEX; ALS PATIENTS; IGG; IMMUNOGLOBULIN; MICE; QUANTITATION AB Our objective was to test the hypothesis that aberrantly modified forms of superoxide dismutase (SOD1) influence the disease course for sporadic amyotrophic lateral sclerosis (SALS). We probed for anti-SOD1 antibodies (IgM and IgG) against both the normal and aberrantly oxidized-SOD1 (SODox) antigens in sera from patients with SALS, subjects diagnosed with other neurological disorders and healthy individuals, and correlated the levels of these antibodies to disease duration and/or severity. Anti-SOD1 antibodies were detected in all cohorts; however, a subset of similar to 5-10% of SALS cases exhibited elevated levels of anti-SOD1 antibodies. Those SALS cases with relatively high levels of IgM antibodies against SODox exhibit a longer survival of 6.4 years, compared to subjects lacking these antibodies. By contrast, SALS subjects expressing higher levels of IgG antibodies reactive for the normal WT-SOD1 antigen exhibit a shorter survival of 4.1 years. Anti-SOD1 antibody levels did not correlate with disease severity in either the Alzheimer's or Parkinson's disease cohorts. In conclusion, the association of longer survival with elevated levels of anti-SODox antibodies suggests that these antibodies may be protective. By extension, these data implicate aberrantly modified forms of WT-SOD1 (e. g. oxidized SOD1) in SALS pathogenesis. In contrast, an immune response against the normal WT-SOD1 appears to be disadvantageous in SALS, possibly because the anti-oxidizing activity of normal WT-SOD1 is beneficial to SALS individuals. C1 [Bosco, Daryl A.] Univ Massachusetts, Med Ctr, Dept Neurol, LRB, Worcester, MA 01655 USA. [Gulati, Sunita] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01655 USA. [Smoot, Elizabeth; Schoenfeld, David A.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Jaffa, Matthew; Cudkowicz, Merit E.] Massachusetts Gen Hosp, Neurol Clin Trials Unit, Charlestown, MA USA. [Maher, Nancy] Brigham & Womens Hosp, Harvard NeuroDiscovery Biomarker Program, Cambridge, MA USA. [Hyman, Bradley T.; Ivinson, Adrian J.; Scherzer, Clemens R.] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr Biomarker Program, Cambridge, MA 02138 USA. [Scherzer, Clemens R.] Brigham & Womens Hosp, Ctr Neurol Dis, Cambridge, MA USA. RP Bosco, DA (reprint author), Univ Massachusetts, Med Ctr, Dept Neurol, LRB, Room 603,364 Plantat Dr, Worcester, MA 01655 USA. EM Daryl.Bosco@umassmed.edu RI van Blitterswijk, Marka/H-7274-2012 OI van Blitterswijk, Marka/0000-0002-3054-7053 FU ALS Therapy Alliance-CVS Pharmacy; ALS Association; US National Institutes of Health; National Institute on Neurological Disorders and Stroke; Angel Fund; Project ALS FX We thank Anne Hunt and the Eunice Kennedy Shriver Center at the University of Massachusetts Medical School (UMMS) for statistical analyses, the UMMS Proteomic and Mass spectrometry Core facility at UMMS, the Northeast ALS Consortium and the Neurology Clinical Trial Unit for contributing sera samples. We acknowledge financial support from the ALS Therapy Alliance-CVS Pharmacy (D. A. B.), the ALS Association (D. A. B., and R. H. B. Jr), the US National Institutes of Health (D. A. B. (National Institute on Neurological Disorders and Stroke)), R. H. B. Jr (National Institute on Neurological Disorders and Stroke), the Angel Fund (R. H. B. Jr) and Project ALS (R.H.B. Jr). NR 39 TC 8 Z9 8 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1748-2968 J9 AMYOTROPH LATERAL SC JI Amyotroph. Lateral. Scler. PD NOV PY 2011 VL 12 IS 6 BP 430 EP 438 DI 10.3109/17482968.2011.585163 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 837AJ UT WOS:000296162500006 PM 22023190 ER PT J AU Schneider, BC Lichtenberg, PA AF Schneider, Brooke C. Lichtenberg, Peter A. TI Influence of Reading Ability on Neuropsychological Performance in African American Elders SO ARCHIVES OF CLINICAL NEUROPSYCHOLOGY LA English DT Article DE Assessment; Elderly; Geriatrics; Aging; Norms; Normative studies ID NORMATIVE DATA; OLDER-ADULTS; LEVEL; EDUCATION; ACCULTURATION; IMPAIRMENT; DEMENTIA; NORMS AB Use of normative data stratified by education may result in misclassification of African American older adults because reading ability, an estimate of educational attainment, is lower than reported years of education for some African American elders. This study examined the contribution of reading ability versus education to neuropsychological test performance in 86 community-dwelling African American elders ages 56-91 with 8-18 years of education. Hierarchical multiple regression analyses revealed that reading ability, but not education, was significantly associated with performances on the Trail Making Test, Controlled Oral Word Association Test, Animal Naming, Digit Span, and the Stroop test. Reading ability was not significantly related to performances on measures of memory. Medium to large effect sizes (Cohen's d = 0.58-1.41) were found when comparing mean performances on neuropsychological measures in groups with low versus high reading scores. Results indicate that reading ability contributes beyond educational attainment to performances on some neuropsychological measures among African American elders. These findings have implications for reducing misclassification among minority populations through the use of appropriate normative data. C1 [Schneider, Brooke C.] Greater Los Angeles VA Healthcare Ctr, Psychol Serv, W Los Angeles VA, Los Angeles, CA 90073 USA. [Lichtenberg, Peter A.] Wayne State Univ, Inst Gerontol, Detroit, MI 48202 USA. RP Schneider, BC (reprint author), Greater Los Angeles VA Healthcare Ctr, Psychol Serv, W Los Angeles VA, 11301 Wilshire Blvd,Room A206, Los Angeles, CA 90073 USA. EM brooke.schneider@va.gov FU NIH/NIA [T32 AG00275-06] FX This work was supported by the NIH/NIA Aging and Urban Health Pre-doctoral Research Training Grant (T32 AG00275-06). NR 30 TC 2 Z9 2 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0887-6177 J9 ARCH CLIN NEUROPSYCH JI Arch. Clin. Neuropsychol. PD NOV PY 2011 VL 26 IS 7 BP 624 EP 631 DI 10.1093/arclin/acr062 PG 8 WC Psychology, Clinical; Psychology SC Psychology GA 836FF UT WOS:000296094800006 PM 21835850 ER PT J AU Grenon, SM Saary, J AF Grenon, S. Marlene Saary, Joan TI Challenges in Aerospace Medicine Education SO AVIATION SPACE AND ENVIRONMENTAL MEDICINE LA English DT Editorial Material DE aerospace medicine; education ID SPECIALTY AB GRENON SM, SAARY J. Challenges in aerospace medicine education. Aviat Space Environ Med 2011; 82:1071-2. Aerospace medicine training and research represents a dream for many and a challenge for most. In Canada, although some opportunities exist for the pursuit of education and research in the aerospace medicine field, they are limited despite the importance of this field for enabling safe human space exploration. In this commentary, we aim to identify some of the challenges facing individuals wishing to get involved in the field as well as the causal factors for these challenges. We also explore strategies to mitigate against these. C1 [Grenon, S. Marlene] Univ Calif San Francisco, Dept Surg, Div Vasc & Endovasc Surg, Surg Serv,San Francisco VAMC, San Francisco, CA 94121 USA. [Saary, Joan] Univ Toronto, Dept Occupat & Environm Hlth, Toronto, ON, Canada. RP Grenon, SM (reprint author), Univ Calif San Francisco, Dept Surg, Div Vasc & Endovasc Surg, Surg Serv,San Francisco VAMC, Mail Code 112 G,4150 Clement St, San Francisco, CA 94121 USA. EM marlene.grenon@ucsfmedctr.org NR 8 TC 0 Z9 0 U1 0 U2 3 PU AEROSPACE MEDICAL ASSOC PI ALEXANDRIA PA 320 S HENRY ST, ALEXANDRIA, VA 22314-3579 USA SN 0095-6562 J9 AVIAT SPACE ENVIR MD JI Aviat. Space Environ. Med. PD NOV PY 2011 VL 82 IS 11 BP 1071 EP 1072 DI 10.3357/ASEM.3073.2011 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Sport Sciences SC Public, Environmental & Occupational Health; General & Internal Medicine; Sport Sciences GA 837DZ UT WOS:000296172600011 PM 22097645 ER PT J AU Malavia, NK Zurakowski, D Schroeder, A Princiotto, AM Laury, AR Barash, HE Sodroski, J Langer, R Madani, N Kohane, DS AF Malavia, Nikita K. Zurakowski, David Schroeder, Avi Princiotto, Amy M. Laury, Anna R. Barash, Hila E. Sodroski, Joseph Langer, Robert Madani, Navid Kohane, Daniel S. TI Liposomes for HIV prophylaxis SO BIOMATERIALS LA English DT Article DE Liposome; HIV; AIDS; Prophylaxis; Cardiolipin ID HUMAN-IMMUNODEFICIENCY-VIRUS; TOPICAL MICROBICIDES; PREVENTION; GP120; TRANSMISSION; VACCINE; MODEL AB There are approximately 33.4 million adults living with HIV worldwide of which an estimated 15.7 million are women. Although there has been enormous progress in the therapy of HIV/AIDS, treatment is not curative. Prevention is therefore of paramount importance, but vaccine-based and microbicidal approaches are still in their infancy. Since women acquire the virus largely through sexual intercourse, we developed liposomal systems potentially suitable for intra-vaginal use to prevent HIV-1 infection. We formulated liposomes from a range of naturally-occurring and synthetic lipids with varying physicochemical properties, and tested their ability to inhibit infection of transformed cells that express receptors specific to the virus. We identified formulations with the most favorable balance between decreasing HIV infection and causing cytotoxicity (i.e. therapeutic index). The therapeutic index improved with increasing cardiolipin content, and degree of unsaturation. Tissue reaction to these formulations was benign after intra-vaginal instillation in an in vivo female mouse model. These results support the potential use of cardiolipin-based liposomes enriched with synthetic lipids as microbicides for the prevention of HIV infection in women. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Malavia, Nikita K.; Barash, Hila E.; Kohane, Daniel S.] Harvard Univ, Sch Med, Lab Biomat & Drug Delivery, Dept Anesthesiol,Div Crit Care Med,Childrens Hosp, Boston, MA 02115 USA. [Malavia, Nikita K.; Schroeder, Avi; Barash, Hila E.; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02142 USA. [Princiotto, Amy M.; Sodroski, Joseph; Madani, Navid] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Princiotto, Amy M.; Sodroski, Joseph; Madani, Navid] Harvard Univ, Sch Med, Dept Pathol, Div Aids, Boston, MA 02115 USA. [Laury, Anna R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. RP Kohane, DS (reprint author), Harvard Univ, Sch Med, Lab Biomat & Drug Delivery, Dept Anesthesiol,Div Crit Care Med,Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM daniel.kohane@childrens.harvard.edu OI Schroeder, Avi/0000-0003-2571-5937 FU Bill and Melinda Gates Foundation; NIH [GM073626]; Misrock Foundation; American Foundation for AIDS Research [107431-45-RFRL] FX This work was supported by Bill and Melinda Gates Foundation Grand Challenges Explorations (GCE) Phase I grant (to R.L., D.S.K and N.K. Malavia), and NIH GM073626 (D.S.K). A.S. thanks the Misrock Foundation for a postdoctoral fellowship. N. Madani was supported by an American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research # 107431-45-RFRL. JC53 cells were the generous gift of Dr. David Kabat at Oregon Health Sciences University. NR 27 TC 15 Z9 15 U1 0 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD NOV PY 2011 VL 32 IS 33 BP 8663 EP 8668 DI 10.1016/j.biomaterials.2011.07.068 PG 6 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 833CF UT WOS:000295858700033 PM 21862123 ER PT J AU Walsh, MJ Brimacombe, KR Veith, H Bougie, JM Daniel, T Leister, W Cantley, LC Israelsen, WJ Vander Heiden, MG Shen, M Auld, DS Thomas, CJ Boxer, MB AF Walsh, Martin J. Brimacombe, Kyle R. Veith, Henrike Bougie, James M. Daniel, Thomas Leister, William Cantley, Lewis C. Israelsen, William J. Vander Heiden, Matthew G. Shen, Min Auld, Douglas S. Thomas, Craig J. Boxer, Matthew B. TI 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE PKM2; Pyruvate kinase; Cellular metabolism; Anti-cancer strategies; Small molecule activators ID GENE; RAT; ISOZYMES; GROWTH; SYSTEM AB Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. Published by Elsevier Ltd. C1 [Walsh, Martin J.; Brimacombe, Kyle R.; Veith, Henrike; Bougie, James M.; Daniel, Thomas; Leister, William; Shen, Min; Auld, Douglas S.; Thomas, Craig J.; Boxer, Matthew B.] NHGRI, NIH Chem Genom Ctr, NIH Ctr Translat Therapeut, NIH, Rockville, MD 20850 USA. [Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. [Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Israelsen, William J.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Boxer, MB (reprint author), NHGRI, NIH Chem Genom Ctr, NIH Ctr Translat Therapeut, NIH, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM boxerm@mail.nih.gov RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU Molecular Libraries Initiative of the NIH Roadmap for Medical Research; National Human Genome Research Institute, National Institutes of Health FX We thank Paul Shinn, Danielle VanLeer and Christopher LeClair for assistance with compound management. This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 17 TC 29 Z9 30 U1 0 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD NOV 1 PY 2011 VL 21 IS 21 BP 6322 EP 6327 DI 10.1016/j.bmcl.2011.08.114 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 835HA UT WOS:000296025900021 PM 21958545 ER PT J AU Jacobus, SJ Kumar, S Uno, H Van Wier, SA Ahmann, GJ Henderson, KJ Callander, NS Williams, ME Siegel, DS Greipp, PR Rajkumar, SV Fonseca, R AF Jacobus, Susanna J. Kumar, Shaji Uno, Hajime Van Wier, Scott A. Ahmann, Greg J. Henderson, Kimberly J. Callander, Natalie S. Williams, Michael E. Siegel, David S. Greipp, Philip R. Rajkumar, S. Vincent Fonseca, Rafael TI Impact of high-risk classification by FISH: an Eastern Cooperative Oncology Group (ECOG) study E4A03 SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE myeloma; lenalidomide; dexamethasone; bortezomib; FISH ID DIAGNOSED MULTIPLE-MYELOMA; LENALIDOMIDE PLUS DEXAMETHASONE; MOLECULAR CLASSIFICATION; INTERGROUPE FRANCOPHONE; INDUCTION THERAPY; PROGNOSTIC-FACTOR; BORTEZOMIB; STRATIFICATION; SURVIVAL; DELETION AB Lenalidomide with dexamethasone is a standard induction treatment regimen for newly diagnosed myeloma (although a Federal Drug Administration indication is still absent). In the context of the Phase 3 clinical trial E4A03 (lenalidomide plus dexamethasone in low or high doses), we queried whether a fluorescence in situ hybridization (FISH)-based genetic classification into high risk (HR) and standard risk (SR) multiple myeloma (MM) would remain clinically significant. Of 445 E4A03 patients, 126 had FISH analysis; 21 were classified HR with t(4;14), t(14;16), or 17p13 deletions. Median survival follow-up approached 3 years. Patients with FISH data tended to be younger and healthier compared to the rest of the study population and, consequently, had superior overall survival (OS) results. Within the FISH cohort, shorter OS in the HR versus SR group (P = 0.004) corresponded to a hazard ratio of 3 48 [95% confidence interval: (1.42-8.53)], an effect also observed in multivariate analysis. Two-year OS rates were 91% for SR MM and 76% for HR MM. There was also evidence of interaction between risk status and treatment (P = 0.026). HR patients were less likely to attain good partial response (SR 46% and HR 30%, Odds Ratio = 2 0 [0.7-5.6]), but overall response rates were not different. FISH-based risk classification retained prognostic significance in patients receiving lenalidomide-based induction. C1 [Van Wier, Scott A.; Ahmann, Greg J.; Fonseca, Rafael] Mayo Clin, Scottsdale, AZ 85259 USA. [Jacobus, Susanna J.; Uno, Hajime] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kumar, Shaji; Henderson, Kimberly J.; Greipp, Philip R.; Rajkumar, S. Vincent] Mayo Clin, Rochester, MN USA. [Callander, Natalie S.] Univ Wisconsin, Madison, WI USA. [Williams, Michael E.] Univ Virginia, Med Ctr, Charlottesville, VA USA. [Siegel, David S.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. RP Fonseca, R (reprint author), Mayo Clin, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM fonseca.rafael@mayo.edu RI Kumar, Shaji/A-9853-2008; OI Kumar, Shaji/0000-0001-5392-9284; Fonseca, Rafael/0000-0002-5938-3769; Rajkumar, S. Vincent/0000-0002-5862-1833 FU Celgene Clinical Trial Data Safety Committee; Cephalon; Genentech; Millennium; Novartis; Celgene; Onyx; Public Health Service [CA23318, CA66636, CA21115, CA13650]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX S. K.: Clinical Trial Support - Celgene, Millennium, Genzyme, Novartis, Cephalon; consultant in Merck. M. E. W.: Celgene Clinical Trial Research funding; consultant and member of a Celgene Clinical Trial Data Safety Committee (total compensation <$10 000); Cephalon, Genentech, Millennium, Novartis: Clinical Trial Research funding. D. S. S.: Celgene - Honoraria/Speakers Bureau/Research Support, Millennium - Honoraria/Speakers Bureau; Onyx-Honoraria. R. F.: Patent for prognostication of MM based on genetic categorization of the disease; Consulting fees from Medtronic, Otsuka, Celgene, Genzyme, BMS and Amgen. Research funding from Cylene, Onyx. All other authors have no conflicts of interest to disclose.; This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M. D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA13650 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. NR 28 TC 11 Z9 11 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD NOV PY 2011 VL 155 IS 3 BP 340 EP 348 DI 10.1111/j.1365-2141.2011.08849.x PG 9 WC Hematology SC Hematology GA 835VG UT WOS:000296063700006 PM 21902684 ER PT J AU Bae, J Tai, YT Anderson, KC Munshi, NC AF Bae, Jooeun Tai, Yu-Tzu Anderson, Kenneth C. Munshi, Nikhil C. TI Novel epitope evoking CD138 antigen-specific cytotoxic T lymphocytes targeting multiple myeloma and other plasma cell disorders SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE CD138 peptide; multiple myeloma; peptide vaccine; cytotoxic T lymphocytes ID BONE-MARROW BIOPSIES; HIGH-DOSE THERAPY; BREAST-CANCER; IDENTIFICATION; SYNDECAN-1; EXPRESSION; LEUKEMIA; VACCINES; IMMUNOTHERAPY; MALIGNANCIES AB The development of an immunotherapeutic strategy targeting CD138 antigen could potentially represent a new treatment option for multiple myeloma (MM). This study evaluated the immune function of CD138 peptide-specific cytotoxic T lymphocytes (CTL), generated ex vivo using an HLA-A2-specific CD138 epitope against MM cells. A novel immunogenic HLA-A2-specific CD138(260-268) (GLVGLIFAV) peptide was identified from the full-length protein sequence of the CD138 antigen, which induced CTL specific to primary CD138(+) MM cells. The peptide-induced CD138-CTL contained a high percentage of CD8(+) activated/memory T cells with a low percentage of CD4(+) T cell and naive CD8(+) T cell subsets. The CTL displayed HLA-A2-restricted and CD138 antigen-specific cytotoxicity against MM cell lines. In addition, CD138-CTL demonstrated increased degranulation, proliferation and gamma-interferon secretion to HLA-A2(+)/CD138(+) myeloma cells, but not HLA-A2)/CD138(+) or HLA-A2(+)/CD138) cells. The immune functional properties of the CD138-CTL were also demonstrated using primary HLA-A2(+)/CD138(+) cells isolated from myeloma patients. In conclusion, a novel immunogenic CD138(260-268) (GLVGLIFAV) peptide can induce antigen-specific CTL, which might be useful for the treatment of MM patients with peptide-based vaccine or cellular immunotherapy strategies. C1 [Bae, Jooeun; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bae, Jooeun; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.] Harvard Univ, Sch Med, Boston, MA USA. [Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA USA. RP Munshi, NC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM nikhil_munshi@dfci.harvard.edu FU NIH [P50-100707, PO1-78378, RO1-129295, RO1-50947]; Multiple Myeloma Research Foundation; Leukaemia and Lymphoma Society; Department of Veteran's Affairs FX This work is supported by: NIH grants; P50-100707, PO1-78378, (K. C. A. and N.C.M.), RO1-129295 (N.C.M.) and RO1-50947 (K. C. A.), Multiple Myeloma Research Foundation Awards, Leukaemia and Lymphoma Society Scholar in Translational Research Award, and Department of Veteran's Affairs merit review award. NR 59 TC 14 Z9 15 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD NOV PY 2011 VL 155 IS 3 BP 349 EP 361 DI 10.1111/j.1365-2141.2011.08850.x PG 13 WC Hematology SC Hematology GA 835VG UT WOS:000296063700007 PM 21902685 ER PT J AU Williams, SB Gu, XM Lipsitz, SR Nguyen, PL Choueiri, TK Hu, JC AF Williams, Stephen B. Gu, Xiangmei Lipsitz, Stuart R. Nguyen, Paul L. Choueiri, Toni K. Hu, Jim C. TI Utilization and Expense of Adjuvant Cancer Therapies Following Radical Prostatectomy SO CANCER LA English DT Article DE prostatectomy; adjuvant therapy; utilization; expenditures; outcomes ID POSITIVE SURGICAL MARGINS; BIOCHEMICAL RECURRENCE; PELVIC LYMPHADENECTOMY; SALVAGE THERAPY; UNITED-STATES; OUTCOMES; MEN; RADIOTHERAPY; FAILURE; PATTERNS AB BACKGROUND: We sought to identify the costs of adjuvant therapies following radical prostatectomy (RP) and factors associated with their receipt. METHODS: We used SEER-Medicare data from 2004-2006 to identify 4247 men who underwent RP, of whom 600 subsequently received adjuvant therapies. We used Cox regression to identify factors associated with receipt of adjuvant therapies. Health care expenditures within 12 months of diagnosis were compared for RP alone versus RP with adjuvant therapies. RESULTS: Biopsy Gleason score, prostate-specific antigen, risk group, and SEER region were significantly associated with receipt of adjuvant treatments (all P < .001). Higher surgeon volume was associated with lower odds of receiving adjuvant therapies (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.46-0.78 [P < .001]). Factors associated with increased receipt of adjuvant therapies were positive surgical margins (HR, 3.02; 95% CI, 2.55-3.57 [P < .001]), high-risk group versus low-risk group (HR, 7.65; 95% CI, 5.64-10.37 [P < .001]), lymph node-positive disease (HR, 5.36; 95% CI, 3.71-7.75 [P < .001]), and treatment in Iowa (HR, 1.93; 95% CI, 1.12-3.32 [P = .019]) and New Mexico/Georgia/Hawaii (HR, 1.92; 95% CI, 1.09-3.39 [P = .025]) versus San Francisco SEER regions (baseline). Age, race, comorbidities, and surgical approach were not associated with use of adjuvant therapies. The median expenditures attributable to postprostatectomy hormonal therapy, radiation therapy, and radiation with hormonal therapy versus were $1361, $12,040, and $23,487. CONCLUSIONS: Men treated by high-volume surgeons were less likely to receive adjuvant therapies. Regional variation and high-risk disease characteristics were associated with increased receipt of adjuvant therapies, which increased health care expenditures by 2-to 3-fold when radiotherapy was administered. Cancer 2011; 117: 4846-54. (C) 2011 American Cancer Society. C1 [Williams, Stephen B.; Hu, Jim C.] Brigham & Womens Hosp, Div Urol Surg, Boston, MA 02115 USA. [Gu, Xiangmei; Lipsitz, Stuart R.; Hu, Jim C.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Nguyen, Paul L.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dept Radiat Oncol, Boston, MA 02115 USA. RP Hu, JC (reprint author), ASBII 3, Div Urol, 45 Francis St, Boston, MA 02115 USA. EM jhu2@partners.org FU Department of Defense [W81XWH-08-1-0283] FX This work was supported by a Department of Defense Prostate Cancer Physician Training Award (W81XWH-08-1-0283) presented to J. C. Hu. NR 40 TC 22 Z9 22 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD NOV 1 PY 2011 VL 117 IS 21 BP 4846 EP 4854 DI 10.1002/cncr.26012 PG 9 WC Oncology SC Oncology GA 836UR UT WOS:000296139600007 PM 21365630 ER PT J AU Rhee, EP Thadhani, R AF Rhee, Eugene P. Thadhani, Ravi TI New insights into uremia-induced alterations in metabolic pathways SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE ESRD; metabolite profiling; metabolomics; uremia; uremic toxin ID CHRONIC KIDNEY-DISEASE; INDOXYL SULFATE; ENDOTHELIAL DYSFUNCTION; MASS-SPECTROMETRY; OXIDATIVE STRESS; KYNURENIC ACID; HEMODIALYSIS; TOXINS; GUT; INFLAMMATION AB Purpose of review This article summarizes recent studies on uremia-induced alterations in metabolism, with particular emphasis on the application of emerging metabolomics technologies. Recent findings The plasma metabolome is estimated to include more than 4000 distinct metabolites. Because these metabolites can vary dramatically in size and polarity and are distributed across several orders of magnitude in relative abundance, no single analytical method is capable of comprehensive metabolomic profiling. Instead, a variety of analytical techniques, including targeted and nontargeted liquid chromatography-mass spectrometry, have been employed for metabolomic analysis of human plasma. Recent efforts to apply this technology to study uremia have reinforced the common view that end-stage renal disease is a state of generalized small molecule excess. However, the identification of precursor depletion and downstream metabolite excess - for example, with tryptophan and downstream kynurenine metabolites, with low molecular weight triglycerides and dicarboxylic acids, and with phosphatidylcholines, choline, and trimethylamine-N-oxide - suggest that uremia may directly modulate these metabolic pathways. Metabolomic studies have also begun to expand some of these findings to individuals with chronic kidney disease and in model systems. Summary Uremia is associated with diverse, but incompletely understood metabolic disturbances. Metabolomic approaches permit higher resolution phenotyping of these disturbances, but significant efforts will be required to understand the functional significance of select findings. C1 [Rhee, Eugene P.; Thadhani, Ravi] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Thadhani, Ravi] Broad Inst, Cambridge, MA USA. RP Rhee, EP (reprint author), Massachusetts Gen Hosp E, Div Nephrol, 149 13th St,8th Floor, Charlestown, MA 02129 USA. EM eprhee@partners.org FU NIH [F32-DK-085860-01] FX E.P.R. received support from the NIH F32-DK-085860-01. NR 39 TC 9 Z9 9 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD NOV PY 2011 VL 20 IS 6 BP 593 EP 598 DI 10.1097/MNH.0b013e32834b8a1d PG 6 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 836VD UT WOS:000296141700004 PM 21885966 ER PT J AU Liu, XW Hamnvik, OPR Petrou, M Gong, HZ Chamberland, JP Christophi, CA Kales, SN Christiani, DC Mantzoros, CS AF Liu, Xiaowen Hamnvik, Ole-Petter R. Petrou, Michael Gong, Huizhi Chamberland, John P. Christophi, Costas A. Kales, Stefanos N. Christiani, David C. Mantzoros, Christos S. TI Circulating lipocalin 2 is associated with body fat distribution at baseline but is not an independent predictor of insulin resistance: the prospective Cyprus Metabolism Study SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID GELATINASE-ASSOCIATED LIPOCALIN; NEUTROPHIL GELATINASE; PROTEIN; OBESITY; LEPTIN; NGAL; IDENTIFICATION; MARKER AB Objective: Lipocalin 2 (LCN2 or NGAL), a protein derived from neutrophils, macrophages, adipocytes, and other cells, has been proposed to be a link between obesity and insulin resistance (IR), but animal and cross-sectional human studies have revealed conflicting results. We studied the association of serum lipocalin 2 with anthropometric, metabolic, and cardiovascular risk markers in young healthy men cross-sectionally and, for the first time, prospectively after 2 years of follow-up, with and without adjustment for potential confounders including serum creatinine. Design: Two hundred and seventy-two participants were randomly selected from the Cyprus Metabolism Study (1056 men, 18 years), of whom 93 subjects participated in the follow-up study 2 years after baseline assessment. Associations were also explored between total and free leptin levels (to serve as positive controls) and anthropometric metabolic variables. Results: In the cross-sectional study, lipocalin 2 levels were marginally correlated in the unadjusted model with central fat distribution but not with body weight or total body fat mass. After adjusting for age, smoking, activity, body mass index, fat percentage, waist-to-hip ratio, and serum creatinine, no correlation was found with any cardiovascular risk factor. There was no correlation with the homeostasis model assessment of IR (HOMA-IR) at baseline. In the prospective analyses, baseline levels of lipocalin 2 were not predictive of any variables in unadjusted or adjusted models. As expected, total and free leptin were associated with anthropometric and metabolic variables both cross-sectionally and prospectively. Conclusions: We demonstrate that lipocalin 2 is not an independent predictor of metabolic and cardiovascular risk factors in young men cross-sectionally or prospectively. C1 [Liu, Xiaowen; Gong, Huizhi; Chamberland, John P.; Mantzoros, Christos S.] Harvard Univ, Div Endocrinol Diabet & Metab, Dept Med, Med Sch,Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Hamnvik, Ole-Petter R.; Mantzoros, Christos S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Petrou, Michael; Christophi, Costas A.] Cyprus Univ Technol, Harvard Univ, Cyprus Int Inst Environm & Publ Hlth, Sch Publ Hlth, Limassol, Cyprus. [Christophi, Costas A.; Kales, Stefanos N.; Christiani, David C.; Mantzoros, Christos S.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02215 USA. [Chamberland, John P.; Mantzoros, Christos S.] Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA USA. RP Mantzoros, CS (reprint author), Harvard Univ, Div Endocrinol Diabet & Metab, Dept Med, Med Sch,Beth Israel Deaconess Med Ctr, 330 Brookline Ave,Feldberg 875, Boston, MA 02215 USA. EM cmantzor@bidmc.harvard.edu RI Hamnvik, Ole-Petter/D-1719-2011; OI Chamberland, John/0000-0002-7862-1371 FU Cyprus Research Promotion Foundation [EPgammaEXi/0205/10]; Beth Israel Deaconess Medical Center FX The study was supported by the Cyprus Research Promotion Foundation (EP gamma E Xi/0205/10). The Mantzoros Lab is supported by a discretionary grant from Beth Israel Deaconess Medical Center. NR 22 TC 16 Z9 17 U1 0 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD NOV PY 2011 VL 165 IS 5 BP 805 EP 812 DI 10.1530/EJE-11-0660 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 836BN UT WOS:000296082100015 PM 21885675 ER PT J AU Kelly, SK Shire, DB Chen, JH Doyle, P Gingerich, MD Cogan, SF Drohan, WA Behan, S Theogarajan, L Wyatt, JL Rizzo, JF AF Kelly, Shawn K. Shire, Douglas B. Chen, Jinghua Doyle, Patrick Gingerich, Marcus D. Cogan, Stuart F. Drohan, William A. Behan, Sonny Theogarajan, Luke Wyatt, John L. Rizzo, Joseph F., III TI A Hermetic Wireless Subretinal Neurostimulator for Vision Prostheses SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Biomedical electrodes; integrated circuit design; iridium oxide; neuromuscular stimulation; retinal implant; retinal prosthesis; telemetry ID CHARGE-INJECTION LIMITS; IRIDIUM OXIDE AIROF; ELECTRICAL-STIMULATION; VISUAL-CORTEX; HUMAN RETINA; IMPLANTATION; DEGENERATION; ELECTRODES; RESPONSES; ARRAY AB A miniaturized, hermetically encased, wirelessly operated retinal prosthesis has been developed for preclinical studies in the Yucatan minipig, and includes several design improvements over our previously reported device. The prosthesis attaches conformally to the outside of the eye and electrically drives a microfabricated thin-film polyimide array of sputtered iridium oxide film electrodes. This array is implanted into the subretinal space using a customized ab externo surgical technique. The implanted device includes a hermetic titanium case containing a 15-channel stimulator chip and discrete circuit components. Feedthroughs in the case connect the stimulator chip to secondary power and data receiving coils on the eye and to the electrode array under the retina. Long-term in vitro pulse testing of the electrodes projected a lifetime consistent with typical devices in industry. The final assembly was tested in vitro to verify wireless operation of the system in physiological saline using a custom RF transmitter and primary coils. Stimulation pulse strength, duration, and frequency were programmed wirelessly from a Peripheral Component Interconnect eXtensions for Instrumentation (PXI) computer. Operation of the retinal implant has been verified in two pigs for up to five and a half months by detecting stimulus artifacts generated by the implanted device. C1 [Kelly, Shawn K.; Shire, Douglas B.; Doyle, Patrick; Gingerich, Marcus D.; Drohan, William A.; Rizzo, Joseph F., III] VA Boston Healthcare Syst, Ctr Innovat Visual Rehabil, Boston, MA 02130 USA. [Kelly, Shawn K.; Doyle, Patrick; Drohan, William A.; Wyatt, John L.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Shire, Douglas B.; Gingerich, Marcus D.] Cornell Univ, Ithaca, NY 14853 USA. [Chen, Jinghua; Rizzo, Joseph F., III] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Chen, Jinghua; Rizzo, Joseph F., III] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Cogan, Stuart F.] EIC Labs Inc, Norwood, MA 02062 USA. [Behan, Sonny] Sonny Behan Consulting, Atlanta, GA 30096 USA. [Theogarajan, Luke] Univ Calif Santa Barbara, Santa Barbara, CA 92106 USA. RP Kelly, SK (reprint author), VA Boston Healthcare Syst, Ctr Innovat Visual Rehabil, Boston, MA 02130 USA. EM skkelly@alum.mit.edu; dbs6@cornell.edu; jinghua_chen@meei.harvard.edu; wpd@mit.edu; mdg37@cornell.edu; scogan@eiclabs.com; billd@mit.edu; sbehan@bellsouth.net; ltheogar@ece.ucsb.edu; jlw@mit.edu; joseph_rizzo@meei.harvard.edu OI Kelly, Shawn/0000-0003-3533-5268 FU Department of Veterans Affairs Center for Innovative Visual Rehabilitation; NIH [EY016674-01]; Department of Defense; Massachusetts Lions Foundation; NSF FX This work was supported in part by the Department of Veterans Affairs Center for Innovative Visual Rehabilitation, the NIH under Grant EY016674-01, the Department of Defense, NSF's support to the Cornell NanoScale Science and Technology Facility, and the Massachusetts Lions Foundation. MOSIS provided in-kind foundry services. NR 28 TC 37 Z9 37 U1 3 U2 20 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD NOV PY 2011 VL 58 IS 11 BP 3197 EP 3205 DI 10.1109/TBME.2011.2165713 PG 9 WC Engineering, Biomedical SC Engineering GA 835FA UT WOS:000296019500018 PM 21859595 ER PT J AU Winters, M Lloyd, R Shahidi, A Brown, S Holodniy, M AF Winters, Mark Lloyd, Robert, Jr. Shahidi, Azra Brown, Sheldon Holodniy, Mark TI Use of dried clinical samples for storing and detecting influenza RNA SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article DE Dried samples; influenza; real-time PCR ID HUMAN-IMMUNODEFICIENCY-VIRUS; BLOOD SPOT ASSAY; DRUG-RESISTANCE; H1N1 VIRUS; A H1N1; SURVEILLANCE; COLLECTION; AMPLIFICATION; SENSITIVITY; DIAGNOSIS AB Background Most clinical samples collected for diagnostic influenza testing and monitoring require refrigerated or frozen storage or shipment, which imparts logistic and cost burdens. The ability to store and ship dried clinical specimens under ambient conditions for influenza testing would significantly reduce costs and protect samples from improper storage or equipment failure, especially in remote or resource-limited areas. Objectives To evaluate the collection and storage of dried clinical samples on a transport matrix (ViveST (TM), ST) for influenza RNA testing by real-time reverse-transcription PCR (RT-PCR). Methods Viral transport medium from swab or sputum samples was applied to ST, dried, and stored under ambient conditions from 2 days to 6 months. Additional aliquots of samples were frozen. Testing of frozen and ST-stored samples was performed using the WHO/CDC real-time influenza A (H1N1) RT-PCR protocol and compared to the Luminex xTAG RVP assay. Results ST-stored samples yielded slightly higher threshold cycle values (median 2 54 cycles) compared to frozen samples tested in parallel. This difference was consistent regardless of viral input. There was no significant difference in signal recovery between samples stored for 1 week versus samples stored for 3 weeks, or from three samples stored for 6 months. Qualitatively, clinical specimens stored on ST were 100% concordant (36/36) with frozen samples for detecting the presence of influenza A RNA. Conclusion ST-processed dried specimens produced similar rates of seasonal or novel 2009 HIN1 influenza RNA detection compared to conventional sample processing and thus presents a viable alternative to refrigerated or frozen samples. C1 [Winters, Mark; Holodniy, Mark] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Winters, Mark; Holodniy, Mark] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Lloyd, Robert, Jr.] Res ThinkTank Inc, Buford, GA USA. [Shahidi, Azra; Brown, Sheldon] James J Peters VA Med Ctr, Bronx, NY USA. RP Winters, M (reprint author), AIDS Res Ctr, 3801 Miranda Ave 132, Palo Alto, CA 94304 USA. EM mark.winters@stanford.edu NR 33 TC 1 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD NOV PY 2011 VL 5 IS 6 BP 413 EP 417 DI 10.1111/j.1750-2659.2011.00253.x PG 5 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 836BA UT WOS:000296080300009 PM 21668673 ER PT J AU Bai, XY Ovrutsky, AR Kartalija, M Chmura, K Kamali, A Honda, JR Oberley-Deegan, RE Dinarello, CA Crapo, JD Chang, LY Chan, ED AF Bai, Xiyuan Ovrutsky, Alida R. Kartalija, Marinka Chmura, Kathryn Kamali, Amanda Honda, Jennifer R. Oberley-Deegan, Rebecca E. Dinarello, Charles A. Crapo, James D. Chang, Ling-Yi Chan, Edward D. TI IL-32 expression in the airway epithelial cells of patients with Mycobacterium avium complex lung disease SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE cytokine; immunohistochemistry; non-tuberculous mycobacteria ID NECROSIS-FACTOR-ALPHA; A VIRUS-INFECTION; NONTUBERCULOUS MYCOBACTERIA; PROINFLAMMATORY CYTOKINE; INTERFERON-GAMMA; TNF-ALPHA; MACROPHAGE APOPTOSIS; TUBERCULOSIS; IMMUNITY; PREVALENCE AB Lung disease due to Mycobacterium avium complex (MAC) organisms is increasing. A greater understanding of the host immune response to MAC organisms will provide a foundation to develop novel therapies for these recalcitrant infections. IL-32 is a newly described pro-inflammatory cytokine that enhances host immunity against various microbial pathogens. Cytokines that induce IL-32 such as interferon-gamma, IL-18, IL-12 and tumor necrosis factor-alpha are of considerable importance to mycobacterial immunity. We performed immunohistochemistry and morphometric analysis to quantify IL-32 expression in the lungs of 11 patients with MAC lung disease and 10 controls with normal lung tissues. After normalizing for basement membrane length, there was a profound increase in IL-32 expression in the airway epithelial cells of the MAC-infected lungs compared with controls. Following normalization for alveolar surface area, there was a trend toward increased IL-32 expression in type II alveolar cells and alveolar macrophages in the lungs of MAC patients. Human airway epithelial cells (BEAS-2B) infected with M. avium produced IL-32 by a nuclear factor-kappa B-dependent mechanism. In both BEAS-2B cells and human monocyte-derived macrophages, exogenous IL-32 gamma significantly reduced the growth of intracellular M. avium. This finding was corroborated by an increase in the number of intracellular M. avium recovered from THP-1 monocytes silenced for endogenous IL-32 expression. The anti-mycobacterial effect of IL-32 may be due, in part, to increased apoptosis of infected cells. These findings indicate that IL-32 facilitates host defense against MAC organisms but may also contribute to the airway inflammation associated with MAC pulmonary disease. C1 [Bai, Xiyuan; Ovrutsky, Alida R.; Chmura, Kathryn; Oberley-Deegan, Rebecca E.; Crapo, James D.; Chang, Ling-Yi; Chan, Edward D.] Natl Jewish Hlth, Dept Acad Affairs, Denver, CO 80206 USA. [Bai, Xiyuan; Ovrutsky, Alida R.; Kartalija, Marinka; Chan, Edward D.] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO 80220 USA. [Bai, Xiyuan; Ovrutsky, Alida R.; Honda, Jennifer R.; Chan, Edward D.] Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA. [Kartalija, Marinka; Dinarello, Charles A.] Univ Colorado Denver, Div Infect Dis, Aurora, CO 80045 USA. [Kamali, Amanda; Honda, Jennifer R.; Chan, Edward D.] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Chan, Edward D.] Natl Jewish Hlth, Dept Med, Cell Biol Program, Denver, CO 80206 USA. RP Bai, XY (reprint author), Natl Jewish Hlth, Dept Acad Affairs, 1400 Jackson St, Denver, CO 80206 USA. EM baix@njhealth.org FU Department of Veterans Affairs Veterans Health Administration; Office of Research and Development; National Institutes of Health [AI15614] FX Department of Veterans Affairs Veterans Health Administration, Office of Research and Development (E.D.C.) and National Institutes of Health (AI15614 to C.A.D.). NR 73 TC 11 Z9 12 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD NOV PY 2011 VL 23 IS 11 BP 679 EP 691 DI 10.1093/intimm/dxr075 PG 13 WC Immunology SC Immunology GA 838MG UT WOS:000296295700003 PM 22033195 ER PT J AU Harries, AD Lin, Y Satyanarayana, S Lonnroth, K Li, L Wilson, N Chauhan, LS Zachariah, R Baker, MA Jeon, CY Murray, MB Maher, D Bygbjerg, IC Enarson, DA Billo, NE Kapur, A AF Harries, A. D. Lin, Y. Satyanarayana, S. Loennroth, K. Li, L. Wilson, N. Chauhan, L. S. Zachariah, R. Baker, M. A. Jeon, C. Y. Murray, M. B. Maher, D. Bygbjerg, I. C. Enarson, D. A. Billo, N. E. Kapur, A. TI The looming epidemic of diabetes-associated tuberculosis: learning lessons from HIV-associated tuberculosis SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Review DE diabetes mellitus; tuberculosis; screening; HIV; treatment outcomes; framework ID SUB-SAHARAN AFRICA; PULMONARY TUBERCULOSIS; ANTIRETROVIRAL THERAPY; CHRONIC DISEASES; MELLITUS; PREVALENCE; INFECTION; WILL; RECURRENCE; RELEVANCE AB The prevalence of diabetes mellitus is increasing at a dramatic rate, and countries in Asia, particularly India and China, will bear the brunt of this epidemic. Persons with diabetes have a significantly increased risk of active tuberculosis (TB), which is two to three times higher than in persons without diabetes. In this article, we argue that the epidemiological interactions and the effects on clinical presentation and treatment resulting from the interaction between diabetes and TB are similar to those observed for human immunodeficiency virus (HIV) and TB. The lessons learned from approaches to reduce the dual burden of HIV and TB, and especially the modes of screening for the two diseases, can be adapted and applied to the screening, diagnosis, treatment and prevention of diabetes and TB. The new World Health Organization (WHO) and The Union Collaborative Framework for care and control of TB and diabetes has many similarities to the WHO Policy on Collaborative Activities to reduce the dual burden of TB and HIV, and aims to guide policy makers and implementers on how to move forward and combat this looming dual epidemic. The response to the growing HIV-associated TB epidemic in the 1980s and 1990s was slow and uncoordinated, despite clearly articulated warnings about the scale of the forthcoming problem. We must not make the same mistake with diabetes and TB. The Framework provides a template for action, and it is now up to donors, policy makers and implementers to apply the recommendations in the field and to 'learn by doing'. C1 [Harries, A. D.; Enarson, D. A.; Billo, N. E.] Int Union TB & Lung Dis, Paris, France. [Harries, A. D.; Maher, D.] London Sch Hyg & Trop Med, London WC1, England. [Lin, Y.] China Off, Int Union TB & Lung Dis, Beijing, Peoples R China. [Satyanarayana, S.; Wilson, N.] SE Asia Off, Int Union TB & Lung Dis, Delhi, India. [Loennroth, K.] WHO, Stop TB Dept, CH-1211 Geneva, Switzerland. [Li, L.] Chinese Ctr Dis Control & Prevent, Clin Ctr TB, Beijing, Peoples R China. [Chauhan, L. S.] Govt India, Natl Ctr Dis Control, Minist Hlth & Family Welf, Delhi, India. [Zachariah, R.] Brussels Operat Ctr, Dept Med, Operat Res Unit, Luxembourg, Luxembourg. [Baker, M. A.; Murray, M. B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Baker, M. A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Jeon, C. Y.] Columbia Univ, New York, NY USA. [Murray, M. B.] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Bygbjerg, I. C.] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Copenhagen, Denmark. [Kapur, A.] World Diabet Fdn, Gentofte, Denmark. RP Harries, AD (reprint author), Vears Lane, Winchester SO21 1TQ, Hants, England. EM adharries@theunion.org RI Lonnroth, Knut/L-2339-2014 OI Lonnroth, Knut/0000-0001-5054-8240 NR 73 TC 35 Z9 36 U1 1 U2 10 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD NOV PY 2011 VL 15 IS 11 BP 1436 EP 1444 DI 10.5588/ijtld.11.0503 PG 9 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA 837ER UT WOS:000296174400007 PM 21902876 ER PT J AU Gruber, J Miklowitz, DJ Harvey, AG Frank, E Kupfer, D Thase, ME Sachs, GS Ketter, TA AF Gruber, June Miklowitz, David J. Harvey, Allison G. Frank, Ellen Kupfer, David Thase, Michael E. Sachs, Gary S. Ketter, Terence A. TI Sleep matters: Sleep functioning and course of illness in bipolar disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Sleep; Mania; Depression; Functioning; STEP-BD ID TREATMENT ENHANCEMENT PROGRAM; STEP-BD; MANIA; DEPRIVATION; DEPRESSION; MOOD; EPISODE AB Background: Few studies have prospectively examined the relationships of sleep with symptoms and functioning in bipolar disorder. Methods: The present study examined concurrent and prospective associations between total sleep time (TST) and sleep variability (SV) with symptom severity and functioning in a cohort of DSM-IV bipolar patients (N = 468) participating in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), all of whom were recovered at study entry. Results: Concurrent associations at study entry indicated that shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity. Mixed-effects regression modeling was used to examine prospective associations in the 196 patients for whom follow-up data were available. Consistent with findings at study entry, shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity over 12 months. Discussion: These findings highlight the importance of disrupted sleep patterns in the course of bipolar illness. (C) 2011 Elsevier B.V. All rights reserved. C1 [Gruber, June] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Miklowitz, David J.] Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Semel Inst, Los Angeles, CA USA. [Harvey, Allison G.] Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. [Frank, Ellen; Kupfer, David; Thase, Michael E.] Univ Pittsburgh, Dept Psychiat, Med Ctr, Pittsburgh, PA 15260 USA. [Sachs, Gary S.] Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. [Sachs, Gary S.] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. [Ketter, Terence A.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Gruber, J (reprint author), Yale Univ, Dept Psychol, POB 208205, New Haven, CT 06520 USA. EM june.gruber@yale.edu FU National Institute of Mental Health (NIMH) [N01MH80001] FX The STEP-BD study was supported with Federal funds from the National Institute of Mental Health (NIMH), under contract N01MH80001. Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the NIMH. NR 26 TC 30 Z9 31 U1 3 U2 9 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 NOV PY 2011 VL 134 IS 1-3 BP 416 EP 420 DI 10.1016/j.jad.2011.05.016 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 831TG UT WOS:000295753400053 PM 21683450 ER PT J AU Sung, SC Dryman, MT Marks, E Shear, MK Ghesquiere, A Fava, M Simon, NM AF Sung, Sharon C. Dryman, M. Taylor Marks, Elizabeth Shear, M. Katherine Ghesquiere, Angela Fava, Maurizio Simon, Naomi M. TI Complicated grief among individuals with major depression: Prevalence, comorbidity, and associated features SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Complicated grief; Bereavement; Traumatic grief; Prolonged grief; Major depression ID BEREAVEMENT-RELATED DEPRESSION; TRAUMATIC GRIEF; DIAGNOSTIC-CRITERIA; PANIC DISORDER; ANXIETY; HEALTH; SCALE; LIFE; NORTRIPTYLINE; PSYCHOTHERAPY AB Background: Growing data suggest that complicated grief (CG) may be common in clinical care settings, but there are few prior reports about CG in outpatients presenting with primary mood disorders. Methods: The present study examined rates of bereavement and threshold CG symptoms (defined as a score >= 25 on the Inventory of Complicated Grief scale) in 111 outpatients with major depressive disorder (MDD) and 142 healthy controls participating in a study of stress and depression. Clinical and demographic characteristics were also compared for bereaved individuals with CG (MDD + CG) to those without (MDD - CC). Participants completed structured diagnostic interviews as well as measures of CG, depression, anxiety, exposure to traumatic events, and perceived social support. Results: Lifetime history of a significant loss did not differ for the MDD and control groups (79.3% vs. 76.1%), but bereaved participants with MDD had higher rates of threshold CG (25.0% vs. 2.8%). Among those with MDD, CG was associated with a higher prevalence of lifetime alcohol dependence, greater exposure to traumatic events, and lower perceived social support. Depressed women, but not men, with CG also had higher rates of panic disorder, social anxiety disorder, and posttraumatic stress disorder. Limitations: Our findings are limited by the lack of a clinician confirmatory assessment of CG diagnosis, absence of complete information about the nature and timing of the loss, and relatively narrow generalizability. Conclusions: We found high rates of CG in a group of psychiatric outpatients with chronic MDD, suggesting that patients with depression should be routinely screened for CG. (C) 2011 Elsevier B.V. All rights reserved. C1 [Sung, Sharon C.; Dryman, M. Taylor; Marks, Elizabeth; Simon, Naomi M.] Harvard Univ, Sch Med, Dept Psychiat, Ctr Anxiety & Traumat Stress Disorders,Massachuse, Boston, MA 02115 USA. [Shear, M. Katherine; Ghesquiere, Angela] Columbia Univ, Sch Social Work, New York, NY USA. [Shear, M. Katherine] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Fava, Maurizio] Harvard Univ, Sch Med, Dept Psychiat, Depress Clin & Res Program,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Sung, SC (reprint author), Duke NUS Grad Med Sch Singapore, Off Clin Sci, 8 Coll Rd, Singapore 169857, Singapore. EM sharon.sung@duke-nus.edu.sg FU Massachusetts General Hospital FX The authors wish to thank the staff of the Center for Anxiety and Traumatic Stress Disorders and the Depression Clinical and Research Program at Massachusetts General Hospital for their support and assistance with this project NR 41 TC 17 Z9 19 U1 3 U2 17 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 NOV PY 2011 VL 134 IS 1-3 BP 453 EP 458 DI 10.1016/j.jad.2011.05.017 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 831TG UT WOS:000295753400061 PM 21621849 ER PT J AU Shum, WWC Ruan, YC Da Silva, N Breton, S AF Shum, Winnie W. C. Ruan, Ye Chun Da Silva, Nicolas Breton, Sylvie TI Establishment of Cell-Cell Cross Talk in the Epididymis: Control of Luminal Acidification SO JOURNAL OF ANDROLOGY LA English DT Article DE H(+)-ATPase; V-ATPase; pseudostratified epithelia; basal cells; clear cells; principal cells ID MALE REPRODUCTIVE-TRACT; TRANSMEMBRANE CONDUCTANCE REGULATOR; VACUOLAR H+-ATPASE; ANGIOTENSIN-CONVERTING ENZYME; SOLUBLE ADENYLYL-CYCLASE; TRANSCRIPTION FACTOR FOXI1; MOUSE SPERM CAPACITATION; VAS-DEFERENS EPITHELIA; ACTIN-BINDING SITE; PROTEIN-KINASE-A AB Male infertility is often caused by sperm that have low motility and interact poorly with the oocyte. Spermatozoa acquire these crucial functions in the epididymis. A low luminal bicarbonate (HCO(3)(-)) concentration and low pH keep sperm quiescent during their maturation and storage in this organ. This review describes how epididymal epithelial cells work in a concerted manner, together with spermatozoa, to establish and maintain this acidic luminal environment. Clear cells express the proton-pumping ATPase (V-ATPase) in their apical membrane and actively secrete protons. HCO(3)(-) induces V-ATPase accumulation in apical microvilli in clear cells via HCO(3)(-)-sensitive adenylyl cyclase-dependent cAMP production. HCO(3)(-) is secreted from principal cells following basolateral stimulation, to transiently "prime" spermatozoa before ejaculation. Luminal ATP and adenosine also induce V-ATPase apical accumulation in clear cells via activation of P2 and P1 receptors, respectively. ATP is released into the lumen from sperm and principal cells and is then metabolized into adenosine by local nucleotidases. In addition, the V-ATPase is regulated by luminal angiotensin II via activation of basal cells, which can extend narrow body projections that cross the tight junction barrier. Basal cells then secrete nitric oxide, which diffuses out to stimulate proton secretion in clear cells via activation of the cGMP pathway. Thus, an elaborate communication network is present between principal cells and clear cells, and between basal cells and clear cells, to control luminal acidification. Monitoring and decoding these "intercellular conversations" will help define pathophysiologic mechanisms underlying male infertility. C1 Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Breton, S (reprint author), MGH Simches Res Ctr, Program Membrane Biol, 185 Cambridge St,CPZN 8-204, Boston, MA 02114 USA. EM breton.sylvie@mgh.harvard.edu FU NICHD NIH HHS [HD040793, HD045821, R01 HD040793, R01 HD045821]; NIDDK NIH HHS [DK085715, DK038452, DK43351, DK57521, P01 DK038452, P30 DK043351, P30 DK057521, R01 DK085715] NR 109 TC 35 Z9 38 U1 0 U2 7 PU AMER SOC ANDROLOGY, INC PI LAWRENCE PA C/O ALLEN PRESS, INC PO BOX 368, LAWRENCE, KS 66044 USA SN 0196-3635 J9 J ANDROL JI J. Androl. PD NOV-DEC PY 2011 VL 32 IS 6 BP 576 EP 586 DI 10.2164/jandrol.111.012971 PG 11 WC Andrology SC Endocrinology & Metabolism GA 835LH UT WOS:000296037400004 PM 21441423 ER PT J AU Olson, RA Brastianos, PK Palma, DA AF Olson, Robert A. Brastianos, Priscilla K. Palma, David A. TI Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE MGMT; Meta-analysis; Predictive markers; Prognostic markers; High-grade glioma ID NEWLY-DIAGNOSED GLIOBLASTOMA; O-6-METHYLGUANINE DNA METHYLTRANSFERASE; PHASE-II TRIAL; PROMOTER METHYLATION; MALIGNANT GLIOMA; NCIC TRIAL; TEMOZOLOMIDE; GENE; RADIOTHERAPY; SURVIVAL AB Epigenetic silencing of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is associated with improved survival in patients with high-grade gliomas (HGG), with varying estimates of magnitude. The objective of this meta-analysis is to determine the prognostic value of MGMT silencing, and assess its predictive value by treatment type. MEDLINE and EMBASE databases were searched for studies relating to gliomas and MGMT. Studies reporting overall survival (OS) by MGMT status in patients with HGG were considered potentially eligible. We excluded studies that did not control for potential confounding variables. A meta-analysis of studies was performed via random-effects modelling. Subgroup meta-analyses by treatment were performed according to a priori hypotheses. Twenty studies were ultimately eligible, including 2,018 patients. In the pooled analysis, MGMT silencing was associated with improved OS (HR = 0.436; 95% CI: 0.333-0.571; P < 0.001). The prognostic utility of MGMT status varies significantly by treatment type (P = 0.001): the HR for OS for MGMT silenced tumors is 0.190 (0.047-0.770), 0.403 (0.282-0.576), 0.743 (0.579-0.954), and 1.070 (0.722-1.585) for studies using surgery plus the addition of either: chemotherapy (CT), chemoradiotherapy (CRT), radiotherapy (RT), and nothing (surgery alone), respectively. Epigenetic silencing of MGMT is associated with markedly improved survival in patients with HGG who receive adjuvant therapy. MGMT silencing serves as a predictive marker, with the largest benefit seen in patients receiving CT as a component of adjuvant treatment, an intermediate benefit in patients receiving adjuvant RT, and no evidence to support benefit in those receiving surgery alone. C1 [Olson, Robert A.] Univ British Columbia, Ctr North, Dept Radiat Oncol, Vancouver, BC V5Z 4E6, Canada. [Olson, Robert A.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Olson, Robert A.; Brastianos, Priscilla K.; Palma, David A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Brastianos, Priscilla K.] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. [Brastianos, Priscilla K.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. [Brastianos, Priscilla K.] Massachusetts Gen Hosp, Ctr Canc, Dept Hematol & Oncol, Boston, MA 02114 USA. [Palma, David A.] Univ Western Ontario, Div Radiat Oncol, London, ON N6A 4L6, Canada. [Palma, David A.] London Reg Canc Program, London, ON N6A 4L6, Canada. RP Olson, RA (reprint author), Univ British Columbia, Ctr North, Dept Radiat Oncol, 600 W 10th Ave, Vancouver, BC V5Z 4E6, Canada. EM rolson2@bccancer.bc.ca OI Brastianos, Priscilla/0000-0003-4470-8425 NR 41 TC 37 Z9 38 U1 0 U2 8 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 NOV PY 2011 VL 105 IS 2 BP 325 EP 335 DI 10.1007/s11060-011-0594-5 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 835VK UT WOS:000296064200023 PM 21523485 ER PT J AU Fernando, HN Czamanski, J Yuan, TY Gu, WY Salahadin, A Huang, CYC AF Fernando, Hanan N. Czamanski, Jessica Yuan, Tai-Yi Gu, Weiyong Salahadin, Abdi Huang, Chun-Yuh Charles TI Mechanical Loading Affects the Energy Metabolism of Intervertebral Disc Cells SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE intervertebral disc; ATP; mechanical loading; energy production ID REGULATES MITOCHONDRIAL RESPIRATION; BOVINE NUCLEUS PULPOSUS; DISCOGENIC BACK-PAIN; DYNAMIC COMPRESSION; IN-VITRO; ISOLATED CHONDROCYTES; LUMBAR RHIZOPATHIES; GLUCOSE-TRANSPORT; SYNTHESIS RATES; ATP AB Research has shown that mechanical loading affects matrix biosynthesis of intervertebral disc (IVD) cells; however, the pathway(s) to this effect is currently unknown. Cellular matrix biosynthesis is an energy demanding process. The objective of this study was to investigate the effects of static and dynamic compressive loading on energy metabolism of IVD cells. Porcine annulus fibrosus (AF) and nucleus pulposus (NP) cells seeded in 2% agarose were used in this experiment. Experimental groups included 15% static compression and 0.1 and 1 Hz dynamic compression at 15% strain magnitude for 4 h. ATP, lactate, glucose, and nitric oxide (NO) contents in culture media, and ATP content in cell-agarose construct were measured using biochemical assays. While the total ATP content of AF cells was promoted by static and dynamic loading, only 1 Hz dynamic loading increased total ATP content of NP cells. Increases in lactate production and glucose consumption of AF cells suggest that ATP production via glycolysis is promoted by dynamic compression. ATP release and NO production of AF and NP cells were significantly increased by dynamic loading. Thus, this study clearly illustrates that static and dynamic compressive loading affect IVD cell energy production while cellular responses to mechanical loading were both cell type and compression type dependent. (C) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29: 1634-1641, 2011 C1 [Fernando, Hanan N.; Czamanski, Jessica; Yuan, Tai-Yi; Huang, Chun-Yuh Charles] Univ Miami, Stem Cell & Mechanobiol Lab, Dept Biomed Engn, Coll Engn, Coral Gables, FL 33146 USA. [Yuan, Tai-Yi; Gu, Weiyong] Univ Miami, Tissue Biomech Lab, Dept Biomed Engn, Coral Gables, FL 33146 USA. [Salahadin, Abdi] Harvard Univ, Sch Med, BIDMC, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA. RP Huang, CYC (reprint author), Univ Miami, Stem Cell & Mechanobiol Lab, Dept Biomed Engn, Coll Engn, Coral Gables, FL 33146 USA. EM c.huang@miami.edu FU NIH [AR056101, EB008653] FX This study was supported by the grants (AR056101 and EB008653) from the NIH. The authors have no conflicts of interest in relation to the presented material. NR 50 TC 22 Z9 22 U1 2 U2 8 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 NOV PY 2011 VL 29 IS 11 BP 1634 EP 1641 DI 10.1002/jor.21430 PG 8 WC Orthopedics SC Orthopedics GA 832KO UT WOS:000295803900002 PM 21484859 ER PT J AU Lee, KB Murray, SS Duarte, MEL Spitz, JF Johnson, JS Song, KJ Brochmann, EJ Taghavi, CE Keorochana, G Liao, JC Wang, JC AF Lee, Kwang-Bok Murray, Samuel S. Duarte, M. Eugenia L. Spitz, Juliana F. Johnson, Jared S. Song, Kyung-Jin Brochmann, Elsa J. Taghavi, Cyrus E. Keorochana, Gun Liao, Jen-Chung Wang, Jeffrey C. TI Effects of the Bone Morphogenetic Protein Binding Protein spp24 (Secreted Phosphoprotein 24 kD) on the Growth of Human Lung Cancer Cells SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE spp24; bone morphogenetic proteins; lung cancer; bone tumors; A549 cell line; metastases ID METASTATIC PROSTATE-CANCER; OSTEOLYTIC LESIONS; TUMOR-GROWTH; EXPRESSION; OVEREXPRESSION; ANTAGONISTS; CARCINOMAS; MOUSE AB Bone morphogenetic proteins (BMPs) and transforming growth factor-beta (TGF-beta) contribute to the growth of some skeletal metastases through autocrine stimulation. Secreted phosphoprotein 24 kDa (spp24) has been shown to bind to both BMP-2 and TGF-beta and to markedly inhibit the osteogenic properties of rhBMP-2. We hypothesized that the addition of spp24 would sequester autocrine growth factors (especially BMP-2) and reduce tumor growth in a system (A549 human non-small cell lung cancer cell line) where autocrine stimulation by BMP-2 is known to be important. A549 cells were injected into two sites (subcutaneous and intraosseus) in SCID mice with and without the co-injection of BMP-2 and spp24. Tumor growth after 8 weeks was assessed through gross examination, radiological imaging, and histological analysis. Spp24 attenuated the tumor growth enhancing effects of rhBMP-2 and reduced the tumor growth when added to tumor cells that were not treated with BMP-2. We conclude that spp24 can reduce A549 cell tumor growth in both soft tissue and intraosseus environments. We hypothesize that the mechanism for this inhibition is interruption of autocrine stimulation through the sequestration of BMP-2. Spp24 can be developed into a therapeutic agent that can be employed in clinical situations where the inhibitions of BMPs and related proteins is advantageous. (C) 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:1712-1718, 2011 C1 [Lee, Kwang-Bok; Johnson, Jared S.; Taghavi, Cyrus E.; Keorochana, Gun; Liao, Jen-Chung; Wang, Jeffrey C.] Univ Calif Los Angeles, Dept Orthopaed Surg, UCLA Comprehens Spine Ctr, Los Angeles, CA 90095 USA. [Lee, Kwang-Bok; Song, Kyung-Jin] Chonbuk Natl Univ, Sch Med, Chonbuk Natl Univ Hosp, Dept Orthopaed Surg,Res Inst Clin Med, Jonju, South Korea. [Murray, Samuel S.; Brochmann, Elsa J.] VA Greater Los Angeles Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Sepulveda, CA USA. [Murray, Samuel S.; Brochmann, Elsa J.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Murray, Samuel S.; Wang, Jeffrey C.] Univ Calif Los Angeles, Biomed Engn Interdept Program, Los Angeles, CA 90095 USA. [Duarte, M. Eugenia L.; Spitz, Juliana F.] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. [Duarte, M. Eugenia L.; Spitz, Juliana F.] Natl Inst Traumatol & Orthopaed, Rio De Janeiro, Brazil. RP Wang, JC (reprint author), Univ Calif Los Angeles, Dept Orthopaed Surg, UCLA Comprehens Spine Ctr, 1250 16th St,7th Floor,Tower 745, Los Angeles, CA 90095 USA. EM jwang@mednet.ucla FU Department of Veterans Affairs FX Supported in part by the Department of Veterans Affairs. NR 30 TC 9 Z9 9 U1 0 U2 5 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 NOV PY 2011 VL 29 IS 11 BP 1712 EP 1718 DI 10.1002/jor.21383 PG 7 WC Orthopedics SC Orthopedics GA 832KO UT WOS:000295803900014 PM 21509819 ER PT J AU Wiggers, JK Guitton, TG Smith, RM Vrahas, MS Ring, D AF Wiggers, Jimme K. Guitton, Thierry G. Smith, R. Malcolm Vrahas, Mark S. Ring, David TI Observed and Expected Outcomes in Transfer and Nontransfer Patients With a Hip Fracture SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE hip fracture; mortality; complications; transfer status; operative treatment ID ACADEMIC-MEDICAL-CENTER; INTENSIVE-CARE-UNIT; INTERHOSPITAL TRANSFERS AB Objectives: Hospitals and providers that accept transfer patients risk lower ratings on publically reported quality measures that are inadequately adjusted for infirmity and complexity. We compared the outcomes of transferred patients and nontransferred patients after treatment of a hip fracture and sought to determine if expected outcomes based on an expansion of All Patient Refined-Diagnosis Related Groups (APR-DRGs) norms are accurately adjusted for transfer status. Design: Retrospective cohort study. Setting: Tertiary care referral center. Patients: Four hundred six consecutive patients 65 years and older who received operative treatment of an acute hip fracture. Intervention: Patients who were transferred from another acute care hospital or a skilled nursing facility before treatment were classified as transfer patients (n = 123), and all other patients were nontransfer patients (n = 283). Main Outcome: Groups were compared with respect to in-hospital mortality, length of stay (LOS), excess days over the geometric mean length of stay (GMLOS), and readmission rate as well as expected length of stay (Exp LOS) and expected mortality (Exp Mort) based on APR-DRG norms and additional adjustment for transfer status. Results: Transfer patients had significantly greater LOS (10.2 vs 9.6 days; P < 0.05), Exp LOS (9.7 vs 7.7 days; P < 0.001), Exp Mort (0.07 vs 0.03; P = 0.004), and excess days over the GMLOS (4.1 vs 3.3 days; P = 0.025) than nontransfer patients, near-significant greater in-hospital mortality (9.8 vs 4.9%; P = 0.069), and similar readmission rates. The differences in LOS and Exp LOS were nonsignificant in both transfer (P = 0.49) and nontransfer patients (P = 0.10). Conclusions: Patients 65 years and older transferred to a tertiary care facility for treatment of an acute hip fracture have worse outcome than nontransfer patients. Unadjusted data such as in-hospital mortality may be misleading, but risk adjustment using the APR-DRG methodology and additional correction for transfer status may provide meaningful benchmarks. C1 [Ring, David] Harvard Univ, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Med Sch,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, R. Malcolm; Vrahas, Mark S.] Harvard Univ, Orthopaed Trauma Serv, Massachusetts Gen Hosp, Med Sch,Dept Orthopaed, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Med Sch,Massachusetts Gen Hosp, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Guitton, Thierry/0000-0002-2599-1985 NR 22 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-5339 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD NOV PY 2011 VL 25 IS 11 BP 666 EP 669 DI 10.1097/BOT.0b013e31821146b1 PG 4 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 838BB UT WOS:000296260300008 PM 21857540 ER PT J AU Dehghan, S Seto, J Hudson, NR Robinson, CM Jones, MS Dyer, DW Chodosh, J Seto, D AF Dehghan, Shoaleh Seto, Jason Hudson, Nolan R. Robinson, Christopher M. Jones, Morris S. Dyer, David W. Chodosh, James Seto, Donald TI Complete Genome Sequence of Human Adenovirus Prototype 17 SO JOURNAL OF VIROLOGY LA English DT Article ID VECTOR DEVELOPMENT AB As one of the first five human adenoviruses (HAdVs) to be sequenced, type 17 was important as a reference tool for comparative genomics of recently isolated HAdV pathogens in species D. HAdV-D17 was the first species D adenovirus to be sequenced and was deposited in GenBank in 1999. These genome data were not of high quality, and a redetermination of the same stock virus provides corrected data; among the differences are a length of 35,139 bp versus 35,100 bp in the original, and 160 mismatches to the original genome were found. Annotation of the coding sequences reveals 39 as opposed to 8, a finding which is important for phylogenomic studies. C1 [Dehghan, Shoaleh; Seto, Jason; Seto, Donald] George Mason Univ, Sch Syst Biol, Manassas, VA 20110 USA. [Hudson, Nolan R.; Jones, Morris S.] Calif Dept Publ Hlth, Viral & Rickettsial Dis Lab, Richmond, CA 94804 USA. [Robinson, Christopher M.; Chodosh, James] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Howe Lab, Boston, MA 02114 USA. [Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. RP Seto, D (reprint author), George Mason Univ, Sch Syst Biol, 10900 Univ Blvd,MSN 5B3, Manassas, VA 20110 USA. EM dseto@gmu.edu FU U.S. Public Health Service NIH [EY013124, P30EY014104]; Research to Prevent Blindness, Inc. FX This work was supported in part by U.S. Public Health Service NIH grants EY013124 (D. S., M.S.J., D. W. D., and J.C.) and P30EY014104 (J.C.). J.C. is also funded by an unrestricted grant to the Department of Ophthalmology, Harvard Medical School, from Research to Prevent Blindness, Inc. NR 7 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2011 VL 85 IS 21 BP 11540 EP 11541 DI 10.1128/JVI.06051-11 PG 2 WC Virology SC Virology GA 837ZL UT WOS:000296254400060 PM 21980031 ER PT J AU Chung, JH Wu, CC Gilman, MD Palmer, EL Hasserjian, RP Shepard, JAO AF Chung, Jonathan H. Wu, Carol C. Gilman, Matthew D. Palmer, Edwin L. Hasserjian, Robert P. Shepard, Jo-Anne O. TI Lymphomatoid Granulomatosis: CT and FDG-PET Findings SO KOREAN JOURNAL OF RADIOLOGY LA English DT Article DE Lymphomatoid granulomatosis; Cavitation; Pulmonary nodules; Pulmonary masses; Halo sign; Air-bronchogram sign ID RARE CAUSE; PROLIFERATION; NODULES; DISEASE; LUNG; SIGN AB Objective: Lymphomatoid granulomatosis (LG) is a rare, aggressive extranodal Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disease. The purpose of our study was to analyze the CT and fluorodeoxyglucose positron emission tomography (FOG-PET) findings of pulmonary LG. Materials and Methods: Between 2000 and 2009, four patients with pathologically proven pulmonary LG and chest CT were identified. Two of these patients also had FOG-PET. Imaging features of LG on CT and PET were reviewed. Results: Pulmonary nodules or masses with peribronchovascular, subpleural, and lower lung zonal preponderance were present in all patients. Central low attenuation (4 of 4 patients), ground-glass halo (3 of 4 patients), and peripheral enhancement (4 of 4 patients) were observed in these nodules and masses. An air-bronchogram and cavitation were seen in three of four patients. FDG-PET scans demonstrated avid FOG uptake in the pulmonary nodules and masses. Conclusion: Pulmonary LG presents with nodules and masses with a lymphatic distribution, as would be expected for a lymphoproliferative disease. However, central low attenuation, ground-glass halo and peripheral enhancement of the nodules/masses are likely related to the angioinvasive nature of this disease. Peripheral enhancement and ground-glass halo, in particular, are valuable characteristic not previously reported that can help radiologists suggest the diagnosis of pulmonary LG. C1 [Chung, Jonathan H.] Natl Jewish Hlth, Inst Adv Biomed Imaging, Denver, CO 80206 USA. [Wu, Carol C.; Gilman, Matthew D.; Palmer, Edwin L.; Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Chung, JH (reprint author), Natl Jewish Hlth, Inst Adv Biomed Imaging, 1400 Jackson St, Denver, CO 80206 USA. EM chungj@njhealth.org FU Siemens AG; NIH FX Jonathan H. Chung, MD receives salary support from Siemens AG and the NIH. NR 21 TC 8 Z9 9 U1 0 U2 5 PU KOREAN RADIOLOGICAL SOC PI SEOUL PA 121-8 YANGJAE-DONG, SEOCHO-GU, SEOUL 137-130, SOUTH KOREA SN 1229-6929 J9 KOREAN J RADIOL JI Korean J. Radiol. PD NOV-DEC PY 2011 VL 12 IS 6 BP 671 EP 678 DI 10.3348/kjr.2011.12.6.671 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 838TI UT WOS:000296314700003 PM 22043148 ER PT J AU Mueller, T Beutler, C Pico, AH Shibolet, O Pratt, DS Pascher, A Neuhaus, P Wiedenmann, B Berg, T Podolsky, DK AF Mueller, Tobias Beutler, Claudia Pico, Almudena Hurtado Shibolet, Oren Pratt, Daniel S. Pascher, Andreas Neuhaus, Peter Wiedenmann, Bertram Berg, Thomas Podolsky, Daniel K. TI Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis SO LIVER INTERNATIONAL LA English DT Article DE cholangiocyte; innate immune hypo-responsiveness; intestinal endotoxin; nucleotide-binding oligomerization domain protein; primary sclerosing cholangitis; toll-like receptor ID PRIMARY SCLEROSING CHOLANGITIS; TOLL-LIKE RECEPTOR; INFLAMMATORY-BOWEL-DISEASE; NECROSIS-FACTOR-ALPHA; KAPPA-B ACTIVATION; SIGNALING PATHWAYS; UP-REGULATION; INCREASED EXPRESSION; LIPOTEICHOIC ACID; GAMMA-INTERFERON AB Background: Pattern recognition receptors (PRRs) orchestrate the innate immune defence in human biliary epithelial cells (BECs). Tight control of PRR signalling provides tolerance to physiological amounts of intestinal endotoxins in human bile to avoid constant innate immune activation in BECs. Aims: We wanted to determine whether inappropriate innate immune responses to intestinal endotoxins contribute to the development and perpetuation of chronic biliary inflammation. Methods: We examined PRR-mediated innate immune responses and protective endotoxin tolerance in primary BECs isolated from patients with primary sclerosing cholangitis (PSC), alcoholic liver disease and patients without chronic liver disease. Expression studies comprised northern blots, RT-PCR, Western blots and immunocytochemistry. Functional studies comprised immuno-precipitation Western blots, FACS for endotoxin uptake, and NF-kappa B activation assays and ELISA for secreted IL-8 and tumour necrosis factor (TNF)-alpha. Results: Primary BECs from explanted PSC livers showed reversibly increased TLR and NOD protein expression and activation of the MyD88/IRAK signalling complex. Consecutively, PSC BECs exhibited inappropriate innate immune responses to endotoxins and did not develop immune tolerance after repeated endotoxin exposures. This endotoxin hyper-responsiveness was probably because of the stimulatory effect of abundantly expressed IFN-gamma and TNF-alpha in PSC livers, which stimulated TLR4-mediated endotoxin signalling in BECs, leading to increased TLR4-mediated endotoxin incorporation and impaired inactivation of the TLR4 signalling cascade. As TNF-alpha inhibition partly restored protective innate immune tolerance, endogenous TNF-alpha secretion probably contributed to inappropriate endotoxin responses in BECs. Conclusion: Inappropriate innate immune responses to intestinal endotoxins and subsequent endotoxin intolerance because of enhanced PRR signalling in BECs probably contribute to chronic cholangitis. C1 [Podolsky, Daniel K.] Univ Texas SW Med Ctr Dallas, Dallas, TX USA. [Mueller, Tobias; Beutler, Claudia; Pico, Almudena Hurtado; Wiedenmann, Bertram] Charite, Med Klin Schwerpunkt Hepatol & Gastroenterol, Campus Virchow Klinikum, D-13353 Berlin, Germany. [Shibolet, Oren] Hadassah Hebrew Univ, Dept Med, Liver Unit, Med Ctr Jerusalem, Jerusalem, Israel. [Pratt, Daniel S.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Pratt, Daniel S.] Harvard Univ, Sch Med, Boston, MA USA. [Pascher, Andreas; Neuhaus, Peter] Charite, Klin Allgemein Visceral & Transplantationschirurg, Campus Virchow Klinikum, D-13353 Berlin, Germany. [Berg, Thomas] Univ Klinikum Leipzig, Klin Gastroenterol & Rheumatol, Sekt Hepatol, Leipzig, Germany. RP Podolsky, DK (reprint author), UT SW Med Ctr, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM daniel.podolsky@utsouthwestern.edu OI Berg, Thomas/0000-0003-0003-6241 FU NIDDK NIH HHS [P30 DK043351, R01 DK069344, T32 DK007191] NR 57 TC 29 Z9 30 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1478-3223 J9 LIVER INT JI Liver Int. PD NOV PY 2011 VL 31 IS 10 BP 1574 EP 1588 DI 10.1111/j.1478-3231.2011.02635.x PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 837YM UT WOS:000296249800019 PM 22093333 ER PT J AU Gialamas, SP Petridou, ET Tseleni-Balafouta, S Spyridopoulos, TN Matsoukis, IL Kondi-Pafiti, A Zografos, G Mantzoros, CS AF Gialamas, Spyros P. Petridou, Eleni Th. Tseleni-Balafouta, Sofia Spyridopoulos, Themistoklis N. Matsoukis, Ioannis L. Kondi-Pafiti, Agathi Zografos, George Mantzoros, Christos S. TI Serum adiponectin levels and tissue expression of adiponectin receptors are associated with risk, stage, and grade of colorectal cancer SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID PLASMA ADIPONECTIN; PROGNOSTIC-SIGNIFICANCE; LEPTIN CONCENTRATIONS; METABOLIC SYNDROME; OBESITY; COLON; CARCINOMA; METAANALYSIS; ACTIVATION; SURVIVAL AB Adiponectin has been associated with colorectal cancer (CRC) risk This study aims to investigate the association of both adiponectin and tissue expression of its receptors with CRC risk as well as clinicopathological characteristics, notably stage and grade. Determination of serum adiponectin and immunohistochemical expression of adiponectin receptors in adenocarcinoma/normal colorectal tissue was performed in samples from 104 newly diagnosed CRC patients and 208 age- and sex-matched controls. Multiple logistic regression odds ratios and 95% confidence intervals for CRC risk were derived, controlling for a series of covariates. Serum adiponectin was negatively associated with CRC risk (odds ratio, 0.72; confidence interval, 0.53-0.99) and also with tumor grade (P = .05). Expression of both adiponectin receptors was stronger in adenocarcinoma vs normal tissue (P = .001). AdipoR1 expression was negatively associated with nodal stage (P = .03); AdipoR2 expression was positively associated with tumor, node, metastasis stage (P = .01). Established positive associations with red meat consumption and diabetes, and negative associations with physical exercise and plant food consumption were confirmed along with a more than 60% higher risk associated with central obesity. Adiponectin levels and tissue expression of hormonal receptors seem to be associated not only with CRC risk but also with components of clinicopathological characteristics; given power limitations, these results should be interpreted with caution. The exact nature of the association and the underlying pathophysiological mechanisms need to be further examined in large prospective studies assessing adiponectin and its receptors as novel targets for exploring CRC growth. (C) 2011 Elsevier Inc. All rights reserved. C1 [Gialamas, Spyros P.; Petridou, Eleni Th.; Spyridopoulos, Themistoklis N.; Matsoukis, Ioannis L.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Tseleni-Balafouta, Sofia] Univ Athens, Sch Med, Dept Pathol, GR-11527 Athens, Greece. [Spyridopoulos, Themistoklis N.] Univ Athens, Gen Univ Hosp Attikon, Dept Radiol 2, Athens 12462, Greece. [Kondi-Pafiti, Agathi] Univ Athens, Aretaie Hosp, Dept Obstet & Gynecol 22, Athens 11528, Greece. [Kondi-Pafiti, Agathi] Univ Athens, Aretaieion Hosp, Pathol Lab, Athens 11528, Greece. [Zografos, George] Univ Athens, Sch Med, Hippokrat Hosp, Dept Propaedeut Surg 1, GR-11527 Athens, Greece. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab,Dept Internal Med, Boston, MA 02215 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02215 USA. RP Petridou, ET (reprint author), Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. EM epetrid@med.uoa.gr FU Medical School, National and Kapodistrian University of Athens, Greece; Beth Israel Deaconess Medical Center; National Institute of Diabetes and Digestive and Kidney Diseases [DK81913] FX We thank Dr. D Korkolis; Vicky Kalampoki and Nick Dessypris, statisticians; as well as M Flessa, health visitor, for their valuable contribution to the study. Funding: The project was supported in part by the Medical School, National and Kapodistrian University of Athens, Greece; Beth Israel Deaconess Medical Center; and grant DK81913 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 52 TC 33 Z9 37 U1 1 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD NOV PY 2011 VL 60 IS 11 BP 1530 EP 1538 DI 10.1016/j.metabol.2011.03.020 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 838RQ UT WOS:000296310300006 PM 21632074 ER PT J AU Tam, CS Berthoud, HR Bueter, M Chakravarthy, MV Geliebter, A Hajnal, A Holst, J Kaplan, L Pories, W Raybould, H Seeley, R Strader, A Ravussin, E AF Tam, C. S. Berthoud, H. -R. Bueter, M. Chakravarthy, M. V. Geliebter, A. Hajnal, A. Holst, J. Kaplan, L. Pories, W. Raybould, H. Seeley, R. Strader, A. Ravussin, E. TI Could the mechanisms of bariatric surgery hold the key for novel therapies? SO OBESITY REVIEWS LA English DT Article DE Bariatric surgery; gut hormones; weight loss ID GLUCAGON-LIKE PEPTIDE-1; Y GASTRIC BYPASS; DIET-INDUCED OBESITY; IMPROVES GLUCOSE-TOLERANCE; RESTING ENERGY-EXPENDITURE; WEIGHT-LOSS; BODY-COMPOSITION; GUT MICROBIOTA; 7-36 AMIDE; RATS AB Bariatric surgery is the most effective method for promoting dramatic and durable weight loss in morbidly obese subjects. Furthermore, type 2 diabetes is resolved in over 80% of patients. The mechanisms behind the amelioration in metabolic abnormalities are largely unknown but may be due to changes in energy metabolism, gut peptides and food preference. The goal of this meeting was to review the latest research to better understand the mechanisms behind the 'magic' of bariatric surgery. Replication of these effects in a non-surgical manner remains one of the ultimate challenges for the treatment of obesity and diabetes. Promising data on energy metabolism, gastrointestinal physiology, hedonic response and food intake were reviewed and discussed. C1 [Tam, C. S.; Berthoud, H. -R.; Ravussin, E.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Bueter, M.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [Chakravarthy, M. V.] Merck Res Labs, Rahway, NJ USA. [Geliebter, A.] Columbia Univ, New York, NY USA. [Hajnal, A.] Penn State Univ, Hershey, PA USA. [Holst, J.] Univ Copenhagen, Copenhagen, Denmark. [Kaplan, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pories, W.] E Carolina Univ, Brody Sch Med, Greenville, NC USA. [Raybould, H.] Univ Calif Davis, Davis, CA 95616 USA. [Seeley, R.] Univ Cincinnati, Cincinnati, OH USA. [Strader, A.] So Illinois Univ, Sch Med, Carbondale, IL 62901 USA. RP Ravussin, E (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM eric.ravussin@pbrc.edu FU Ajinomoto Co, Inc.; Amylin/Lilly Alliance; Covidien; Ethicon Endo Surgery, Inc.; GlaxoSmithKline; PepsiCo; The Pennington Biomedical Research Center Foundation FX This meeting was sponsored by Ajinomoto Co, Inc., Amylin/Lilly Alliance, Covidien, Ethicon Endo Surgery, Inc., GlaxoSmithKline, PepsiCo and The Pennington Biomedical Research Center Foundation. NR 50 TC 22 Z9 23 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1467-7881 J9 OBES REV JI Obes. Rev. PD NOV PY 2011 VL 12 IS 11 BP 984 EP 994 DI 10.1111/j.1467-789X.2011.00902.x PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 835UC UT WOS:000296060500007 PM 21729236 ER PT J AU Axelrod, FB Liebes, L Gold-von Simson, G Mendoza, S Mull, J Leyne, M Norcliffe-Kaufmann, L Kaufmann, H Slaugenhaupt, SA AF Axelrod, Felicia B. Liebes, Leonard Gold-von Simson, Gabrielle Mendoza, Sandra Mull, James Leyne, Maire Norcliffe-Kaufmann, Lucy Kaufmann, Horacio Slaugenhaupt, Susan A. TI Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia SO PEDIATRIC RESEARCH LA English DT Article ID EXPRESSION; MUTATION; CELLS AB Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. (Pediatr Res 70: 480-483, 2011) C1 [Axelrod, Felicia B.] NYU, Dysauton Ctr, Langone Med Ctr, Dept Pediat,Sch Med, New York, NY 10016 USA. [Axelrod, Felicia B.; Kaufmann, Horacio] NYU, Dept Neurol, Sch Med, New York, NY 10016 USA. [Liebes, Leonard; Mendoza, Sandra] NYU, Dept Med, Sch Med, New York, NY 10016 USA. [Norcliffe-Kaufmann, Lucy] NYU, Dept Physiol & Neurosci, Sch Med, New York, NY 10016 USA. [Mull, James; Leyne, Maire; Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Dept Neurol Genet, Ctr Human Genet Res, Boston, MA 02114 USA. RP Axelrod, FB (reprint author), NYU, Dysauton Ctr, Langone Med Ctr, Dept Pediat,Sch Med, 530 1st Ave,Suite 9Q, New York, NY 10016 USA. EM felicia.axelrod@nyumc.org FU CTSI [1UL1RR029893]; NIH of the National Center for Research Resources [M01 RR-00096, NIH NS058318, NS036326, U54NS065736, FDA FD-R-3731-01]; Dysautonomia Foundation, Inc, New York, NY FX Supported by CTSI Grant 1UL1RR029893 and grants from the NIH General Clinical Research Centers Program of the National Center for Research Resources M01 RR-00096: NIH NS058318, NS036326, U54NS065736: FDA FD-R-3731-01, and awards from the Dysautonomia Foundation, Inc, New York, NY. NR 17 TC 29 Z9 29 U1 1 U2 7 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 W CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD NOV PY 2011 VL 70 IS 5 BP 480 EP 483 PG 4 WC Pediatrics SC Pediatrics GA 836ON UT WOS:000296121100007 PM 21775922 ER PT J AU Holzel, BK Lazar, SW Gard, T Schuman-Olivier, Z Vago, DR Ott, U AF Hoelzel, Britta K. Lazar, Sara W. Gard, Tim Schuman-Olivier, Zev Vago, David R. Ott, Ulrich TI How Does Mindfulness Meditation Work? Proposing Mechanisms of Action From a Conceptual and Neural Perspective SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Article DE anxiety disorders; attention; cognition; consciousness; neuroscience; positive psychology; stress disorders ID VENTROMEDIAL PREFRONTAL CORTEX; RANDOMIZED CONTROLLED-TRIAL; STRESS REDUCTION PROGRAM; GENERALIZED ANXIETY DISORDER; SHORT-TERM MEDITATION; HIPPOCAMPAL INACTIVATION DISRUPTS; FUNCTIONAL MAGNETIC-RESONANCE; PEDIATRIC BIPOLAR DISORDER; TEMPORO-PARIETAL JUNCTION; CEREBRAL-BLOOD-FLOW AB Cultivation of mindfulness, the nonjudgmental awareness of experiences in the present moment, produces beneficial effects on well-being and ameliorates psychiatric and stress-related symptoms. Mindfulness meditation has therefore increasingly been incorporated into psychotherapeutic interventions. Although the number of publications in the field has sharply increased over the last two decades, there is a paucity of theoretical reviews that integrate the existing literature into a comprehensive theoretical framework. In this article, we explore several components through which mindfulness meditation exerts its effects: (a) attention regulation, (b) body awareness, (c) emotion regulation (including reappraisal and exposure, extinction, and reconsolidation), and (d) change in perspective on the self. Recent empirical research, including practitioners' self-reports and experimental data, provides evidence supporting these mechanisms. Functional and structural neuroimaging studies have begun to explore the neuroscientific processes underlying these components. Evidence suggests that mindfulness practice is associated with neuroplastic changes in the anterior cingulate cortex, insula, temporo-parietal junction, fronto-limbic network, and default mode network structures. The authors suggest that the mechanisms described here work synergistically, establishing a process of enhanced self-regulation. Differentiating between these components seems useful to guide future basic research and to specifically target areas of development in the treatment of psychological disorders. C1 [Hoelzel, Britta K.; Gard, Tim; Ott, Ulrich] Univ Giessen, Bender Inst Neuroimaging, D-35394 Giessen, Germany. [Hoelzel, Britta K.; Lazar, Sara W.; Gard, Tim; Schuman-Olivier, Zev] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Vago, David R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Holzel, BK (reprint author), Univ Giessen, Bender Inst Neuroimaging, Otto Behaghel Str 10 H, D-35394 Giessen, Germany. EM britta@nmr.mgh.harvard.edu RI Lazar, Sara/G-3809-2012 OI Lazar, Sara/0000-0003-1126-8363 FU NCCIH NIH HHS [R01 AT006344, R21 AT003425] NR 243 TC 407 Z9 415 U1 72 U2 372 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD NOV PY 2011 VL 6 IS 6 BP 537 EP 559 DI 10.1177/1745691611419671 PG 23 WC Psychology, Multidisciplinary SC Psychology GA 833LV UT WOS:000295887900003 PM 26168376 ER PT J AU Lee, J Zaki, J Harvey, PO Ochsner, K Green, MF AF Lee, J. Zaki, J. Harvey, P. -O. Ochsner, K. Green, M. F. TI Schizophrenia patients are impaired in empathic accuracy SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Empathic accuracy; expressivity; schizophrenia; social cognition ID NATURALISTIC SOCIAL COGNITION; BASES; NEUROSCIENCE AB Background. Empathy is crucial for successful social relationships. Despite its importance for social interactions, little is known about empathy in schizophrenia. This study investigated the degree to which schizophrenia patients can accurately infer the affective state of another person (i.e. empathic accuracy). Method. A group of 30 schizophrenia patients and 22 healthy controls performed an empathic accuracy task on which they continuously rated the affective state of another person shown in a video (referred to as the 'target'). These ratings were compared with the target's own continuous self-rating of affective state; empathic accuracy was defined as the correlation between participants' ratings and the targets' self-ratings. A separate line-tracking task was administered to measure motoric/attentional factors that could account for group differences in performance. Participants' self-rated empathy was measured using the Interpersonal Reactivity Index, and targets' self-rated emotional expressivity was measured using the Berkeley Expressivity Questionnaire. Results. Compared with controls, schizophrenia patients showed lower empathic accuracy although they performed the motoric tracking task at high accuracy. There was a significant group x target expressivity interaction such that patients showed a smaller increase in empathic accuracy with higher levels of emotional expressivity by the target, compared with controls. Patients' empathic accuracy was uncorrelated with self-reported empathy or clinical symptoms. Conclusions. Schizophrenia patients showed lower empathic accuracy than controls, and their empathic accuracy was less influenced by the emotional expressivity of the target. These findings suggest that schizophrenia patients benefit less from social cues of another person when making an empathic judgement. C1 [Lee, J.; Harvey, P. -O.; Green, M. F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Lee, J.; Harvey, P. -O.; Green, M. F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Zaki, J.; Ochsner, K.] Columbia Univ, Dept Psychol, New York, NY 10027 USA. RP Lee, J (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 300 Med Plaza,Room 2261, Los Angeles, CA 90095 USA. EM jungheelee@ucla.edu RI Lee, Junghee/C-5226-2014 OI Lee, Junghee/0000-0001-9567-8700 FU National Institute of Mental Health (NIMH) [MH043292, MH076137]; National Institute on Drug Abuse (NIDA) [DA022541]; Autism Speaks Grant [4787] FX Support for this study came from a National Institute of Mental Health (NIMH) grant (no. MH043292 to M. F. G.), a National Institute on Drug Abuse (NIDA) grant (no. DA022541 to K.O.), a NIMH grant (no. MH076137 to K.O.) and an Autism Speaks Grant (no. 4787 to J.Z.). The authors thank Mark R. McGee, Shelly Crosby and Cory Tripp for assistance in data collection. NR 43 TC 38 Z9 38 U1 2 U2 14 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD NOV PY 2011 VL 41 IS 11 BP 2297 EP 2304 DI 10.1017/S0033291711000614 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 837XX UT WOS:000296246300006 PM 21524334 ER PT J AU Loscalzo, J Barabasi, AL AF Loscalzo, Joseph Barabasi, Albert-Laszlo TI Systems biology and the future of medicine SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Article ID PROTEIN-INTERACTION NETWORK; HUMAN-DISEASE; COMPLEX NETWORKS; GENETIC INTERACTIONS; METABOLIC NETWORKS; SMALL-WORLD; IDENTIFICATION; ORGANIZATION; INTERACTOME; RESOURCE AB Contemporary views of human disease are based on simple correlation between clinical syndromes and pathological analysis dating from the late 19th century. Although this approach to disease diagnosis, prognosis, and treatment has served the medical establishment and society well for many years, it has serious shortcomings for the modern era of the genomic medicine that stem from its reliance on reductionist principles of experimentation and analysis. Quantitative, holistic systems biology applied to human disease offers a unique approach for diagnosing established disease, defining disease predilection, and developing individualized ( personalized) treatment strategies that can take full advantage of modern molecular pathobiology and the comprehensive data sets that are rapidly becoming available for populations and individuals. In this way, systems pathobiology offers the promise of redefining our approach to disease and the field of medicine. (C) 2011 John Wiley & Sons, Inc. WIREs Syst Biol Med 2011 3 619-627 DOI: 10.1002/wsbm. 144 C1 [Loscalzo, Joseph; Barabasi, Albert-Laszlo] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Loscalzo, Joseph; Barabasi, Albert-Laszlo] Harvard Univ, Sch Med, Boston, MA USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Ctr Canc Syst Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Dana Farber Canc Inst, Ctr Canc Syst Biol, Ctr Complex Networks Res, Boston, MA 02115 USA. RP Loscalzo, J (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM jloscalzo@partners.org FU NIH [HL61795, HL81587, HL70819, HL48743] FX This work was supported in part by NIH grants HL61795, HL81587, HL70819, and HL48743. The author wishes to thank Stephanie Tribuna for expert technical assistance. NR 68 TC 81 Z9 84 U1 2 U2 30 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1939-5094 J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD NOV-DEC PY 2011 VL 3 IS 6 BP 619 EP 627 DI 10.1002/wsbm.144 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 838GQ UT WOS:000296275800001 PM 21928407 ER PT J AU Sargent, DJ Resnick, MB Meyers, MO Goldar-Najafi, A Clancy, T Gill, S Siemons, GO Shi, Q Bot, BM Wu, TT Beaudry, G Haince, JF Fradet, Y AF Sargent, Daniel J. Resnick, Murray B. Meyers, Michael O. Goldar-Najafi, Atoussa Clancy, Thomas Gill, Sharlene Siemons, Gary O. Shi, Qian Bot, Brian M. Wu, Tsung-Teh Beaudry, Guillaume Haince, Jean-Francois Fradet, Yves TI Evaluation of Guanylyl Cyclase C Lymph Node Status for Colon Cancer Staging and Prognosis SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article; Proceedings Paper CT Gastrointestinal Cancers Symposium CY 2011 CL San Francisco, CA ID II COLORECTAL-CANCER; DEFECTIVE MISMATCH REPAIR; POLYMERASE-CHAIN-REACTION; MICROSATELLITE-INSTABILITY; ADJUVANT CHEMOTHERAPY; TUMOR-CELLS; SURVIVAL; MICROMETASTASES; EXPRESSION; NUMBER AB Purpose. The prognostic significance of guanylyl cyclase C (GCC) gene expression in lymph nodes (LNs) was evaluated in patients with stage II colon cancer who were not treated with adjuvant chemotherapy. We report a planned analysis performed on 241 patients. Methods. GCC mRNA was quantified by RT-qPCR using formalin-fixed LN tissues from patients with untreated stage II colon cancer who were diagnosed from 1999-2006 with at least ten LNs examined and blinded to clinical outcomes. Lymph node ratio (LNR) is the number of GCC-positive nodes divided by total number of informative LNs. Risk categories of low (0-0.1) and high (> 0.1) for LNR were chosen by significance using Cox regression models. The data were tested for association with time to recurrence. Results. Twenty-nine patients (12%) had a disease recurrence or cancer death. The LNR significantly predicted higher recurrence risk for 84 patients (34.9%) classified as high risk (hazard ratio (HR), 2.38; P = 0.02). The estimated 5-year recurrence rates were 10% and 27% for the low- and high-risk groups, respectively. After adjusting for age, T stage, number of nodes assessed, and MMR status, a significant association remained (HR, 2.61; P = 0.02). In a subset of patients (n = 181) with T3 tumor, a parts per thousand yen 12 nodes examined and negative margins, a significant association between the GCC LNR and recurrence risk also was observed (HR, 5.06; P = 0.003). Conclusions. Our preliminary results suggest that detection of GCC mRNA in LNs is associated with risk of disease recurrence in patients with untreated stage II colon cancer. A larger validation study is ongoing. C1 [Sargent, Daniel J.; Shi, Qian; Bot, Brian M.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Resnick, Murray B.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Resnick, Murray B.] Rhode Isl Hosp, Providence, RI USA. [Meyers, Michael O.] Univ N Carolina, Div Surg Oncol, Chapel Hill, NC USA. [Goldar-Najafi, Atoussa] Lahey Clin Gordon Canc Ctr, Dept Pathol, Burlington, MA USA. [Clancy, Thomas] Brigham & Womens Hosp, Div Surg Oncol, Boston, MA 02115 USA. [Clancy, Thomas] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gill, Sharlene] Univ British Columbia, Div Med Oncol, BC Canc Agcy, Vancouver, BC V5Z 1M9, Canada. [Siemons, Gary O.] Colon & Rectal Surg Associates S Jersey, Voorhees, NJ USA. [Wu, Tsung-Teh] Mayo Clin, Dept Anat Pathol, Rochester, MN USA. [Beaudry, Guillaume; Haince, Jean-Francois; Fradet, Yves] DiagnoCure Inc, Quebec City, PQ, Canada. RP Sargent, DJ (reprint author), Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. EM sargent.daniel@mayo.edu OI Bot, Brian/0000-0002-2412-6826; Sargent, Daniel/0000-0002-2684-4741 NR 40 TC 11 Z9 12 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2011 VL 18 IS 12 BP 3261 EP 3270 DI 10.1245/s10434-011-1731-2 PG 10 WC Oncology; Surgery SC Oncology; Surgery GA 832XQ UT WOS:000295844400007 PM 21533822 ER PT J AU Biczo, G Hegyi, P Dosa, S Shalbuyeva, N Berczi, S Sinervirta, R Hracsko, Z Siska, A Kukor, Z Jarmay, K Venglovecz, V Varga, IS Ivanyi, B Alhonen, L Wittmann, T Gukovskaya, A Takacs, T Rakonczay, Z AF Biczo, Gyoergy Hegyi, Peter Dosa, Sandor Shalbuyeva, Natalia Berczi, Sandor Sinervirta, Riitta Hracsko, Zsuzsanna Siska, Andrea Kukor, Zoltan Jarmay, Katalin Venglovecz, Viktoria Varga, Ilona S. Ivanyi, Bela Alhonen, Leena Wittmann, Tibor Gukovskaya, Anna Takacs, Tamas Rakonczay, Zoltan, Jr. TI The Crucial Role of Early Mitochondrial Injury in L-Lysine-Induced Acute Pancreatitis SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID KAPPA-B ACTIVATION; L-ARGININE; SUPEROXIDE-DISMUTASE; EXCESS LYSINE; RATS; TRYPSINOGEN; PROTEIN; MODEL; MECHANISMS; ANALOGS AB Aims: Large doses of intraperitoneally injected basic amino acids, L-arginine, or L-ornithine, induce acute pancreatitis in rodents, although the mechanisms mediating pancreatic toxicity remain unknown. Another basic amino acid, L-lysine, was also shown to cause pancreatic acinar cell injury. The aim of the study was to get insight into the mechanisms through which L-lysine damages the rat exocrine pancreas, in particular to characterize the kinetics of L-lysine-induced mitochondrial injury, as well as the pathologic responses (including alteration of antioxidant systems) characteristic of acute pancreatitis. Results: We showed that intraperitoneal administration of 2 g/kg L-lysine induced severe acute necrotizing pancreatitis. L-lysine administration caused early pancreatic mitochondrial damage that preceded the activation of trypsinogen and the proinflammatory transcription factor nuclear factor-kappa B (NF-kappa B), which are commonly thought to play an important role in the development of acute pancreatitis. Our data demonstrate that L-lysine impairs adenosine triphosphate synthase activity of isolated pancreatic, but not liver, mitochondria. Innovation and Conclusion: Taken together, early mitochondrial injury caused by large doses of L-lysine may lead to the development of acute pancreatitis independently of pancreatic trypsinogen and NF-kappa B activation. Antioxid. Redox Signal. 15, 2669-2681. C1 [Biczo, Gyoergy; Hegyi, Peter; Jarmay, Katalin; Wittmann, Tibor; Takacs, Tamas; Rakonczay, Zoltan, Jr.] Univ Szeged, Dept Med 1, H-6701 Szeged, Hungary. [Dosa, Sandor; Berczi, Sandor; Ivanyi, Bela] Univ Szeged, Dept Pathol, H-6701 Szeged, Hungary. [Shalbuyeva, Natalia; Gukovskaya, Anna] Univ Calif Los Angeles, Los Angeles, CA USA. [Shalbuyeva, Natalia; Gukovskaya, Anna] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Sinervirta, Riitta; Alhonen, Leena] Univ Eastern Finland, AI Virtanen Inst Mol Sci, Bioctr Kuopio, Kuopio, Finland. [Hracsko, Zsuzsanna; Varga, Ilona S.] Univ Szeged, Dept Biochem & Mol Biol, H-6701 Szeged, Hungary. [Siska, Andrea] Univ Szeged, Dept Clin Chem, H-6701 Szeged, Hungary. [Kukor, Zoltan] Semmelweis Univ, Dept Med Chem Mol Biol & Pathobiochem, Budapest, Hungary. [Venglovecz, Viktoria] Univ Szeged, Dept Pharmacol & Pharmacotherapy, H-6701 Szeged, Hungary. RP Rakonczay, Z (reprint author), Univ Szeged, Dept Med 1, POB 427, H-6701 Szeged, Hungary. EM raz@in1st.szote.u-szeged.hu FU National Development Agency [TAMOP-4.2.2-08/1/2008-0002, 0013, TAMOP-4.2.1.B-09/1/KONV-2010-0005]; Hungarian Scientific Research Fund [K78311, NNF 78851, PD78087]; Hungarian Academy of Sciences [BO 00334/08/5, BO 00174/10/5]; Academy of Finland [130087] FX This study was supported by National Development Agency grants (TAMOP-4.2.2-08/1/2008-0002 and 0013; TAMOP-4.2.1.B-09/1/KONV-2010-0005), the Hungarian Scientific Research Fund (K78311 to Z.R., NNF 78851 to P.H., and PD78087 to V.V.), the Hungarian Academy of Sciences (BO 00334/08/5 to P.H. and BO 00174/10/5 to Z.R.), and the Academy of Finland (130087 to L.A.). The authors would like to thank Dr. Gizella Karacsony for her help with the TUNEL assay. The rabbit anti-HSP72 antibody was a generous gift from Dr. Istvan Kurucz. NR 31 TC 12 Z9 13 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD NOV PY 2011 VL 15 IS 10 BP 2669 EP 2681 DI 10.1089/ars.2011.4065 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 831MF UT WOS:000295734400003 PM 21644850 ER PT J AU Gukovsky, I Pandol, SJ Gukovskaya, AS AF Gukovsky, Ilya Pandol, Stephen J. Gukovskaya, Anna S. TI Organellar Dysfunction in the Pathogenesis of Pancreatitis SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID MITOCHONDRIAL PERMEABILITY TRANSITION; CYTOCHROME-C RELEASE; SMALL-MOLECULE INHIBITORS; BCL-X-L; CELL-DEATH; ACINAR-CELLS; OXIDATIVE STRESS; MEMBRANE PERMEABILIZATION; TRYPSINOGEN ACTIVATION; CASPASE ACTIVATION AB Significance: Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis. Recent Advances: This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca(2+), reactive oxygen species, and BclxL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis-accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen. Critical Issues and Future Directions: The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage. Antioxid. Redox Signal. 15, 2699-2710. C1 [Gukovsky, Ilya; Pandol, Stephen J.; Gukovskaya, Anna S.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Gukovsky, I (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. EM igukovsk@ucla.edu; agukovsk@ucla.edu FU NIH [DK59936, AA19730] FX Department of Veterans Affairs; NIH R01 grants DK59936 and AA19730; Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis (NIH P50AA11999). NR 92 TC 23 Z9 24 U1 0 U2 10 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD NOV PY 2011 VL 15 IS 10 BP 2699 EP 2710 DI 10.1089/ars.2011.4068 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 831MF UT WOS:000295734400005 PM 21834686 ER PT J AU Bigdeli, T Neale, M Neale, B AF Bigdeli, Tim Neale, Michael Neale, Benjamin TI Empirical significance for low-frequency common variants SO BEHAVIOR GENETICS LA English DT Meeting Abstract CT 41st Annual Meeting of the Behaviour-Genetics-Association CY JUN 06-09, 2011 CL Newport, RI SP Behav Genet Assoc C1 [Neale, Michael] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Neale, Benjamin] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD NOV PY 2011 VL 41 IS 6 SI SI BP 894 EP 894 PG 1 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 826BO UT WOS:000295326600024 ER PT J AU Neale, B AF Neale, Benjamin TI Analytic issues in next generation sequencing: Lessons from exome-wide sequencing of autism SO BEHAVIOR GENETICS LA English DT Meeting Abstract CT 41st Annual Meeting of the Behaviour-Genetics-Association CY JUN 06-09, 2011 CL Newport, RI SP Behav Genet Assoc C1 [Neale, Benjamin] Massachusetts Gen Hosp, Boston, MA 02114 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 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD NOV PY 2011 VL 41 IS 6 SI SI BP 927 EP 927 PG 1 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 826BO UT WOS:000295326600132 ER PT J AU Lee, J Hwang, YJ Boo, JH Han, D Kwon, OK Todorova, K Kowall, NW Kim, Y Ryu, H AF Lee, J. Hwang, Y. J. Boo, J. H. Han, D. Kwon, O. K. Todorova, K. Kowall, N. W. Kim, Y. Ryu, H. TI Dysregulation of upstream binding factor-1 acetylation at K352 is linked to impaired ribosomal DNA transcription in Huntington's disease SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE UBF1; rDNA transcription; CBP; acetylation; Huntington's disease ID RNA-POLYMERASE-I; GENE-EXPRESSION; CREB-BINDING; CAG REPEAT; FACTOR UBF; POLYGLUTAMINE; NEURONS; CBP; PROTEIN; NEURODEGENERATION AB Huntington's disease (HD) is an autosomal-dominant neurological disorder caused by expanded CAG repeats in the Huntingtin (Htt) gene, but it is not known how this mutation causes neurodegeneration. Herein, we found that dysfunction of upstream binding factor-1 (UBF-1) is linked to reduced ribosomal DNA (rDNA) transcription in HD. We identified that UBF1 acetylation at Lys (K) 352 by CREB binding protein (CBP) is crucial for the transcriptional activity of rDNA. UBF1 mutation (K352A, K352Q, and K352R) decreased rDNA transcriptional activity. Moreover, both CBP-dHAT mutant and knockdown of CBP by siRNA reduced acetylation of UBF1 and resulted in the decreased transcription of rDNA into rRNA. ChIP analysis showed a significant reduction of UBF1 occupancy in the promoter of rDNA in STHdh(Q111) cell line model of HD. These results demonstrate that abnormal activity of UBF1 and its acetylation by CBP are linked to impaired rDNA transcription in HD. This novel mechanism suggests that modulation of UBF-mediated rDNA synthesis by CBP may be a therapeutic target for improving neuronal rDNA transcription in HD. Cell Death and Differentiation (2011) 18, 1726-1735; doi: 10.1038/cdd.2011.38; published online 6 May 2011 C1 [Lee, J.; Todorova, K.; Kowall, N. W.; Ryu, H.] Boston Univ, Sch Med, Dept Neurol, Boston VA Healthcare Syst, Boston, MA 02130 USA. [Hwang, Y. J.; Boo, J. H.; Ryu, H.] Seoul Natl Univ, Coll Med, Dept Biomed Sci, World Class Univ Neurocyt Grp, Seoul, South Korea. RP Ryu, H (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston VA Healthcare Syst, Bldg 1A,Rm109,150 S Huntington Ave, Boston, MA 02130 USA. EM hoonryu@bu.edu RI Kowall, Neil/G-6364-2012; Kim, Youngsoo/D-6046-2012 OI Kowall, Neil/0000-0002-6624-0213; FU WCU [800-20080848]; KOSEF [2010-0029-403]; NIH [NS52724]; Converging Research Center through NRF of Korea [20090094081] FX We thank Dr. Samson T. Jacob for pIRES-Luc and Human rRNA-luciferase Vector and Dr. Marcy MacDonald for STHdhQ7/7 and STHdhQ111/111 cells. We thank Dr. Byoung Yul Soh for his technical assistance. This study was supported by WCU Neurocytomics Program Grant (800-20080848) (H. R.) and SRC Grant (2010-0029-403) (H. R.) from KOSEF and NIH NS52724 (H. R.). This work was also supported in part by the Converging Research Center Program (20090094081) (Y.K.) through NRF of Korea. NR 36 TC 13 Z9 13 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD NOV PY 2011 VL 18 IS 11 BP 1726 EP 1735 DI 10.1038/cdd.2011.38 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 834AQ UT WOS:000295929600005 PM 21546905 ER PT J AU Fish, KN Sweet, RA Lewis, DA AF Fish, Kenneth N. Sweet, Robert A. Lewis, David A. TI Differential Distribution of Proteins Regulating GABA Synthesis and Reuptake in Axon Boutons of Subpopulations of Cortical Interneurons SO CEREBRAL CORTEX LA English DT Article DE cannabinoid 1 receptor; GABA; GABA membrane transporter 1; glutamic acid decarboxylase; parvalbumin ID GLUTAMIC-ACID DECARBOXYLASE; GAMMA-AMINOBUTYRIC-ACID; MONKEY PREFRONTAL CORTEX; CANNABINOID CB1 RECEPTOR; GAD(67) MESSENGER-RNAS; RAT SPINAL-CORD; POSTNATAL-DEVELOPMENT; 2 FORMS; MONOCLONAL-ANTIBODIES; TRANSIENT INCREASE AB Subclasses of gamma-aminobutyric acid (GABA) interneurons differentially influence cortical network activity. The contribution of differences in GABA synthesis and reuptake in axon boutons to cell type-specific functions is unknown. GABA is synthesized within boutons by glutamic acid decarboxylase 65 (GAD65) and GAD67, while GAT1 is responsible for GABA reuptake. Using an imaging methodology capable of determining the colocalization frequency of different immunocytochemical labels in the same bouton and the quantification of the fluorescence intensity of each label in these same structures, we assessed the bouton levels of GAD65, GAD67, and GAT1 in parvalbumin-expressing chandelier (PV(ch)) and basket (PV(b)) neurons and cannabinoid 1 receptor-expressing basket (CB1r(b)) neurons in the monkey prefrontal cortex. We show that PV(ch) boutons almost exclusively contained GAD67, relative to GAD65, whereas CB1r(b) boutons contained mostly GAD65. In contrast, both GAD65 and GAD67 were easily detected in PV(b) boutons. Furthermore, in comparison with PV(ch) boutons, CB1r(b) boutons expressed low to undetectable levels of GAT1. Our findings provide a new basis for the distinctive functional roles of these perisomatic-innervating interneurons in cortical circuits. In addition, they strongly suggest that altered levels of GAD67 or GAD65, as seen in some psychiatric diseases, would have cell type-specific consequences on the modulation of GABA neurotransmission. C1 [Fish, Kenneth N.] Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Translat Neurosci Program, Pittsburgh, PA 15213 USA. [Sweet, Robert A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, VISN MIRECC 4, Pittsburgh, PA 15206 USA. [Lewis, David A.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA 15213 USA. RP Fish, KN (reprint author), Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Translat Neurosci Program, Biomed Sci Tower,Room E1652,3811 OHara St, Pittsburgh, PA 15213 USA. EM fishkn@upmc.edu RI Lewis, David/G-4053-2014 OI Lewis, David/0000-0002-3225-6778 FU National Institutes of Health [MH051234, MH084053, MH071533, MH085108]; BMS foundation; Bristol-Myers Squibb; Curridium Ltd; Pfizer FX This work was supported by the National Institutes of Health (grant numbers MH051234 and MH084053 to D. A. L., MH071533 to R. A. S., MH085108 to K.N.F.).; Conflict of Interest: D. A. L. currently receives investigator-initiated research support from the BMS foundation, Bristol-Myers Squibb, Curridium Ltd, and Pfizer and in 2007-2009 served as a consultant in the areas of target identification and validation, and new compound development to AstraZeneca, BioLine RX, Bristol-Myers Squibb, Hoffman-Roche, Lilly, Merck, Neurogen, and SK Life Science. All other authors report no competing interest. NR 56 TC 24 Z9 24 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD NOV PY 2011 VL 21 IS 11 BP 2450 EP 2460 DI 10.1093/cercor/bhr007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 827FK UT WOS:000295413200003 PM 21422269 ER PT J AU Li, YX Tafti, BA Shaba, W Berenji, GR AF Li, Yuxin Tafti, Bashir A. Shaba, Wisam Berenji, Gholam R. TI Superscan Pattern of F-18 Sodium Fluoride PET/CT Study in a Case of Prostate Cancer SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE F-18 fluoride; superscan; positron emission tomography; bone scan; prostate cancer ID BONE-SCAN; DISEASE; ABSENT AB A 63-year-old man with a history of prostate cancer (Gleason score, 9/10) received brachytherapy 2 years ago. The patient had been diagnosed with bone metastases 7 months ago and received treatment with dexamethasone and flutamide. Recently, the patient complained of worsening bone pain with rapid rising of prostate-specific antigen from 45 to 189. F-18 sodium fluoride PET/CT bone scan was conducted to evaluate for progression of bone metastases. Review of the PET/CT images demonstrated a "superscan" pattern of bone metastases with extensive sodium fluoride uptake in the axial skeleton, and poor visualization of distal appendicular skeleton and kidneys. C1 [Berenji, Gholam R.] VA Greater Los Angeles Healthcare Syst, Nucl Med Serv 115, Dept Nucl Med, Los Angeles, CA 90073 USA. RP Berenji, GR (reprint author), VA Greater Los Angeles Healthcare Syst, Nucl Med Serv 115, Dept Nucl Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Gholam.Berenji@va.gov NR 8 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD NOV PY 2011 VL 36 IS 11 BP 1046 EP 1048 DI 10.1097/RLU.0b013e3182291c3d PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 833GV UT WOS:000295871900028 PM 21975402 ER PT J AU Wang, ZW Olumi, AF AF Wang, Zongwei Olumi, Aria F. TI Diabetes, growth hormone-insulin-like growth factor pathways and association to benign prostatic hyperplasia SO DIFFERENTIATION LA English DT Review DE Diabetes; Hyperinsulinaemia; Benign prostatic hyperplasia; Insulin-like growth factor; Insulin-like growth factor binding protein; c-Jun ID FACTOR-BINDING PROTEIN-3; I IGF-I; MESSENGER-RNA LEVELS; IMPROVES GLYCEMIC CONTROL; METABOLIC SYNDROME; GLUCOSE-TOLERANCE; EPITHELIAL-CELLS; SKELETAL-MUSCLE; GENE-EXPRESSION; STROMAL CELLS AB Diabetes significantly increases the risk of benign prostatic hyperplasia (BPH) and low urinary tract symptoms (LUTS). The major endocrine aberration in connection with the metabolic syndrome is hyperinsulinemia. Insulin is an independent risk factor and a promoter of BPH. Insulin resistance may change the risk of BPH through several biological pathways. Hyperinsulinemia stimulates the liver to produce more insulin-like growth factor (IGF), another mitogen and an anti-apoptotic agent which binds insulin receptor/IGF receptor and stimulates prostate growth. The levels of IGFs and IGF binding proteins (IGFBPs) in prostate tissue and in blood are associated with BPH risk, with the regulation of circulating androgen and growth hormone. Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Previously, we have shown that the expression of c-Jun in the fibroblastic stroma can promote secretion of IGF-I, which stimulates prostate epithelial cell proliferation through activating specific target genes. Here, we will review the epidemiologic, clinical, and molecular findings which have evaluated the relation between diabetes and development of BPH. (C) 2011 International Society of Differentiation. Published by Elsevier B.V. All rights reserved. C1 [Wang, Zongwei; Olumi, Aria F.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Wang, Zongwei; Olumi, Aria F.] Harvard Univ, Sch Med, Boston, MA USA. RP Olumi, AF (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St,Yawkey Bldg 7E, Boston, MA 02114 USA. EM Olumi.Aria@mgh.harvard.edu NR 147 TC 15 Z9 20 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 EI 1432-0436 J9 DIFFERENTIATION JI Differentiation PD NOV-DEC PY 2011 VL 82 IS 4-5 SI SI BP 261 EP 271 DI 10.1016/j.diff.2011.04.004 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 832VO UT WOS:000295837300011 PM 21536370 ER PT J AU Kim, S Lewis, C Nadel, JA AF Kim, Suil Lewis, Courtney Nadel, Jay A. TI Epidermal growth factor receptor reactivation induced by E-prostanoid-3 receptor- and tumor necrosis factor-alpha-converting enzyme-dependent feedback exaggerates interleukin-8 production in airway cancer (NCI-H292) cells SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Epidermal growth factor receptor; Cyclooxygenase-2; Prostaglandin E2; E-prostanoid-3 receptor; Interleukin-8; Positive feedback ID BRONCHIAL EPITHELIAL-CELLS; PROSTAGLANDIN E-2; HUMAN-LUNG; PROSTANOID RECEPTORS; SIGNALING CASCADE; CIGARETTE-SMOKE; EGF RECEPTOR; EXPRESSION; ACTIVATION; LINES AB Airway epithelial cancer cells produce increased amounts of the chemokine interleukin-8 (IL-8), inducing pro-tumor responses. Multiple stimuli induce airway epithelial IL-8 production epidermal growth factor receptor (EGFR) dependently, but the mechanisms that exaggerate IL-8 production in airway cancers remain unknown. Here we show that direct activation of EGFR (EGFR-P) by its ligand transforming growth factor (TGF)-alpha induces a second EGFR-P in human airway (NCI-H292) cancer cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating IL-8 production in these cancer cells. The second EGFR-P in NCI-H292 cells was caused by metalloprotease INF-alpha-converting enzyme (TACE)-dependent cleavage of EGFR pro-ligands and was responsible for most of the total IL-8 induced by TGF-alpha. In NCI-H292 cells, TGF-alpha induced cyclooxygenase (COX)-2-dependent prostaglandin (PG)E2 production and release. PGE2 increased the second EGFR-P and IL-8 production via binding to its Gi-protein-coupled E-prostanoid (EP)3 receptor. In NHBE cells, TGF-alpha-induced EGFR-P did not lead to PGE2 production or to a second EGFR-P, and less IL-8 was produced. Thus, we conclude that a positive feedback pathway involving COX-2/PGE2/EP3 receptor-dependent EGFR reactivation exaggerates IL-8 production in NCI-H292 cancer cells but not in NHBE (normal) cells. Published by Elsevier Inc. C1 [Kim, Suil; Lewis, Courtney; Nadel, Jay A.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Kim, Suil; Lewis, Courtney; Nadel, Jay A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Nadel, Jay A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. RP Kim, S (reprint author), Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland VA Med Ctr, 3710 SW US Vet Hosp Rd,Mailcode R&D 6, Portland, OR 97239 USA. EM kimsui@ohsu.edu; courtney.lewis@ucsf.edu; jay.nadel@ucsf.edu FU National Institutes of Health [HL073906]; American Lung Association; UCSF; Cystic Fibrosis Foundation; Cardiovascular Research Institute FX We thank Dr. Jonathan Koff for his generous advice and for stimulating discussions. This work was supported by National Institutes of Health Grant HL073906 (SK), American Lung Association Biomedical Research Award (SK), UCSF Clinical and Translational Sciences Pilot Research Award (SK), Cystic Fibrosis Foundation Pilot Research Award (SK), and by Cardiovascular Research Institute funding (JAN). NR 44 TC 7 Z9 7 U1 0 U2 3 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD NOV 1 PY 2011 VL 317 IS 18 BP 2650 EP 2660 DI 10.1016/j.yexcr.2011.08.023 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 833UA UT WOS:000295909200010 PM 21925169 ER PT J AU Kadakia, MB Fox, CS Scirica, BM Murphy, SA Bonaca, MP Morrow, DA AF Kadakia, Mitul B. Fox, Caroline S. Scirica, Benjamin M. Murphy, Sabina A. Bonaca, Marc P. Morrow, David A. TI Central obesity and cardiovascular outcomes in patients with acute coronary syndrome: observations from the MERLIN-TIMI 36 trial SO HEART LA English DT Article ID BODY-MASS INDEX; ACUTE MYOCARDIAL-INFARCTION; META-REGRESSION ANALYSIS; WAIST CIRCUMFERENCE; ABDOMINAL OBESITY; METABOLIC SYNDROME; HEART-ASSOCIATION; UNSTABLE ANGINA; ARTERY-DISEASE; ADIPOSE-TISSUE AB Objective Despite the association of obesity with incident cardiovascular disease, obese patients with acute coronary syndrome (ACS) appear to have more favourable short-term outcomes. A study was undertaken to determine whether this 'obesity paradox' persists in the long term and to examine the specific relationship of central obesity with outcomes after ACS. Methods The relationship was investigated between two measures of obesity-body mass index (BMI) and waist circumference (WC)-and 30-day and 1-year outcomes after ACS. 6560 patients with non-ST elevation ACS in the MERLIN-TIMI 36 trial were followed for 1 year. Patients were stratified into three BMI groups (<25, 25-30, >= 30 kg/m(2)) and gender-specific tertiles of WC. The primary endpoint was cardiovascular death, myocardial infarction or recurrent ischaemia. Results Patients with BMI >= 30 kg/m(2) had a significantly lower risk of the primary endpoint than those with BMI <25 kg/m(2) (HR 0.64; 95% CI 0.51 to 0.81, p<0.0001) at 30 days. However, after the 30-day acute phase, landmark analysis from 30 days to 1 year showed no difference in risk between BMI groups (HR 1.09; 95% CI 0.92 to 1.29, p=0.34). WC tertiles demonstrated a similar relationship. When BMI groups were stratified by WC there was a trend towards more adverse outcomes in higher WC groups among those in lower BMI groups. The group with the lowest BMI and highest WC had the highest risk (HR 2.8; 95% CI 0.93 to 8.3; p=0.067). Conclusions Obesity is associated with more favourable short-term outcomes after ACS. However, in the longer term the obesity paradox is no longer present and may reverse. Those with WC out of proportion to BMI suggestive of significant central adiposity may be at highest risk following ACS. C1 [Kadakia, Mitul B.] Hosp Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19103 USA. [Kadakia, Mitul B.; Scirica, Benjamin M.; Murphy, Sabina A.; Bonaca, Marc P.; Morrow, David A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, NHBLIs Framingham Heart Study, Framingham, MA USA. [Kadakia, Mitul B.; Fox, Caroline S.; Scirica, Benjamin M.; Murphy, Sabina A.; Bonaca, Marc P.; Morrow, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Kadakia, MB (reprint author), Hosp Univ Penn, Div Cardiovasc Med, 3400 Spruce St, Philadelphia, PA 19103 USA. EM kadakia@post.harvard.edu FU CV Therapeutics (now Gilead Science Inc); Novartis Pharmaceuticals Corporation; AstraZeneca Pharmaceuticals LP; Daiichi-Sankyo Inc; Merck Co Inc; Johnson and Johnson Pharmaceutical Research & Development LLC; Bayer HealthCare Pharmaceuticals; Bristol-Myers-Squibb Company; CV Therapeutics FX MERLIN-TIMI 36 was supported by CV Therapeutics (now Gilead Science Inc).; BMS has received grants for clinical research via the TIMI Study Group and Brigham and Women's Hospital from CV Therapeutics, Novartis Pharmaceuticals Corporation, AstraZeneca Pharmaceuticals LP, Daiichi-Sankyo Inc, Merck & Co Inc, Johnson and Johnson Pharmaceutical Research & Development LLC, Bayer HealthCare Pharmaceuticals and Bristol-Myers-Squibb Company and has served as a consultant for AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation, CV Therapeutics, Cogentus, Shionogi & Co Ltd, Gilead Sciences Inc, Merck & Co Inc and Schering-Plough Corporation. DAM has received grants for clinical research via the TIMI Study Group and Brigham & Women's Hospital from CV Therapeutics, served as a consultant for Menarini Group and received honoraria for educational presentations from CV Therapeutics. MBK, CSF, MPB and SAM do not report any potential conflicts. NR 33 TC 30 Z9 32 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD NOV PY 2011 VL 97 IS 21 BP 1782 EP 1787 DI 10.1136/heartjnl-2011-300231 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 829VK UT WOS:000295612600013 PM 21865203 ER PT J AU Chiang, CWK Gajdos, ZKZ Korn, JM Butler, JL Hackett, R Guiducci, C Nguyen, TT Wilks, R Forrester, T Henderson, KD Le Marchand, L Henderson, BE Haiman, CA Cooper, RS Lyon, HN Zhu, XF McKenzie, CA Palmert, MR Hirschhorn, JN AF Chiang, Charleston W. K. Gajdos, Zofia K. Z. Korn, Joshua M. Butler, Johannah L. Hackett, Rachel Guiducci, Candace Nguyen, Thutrang T. Wilks, Rainford Forrester, Terrence Henderson, Katherine D. Le Marchand, Loic Henderson, Brian E. Haiman, Christopher A. Cooper, Richard S. Lyon, Helen N. Zhu, Xiaofeng McKenzie, Colin A. Palmert, Mark R. Hirschhorn, Joel N. TI The efficacy of detecting variants with small effects on the Affymetrix 6.0 platform using pooled DNA SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MICROARRAYS; ABILITY; LOCI; EFFICIENT; TRAITS; IDENTIFICATION; POPULATIONS; DISABILITY; CHILDREN AB Genome-wide genotyping of a cohort using pools rather than individual samples has long been proposed as a cost-saving alternative for performing genome-wide association (GWA) studies. However, successful disease gene mapping using pooled genotyping has thus far been limited to detecting common variants with large effect sizes, which tend not to exist for many complex common diseases or traits. Therefore, for DNA pooling to be a viable strategy for conducting GWA studies, it is important to determine whether commonly used genome-wide SNP array platforms such as the Affymetrix 6.0 array can reliably detect common variants of small effect sizes using pooled DNA. Taking obesity and age at menarche as examples of human complex traits, we assessed the feasibility of genome-wide genotyping of pooled DNA as a single-stage design for phenotype association. By individually genotyping the top associations identified by pooling, we obtained a 14- to 16-fold enrichment of SNPs nominally associated with the phenotype, but we likely missed the top true associations. In addition, we assessed whether genotyping pooled DNA can serve as an inexpensive screen as the second stage of a multi-stage design with a large number of samples by comparing the most cost-effective 3-stage designs with 80% power to detect common variants with genotypic relative risk of 1.1, with and without pooling. Given the current state of the specific technology we employed and the associated genotyping costs, we showed through simulation that a design involving pooling would be 1.07 times more expensive than a design without pooling. Thus, while a significant amount of information exists within the data from pooled DNA, our analysis does not support genotyping pooled DNA as a means to efficiently identify common variants contributing small effects to phenotypes of interest. While our conclusions were based on the specific technology and study design we employed, the approach presented here will be useful for evaluating the utility of other or future genome-wide genotyping platforms in pooled DNA studies. C1 [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Korn, Joshua M.; Hackett, Rachel; Guiducci, Candace; Lyon, Helen N.; Hirschhorn, Joel N.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Korn, Joshua M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Korn, Joshua M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Wilks, Rainford] Univ W Indies, Epidemiol Res Unit, Res Inst Trop Med, Kingston 7, Jamaica. [Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, Trop Metab Res Unit, Res Inst Trop Med, Kingston 7, Jamaica. [Henderson, Katherine D.] City Hope Natl Med Ctr, Div Canc Etiol, Dept Populat Sci, Duarte, CA 91010 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr Hawaii, Program Epidemiol, Honolulu, HI 96813 USA. [Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Cooper, Richard S.] Loyola Univ Chicago, Dept Prevent Med & Epidemiol, Stritch Sch Med, Maywood, IL USA. [Zhu, Xiaofeng] Case Western Reserve Univ, Dept Biostat & Epidemiol, Cleveland, OH 44106 USA. [Palmert, Mark R.] Hosp Sick Children, Div Endocrinol, Toronto, ON M5G 1X8, Canada. [Palmert, Mark R.] Univ Toronto, Dept Pediat, Toronto, ON, Canada. RP Hirschhorn, JN (reprint author), Childrens Hosp, Program Genom, CLS 16065,300 Longwood Ave, Boston, MA 02115 USA. EM joelh@broadinstitute.org OI Chiang, Charleston/0000-0002-0668-7865 FU National Science Foundation; National Institutes of Health [R01DK075787, R37HL45508, R01HL53353, R01HL074166, R01HD048960] FX The principal acknowledgement is to the participants who contributed their time, biological samples, and phenotype data to the different projects. The authors also thank P. I. de Bakker, P. Sklar, and past and present members of the Hirschhorn laboratory for comments, ideas, and discussions; the past and present team members and investigators at the Tropical Medicine Research Institute and the Hawai'i and Los Angeles Multi-Ethnic Cohort for collecting samples and data. This work was supported by a graduate research fellowship from the National Science Foundation to C. W. K. C. and grants from the National Institutes of Health to J.N.H. (R01DK075787), to R. S. C. (R37HL45508 and R01HL53353), to X.Z. (R01HL074166), and to M. R. P. (R01HD048960). The funders had no role in study design, data collection, analysis, interpretation, decision to publish, or preparation of the manuscript. NR 37 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD NOV PY 2011 VL 130 IS 5 BP 607 EP 621 DI 10.1007/s00439-011-0974-0 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 834DP UT WOS:000295939900002 PM 21424828 ER PT J AU Im, KM Kirchhoff, T Wang, XS Green, T Chow, CY Vijai, J Korn, J Gaudet, MM Fredericksen, Z Pankratz, VS Guiducci, C Crenshaw, A McGuffog, L Kartsonaki, C Morrison, J Healey, S Sinilnikova, OM Mai, PL Greene, MH Piedmonte, M Rubinstein, WS Hogervorst, FB Rookus, MA Collee, JM Hoogerbrugge, N van Asperen, CJ Meijers-Heijboer, HEJ van Roozendaal, CE Caldes, T Perez-Segura, P Jakubowska, A Lubinski, J Huzarski, T Blecharz, P Nevanlinna, H Aittomaki, K Lazaro, C Blanco, I Barkardottir, RB Montagna, M D'Andrea, E Devilee, P Olopade, OI Neuhausen, SL Peissel, B Bonanni, B Peterlongo, P Singer, CF Rennert, G Lejbkowicz, F Andrulis, IL Glendon, G Ozcelik, H Toland, AE Caligo, MA Beattie, MS Chan, S Domchek, SM Nathanson, KL Rebbeck, TR Phelan, C Narod, S John, EM Hopper, JL Buys, SS Daly, MB Southey, MC Terry, MB Tung, N Hansen, TVO Osorio, A Benitez, J Duran, M Weitzel, JN Garber, J Hamann, U Peock, S Cook, M Oliver, CT Frost, D Platte, R Evans, DG Eeles, R Izatt, L Paterson, J Brewer, C Hodgson, S Morrison, PJ Porteous, M Walker, L Rogers, MT Side, LE Godwin, AK Schmutzler, RK Wappenschmidt, B Laitman, Y Meindl, A Deissler, H Varon-Mateeva, R Preisler-Adams, S Kast, K Venat-Bouvet, L Stoppa-Lyonnet, D Chenevix-Trench, G Easton, DF Klein, RJ Daly, MJ Friedman, E Dean, M Clark, AG Altshuler, DM Antoniou, AC Couch, FJ Offit, K Gold, B AF Im, Kate M. Kirchhoff, Tomas Wang, Xianshu Green, Todd Chow, Clement Y. Vijai, Joseph Korn, Joshua Gaudet, Mia M. Fredericksen, Zachary Pankratz, V. Shane Guiducci, Candace Crenshaw, Andrew McGuffog, Lesley Kartsonaki, Christiana Morrison, Jonathan Healey, Sue Sinilnikova, Olga M. Mai, Phuong L. Greene, Mark H. Piedmonte, Marion Rubinstein, Wendy S. Hogervorst, Frans B. Rookus, Matti A. Collee, J. Margriet Hoogerbrugge, Nicoline van Asperen, Christi J. Meijers-Heijboer, Hanne E. J. van Roozendaal, Cees E. Caldes, Trinidad Perez-Segura, Pedro Jakubowska, Anna Lubinski, Jan Huzarski, Tomasz Blecharz, Pawel Nevanlinna, Heli Aittomaki, Kristiina Lazaro, Conxi Blanco, Ignacio Barkardottir, Rosa B. Montagna, Marco D'Andrea, Emma Devilee, Peter Olopade, Olufunmilayo I. Neuhausen, Susan L. Peissel, Bernard Bonanni, Bernardo Peterlongo, Paolo Singer, Christian F. Rennert, Gad Lejbkowicz, Flavio Andrulis, Irene L. Glendon, Gord Ozcelik, Hilmi Toland, Amanda Ewart Caligo, Maria Adelaide Beattie, Mary S. Chan, Salina Domchek, Susan M. Nathanson, Katherine L. Rebbeck, Timothy R. Phelan, Catherine Narod, Steven John, Esther M. Hopper, John L. Buys, Saundra S. Daly, Mary B. Southey, Melissa C. Terry, Mary-Beth Tung, Nadine Hansen, Thomas V. O. Osorio, Ana Benitez, Javier Duran, Mercedes Weitzel, Jeffrey N. Garber, Judy Hamann, Ute Peock, Susan Cook, Margaret Oliver, Clare T. Frost, Debra Platte, Radka Evans, D. Gareth Eeles, Ros Izatt, Louise Paterson, Joan Brewer, Carole Hodgson, Shirley Morrison, Patrick J. Porteous, Mary Walker, Lisa Rogers, Mark T. Side, Lucy E. Godwin, Andrew K. Schmutzler, Rita K. Wappenschmidt, Barbara Laitman, Yael Meindl, Alfons Deissler, Helmut Varon-Mateeva, Raymonda Preisler-Adams, Sabine Kast, Karin Venat-Bouvet, Laurence Stoppa-Lyonnet, Dominique Chenevix-Trench, Georgia Easton, Douglas F. Klein, Robert J. Daly, Mark J. Friedman, Eitan Dean, Michael Clark, Andrew G. Altshuler, David M. Antoniou, Antonis C. Couch, Fergus J. Offit, Kenneth Gold, Bert TI Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers SO HUMAN GENETICS LA English DT Article ID TAY-SACHS DISEASE; BREAST-CANCER; POSITIVE SELECTION; GENETIC-VARIATION; POPULATION; FREQUENCY; GENOME; JEWS; ASSOCIATION; SIGNATURES AB Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews. C1 [Gold, Bert] NCI, Frederick, MD 21702 USA. [Im, Kate M.; Dean, Michael; Gold, Bert] NCI, Ctr Canc Res, Canc Inflammat Program, Human Genet Sect, Frederick, MD 21701 USA. [Kirchhoff, Tomas; Vijai, Joseph; Klein, Robert J.; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, Program Canc Prevent & Populat Res,Program Canc P, New York, NY 10021 USA. [Wang, Xianshu; Fredericksen, Zachary; Pankratz, V. Shane; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Green, Todd; Korn, Joshua; Guiducci, Candace; Crenshaw, Andrew; Collee, J. Margriet; Montagna, Marco] Harvard Univ, Sch Med, Dept Genet & Med, Boston, MA USA. [Green, Todd; Korn, Joshua; Guiducci, Candace; Crenshaw, Andrew; Daly, Mark J.; Altshuler, David M.] Harvard Univ, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02138 USA. [Green, Todd; Korn, Joshua; Guiducci, Candace; Crenshaw, Andrew; Daly, Mark J.; Altshuler, David M.] Massachusetts Gen Hosp, Dept Mol Biol, Ctr Human Genet Res, Boston, MA 02114 USA. [Chow, Clement Y.; Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA. [Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Healey, Sue; Chenevix-Trench, Georgia; Antoniou, Antonis C.] Queensland Inst Med Res, Genet & Populat Hlth Div, Brisbane, Qld 4006, Australia. [Sinilnikova, Olga M.] Ctr Hosp Univ Lyon, Unite Mixte Genet Constitut Canc Frequents, Ctr Lyon Berard, Lyon, France. [Sinilnikova, Olga M.] Univ Lyon, Ctr Leon Berard, Lyon, France. [Mai, Phuong L.; Greene, Mark H.] NCI, Clin Genet Branch, Rockville, MD USA. [Piedmonte, Marion] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Rubinstein, Wendy S.] NorthShore Univ Hlth Syst, Evanston, IL USA. [Hogervorst, Frans B.] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Collee, J. Margriet] Erasmus Univ, Dept Clin Genet, Family Canc Clin, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Hoogerbrugge, Nicoline] Radboud Univ Nijmegen, Hereditary Canc Clin, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Meijers-Heijboer, Hanne E. J.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Leiden, Netherlands. [van Roozendaal, Cees E.] Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Caldes, Trinidad; Perez-Segura, Pedro] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Blecharz, Pawel] Maria Sklodowska Curie Mem Inst Oncol, Ctr Oncol, Krakow, Poland. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, FIN-00290 Helsinki, Finland. [Lazaro, Conxi; Blanco, Ignacio] Catalan Inst Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain. [Barkardottir, Rosa B.] Landspitali LSH, Dept Pathol, Reykjavik, Iceland. [Barkardottir, Rosa B.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Montagna, Marco; D'Andrea, Emma] IRCCS, Immunol & Mol Oncol Unit, Ist Oncol Veneto IOV, Padua, Italy. [D'Andrea, Emma] Univ Padua, Dept Oncol & Surg Sci, Padua, Italy. Peter MacCallum Canc Ctr, Kathleen Cuningham Fdn Consortium Res Familial Br, Melbourne, Vic, Australia. [Devilee, Peter] Leiden Univ, Dept Human Genet & Pathol, Med Ctr, Leiden, Netherlands. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Dept Med, Chicago, IL 60637 USA. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Peissel, Bernard] Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, Milan, Italy. [Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Dept Expt Oncol & Mol Med, Milan, Italy. [Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Singer, Christian F.] Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria. [Singer, Christian F.] Univ Vienna, Comprehens Canc Med Ctr, Vienna, Austria. [Rennert, Gad; Lejbkowicz, Flavio] Carmel Hosp, CHS Natl Canc Control Ctr, Haifa, Israel. [Andrulis, Irene L.; Ozcelik, Hilmi] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi] Technion Israel Inst Technol, Fac Med, Haifa, Israel. [Andrulis, Irene L.; Ozcelik, Hilmi] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Genet Network, Toronto, ON, Canada. Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Toland, Amanda Ewart] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Caligo, Maria Adelaide] Univ Pisa, Sect Genet Oncol, Dept Lab Med, Pisa, Italy. Santa Chiara Univ Hosp, Pisa, Italy. Lund Univ, Dept Oncol, Lund, Sweden. [Beattie, Mary S.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Chan, Salina] Univ Calif San Francisco, Canc Risk Program, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. Univ Cambridge, Dept Oncol, Cambridge, England. [Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Phelan, Catherine] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Narod, Steven] Womens Coll Res Inst, Toronto, ON, Canada. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Hopper, John L.] Univ Melbourne, Ctr Genet Epidemiol, Melbourne, Vic 3010, Australia. [Buys, Saundra S.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Terry, Mary-Beth] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Tung, Nadine] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Hansen, Thomas V. O.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Osorio, Ana] Copenhagen Univ Hosp, Dept Clin Biochem, Rigshosp, Copenhagen, Denmark. [Osorio, Ana] Spanish Natl Canc Res Ctr, Human Genet Grp, Canc Genet Programme, Madrid, Spain. [Osorio, Ana; Benitez, Javier] Spanish Network Rare Dis CIBERER, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Genet Grp & Genotyping Unit, Human Canc Genet Programme, Madrid, Spain. [Duran, Mercedes] Univ Valladolid IBGM UVA, Inst Biol & Mol Genet, Valladolid, Spain. [Weitzel, Jeffrey N.] City Hope Canc Ctr, Div Clin Canc Genet, Duarte, CA USA. [Garber, Judy] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hamann, Ute] Deutsch Krebsforschungszentrum DKFZ, Heidelberg, Germany. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eeles, Ros] Inst Canc Res, Oncogenet Team, Surrey, England. [Izatt, Louise] Royal Marsden NHS Fdn Trust, Surrey, England. [Paterson, Joan] Guys & St Thomas NHS Fdn Trust, London, England. [Brewer, Carole] Addenbrookes Hosp, Dept Clin Genet, E Anglian Reg Genet Serv, Cambridge, England. [Hodgson, Shirley] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England. [Morrison, Patrick J.] Univ London, Dept Clin Genet, London, England. [Porteous, Mary] Belfast City Hosp, No Ireland Reg Genet Ctr, Belfast BT9 7AD, Antrim, North Ireland. [Walker, Lisa] Western Gen Hosp, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. [Rogers, Mark T.] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Side, Lucy E.] Univ Wales Hosp, All Wales Med Genet Serv, Cardiff CF4 4XW, S Glam, Wales. [Godwin, Andrew K.] Great Ormond St Hosp Sick Children, NE Thames Reg Genet Serv, London WC1N 3JH, England. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Kansas, Med Ctr, Dept Pathol & Lab, Kansas City, KS 66103 USA. [Venat-Bouvet, Laurence] Univ Hosp Cologne, Cologne, Germany. [Stoppa-Lyonnet, Dominique] Ctr Hosp Univ Dupuytren, Dept Med Oncol, Limoges, France. [Laitman, Yael; Friedman, Eitan] Univ Paris 05, INSERM, U509, Serv Genet Oncol,Inst Curie, Paris, France. [Meindl, Alfons] Chaim Sheba Med Ctr, Susan Levy Gertner Oncogenet Unit, Inst Genet, IL-52621 Tel Hashomer, Israel. [Deissler, Helmut] Tech Univ Munich, Munich, Germany. [Varon-Mateeva, Raymonda] Univ Hosp Ulm, Ulm, Germany. [Preisler-Adams, Sabine] Charite Campus Virchow Klinikum, Inst Human Genet, Berlin, Germany. [Kast, Karin] Univ Munster, Inst Human Genet, D-4400 Munster, Germany. [Gold, Bert] Tech Univ Dresden, Dept Obstet & Gynaecol, Univ Hosp Carl Gustav, Dresden, Germany. RP Gold, B (reprint author), NCI, Box B,Boyles St Ft Detrick, Frederick, MD 21702 USA. EM golda@mail.nih.gov RI Osorio, Ana/I-4324-2014; Bernard, Loris/K-5953-2014; Ehrencrona, Hans/M-5619-2014; Jakubowska, Anna/O-8050-2014; GLADIEFF, Laurence/O-5129-2014; Ligtenberg, Marjolijn/N-9666-2013; Ripamonti, Carla Barbara/D-2247-2017; Peissel, Bernard/E-8187-2017; Oosterwijk, Jan C./G-5770-2011; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Blanco, Ignacio/D-2565-2013; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Dean, Michael/G-8172-2012; D'Andrea, Emma/B-4374-2013; Andrulis, Irene/E-7267-2013; Joseph, Vijai/J-9158-2013; Klein, Robert/K-1888-2013; Altshuler, David/A-4476-2009 OI Evans, Gareth/0000-0002-8482-5784; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364; Bossi, Paolo/0000-0003-0135-0224; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Osorio, Ana/0000-0001-8124-3984; Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719; Ligtenberg, Marjolijn/0000-0003-1290-1474; Ripamonti, Carla Barbara/0000-0002-2892-8164; Peissel, Bernard/0000-0001-9233-3571; Nordling, Margareta/0000-0002-4047-4994; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Blanco, Ignacio/0000-0002-7414-7481; montagna, marco/0000-0002-4929-2150; Dean, Michael/0000-0003-2234-0631; Joseph, Vijai/0000-0002-7933-151X; Klein, Robert/0000-0003-3539-5391; Altshuler, David/0000-0002-7250-4107 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; Starr Foundation; Breast Cancer Research Foundation; Sabin Family Fund; CRUK; Ligue National Contre le Cancer; Association for International Cancer Research [AICR-07-0454]; Association "Le cancer du sein, parlons-en"; NHMRC; National Breast Cancer Foundation; Cancer Australia [628333]; Queensland Cancer Fund; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; Italian citizens; Fondazione IRCCS Istituto Nazionale Tumori; Komen Foundation; National Cancer Institute, National Institutes of Health [RFA-CA-06-503]; ISCIII [RD06/0020/0021]; Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]; OSU Comprehensive Cancer Center; Cancer Care Ontario; US National Cancer Institute, National Institutes of Health [RFA CA-06-503]; Cancer Research UK [C1287/A10118, C1287/A11990, C5047/A8385]; NIHR; Biomedical Research Centre, Manchester; Biomedical Research Centre at The Institute of Cancer Research; Royal Marsden NHS Foundation Trust; NEYE foundation; [NIHCA116167] FX This work was supported in part by federal funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We also acknowledge the support of the Starr Foundation, the Breast Cancer Research Foundation and the Sabin Family Fund. The content of this publication does not necessarily reflect the views of the Department of Health and Human Services nor does its mention of trade names, commercial products or organizations imply endorsement by the US government. The authors wish to thank Dr. Colm O'hUigin, who provided valuable comments on an early version of this manuscript.; UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Paul Pharoah, Simon Gayther, Susan Ramus, Carole Pye and Patricia Harrington for their contributions toward the UKFOCR.; The GEMO study (Cancer Genetics Network "Groupe Genetique et Cancer'', Federation Nationale des Centres de Lutte Contre le Cancer, France) is supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association "Le cancer du sein, parlons-en!'' Award.; For kConFab, we wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinic and the Clinical Follow Up Study (funded 2001-2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contributed to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia.; The CONSIT TEAM study (Consorzio degli Studi Italiani Tumori Ereditari Alla Mammella), acknowledges Marco Pierotti, Siranoush Manoukian, Daniela Zaffaroni, Carla B. Ripamonti and Paolo Radice of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Monica Barile of the Istituto Europeo di Oncologia, Milan, Italy and Loris Bernard of the Cogentech, Consortium for Genomic Technologies, Milan, Italy. We thank all patients and families who participated in this study. This study was supported by funds from Italian citizens who allocated the 5 9 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects '5 x 1,000').; For the Mayo Study, the authors would like to acknowledge funding from the Breast Cancer Research Foundation, Komen Foundation, and NIHCA116167.; The Cancer Prevention Institute of California was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and P.I.s. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Cancer Family Registry (CFR), nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the CFR.; The SWE-BRCA study acknowledge the study collaborators: Per Karlsson, Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie StenmarkAskmalm and Sigrun Liedgren Linko "ping University Hospital; A angstrom ke Borg, Niklas Loman, Hakan Olsson, Ulf Kristoffersson, Helena Jernstrom, Katja Harbst and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Gronberg, Eva-Lena Stattin and Monica Emanuelsson, Umea University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital. The HCSC study was supported by RD06/0020/0021 from ISCIII.; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Collaborating Centers are Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.B.L. Hogervorst, S. Verhoef, M. Verheus, L.J. van 't Veer, F.E. van Leeuwen, M.A. Rookus; Erasmus Medical Center, Rotterdam, NL: M. Collee, A. M.W. van den Ouweland, A. Jager, M.J. Hooning, M. M.A. Tilanus-Linthorst, C. Seynaeve; Leiden University Medical Center, NL, Leiden: C.J. van Asperen, J.T. Wijnen, M. P. Vreeswijk, R.A. Tollenaar, P. Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: M.J. Ligtenberg, N. Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: M.G. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL: C.M. Aalfs, T.A. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: E. B. Gomez-Garcia, C.E. van Roozendaal, Marinus J. Blok, B. Caanen; University Medical Center Groningen University, NL: J.C. Oosterwijk, A. H. van der Hout, M.J. Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088 and NKI2007-3756.; The Ohio State University Clinical Cancer Genetics (OSU CCG) study is supported by the OSU Comprehensive Cancer Center. We thank Leigha Senter and Kevin Sweet for patient accrual, sample ascertainment and database management. The Human Genetics Sample bank processed the samples.; This work was supported by Cancer Care Ontario and the US National Cancer Institute, National Institutes of Health under RFA #CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and principal investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the BCFR. We wish to thank Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study.; Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centers are Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins, Kashmir Randhawa. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell, Nafisa Patel. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D'Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D'Mello are also supported by Cancer Research UK Grant C5047/A8385.; CBCS: We thank Bent Ejlertsen, Mette K. Andersen, Anne-Marie Gerdes and Susanne Kjaergaard for clinical data. Moreover, we thank the NEYE foundation for financial support. NR 38 TC 8 Z9 8 U1 2 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD NOV PY 2011 VL 130 IS 5 BP 685 EP 699 DI 10.1007/s00439-011-1003-z PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 834DP UT WOS:000295939900009 PM 21597964 ER PT J AU Fayaz, HC Giannoudis, PV Vrahas, MS Smith, RM Moran, C Pape, HC Krettek, C Jupiter, JB AF Fayaz, Hangama C. Giannoudis, Peter V. Vrahas, Mark S. Smith, Raymond Malcolm Moran, Christopher Pape, Hans Christoph Krettek, Christian Jupiter, Jesse B. TI The role of stem cells in fracture healing and nonunion SO INTERNATIONAL ORTHOPAEDICS LA English DT Review ID MARROW STROMAL CELLS; PROGENITOR CELLS; TIBIAL NONUNION; BONE DEFECTS; REPAIR; RECONSTRUCTION; REGENERATION; DIFFERENTIATION; OSTEOGENESIS; OSTEOBLASTS AB Nonunion and large bone defects present a therapeutic challenge to the surgeon and are often associated with significant morbidity. These defects are expensive to both the health care system and society. However, several surgical procedures have been developed to maximise patient satisfaction and minimise health-care-associated and socioeconomic costs. Integrating recent evidence into the diamond concept leads to one simple conclusion that not only provides us with answers to the "open questions" but also simplifies our entire understanding of bone healing. It has been shown that a combination of neo-osteogenesis and neovascularisation will restore tissue deficits, and that the optimal approach includes a biomaterial scaffold, cell biology techniques, a growth factor and optimisation of the mechanical environment. Further prospective, controlled, randomised clinical studies will determine the effectiveness and economic benefits of treatment with mesenchymal stem cells, not in comparison to other conventional surgical approaches but in direct conjunction with them. C1 [Giannoudis, Peter V.] Univ Leeds, Sch Med, Acad Dept Trauma & Orthopaed Surg, Leeds LS2 9JT, W Yorkshire, England. [Smith, Raymond Malcolm] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Trauma Serv,Dept Orthopaed Surg, Boston, MA USA. [Vrahas, Mark S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners Orthopaed Trauma Serv, Boston, MA USA. [Moran, Christopher] Univ Hosp, Queens Med Ctr, Nottingham NG7 2UH, England. [Pape, Hans Christoph] Univ Aachen, Med Ctr, Dept Orthopaed Trauma, D-5100 Aachen, Germany. [Krettek, Christian] Hannover Med Sch, Dept Trauma Surg, D-3000 Hannover, Germany. RP Giannoudis, PV (reprint author), Univ Leeds, Sch Med, Acad Dept Trauma & Orthopaed Surg, Leeds LS2 9JT, W Yorkshire, England. EM dr.hana.fayaz@hotmail.de; pgiannoudi@aol.com; mvrahas@partners.org; rmsmith1@partners.org; chris.moran1@me.com; hpape@ukaachen.de; krettek.christian@mh-hannover.de; jjupiter1@partners.org OI Krettek, Christian/0000-0001-9807-0020 NR 53 TC 40 Z9 42 U1 2 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2695 J9 INT ORTHOP JI Int. Orthop. PD NOV PY 2011 VL 35 IS 11 BP 1587 EP 1597 DI 10.1007/s00264-011-1338-z PG 11 WC Orthopedics SC Orthopedics GA 834RW UT WOS:000295982400001 PM 21863226 ER PT J AU Smith, MR Klotz, L van der Meulen, E Colli, E Tanko, LB AF Smith, Matthew R. Klotz, Laurence van der Meulen, Egbert Colli, Enrico Tanko, Laszlo B. TI Gonadotropin-Releasing Hormone Blockers and Cardiovascular Disease Risk: Analysis of Prospective Clinical Trials of Degarelix SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; cardiovascular diseases; GnRH; risk ID ANDROGEN-DEPRIVATION THERAPY; GROUP PHASE-III; PROSTATE-CANCER; OPEN-LABEL; SUPPRESSION THERAPY; TESTOSTERONE SURGE; FREQUENCY; 12-MONTH; CORONARY; SAFETY AB Purpose: We investigated associations of baseline cardiovascular disease risk profile, dosing regimen and treatment duration with incident cardiovascular disease events during androgen deprivation therapy with degarelix in patients with prostate cancer. Materials and Methods: Data on 1,704 men who participated in a total of 9 clinical trials were pooled for analysis. Patients received treatment with 1-month (20 to 240 mg) or 3-month (240 to 480 mg) doses of degarelix for an average of 22 months. End points were ischemic heart disease, cerebrovascular disorders, arterial thrombotic/embolic events and intermittent claudication. Results: First time cardiovascular disease events were reported in 92 men in the year before study entry and in 168 after degarelix treatment. Event rates were similar before and after degarelix treatment in the total population (5.5 vs 6.1/100 person-years, p = 0.45) and in men without cardiovascular disease (5.6 vs 4.3/100 person-years, p = 0.11). In contrast, event rates appeared higher after degarelix treatment in men with cardiovascular disease at baseline (5.3 to 10.5 events per 100 person-years, p = 0.0013). On multivariate analysis cardiovascular disease at baseline was the strongest independent predictor of events, followed by older age, alcohol abstinence and obesity (each p <0.05). Degarelix dose and schedule were not independently associated with cardiovascular disease events. Conclusions: In men with prostate cancer observed rates of cardiovascular disease events were similar before and after degarelix treatment. Events were largely confined to men with preexisting cardiovascular disease and further modulated by age and modifiable risk factors. Randomized, controlled trials and longer followup are key to fully clarify the comparative safety of gonadotropin-releasing hormone antagonists vs agonists. C1 [Smith, Matthew R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Klotz, Laurence] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [van der Meulen, Egbert; Colli, Enrico; Tanko, Laszlo B.] Ferring Pharmaceut AS, Global Clin R&D, Copenhagen, Denmark. RP Smith, MR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Yawkey 7030,55 Fruit St, Boston, MA 02114 USA. EM smith.matthew@mgh.harvard.edu FU National Institutes of Health [5K24CA121990]; Prostate Cancer Foundation FX Supported by National Institutes of Health Midcareer Investigator Award 5K24CA121990 and Prostate Cancer Foundation competitive research awards. NR 27 TC 28 Z9 29 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD NOV PY 2011 VL 186 IS 5 BP 1835 EP 1842 DI 10.1016/j.juro.2011.07.035 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 835FX UT WOS:000296022200027 PM 21944083 ER PT J AU Taylor, EN Chan, AT Giovannucci, EL Curhan, GC AF Taylor, Eric N. Chan, Andrew T. Giovannucci, Edward L. Curhan, Gary C. TI Cholelithiasis and the Risk of Nephrolithiasis SO JOURNAL OF UROLOGY LA English DT Article DE kidney calculi; gallstones; risk factors ID SYMPTOMATIC GALLSTONE DISEASE; FOOD FREQUENCY QUESTIONNAIRE; DIABETES-MELLITUS; PHYSICAL-ACTIVITY; KIDNEY-STONES; WOMEN; CONSUMPTION; CALCIUM; MEN; CHOLESTEROL AB Purpose: Existing data on the relation between gallstones and kidney stones are provocative but limited. Therefore, we determined whether symptomatic radio-graphically confirmed gallstones (and/or cholecystectomy) and symptomatic kidney stone disease are independently associated. Materials and Methods: We conducted cross-sectional and prospective analyses in the Nurses' Health Studies I and II (older and younger women, respectively) and the Health Professionals Follow-Up Study (men) that included more than 240,000 participants followed for 14 to 24 years. Regression models adjusted for age, body size, thiazide use, diet and other factors. Results: At baseline the multivariate odds ratio of kidney stone history in individuals with gallstone history compared to those without was 1.65 (95% CI 1.46-1.86) in older women, 1.85 (95% CI 1.65-2.07) in younger women and 1.61 (95% CI 1.41-1.85) in men. Prospectively, the multivariate relative risk of incident kidney stones in participants with gallstone history compared to those without was 1.26 (95% CI 1.09-1.44) in older women, 1.32 (95% CI 1.14-1.52) in younger women and 1.28 (95% CI 1.03-1.57) in men. The multivariate relative risk of incident gallstones in participants with kidney stone history compared to those without was 1.17 (95% CI 1.06-1.29) in older women, 1.31 (95% CI 1.19-1.45) in younger women and 1.51 (95% CI 1.35-1.68) in men. Prospective lag analyses instituting a delay of 4 years between the diagnoses of gallstones and kidney stones yielded similar results. Conclusions: Gallstones and kidney stones are independently associated. Additional studies are needed to identify shared mechanisms underlying both diseases. C1 [Taylor, Eric N.] Maine Med Ctr, Div Nephrol & Transplantat, Portland, ME 04102 USA. [Taylor, Eric N.; Chan, Andrew T.; Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Giovannucci, Edward L.; Curhan, Gary C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Curhan, Gary C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Taylor, EN (reprint author), Maine Med Ctr, Div Nephrol & Transplantat, 22 Bramhall St, Portland, ME 04102 USA. EM entaylor@partners.org FU National Institutes of Health [DK59583, DK70756, CA87969, CA55075, CA50385] FX Supported by Grants DK59583, DK70756, CA87969, CA55075 and CA50385 from the National Institutes of Health. NR 30 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD NOV PY 2011 VL 186 IS 5 BP 1882 EP 1887 DI 10.1016/j.juro.2011.06.067 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 835FX UT WOS:000296022200044 PM 21944091 ER PT J AU Vadysirisack, DD Baenke, F Ory, B Lei, K Ellisen, LW AF Vadysirisack, Douangsone D. Baenke, Franziska Ory, Benjamin Lei, Kui Ellisen, Leif W. TI Feedback Control of p53 Translation by REDD1 and mTORC1 Limits the p53-Dependent DNA Damage Response SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR; IN-VIVO; HYPOXIA; CELLS; ACTIVATION; APOPTOSIS; STRESS; IDENTIFICATION; RTP801; GROWTH AB Exquisite control of the level and activity of p53 are required in order to preserve cellular homeostasis following DNA damage. How this regulation is integrated with other key metabolic pathways in vivo is poorly understood. Here, we describe an endogenous feedback circuit for regulation of p53 through its transcriptional target gene, Redd1, a stress-induced inhibitor of TOR complex 1 (TORC1) activity. Cells and tissues of Redd1(-/-) mice exhibit enhanced sensitivity to ionizing radiation and chemotherapy treatment, which we demonstrate is attributable to abnormally increased p53 protein level and activity in the absence of Redd1. We find that deregulation of p53 in this setting is not due to failed DNA repair or to increased p53 stabilization but, instead, to increased p53 translation. We show that Redd1 loss leads to elevated mammalian TORC1 (mTORC1) activity, which explains the increased p53 translation and protein levels. Together, these findings suggest that REDD1-mediated suppression of mTORC1 activity exerts feedback control on p53, thereby limiting the apoptotic response and contributing to cellular survival following DNA damage. This work therefore defines a role for REDD1 in the control of p53 in vivo, with potential therapeutic implications for cancer and for the variety of genetic diseases involving TOR pathway signaling components. C1 [Ellisen, Leif W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ellisen, LW (reprint author), Massachusetts Gen Hosp, Ctr Canc, GRJ-904,55 Fruit St, Boston, MA 02114 USA. EM ellisen@helix.mgh.harvard.edu RI ory, benjamin/K-8231-2015 FU NRSA [F32 CA150633]; [RO1 CA-122589] FX This work was supported by RO1 CA-122589 to L.W.E. and by NRSA postdoctoral fellowship award F32 CA150633 to D.D.V. NR 37 TC 11 Z9 14 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2011 VL 31 IS 21 BP 4356 EP 4365 DI 10.1128/MCB.05541-11 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 834NQ UT WOS:000295968900009 PM 21896779 ER PT J AU Pastor, R Reed, C Burkhart-Kasch, S Li, N Sharpe, AL Coste, SC Stenzel-Poore, MP Phillips, TJ AF Pastor, Raul Reed, Cheryl Burkhart-Kasch, Sue Li, Na Sharpe, Amanda L. Coste, Sarah C. Stenzel-Poore, Mary P. Phillips, Tamara J. TI Ethanol concentration-dependent effects and the role of stress on ethanol drinking in corticotropin-releasing factor type 1 and double type 1 and 2 receptor knockout mice SO PSYCHOPHARMACOLOGY LA English DT Article DE CRF; Stress; Knockout; Alcohol; Drinking; Swim stress ID ALCOHOL-DRINKING; INDUCED INCREASES; CENTRAL NUCLEUS; ANIMAL-MODELS; C57BL/6J MICE; RAT-BRAIN; CRF; ANTAGONIST; ANXIETY; WITHDRAWAL AB Exposure to stressors promotes ethanol (EtOH) consumption and enhances drug craving during abstinence. Corticotropin-releasing factor (CRF), and in particular, CRF actions via type 1 CRF receptors (CRF(1)) are critical in behavioral responses to stressors. CRF(1) play a role in EtOH-induced behavioral neuroadaptation, in binge-like EtOH consumption, and in heightened EtOH consumption in dependent animals. We investigated the involvement of CRF(1) in swim-stress-induced changes in EtOH consumption and in baseline consumption as a function of EtOH concentration. The role of CRF(2) in adapting to effects of the stressor was also examined. Wild-type mice and knockout mice lacking CRF(1) were tested for two-bottle choice EtOH consumption at concentrations of 3-20%. Also, intake of 10% EtOH was examined in wild-type mice and knockout mice lacking CRF(1), or lacking both CRF(1) and CRF(2), before and after acute or repeated swim stress exposures. EtOH intake was reduced in CRF(1) compared with wild-type mice when presented at a concentration of 20% but not when presented at lower concentrations. No genotype-dependent effects were found for saccharin or quinine drinking. Acute swim stress had no effect, but repeated swim stress resulted in higher levels of EtOH consumption in wild-type mice, compared with both types of knockout mice. Stress effects on EtOH drinking were longer lasting in double knockout mice. These data suggest a prominent role of CRF(1) in stressor-induced changes in EtOH consumption, with involvement of CRF(2) in recovery from stressor effects. C1 [Phillips, Tamara J.] Portland VA Med Ctr, Res Serv, Portland, OR 97239 USA. [Pastor, Raul; Reed, Cheryl; Burkhart-Kasch, Sue; Li, Na; Sharpe, Amanda L.; Phillips, Tamara J.] Oregon Hlth & Sci Univ, Behav Neurosci Dept, Portland, OR 97201 USA. [Pastor, Raul; Reed, Cheryl; Burkhart-Kasch, Sue; Li, Na; Sharpe, Amanda L.; Phillips, Tamara J.] Oregon Hlth & Sci Univ, Portland Alcohol Res Ctr, Portland, OR 97201 USA. [Coste, Sarah C.; Stenzel-Poore, Mary P.] Oregon Hlth & Sci Univ, Mol Microbiol & Immunol Dept, Portland, OR 97201 USA. [Pastor, Raul] Univ Jaume 1, Area Psicobiol, Castellon de La Plana, Spain. RP Phillips, TJ (reprint author), Portland VA Med Ctr, Res Serv, R&D32,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM phillipt@ohsu.edu FU Department of Veterans Affairs; NIH from the National Institute of Alcohol Abuse and Alcoholism [R01AA13331, P60AA010760]; NIH from Mental Health [R01MH65689] FX This work was supported by a grant from the Department of Veterans Affairs and NIH grants from the National Institute of Alcohol Abuse and Alcoholism (R01AA13331 and P60AA010760) and from Mental Health (R01MH65689). NR 47 TC 10 Z9 10 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2011 VL 218 IS 1 SI SI BP 169 EP 177 DI 10.1007/s00213-011-2284-6 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 833EP UT WOS:000295865000015 PM 21487655 ER PT J AU Clark, DG AF Clark, David Glenn CA Alzheimer Dis Neuroimaging Initiat TI Residual vectors for Alzheimer disease diagnosis and prognostication SO BRAIN AND BEHAVIOR LA English DT Article DE ADNI; Alzheimer disease; Bioinformatics; Mild cognitive impairment; PET scan AB Alzheimer disease (AD) is an increasingly prevalent neurodegenerative condition and a looming socioeconomic threat. A biomarker for the disease could make the process of diagnosis easier and more accurate, and accelerate drug discovery. The current work describes amethod for scoring brain images that is inspired by fundamental principles from information retrieval (IR), a branch of computer science that includes the development of Internet search engines. For this research, a dataset of 254 baseline 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) scans was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For a given contrast, a subset of scans (nine of every 10) was used to compute a residual vector that typified the difference, at each voxel, between the two groups being contrasted. Scans that were not used for computing the residual vector (the remaining one of 10 scans) were then compared to the residual vector using a cosine similarity metric. This process was repeated sequentially, each time generating cosine similarity scores on 10% of the FDG-PET scans for each contrast. Statistical analysis revealed that the scores were significant predictors of functional decline as measured by the Functional Activities Questionnaire (FAQ). When logistic regression models that incorporated these scores were evaluated with leave-one-out cross-validation, cognitively normal controls were discerned from AD with sensitivity and specificity of 94.4% and 84.8%, respectively. Patients who converted from mild cognitive impairment (MCI) to AD were discerned from MCI nonconverters with sensitivity and specificity of 89.7% and 62.9%, respectively, when FAQ scores were brought into the model. Residual vectors are easy to compute and provide a simple method for scoring the similarity between an FDG-PET scan and sets of examples from a given diagnostic group. The method is readily generalizable to any imaging modality. Further interdisciplinary work between IR and clinical neuroscience is warranted. C1 [Clark, David Glenn] Birmingham VA Med Ctr, Birmingham, AL USA. [Clark, David Glenn] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. RP Clark, DG (reprint author), 1720 7th Ave South,SC 620C, Birmingham, AL 35294 USA. EM dgclark@uab.edu FU Department of Veterans Affairs [E6553W]; ADNI (National Institutes of Health) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; NIH [P30 AG010129, K01 AG030514]; Dana Foundation FX Dr. Clark is supported by a Career Development Award from the Department of Veterans Affairs (E6553W), entitled "Semantic Memory, Financial Capacity, and Brain Perfusion in MCI."; Data collection and sharing for this project were funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glax-oSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace Inc., Merck and Co. Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche, Schering-Plough, Synarc Inc., as well as nonprofit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www. fnih. org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. NR 23 TC 4 Z9 4 U1 3 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD NOV PY 2011 VL 1 IS 2 BP 142 EP 152 DI 10.1002/brb3.19 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA V35UO UT WOS:000209173700010 PM 22399094 ER PT J AU Podar, K Anderson, KC AF Podar, K. Anderson, K. C. TI Emerging Therapies Targeting Tumor Vasculature in Multiple Myeloma and other Hematologic and Solid Malignancies SO CURRENT CANCER DRUG TARGETS LA English DT Article DE AMG-386; AVE8062; axitinib; bevacizumab; CDP860; CE-245677; CEP-11981; cilengitide; combretastatin; CP-868,596; enzastaurin; exherin; HuMV833; lenalidomide; metronomic chemotherapy; MN-029; OMP-21M18; pazopanib; PF-4856884; pomalidomide; Reg421; semaxanib; sorafenib and sunitinib; TB403; thalidomide; TZT-1027; vadimezan; vandetanib; vatalanib; VEGFR antibodies; VEGF-trap; ZD6126 AB Research on the formation of new blood vessels (angiogenesis) in general and vascular endothelial growth factor (VEGF) in particular is a major focus in biomedicine and has led to the clinical approval of the monoclonal anti-VEGF antibody bevazicumab; and the second-generation multitargeted receptor kinase inhibitors (RTKIs) sorafenib, sunitinib, and pazopanib. Although these agents show significant preclinical and clinical anti-cancer activity, they prolong overall survival of cancer patients for only months, followed by a restoration of tumor growth and progression. Therefore, there is a clear need to increase our understanding of tumor angiogenesis and the development of resistance. In this review we discuss up-to-date knowledge on mechanisms of tumor angiogenesis, and summarize preclinical and clinical data on existing and potential future anti-angiogenic agents and treatment strategies for Multiple Myeloma (MM) and other hematologic and solid malignancies. C1 [Podar, K.; Anderson, K. C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Podar, K.] Heidelberg Univ, Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany. [Podar, K.] German Canc Res Ctr, D-69120 Heidelberg, Germany. RP Podar, K (reprint author), Heidelberg Univ, Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany. EM klaus.podar@med.uni-heidelberg.de FU MMRF Senior Research grant award; National Institutes of Health [RO CA50947, PO-1 CA78378, P50 CA100707]; Doris Duke Distinguished Clinical Research Scientist Award FX This work was supported by a MMRF Senior Research grant award (to K.P.); National Institutes of Health Grants RO CA50947, PO-1 CA78378, and P50 CA100707; and the Doris Duke Distinguished Clinical Research Scientist Award (to K.C.A.) NR 304 TC 15 Z9 15 U1 3 U2 8 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0096 EI 1873-5576 J9 CURR CANCER DRUG TAR JI Curr. Cancer Drug Targets PD NOV PY 2011 VL 11 IS 9 BP 1005 EP 1024 PG 20 WC Oncology SC Oncology GA V28BX UT WOS:000208657400003 PM 21933109 ER PT J AU Sacco, A Ghobrial, IM Roccaro, AM AF Sacco, A. Ghobrial, I. M. Roccaro, A. M. TI Anti-Angiogenic Therapies in the Treatment of Waldenstrom's Macroglobulinemia SO CURRENT CANCER DRUG TARGETS LA English DT Article DE Anti-angiogenic approach; Waldenstrom's Macroglobulinemia AB Bone marrow microenvironment has been shown to play a crucial role in supporting the pathogenesis and the progression of several B-cell malignancies, including Waldenstrom's Macroglobulinemia (WM). Among the different cell types within the bone marrow milieu, endothelial cells have been proven to support WM cells growth. Based on the understanding of bone marrow neo-angiogenesis in plasma cell dyscrasias, a number of anti-angiogenic molecules are now available for the treatment of these diseases. Indeed, anti-angiogenic drugs, such as proteasome-, proteins kinase-C (PKC)-, phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR)-, and histone deacetylase (HDAC)-inhibitors are now available, playing a key role in the treatment of WM both in the preclinical settings and as part of clinical trials. C1 [Roccaro, A. M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Roccaro, A. M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Roccaro, AM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM aldo_roccaro@dfci.harvard.edu NR 37 TC 0 Z9 0 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0096 J9 CURR CANCER DRUG TAR JI Curr. Cancer Drug Targets PD NOV PY 2011 VL 11 IS 9 BP 1025 EP 1029 PG 5 WC Oncology SC Oncology GA V28BX UT WOS:000208657400004 PM 21933107 ER PT J AU Cheng, YC O'Connell, JR Cole, JW Stine, OC Dueker, N McArdle, PF Sparks, MJ Shen, J Laurie, CC Nelson, S Doheny, KF Ling, H Pugh, EW Brott, TG Brown, RD Meschia, JF Nalls, M Rich, SS Worrall, B Anderson, CD Biffi, A Cortellini, L Furie, KL Rost, NS Rosand, J Manolio, TA Kittner, SJ Mitchell, BD AF Cheng, Yu-Ching O'Connell, Jeffrey R. Cole, John W. Stine, O. Colin Dueker, Nicole McArdle, Patrick F. Sparks, Mary J. Shen, Jess Laurie, Cathy C. Nelson, Sarah Doheny, Kimberly F. Ling, Hua Pugh, Elizabeth W. Brott, Thomas G. Brown, Robert D., Jr. Meschia, James F. Nalls, Michael Rich, Stephen S. Worrall, Bradford Anderson, Christopher D. Biffi, Alessandro Cortellini, Lynelle Furie, Karen L. Rost, Natalia S. Rosand, Jonathan Manolio, Teri A. Kittner, Steven J. Mitchell, Braxton D. TI Genome-Wide Association Analysis of Ischemic Stroke in Young Adults SO G3-GENES GENOMES GENETICS LA English DT Article DE epidemiology; genetics; brain infarction; FMNL2 ID VARIANTS; RISK; CLASSIFICATION; DISEASE; IMPUTATION; INFARCTION; SUBTYPE; LINKAGE; LOCI; TOOL AB Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15-49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P < 5 x 10(-8)), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 x 10(-7)) and rs1986743 (in ARL6IP6; P = 2.7 x 10(-7)), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults. C1 [Cheng, Yu-Ching; O'Connell, Jeffrey R.; McArdle, Patrick F.; Mitchell, Braxton D.] Univ Maryland, Dept Med, Sch Med, Baltimore, MD 21201 USA. [Cole, John W.; Sparks, Mary J.; Kittner, Steven J.] Univ Maryland, Dept Neurol, Sch Med, Baltimore, MD 21201 USA. [Stine, O. Colin; Dueker, Nicole] Univ Maryland, Dept Epidemiol & Publ Hlth, Sch Med, Baltimore, MD 21201 USA. [Cole, John W.; Kittner, Steven J.] Vet Affairs Med Ctr, Dept Neurol, Baltimore, MD 21201 USA. [Shen, Jess; Laurie, Cathy C.; Nelson, Sarah] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Doheny, Kimberly F.; Ling, Hua; Pugh, Elizabeth W.] Johns Hopkins Univ, Ctr Inherited Dis Res, Sch Med, Baltimore, MD 21224 USA. [Brott, Thomas G.; Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Brown, Robert D., Jr.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Nalls, Michael] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Mitchell, Braxton D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Rich, Stephen S.; Worrall, Bradford] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Worrall, Bradford] Univ Virginia, Dept Neurol, Charlottesville, VA 22908 USA. [Anderson, Christopher D.; Biffi, Alessandro; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Cortellini, Lynelle; Furie, Karen L.; Rost, Natalia S.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Anderson, Christopher D.; Biffi, Alessandro; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. RP Mitchell, BD (reprint author), Univ Maryland, Dept Med, Sch Med, 660 W Redwood St,Howard Hall,Room 492, Baltimore, MD 21201 USA. EM bmitchel@medicine.umaryland.edu OI Anderson, Christopher/0000-0002-0053-2002; Mitchell, Braxton/0000-0003-4920-4744 FU National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) [U01 HG-004436]; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK-072488]; Office of Research and Development, Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; GEI [U01 HG-004438-01]; Division of Adult and Community Health, Centers for Disease Control; National Institute of Neurological Disorders and Stroke (NINDS); NIH Office of Research on Women's Health [R01 NS-45012, U01 NS-069208-01]; National Institute on Aging, NIH [Z01 AG-000954-06, Z01 AG-000015-50]; NIH-NINDS [R01 NS-42733, R01 NS-39987, K23 NS-064052, R01 NS-063925, P50 NS-051343]; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]; Deane Institute for Integrative Study of Atrial Fibrillation and Stroke; Keane Stroke Genetics Research Fund; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research FX GEOS was supported by the National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI) Grant U01 HG-004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK-072488); and by the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR) and funded by GEI Grant U01 HG-004438-01. Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG-004446; Bruce S. Weir, P. I.). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control, and by National Institute of Neurological Disorders and Stroke (NINDS) and NIH Office of Research on Women's Health Grants R01 NS-45012 and U01 NS-069208-01. The ISGS/SWISS study was supported in part by the Intramural Research Program of the National Institute on Aging, NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), human subjects protocol numbers 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the National Institute on Aging, NIH project Z01 AG-000015-50, human subjects protocol number 2003-078. The ISGS study was funded by NIH-NINDS Grant R01 NS-42733 (J. F. Meschia, P. I.). The SWISS study was funded by NIH-NINDS Grant R01 NS-39987 (J. F. Meschia, P. I.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov). GASROS was supported by American Heart Association/Bugher Foundation Centers for Stroke Prevention Research Grant 0775010N; NIH-NINDS Grants K23 NS-064052 (N. S. Rost), R01 NS-063925 (J. Rosand), and P50 NS-051343 (J. Rosand and K. L. Furie); the Deane Institute for Integrative Study of Atrial Fibrillation and Stroke; and the Keane Stroke Genetics Research Fund. Drs. A. Biffi, N. S. Rost, and C. D. Anderson were supported in part by the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research. NR 31 TC 12 Z9 12 U1 0 U2 0 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD NOV 1 PY 2011 VL 1 IS 6 BP 505 EP 513 DI 10.1534/g3.111.001164 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 055IP UT WOS:000312409400011 PM 22384361 ER PT J AU Abi-Raad, R Boutrus, R Wang, R Niemierko, A Smith, B Taghian, AG AF Abi-Raad, Rita Boutrus, Rimoun Wang, Rui Niemierko, Andrzej Smith, Barbara Taghian, Alphonse G. TI PATTERNS AND RISK FACTORS OF LOCOREGIONAL RECURRENCE IN T1-T2 NODE NEGATIVE BREAST CANCER PATIENTS TREATED WITH MASTECTOMY: IMPLICATIONS FOR POSTMASTECTOMY RADIOTHERAPY SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Breast cancer; Mastectomy; Postmastectomy radiation; Risk factors; Locoregional recurrence AB Purpose: Postmastectomy radiation therapy (PMRT) can reduce locoregional recurrences (LRR) in high-risk patients, but its role in the treatment of lymph node negative (LN-) breast cancer remains unclear. The aim of this study was to identify a subgroup of T1-T2 breast cancer patients with LN-who might benefit from PMRT. Methods and Materials: We retrospectively reviewed 1,136 node-negative T1-T2 breast cancer cases treated with mastectomy without PMRT at the Massachusetts General Hospital between 1980 and 2004. We estimated cumulative incidence rates for LRR overall and in specific subgroups, and used Cox proportional hazards models to identify potential risk factors. Results: Median follow-up was 9 years. The 10-year cumulative incidence of LRR was 5.2% (95% CI: 3.9-6.7%). Chest wall was the most common (73%) site of LRR. Tumor size, margin, patient age, systemic therapy, and lymphovascular invasion (LVI) were significantly associated with LRR on multivariate analysis. These five variables were subsequently used as risk factors for stratified analysis. The 10-year cumulative incidence of LRR for patients with no risk factors was 2.0% (95% CI: 0.5-5.2%), whereas the incidence for patients with three or more risk factors was 19.7% (95% CI: 12.2-28.6%). Conclusion: It has been suggested that patients with T1-T2N0 breast cancer who undergo mastectomy represent a favorable group for which PMRT renders little benefit. However, this study suggests that select patients with multiple risk factors including LVI, tumor size >= 2 cm, close or positive margin, age <= 50, and no systemic therapy are at higher risk of LRR and may benefit from PMRT. (c) 2011 Elsevier Inc. C1 [Abi-Raad, Rita; Boutrus, Rimoun; Niemierko, Andrzej; Taghian, Alphonse G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Wang, Rui; Niemierko, Andrzej] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Biostat, Boston, MA USA. [Smith, Barbara] Harvard Univ, Sch Med, Dept Surg, Div Surg Oncol,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Taghian, AG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St Cox Bldg 302, Boston, MA 02114 USA. EM ataghian@partners.org FU National Cancer Institute [R01CA139118, P50CA089393]; National Institutes of Health [CA50628]; Jane Mailloux Research Fund; Blanche Montesi Fund; Tim Levy Fund FX Supported in part by Award Number R01CA139118 (AGT) and Award Number P50CA089393 (AGT) from the National Cancer Institute, in part by grant CA50628 from the National Institutes of Health (AN). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The study was also partially supported by the Jane Mailloux Research Fund (AGT), the Blanche Montesi Fund (AGT), Tim Levy Fund for breast cancer research (AGT). NR 38 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2011 VL 81 IS 3 BP E151 EP E157 DI 10.1016/j.ijrobp.2011.01.015 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA V33MZ UT WOS:000209024200019 PM 21420245 ER PT J AU Ahern, RL Corless, IB Davis, SM Kwong, JJ AF Ahern, Richard L. Corless, Inge B. Davis, Sheila M. Kwong, Jeffrey J. TI Infusing Swanson's Theory of Caring into an Advanced Practice Nursing Model for an Infectious Diseases Anal Dysplasia Clinic SO JANAC-JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE LA English DT Article DE advanced practice nursing; anal dysplasia; HIV; theory of caring AB The incidence of anal cancer is increasing among HIV-infected men and women. The process of screening for anal dysplasia and the management of abnormal findings are currently and most often based on a medical model. The needs of these patients, however, go well beyond medical care. A more comprehensive and holistic approach to health care is, therefore, required. Given the scope of practice of advanced practice nurses who are involved in the diagnosis and treatment of patients with anal dysplasia, it is appropriate for them to assume leadership roles in addressing the needs of these patients. This article describes the application of a theory of caring to create an advanced practice nursing model of care for HIV-infected men and women in infectious diseases anal dysplasia clinics. Copyright (C) 2011 Association of Nurses in AIDS Care C1 [Ahern, Richard L.; Davis, Sheila M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Corless, Inge B.] MGH Inst Hlth Profess, Sch Nursing, Boston, MA USA. [Kwong, Jeffrey J.] Rutgers Coll Nursing, Newark, NJ USA. RP Ahern, RL (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. OI Corless, Inge/0000-0003-0438-2037 NR 30 TC 1 Z9 1 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1055-3290 J9 J ASSOC NURSE AIDS C JI J. Assoc. Nurses Aids Care PD NOV-DEC PY 2011 VL 22 IS 6 SI SI BP 478 EP 488 DI 10.1016/j.jana.2011.06.010 PG 11 WC Nursing SC Nursing GA V28YQ UT WOS:000208716500007 PM 22035527 ER PT J AU Bezerra, HG Loureiro, R Irlbeck, T Bamberg, F Schlett, CL Rogers, I Blankstein, R Truong, QA Brady, TJ Cury, RC Hoffmann, U AF Bezerra, Hiram G. Loureiro, Ricardo Irlbeck, Thomas Bamberg, Fabian Schlett, Christopher L. Rogers, Ian Blankstein, Ron Truong, Quynh A. Brady, Thomas J. Cury, Ricardo C. Hoffmann, Udo TI Incremental value of myocardial perfusion over regional left ventricular function and coronary stenosis by cardiac CT for the detection of acute coronary syndromes in high-risk patients: A subgroup analysis of the ROMICAT trial SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Myocardial perfusion; Cardiac CT; Acute coronary syndrome ID ACUTE CHEST-PAIN; MULTIDETECTOR COMPUTED-TOMOGRAPHY; EMERGENCY-DEPARTMENT PATIENTS; DUAL-SOURCE CT; ARTERY-DISEASE; INFARCTION; ANGIOGRAPHY; CARDIOLOGY; STATEMENT; MDCT AB OBJECTIVES: To determine the incremental benefit of assessing myocardial perfusion defects (MPD) for acute coronary syndromes (ACS) over coronary and functional assessment by rest cardiac computed tomography (CT) in patients with acute chest pain. BACKGROUND: Assessment of myocardial perfusion is feasible with cardiac CT; however, the diagnostic value of this assessment in patients at risk for ACS has not been demonstrated. METHODS: The study included patients who presented to the emergency department with acute chest pain, nonischemic initial electrocardiogram (ECG), and negative cardiac biomarkers but had clinical suspicion for ACS and underwent invasive coronary angiography (ICA). Results were blinded to caregivers and patients. CT data sets were independently assessed for the presence of coronary plaque and stenosis, regional left ventricular function, and myocardial perfusion deficits by 2 blinded observers. Coronary angiography was assessed for the presence of stenosis, TIMI myocardial perfusion grade, and corrected TIMI frame count. The endpoint was ACS during index hospitalization. RESULTS: We analyzed data from 35 subjects (69% male, mean age 58 +/- 9 years) of whom 22 (63%) had ACS. The sensitivity and specificity of MPD for ACS were 86% (95% CI: 64%-96%) and 62% (95% Cl: 32%-85%), respectively. Combined, MPD and RWMA assessment resulted in specificity and sensitivity of 86% (95% CI: 64%-96%) and 85% (95% CI: 54%-97%), respectively. Adding MPD and RWMA to the assessment for significant stenosis (>50%) resulted in a higher sensitivity of 91% (69-98%) and specificity of 85% (54-97%) and a significantly increased overall diagnostic accuracy when compared with assessment for stenosis (AUC: 0.88 vs 0.79; respectively, P = 0.02). Diagnostic accuracy of CT was not associated with impaired CTFC >40 or myocardial TIMI perfusion grade < 3. CONCLUSIONS: Assessment of myocardial perfusion and regional wall motion abnormalities may enhance the ability of CT to detect ACS in patients with acute chest pain. (C) 2011 Society of Cardiovascular Computed Tomography. All rights reserved. C1 [Bezerra, Hiram G.; Loureiro, Ricardo; Irlbeck, Thomas; Bamberg, Fabian; Schlett, Christopher L.; Rogers, Ian; Blankstein, Ron; Truong, Quynh A.; Brady, Thomas J.; Cury, Ricardo C.; Hoffmann, Udo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Bezerra, Hiram G.] Univ Hosp Case Med Ctr, Harrington McLaughlin Heart & Vasc Inst, Cleveland, OH USA. [Loureiro, Ricardo; Irlbeck, Thomas; Bamberg, Fabian; Schlett, Christopher L.; Brady, Thomas J.; Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rogers, Ian; Blankstein, Ron; Truong, Quynh A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Cardiovasc MR & CT Program, Miami, FL USA. RP Hoffmann, U (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org FU National Institutes of Health (NIH) [R01 HL080053, T32 HL076136] FX This work was supported by National Institutes of Health (NIH) grant R01 HL080053. R.B., I.R., and Q.A.T. received salary support from NIH T32 HL076136. NR 27 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD NOV-DEC PY 2011 VL 5 IS 6 BP 382 EP 391 DI 10.1016/j.jcct.2011.10.004 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 035HJ UT WOS:000310933700005 PM 22146497 ER PT J AU Ghoshhajra, BB Rogers, IS Maurovich-Horvat, P Techasith, T Verdini, D Sidhu, MS Drzezga, NK Medina, HM Blankstein, R Brady, TJ Cury, RC AF Ghoshhajra, Brian B. Rogers, Ian S. Maurovich-Horvat, Pal Techasith, Tust Verdini, Daniel Sidhu, Manavjot S. Drzezga, Nicola K. Medina, Hector M. Blankstein, Ron Brady, Thomas J. Cury, Ricardo C. TI A comparison of reconstruction and viewing parameters on image quality and accuracy of stress myocardial CT perfusion SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Optimal viewing parameters; Cardiac computed tomography; Perfusion defects ID COMPUTED-TOMOGRAPHY; MULTIDETECTOR CT; ANGIOGRAPHY; DEFECTS; EXTENT; SPECT AB BACKGROUND: Myocardial stress computed tomography perfusion (CTP) has similar diagnostic accuracy for detecting perfusion defects (PDs) versus single-photon emission computed tomography (SPECT). However, the optimal diagnostic viewing and image processing parameters for CTP are unknown. OBJECTIVE: We sought to compare the diagnostic accuracy of different image processing techniques, cardiac phases, slice thicknesses, and viewing parameters for detection of PDs. METHODS: A stress and rest dual-source CTP protocol was performed with adenosine. Twelve subjects with severe stenosis proven by quantitative coronary angiography (QCA), with corresponding territorial defects at SPECT, were selected as well as 7 controls (subjects with similar clinical suspicion but negative QCA and SPECT). Short-axis stress images were processed with 3 techniques: minimum intensity projection (MinIP), maximum intensity projection, and average intensity multiplanar reconstruction (MPR), 3 thicknesses (1, 3, 8 mm), and 2 phases (systolic, mid-diastolic). The resulting images (n = 1026) were randomized and interpreted by independent readers. RESULTS: Diastolic reconstructions (8-mm MPR) showed the highest sensitivity (81%) to detect true PDs. The highest accuracy was achieved with the 8-mm (61%) and 1-mm (61%) MPR diastolic images. The most sensitive and accurate systolic reconstructions were 3-mm MinIP images. These findings related to viewing in relatively narrow window width and window level settings. CONCLUSION: Viewing parameters for optimal accuracy in detection of perfusion defects on CTP differ for systolic and diastolic images. (C) 2011 Society of Cardiovascular Computed Tomography. All rights reserved. C1 [Ghoshhajra, Brian B.; Rogers, Ian S.; Maurovich-Horvat, Pal; Techasith, Tust; Verdini, Daniel; Sidhu, Manavjot S.; Drzezga, Nicola K.; Medina, Hector M.; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02114 USA. [Ghoshhajra, Brian B.; Rogers, Ian S.; Maurovich-Horvat, Pal; Techasith, Tust; Verdini, Daniel; Sidhu, Manavjot S.; Drzezga, Nicola K.; Medina, Hector M.; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Ghoshhajra, Brian B.; Rogers, Ian S.; Maurovich-Horvat, Pal; Techasith, Tust; Verdini, Daniel; Sidhu, Manavjot S.; Drzezga, Nicola K.; Medina, Hector M.; Brady, Thomas J.; Cury, Ricardo C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Rogers, Ian S.] Stanford Univ, Falk Cardiovasc Res Ctr, Div Cardiovasc Med, Stanford, CA 94305 USA. [Blankstein, Ron] Brigham & Womens Hosp, Div Cardiovasc, Noninvas Cardiovasc Imaging Program, Boston, MA 02115 USA. [Blankstein, Ron] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Cardiovasc MRI & CT Program, Miami, FL USA. RP Ghoshhajra, BB (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM bghoshhajra@partners.org RI Ghoshhajra, Brian/J-2114-2016; OI Ghoshhajra, Brian/0000-0002-3865-3432; Maurovich-Horvat, Pal/0000-0003-0885-736X FU Astellas Pharmaceuticals Inc. FX Astellas Pharmaceuticals Inc. provided grant support for the initial study. The authors maintained full control over this study design and data. NR 15 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD NOV-DEC PY 2011 VL 5 IS 6 BP 459 EP 466 DI 10.1016/j.jcct.2011.10.011 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 035HJ UT WOS:000310933700013 PM 22146505 ER PT J AU Fortney, JC Burgess, JF Bosworth, HB Booth, BM Kaboli, PJ AF Fortney, John C. Burgess, James F., Jr. Bosworth, Hayden B. Booth, Brenda M. Kaboli, Peter J. TI A Re-conceptualization of Access for 21st Century Healthcare SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE access; e-health; digital; connectivity; veterans AB Many e-health technologies are available to promote virtual patient-provider communication outside the context of face-to-face clinical encounters. Current digital communication modalities include cell phones, smartphones, interactive voice response, text messages, e-mails, clinic-based interactive video, home-based web-cams, mobile smartphone two-way cameras, personal monitoring devices, kiosks, dashboards, personal health records, web-based portals, social networking sites, secure chat rooms, and on-line forums. Improvements in digital access could drastically diminish the geographical, temporal, and cultural access problems faced by many patients. Conversely, a growing digital divide could create greater access disparities for some populations. As the paradigm of healthcare delivery evolves towards greater reliance on non-encounter-based digital communications between patients and their care teams, it is critical that our theoretical conceptualization of access undergoes a concurrent paradigm shift to make it more relevant for the digital age. The traditional conceptualizations and indicators of access are not well adapted to measure access to health services that are delivered digitally outside the context of face-to-face encounters with providers. This paper provides an overview of digital "encounterless" utilization, discusses the weaknesses of traditional conceptual frameworks of access, presents a new access framework, provides recommendations for how to measure access in the new framework, and discusses future directions for research on access. C1 [Fortney, John C.; Booth, Brenda M.] Cent Arkansas Vet Healthcare Syst, Hlth Serv Res & Dev HSRD, Ctr Mental Hlth & Outcomes Res, North Little Rock, AR 72114 USA. [Fortney, John C.] Cent Arkansas Vet Healthcare Syst, South Cent Mental Illness Res Educ & Clin Ctr, North Little Rock, AR 72114 USA. [Fortney, John C.; Booth, Brenda M.] Univ Arkansas Med Sci, Div Hlth Serv Res, Dept Psychiat, Coll Med, North Little Rock, AR USA. [Burgess, James F., Jr.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. [Burgess, James F., Jr.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Bosworth, Hayden B.] Durham VA Med Ctr, Hlth Serv Res & Dev Serv HSR & D, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Bosworth, Hayden B.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Bosworth, Hayden B.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Bosworth, Hayden B.] Duke Univ, Med Ctr, Sch Nursing, Durham, NC 27710 USA. [Kaboli, Peter J.] Vet Rural Hlth Resource Ctr Cent Reg, VA Off Rural Hlth ORH, Iowa City, IA USA. [Kaboli, Peter J.] Iowa City VA Healthcare Syst, CRIISP, Iowa City, IA USA. [Kaboli, Peter J.] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. RP Fortney, JC (reprint author), Cent Arkansas Vet Healthcare Syst, Hlth Serv Res & Dev HSRD, Ctr Mental Hlth & Outcomes Res, 2200 Ft Roots Dr, North Little Rock, AR 72114 USA. EM fortneyjohnc@uams.edu OI Burgess, James/0000-0002-6646-7071 FU Department of Veterans Affairs, South Central Mental Illness Research Education and Clinical Center; Health Services Research and Development Service Center for Mental Healthcare and Outcomes Research; Department of Veterans Affairs, Health Services Research and Development Service Career Scientist Award [08-027]; Department of Veterans Affairs Health Services Research and Development Service Center for Mental Healthcare and Outcomes Research; Department of Veterans Affairs, Office of Rural Health, Veterans Rural Health Resource Center-Central Region FX Dr. Fortney was funded by the Department of Veterans Affairs, South Central Mental Illness Research Education and Clinical Center, and the Health Services Research and Development Service Center for Mental Healthcare and Outcomes Research. Dr. Bosworth was funded by the Department of Veterans Affairs, Health Services Research and Development Service Career Scientist Award 08-027. Dr. Booth was funded by the Department of Veterans Affairs Health Services Research and Development Service Center for Mental Healthcare and Outcomes Research. Dr. Kaboli was supported by the Department of Veterans Affairs, Office of Rural Health, Veterans Rural Health Resource Center-Central Region. The views expressed in this paper are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 56 TC 52 Z9 52 U1 2 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 SU 2 BP S639 EP S647 DI 10.1007/s11606-011-1806-6 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA V30JP UT WOS:000208812600005 PM 21989616 ER PT J AU Hogan, TP Wakefield, B Nazi, KM Houston, TK Weaver, FM AF Hogan, Timothy P. Wakefield, Bonnie Nazi, Kim M. Houston, Thomas K. Weaver, Frances M. TI Promoting Access Through Complementary eHealth Technologies: Recommendations for VA's Home Telehealth and Personal Health Record Programs SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE eHealth; patient-centered medical home; telehealth; personal health records; veteran AB BACKGROUND: Many healthcare organizations have embraced eHealth technologies in their efforts to promote patient-centered care, increase access to services, and improve outcomes. OBJECTIVE: Using the Department of Veterans Affairs (VA) as a case study, this paper presents two specific eHealth technologies, the Care Coordination Home Telehealth (CCHT) Program and the My HealtheVet (MHV) personal health record (PHR) portal with integrated secure messaging, and articulates a vision of how they might be implemented as part of a patient-centric healthcare model and used in a complementary manner to enhance access to care and to support patient-centered care. METHODS: Based on our experience and ongoing work with both programs, we offer a series of recommendations for pursuing and ultimately achieving this vision. CONCLUSION: VA's CCHT and MHV programs are examples of an expanding repertoire of eHealth applications available to patients and healthcare teams. VA's new patient-centric healthcare model represents a significant shift in the way that services are delivered and a profound opportunity to incorporate eHealth technologies like the CCHT and MHV programs into clinical practice to increase access to care, and to ensure the responsiveness of such technologies to the preferences and circumstances of patients. C1 [Hogan, Timothy P.; Weaver, Frances M.] Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL 60141 USA. [Hogan, Timothy P.; Weaver, Frances M.] Jr VA Hosp, Spinal Cord Injury Qual Enhancement Res Initiat, Hines, IL 60141 USA. [Hogan, Timothy P.; Wakefield, Bonnie; Houston, Thomas K.; Weaver, Frances M.] Edith Nourse Rogers Mem Vet Hosp, eHlth Qual Enhancement Res Initiat, Natl eHlth QUERI Coordinating Ctr, Bedford, MA USA. [Hogan, Timothy P.; Weaver, Frances M.] Loyola Univ Chicago, Program Hlth Serv Res, Stritch Sch Med, Loyola Univ Hlth Syst, Maywood, IL USA. [Wakefield, Bonnie] Iowa City VA Med Ctr, VA Hlth Serv Res & Dev, Ctr Comprehens Access & Delivery Res & Evaluat CA, Iowa City, IA USA. [Nazi, Kim M.] US Dept Vet Affairs, Vet & Consumers Hlth Informat Off, Off Hlth Informat, Vet Hlth Adm, Washington, DC USA. [Houston, Thomas K.] Bedford VAMC, Ctr Hlth Qual Outcomes & Econ Res CHQOER, Bedford, MA USA. [Houston, Thomas K.] Univ Massachusetts, Sch Med, Div Hlth Informat & Implementat Sci, Worcester, MA USA. RP Hogan, TP (reprint author), Jr VA Hosp, Ctr Management Complex Chron Care, Edward Hines, 5000 S 5th Ave, Hines, IL 60141 USA. EM timothy.hogan@va.gov NR 59 TC 19 Z9 19 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 SU 2 BP S628 EP S635 DI 10.1007/s11606-011-1765-y PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA V30JP UT WOS:000208812600003 PM 21989614 ER PT J AU Jackson, GL Krein, SL Alverson, DC Darkins, AW Gunnar, W Harada, ND Helfrich, CD Houston, TK Klobucar, TF Nazi, KM Poropatich, RK Ralston, JD Bosworth, HB AF Jackson, George L. Krein, Sarah L. Alverson, Dale C. Darkins, Adam W. Gunnar, William Harada, Nancy D. Helfrich, Christian D. Houston, Thomas K. Klobucar, Thomas F. Nazi, Kim M. Poropatich, Ronald K. Ralston, James D. Bosworth, Hayden B. TI Defining Core Issues in Utilizing Information Technology to Improve Access: Evaluation and Research Agenda SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE access to care; medical informatics; veterans AB The Department of Veterans Affairs (VA) has been at the vanguard of information technology (IT) and use of comprehensive electronic health records. Despite the widespread use of health IT in the VA, there are still a variety of key questions that need to be answered in order to maximize the utility of IT to improve patient access to quality services. This paper summarizes the potential of IT to enhance healthcare access, key gaps in current evidence linking IT and access, and methodologic challenges for related research. We also highlight four key issues to be addressed when implementing and evaluating the impact of IT interventions on improving access to quality care: 1) Understanding broader needs/perceptions of the Veteran population and their caregivers regarding use of IT to access healthcare services and related information. 2) Understanding individual provider/clinicianneeds/perceptions regarding use of IT for patient access to healthcare. 3) System/Organizational issues within the VA and other organizations related to the use of IT to improve access. 4) IT integration and information flow with non-VA entities. While the VA is used as an example, the issues are salient for healthcare systems that are beginning to take advantage of IT solutions. C1 [Jackson, George L.; Bosworth, Hayden B.] Durham Vet Affairs Med Ctr, Hlth Serv Res & Dev HSR& D Ctr Hlth Serv Res Prim, Durham, NC 27705 USA. [Jackson, George L.; Bosworth, Hayden B.] Duke Univ, Med Ctr, Div Gen Internal Med, Durham, NC 27710 USA. [Krein, Sarah L.] Ann Arbor Vet Affairs Med Ctr, HSR & D Ctr Clin Management Res, Ann Arbor, MI USA. [Krein, Sarah L.] Univ Michigan, Sch Med, Div Gen Med, Ann Arbor, MI USA. [Alverson, Dale C.] Univ New Mexico, Hlth Sci Ctr, Ctr Telehealth & Cybermed Res, Albuquerque, NM 87131 USA. [Darkins, Adam W.] Vet Hlth Adm, Off Care Coordinat Serv, Washington, DC USA. [Gunnar, William] Vet Hlth Adm, Off Patient Care Serv, Washington, DC USA. [Harada, Nancy D.] Veteran Affairs Greater Los Angeles Healthcare Sy, Off Grad Med Educ & Geriatr Res, Educ & Clin Ctr, Los Angeles, CA USA. [Harada, Nancy D.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Helfrich, Christian D.] Vet Affairs Puget Sound Hlth Care Syst, HSR & D Northwest Outcomes Res Older Adults, Seattle, WA USA. [Helfrich, Christian D.; Ralston, James D.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Houston, Thomas K.] Edith Nourse Rogers Mem Vet Hosp, HSR & D Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Houston, Thomas K.] Univ Massachusetts, Sch Med, Dept Qualitat Hlth Sci, Worcester, MA USA. [Klobucar, Thomas F.] Cent Reg, Vet Rural Hlth Resource Ctr, Iowa City, IA USA. [Nazi, Kim M.] Vet Hlth Adm, Vet & Consumers Hlth Informat Off, Off Hlth Informat, Washington, DC USA. [Poropatich, Ronald K.] Telemed & Adv Technol Res Ctr, Ft Detrick, MD USA. [Ralston, James D.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. RP Jackson, GL (reprint author), Durham Vet Affairs Med Ctr, Hlth Serv Res & Dev HSR& D Ctr Hlth Serv Res Prim, Durham, NC 27705 USA. EM george.l.jackson@duke.edu RI Krein, Sarah/E-2742-2014; Helfrich, Christian/D-2382-2016 OI Krein, Sarah/0000-0003-2111-8131; Helfrich, Christian/0000-0002-9827-4768 FU VA HSR&D Career Scientist Award [08-027] FX This paper summarizes deliberations of the Adoption and Implementation of IT Workgroup at the VA Health Services Research & Development (HSR&D) State of the Art Conference on Improving Access to VA Care held September 21-22 2010 in Arlington, VA. In addition to the authors, the following individuals were part of the workgroup: Leigh Anderson, MD; David Atkins, MD, MPH; Nancy Maher, Ph.D.; Kevin Vigilante, MD, MPH; and Kenneth R. Wingart, Ph.D. The last author was supported by a VA HSR&D Career Scientist Award (08-027). NR 50 TC 7 Z9 7 U1 4 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 SU 2 BP S623 EP S627 DI 10.1007/s11606-011-1789-3 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA V30JP UT WOS:000208812600002 PM 21989613 ER PT J AU Kramer, BJ Jouldjian, S Wang, MM Dang, J Mitchell, MN Finke, B Saliba, D AF Kramer, B. Josea Jouldjian, Stella Wang, Mingming Dang, Jeff Mitchell, Michael N. Finke, Bruce Saliba, Debra TI Do Correlates of Dual Use by American Indian and Alaska Native Veterans Operate Uniformly Across the Veterans Health Administration and the Indian Health Service? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE access; underserved populations; health services research AB OBJECTIVE: To determine if the combined effects of patient-level (demographic and clinical characteristics) and organizational-level (structure and strategies to improve access) factors are uniformly associated with utilization of Indian Health Service (IHS) and/or Veterans Health Administration (VHA) by American Indian and Alaska Native (AIAN) Veterans to inform policy which promotes dual use. METHODS: We estimated correlates and compared two separate multilevel logistic regression models of VHA-IHS dual versus IHS-only and VHA-IHS dual versus VHA-only in a sample of 18,892 AIAN Veterans receiving care at 201 VHA and IHS facilities during FY02 and FY03. Demographic, diagnostic, eligibility, and utilization data were drawn from administrative records. A survey of VHA and IHS facilities defined availability of services and strategies to enhance access to healthcare for AIAN Veterans. RESULTS: Facility level strategies that are generally associated with enhancing access to healthcare (e. g., population-based services and programs, transportation or co-location) were not significant factors associated with dual use. In both models the common variable of dual use was related to medical need, defined as the number of diagnoses per patient. Other significant demographic, medical need and organizational factors operated in opposing manners. For instance, age increased the likelihood of dual use versus IHS-only but decreased the likelihood of dual use versus VHA-only. CONCLUSIONS: Efforts to enhance access through population-based and consumer-driven strategies may add value but be less important to utilization than availability of healthcare resources needed by this population. Sharing health records and co-management strategies would improve quality of care while policies allow and promote dual use. C1 [Kramer, B. Josea; Jouldjian, Stella; Saliba, Debra] VA Greater Los Angeles Healthcare Syst, Geriatr Res Educ Clin Ctr, Sepulveda, CA 91343 USA. [Kramer, B. Josea; Saliba, Debra] Univ Calif Los Angeles, David Geffen Sch Med, Div Geriatr Med, Los Angeles, CA 90095 USA. [Wang, Mingming; Mitchell, Michael N.; Saliba, Debra] VA Greater Los Angeles Healthcare Syst, Hlth Serv Res Ctr Excellence, Sepulveda, CA USA. [Dang, Jeff] Consulting Measurement Grp Inc, Torrance, CA USA. [Finke, Bruce] Indian Hlth Serv, Nashville, TN USA. [Saliba, Debra] Univ Calif Los Angeles, Jewish Home Borun Ctr Gerontol Res, Los Angeles, CA USA. [Saliba, Debra] RAND Corp, Santa Monica, CA USA. RP Kramer, BJ (reprint author), VA Greater Los Angeles Healthcare Syst, Geriatr Res Educ Clin Ctr, 16111 Plummer St 11E, Sepulveda, CA 91343 USA. EM Josea.Kramer@va.gov FU VA Health Services Research and Development [ACC 03-304] FX This research was supported by a grant from the VA Health Services Research and Development, ACC 03-304. This report presents findings and conclusions of the authors; it does not necessarily reflect the opinions or policies of the Department of Veterans Affairs or the Indian Health Service. An earlier version of this paper was presented in a paper session at the Gerontological Society of America, annual scientific meetings in New Orleans, November 2010. NR 23 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 SU 2 BP S662 EP S668 DI 10.1007/s11606-011-1834-2 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA V30JP UT WOS:000208812600008 PM 21989619 ER PT J AU Pizer, SD Prentice, JC AF Pizer, Steven D. Prentice, Julia C. TI What Are the Consequences of Waiting for Health Care in the Veteran Population? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE wait times; health outcomes; chronic conditions; health care utilization; VA ID MEDICAL-CARE; MANAGEMENT; ACCESS; STRATEGIES; INSURANCE; MORTALITY; OUTCOMES; QUALITY; DISEASE; PEOPLE AB National health reform is expected to increase how long individuals have to wait between requests for appointments and when their appointment is scheduled. The increase in demand for care due to more widespread insurance will result in longer waits if there is not also a concomitant increase in supply of healthcare services. Long waits for healthcare are hypothesized to compromise health because less frequent outpatient visits result in delays in diagnosis and treatment. Research testing this hypothesis is scarce due to a paucity of data on how long individuals wait for healthcare in the United States. The main exception is the Veterans Health Administration (VA) that has been routinely collecting data on how long veterans wait for outpatient care for over a decade. This narrative review summarizes the results of studies using VA wait time data to answer two main questions: 1) How much do longer wait times decrease healthcare utilization and 2) Do longer wait times cause poorer health outcomes? Longer VA wait times lead to small, yet statistically significant decreases in utilization and are related to poorer health in elderly and vulnerable veteran populations. Both long-term outcomes (e. g. mortality, preventable hospitalizations) and intermediate outcomes such as hemoglobin A1C levels are worse for veterans who seek care at facilities with longer waits compared to veterans who visit facilities with shorter waits. Further research is needed on the mechanisms connecting longer wait times and poorer outcomes including identifying patient sub-populations whose risks are most sensitive to delayed access to care. If wait times increase for the general patient population with the implementation of national reform as expected, U.S. healthcare policymakers and clinicians will need to consider policies and interventions that minimize potential harms for all patients. C1 [Pizer, Steven D.; Prentice, Julia C.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02130 USA. RP Pizer, SD (reprint author), Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, VA Boston Hlth Care Syst, 150 South Huntington Ave,Mail Stop 152H, Boston, MA 02130 USA. EM pizer@bu.edu FU Health Services Research and Development Service, Department of Veterans Affairs [IAD-06-112, IIR 04-233]; Health Care Financing and Organization Initiative under the Robert Wood Johnson Foundation [62967] FX Funding for this research was provided by Grant No: IAD-06-112 and IIR 04-233 from the Health Services Research and Development Service, Department of Veterans Affairs and Grant No: 62967 from the Health Care Financing and Organization Initiative under the Robert Wood Johnson Foundation. Neither author has any conflicts of interest to report. The authors are indebted to Matthew Neuman and John Gardner for programming support. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. This research was approved by the VA Boston Health Care System institutional review board. NR 40 TC 9 Z9 9 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 SU 2 BP S676 EP S682 DI 10.1007/s11606-011-1819-1 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA V30JP UT WOS:000208812600010 PM 21989621 ER PT J AU Washington, DL Bean-Mayberry, B Riopelle, D Yano, EM AF Washington, Donna L. Bean-Mayberry, Bevanne Riopelle, Deborah Yano, Elizabeth M. TI Access to Care for Women Veterans: Delayed Healthcare and Unmet Need SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE access to care; women veterans; VA healthcare; health services need; health services utilization AB BACKGROUND: Timely access to healthcare is essential to ensuring optimal health outcomes, and not surprisingly, is at the heart of healthcare reform efforts. While the Veterans Health Administration (VA) has made improved access a priority, women veterans still under-utilize VA healthcare relative to men. Eliminating access disparities requires a better understanding of the barriers to care that women veterans' experience. OBJECTIVE: We examined the association of general and veteran-specific barriers on access to healthcare among women veterans. DESIGN AND PARTICIPANTS: Cross-sectional, population-based national telephone survey of 3,611 women veterans. MAIN MEASURE: Delayed healthcare or unmet healthcare need in the prior 12 months. KEY RESULTS: Of women veterans, 19% had delayed healthcare or unmet need, with higher rates in younger age groups (36%, 29%, 16%, 7%, respectively, in 18-34, 35-49, 50-64, and 65-plus age groups; p<0.001). Among those delaying or going without care, barriers that varied by age group were: unaffordable healthcare (63% of 18-34 versus 12% of 65-plus age groups); inability to take off from work (39% of those <50); and transportation difficulties (36% of 65-plus). Controlling for age, race/ethnicity, regular source of care, and health status, being uninsured (OR=6.5; confidence interval [CI] 3.0-14.0), knowledge gaps about VA care (OR=2.1; 95% CI 1.1-4.0), perception that VA providers are not gender-sensitive (OR=2.4; CI 1.2-4.7), and military sexual assault history (OR=2.1; CI 1.1-4.0) predicted delaying or foregoing care, whereas VA use and enrollment priority did not. CONCLUSIONS: Both general and veteran-specific factors impact women veterans' access to needed services. Many of the identified access barriers are potentially modifiable through expanded VA healthcare and social services. Health reform efforts should address these barriers for VA nonusers. Efforts are also warranted to improve women veterans' knowledge of availability and affordability of VA healthcare, and to enhance the gender-sensitivity of this care. C1 [Washington, Donna L.; Bean-Mayberry, Bevanne; Riopelle, Deborah; Yano, Elizabeth M.] VA Greater Los Angeles Hlth Serv Res & Dev HSR &, Sepulveda, CA USA. [Washington, Donna L.; Bean-Mayberry, Bevanne] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Dept Hlth Serv, ServicesUCLA Sch Publ Hlth, Los Angeles, CA USA. [Washington, Donna L.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Washington, DL (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,111G, Los Angeles, CA 90073 USA. EM donna.washington@va.gov FU Department of Veterans Affairs (VA) Office of Public Health and Environmental Hazards, Women Veterans Health Strategic Healthcare Group; VA Health Services Research and Development (HSRD) Service [SDR-08-270]; VA HSR&D Research Career Scientist award [RCS-05-195]; VA HSR&D Research Career Development Transition award [RCD 02-039] FX This study was funded by the Department of Veterans Affairs (VA) Office of Public Health and Environmental Hazards, Women Veterans Health Strategic Healthcare Group, and the VA Health Services Research and Development (HSR&D) Service (#SDR-08-270). Dr. Yano is supported by a VA HSR&D Research Career Scientist award (#RCS-05-195). Dr. Bean-Mayberry was supported by a VA HSR&D Research Career Development Transition award (#RCD 02-039) during this study. Dr. Washington 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. The authors gratefully acknowledge Mark Canning for project management, Julia Yosef, MA for assistance with survey fieldwork, Su Sun, MPH for assistance with data management, and Michael Mitchell, PhD, for statistical assistance. The views expressed within are solely those of the authors, and do not necessarily represent the views of the Department of Veterans Affairs or the United States government. NR 30 TC 51 Z9 51 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 SU 2 BP S655 EP S661 DI 10.1007/s11606-011-1772-z PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA V30JP UT WOS:000208812600007 PM 21989618 ER PT J AU Dahlin, CM Mazanec, P AF Dahlin, Constance M. Mazanec, Polly TI Building From Our Past Celebrating 25 Years of Clinical Practice in Hospice and Palliative Nursing SO JOURNAL OF HOSPICE & PALLIATIVE NURSING LA English DT Article DE 25 years; clinical practice; hospice and palliative nursing AB Nursing has been leading the way to improve and advance care of patients struggling with life-limiting illnesses since hospice began. The growth and development of clinical hospice and palliative care nursing practice over the past 25 years have been tremendous. This article reviews the powerful legacy of hospice and palliative care, from the early beginnings in Connecticut, caring for patients with terminal cancer, to the development of palliative care nursing. Nurses have been meeting the needs of those with life-limiting illnesses and advocating for better care for patients and families by working at the bedside, working collaboratively within teams, developing practice guidelines, and shaping healthcare for those nearing end of life. C1 [Dahlin, Constance M.] Massachusetts Gen Hosp, Palliat Care Serv, Boston, MA 02114 USA. [Mazanec, Polly] Case Western Reserve Univ, Frances Payne Bolton Sch Nursing, Cleveland, OH 44106 USA. [Mazanec, Polly] Univ Hosp Seidman Canc Ctr, Cleveland, OH USA. RP Dahlin, CM (reprint author), 949 Hale St, Beverly, MA 01915 USA. EM cdahlin@partners.org NR 52 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1522-2179 EI 1539-0705 J9 J HOSP PALLIAT NURS JI J. Hosp. Palliat. Nurs. PD NOV-DEC PY 2011 VL 13 SU 6 BP S20 EP S28 DI 10.1097/NJH.0b013e3182331016 PG 9 WC Nursing SC Nursing GA V34HE UT WOS:000209076700003 ER PT J AU McAndrew, EG Dugast, AS Licht, AF Eusebio, JR Alter, G Ackerman, ME AF McAndrew, Elizabeth G. Dugast, Anne-Sophie Licht, Anna F. Eusebio, Justin R. Alter, Galit Ackerman, Margaret E. TI Determining the Phagocytic Activity of Clinical Antibody Samples SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 57; Phagocytosis; Antibody; ADCC; Effector Function; Fc receptor; antibody-dependent phagocytosis; monocytes AB Antibody-driven phagocytosis is induced via the engagement of Fc receptors on professional phagocytes, and can contribute to both clearance as well as pathology of disease. While the properties of the variable domains of antibodies have long been considered critical to in vivo function, the ability of antibodies to recruit innate immune cells via their Fc domains has become increasingly appreciated as a major factor in their efficacy, both in the setting of recombinant monoclonal antibody therapy, as well as in the course of natural infection or vaccination(1-3). Importantly, despite its nomenclature as a constant domain, the antibody Fc domain does not have constant function, and is strongly modulated by IgG subclass (IgG1-4) and glycosylation at Asparagine 297(4-6). Thus, this method to study functional differences of antigen-specific antibodies in clinical samples will facilitate correlation of the phagocytic potential of antibodies to disease state, susceptibility to infection, progression, or clinical outcome. Furthermore, this effector function is particularly important in light of the documented ability of antibodies to enhance infection by providing pathogens access into host cells via Fc receptor-driven phagocytosis(7). Additionally, there is some evidence that phagocytic uptake of immune complexes can impact the Th1/Th2 polarization of the immune response(8). Here, we describe an assay designed to detect differences in antibody-induced phagocytosis, which may be caused by differential IgG subclass, glycan structure at Asn297, as well as the ability to form immune complexes of antigen-specific antibodies in a high-throughput fashion. To this end, 1 mu m fluorescent beads are coated with antigen, then incubated with clinical antibody samples, generating fluorescent antigen specific immune complexes. These antibody-opsonized beads are then incubated with a monocytic cell line expressing multiple Fc gamma Rs, including both inhibitory and activating. Assay output can include phagocytic activity, cytokine secretion, and patterns of Fc gamma Rs usage, and are determined in a standardized manner, making this a highly useful system for parsing differences in this antibody-dependent effector function in both infection and vaccine-mediated protection(9). C1 [McAndrew, Elizabeth G.; Dugast, Anne-Sophie; Licht, Anna F.; Eusebio, Justin R.; Alter, Galit] Ragon Inst MGH MIT & Harvard, Massachusetts Gen Hosp, Cambridge, MA USA. [Ackerman, Margaret E.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. RP Ackerman, ME (reprint author), Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. EM margaret.e.ackerman@dartmouth.edu RI Dugast, AnneSophie/L-9541-2015 FU NIH [3R01AI080289-02S1]; Harvard University Center for AIDS Research Scholar Fellowship under NIH/NIAID [2P30AI060354-07] FX The authors wish to acknowledge funding from NIH 3R01AI080289-02S1, and a Harvard University Center for AIDS Research Scholar Fellowship under NIH/NIAID 2P30AI060354-07. NR 18 TC 4 Z9 4 U1 0 U2 0 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD NOV PY 2011 IS 57 AR UNSP e3588 DI 10.3791/3588 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36OZ UT WOS:000209222200047 PM 22143444 ER PT J AU Parsons, XH Teng, YD Parsons, JF Snyder, EY Smotrich, DB Moore, DA AF Parsons, Xuejun H. Teng, Yang D. Parsons, James F. Snyder, Evan Y. Smotrich, David B. Moore, Dennis A. TI Efficient Derivation of Human Cardiac Precursors and Cardiomyocytes from Pluripotent Human Embryonic Stem Cells with Small Molecule Induction SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Developmental Biology; Issue 57; human embryonic stem cell; human; cardiac progenitor; cardiomyocytes; human pluripotent cell; cardiac differentiation; small molecule induction; cell culture; cell therapy AB To date, the lack of a suitable human cardiac cell source has been the major setback in regenerating the human myocardium, either by cell-based transplantation or by cardiac tissue engineering(1-3). Cardiomyocytes become terminally-differentiated soon after birth and lose their ability to proliferate. There is no evidence that stem/progenitor cells derived from other sources, such as the bone marrow or the cord blood, are able to give rise to the contractile heart muscle cells following transplantation into the heart(1-3). The need to regenerate or repair the damaged heart muscle has not been met by adult stem cell therapy, either endogenous or via cell delivery(1-3). The genetically stable human embryonic stem cells hESCs) have unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of large supplies of human somatic cells that are restricted to the lineage in need of repair and regeneration(4,5). Due to the prevalence of cardiovascular disease worldwide and acute shortage of donor organs, there is intense interest in developing hESC-based therapies as an alternative approach. However, how to channel the wide differentiation potential of pluripotent hESCs efficiently and predictably to a desired phenotype has been a major challenge for both developmental study and clinical translation. Conventional approaches rely on multi-lineage inclination of pluripotent cells through spontaneous germ layer differentiation, resulting in inefficient and uncontrollable lineage-commitment that is often followed by phenotypic heterogeneity and instability, hence, a high risk of tumorigenicity(6-8) see a schematic in Fig. 1A). In addition, undefined foreign/animal biological supplements and/or feeders that have typically been used for the isolation, expansion, and differentiation of hESCs may make direct use of such cell-specialized grafts in patients problematic(9-11). To overcome these obstacles, we have resolved the elements of a defined culture system necessary and sufficient for sustaining the epiblast pluripotence of hESCs, serving as a platform for de novo derivation of clinically-suitable hESCs and effectively directing such hESCs uniformly towards clinically-relevant lineages by small molecules(12) see a schematic in Fig. 1B). After screening a variety of small molecules and growth factors, we found that such defined conditions rendered nicotinamide (NAM) sufficient to induce the specification of cardiomesoderm direct from pluripotent hESCs that further progressed to cardioblasts that generated human beating cardiomyocytes with high efficiency Fig. 2). We defined conditions for induction of cardioblasts direct from pluripotent hESCs without an intervening multi-lineage embryoid body stage, enabling well-controlled efficient derivation of a large supply of human cardiac cells across the spectrum of developmental stages for cell-based therapeutics. C1 [Parsons, Xuejun H.; Parsons, James F.; Snyder, Evan Y.; Smotrich, David B.; Moore, Dennis A.] San Diego Regenerat Med Inst, San Diego, CA 92109 USA. [Parsons, Xuejun H.; Parsons, James F.; Snyder, Evan Y.; Smotrich, David B.; Moore, Dennis A.] Xcelthera, San Diego, CA USA. [Teng, Yang D.] Harvard Univ, Sch Med, Dept Neurosurg, Cambridge, MA 02138 USA. [Teng, Yang D.] VA Boston Healthcare Syst, Div SCI Res, Boston, MA USA. [Snyder, Evan Y.] Sanford Burnham Med Res Inst, Program Stem Cell & Regenerat Biol, La Jolla, CA USA. [Smotrich, David B.] La Jolla IVF, La Jolla, CA USA. RP Parsons, XH (reprint author), San Diego Regenerat Med Inst, San Diego, CA 92109 USA. EM parsons@SDRMI.org FU National Institute of Health (NIH); National Institute on Aging [NIHK01AG024496]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [NIHR21HD056530] FX XHP has been supported by National Institute of Health (NIH) grants from National Institute on Aging (NIHK01AG024496) and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIHR21HD056530). NR 23 TC 2 Z9 2 U1 0 U2 1 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD NOV PY 2011 IS 57 AR UNSP e3274 DI 10.3791/3274 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36OZ UT WOS:000209222200019 PM 22083019 ER PT J AU Ficarro, SB Zhang, Y Carrasco-Alfonso, MJ Garg, B Adelmant, G Webber, JT Luckey, CJ Marto, JA AF Ficarro, Scott B. Zhang, Yi Carrasco-Alfonso, Marlene J. Garg, Brijesh Adelmant, Guillaume Webber, James T. Luckey, C. John Marto, Jarrod A. TI Online Nanoflow Multidimensional Fractionation for High Efficiency Phosphopeptide Analysis SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID IONIZATION MASS-SPECTROMETRY; PERFORMANCE LIQUID-CHROMATOGRAPHY; HYDROPHILIC INTERACTION CHROMATOGRAPHY; EMBRYONIC STEM-CELLS; LARGE-SCALE ANALYSIS; PROTEIN IDENTIFICATION TECHNOLOGY; CHRONIC MYELOGENOUS LEUKEMIA; ION AFFINITY-CHROMATOGRAPHY; ACUTE MYELOID-LEUKEMIA; PHOSPHOPROTEOME ANALYSIS AB Despite intense, continued interest in global analyses of signaling cascades through mass spectrometry-based studies, the large-scale, systematic production of phosphoproteomics data has been hampered in-part by inefficient fractionation strategies subsequent to phosphopeptide enrichment. Here we explore two novel multidimensional fractionation strategies for analysis of phosphopeptides. In the first technique we utilize aliphatic ion pairing agents to improve retention of phosphopeptides at high pH in the first dimension of a two-dimensional RP-RP. The second approach is based on the addition of strong anion exchange as the second dimension in a three-dimensional reversed phase RP)-strong anion exchange (SAX)-RP configuration. Both techniques provide for automated, online data acquisition, with the 3-D platform providing the highest performance both in terms of separation peak capacity and the number of unique phosphopeptide sequences identified per mu g of cell lysate consumed. Our integrated RP-SAX-RP platform provides several analytical figures of merit, including: 1) orthogonal separation mechanisms in each dimension; 2) high separation peak capacity 3) efficient retention of singly-and multiply-phosphorylated peptides; 4) compatibility with automated, online LC-MS analysis. We demonstrate the reproducibility of RP-SAX-RP and apply it to the analysis of phosphopeptides derived from multiple biological contexts, including an in vitro model of acute myeloid leukemia in addition to primary polyclonal CD8(+) T-cells activated in vivo through bacterial infection and then purified from a single mouse. Molecular & Cellular Proteomics 10: 10.1074/mcp.O111.011064, 1-19, 2011. C1 [Ficarro, Scott B.; Zhang, Yi; Garg, Brijesh; Adelmant, Guillaume; Webber, James T.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ficarro, Scott B.; Zhang, Yi; Garg, Brijesh; Adelmant, Guillaume; Webber, James T.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Ficarro, Scott B.; Zhang, Yi; Adelmant, Guillaume; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Carrasco-Alfonso, Marlene J.; Luckey, C. John] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Marto, JA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St,Smith 1158A, Boston, MA 02115 USA. EM jarrod_marto@dfci.harvard.edu OI Webber, James/0000-0001-8594-9888 FU Brigham & Women's Hospital; Dana-Farber Cancer Institute; National Institutes of Health; NHGRI [P50HG004233]; NINDS [P01NS047572] FX This work was supported by the Brigham & Women's Hospital, the Dana-Farber Cancer Institute, and the National Institutes of Health, NHGRI (P50HG004233), and NINDS (P01NS047572). NR 124 TC 10 Z9 10 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD NOV PY 2011 VL 10 IS 11 AR O111.011064 DI 10.1074/mcp.O111.011064 PG 19 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 844PK UT WOS:000296759400018 PM 21788404 ER PT J AU Brown, JK Cooley, ME Chernecky, C Sarna, L AF Brown, Jean K. Cooley, Mary E. Chernecky, Cynthia Sarna, Linda TI A Symptom Cluster and Sentinel Symptom Experienced by Women With Lung Cancer SO ONCOLOGY NURSING FORUM LA English DT Article AB Purpose/Objectives: To determine the symptom experience and a sentinel symptom and to describe the relationship of participant characteristics with symptom clusters. Design: Prospective, correlational study. Setting: Clinical sites in five U.S. states. Sample: 196 women six months to five years after non-small cell lung cancer diagnosis. Methods: Symptoms were measured during the past day and past four weeks. Symptom clusters were described using a novel dummy coding approach. Main Research Variables: Symptom occurrence and severity, demographic and clinical characteristics, health status factors, and meaning of illness. Findings: About 98% of women experienced three or more symptoms in the past day. The most common symptoms reported by more than 80% of the women were fatigue, shortness of breath, anorexia, cough, and pain, with fatigue and shortness of breath rated as most severe. Sleep problems, concentration problems, and weight loss also were reported during the past four weeks. A five-symptom cluster including fatigue, shortness of breath, cough, pain, and anorexia was reported by 64% of women. Pain was identified as a sentinel symptom for that cluster. Conclusions: Most women experienced at least three symptoms in the past day, and a five-symptom cluster occurred frequently and continued post-treatment. Implications for Nursing: Women who participated in the study were, on average, two years postdiagnosis, but most experienced three or more symptoms well past treatment; therefore, vigilant ongoing clinical assessment of these women is essential. A co-occurring sentinel symptom used as a clinical indicator for the presence of a symptom cluster may be useful for clinical assessment. C1 [Brown, Jean K.] SUNY Buffalo, Sch Nursing, Buffalo, NY 14260 USA. [Cooley, Mary E.] Dana Farber Canc Inst, Ctr Res Nursing & Patient Care Serv, Boston, MA 02115 USA. [Chernecky, Cynthia] Med Coll Georgia, Sch Nursing, Augusta, GA 30912 USA. [Sarna, Linda] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. RP Brown, JK (reprint author), SUNY Buffalo, Sch Nursing, Buffalo, NY 14260 USA. EM jebrown@buffalo.edu FU ONS Foundation from Ortho Biotech, Inc. [018652] FX Jean K. Brown, PhD, RN, FAAN, is a professor emeritus in the School of Nursing at the University at Buffalo, the State University of New York; Mary E. Cooley, PhD, RN, is a nurse scientist in the Phyllis F. Cantor Center for Research in Nursing and Patient Care Services at Dana-Farber Cancer Institute in Boston, MA; Cynthia Chernecky, PhD, RN, FAAN, is a professor in the School of Nursing at the Medical College of Georgia in Augusta; and Linda Sarna, DNSc, RN, FAAN, is a professor and the Lulu Wolf-Hassenplug Endowed Chair in Nursing in the School of Nursing at the University of California, Los Angeles. This research was funded by the ONS Foundation through an unrestricted grant from Ortho Biotech, Inc. (#018652). Brown can be reached at jebrown@buffalo.edu, with copy to editor at ONFEditor@ons.org. (Submitted March 2009. Accepted for publication December 3, 2010.) NR 47 TC 19 Z9 19 U1 3 U2 3 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X EI 1538-0688 J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2011 VL 38 IS 6 BP E425 EP E435 DI 10.1188/11.ONF.E425-E435 PG 11 WC Oncology; Nursing SC Oncology; Nursing GA V35IY UT WOS:000209144600005 PM 22037342 ER PT J AU Patel, A Borkar, J Badhoniya, N Pusdekar, Y Hibberd, P AF Patel, A. Borkar, J. Badhoniya, N. Pusdekar, Y. Hibberd, P. TI USE OF BIOMASS FUEL FOR HOUSEHOLD COOKING IS ASSOCIATED WITH NEONATAL MORTALITY IN INDIA SO PEDIATRIC RESEARCH LA English DT Meeting Abstract C1 [Patel, A.] Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Patel, A.; Borkar, J.; Badhoniya, N.; Pusdekar, Y.] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Hibberd, P.] Massachusetts Gen Hosp, Div Global Hlth, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD NOV PY 2011 VL 70 SU 5 MA 051 BP 51 EP 51 DI 10.1038/pr.2011.276 PG 1 WC Pediatrics SC Pediatrics GA V31FS UT WOS:000208870100052 ER PT J AU Sinha, B Balahara, B Fujii, A Ringer, SA AF Sinha, B. Balahara, B. Fujii, A. Ringer, S. A. TI PATENT DUCTUS ARTERIOSUS LIGATION IN PREMATURE INFANTS: UNPROVEN LONG TERM BENEFIT AT THE COST OF SHORT TERM MORBIDITIES? SO PEDIATRIC RESEARCH LA English DT Meeting Abstract C1 [Sinha, B.; Fujii, A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Sinha, B.; Ringer, S. A.] Harvard Univ, Sch Med, Boston, MA USA. [Balahara, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ringer, S. A.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0031-3998 EI 1530-0447 J9 PEDIATR RES JI Pediatr. Res. PD NOV PY 2011 VL 70 SU 5 MA 280 BP 280 EP 280 DI 10.1038/pr.2011.505 PG 1 WC Pediatrics SC Pediatrics GA V31FS UT WOS:000208870100281 ER PT J AU Khodyakov, D Stockdale, S Jones, F Ohito, E Jones, A Lizaola, E Mango, J AF Khodyakov, Dmitry Stockdale, Susan Jones, Felica Ohito, Elizabeth Jones, Andrea Lizaola, Elizabeth Mango, Joseph TI An Exploration of the Effect of Community Engagement in Research on Perceived Outcomes of Partnered Mental Health Services Projects SO SOCIETY AND MENTAL HEALTH LA English DT Article DE CBPR; community-based mental health; mental health; community engagement in research; community-academic partnerships AB Mental health research projects address sensitive issues for vulnerable populations and are implemented in complex environments. Community-based participatory research approaches are recommended for health research on vulnerable populations, but little is known about how variation in participation affects outcomes of partnered research projects. We developed a conceptual model demonstrating the impact of community engagement in research on outcomes of partnered projects. We collected data on key constructs from community and academic leaders of 21 sampled partnered research projects in two cycles of a research center funded by the National Institute of Mental Health. We conducted empirical analyses to test the model. Our findings suggest that community engagement in research is positively associated with perceived professional development as well as political and community impact. C1 [Khodyakov, Dmitry] RAND Corp, Santa Monica, CA 90407 USA. [Stockdale, Susan] US Dept Vet Affairs, Los Angeles, CA USA. [Stockdale, Susan; Lizaola, Elizabeth; Mango, Joseph] Univ Calif Los Angeles, Los Angeles, CA USA. [Jones, Felica; Jones, Andrea] Hlth African Amer Families, Los Angeles, CA USA. [Ohito, Elizabeth] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Jones, Andrea] Charles Drew Univ Med & Sci, Los Angeles, CA USA. RP Khodyakov, D (reprint author), RAND Corp, 1776 Main St,POB 2138, Santa Monica, CA 90407 USA. EM dkhodyak@rand.org FU NIMH NIH HHS [P30 MH068639-05, P30 MH082760, P30 MH082760-01, P30 MH068639] NR 45 TC 11 Z9 11 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2156-8693 EI 2156-8731 J9 SOC MENT HEALTH JI Soc. Ment. Health PD NOV PY 2011 VL 1 IS 3 BP 185 EP 199 DI 10.1177/2156869311431613 PG 15 WC Sociology SC Sociology GA V36AA UT WOS:000209184800004 PM 22582144 ER PT J AU Guanci, MM AF Guanci, Mary McKenna TI In order to maintain normothermia in a neuro patient what options can be used besides connecting them to a temperature machine? SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Guanci, MM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD NOV 1 PY 2011 VL 1 IS 3 BP 169 EP 170 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA V38QI UT WOS:000209357500009 ER PT J AU Li, M Dickinson, CE Finkelstein, EB Neville, CM Sundback, CA AF Li, Mei Dickinson, Caitlyn E. Finkelstein, Eric B. Neville, Craig M. Sundback, Cathryn A. TI The Role of Fibroblasts in Self-Assembled Skeletal Muscle SO TISSUE ENGINEERING PART A LA English DT Article ID IN-VITRO; BASEMENT-MEMBRANE; CELL-CULTURES; BASAL LAMINA; COLLAGEN; MYOSIN; MYOTUBES; STIMULATION; FIBRONECTIN; MYOGENESIS AB Small facial skeletal muscles often have no autologous donor source to effect surgical reconstruction. Autologously derived muscles could be engineered for replacement tissue, but must be vascularized and innervated to be functional. As a critical step, engineered muscle must mimic the morphology, protein and gene expression, and function of native muscle. This study utilized a self-assembly process to engineer three-dimensional (3D) muscle from a statically strained muscle cell monolayer. Primary mouse myoblasts (PMMs) and mouse embryonic fibroblasts (MEFs) were separately proliferated and coseeded on a fibrin sheet with anchored sutures. Within 10 days of initiating PMM differentiation, the cell-gel layer contracted, lifted, and rolled into a cylindrical 3D structure around the tendon-like suture anchors; the myotubes longitudinally aligned along the lines of tensile force. The objectives of this study were to characterize these engineered muscles and to elucidate the role of the fibroblasts in the self-assembly process. Fibroblasts maintained myotube viability, mediated fibrin degradation, and assisted in muscle self-assembly. The optimal 1: 1 PMM:MEF ratio resulted in tissue morphology remarkably similar to native muscle. Through gene and protein expression assays, the development and maturation of the engineered muscle tissue was demonstrated to recapitulate normal skeletal muscle development. C1 [Li, Mei; Dickinson, Caitlyn E.; Finkelstein, Eric B.; Neville, Craig M.; Sundback, Cathryn A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Finkelstein, Eric B.; Neville, Craig M.; Sundback, Cathryn A.] Harvard Univ, Sch Med, Boston, MA USA. RP Sundback, CA (reprint author), Massachusetts Gen Hosp, Dept Surg, CPZN 4809,185 Cambridge St, Boston, MA 02114 USA. EM csundback@partners.org FU Center for Military Biomaterials Research [W81XWH-04-2-0031]; U.S. Army Telemedicine and Advanced Technology Research Center; Armed Forces Institute of Regenerative Medicine [W81XWH-08-2-0034]; U.S. Army Medical Research Acquisition Activity; administering acquisition office FX This research was sponsored by the Center for Military Biomaterials Research award number W81XWH-04-2-0031 funded by the U.S. Army Telemedicine and Advanced Technology Research Center. This work was also sponsored by the Armed Forces Institute of Regenerative Medicine award number W81XWH-08-2-0034; the U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014, is the awarding and administering acquisition office. The content of the article does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. NR 47 TC 13 Z9 13 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD NOV PY 2011 VL 17 IS 21-22 BP 2641 EP 2650 DI 10.1089/ten.tea.2010.0700 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 842SD UT WOS:000296619500006 PM 21657983 ER PT J AU Haas, JS Liang, SY Hassett, MJ Shiboski, S Elkin, EB Phillips, KA AF Haas, Jennifer S. Liang, Su-Ying Hassett, Michael J. Shiboski, Stephen Elkin, Elena B. Phillips, Kathryn A. TI Gene expression profile testing for breast cancer and the use of chemotherapy, serious adverse effects, and costs of care SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Utilization; Genomics ID RECURRENCE SCORE ASSAY; RT-PCR ASSAY; ECONOMIC-IMPLICATIONS; TREATMENT SELECTION; PROPENSITY SCORE; THERAPY; RISK; MULTICENTER; SURVIVAL; IMPACT AB As gene expression profile (GEP) testing for breast cancer may provide additional prognostic information to guide the use of adjuvant chemotherapy, we examined the association between GEP testing and use of chemotherapy, serious chemotherapy-related adverse effects, and total charges during the 12 months following diagnosis. Medical record review was conducted for women age 30-64 years, with incident, non-metastatic, invasive breast cancer diagnosed 2006-2008 in a large, national health plan. Of 534 patients, 25.8% received GEP testing, 68.2% received chemotherapy, and 10.5% experienced a serious chemotherapy-related adverse effect. GEP testing was most commonly used in women at moderate clinical risk of recurrence (52.0 vs. 25.0% of low-risk women and 5.5% of high-risk). Controlling for the propensity to receive GEP testing, women who had GEP were less likely to receive chemotherapy (propensity adjusted odds ratio, 95% confidence interval 0.62, 0.39-0.99). Use of GEP was associated with more chemotherapy use among women at low risk based on clinical characteristics (OR = 42.19; CI 2.50-711.82), but less use among women with a high risk based on clinical characteristics (OR = 0.12; CI 0.03-0.47). Use of GEP was not associated with chemotherapy for the moderate risk group. There was no significant relationship between GEP use and either serious chemotherapy-associated adverse effects or total charges. While GEP testing was associated with an overall decrease in adjuvant chemotherapy, we did not find differences in serious chemotherapy-associated adverse events or charges during the 12 months following diagnosis. C1 [Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02120 USA. [Liang, Su-Ying; Shiboski, Stephen; Phillips, Kathryn A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hassett, Michael J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Elkin, Elena B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Haas, JS (reprint author), Brigham & Womens Hosp, Div Gen Med & Primary Care, 1620 Tremont St, Boston, MA 02120 USA. EM jhaas@partners.org FU National Cancer Institute [P01CA130818]; Aetna Foundation FX The study was supported by a grant from the National Cancer Institute (P01CA130818). Drs. Haas, Phillips, and Liang received funding from a research grant from the Aetna Foundation for earlier related research. NR 34 TC 7 Z9 7 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2011 VL 130 IS 2 BP 619 EP 626 DI 10.1007/s10549-011-1628-6 PG 8 WC Oncology SC Oncology GA 830RY UT WOS:000295675700026 PM 21681446 ER PT J AU Holmes, MD Chen, WY Schnitt, SJ Collins, L Colditz, GA Hankinson, SE Tamimi, RM AF Holmes, Michelle D. Chen, Wendy Y. Schnitt, Stuart J. Collins, Laura Colditz, Graham A. Hankinson, Susan E. Tamimi, Rulla M. TI COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast neoplasms; Cyclooxygenase-2; Tumor markers; Prognosis; Survival; Aspirin ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CYCLOOXYGENASE-2 EXPRESSION; TISSUE MICROARRAY; SURVIVAL; RISK; OVEREXPRESSION; CARCINOMA; DIAGNOSIS; WOMEN AB Some previous studies have found worse prognosis among cyclooxygenase-2 (COX-2)-expressing breast cancers. Aspirin and NSAIDs inhibit COX-2. Three studies, including ours, have reported a survival advantage among women with breast cancer who take either aspirin or NSAIDs. Through this study we hypothesized that in the Nurses' Health Study (NHS), COX-2 expression would be associated with worse prognosis, and aspirin use would be associated with better survival particularly among women with COX-2 positive tumors. In this study we investigated 2,001 women presenting with invasive breast cancers stained for COX-2 by immunohistochemistry. Tumor prognostic factors were from medical records. Aspirin use was assessed at least 12 months after diagnosis and updated. Cause of death was identified from death certificates. Statistical analyses included logistic regression of prognostic factors with COX-2 status as the outcome, and proportional hazards regression with breast cancer death as the outcome. Tumor COX-2 expression was associated with higher diagnostic stage. Compared with stage I, the RR(95% CI) for stages II-IV were 1.16 (0.93-1.45), 1.68 (1.27-2.22), and 1.76 (0.93-3.32). COX-2 expression was associated with lobular compared with ductal histology (1.40 [1.02-1.92]), and estrogen receptor positive compared with negative (2.22 [1.66-2.95]). The RR(95% CI) of breast cancer death for current aspirin use was similar for women with COX-2-positive and COX-2-negative tumors; 0.64 (0.43-0.96) and 0.57 (0.44-0.74), respectively. In the NHS, COX-2 breast cancer expression was associated with higher stage at diagnosis. The survival benefit associated with aspirin use did not differ by COX-2 status. COX-2 breast cancer expression is associated with worse prognosis. If aspirin truly impacts breast cancer survival, then it is not solely via COX-2. C1 [Holmes, Michelle D.; Chen, Wendy Y.; Hankinson, Susan E.; Tamimi, Rulla M.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Holmes, Michelle D.; Chen, Wendy Y.; Hankinson, Susan E.; Tamimi, Rulla M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Holmes, Michelle D.; Colditz, Graham A.; Hankinson, Susan E.; Tamimi, Rulla M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Schnitt, Stuart J.; Collins, Laura] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. RP Holmes, MD (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM michelle.holmes@channing.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU National Institutes of Health [CA87969]; Breast Cancer Research Fund; GlaxoSmithKline [WE234 [EPI40307]] FX This study was supported by the National Institutes of Health grant CA87969 and a grant from the Breast Cancer Research Fund and GlaxoSmithKline (WE234 [EPI40307]). NR 21 TC 40 Z9 41 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2011 VL 130 IS 2 BP 657 EP 662 DI 10.1007/s10549-011-1651-7 PG 6 WC Oncology SC Oncology GA 830RY UT WOS:000295675700030 PM 21728052 ER PT J AU Hoyer, D Boyko, E McNeely, M Leonetti, D Kahn, S Fujimoto, W AF Hoyer, D. Boyko, E. J. McNeely, M. J. Leonetti, D. L. Kahn, S. E. Fujimoto, W. Y. TI Subcutaneous thigh fat area is unrelated to risk of type 2 diabetes in a prospective study of Japanese Americans SO DIABETOLOGIA LA English DT Article DE Adiposity; Computed tomography; Diabetes mellitus; Epidemiology; Japanese American; Prospective study; Thigh circumference; Thigh subcutaneous fat; Visceral fat; Waist circumference ID ADIPOSE-TISSUE DISTRIBUTION; IMPAIRED GLUCOSE-TOLERANCE; BODY-FAT; POSTMENOPAUSAL WOMEN; INSULIN-RESISTANCE; MEN; OBESE; MASS; DYSLIPIDEMIA; ASSOCIATIONS AB Cross-sectional research has reported a negative association between subcutaneous thigh fat (STF) and type 2 diabetes prevalence but no prospective research on this association exists using direct measurements of STF obtained from imaging studies while adjusting for other fat depots. We studied the independent associations of intra-abdominal fat (IAF), subcutaneous abdominal fat (SAF) and STF with future risk of diabetes. We prospectively followed 489 non-diabetic Japanese Americans (BMI 25.0-29.9 kg/m(2) 32.7%, a parts per thousand yen30.0 kg/m(2) 5.4%) over 10 years for the development of diabetes defined by use of hypoglycaemic medication or a fasting plasma glucose a parts per thousand yen7.0 mmol/l or 2 h a parts per thousand yen11.1 mmol/l during an OGTT. STF, SAF and IAF area were measured by computed tomography scan and mid-thigh circumference (TC) by tape measure at baseline. Over 10 years, 103 people developed diabetes. STF area was not independently associated with the odds of developing diabetes in a univariate or multiple logistic regression model (OR for a 1 SD increase 0.8 [95% CI 0.5, 1.2]) adjusted for age, sex, BMI, IAF and SAF. The only fat depot associated with diabetes odds in this model was IAF. TC was borderline significantly associated with a lower odds of developing diabetes (0.7 [95% CI 0.5, 1.0], p = 0.052). Similar to other research, TC was negatively associated with diabetes risk, whereas STF was not, arguing that the negative association between TC and diabetes observed in other research is not due to STF mass. IAF area emerged as the only measured fat depot that was independently associated with type 2 diabetes risk. C1 [Boyko, E. J.; Kahn, S. E.] VA Puget Sound Hlth Care Syst, Seattle, WA 98101 USA. [Hoyer, D.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Boyko, E. J.; McNeely, M. J.; Kahn, S. E.; Fujimoto, W. Y.] Univ Washington, Dept Med, Seattle, WA USA. [Leonetti, D. L.] Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. RP Boyko, E (reprint author), VA Puget Sound Hlth Care Syst, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM eboyko@uw.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health [DK-31170, HL-49293, DK-02654]; VA Puget Sound Health Care System FX This work was supported by National Institutes of Health Grants DK-31170, HL-49293 and DK-02654; by facilities and services provided by the Diabetes and Endocrinology Research Center (DK-17047), Clinical Nutrition Research Unit (DK-35816), and the General Clinical Research Center (RR-00037) at the University of Washington. VA Puget Sound Health Care System provided support for the involvement of E.J. Boyko and S.E. Kahn in this research. We are grateful to the King County Japanese-American community for their support and cooperation. NR 20 TC 7 Z9 7 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD NOV PY 2011 VL 54 IS 11 BP 2795 EP 2800 DI 10.1007/s00125-011-2275-5 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 830TJ UT WOS:000295679800008 PM 21837509 ER PT J AU Shetty, RS Gallagher, CS Chen, YT Hims, MM Mull, J Leyne, M Pickel, J Kwok, D Slaugenhaupt, SA AF Shetty, Ranjit S. Gallagher, Cary S. Chen, Yei-Tsung Hims, Matthew M. Mull, James Leyne, Maire Pickel, James Kwok, David Slaugenhaupt, Susan A. TI Specific correction of a splice defect in brain by nutritional supplementation SO HUMAN MOLECULAR GENETICS LA English DT Article ID B KINASE COMPLEX; FAMILIAL DYSAUTONOMIA; MESSENGER-RNA; ELONGATOR COMPLEX; TRANSCRIPTIONAL ELONGATION; DISEASE; IKBKAP; PROTEIN; GENE; EXPRESSION AB Recent studies emphasize the importance of mRNA splicing in human genetic disease, as 20-30% of all disease-causing mutations are predicted to result in mRNA splicing defects. The plasticity of the mRNA splicing reaction has made these mutations attractive candidates for the development of therapeutics. Familial dysautonomia (FD) is a severe neurodegenerative disorder, and all patients have an intronic IVS2016T>C splice site mutation in the IKBKAP gene, which results in tissue-specific skipping of exon 20 and a corresponding reduction in ikappaB kinase complex associated protein (IKAP) levels. We created transgenic mouse lines using a human IKBKAP bacterial artificial chromosome (BAC) into which we inserted the IKBKAP splice mutation (FD BAC) and have shown that the transgenic mice exhibit the same tissue-specific aberrant splicing patterns as seen in FD patients. We have previously demonstrated that the plant cytokinin kinetin can significantly improve the production of wild-type IKBKAP transcripts in FD lymphoblast cell lines by improving exon inclusion. In this study, we tested the ability of kinetin to alter IKBKAP splicing in the transgenic mice carrying the FD BAC and show that it corrects IKBKAP splicing in all major tissues assayed, including the brain. The amount of wild-type IKBKAP mRNA and IKAP protein was significantly higher in the kinetin-treated mice. These exciting results prove that treatment of FD, as well as other mechanistically related splicing disorders, with kinetin holds great promise as a potential therapeutic aimed at increasing normal protein levels, which may, in turn, slow disease progression. C1 [Shetty, Ranjit S.; Gallagher, Cary S.; Chen, Yei-Tsung; Hims, Matthew M.; Mull, James; Leyne, Maire; Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Shetty, Ranjit S.; Gallagher, Cary S.; Chen, Yei-Tsung; Hims, Matthew M.; Mull, James; Leyne, Maire; Slaugenhaupt, Susan A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Pickel, James] NIMH, NIH, Bethesda, MD 20892 USA. [Kwok, David] BRI Biopharmaceut Res Inc, Vancouver, BC V6P 3S8, Canada. RP Slaugenhaupt, SA (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 5254, Boston, MA 02114 USA. EM slaugenhaupt@chgr.mgh.harvard.edu FU Dysautonomia Foundation, Inc; NIH [R01 NS36326, R21 NS R21NS058318]; Massachusetts General Hospital FX This work was supported by a grant from the Dysautonomia Foundation, Inc, and NIH (R01 NS36326 and R21 NS R21NS058318) to S. A. S. R. S. S. was supported by a Massachusetts General Hospital ECOR Fund for Medical Discovery Award. NR 46 TC 8 Z9 8 U1 0 U2 3 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 NOV 1 PY 2011 VL 20 IS 21 BP 4093 EP 4101 DI 10.1093/hmg/ddr333 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 830VO UT WOS:000295686000001 PM 21821670 ER PT J AU Takakura, A Nelson, EA Haque, N Humphreys, BD Zandi-Nejad, K Frank, DA Zhou, J AF Takakura, Ayumi Nelson, Erik A. Haque, Nadeem Humphreys, Benjamin D. Zandi-Nejad, Kambiz Frank, David A. Zhou, Jing TI Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways SO HUMAN MOLECULAR GENETICS LA English DT Article ID ACUTE-RENAL-FAILURE; CELL-CYCLE ARREST; JAK-STAT; TARGETED DISRUPTION; EPITHELIAL-CELLS; CYST FORMATION; ACTIVATION; MTOR; PKD1; INACTIVATION AB Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder mostly caused by mutations in PKD1, encoding polycystin-1 (PC1). The disease is characterized by development and growth of epithelium-lined cyst in both kidneys, often leading to renal failure. There is no specific treatment for this disease. Here, we report a sustained activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in ischemic injured and uninjured Pkd1 knockout polycystic kidneys and in human ADPKD kidneys. Through a chemical library screen, we identified the anti-parasitic compound pyrimethamine as an inhibitor of STAT3 function. Treatment with pyrimethamine decreases cell proliferation in human ADPKD cells and blocks renal cyst formation in an adult and a neonatal PKD mouse model. Moreover, we demonstrated that a specific STAT3 inhibitor, S3I-201, reduces cyst formation and growth in a neonatal PKD mouse model. Our results suggest that PC1 acts as a negative regulator of STAT3 and that blocking STAT3 signaling with pyrimethamine or similar drugs may be an attractive therapy for human ADPKD. C1 [Takakura, Ayumi; Haque, Nadeem; Humphreys, Benjamin D.; Zandi-Nejad, Kambiz; Zhou, Jing] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Nelson, Erik A.; Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nelson, Erik A.; Frank, David A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Takakura, A (reprint author), Harvard Inst Med, Room 520,4 Blackfan Circle, Boston, MA 02115 USA. EM atakakura@rics.bwh.harvard.edu; zhou@rics.bwh.harvard.edu FU Zhou Lab; Harvard Center of Polycystic Kidney Disease Research FX The authors would like to thank Ms C LaPierre for excellent technical assistance and other members of Zhou Lab and the Harvard Center of Polycystic Kidney Disease Research for scientific discussions and support. NR 44 TC 33 Z9 36 U1 2 U2 7 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 NOV 1 PY 2011 VL 20 IS 21 BP 4143 EP 4154 DI 10.1093/hmg/ddr338 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 830VO UT WOS:000295686000005 PM 21821671 ER PT J AU Fossale, E Seong, IS Coser, KR Shioda, T Kohane, IS Wheeler, VC Gusella, JF MacDonald, ME Lee, JM AF Fossale, Elisa Seong, Ihn Sik Coser, Kathryn R. Shioda, Toshi Kohane, Isaac S. Wheeler, Vanessa C. Gusella, James F. MacDonald, Marcy E. Lee, Jong-Min TI Differential effects of the Huntington's disease CAG mutation in striatum and cerebellum are quantitative not qualitative SO HUMAN MOLECULAR GENETICS LA English DT Article ID ENERGY-METABOLISM; SPINOCEREBELLAR ATAXIA; IN-VIVO; REPEAT; IMPAIRMENT; DEFECTS; ATROPHY; TYPE-1; SCAN AB Huntington's disease (HD) involves marked early neurodegeneration in the striatum, whereas the cerebellum is relatively spared despite the ubiquitous expression of full-length mutant huntingtin, implying that inherent tissue-specific differences determine susceptibility to the HD CAG mutation. To understand this tissue specificity, we compared early mutant huntingtin-induced gene expression changes in striatum to those in cerebellum in young Hdh CAG knock-in mice, prior to onset of evident pathological alterations. Endogenous levels of full-length mutant huntingtin caused qualitatively similar, but quantitatively different gene expression changes in the two brain regions. Importantly, the quantitatively different responses in the striatum and cerebellum in mutant mice were well accounted for by the intrinsic molecular differences in gene expression between the striatum and cerebellum in wild-type animals. Tissue-specific gene expression changes in response to the HD mutation, therefore, appear to reflect the different inherent capacities of these tissues to buffer qualitatively similar effects of mutant huntingtin. These findings highlight a role for intrinsic quantitative tissue differences in contributing to HD pathogenesis, and likely to other neurodegenerative disorders exhibiting tissue-specificity, thereby guiding the search for effective therapeutic interventions. C1 [Fossale, Elisa; Seong, Ihn Sik; Wheeler, Vanessa C.; Gusella, James F.; MacDonald, Marcy E.; Lee, Jong-Min] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Coser, Kathryn R.; Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA 02129 USA. [Kohane, Isaac S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02114 USA. [Kohane, Isaac S.] I2b2 Natl Ctr Biomed Comp, Boston, MA 02115 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM jlee51@partners.org RI Kohane, Isaac Kohane/K-3716-2012 OI Kohane, Isaac Kohane/0000-0003-2192-5160 FU National Institutes of Health [NS32765, NS049206]; Massachusetts HD Center Without Walls [NS16367]; i2b2 [LM008748-01]; Huntington's Disease Society of America Coalition for the Cure Normal Function Team FX This research was supported by National Institutes of Health (NS32765 to M. E. M.; NS049206 to V. C. W.), The Massachusetts HD Center Without Walls (NS16367 to M. E. M. and J.F.G.), i2b2 (LM008748-01 to I. S. K.), the Huntington's Disease Society of America Coalition for the Cure Normal Function Team (to M. E. M. and J.F.G.) and an Anonymous Donor. NR 22 TC 11 Z9 11 U1 2 U2 4 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 NOV 1 PY 2011 VL 20 IS 21 BP 4258 EP 4267 DI 10.1093/hmg/ddr355 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 830VO UT WOS:000295686000015 PM 21840924 ER PT J AU de Lange, C Brabrand, K Emblem, KE Bjornerud, A Loberg, EM Saugstad, OD Munkeby, BH AF de Lange, Charlotte Brabrand, Knut Emblem, Kyrre E. Bjornerud, Atle Loberg, Else Marit Saugstad, Ola Didrik Munkeby, Berit H. TI Cerebral Perfusion in Perinatal Hypoxia and Resuscitation Assessed by Transcranial Contrast-Enhanced Ultrasound and 3 T MRI in Newborn Pigs SO INVESTIGATIVE RADIOLOGY LA English DT Article DE cerebral perfusion; contrast-enhanced ultrasound; MRI; perfusion weighted imaging; perinatal encephalopathy; piglet ID BRAIN-INJURY; ISCHEMIC ENCEPHALOPATHY; BLOOD-FLOW; 100-PERCENT OXYGEN; TERM INFANT; SPECTROSCOPY; ASPHYXIA; PIGLETS; STROKE; HYPOTENSION AB Objective: Cerebrovascular factors are crucially involved in the early injury after perinatal asphyxia. With magnetic resonance imaging (MRI) and ultrasonography (US), this study aimed to quantify microvascular perfusion changes due to hypoxia and resuscitation, by comparing contrast-enhanced ultrasound (CEUS) to dynamic susceptibility contrast-enhanced (DSC)-MRI and diffusion-weighted MRI. Material and Methods: Newborn piglets (n = 12/17) were reoxygenated with 21% (n = 6) or 100% O(2) (n = 6) after global hypoxia. Five piglets served as controls. CEUS and MRI were performed before, during, and up to 7 hours after hypoxia. Following are the perfusion parameters for CEUS: peak intensity (PI), area under the curve (AUC), time to peak (TTP), and upslope a and perfusion/diffusion parameters for MRI: relative cerebral blood volume, relative cerebral blood flow, mean transit time, and apparent diffusion coefficient were compared between different regions in the brain across time points and also compared with histology at the end. Results: In CEUS, compared with the control group, perfusion changed significantly over time, in the hyperoxic group in all regions for PI, AUC in all regions of interests. The changes presented mainly as decreased perfusion during and shortly after resuscitation: for PI in the basal ganglia (BG), cortex, and the whole brain with 50 to 60% (P <= 0.001); for AUC in the BG and cortex with 90% (P <= 0.02) and in the whole brain with 70% (P = 0.004). In the injured brains (confirmed by histology), significant changes over time were seen in TTP and AUC with mainly increased perfusion during hypoxia: for TTP in the cortex, AUC in the BG and whole brain with 90 to 100% (P <= 0.04), and for TTP in the whole brain with 50% (P = 0.02). DSC-MRI showed the same trends in perfusion with regard to relative cerebral blood volume as CEUS. In all pigs exposed to hypoxia, perfusion returned toward baseline values at 7 hours after hypoxia in both methods. Apparent diffusion coefficient decreased significantly after 7 hours in the injured brains in the BG from 114.6 +/- 1.2 x 10(-5) mm(2)/s to 90.3 +/- 24 x 10(-5) mm(2)/s (P = 0.03). Conclusions: CEUS and DSC-MRI can detect an early temporal evolution of cerebral perfusion in perinatal hypoxia and resuscitation, reversible after 7 hours. Hyperoxic resuscitation caused early decreased cerebral perfusion, not present in the normoxic group. The combined use of CEUS and DSC-MRI can provide important diagnostic information and give new insights into perinatal vascular hypoxia mechanisms. C1 [de Lange, Charlotte] Oslo Univ Hosp, Rikshosp, Dept Paediat Res, N-0424 Oslo, Norway. [de Lange, Charlotte; Brabrand, Knut] Oslo Univ Hosp, Dept Diagnost Imaging & Intervent, N-0424 Oslo, Norway. [Emblem, Kyrre E.; Bjornerud, Atle] Oslo Univ Hosp, Intervent Ctr, N-0424 Oslo, Norway. [Emblem, Kyrre E.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Bjornerud, Atle] Univ Oslo, Dept Phys, Oslo, Norway. [Loberg, Else Marit] Oslo Univ Hosp, Dept Pathol, N-0424 Oslo, Norway. [Saugstad, Ola Didrik] Univ Oslo, Dept Med, Oslo, Norway. RP de Lange, C (reprint author), Oslo Univ Hosp, Rikshosp, Dept Paediat Res, Postboks 4950 Nydalen, N-0424 Oslo, Norway. EM charlotte.de.lange@rr-research.no RI Emblem, Kyrre/H-6691-2012 OI Emblem, Kyrre/0000-0002-6580-9519 FU Norwegian SIDS; Stillbirth Society; Child Foundation of Oslo University Hospital FX supported by the Norwegian SIDS and Stillbirth Society and the Child Foundation of Oslo University Hospital. The authors declare nothing to disclose. NR 50 TC 8 Z9 8 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD NOV PY 2011 VL 46 IS 11 BP 686 EP 696 DI 10.1097/RLI.0b013e3182266431 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 832TK UT WOS:000295830600004 PM 21730873 ER PT J AU Ohta, K Laborde, NJ Kajiya, M Shin, J Zhu, T Thondukolam, AK Min, C Kamata, N Karimbux, NY Stashenko, P Kawai, T AF Ohta, K. Laborde, N. J. Kajiya, M. Shin, J. Zhu, T. Thondukolam, A. K. Min, C. Kamata, N. Karimbux, N. Y. Stashenko, P. Kawai, T. TI Expression and Possible Immune-regulatory Function of Ghrelin in Oral Epithelium SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE ghrelin; gingival crevicular fluid; saliva; gingival epithelium; IL-8; lipopolysaccharide ID LOCALIZED AGGRESSIVE PERIODONTITIS; GINGIVAL CREVICULAR FLUID; CYTOKINE EXPRESSION; CELLS; HORMONE; GROWTH; KERATINOCYTES; RELEASE; TISSUE; PROLIFERATION AB Originally found in stomach mucosa, ghrelin is a peptide appetite hormone that has been implicated as an immuno-modulatory factor. Ghrelin has also been found in salivary glands and saliva; however, its expression patterns and biological properties in the oral cavity remain unclear. Therefore, we investigated the expression patterns of ghrelin in saliva, gingival crevicular fluid (GCF), and gingival tissue, as well as its in vitro effects on IL-8 production by TNF-alpha or LPS-stimulated oral epithelial cells. In the clinical samples obtained from 12 healthy volunteers, the concentration of ghrelin in GCF remarkably exceeded that detected in saliva. The expression of ghrelin mRNAs and growth hormone secretagogue (GHS) receptors could be detected in human oral epithelial cells. Immunohistochemical analysis revealed the expression of ghrelin in gingival epithelium, as well as in fibroblasts in the lamina propria. Ghrelin increased intracellular calcium mobilization and cAMP levels in oral epithelial cells, suggesting that ghrelin acts on epithelial cells to induce cell signaling. Furthermore, synthetic ghrelin inhibited the production of IL-8 from TNF-alpha or LPS-stimulated oral epithelial cells. These results indicate that ghrelin produced in the oral cavity appears to play a regulatory role in innate immune responses to inflammatory infection. C1 [Ohta, K.; Kajiya, M.; Shin, J.; Zhu, T.; Min, C.; Kawai, T.] Harvard Univ, Sch Dent Med, Dept Immunol, Boston, MA 02115 USA. [Ohta, K.; Laborde, N. J.; Kajiya, M.; Zhu, T.; Thondukolam, A. K.; Karimbux, N. Y.; Kawai, T.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Ohta, K.; Kamata, N.] Hiroshima Univ, Dept Oral & Maxillofacial Surg, Div Cervicognathostomatol, Programs Appl Biomed,Grad Sch Biomed Sci, Hiroshima, Japan. [Stashenko, P.] Forsyth Inst, Dept Cytokine Biol, Cambridge, MA 02142 USA. RP Kawai, T (reprint author), Harvard Univ, Sch Dent Med, Dept Immunol, 188 Longwood Ave, Boston, MA 02115 USA. EM tkawai@forsyth.org FU NIH [DE-018310, DE-018499]; NIDCR; Harvard Catalyst; AADR FX This study was supported by NIH grants DE-018310 and DE-018499 from the NIDCR and by a Pilot Grant from Harvard Catalyst. Jane Shin was the recipient of a 2010 Student Research Fellowship from the AADR. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 30 TC 12 Z9 12 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD NOV PY 2011 VL 90 IS 11 BP 1286 EP 1292 DI 10.1177/0022034511420431 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 830XM UT WOS:000295692600005 PM 21865591 ER PT J AU Tanner, ACR Kent, RL Holgerson, PL Hughes, CV Loo, CY Kanasi, E Chalmers, NI Johansson, I AF Tanner, A. C. R. Kent, R. L., Jr. Holgerson, P. Lif Hughes, C. V. Loo, C. Y. Kanasi, E. Chalmers, N. I. Johansson, I. TI Microbiota of Severe Early Childhood Caries before and after Therapy SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE pediatric dentistry; clinical outcomes; microbial ecology; Streptococcus mutans; Scardovia wiggsiae ID STREPTOCOCCUS-SOBRINUS; MOLECULAR ANALYSIS; MICROFLORA; CHILDREN; BACTERIA; MUTANS AB Severe early childhood caries (ECC) is difficult to treat successfully. This study aimed to characterize the microbiota of severe ECC and evaluate whether baseline or follow-up microbiotas are associated with new lesions post-treatment. Plaque samples from 2- to 6-year-old children were analyzed by a 16S rRNA-based microarray and by PCR for selected taxa. Severe-ECC children were monitored for 12 months post-therapy. By microarray, species associated with severe-ECC (n = 53) compared with caries-free (n = 32) children included Slackia exigua (p = 0.002), Streptococcus parasanguinis (p = 0.013), and Prevotella species (p < 0.02). By PCR, severe-ECC-associated taxa included Bifidobacteriaceae (p < 0.001), Scardovia wiggsiae (p = 0.003), Streptococcus mutans with bifidobacteria (p < 0.001), and S. mutans with S. wiggsiae (p = 0.001). In follow-up, children without new lesions (n = 36) showed lower detection of taxa including S. mutans, changes not observed in children with follow-up lesions (n = 17). Partial least-squares modeling separated the children into caries-free and two severe-ECC groups with either a stronger bacterial or a stronger dietary component. We conclude that several species, including S. wiggsiae and S. exigua, are associated with the ecology of advanced caries, that successful treatment is accompanied by a change in the microbiota, and that severe ECC is diverse, with influences from selected bacteria or from diet. C1 [Tanner, A. C. R.; Holgerson, P. Lif; Kanasi, E.; Chalmers, N. I.] Forsyth Inst, Dept Mol Genet, Cambridge, MA 02142 USA. [Kent, R. L., Jr.] Forsyth Inst, Dept Biostat, Cambridge, MA 02142 USA. [Tanner, A. C. R.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Kent, R. L., Jr.; Kanasi, E.] Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. [Holgerson, P. Lif; Johansson, I.] Umea Univ, Dept Odontol, Cariol Sect, Fac Med, SE-90187 Umea, Sweden. [Hughes, C. V.] Boston Univ, Goldman Sch Dent Med, Dept Pediat Dent, Boston, MA 02118 USA. [Loo, C. Y.] Tufts Univ, Tufts Sch Dent Med, Dept Pediat Dent, Boston, MA 02111 USA. RP Tanner, ACR (reprint author), Forsyth Inst, Dept Mol Genet, 245 1st St, Cambridge, MA 02142 USA. EM annetanner@forsyth.org RI Hughes, Christopher/E-1438-2014 FU USPHS from the NIDCR of NIH [DE-015847, DE-007327]; Colgate-Palmolive Company; Henning and Johan Throne-Holst's Foundation FX This investigation was supported by USPHS grants DE-015847 and DE-007327 from the NIDCR of NIH, the Colgate-Palmolive Company, and the Henning and Johan Throne-Holst's Foundation. NR 28 TC 44 Z9 46 U1 3 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD NOV PY 2011 VL 90 IS 11 BP 1298 EP 1305 DI 10.1177/0022034511421201 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 830XM UT WOS:000295692600007 PM 21868693 ER PT J AU Mawardi, H Giro, G Kajiya, M Ohta, K Almazrooa, S Alshwaimi, E Woo, SB Nishimura, I Kawai, T AF Mawardi, H. Giro, G. Kajiya, M. Ohta, K. Almazrooa, S. Alshwaimi, E. Woo, S-B. Nishimura, I. Kawai, T. TI A Role of Oral Bacteria in Bisphosphonate-induced Osteonecrosis of the Jaw SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE bisphosphonate-induced osteonecrosis of the jaw; pamidronate; gingival fibroblast; KGF; wound healing; Fusobacterium nucleatum ID INFECTED OSTEORADIONECROSIS; ZOLEDRONIC ACID; RECOGNITION; GROWTH; TISSUE; CELLS; RATS AB No consensus has yet been reached to associate oral bacteria conclusively with the etio-pathogenesis of bisphosphonate-induced osteonecrosis of the jaw (BONJ). Therefore, the present study examined the effects of oral bacteria on the development of BONJ-like lesions in a mouse model. In the pamidronate (Pam)-treated mice, but not control non-drug-treated mice, tooth extraction followed by oral infection with Fusobacterium nucleatum caused BONJ-like lesions and delayed epithelial healing, both of which were completely suppressed by a broad-spectrum antibiotic cocktail. Furthermore, in both in vitro and in vivo experiments, the combination of Pam and Fusobacterium nucleatum caused the death of gingival fibroblasts (GFs) and down-regulated their production of keratinocyte growth factor (KGF), which induces epithelial cell growth and migration. Therefore, in periodontal tissues pre-exposed to bisphosphonate, bacterial infection at tooth extraction sites caused diminished KGF expression in GFs, leading to a delay in the epithelial wound-healing process that was mitigated by antibiotics. C1 [Mawardi, H.; Giro, G.; Kajiya, M.; Ohta, K.; Almazrooa, S.; Kawai, T.] Forsyth Inst, Dept Immunol, Cambridge, MA 02142 USA. [Mawardi, H.; Kajiya, M.; Ohta, K.; Almazrooa, S.; Woo, S-B.; Kawai, T.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Mawardi, H.; Almazrooa, S.] King Abdulaziz Univ, Oral Med Div, Fac Dent, Jeddah 21589, Saudi Arabia. [Giro, G.] UNESP Sao Paulo State Univ, Sch Dent Araraquara, Dept Oral Diag & Surg, BR-14801903 Sao Paulo, SP, Brazil. [Alshwaimi, E.] Univ Dammam, Coll Dent, Restorat Dent Sci Dept, Dammam 31441, Saudi Arabia. [Nishimura, I.] UCLA Sch Dent, Div Adv Prosthodont Biomat & Hosp Dent, Los Angeles, CA 90095 USA. RP Kawai, T (reprint author), Forsyth Inst, Dept Immunol, 245 1st St, Cambridge, MA 02142 USA. EM tkawai@forsyth.org RI AlShwaimi, Emad /F-4077-2012; Giro, Gabriela/D-2746-2009 OI Giro, Gabriela/0000-0002-7590-8158 FU NIH from the NIDCR [DE-18499, DE-19917] FX This study was supported by NIH grants DE-18499 (TK) and DE-19917 (TK) from the NIDCR. We acknowledge the assistance of Hajime Yamazaki in taking x-rays. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 25 TC 31 Z9 32 U1 0 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD NOV PY 2011 VL 90 IS 11 BP 1339 EP 1345 DI 10.1177/0022034511420430 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 830XM UT WOS:000295692600013 PM 21921248 ER PT J AU Pugach, MK Ozer, F Li, Y Sheth, K Beasley, R Resnick, A Daneshmehr, L Kulkarni, AB Bartlett, JD Gibson, CW Lindemeyer, RG AF Pugach, M. K. Ozer, F. Li, Y. Sheth, K. Beasley, R. Resnick, A. Daneshmehr, L. Kulkarni, A. B. Bartlett, J. D. Gibson, C. W. Lindemeyer, R. G. TI The Use of Mouse Models to Investigate Shear Bond Strength in Amelogenesis Imperfecta SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE enamel; acid-etching; amelogenesis imperfecta; shear bond strength; amelogenin; matrix metalloproteinase-20 ID CONSERVATIVE TREATMENT; MICE DISPLAY; PHENOTYPE; MUTATION; ENAMEL; RESTORATIONS AB Patients with amelogenesis imperfecta (AI) have defective enamel; therefore, bonded restorations of patients with AI have variable success rates. To distinguish which cases of AI may have good clinical outcomes with bonded materials, we evaluated etching characteristics and bond strength of enamel in mouse models, comparing wild-type (WT) with those having mutations in amelogenin (Amelx) and matrix metalloproteinase-20 (Mmp20), which mimic 2 forms of human AI. Etched enamel surfaces were compared for roughness by scanning electron microscopy (SEM) images. Bonding was compared through shear bond strength (SBS) studies with 2 different systems (etch-and-rinse and self-etch). Etched enamel surfaces of incisors from Amelx knockout (AmelxKO) mice appeared randomly organized and non-uniform compared with WT. Etching of Mmp20KO surfaces left little enamel, and the etching pattern was indistinguishable from unetched surfaces. SBS results were significantly different when AmelxKO and Mmp20KO enamel surfaces were compared. A significant increase in SBS was measured for all samples when the self-etch system was compared with the etch-and-rinse system. We have developed a novel system for testing shear bond strength of mouse incisors with AI variants, and analysis of these data may have important clinical implications for the treatment of patients with AI. C1 [Lindemeyer, R. G.] Univ Penn, Sch Dent Med, Div Pediat Dent, Philadelphia, PA 19104 USA. [Pugach, M. K.; Li, Y.; Sheth, K.; Beasley, R.; Resnick, A.; Gibson, C. W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Ozer, F.; Daneshmehr, L.] Univ Penn, Sch Dent Med, Dept Prevent & Restorat Sci, Philadelphia, PA 19104 USA. [Kulkarni, A. B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Bartlett, J. D.] Harvard Univ, Sch Dent Med, Dept Cytokine Biol, Forsyth Inst, Cambridge, MA 02142 USA. [Bartlett, J. D.] Harvard Univ, Sch Dent Med, Dept Dev Biol, Cambridge, MA 02142 USA. RP Lindemeyer, RG (reprint author), Univ Penn, Sch Dent Med, Div Pediat Dent, 240 S 40th St, Philadelphia, PA 19104 USA. EM lindemey@dental.upenn.edu FU National Institute of Dental and Craniofacial Research (National Institutes of Health) [DE011089, DE019968, DE016276] FX The authors acknowledge Z. Nelson and A. Clark for assistance with sample preparation, B. Winkelstein and Y. Shimada for technical discussions, M. Blatz for clinical insights, and the National Institute of Dental and Craniofacial Research (National Institutes of Health) grants DE011089, DE019968, and DE016276 for supporting this study. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 29 TC 1 Z9 1 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD NOV PY 2011 VL 90 IS 11 BP 1352 EP 1357 DI 10.1177/0022034511421929 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 830XM UT WOS:000295692600015 PM 21917602 ER PT J AU Hochman, M McCormick, D AF Hochman, Michael McCormick, Danny TI Endpoint Selection and Relative (Versus Absolute) Risk Reporting in Published Medication Trials SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE surrogate endpoints; composite endpoints; disease-specific mortality; relative risk reduction ID RANDOMIZED CONTROLLED-TRIALS; CLINICAL-TRIALS; COMPOSITE OUTCOMES; USERS GUIDES; INTERVENTION; ASSOCIATION; CONCLUSIONS; PREVENTION; BENEFITS; ARTICLE AB The use of surrogate and composite endpoints, disease-specific mortality as an endpoint, and relative (rather than absolute) risk reporting in clinical trials may produce results that are misleading or difficult to interpret. To describe the prevalence of these endpoints and of relative risk reporting in medication trials. We analyzed all randomized medication trials published in the six highest impact general medicine journals between June 1, 2008 and September 30, 2010 and determined the percentage using these endpoints and the percentage reporting results in the abstract exclusively in relative terms. We identified 316 medication trials, of which 116 (37%) used a surrogate primary endpoint and 106 (34%) used a composite primary endpoint. Among 118 trials in which the primary endpoint involved mortality, 32 (27%) used disease-specific mortality rather than all-cause mortality. Among 157 trials with positive results, 69 (44%) reported these results in the abstract exclusively in relative terms. Trials using surrogate endpoints and disease-specific mortality as an endpoint were more likely to be exclusively commercially funded (45% vs. 29%, difference 15% [95% CI 5%-26%], P = 0.004, and 39% vs. 16%, difference 22% [95% CI 6%-37%], P = 0.007, respectively). Trials using surrogate endpoints were more likely to report positive results (66% vs. 49%, difference 17% [95% CI 5%-28%], P = 0.006) while those using mortality endpoints were less likely to be positive (46% vs. 62%, difference -16% [95% CI -27%--4%], P = 0.01). The use of surrogate and composite endpoints, endpoints involving disease-specific mortality, and relative risk reporting is common. Articles should highlight the limitations of these endpoints and should report results in absolute terms. C1 [Hochman, Michael] Univ Calif Los Angeles, Robert Wood Johnson Clin Scholars Program, Los Angeles, CA 90024 USA. [Hochman, Michael] US Dept Vet Affairs, Los Angeles, CA 90024 USA. [McCormick, Danny] Cambridge Hlth Alliance, Dept Med, Cambridge, MA USA. [McCormick, Danny] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Hochman, M (reprint author), Univ Calif Los Angeles, Robert Wood Johnson Clin Scholars Program, 911 Broxton Ave,3rd Floor, Los Angeles, CA 90024 USA. EM Meh1979@gmail.com NR 32 TC 3 Z9 3 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 IS 11 BP 1246 EP 1252 DI 10.1007/s11606-011-1813-7 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 830UU UT WOS:000295683500007 PM 21842324 ER PT J AU Bass, MG Korthuis, PT Cofrancesco, J Berkenblit, GV Sullivan, LE Asch, SM Bashook, PG Edison, M Sosman, JM Cook, RL AF Bass, Michael G. Korthuis, P. Todd Cofrancesco, Joseph, Jr. Berkenblit, Gail V. Sullivan, Lynn E. Asch, Steve M. Bashook, Philip G. Edison, Marcia Sosman, James M. Cook, Robert L. TI Provider and Practice Characteristics Associated with Use of Rapid HIV Testing by General Internists SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE testing; rapid HIV testing; HIV/AIDS; general internal medicine physicians; HIV prevention; medical practice setting ID HEALTH-CARE SETTINGS; EMERGENCY-DEPARTMENT; SCREENING-PROGRAM; ROUTINE; PHYSICIANS; VIRUS; RECOMMENDATIONS; ADOLESCENTS; PREVALENCE AB Rapid HIV testing could increase routine HIV testing. Most previous studies of rapid testing were conducted in acute care settings, and few described the primary care providers' perspective. To identify characteristics of general internal medicine physicians with access to rapid HIV testing, and to determine whether such access is associated with differences in HIV-testing practices or perceived HIV-testing barriers. Web-based cross-sectional survey conducted in 2009. A total of 406 physician members of the Society of General Internal Medicine who supervise residents or provide care in outpatient settings. Surveys assessed provider and practice characteristics, HIV-testing types, HIV-testing behavior, and potential barriers to HIV testing. Among respondents, 15% had access to rapid HIV testing. In multivariable analysis, physicians were more likely to report access to rapid testing if they were non-white (OR 0.45, 95% CI 0.22, 0.91), had more years since completing training (OR 1.06, 95% CI 1.02, 1.10), practiced in the northeastern US (OR 2.35; 95% CI 1.28, 4.32), or their practice included a higher percentage of uninsured patients (OR 1.03; 95% CI 1.01, 1.04). Internists with access to rapid testing reported fewer barriers to HIV testing. More respondents with rapid than standard testing reported at least 25% of their patients received HIV testing (51% versus 35%, p = 0.02). However, access to rapid HIV testing was not significantly associated with the estimated proportion of patients receiving HIV testing within the previous 30 days (7.24% vs. 4.58%, p = 0.06). Relatively few internists have access to rapid HIV testing in outpatient settings, with greater availability of rapid testing in community-based clinics and in the northeastern US. Future research may determine whether access to rapid testing in primary care settings will impact routinizing HIV testing. C1 [Cook, Robert L.] Univ Florida, Dept Epidemiol, Gainesville, FL 32610 USA. [Cook, Robert L.] Univ Florida, Dept Med, Gainesville, FL 32610 USA. [Bass, Michael G.; Bashook, Philip G.; Edison, Marcia] Univ Illinois, Coll Med, Dept Med Educ, Chicago, IL USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Cofrancesco, Joseph, Jr.; Berkenblit, Gail V.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Sullivan, Lynn E.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Asch, Steve M.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Sosman, James M.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. RP Cook, RL (reprint author), Univ Florida, Dept Epidemiol, CB 100231, Gainesville, FL 32610 USA. EM cookrl@ufl.edu FU Centers for Disease Control and Prevention; Centers for Disease Control (CDC) [1 U22 PS00551-02]; Robert Wood Johnson Foundation; Health Resources Services Administration for the Midwest AIDS Education and Training Center; National Institutes of Health, National Institute on Drug Abuse [K23 DA019809] FX We want to thank our colleagues at the Society for General Internal Medicine for responding to our survey, and providing thoughtful feedback. We appreciate the funding we received from the Centers for Disease Control and Prevention, and our respective agencies, which allowed us to carry on this work. We wish to especially thank Leslie Dunne, our SGIM project manager, who facilitated this effort to completion.; This work was supported by a grant from the Centers for Disease Control (CDC grant number 1 U22 PS00551-02 HIV Prevention with National Medical Associations), in conjunction with the Society of General Internal Medicine, HIV/AIDS Task Force. Dr. Sullivan was supported by the Robert Wood Johnson Foundation Physician Faculty Scholars Program during the conduct of this work. Drs. Bashook and Edison were supported by a grant from the Health Resources Services Administration for the Midwest AIDS Education and Training Center during the conduct of this work. Dr. Korthuis was supported by the National Institutes of Health, National Institute on Drug Abuse (K23 DA019809) during the conduct of this work. NR 36 TC 4 Z9 4 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 IS 11 BP 1258 EP 1264 DI 10.1007/s11606-011-1764-z PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 830UU UT WOS:000295683500009 PM 21710314 ER PT J AU Joo, MJ Au, DH Fitzgibbon, ML McKell, J Lee, TA AF Joo, Min J. Au, David H. Fitzgibbon, Marian L. McKell, Joanne Lee, Todd A. TI Determinants of Spirometry Use and Accuracy of COPD Diagnosis in Primary Care SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE chronic disease; diagnosis; health care delivery; chronic obstructive pulmonary disease; spirometry; quality of care ID OBSTRUCTIVE PULMONARY-DISEASE; INHALED CORTICOSTEROID USE; LUNG-FUNCTION; SALMETEROL/FLUTICASONE PROPIONATE; FLUTICASONE PROPIONATE; SALMETEROL; METAANALYSIS; TIOTROPIUM; FORMOTEROL; EFFICACY AB It is unclear if primary care physicians are following guidelines or using other patient characteristics and factors to determine when to perform spirometry in patients at risk for COPD. It is also unclear to what degree a diagnosis of COPD is accurately reflected by spirometry results. To examine characteristics associated with use of spirometry in primary care for patients with increased risk for COPD and to determine the accuracy of COPD diagnosis in patients with spirometry. Retrospective cohort study. A cohort that met the following criteria was identified: a parts per thousand yen35 years of age; a parts per thousand yen 2 primary care visits in internal medicine clinic in 2007; at least one respiratory or smoking cessation medication, or diagnosis of COPD or shortness of breath or dyspnea in 2007. Medical records of all primary care physician visits prior to the time of inclusion in 2007 were reviewed. Data on patient demographics, co-morbidities, respiratory medication use, presence of symptoms, history of tobacco use, and pulmonary function tests were extracted. A total 1052 patients were identified. Dyspnea on exertion (Adjusted odds ratio (AOR) 1.52 [95% CI 1.06-2.18]) and chronic cough (AOR 1.71 [1.07-2.72]) were the only chronic symptoms associated with use of spirometry. Current (AOR 1.54 [0.99-2.40]) or past smoking (AOR 1.09 [0.72-1.65]) status were not associated with use of spirometry. Of the 159 patients with a diagnosis of COPD, 93 (58.5%) met GOLD criteria and 81(50.9%) met lower limit of normal (LLN) criteria for COPD. Clinicians use spirometry more often among patients with symptoms suggestive of COPD but not more often among patients with current or past tobacco use. For patients who had a spirometry and a diagnosis of COPD, primary care physicians were accurate in their diagnosis only half of the time. C1 [Joo, Min J.; Fitzgibbon, Marian L.] Univ Illinois, Dept Med, Sect Hlth Promot Res, Chicago, IL 60612 USA. [Joo, Min J.; McKell, Joanne] Univ Illinois, Dept Med, Sect Pulm Crit Care Sleep & Allergy Med, Chicago, IL 60612 USA. [Au, David H.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Au, David H.] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [Lee, Todd A.] Hines VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Lee, Todd A.] Univ Illinois, Dept Pharm Practice, Ctr Pharmacoecon Res, Chicago, IL 60612 USA. RP Joo, MJ (reprint author), Univ Illinois, Dept Med, Sect Hlth Promot Res, 840 S Wood St,M-C 719, Chicago, IL 60612 USA. EM joo@uic.edu FU National Heart, Lung, and Blood Institute [K23HL094461] FX This work was supported by the National Heart, Lung, and Blood Institute [K23HL094461]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI, the National Institutes. The views expressed in this manuscript reflect those of the authors and not necessarily those of the Department of Veterans Affairs. NR 33 TC 16 Z9 16 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 IS 11 BP 1272 EP 1277 DI 10.1007/s11606-011-1770-1 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 830UU UT WOS:000295683500011 PM 21713542 ER PT J AU Axon, RN Gebregziabher, M Echols, C Gilbert, G Egede, LE AF Axon, R. Neal Gebregziabher, Mulugeta Echols, Carrae Gilbert, Gregory Egede, Leonard E. TI Racial and Ethnic Differences in Longitudinal Blood Pressure Control in Veterans with Type 2 Diabetes Mellitus SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE blood pressure control; diabetes; epidemiology; race/ethnicity ID CARDIOVASCULAR-DISEASE RISK; SYSTOLIC HYPERTENSION; AFRICAN-AMERICANS; DISPARITIES; CARE; STROKE; RACE; PREVALENCE; MORTALITY; OUTCOMES AB Few studies have examined racial/ethnic differences in blood pressure (BP) control over time, especially in an equal access system. We examined racial/ethnic differences in longitudinal BP control in Veterans with type 2 diabetes. We collected data on a retrospective cohort of 5,319 Veterans with type 2 diabetes and initially uncontrolled BP followed from 1996 to 2006 at a Veterans Administration (VA) facility in the southeastern United States. The mean blood pressure value for each subject for each year was used for the analysis with BP control defined as < 140/< 90 mmHg. The primary outcome measure was proportion with controlled BP. The main predictor variable was race/ethnicity categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic/Other (H/O). Other covariates included age, gender, employment, marital status, service connectedness, and ICD-9 coded medical and psychiatric comorbidities. Generalized linear mixed models were used to assess the relationship between race/ethnicity and BP control after adjusting for covariates. Mean follow-up was 5.0 years. The sample was 46% NHW, 26% NHB, 19% H/O, and 9% unknown. The average age was 68 years. In the final model, after adjusting for covariates, NHB race (OR = 1.38, 95%CI: 1.2, 1.6) and H/O race (OR = 1.57, 95% CI: 1.3, 1.8) were associated with increased likelihood of poor BP control (> 140/> 90 mmHg) over time compared to NHW patients. Ethnic minority Veterans with type 2 diabetes have significantly increased odds of poor BP control over similar to 5 years of follow-up compared to their non-Hispanic White counterparts independent of sociodemographic factors and comorbidity patterns. C1 [Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Axon, R. Neal; Gebregziabher, Mulugeta; Echols, Carrae; Gilbert, Gregory; Egede, Leonard E.] Ralph H Johnson VAMC, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. [Axon, R. Neal; Egede, Leonard E.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Gebregziabher, Mulugeta] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. RP Egede, LE (reprint author), Med Univ S Carolina, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280H,POB 250593, Charleston, SC 29425 USA. EM egedel@musc.edu RI Gilbert, Gregory/C-7735-2016; OI Gilbert, Gregory/0000-0003-0879-5496; Gebregziabher, Mulugeta/0000-0002-4826-481X FU Center for Disease Prevention and Health Interventions for Diverse Populations [REA 08-261]; Veterans Affairs Health Services Research and Development FX This study was supported by Grant # REA 08-261, Center for Disease Prevention and Health Interventions for Diverse Populations funded by Veterans Affairs Health Services Research and Development (PI - Leonard Egede). NR 37 TC 10 Z9 10 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 IS 11 BP 1278 EP 1283 DI 10.1007/s11606-011-1752-3 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 830UU UT WOS:000295683500012 PM 21671132 ER PT J AU Ly, DP Jha, AK Epstein, AM AF Ly, Dan P. Jha, Ashish K. Epstein, Arnold M. TI The Association Between Hospital Margins, Quality of Care, and Closure or Other Change in Operating Status SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE margins; quality; closure ID ACUTE MYOCARDIAL-INFARCTION; URBAN; MEDICARE; PERFORMANCE AB Hospitals face increased pressure to improve their quality of care in an environment of dwindling hospital payments. It is unclear whether lower hospital margins are associated with worse quality of care or closure. To determine the association of hospital margins with quality of care and changes in operating status. We conducted an observational cross-sectional study analyzing hospitals' margin, quality of care (process quality, risk-adjusted readmission rates, and risk-adjusted mortality rates), and changes in operating status (rates of closure, merger and acquisition, and conversion to a critical access hospital) for 3,262 non-public U.S. hospitals with data from the Hospital Quality Alliance and Medicare Cost Reports. Compared to those in the bottom 10% of operating margin, those in the top 10% had higher process quality (e.g. 95.3 vs. 93.7, p = 0.002 for acute myocardial infarction [AMI]) and lower readmission rates (e.g. 19.7% vs. 22.4%, p < 0.001 for AMI). We found no association between margins and mortality rates. Hospitals in the bottom 10% were more likely than those in the top 10% to close (5.7% vs. 2.0%), merge or become acquired (4.0% vs. 0.3%), or convert to a Critical Access Hospital (5.4% vs. 0.6%). Over 15% of hospitals in the lowest decile of hospital margin changed operating status in the subsequent year. Low hospital margins are associated with worse processes of care and readmission rates and with changes in operating status. We should monitor low-margin hospitals closely for declining quality of care. C1 [Ly, Dan P.] Weill Cornell Med Coll, New York, NY 10021 USA. [Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. [Jha, Ashish K.; Epstein, Arnold M.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Epstein, Arnold M.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. RP Ly, DP (reprint author), Weill Cornell Med Coll, 420 E 70th St,Rm 11C, New York, NY 10021 USA. EM dpl2001@med.cornell.edu NR 23 TC 14 Z9 14 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 IS 11 BP 1291 EP 1296 DI 10.1007/s11606-011-1815-5 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 830UU UT WOS:000295683500014 PM 21837374 ER PT J AU Lee, CA Chang, A Chou, CL Boscardin, C Hauer, KE AF Lee, Christina A. Chang, Anna Chou, Calvin L. Boscardin, Christy Hauer, Karen E. TI Standardized Patient-Narrated Web-Based Learning Modules Improve Students' Communication Skills on a High-stakes Clinical Skills Examination SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE medical education; clinical skills; standardized patient; communication ID MEDICAL-STUDENTS; HEALTH-PROFESSIONS; PERFORMANCE; SCORES; EDUCATION; CARE; METAANALYSIS; STRATEGIES; MOTIVATION; RESIDENTS AB BACKGROUND: Use of web-based standardized patient (SP) modules is associated with improved medical student history-taking and physical examination skills on clinical performance examinations (CPX), but a benefit for communication skills has not been shown. AIM: We describe an innovative web-based SP module using detailed SP and faculty commentary to teach communication skills. SETTING: A public medical school in 2008-2009. PARTICIPANTS: Fourth-year medical students. PROGRAM DESCRIPTION: A 90-minute web-based module with three simulated clinical encounters was narrated by an expert clinician and SP to explain expected history-taking, physical examination, and communication skills behaviors. All 147 students were encouraged to review the module one month before the CPX. PROGRAME VALUATION: One hundred and six students (72%) viewed the web-based module. Students who watched the module performed significantly higher on the CPX communication score (+2.67%, p < 0.01) and overall score (+2.12%, p = 0.03), even after controlling for USMLE Step 1 and clerkship summary ratings. Use of the module did not significantly affect history/physical examination scores (+1.89%, p = 0.12). DISCUSSION: Students who watched an optional web-based SP module prior to the CPX performed higher than those who did not on communication skills. The web-based module appears to be an effective CPX preparatory activity to enhance communication performance. C1 [Lee, Christina A.] Palo Alto Med Fdn, Palo Alto, CA 94301 USA. [Chang, Anna; Chou, Calvin L.; Boscardin, Christy; Hauer, Karen E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Chang, Anna; Chou, Calvin L.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Lee, CA (reprint author), Palo Alto Med Fdn, 795 El Camino Real, Palo Alto, CA 94301 USA. EM christinaaudreylee@gmail.com OI Boscardin, Christy/0000-0002-9070-8859 FU University of California, San Francisco Academy of Medical Educators FX We thank Bernie Miller and Jewel Smally for assistance with module creation and examination administration and Christian Burke for technical assistance. This study was supported by a University of California, San Francisco Academy of Medical Educators Innovations Grant. NR 34 TC 9 Z9 9 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2011 VL 26 IS 11 BP 1374 EP 1377 DI 10.1007/s11606-011-1809-3 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 830UU UT WOS:000295683500027 PM 21769506 ER PT J AU Shin, OS Uddin, T Citorik, R Wang, JP Della Pelle, P Kradin, RL Bingle, CD Bingle, L Camilli, A Bhuiyan, TR Shirin, T Ryan, ET Calderwood, SB Finberg, RW Qadri, F LaRocque, RC Harris, JB AF Shin, Ok S. Uddin, Taher Citorik, Robert Wang, Jennifer P. Della Pelle, Patricia Kradin, Richard L. Bingle, Colin D. Bingle, Lynne Camilli, Andrew Bhuiyan, Taufiqur R. Shirin, Tahmina Ryan, Edward T. Calderwood, Stephen B. Finberg, Robert W. Qadri, Firdausi LaRocque, Regina C. Harris, Jason B. TI LPLUNC1 Modulates Innate Immune Responses to Vibrio cholerae SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PERMEABILITY-INCREASING PROTEIN; INFLAMMATORY MEDIATORS; HOST-DEFENSE; LIPOPOLYSACCHARIDE; FAMILY; GENE; BINDING; CELLS; PLUNC; BACTERICIDAL/PERMEABILITY AB Metods. We investigated the role of LPLUNC1 in immune responses to V. cholerae, assessing its affect on bacterial growth and killing and on innate inflammatory responses to bacterial outer membrane components, including purified lipopolysaccharide (LPS) and outer membrane vesicles. We performed immunostaining for LPLUNC1 in duodenal biopsies from cholera patients and uninfected controls. Results. LPLUNC1 decreased proinflammatory innate immune responses to V. cholerae and Escherichia coli LPS. The effect of LPLUNC1 was dose-dependent and occurred in a TLR4-dependent manner. LPLUNC1 did not affect lipoprotein-mediated TLR2 activation. Immunostaining demonstrated expression of LPLUNC1 in Paneth cells in cholera patients and controls. Conclusions. Our results demonstrate that LPLUNC1 is expressed in Paneth cells and likely plays a role in modulating host inflammatory responses to V. cholerae infection. Attenuation of innate immune responses to LPS by LPLUNC1 may have implications for the maintenance of immune homeostasis in the intestine. C1 [Shin, Ok S.; Citorik, Robert; Ryan, Edward T.; Calderwood, Stephen B.; LaRocque, Regina C.; Harris, Jason B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Della Pelle, Patricia; Kradin, Richard L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Shin, Ok S.; Ryan, Edward T.; Calderwood, Stephen B.; LaRocque, Regina C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Camilli, Andrew] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Wang, Jennifer P.; Finberg, Robert W.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Uddin, Taher; Bhuiyan, Taufiqur R.; Shirin, Tahmina; Qadri, Firdausi] Int Ctr Diarrheal Dis Res, Lab Sci Div, Dhaka, Bangladesh. [Bingle, Colin D.] Univ Sheffield, Dept Infect & Immun, Acad Unit Resp Med, Sheffield S10 2TN, S Yorkshire, England. [Bingle, Colin D.] Univ Sheffield, Sch Clin Dent, Sheffield S10 2TN, S Yorkshire, England. RP Harris, JB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. EM jbharris@partners.org OI wang, jennifer/0000-0002-2556-9100; Bingle, Colin/0000-0002-5405-6988; Citorik, Robert/0000-0002-6397-5417 FU ICDDR, B: Centre for Health and Population Research; National Institute of Allergy and Infectious Diseases, National Institutes of Health [U01 AI058935, RO3 AI063079, U01 AI077883]; International Research Scientist Development Award [K01 TW07409, K01 TW07144]; Charles H. Hood Foundation; Howard Hughes Medical Institute FX This work was supported by the ICDDR, B: Centre for Health and Population Research; the National Institute of Allergy and Infectious Diseases, National Institutes of Health (U01 AI058935 to S. B. C., RO3 AI063079 to F. Q., and U01 AI077883 to E. T. R.); International Research Scientist Development Award (K01 TW07409 to J. B. H.); Charles H. Hood Foundation Child Health Research Award (J. B. H.); International Research Scientist Development Award (K01 TW07144 to R. C. L.); and Physician-Scientist Early Career Award from the Howard Hughes Medical Institute (R. C. L.). NR 36 TC 18 Z9 20 U1 1 U2 8 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 NOV 1 PY 2011 VL 204 IS 9 BP 1349 EP 1357 DI 10.1093/infdis/jir544 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 828NS UT WOS:000295509300008 PM 21900486 ER PT J AU Kopell, BH Halverson, J Butson, CR Dickinson, M Bobholz, J Harsch, H Rainey, C Kondziolka, D Howland, R Eskandar, E Evans, KC Dougherty, DD AF Kopell, Brian Harris Halverson, Jerry Butson, Christopher R. Dickinson, Mercedes Bobholz, Julie Harsch, Harold Rainey, Charles Kondziolka, Douglas Howland, Robert Eskandar, Emad Evans, Karleyton C. Dougherty, Darin D. TI Epidural Cortical Stimulation of the Left Dorsolateral Prefrontal Cortex for Refractory Major Depressive Disorder SO NEUROSURGERY LA English DT Article DE Cortical stimulation; DLPFC; Major depressive disorder; Neuromodulation; PET ID TRANSCRANIAL MAGNETIC STIMULATION; TREATMENT-RESISTANT DEPRESSION; VAGUS NERVE-STIMULATION; DEEP BRAIN-STIMULATION; RANDOMIZED CONTROLLED-TRIAL; CEREBRAL-BLOOD-FLOW; ELECTROCONVULSIVE-THERAPY; MOTOR CORTEX; BURST STIMULATION; LONG-TERM AB BACKGROUND: A significant number of patients with major depressive disorder are unresponsive to conventional therapies. For these patients, neuromodulation approaches are being investigated. OBJECTIVE: To determine whether epidural cortical stimulation at the left dorsolateral prefrontal cortex is safe and efficacious for major depressive disorder through a safety and feasibility study. METHODS: Twelve patients were recruited in this randomized, single-blind, sham-controlled study with a 104-week follow-up period. The main outcome measures were Hamilton Depression Rating Scale-28 (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Function (GAF), and Quality of Life Enjoyment and Satisfaction (QLES) questionnaire. An electrode was implanted over Brodmann area 9/46 in the left hemisphere. The electrode provided long-term stimulation to this target via its connections to an implanted neurostimulator in the chest. RESULTS: During the sham-controlled phase, there was no statistical difference between sham and active stimulation, although a trend toward efficacy was seen with the active stimulation group. In the open-label phase, we observed a significant improvement in outcome scores for the HDRS, MADRS, and GAF but not the QLES (HDRS: df = 7, F = 7.72, P < .001; MADRS: df = 7, F = 8.2, P < .001; GAF: df = 5, F = 16.87, P < .001; QLES: df = 5, F = 1.32, P > .2; repeated measures ANOVA). With regard to the HDRS, 6 patients had >= 40% improvement, 5 patients had >= 50% improvement, and 4 subjects achieved remission (HDRS < 10) at some point during the study. CONCLUSION: Epidural cortical stimulation of the left dorsolateral prefrontal cortex appears to be a safe and potentially efficacious neuromodulation approach for treatment-refractory major depressive disorder. C1 [Kopell, Brian Harris; Butson, Christopher R.] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Kopell, Brian Harris; Halverson, Jerry; Harsch, Harold; Rainey, Charles] Med Coll Wisconsin, Dept Psychiat, Milwaukee, WI 53226 USA. [Butson, Christopher R.; Dickinson, Mercedes; Bobholz, Julie] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Kondziolka, Douglas] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15260 USA. [Howland, Robert] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Eskandar, Emad] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA USA. [Evans, Karleyton C.; Dougherty, Darin D.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Kopell, BH (reprint author), Med Coll Wisconsin, Dept Neurosurg, 9200 Wisconsin Ave, Milwaukee, WI 53226 USA. EM bkopell@mcw.edu RI Butson, Christopher/J-8034-2013; Howland, Robert/K-6937-2015 OI Butson, Christopher/0000-0002-2319-1263; Howland, Robert/0000-0002-6533-6010 FU Pfizer; Takeda; Novartis; Cyberonics; St. Jude Medical Neuromodulation; Sanofi-aventis; Otsuka; GlaxoSmithKline; Medtronic; Eli Lilly; McNeil; Northstar Neuroscience (Seattle, Washington) FX Dr Kopell was a consultant to Northstar Neuroscience, is on the scientific advisory board of Prism Clinical Imaging, and is a consultant and member of the clinical advisory board of Neurostream Technologies. Dr Butson is a consultant and shareholder of Intelect Medical and a consultant to NeuroPace and Advanced Bionics. Dr Harsch reports the following conflicts of interest: Forest Lab (honorarium, speaker), Pfizer (honorarium, grant, speaker, consultant, principal investigator), Lilly (honorarium, speaker, consultant), AstraZeneca (honorarium, speaker, consultant), Merck (honorarium, speaker), Takeda (educational grant, teaching), e-Medicine (honorarium, editor), Novartis (grant, principal investigator), Cyberonics (grant, principal investigator), St. Jude Medical Neuromodulation (grant, principal investigator), Sanofi-aventis (grant, principal investigator), Otsuka (grant, principal investigator), and GlaxoSmithKline (grant, principal investigator). Dr Kondziolka is a consultant to Elekta Instruments. Dr Eskandar has received a consultant honorarium from Medtronic. Dr Evans has received research support from Cyberonics, Medtronic, and Pfizer and has received an honorarium from Medtronic. Dr Dougherty has the following conflicts of interest to report: Medtronic (research support, consultant, honorarium), Eli Lilly (research support, consultant, honorarium), Brand Ideas (consultant, honorarium), McNeil (research support, consultant, honorarium), Reed Elsevier (consultant, honorarium), and Cyberonics (research support). This study was sponsored by Northstar Neuroscience (Seattle, Washington). At the time of this publication, Northstar Neuroscience has ceased operations. This trial, Assessment of the Safety and Effectiveness of Cortical Stimulation in Subjects With Major Depressive Disorder (PROSPECT), is registered at www.ClinicalTrials.gov; unique identifier, NCT00380042. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 56 TC 21 Z9 21 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD NOV PY 2011 VL 69 IS 5 BP 1015 EP 1029 DI 10.1227/NEU.0b013e318229cfcd PG 15 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 832UV UT WOS:000295835300021 PM 21709597 ER PT J AU Houlahan, K Temple, K Young, M AF Houlahan, Kathleen Temple, Kendal Young, Martha TI CANCER PREVENTION EDUCATION FOR THE HEALTHY CHILD SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Houlahan, Kathleen] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 716 EP 716 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600036 ER PT J AU Steven, D Shusterman, S Reid, J Ingle, A Ahern, C Baruchel, S Glade-Bender, J Ivy, P Grier, H Adamson, P Blaney, S AF Steven, DuBois Shusterman, Suzanne Reid, Joel Ingle, Ashish Ahern, Charlotte Baruchel, Sylvain Glade-Bender, Julie Ivy, Percy Grier, Holcombe Adamson, Peter Blaney, Susan TI TOLERABILITY AND PHARMACOKINETIC PROFILE OF SUNITINIB GIVEN AS A POWDER FORMULATION TO CHILDREN WITH REFRACTORY SOLID TUMORS: A CHILDREN'S ONCOLOGY GROUP STUDY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Steven, DuBois] UCSF Sch Med, Dept Pediat, San Francisco, CA USA. [Shusterman, Suzanne; Grier, Holcombe] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shusterman, Suzanne; Grier, Holcombe] Harvard Univ, Sch Med, Boston, MA USA. [Reid, Joel] Mayo Coll Med, Rochester, NY USA. [Ingle, Ashish] Childrens Oncol Grp, Arcadia, CA USA. [Ahern, Charlotte; Blaney, Susan] Baylor Coll Med, Houston, TX 77030 USA. [Baruchel, Sylvain] Univ Toronto, Toronto, ON, Canada. [Baruchel, Sylvain] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Glade-Bender, Julie] Columbia Univ, New York, NY USA. [Glade-Bender, Julie] Morgan Stanley Childrens Hosp, New York, NY USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Adamson, Peter] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Blaney, Susan] Texas Childrens Canc Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 717 EP 718 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600043 ER PT J AU Lindsay, F Nicholson, J Olson, T Dang, H Krailo, M Billmire, D Thornton, C Hale, J AF Lindsay, Frazier Nicholson, James Olson, Thomas Dang, Ha Krailo, Mark Billmire, Deborah Thornton, Claire Hale, Juliet TI PROGNOSTIC CLASSIFICATION OF PEDIATRIC GERM CELL TUMORS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Lindsay, Frazier] DFCI, Boston, MA USA. [Nicholson, James] Addenbrookes Hosp, Dept Paediat Haematol & Oncol, Cambridge, England. [Olson, Thomas] Emory Univ, Atlanta, GA 30322 USA. [Dang, Ha; Krailo, Mark] Childrens Oncol Grp, Arcadia, CA USA. [Billmire, Deborah] Indiana Univ, James Whitcomb Riley Hosp Children, Bloomington, IN 47405 USA. [Thornton, Claire] Royal Grp Hosp Trust, Belfast, Antrim, North Ireland. [Hale, Juliet] Univ Nottingham Hosp, Natl Hlth Serv, Newcastle Upon Tyne, Tyne & Wear, England. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 743 EP 743 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600146 ER PT J AU Lai, JS Zelko, F Butt, Z Krull, K Manley, P Goldman, S AF Lai, Jin-Shei Zelko, Frank Butt, Zeeshan Krull, Kevin Manley, Peter Goldman, Stewart TI CAN PARENT-REPORTED PERCEIVED COGNITIVE FUNCTION BE USEFUL IN PEDIATRIC ONCOLOGY CLINICS? SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Lai, Jin-Shei; Butt, Zeeshan] Northwestern Univ, Chicago, IL 60611 USA. [Zelko, Frank] Childrens Mem Hosp, Pediat Neuropsychol Serv, Chicago, IL 60614 USA. [Krull, Kevin] St Jude Childrens Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Manley, Peter] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2011 VL 57 IS 5 BP 745 EP 745 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600153 ER PT J AU Yagyu, S Tanaka, S Gotoh, T London, W Misawa-Furihata, A Iehara, T Hogarty, M Teramukai, S Sugimoto, T Nakagawara, A Hiyama, E Maris, J Hosoi, H AF Yagyu, Shigeki Tanaka, Shiro Gotoh, Takahiro London, Wendy Misawa-Furihata, Akiko Iehara, Tomoko Hogarty, Michael Teramukai, Satoshi Sugimoto, Tohru Nakagawara, Akira Hiyama, Eiso Maris, John Hosoi, Hajime TI PROGNOSIS OF NEUROBLASTOMA PATIENTS LESS THAN EIGHTEEN MONTHS OLD USING SERUM-BASED QUANTIFICATION OF MYCN GENE AMPLIFICATION SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Yagyu, Shigeki; Gotoh, Takahiro; Misawa-Furihata, Akiko; Iehara, Tomoko; Sugimoto, Tohru; Hosoi, Hajime] Kyoto Prefectural Univ Med, Dept Pediat, Kyoto 602, Japan. [Tanaka, Shiro; Teramukai, Satoshi] Kyoto Univ Hosp, Dept Clin Trial Design & Management, Kyoto 606, Japan. [London, Wendy] Harvard Univ, Sch Med, Dana Farber Canc Inst, Childrens Hosp Boston,Div Hematol Oncol, Boston, MA 02115 USA. [Hogarty, Michael; Maris, John] Childrens Hosp Philadelphia, Philadelphia, Japan. [Hogarty, Michael; Maris, John] Univ Pennsylvania, Div Oncol, Philadelphia, Japan. [Hogarty, Michael; Maris, John] Ctr Childhood Canc Res, Philadelphia, Japan. [Nakagawara, Akira] Chiba Canc Ctr, Div Biochem & Innovat Canc Therapeut, Chiba 2608717, Japan. [Hiyama, Eiso] Hiroshima Univ, Dept Pediat Surg, Hiroshima, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 788 EP 788 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600326 ER PT J AU Childs, S Nguyen, P Chi, S Marcus, K AF Childs, Stephanie Nguyen, Paul Chi, Susan Marcus, Karen TI INCIDENCE, OUTCOMES, AND PROGNOSTIC FACTORS IN CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMORS (ATRT) USING THE SURVEILLANCE EPIDEMIOLOGY AND END RESULT (SEER) DATA-BASE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Childs, Stephanie] Harvard Radiat Oncol Pmgram, Boston, MA USA. [Nguyen, Paul] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Chi, Susan; Marcus, Karen] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 802 EP 802 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600386 ER PT J AU Slavc, I Peyrl, A Heinrich, M Reismueller, B Azizi, A Kieran, M Czech, T Dieckmann, K AF Slavc, Irene Peyrl, Andreas Heinrich, Monika Reismueller, Bettina Azizi, Amedeo Kieran, Mark Czech, Thomas Dieckmann, Karin TI METRONOMIC AND TARGETED ANTIANGIOGENESIS THERAPY FOR CHILDREN WITH RECURRENT EMBRYONAL BRAIN TUMORS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Slavc, Irene; Peyrl, Andreas; Heinrich, Monika; Reismueller, Bettina; Azizi, Amedeo] Med Univ Vienna, Dept Pediat, Vienna, Austria. [Czech, Thomas] Med Univ Vienna, Dept Neurosurg, Vienna, Austria. [Dieckmann, Karin] Med Univ Vienna, Dept Radiotherapy, Vienna, Austria. [Kieran, Mark] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 804 EP 804 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600394 ER PT J AU Robison, N Campigotta, F Chi, SS Manley, P Turner, C Zimmerman, MA Chordas, C Allen, J Goldman, S Rubin, J Isakoff, M Pan, W Khatib, Z Comito, M Bendel, A Pietrantonio, J Kondrat, L Hubbs, S Neuberg, D Kieran, M AF Robison, Nathan Campigotta, Federico Chi, Susan Manley, Peter Turner, Christopher Zimmerman, Mary Ann Chordas, Christine Allen, Jeffrey Goldman, Stewart Rubin, Joshua Isakoff, Michael Pan, Wilbur Khatib, Ziad Comito, Melanie Bendel, Anne Pietrantonio, Jay Kondrat, Laura Hubbs, Shannon Neuberg, Donna Kieran, Mark TI A PHASE II TRIAL OF A MULTI-AGENT ORAL ANTIANGIOGENIC (METRONOMIC) REGIMEN IN CHILDREN WITH RECURRENT OR PROGRESSIVE CANCER SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Campigotta, Federico; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Chi, Susan; Manley, Peter; Turner, Christopher; Zimmerman, Mary Ann; Chordas, Christine; Pietrantonio, Jay; Kondrat, Laura; Hubbs, Shannon; Kieran, Mark] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Allen, Jeffrey] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Goldman, Stewart] Childrens Mem Hosp, Dept Pediat, Chicago, IL 60614 USA. [Rubin, Joshua] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Isakoff, Michael] Connecticut Childrens Med Ctr, Dept Pediat, Hartford, CT USA. [Pan, Wilbur] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pediat, New Brunswick, NJ 08903 USA. [Khatib, Ziad] Miami Childrens Hosp, Dept Pediat, Miami, FL USA. [Comito, Melanie] Penn State Hershey Childrens Hosp, Dept Pediat, Hershey, PA USA. [Bendel, Anne] Childrens Hosp & Clin Minnesota, Dept Pediat Hematol Oncol, Minneapolis, MN USA. NR 0 TC 2 Z9 2 U1 0 U2 1 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 NOV PY 2011 VL 57 IS 5 BP 815 EP 815 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600438 ER PT J AU Denburg, A Sung, L Joffe, S Howard, S AF Denburg, Avram Sung, Lillian Joffe, Steven Howard, Scott TI PEDIATRIC ONCOLOGY RESEARCH IN LOW INCOME COUNTRIES: ETHICAL CONCEPTS AND CHALLENGES SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Denburg, Avram] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Joffe, Steven] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Howard, Scott] St Jude Childrens Hosp, Memphis, TN 38105 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 835 EP 836 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600524 ER PT J AU Reilly, C Porter, J AF Reilly, Christine Porter, Janet TI PARENT ENGAGEMENT IN DESIGNING CARE AT DANA-FARBER CHILDREN'S HOSPITAL CANCER CENTER SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Reilly, Christine] Dana Farber Childrens Hosp, Ctr Canc, Whitman, MA USA. [Porter, Janet] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2011 VL 57 IS 5 BP 836 EP 836 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 824ZB UT WOS:000295239600527 ER PT J AU Kunadian, V Pride, YB Buros, JL Ciaglo, LN Morrow, DA Gibson, CM AF Kunadian, Vijayalakshmi Pride, Yuri B. Buros, Jacqueline L. Ciaglo, Lauren N. Morrow, David A. Gibson, C. Michael TI Coronary flow reserve varies depending upon the location within the artery it is assessed and the TIMI myocardial perfusion grade: a PROTECT TIMI-30 analysis SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE TIMI myocardial perfusion grade; Corrected TIMI frame count; Coronary flow reserve; Adenosine; Myocardial perfusion ID FRAME COUNT METHOD; INTRACORONARY DOPPLER; REACTIVE HYPEREMIA; BLOOD-FLOW; ANGIOPLASTY; INFARCTION; MECHANISM; VELOCITY AB Coronary flow reserve (CFR) is a measure of the capacity of the epicardial coronary artery and the microvasculature to achieve maximal blood flow in response to hyperemic stimulation. It is not known whether the CFR varies along the length of the artery. Likewise, the interaction between CFR and the thrombolysis in myocardial infarction (TIMI) myocardial perfusion grade (TMPG) is unknown. CFR was measured using the number of cineframes required for the contrast to traverse the same length of the coronary artery before and following the administration of intracoronary adenosine. Following percutaneous coronary intervention (PCI), CFR was assessed both proximal and distal to the lesion in 192 consecutive patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) from the PROTECT TIMI-30 trial. TMPG was also assessed. The difference between the distal and proximal CFR for patients with TMPG 0/1 (n = 76) was 0.11 (95% CI 0.01-0.20, P = 0.026), while among those with TMPG 2/3 (n = 114) it was -0.02 (95% CI -0.09-0.06, P = 0.65). The difference in the CFR between the distal and proximal segments among patients with TMPG 0/1 and TMPG 2/3 was significant (P interaction = 0.044). Following PCI among patients with impaired TMPG (0/1) in the setting of NSTEACS, CFR varies significantly between the proximal and distal segment of coronary arteries and is associated with higher (greater) distal CFR. C1 [Pride, Yuri B.; Buros, Jacqueline L.; Ciaglo, Lauren N.; Gibson, C. Michael] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Cardiovasc Div,Dept Med,PERFUSE Study Grp, Boston, MA 02115 USA. [Kunadian, Vijayalakshmi] Newcastle Univ, Inst Cellular Med, Fac Med Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Kunadian, Vijayalakshmi] Newcastle Upon Tyne Hosp NHS Fdn Trust, Freeman Hosp, Newcastle Upon Tyne, Tyne & Wear, England. [Morrow, David A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiovasc Div,Dept Med,TIMI Study Grp, Boston, MA 02115 USA. RP Gibson, CM (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Cardiovasc Div,Dept Med,PERFUSE Study Grp, Boston, MA 02115 USA. EM mgibson@perfuse.org OI Buros, Jacqueline/0000-0001-9588-4889 FU Schering-Plough Research Institute in Kennilworth, NJ FX PROTECT-TIMI 30 was supported in part by a grant from Schering-Plough Research Institute in Kennilworth, NJ. NR 13 TC 2 Z9 4 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD NOV PY 2011 VL 32 IS 4 BP 448 EP 452 DI 10.1007/s11239-011-0617-2 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 826CW UT WOS:000295330000009 PM 21713377 ER PT J AU Sarma, SV Nguyen, DP Czanner, G Wirth, S Wilson, MA Suzuki, W Brown, EN AF Sarma, Sridevi V. Nguyen, David P. Czanner, Gabriela Wirth, Sylvia Wilson, Matthew A. Suzuki, Wendy Brown, Emery N. TI Computing Confidence Intervals for Point Process Models SO NEURAL COMPUTATION LA English DT Article ID RECEPTIVE-FIELD PLASTICITY; CORTEX; HIPPOCAMPUS; MONKEYS; ADULT; MAP AB Characterizing neural spiking activity as a function of intrinsic and extrinsic factors is important in neuroscience. Point process models are valuable for capturing such information; however, the process of fully applying these models is not always obvious. A complete model application has four broad steps: specification of the model, estimation of model parameters given observed data, verification of the model using goodness of fit, and characterization of the model using confidence bounds. Of these steps, only the first three have been applied widely in the literature, suggesting the need to dedicate a discussion to how the time-rescaling theorem, in combination with parametric bootstrap sampling, can be generally used to compute confidence bounds of point process models. In our first example, we use a generalized linear model of spiking propensity to demonstrate that confidence bounds derived from bootstrap simulations are consistent with those computed from closed-form analytic solutions. In our second example, we consider an adaptive point process model of hippocampal place field plasticity for which no analytical confidence bounds can be derived. We demonstrate how to simulate bootstrap samples from adaptive point process models, how to use these samples to generate confidence bounds, and how to statistically test the hypothesis that neural representations at two time points are significantly different. These examples have been designed as useful guides for performing scientific inference based on point process models. C1 [Sarma, Sridevi V.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. [Nguyen, David P.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neurosci Stat Res Lab, Boston, MA 02114 USA. [Nguyen, David P.; Wilson, Matthew A.; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Czanner, Gabriela] Univ Warwick, Warwick Mfg Grp, Coventry CV4 7AL, W Midlands, England. [Czanner, Gabriela] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Wirth, Sylvia] CNRS, Inst Cognit Sci, F-69675 Bron, France. [Suzuki, Wendy] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Neurosci Stat Res Lab, Boston, MA 02114 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Sarma, SV (reprint author), Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. EM sree@jhu.edu; dpnguyen@alum.mit.edu; gabriela.czanner@warwick.ac.uk; swirth@isc.cnrs.fr; mwilson@mit.edu; wendy@cns.nyu.edu; enb@neurostat.mit.edu FU Burrough's Wellcome Fund; L'Oreal for Women in Science fellowship; NIH [MH59733, DP1 OD003646-01, DA015644, MH58847]; McKnight Foundation; John Merck Scholars Award FX We thank Uri Eden for valuable discussions. Support was provided by Burrough's Wellcome Fund and L'Oreal for Women in Science fellowship to S. V. S, NIH MH59733 and NIH Pioneer Award DP1 OD003646-01 to E.N.B, NIH DA015644 to E.N.B. and W. A. S., NIH MH58847 to W. A. S., a McKnight Foundation grant to W. A. S., and a John Merck Scholars Award to W.A.S. NR 28 TC 4 Z9 4 U1 0 U2 4 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD NOV PY 2011 VL 23 IS 11 BP 2731 EP 2745 PG 15 WC Computer Science, Artificial Intelligence; Neurosciences SC Computer Science; Neurosciences & Neurology GA 825ZO UT WOS:000295321100001 PM 21851280 ER PT J AU Tantawy, MN Peterson, TE Jones, CK Johnson, K Rook, JM Conn, PJ Baldwin, RM Ansari, MS Kessler, RM AF Tantawy, Mohammed N. Peterson, Todd E. Jones, Carrie K. Johnson, Kari Rook, Jerri M. Conn, P. Jeffrey Baldwin, Ronald M. Ansari, M. Sib Kessler, Robert M. TI Impact of Isoflurane Anesthesia on D2 Receptor Occupancy by [F-18]fallypride Measured by MicroPET With a Modified Logan Plot SO SYNAPSE LA English DT Article DE [F-18]fallypride; dopamine (DA) receptors; isoflurane; graphical analysis; microPET ID POSITRON-EMISSION-TOMOGRAPHY; DOPAMINE RELEASE; RAT-BRAIN; NONHUMAN-PRIMATES; IN-VIVO; BINDING; PET; RADIOLIGAND; STRIATUM; REGIONS AB In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [F-18] fallypride administration to estimate the distribution volume ratio DVR' (DVR' proportional to DVR; DVR = 1 + BPND, where BPND is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [F-18] fallypride DVR'. Methods: Rats were injected with [F-18] fallypride either unconsciously under similar to 1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [F-18]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [F-18]fallypride i.v. while under 1.5% isoflurane. The DVR' estimates from the 60 min acquisitions were compared with the DVR' from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time-activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k(3)/k(4) (approximate to BPND) for the 60 and 120 min acquisitions. Results: Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR' estimates, which were 15.7 +/- 0.3 (mean +/- SE) for the controls, 17.7 +/- 0.3 for Group 1, 19.2 +/- 0.4 for Group 2, and 18.8 +/- 0.7 for Group 3. The compartmental model fit produced similar results, similar to 30% reduction in k(3)/k(4) for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer). Conclusion: The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [F-18] fallypride BPND in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors. Synapse 65:1173-1180, 2011. (C) 2011 Wiley-Liss, Inc. C1 [Tantawy, Mohammed N.; Peterson, Todd E.; Baldwin, Ronald M.; Ansari, M. Sib; Kessler, Robert M.] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA. [Tantawy, Mohammed N.; Peterson, Todd E.; Baldwin, Ronald M.] Vanderbilt Univ, Med Ctr, Inst Imaging Sci, Nashville, TN 37232 USA. [Jones, Carrie K.; Johnson, Kari; Rook, Jerri M.; Conn, P. Jeffrey] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Jones, Carrie K.; Johnson, Kari; Rook, Jerri M.; Conn, P. Jeffrey] Vanderbilt Univ, Med Ctr, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA. [Jones, Carrie K.] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. EM n.tantawy@vanderbilt.edu RI Conn, Peter/D-7848-2012 FU NCRR [1S10 RR17858]; Burroughs Welcome Fund FX Contract grant sponsor: NCRR; Contract grant number: 1S10 RR17858; The authors thank Jarrod True, Zou Yue, and Silvia Cambronero for their assistance with the animal handling and injections. The research of Todd E. Peterson, Ph.D. is supported by a Career Award at the Scientific Interface from the Burroughs Welcome Fund. NR 35 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-4476 J9 SYNAPSE JI Synapse PD NOV PY 2011 VL 65 IS 11 BP 1173 EP 1180 DI 10.1002/syn.20955 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 827UU UT WOS:000295455100007 PM 21584868 ER PT J AU Tran, HT Barnich, N Mizoguchi, E AF Tran, Hoa T. Barnich, Nicolas Mizoguchi, Emiko TI Potential role of chitinases and chitin-binding proteins in host-microbial interactions during the development of intestinal inflammation SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Review DE Chitinase; Inflammatory bowel disease; Bacteria; Colonic epithelial cells; CEACAM ID INVASIVE ESCHERICHIA-COLI; BACILLUS-CIRCULANS WL-12; FIBROSIS EPIDEMIC STRAIN; COLONIC EPITHELIAL-CELLS; CROHNS-DISEASE; PSEUDOMONAS-AERUGINOSA; VIBRIO-CHOLERAE; GENE-EXPRESSION; ILEAL MUCOSA; SERRATIA-MARCESCENS AB The small and large intestines contain an abundance of luminal antigens derived from food products and enteric microorganisms. The function of intestinal epithelial cells is tightly regulated by several factors produced by enteric bacteria and the epithelial cells themselves. Epithelial cells actively participate in regulating the homeostasis of intestine, and failure of this function leads to abnormal and host-microbial interactions resulting in the development of intestinal inflammation. Major determinants of host susceptibility against luminal commensal bacteria include genes regulating mucosal immune responses, intestinal barrier function and microbial defense. Of note, it has been postulated that commensal bacterial adhesion and invasion on/into host cells may be strongly involved in the pathogenesis of inflammatory bowel disease (IBD). During the intestinal inflammation, the composition of the commensal flora is altered, with increased population of aggressive and detrimental bacteria and decreased populations of protective bacteria. In fact, some pathogenic bacteria, including Adherent-Invasive Escherichia coli, Listeria monocytogenes and Vibrio cholerae are likely to initiate their adhesion to the host cells by expressing accessory molecules such as chitinases and/or chitin-binding proteins on themselves. In addition, several inducible molecules (e.g., chitinase 3-like 1, CEACAM6) are also induced on the host cells (e.g. epithelial cells, lamina proprial macrophages) under inflammatory conditions, and are actively participated in the host-microbial interactions. In this review, we will summarize and discuss the potential roles of these important molecules during the development of acute and chronic inflammatory conditions. C1 [Tran, Hoa T.; Mizoguchi, Emiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA 02114 USA. [Barnich, Nicolas] Univ Clermont 1, Inst Natl Rech Agnom 2018, JE2526, Unite Contrat, Clermont Ferrand, France. [Barnich, Nicolas] Inst Univ Technol Genie Biol, Aubiere, France. [Mizoguchi, Emiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Mizoguchi, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, GRJ 825D,55 Fruit St, Boston, MA 02114 USA. EM emizoguchi@partners.org FU National Institute of Health [DK 80070, DK74454, DK64289, DK43351]; Eli and Edythe L. Broad Medical Foundation; American Gastroenterological Association Foundation FX We would like to thank Mr. Terry Danford Lott and Ms. Cindy W. Lau for their excellent assistance in preparing this manuscript. This work has been supported by National Institute of Health (DK 80070, DK74454, DK64289 and DK43351), and grants from the Eli and Edythe L. Broad Medical Foundation and American Gastroenterological Association Foundation to EM. NR 91 TC 18 Z9 20 U1 0 U2 13 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD NOV PY 2011 VL 26 IS 11 BP 1453 EP 1464 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 823LN UT WOS:000295123900010 PM 21938682 ER PT J AU Ng, KK Thatte, HS Spector, M AF Ng, Karen K. Thatte, Hemant S. Spector, Myron TI Chondrogenic differentiation of adult mesenchymal stem cells and embryonic cells in collagen scaffolds SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE cartilage tissue engineering; mesenchymal stem cell; embryonic cell; collagen scaffold ID SMOOTH-MUSCLE ACTIN; CARCINOMA-CELLS; IN-VITRO; CROSS-LINKING; PROGENITOR CELLS; RETINOIC ACID; GAG SCAFFOLDS; MARROW; MODEL; CONTRACTION AB Many cell types and cellular microenvironments have been explored for articular cartilage tissue engineering. We compared the potential of bone marrow-derived mesenchymal stem cells (MSCs) and P19 embryonic carcinoma cells (ECCs), a pluripotent derivative of embryonic stem cells (ESCs), for cartilage histogenesis in porous collagen scaffolds in vitro. We found that while both MSCs and ECCs express alpha-smooth muscle actin (alpha-SMA), only MSCs exhibit condensation and contraction necessary for cartilage histogenesis. Furthermore, histology confirmed that only MSCs exhibited sulfated glycosaminoglycans and collagen type II formation after 14 days in culture. We conclude that MSCs appear to be superior over ECCs for cartilage regeneration under particular culture conditions. The alpha-SMA-expressing ECCs may not have contracted due to the absence of actin unit polymerization or the absence of myosin molecules. Our observations may explain the absence of a contractile scar in fetal wound healing. 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 99A: 275-282, 2011. C1 [Ng, Karen K.; Spector, Myron] MIT, Cambridge, MA 02139 USA. [Ng, Karen K.; Thatte, Hemant S.; Spector, Myron] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Thatte, Hemant S.; Spector, Myron] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Spector, M (reprint author), MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mspector@rics.bwh.harvard.edu FU Department of Veterans Affairs; Veterans Health Administration; Rehabilitation Research and Development Service FX Contract grant sponsors: Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service NR 34 TC 14 Z9 14 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1549-3296 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD NOV PY 2011 VL 99A IS 2 BP 275 EP 282 DI 10.1002/jbm.a.33163 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 823RQ UT WOS:000295142400015 PM 21858916 ER PT J AU Ticozzi, N LeClerc, AL van Blitterswijk, M Keagle, P McKenna-Yasek, DM Sapp, PC Silani, V Wills, AM Brown, RH Landers, JE AF Ticozzi, Nicola LeClerc, Ashley Lyn van Blitterswijk, Marka Keagle, Pamela McKenna-Yasek, Diane M. Sapp, Peter C. Silani, Vincenzo Wills, Anne-Marie Brown, Robert H., Jr. Landers, John E. TI Mutational analysis of TARDBP in neurodegenerative diseases SO NEUROBIOLOGY OF AGING LA English DT Article DE ALS; PD; AD; Genetics; TARDBP; TDP-43 ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; TDP-43 IMMUNOREACTIVITY; ALZHEIMERS-DISEASE; CLINICAL-DIAGNOSIS AB Neurodegenerative diseases are often characterized by the presence of aggregates of misfolded proteins. TDP-43 is a major component of these aggregates in amyotrophic lateral sclerosis (ALS), but has also been observed in Alzheimer's (AD) and Parkinson's Diseases (PD). In addition, mutations in the TARDBP gene, encoding TDP-43, have been found to be a significant cause of familial ALS (FALS). All mutations, except for one, have been found in exon 6. To confirm this observation in ALS and to investigate whether TARDBP may play a role in the pathogenesis of AD and PD, we screened for mutations in exon 6 of the TARDBP gene in three cohorts composed of 376 AD, 463 PD (18% familial PD) and 376 ALS patients (50% FALS). We found mutations in similar to 7% of FALS and similar to 0.5% of sporadic ALS (SALS) patients, including two novel mutations, p.N352T and p.G384R. In contrast, we did not find TARDBP mutations in our cohort of AD and PD patients. These results suggest that mutations in TARDBP are not a significant cause of AD and PD. (C) 2009 Elsevier Inc. All rights reserved. C1 [Ticozzi, Nicola; LeClerc, Ashley Lyn; van Blitterswijk, Marka; Keagle, Pamela; McKenna-Yasek, Diane M.; Sapp, Peter C.; Brown, Robert H., Jr.; Landers, John E.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01605 USA. [Ticozzi, Nicola; Silani, Vincenzo] Univ Milan, IRCCS Ist Auxol Italiano, Dino Ferrari Ctr, Dept Neurol, I-20149 Milan, Italy. [Ticozzi, Nicola; Silani, Vincenzo] Univ Milan, IRCCS Ist Auxol Italiano, Dino Ferrari Ctr, Neurosci Lab, I-20149 Milan, Italy. [Sapp, Peter C.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Sapp, Peter C.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Wills, Anne-Marie] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02129 USA. RP Landers, JE (reprint author), LRB604,364 Plantat St, Worcester, MA 01605 USA. EM n.ticozzi@fastwebnet.it; ashley.leclerc@umassmed.edu; marka.van-blitterswijk@umassmed.edu; pamela.keagle@umassmed.edu; diane.mckenna-yasek@umassmed.edu; peter.sapp@umassmed.edu; vincenzo@silani.com; awills@partners.org; brownrhjr@aol.com; john.landers@umassmed.edu RI van Blitterswijk, Marka/H-7274-2012; Ticozzi, Nicola/K-8094-2016; OI van Blitterswijk, Marka/0000-0002-3054-7053; Ticozzi, Nicola/0000-0001-5963-7426; Silani, Vincenzo/0000-0002-7698-3854 FU ALS Therapy Alliance; Angel Fund; Pierre L. de Bourgknecht ALS Research Foundation; Al-Athel ALS Research Foundation; ALS Family Charitable Foundation; NINDS [NS050557]; Italian Ministry of Health [Art.56, 533F/N1]; Howard Hughes Medical Institute (HHMI); National Parkinson Foundation; NIH [5P50NS038372-10]; Project ALS FX A special thanks to the patients and their caregivers. Generous support was provided by the ALS Therapy Alliance, Project ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation and the NINDS (NS050557). NT and VS were supported by the Italian Ministry of Health (Malattie Neurodegenerative, ex Art.56, n.533F/N1). PS was supported by the Howard Hughes Medical Institute (HHMI) through the auspices of Prof. H. Robert Horvitz, an Investigator in the HHMI. The MGH PD DNA Bank is supported by the National Parkinson Foundation and the NIH (5P50NS038372-10). NR 20 TC 18 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD NOV PY 2011 VL 32 IS 11 BP 2096 EP 2099 DI 10.1016/j.neurobiolaging.2009.11.018 PG 4 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 824RV UT WOS:000295220700017 PM 20031275 ER PT J AU Klein, AA Slaymaker, VJ Kelly, JF AF Klein, Audrey A. Slaymaker, Valerie J. Kelly, John F. TI The 12 Step Affiliation and Practices Scale: Development and initial validation of a measure assessing 12 step affiliation SO ADDICTIVE BEHAVIORS LA English DT Article DE 12 Step affiliation; Psychometric; Alcohol dependence ID CHEMICAL DEPENDENCY TREATMENT; 12-STEP PARTICIPATION; INPATIENT TREATMENT; RELIABILITY; ABSTINENCE; MODEL; QUESTIONNAIRE; ADOLESCENTS; ATTENDANCE; MEDIATORS AB Objective: Research on instruments designed to measure endorsement of 12 step beliefs and practices among individuals with substance use disorders is virtually nonexistent. The goal of this study was to examine the psychometric properties of a novel instrument called the 12 Step Affiliation and Practices Scale (TSAPS) using a sample of young adults receiving 12 step-based residential treatment for alcohol and drug dependence. Method: As part of a naturalistic treatment outcome study, 300 young adults receiving residential treatment completed the TSAPS and several other assessments during and after treatment. Analyses of the TSAPS examined its factor structure, internal consistency, sensitivity to change over time, and convergent and predictive validity. Results: A maximum likelihood estimation factor analysis using oblique rotation produced 4 factors accounting for 61.16% of the variance. Internal consistency was very high and scores on the TSAPS significantly increased across the course of treatment. Convergent validity was demonstrated by relationships with scales of treatment attitudes, twelve step expectancies and commitment to sobriety. Predictive validity was also found, as evidenced by a relationship between total TSAPS score at 3 months post-treatment and percent of abstinent days at 6 months post-treatment. Conclusions: The TSAPS shows promise as a psychometrically sound, internally reliable measure of 12 step affiliation and practices among individuals with substance dependence. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Klein, Audrey A.; Slaymaker, Valerie J.] Hazelden Fdn, Hazelden Butler Ctr Res, Center City, MN USA. [Kelly, John F.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Addict Med,Dept Psychiat, Cambridge, MA 02138 USA. RP Klein, AA (reprint author), 15251 Pleasant Valley Rd,BC4, Center City, MN 55012 USA. EM aklein@hazelden.org FU NIAAA NIH HHS [R21 AA018185] NR 27 TC 2 Z9 2 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD NOV PY 2011 VL 36 IS 11 BP 1045 EP 1051 DI 10.1016/j.addbeh.2011.06.011 PG 7 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 821OM UT WOS:000294984300004 PM 21764222 ER PT J AU Doyle, SR Donovan, DM Simpson, TL AF Doyle, Suzanne R. Donovan, Dennis M. Simpson, Tracy L. TI Validation of a nine-dimensional measure of drinking motives for use in clinical applications: The desired effects of drinking scale SO ADDICTIVE BEHAVIORS LA English DT Article DE Drinking motives; Confirmatory factor analysis; Concurrent validity; Predictive validity ID ALCOHOL-RELATED PROBLEMS; COLLEGE-STUDENTS; YOUNG-PEOPLE; REASONS; EXPECTANCIES; SAMPLE; QUESTIONNAIRE; DRINKERS; BEHAVIOR; INSTRUMENT AB The Desired Effects of Drinking (DEOD) is a 36-item, 9-subscale, self-report measure assessing reasons for drinking, concerning three general motives for alcohol use: Coping, Social, and Enhancement. These subscales include Negative Feelings, Self-esteem, Relief, Positive Feelings, Social Facilitation, Assertion, Drug Effects, Sexual Enhancement, and Mental effects. As part of the COMBINE study, scores from the nine DEOD subscales, along with additional information about alcohol consumption and consequences, were incorporated into personalized client feedback as part of a motivational enhancement intervention and as a guide for the development of a plan for treatment and change. With responses from a clinical sample of 572 individuals seeking alcohol treatment, the 9-subscale structure of the instrument was substantiated through a second-order confirmatory factor analysis, revealing moderately large to large factor loadings and good indices of model fit. A third-order factor analysis indicated these nine subscales adequately represented the three drinking motives. It is suggested these three general motives for alcohol use, which may be more distinctly delineated into the nine dimensions reflected in the DEOD structure, can be used clinically to help plan appropriate interventions and facilitate behavior change. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Doyle, Suzanne R.; Donovan, Dennis M.] Univ Washington, Alcohol & Drug Abuse Inst, Seattle, WA 98105 USA. [Donovan, Dennis M.; Simpson, Tracy L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Doyle, SR (reprint author), Univ Washington, Alcohol & Drug Abuse Inst, 1107 NE 45th St,Suite 120, Seattle, WA 98105 USA. EM srdoyle@u.washington.edu FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U10AA11715, 11716, 11721, 11727, 11756, 11768, 11773, 11776, 11777, 11783, 11787, 11799]; Combine Study Research Group; [U10AA011799] FX The authors gratefully acknowledge support of the COMBINE study by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) through Cooperative Agreements U10AA11715, 11716, 11721, 11727, 11756, 11768, 11773, 11776, 11777, 11783, 11787, 11799, and 11773.; Data presented in this report were collected as part of the multisite COMBINE trial Sponsored by the National Institute on Alcohol Abuse and Alcoholism, in collaboration with the Combine Study Research Group. Preparation of this report was supported in part by grant U10AA011799. A full listing of the staff of the COMBINE study can be found at http://www.cscc.unc.edu/combine/. NR 64 TC 12 Z9 12 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD NOV PY 2011 VL 36 IS 11 BP 1052 EP 1060 DI 10.1016/j.addbeh.2011.06.012 PG 9 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 821OM UT WOS:000294984300005 PM 21782346 ER PT J AU Furuno, JP Johnson, JK Schweizer, ML Uche, A Stine, OC Shurland, SM Forrest, GN AF Furuno, Jon P. Johnson, Jennifer K. Schweizer, Marin L. Uche, Anayochukwu Stine, Oscar C. Shurland, Simone M. Forrest, Graeme N. TI Community-associated Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis among HIV Patients: A cohort study SO BMC INFECTIOUS DISEASES LA English DT Article ID INJECTION-DRUG USERS; INFECTIVE ENDOCARDITIS; RISK-FACTORS; ANTIRETROVIRAL THERAPY; ANTIBIOTIC-THERAPY; MRSA BACTEREMIA; UNITED-STATES; MORTALITY; USA300; STRAINS AB Background: HIV patients are at increased risk of development of infections and infection-associated poor health outcomes. We aimed to 1) assess the prevalence of USA300 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) among HIV-infected patients with S. aureus bloodstream infections and. 2) determine risk factors for infective endocarditis and in-hospital mortality among patients in this population. Methods: All adult HIV-infected patients with documented S. aureus bacteremia admitted to the University of Maryland Medical Center between January 1, 2003 and December 31, 2005 were included. CA-MRSA was defined as a USA300 MRSA isolate with the MBQBLO spa-type motif and positive for both the arginine catabolic mobile element and Panton-Valentin Leukocidin. Risk factors for S. aureus-associated infective endocarditis and mortality were determined using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Potential risk factors included demographic variables, comorbid illnesses, and intravenous drug use. Results: Among 131 episodes of S. aureus bacteremia, 85 (66%) were MRSA of which 47 (54%) were CA-MRSA. Sixty-three patients (48%) developed endocarditis and 10 patients (8%) died in the hospital on the index admission Patients with CA-MRSA were significantly more likely to develop endocarditis (OR = 2.73, 95% CI = 1.30, 5.71). No other variables including comorbid conditions, current receipt of antiretroviral therapy, pre-culture severity of illness, or CD4 count were significantly associated with endocarditis and none were associated with in-hospital mortality. Conclusions: CA-MRSA was significantly associated with an increased incidence of endocarditis in this cohort of HIV patients with MRSA bacteremia. In populations such as these, in which the prevalence of intravenous drug use and probability of endocarditis are both high, efforts must be made for early detection, which may improve treatment outcomes. C1 [Forrest, Graeme N.] Portland VA Med Ctr, Div Infect Dis, Portland, OR USA. [Forrest, Graeme N.] Oregon Hlth & Sci Univ, Portland, OR USA. [Furuno, Jon P.] Oregon State Univ, Oregon Hlth & Sci Coll Pharm, Dept Pharm Practice, Portland, OR USA. [Johnson, Jennifer K.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Schweizer, Marin L.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Furuno, Jon P.; Stine, Oscar C.; Shurland, Simone M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Uche, Anayochukwu] Oro Valley Hosp, Oro Valley, AZ USA. [Shurland, Simone M.] US FDA, Silver Spring, MD USA. RP Forrest, GN (reprint author), Portland VA Med Ctr, Div Infect Dis, Portland, OR USA. EM forrestg@ohsu.edu FU National Institutes of Health [M01 RR16500]; University of Maryland General Clinical Research Center [1K01AI071015-03, 1K12RR023250-04]; Southern Medical Association; Cubist Pharmaceuticals, Inc.; Pfizer Inc. FX National Institutes of Health Grants M01 RR16500, University of Maryland General Clinical Research Center, 1K01AI071015-03 (J.P.F.) and 1K12RR023250-04 (J.K.J.) and a grant from the Southern Medical Association (A.U.).; In the past 5 years J.P.F. and M.L.S. have served as consults for Cubist Pharmaceuticals, Inc. Also, G.N.F. has received research funding and honoraria from Cubist Pharmaceuticals, Inc. and Pfizer Inc. M.L.S. has received research funding from Pfizer, Inc. NR 43 TC 20 Z9 21 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD OCT 31 PY 2011 VL 11 AR 298 DI 10.1186/1471-2334-11-298 PG 7 WC Infectious Diseases SC Infectious Diseases GA 846MX UT WOS:000296909000001 PM 22040268 ER PT J AU Brunet, A Ashbaugh, AR Saumier, D Nelson, M Pitman, RK Tremblay, J Roullet, P Birmes, P AF Brunet, Alain Ashbaugh, Andrea R. Saumier, Daniel Nelson, Marina Pitman, Roger K. Tremblay, Jacques Roullet, Pascal Birmes, Philippe TI Does reconsolidation occur in humans: a reply SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Editorial Material ID FEAR; PROPRANOLOL; EXTINCTION; MEMORIES; REACTIVATION; ATTENUATION; DISORDER; RETURN C1 [Brunet, Alain; Ashbaugh, Andrea R.; Saumier, Daniel; Nelson, Marina; Tremblay, Jacques] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. [Pitman, Roger K.] Massachusetts Gen Hosp, Charlestown, MA USA. [Pitman, Roger K.] Harvard Univ, Sch Med, Charlestown, MA USA. [Roullet, Pascal] Univ Toulouse 3, CRCA, F-31062 Toulouse, France. [Birmes, Philippe] Univ Toulouse UPS, Toulouse, France. [Birmes, Philippe] CHU Toulouse, Toulouse, France. RP Brunet, A (reprint author), McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. EM alain.brunet@mcgill.ca NR 10 TC 13 Z9 13 U1 3 U2 18 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD OCT 31 PY 2011 VL 5 AR 74 DI 10.3389/fnbeh.2011.00074 PG 2 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 844EQ UT WOS:000296730900001 PM 22065414 ER PT J AU Poulin, SP Dautoff, R Morris, JC Barrett, LF Dickerson, BC AF Poulin, Stephane P. Dautoff, Rebecca Morris, John C. Barrett, Lisa Feldman Dickerson, Bradford C. CA Alzheimers Dis Neuroimaging Initia TI Amygdala atrophy is prominent in early Alzheimer's disease and relates to symptom severity SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Hippocampus; Magnetic resonance imaging; Neuropsychiatric symptoms ID MILD COGNITIVE IMPAIRMENT; MEDIAL TEMPORAL ATROPHY; MEMORY IMPAIRMENT; INTRACRANIAL VOLUME; EARLY-STAGE; MRI; HIPPOCAMPUS; DISORDERS; DEMENTIA; PLAQUES AB Despite numerous studies on the role of medial temporal lobe structures in Alzheimer's disease (AD), the magnitude and clinical significance of amygdala atrophy have been relatively sparsely investigated. In this study, we used magnetic resonance imaging (MRI) to compare the level of amygdala atrophy to that of the hippocampus in very mild and mild AD subjects in two large samples (Sample 1 n = 90; Sample 2 n = 174). Using a series of linear regression analyses, we investigated whether amygdala atrophy is related to global cognitive functioning (Clinical Dementia Rating Sum of Boxes: CDR-SB: Mini Mental State Examination: MMSE) and neuropsychiatric status. Results indicated that amygdala atrophy was comparable to hippocampal atrophy in both samples. MMSE and CDR-SB were strongly related to amygdala atrophy, with amygdala atrophy predicting MMSE scores as well as hippocampal atrophy, but predicting CDR-SB scores less robustly. Amygdala atrophy was related to aberrant motor behavior, with potential relationships to anxiety and irritability. These results suggest that the magnitude of amygdala atrophy is comparable to that of the hippocampus in the earliest clinical stages of AD, and is related to global illness severity. There also appear to be specific relationships between the level of amygdala atrophy and neuropsychiatric symptoms that deserve further investigation. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Poulin, Stephane P.; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Dautoff, Rebecca; Barrett, Lisa Feldman; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Frontotemporal Dementia Unit, Boston, MA 02114 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Massachusetts Alzheimers Dis Res Ctr, Boston, MA 02114 USA. [Poulin, Stephane P.; Barrett, Lisa Feldman; Dickerson, Bradford C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Poulin, Stephane P.; Dautoff, Rebecca; Barrett, Lisa Feldman; Dickerson, Bradford C.] Harvard Univ, Sch Med, Boston, MA USA. [Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Morris, John C.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Morris, John C.] Washington Univ, Sch Med, Alzheimers Dis Res Ctr, St Louis, MO USA. RP Dickerson, BC (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM spoulin@nmr.mgh.harvard.edu; dautoff@nmr.mgh.harvard.edu; morrisj@abraxas.wustl.edu; lisa@affective-science.org; bradd@nmr.mgh.harvard.edu RI Morris, John/A-1686-2012 FU Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; NIH [P30 AG010129, K01 AG030514]; Dana Foundation; Laval University, Quebec City, Canada; [R01-AG029411]; [R21-AG029840]; [P50-AG05134]; [P50-AG05681]; [P01-AG003991]; [U24-RR021382]; [R01-MH56584]; [R01-AG030311]; [DP1OD003312] FX Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F: Hoffman-La Roche, Schering-Plough, Synarc, Inc., as well as non-profit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the U.S. Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. This work was also supported by R01-AG029411, R21-AG029840, P50-AG05134, P50-AG05681, and P01-AG003991, U24-RR021382, R01-MH56584, R01-AG030311, and DP1OD003312. This work was supported in part by the McLaughlin Dean's grant, Laval University, Quebec City, Canada. NR 45 TC 73 Z9 76 U1 3 U2 23 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 OCT 31 PY 2011 VL 194 IS 1 BP 7 EP 13 DI 10.1016/j.pscychresns.2011.06.014 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 841VW UT WOS:000296544300002 PM 21920712 ER PT J AU Milane, L Ganesh, S Shah, S Duan, ZF Amiji, M AF Milane, Lara Ganesh, Shanthi Shah, Shruti Duan, Zhen-feng Amiji, Mansoor TI Multi-modal strategies for overcoming tumor drug resistance: Hypoxia, the Warburg effect, stem cells, and multifunctional nanotechnology SO JOURNAL OF CONTROLLED RELEASE LA English DT Article; Proceedings Paper CT 15th International Symposium on Recent Advances in Drug Delivery Systems CY FEB 13-16, 2011 CL Salt Lake City, UT SP Samyang Co, Abbott Vasc, Watson Pharmaceut, CibaVis, NOF, Boryung Pharmaceut, Green Cross, Kanarb, Univ Utah Coll Pharm, Teikoku Seiyako, Shiseido DE Tumor hypoxia; Warburg's effect; Multidrug resistance; Cancer-initiating (stem) cells; Multifunctional nanoparticles ID IN-VIVO REVERSAL; MULTIDRUG-RESISTANCE; CANCER-CELLS; P-GLYCOPROTEIN; BREAST-CANCER; TARGETED DELIVERY; RNA INTERFERENCE; GENE DELIVERY; SOLID TUMOR; GLUCOSYLCERAMIDE SYNTHASE AB Inefficiencies in systemic drug delivery and tumor residence as well as micro-environmental selection pressures contribute to the development of multidrug resistance (MDR) in cancer. Characteristics of MDR include abnormal vasculature, regions of hypoxia, up-regulation of ABC-transporters, aerobic glycolysis, and an elevated apoptotic threshold. Nano-sized delivery vehicles are ideal for treating MDR cancer as they can improve the therapeutic index of drugs and they can be engineered to achieve multifunctional parameters. The multifunctional ability of nanocarriers makes them more adept at treating heterogeneous tumor mass than traditional chemotherapy. Nanocarriers also have preferential tumor accumulation via the EPR effect; this accumulation can be further enhanced by actively targeting the biological profile of MDR cells. Perhaps the most significant benefit of using nanocarrier drug delivery to treat MDR cancer is that nanocarrier delivery diverts the effects of ABC-transporter mediated drug efflux; which is the primary mechanism of MDR. This review discusses the capabilities, applications, and examples of multifunctional nanocarriers for the treatment of MDR. This review emphasizes multifunctional nanocarriers that enhance drug delivery efficiency, the application of RNAi, modulation of the tumor apoptotic threshold, and physical approaches to overcome MDR. (C) 2011 Elsevier B.V. All rights reserved. C1 [Milane, Lara; Ganesh, Shanthi; Shah, Shruti; Amiji, Mansoor] Northeastern Univ, Sch Pharm, Dept Pharmaceut Sci, Boston, MA 02115 USA. [Duan, Zhen-feng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. RP Amiji, M (reprint author), Northeastern Univ, Sch Pharm, Dept Pharmaceut Sci, 360 Huntington Ave, Boston, MA 02115 USA. EM m.amiji@neu.edu RI Amiji, Mansoor/A-4365-2014 OI Amiji, Mansoor/0000-0001-6170-881X FU NCI NIH HHS [R01-CA119617, R01 CA119617, R01 CA119617-01, R01 CA119617-02, R01 CA119617-03, R01 CA119617-04, R01 CA119617-04S1, R01-CA119617S1, R21 CA135594, R21 CA135594-01A2, R21 CA135594-02, U01 CA151452, U01-CA151452] NR 125 TC 57 Z9 59 U1 3 U2 62 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD OCT 30 PY 2011 VL 155 IS 2 BP 237 EP 247 DI 10.1016/j.jconrel.2011.03.032 PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 849CD UT WOS:000297102200017 PM 21497176 ER PT J AU Steinbicker, AU Liu, HL Jiramongkolchai, K Malhotra, R Choe, EY Busch, CJ Graveline, AR Kao, SM Nagasaka, Y Ichinose, F Buys, ES Brouckaert, P Zapol, WM Bloch, KD AF Steinbicker, Andrea U. Liu, Heling Jiramongkolchai, Kim Malhotra, Rajeev Choe, Elizabeth Y. Busch, Cornelius J. Graveline, Amanda R. Kao, Sonya M. Nagasaka, Yasuko Ichinose, Fumito Buys, Emmanuel S. Brouckaert, Peter Zapol, Warren M. Bloch, Kenneth D. TI Nitric oxide regulates pulmonary vascular smooth muscle cell expression of the inducible cAMP early repressor gene SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Nitric oxide; Vascular smooth muscle; cAMP-response element; Cyclic GMP; Protein kinase A ID DEPENDENT PROTEIN-KINASE; ELEMENT-BINDING PROTEIN; CYCLIC-GMP; TRANSCRIPTION FACTOR; CREB PHOSPHORYLATION; SIGNAL-TRANSDUCTION; CGMP; ACTIVATION; CALCIUM; MECHANISMS AB Nitric oxide (NO) regulates vascular smooth muscle cell (VSMC) structure and function, in part by activating soluble guanylate cyclase (sGC) to synthesize cGMP. The objective of this study was to further characterize the signaling mechanisms by which NO regulates VSMC gene expression using transcription profiling. DNA microarrays were hybridized with RNA extracted from rat pulmonary artery smooth muscle cells (RPaSMC) exposed to the NO donor compound, S-nitroso-glutathione (GSNO). Many of the genes, whose expression was induced by GSNO, contain a cAMP-response element (CRE), of which one encoded the inducible cAMP early repressor (ICER). sGC and cAMP-dependent protein kinase, but not cGMP-dependent protein kinase, were required for NO-mediated phosphorylation of CRE-binding protein (CREB) and induction of ICER gene expression. Expression of a dominant-negative CREB in RPaSMC prevented the NO-mediated induction of CRE-dependent gene transcription and ICER gene expression. Pre-treatment of RPaSMC with the intracellular calcium (Ca(2+)) chelator, BAPTA-AM, blocked the induction of ICER gene expression by GSNO. The store-operated Ca(2+) channel inhibitors, 2-ABP, and SKF-96365, reduced the GSNO-mediated increase in ICER mRNA levels, while 2-ABP did not inhibit GSNO-induced CREB phosphorylation. Our results suggest that induction of ICER gene expression by NO requires both CREB phosphorylation and Ca(2+) signaling. Transcription profiling of RPaSMC exposed to GSNO revealed important roles for sGC, PKA, CREB, and Ca(2+) in the regulation of gene expression by NO. The induction of ICER in GSNO-treated RPaSMC highlights a novel crosstalk mechanism between cGMP and cAMP signaling pathways. (C) 2011 Elsevier Inc. All rights reserved. C1 [Steinbicker, Andrea U.; Jiramongkolchai, Kim; Graveline, Amanda R.; Nagasaka, Yasuko; Ichinose, Fumito; Buys, Emmanuel S.; Zapol, Warren M.; Bloch, Kenneth D.] Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Liu, Heling; Malhotra, Rajeev; Choe, Elizabeth Y.; Busch, Cornelius J.; Kao, Sonya M.; Bloch, Kenneth D.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Liu, Heling; Malhotra, Rajeev; Choe, Elizabeth Y.; Busch, Cornelius J.; Kao, Sonya M.; Bloch, Kenneth D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Brouckaert, Peter] Univ Ghent VIB, Dept Mol Biomed Res, B-9052 Ghent, Belgium. RP Steinbicker, AU (reprint author), Univ Munster, Dept Anesthesiol & Intens Care Med, D-48149 Munster, Germany. EM andrea.steinbicker@ukmuenster.de OI Malhotra, Rajeev/0000-0003-0120-4630 FU German DFG [SW 119-3/1]; American Heart Association [9930085N, 10SDG2610313]; Howard Hughes Medical Institute [NHLBI T32HL007208]; FWO-Vlaanderen; UGent-GOA programs; Department of Anesthesia; NHLBI [HL-57172, R01 HL074352]; INOTherapeutics; Massachusetts General Hospital; Massachusetts General Hospital to Linde Corp (Munich, Germany); Ikaria (Clinton, New Jersey) FX This work was supported by the German DFG grant SW 119-3/1 (AUS), a Scientist Development Grant 9930085N from the American Heart Association (HL), a Research Training Fellowship for Medical Students from the Howard Hughes Medical Institute (KJ), NHLBI T32HL007208 (RM), a Scientist Development Grant 10SDG2610313 from the American Heart Association (ESB), grants from the FWO-Vlaanderen and the UGent-GOA programs (PB), as well as grants from the Department of Anesthesia at MGH (WMZ) and grants from the NHLBI, HL-57172 and R01 HL074352 (KDB).; KDB receives research Grant support via a sponsored research agreement with INOTherapeutics and the Massachusetts General Hospital. WMZ receives royalties on patents licensed by Massachusetts General Hospital to Linde Corp (Munich, Germany) and Ikaria (Clinton, New Jersey) on inhaled NO. NR 43 TC 6 Z9 6 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD OCT 30 PY 2011 VL 25 IS 3 BP 294 EP 302 DI 10.1016/j.niox.2011.05.006 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837FZ UT WOS:000296177800007 PM 21642009 ER PT J AU Houston, JP Kohler, J Ostbye, KM Heinloth, A Perlis, RH AF Houston, John P. Kohler, Jared Ostbye, Katherine M. Heinloth, Alexandra Perlis, Roy H. TI Association of catechol-O-methyltransferase variants with duloxetine response in major depressive disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Single nucleotide polymorphisms; Diplotype; rs165737 AB Single-nucleotide and diplotype associations with 17-item Hamilton Depression Rating Scale (HAMD(17)) total score changes were examined, based on catechol-O-methyltransferase (COMT) rs165599 status in duloxetine-treated, self-identified white patients with major depressive disorder. COMT rs165737 and a diplotype containing COMT rs165599 and COMT rs165737 were associated with HAMD17 total score changes. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Houston, John P.] Eli Lilly & Co, LLC, Dept Neurosci, Indianapolis, IN 46285 USA. [Houston, John P.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA. [Kohler, Jared; Ostbye, Katherine M.] BioStat Solut Inc, Pharmacogen, Mt Airy, MD USA. [Heinloth, Alexandra] i3, Sci Commun, Ann Arbor, MI USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat Pharmacogen Lab, Boston, MA 02114 USA. [Perlis, Roy H.] Harvard Univ, Sch Med, Boston, MA USA. RP Houston, JP (reprint author), Eli Lilly & Co, LLC, Dept Neurosci, Mail Code 4103, Indianapolis, IN 46285 USA. EM houston_john_p@lilly.com NR 9 TC 3 Z9 5 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD OCT 30 PY 2011 VL 189 IS 3 BP 475 EP 477 DI 10.1016/j.psychres.2011.07.002 PG 3 WC Psychiatry SC Psychiatry GA 836QM UT WOS:000296126200027 PM 21788083 ER PT J AU Fayad, ZA Mani, V Woodward, M Kallend, D Abt, M Burgess, T Fuster, V Ballantyne, CM Stein, EA Tardif, JC Rudd, JHF Farkouh, ME Tawakol, A AF Fayad, Zahi A. Mani, Venkatesh Woodward, Mark Kallend, David Abt, Markus Burgess, Tracy Fuster, Valentin Ballantyne, Christie M. Stein, Evan A. Tardif, Jean-Claude Rudd, James H. F. Farkouh, Michael E. Tawakol, Ahmed CA Dal-PLAQUE Investigators TI Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial SO LANCET LA English DT Article ID ESTER TRANSFER PROTEIN; HIGH-DENSITY-LIPOPROTEIN; POSITRON-EMISSION-TOMOGRAPHY; CORONARY-HEART-DISEASE; RAPID EXTENDED COVERAGE; CARDIOVASCULAR EVENTS; CHOLESTEROL LEVELS; HIGH-RESOLUTION; STATIN THERAPY; BLOOD-PRESSURE AB Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. Methods In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473. Findings 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4.01 mm(2) (90% CI -7.23 to -0.80; nominal p=0.04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7.3 [90% CI -13.5 to -0.8]; nominal p=0.07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Interpretation Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. C1 [Fayad, Zahi A.; Mani, Venkatesh] Mt Sinai Sch Med, Dept Radiol, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Fayad, Zahi A.; 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. [Kallend, David] F Hoffmann La Roche Ltd, Basel, Switzerland. [Burgess, Tracy] Hoffmann La Roche Inc, Nutley, NJ 07110 USA. [Fuster, Valentin] CNIC, Madrid, Spain. [Ballantyne, Christie M.] Baylor Coll Med, Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [Stein, Evan A.] Metab & Atherosclerosis Res Ctr, Cincinnati, OH USA. [Tardif, Jean-Claude] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Rudd, James H. F.] Univ Cambridge, Div Cardiovasc Med, Cambridge, England. [Farkouh, Michael E.] Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Farkouh, Michael E.] Li Ka Shing Knowledge Inst, Toronto, ON, Canada. [Tawakol, Ahmed] Harvard Univ, Sch Med, Boston, MA USA. [Tawakol, Ahmed] Massachusetts Gen Hosp, Boston, MA 02114 USA. 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 F Hoffmann-La Roche Ltd.; Roche; GlaxoSmithKline; Merck; VBL Therapeutics; Novartis; Bristol-Myers Squibb; Via Pharmaceuticals; Abbott; AstraZeneca; diaDexus; Kowa; Sanofi-Synthelabo; Takeda; National Institutes of Health; American Diabetes Association; American Heart Association; Amarin; F Hoffmann-La Roche Inc; Sanofi-Aventis; Schering-Plough; National Institute for Health Research Cambridge Biomedical Research Centre; BMS; Genentech; VBL FX F Hoffmann-La Roche Ltd.; ZAF has received research grants from Roche, GlaxoSmithKline, Merck, VBL Therapeutics, Novartis, Bristol-Myers Squibb, and Via Pharmaceuticals, and honoraria from Roche. MW has received honoraria from Roche. DK and MA are employees of F Hoffmann-La Roche Ltd and receive share options. TB is an employee of F Hoffmann-La Roche Inc. CMB has received grant or research support (paid to institution, not individual) from Abbott, AstraZeneca, Bristol-Myers Squibb, diaDexus, GlaxoSmithKline, Kowa, Merck, Novartis, Roche, Sanofi-Synthelabo, Takeda, National Institutes of Health, American Diabetes Association, and American Heart Association; is a consultant for Abbott, Adnexus, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, and Takeda; serves on the speaker's bureau of Abbott, AstraZeneca, GlaxoSmithKline, and Merck; and has received honoraria from Abbott, AstraZeneca, GlaxoSmithKline, Merck, Sanofi-Synthelabo, and Takeda. EAS has received grant support (paid to institution, not individual) from AstraZeneca, Abbott, GlaxoSmithKline, Amarin, F Hoffmann-La Roche Inc, Sanofi-Aventis, Schering-Plough; serves on the speakers' bureau of AstraZeneca; is a consultant or served on advisory board for F Hoffmann-La Roche Inc, Sanofi-Aventis, and Schering-Plough. J-CT has received research grants and honoraria from Roche. JHFR has received honoraria from Roche and is part-supported by the National Institute for Health Research Cambridge Biomedical Research Centre. MEF has received honoraria from Roche. AT has received honoraria from Roche, BMS, and Novartis; and research grants from Merck, BMS, Genentech, GlaxoSmithKline, and VBL. VM and VF declare that they have no conflicts of interest. NR 64 TC 244 Z9 244 U1 1 U2 19 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 OCT 29 PY 2011 VL 378 IS 9802 BP 1547 EP 1559 DI 10.1016/S0140-6736(11)61383-4 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 844SL UT WOS:000296767500020 PM 21908036 ER PT J AU Ellis, LZ Liu, WM Luo, YC Okamoto, M Qu, D Dunn, JH Fujita, M AF Ellis, Lixia Z. Liu, Weimin Luo, Yuchun Okamoto, Miyako Qu, Dovina Dunn, Jeffrey H. Fujita, Mayumi TI Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1 beta secretion SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Green tea; Epigallocatechin-3-gallate; Melanoma; IL-1; Inflammasome; NLRP1 ID NF-KAPPA-B; CELLS; (-)-EPIGALLOCATECHIN-3-GALLATE; ACTIVATION; MICE; CANCER; PHARMACOKINETICS; METABOLITES; APOPTOSIS; CATECHINS AB Epigallocatechin-3-gallate (EGCG), the major polyphenolic component of green tea, has been demonstrated to possess anti-inflammatory, antioxidant, anti-mutagenic and anti-carcinogenic properties. The anti-melanoma effect of EGCG has been previously suggested, but no clear mechanism of action has been established. In this study, we demonstrated that EGCG inhibits melanoma cell growth at physiological doses (0.1-1 mu M). In the search for mechanisms of EGCG-mediated melanoma cell suppression, we found that NF-kappa B was inhibited, and that reduced NF-kappa B activity was associated with decreased IL-1 beta secretion from melanoma cells. Since inflammasomes are involved in IL-1 beta secretion, we investigated whether IL-1 beta suppression was mediated by inflammasomes, and found that EGCG treatment led to downregulation of the inflammasome component, NLRP1, and reduced caspase-1 activation. Furthermore, silencing the expression of NLRP1 abolished EGCG-induced inhibition of tumor cell proliferation both in vitro and in vivo, suggesting a key role of inflammasomes in EGCG efficacy. This paper provides a novel mechanism for EGCG-induced melanoma inhibition: inflammasome downregulation -> decreased IL-1 beta secretion -> decreased NF-kappa B activities -> decreased cell growth. In addition, it suggests inflammasomes and IL-1 beta could be potential targets for future melanoma therapeutics. Published by Elsevier Inc. C1 [Ellis, Lixia Z.; Liu, Weimin; Luo, Yuchun; Okamoto, Miyako; Qu, Dovina; Dunn, Jeffrey H.; Fujita, Mayumi] Univ Colorado, Sch Med, Dept Dermatol, Aurora, CO 80045 USA. [Fujita, Mayumi] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. RP Fujita, M (reprint author), Univ Colorado, Sch Med, Dept Dermatol, Mail Stop 8127,12801 E 17th Ave,Room 4124, Aurora, CO 80045 USA. EM mayumi.fujita@ucdenver.edu RI Luo, Yuchun/B-8683-2014 FU Dermatology Foundation; Tadamitsu Cancer Research Fund; NIH [CA125833, 5T32AR007411]; Wendy Will Cancer Center FX This work was supported by Grants from the Dermatology Foundation (to M.F.), the Tadamitsu Cancer Research Fund (to M.F.), NIH Grants CA125833 (to M.F.), and the Wendy Will Cancer Center Fund (to M.F.). W.L. and M.O. were supported by a training grant from NIH (5T32AR007411). NR 32 TC 40 Z9 44 U1 5 U2 16 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 OCT 28 PY 2011 VL 414 IS 3 BP 551 EP 556 DI 10.1016/j.bbrc.2011.09.115 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 868JL UT WOS:000298519500019 PM 21982776 ER PT J AU Sarkar, A Hochedlinger, K AF Sarkar, Abby Hochedlinger, Konrad TI A Gutsy Way to Grow: Intestinal Stem Cells as Nutrient Sensors SO CELL LA English DT Editorial Material ID BEHAVIOR AB Adult tissues can rapidly and reversibly change size to adapt to environmental and behavioral influences. In this issue, O'Brien et al. (2011) demonstrate that fly intestinal stem cells alter their division patterns in response to food availability to drive organ growth. C1 [Sarkar, Abby; Hochedlinger, Konrad] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Sarkar, Abby; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Sarkar, Abby; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Sarkar, Abby; Hochedlinger, Konrad] Ctr Regenerat Med, Boston, MA 02114 USA. [Sarkar, Abby; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Hochedlinger, K (reprint author), Harvard Univ, Howard Hughes Med Inst, 7 Divin Ave, Cambridge, MA 02138 USA. EM khochedlinger@helix.mgh.harvard.edu NR 10 TC 2 Z9 2 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 28 PY 2011 VL 147 IS 3 BP 483 EP 486 DI 10.1016/j.cell.2011.10.006 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 842EH UT WOS:000296573700002 PM 22036555 ER PT J AU Trompouki, E Bowman, TV Lawton, LN Fan, ZP Wu, DC DiBiase, A Martin, CS Cech, JN Sessa, AK Leblanc, JL Li, PL Durand, EM Mosimann, C Heffner, GC Daley, GQ Paulson, RF Young, RA Zon, LI AF Trompouki, Eirini Bowman, Teresa V. Lawton, Lee N. Fan, Zi Peng Wu, Dai-Chen DiBiase, Anthony Martin, Corey S. Cech, Jennifer N. Sessa, Anna K. Leblanc, Jocelyn L. Li, Pulin Durand, Ellen M. Mosimann, Christian Heffner, Garrett C. Daley, George Q. Paulson, Robert F. Young, Richard A. Zon, Leonard I. TI Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs during Differentiation and Regeneration SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; UCSC GENOME BROWSER; TRANSCRIPTION FACTORS; BETA-CATENIN; MEGAKARYOCYTIC DIFFERENTIATION; HEMATOPOIETIC PROGENITORS; SIGNALING PATHWAYS; GENE ACTIVATION; GAMMA-CATENIN; PROTEIN AB BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic lineages following acute injury depends on the activation of each of these signaling pathways to induce expression of key blood genes. Both SMAD1 and TCF7L2 co-occupy sites with master regulators adjacent to hematopoietic genes. In addition, both SMAD1 and TCF7L2 follow the binding of the predominant lineage regulator during differentiation from multipotent hematopoietic progenitor cells to erythroid cells. Furthermore, induction of the myeloid lineage regulator C/EBP alpha in erythroid cells shifts binding of SMAD1 to sites newly occupied by C/EBP alpha, whereas expression of the erythroid regulator GATA1 directs SMAD1 loss on nonerythroid targets. We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control the gene programs defining cellular identity. C1 [Trompouki, Eirini; Bowman, Teresa V.; DiBiase, Anthony; Martin, Corey S.; Cech, Jennifer N.; Sessa, Anna K.; Leblanc, Jocelyn L.; Li, Pulin; Durand, Ellen M.; Mosimann, Christian; Zon, Leonard I.] Harvard Univ, Sch Med, Stem Cell Program, Boston, MA 02115 USA. [Trompouki, Eirini; Bowman, Teresa V.; DiBiase, Anthony; Martin, Corey S.; Cech, Jennifer N.; Sessa, Anna K.; Leblanc, Jocelyn L.; Li, Pulin; Durand, Ellen M.; Mosimann, Christian; Zon, Leonard I.] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston,Harvard Stem Cell Inst, Boston, MA 02115 USA. [Trompouki, Eirini; Bowman, Teresa V.; DiBiase, Anthony; Martin, Corey S.; Cech, Jennifer N.; Sessa, Anna K.; Leblanc, Jocelyn L.; Li, Pulin; Durand, Ellen M.; Mosimann, Christian; Zon, Leonard I.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Lawton, Lee N.; Fan, Zi Peng; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Wu, Dai-Chen; Paulson, Robert F.] Penn State Univ, Grad Program Biochem Microbiol & Mol Biol, University Pk, PA 16802 USA. [Wu, Dai-Chen; Paulson, Robert F.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Heffner, Garrett C.; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Heffner, Garrett C.; Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Heffner, Garrett C.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Fan, Zi Peng] MIT, Computat & Syst Biol Program, Cambridge, MA 02142 USA. RP Zon, LI (reprint author), Harvard Univ, Sch Med, Stem Cell Program, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu RI Young, Richard/F-6495-2012; cheng, yong/I-4270-2012; OI Young, Richard/0000-0001-8855-8647; Trompouki, Eirini/0000-0002-7242-8810 FU NIH [P50-NS40828, NIH-P30-HD18655, 5PO1HL32262-29, 5R01HL048801-18, 1R01DK080040-01, R01-HG002668, K01 DK085270-02, U01 HL100001, 1 RC2HL102815, T32HL007623]; ROFAR; HHMI; EMBO; Jane Coffin Childs Memorial Fund FX We would like to acknowledge A. Mullen and D. Orlando for helpful discussions and sharing critical insights prior to publication and G. Frampton for analytical advice and development of the ChIP-seq analysis platform. We thank F. Rentzsch and M. Hammerschmidt for the Hs: BMP zebrafish line, J. Tucker and M. Mullins for the Hs: Chordin zebrafish line, and T. Schlaeger for the GATA2 expression plasmid. We are grateful to X. Bai and R. White for critical reviews of the manuscript and O. Tamplin for computational advice. The Whitehead Genome Technology Core was instrumental in timely data production and analysis support, especially S. Gupta. Microarray studies were performed by the Molecular Genetics Core Facility at Children's Hospital Boston, supported by NIH-P50-NS40828 and NIH-P30-HD18655. This work was supported by NIH # 5PO1HL32262-29 and # 5R01HL048801-18 (to L.I.Z), NIH 1R01DK080040-01 (to R. F. P.), R01-HG002668 (to R. A. Y.), NIH K01 DK085270-02 (to T. V. B.), NIH U01 HL100001, NIH 1 RC2HL102815, and ROFAR (to G. Q. D.), NIH T32HL007623 (to G. C. H.), HHMI (to L.I.Z. and G. Q. D.), and EMBO fellowship and Jane Coffin Childs Memorial Fund (to E. T.). L.I.Z. is a founder and stock holder of Fate, Inc. and a scientific advisor for Stemgent. G. Q. D. is a member of the Scientific Advisory Boards of MPM Capital, Inc., Epizyme, Inc., and iPierian, Inc. NR 60 TC 140 Z9 144 U1 2 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 28 PY 2011 VL 147 IS 3 BP 577 EP 589 DI 10.1016/j.cell.2011.09.044 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 842EH UT WOS:000296573700013 PM 22036566 ER PT J AU Boyer, L Magoc, L Dejardin, S Cappillino, M Paquette, N Hinault, C Charriere, GM Ip, WKE Fracchia, S Hennessy, E Erturk-Hasdemir, D Reichhart, JM Silverman, N Lacy-Hulbert, A Stuart, LM AF Boyer, Laurent Magoc, Lorin Dejardin, Stephanie Cappillino, Michael Paquette, Nicholas Hinault, Charlotte Charriere, Guillaume M. Ip, W. K. Eddie Fracchia, Shannon Hennessy, Elizabeth Erturk-Hasdemir, Deniz Reichhart, Jean-Marc Silverman, Neal Lacy-Hulbert, Adam Stuart, Lynda M. TI Pathogen-Derived Effectors Trigger Protective Immunity via Activation of the Rac2 Enzyme and the IMD or Rip Kinase Signaling Pathway SO IMMUNITY LA English DT Article ID NECROTIZING FACTOR-I; INNATE IMMUNITY; RHO-GTPASES; DROSOPHILA-MELANOGASTER; BACTERIAL EFFECTORS; FUNGAL-INFECTIONS; ESCHERICHIA-COLI; TOXINS; SYSTEM; COMPLEX AB Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential. C1 [Boyer, Laurent; Magoc, Lorin; Dejardin, Stephanie; Cappillino, Michael; Paquette, Nicholas; Charriere, Guillaume M.; Ip, W. K. Eddie; Fracchia, Shannon; Hennessy, Elizabeth; Lacy-Hulbert, Adam; Stuart, Lynda M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hinault, Charlotte] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Hinault, Charlotte] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Erturk-Hasdemir, Deniz; Silverman, Neal] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis, Worcester, MA 01605 USA. [Reichhart, Jean-Marc] Univ Strasbourg, IBMC, UPR 9022, CNRS, F-67084 Strasbourg, France. [Stuart, Lynda M.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Boyer, L (reprint author), Ctr Mediterraneen Med Mol, INSERM, U895, C3M, F-06204 Nice 3, France. EM boyerl@unice.fr; lstuart@partners.org RI Ip, Eddie/C-3042-2012; Boyer, laurent/F-8921-2015; Charriere, Guillaume/O-8317-2014; OI Boyer, laurent/0000-0002-1375-1706; Charriere, Guillaume/0000-0002-4796-1488; Lacy-Hulbert, Adam/0000-0003-2162-0156; Silverman, Neal/0000-0002-4259-456X; hinault, charlotte/0000-0002-3588-039X FU Fondation Recherche Medical; MGH ECOR Fund for Medical Discovery; Ligue Nationale Contre le Cancer; NIH/NIAID [PO1: A104420, RO1: A160025]; MGH ECOR; NIH/NIAID FX We would like to thank D. Ferrandon, J.L. Imler, and C. Kocks for sharing fly stocks, K. Fitzgerald, J. Tschopp, G. Gacon, and the Drosophila Genomics Resource Center for plasmids and E. Lemichez and G. Flatau for providing CNF1 and CNF1 mutant purified proteins and cDNA and anti-CNF1 antibody. We thank J. Dejardin, O. Visvikis, P. Leopold, M. Maddugoda, A. Mettouchi, B. Ferrua, P. Munro, and A. Doye for technical suggestions and F. Ausubel, A Ezekowitz, and E. Lemichez for critical discussion and reading the manuscript. Technical support was provided by the C3M Cell Imaging Facility (Francois Prodon) and the Taplin Mass Spectrometric Facility (Ross Tomaino). L.B. was supported by Fondation Recherche Medical, MGH ECOR Fund for Medical Discovery and Ligue Nationale Contre le Cancer. This work was supported by NIH/NIAID grants to J-M.R. (PO1: A104420) and N.S (RO1: A160025) and grants to L.S from MGH ECOR and NIH/NIAID. All experiments were designed and interpreted by L.B. and L.M.S. L.M.S. supervised the work with assistance from A.L-H. L.B. and L.M.S. wrote the manuscript with input from A.L.-H. and N.S. In vitro experiments were performed by L.B., S.D., C.H., G.M.C., EN., and W.K.I. Flies were generated and maintained by L.B., M.C., and L.M. In vivo experiments were performed by L.B., L.M., M.C., N.P., and S.F. IMD, Relish, Dorsal and PGRP-LC reagents (constructs antibodies, etc.) were generated and supplied by D.E.-H., J.M.R., and N.S. NR 39 TC 44 Z9 44 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 28 PY 2011 VL 35 IS 4 BP 536 EP 549 DI 10.1016/j.immuni.2011.08.015 PG 14 WC Immunology SC Immunology GA 843FM UT WOS:000296657700013 PM 22018470 ER PT J AU Chauhan, D Anderson, KC AF Chauhan, Dharminder Anderson, Kenneth C. TI Proteasome inhibition, the pursuit of new cancer therapeutics, and the adaptor molecule p130Cas SO BMC BIOLOGY LA English DT Editorial Material ID MULTIPLE-MYELOMA; DEGRADATION; AUTOPHAGY AB Current interest in proteasome inhibitors for cancer therapy has stimulated considerable research efforts to identify the molecular pathway to their cytotoxicity with a view to identifying the mechanisms of sensitivity and resistance as well as informing the development of new drugs. Zhao and Vuori describe this month in BMC Biology experiments indicating a novel role of the adaptor protein p130Cas in sensitivity to apoptosis induced not only by proteasome inhibitors but also by the unrelated drug doxorubicin. C1 [Chauhan, Dharminder] Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Myeloma Ctr,Dept Med Oncol, Boston, MA 02115 USA. RP Chauhan, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, 44 Binney St, Boston, MA 02115 USA. EM Dharminder_Chauhan@dfci.harvard.edu FU NCI NIH HHS [R01CA050947, P01-CA078378]; PHS HHS [SPORE-P50100707] NR 12 TC 2 Z9 2 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD OCT 28 PY 2011 VL 9 AR 72 DI 10.1186/1741-7007-9-72 PG 4 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 838GY UT WOS:000296276600002 PM 22034840 ER PT J AU Chaney, EF Rubenstein, LV Liu, CF Yano, EM Bolkan, C Lee, M Simon, B Lanto, A Felker, B Uman, J AF Chaney, Edmund F. Rubenstein, Lisa V. Liu, Chuan-Fen Yano, Elizabeth M. Bolkan, Cory Lee, Martin Simon, Barbara Lanto, Andy Felker, Bradford Uman, Jane TI Implementing collaborative care for depression treatment in primary care: A cluster randomized evaluation of a quality improvement practice redesign SO IMPLEMENTATION SCIENCE LA English DT Article ID MENTAL-HEALTH; QUERI SERIES; VETERANS; OUTCOMES; INTERVENTIONS; MANAGEMENT; PROGRAMS; IMPACT; ORGANIZATIONS; GUIDELINES AB Background: Meta-analyses show collaborative care models (CCMs) with nurse care management are effective for improving primary care for depression. This study aimed to develop CCM approaches that could be sustained and spread within Veterans Affairs (VA). Evidence-based quality improvement (EBQI) uses QI approaches within a research/clinical partnership to redesign care. The study used EBQI methods for CCM redesign, tested the effectiveness of the locally adapted model as implemented, and assessed the contextual factors shaping intervention effectiveness. Methods: The study intervention is EBQI as applied to CCM implementation. The study uses a cluster randomized design as a formative evaluation tool to test and improve the effectiveness of the redesign process, with seven intervention and three non-intervention VA primary care practices in five different states. The primary study outcome is patient antidepressant use. The context evaluation is descriptive and uses subgroup analysis. The primary context evaluation measure is naturalistic primary care clinician (PCC) predilection to adopt CCM. For the randomized evaluation, trained telephone research interviewers enrolled consecutive primary care patients with major depression in the evaluation, referred enrolled patients in intervention practices to the implemented CCM, and re-surveyed at seven months. Results: Interviewers enrolled 288 CCM site and 258 non-CCM site patients. Enrolled intervention site patients were more likely to receive appropriate antidepressant care (66% versus 43%, p = 0.01), but showed no significant difference in symptom improvement compared to usual care. In terms of context, only 40% of enrolled patients received complete care management per protocol. PCC predilection to adopt CCM had substantial effects on patient participation, with patients belonging to early adopter clinicians completing adequate care manager follow-up significantly more often than patients of clinicians with low predilection to adopt CCM (74% versus 48%%, p = 0.003). Conclusions: Depression CCM designed and implemented by primary care practices using EBQI improved antidepressant initiation. Combining QI methods with a randomized evaluation proved challenging, but enabled new insights into the process of translating research-based CCM into practice. Future research on the effects of PCC attitudes and skills on CCM results, as well as on enhancing the link between improved antidepressant use and symptom outcomes, is needed. C1 [Chaney, Edmund F.; Liu, Chuan-Fen; Felker, Bradford] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Rubenstein, Lisa V.; Yano, Elizabeth M.; Lee, Martin; Simon, Barbara; Lanto, Andy] VA Greater Los Angeles Healthcare Syst, VA Ctr Study Healthcare Provider Behav, Los Angeles, CA USA. [Rubenstein, Lisa V.] RAND Hlth Program, Santa Monica, CA USA. [Rubenstein, Lisa V.; Yano, Elizabeth M.; Lee, Martin] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.; Yano, Elizabeth M.; Lee, Martin] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Liu, Chuan-Fen; Uman, Jane] VA Puget Sound Hlth Care Syst, HSR&D NW Ctr Excellence Outcomes Res Older Adults, Seattle, WA USA. [Bolkan, Cory] Washington State Univ, Dept Human Dev, Vancouver, WA USA. RP Chaney, EF (reprint author), Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. EM chaney@u.washington.edu FU Department of Veterans Affairs (VA) Health Services Research and Development (HSRD) Service [MHI-99-375]; VA HSR&D Research Career Scientist award [RCS 09-095] FX Funding was provided by Department of Veterans Affairs (VA) Health Services Research and Development (HSR&D) Service (grant number MHI-99-375). The VA HSR&D Mental Health Quality Enhancement Research Initiative (QUERI) staff provided critical assistance and oversight. Dr. Yano's salary support during a portion of this work was provided by a VA HSR&D Research Career Scientist award (grant number RCS 09-095). We would like to specifically acknowledge the contributions of Laura Bonner, Duncan Campbell, Jonathan Kanter, Debbie Mittman, Carol Oken, Carol Simons, Susan Vivell and all other WAVES project research staff. The study would not have been possible without the active partnership and leadership of Randy Petzel, Scott Ober, Kathy Henderson, Joanne Kirchner, Mike Davies, and all other participating administrators and clinicians of VA VISNs 10, 16, and 23. Finally we thank VA Nursing Service and more specifically Karen Vollen and Barbara Revay, pioneering TIDES DCMs and the first TIDES nurse trainers. There are no contractual rights to review the manuscript before submission, but there is a requirement that Health Services Research and Development, Department of Veterans Affairs, be given a copy of the accepted manuscript NR 61 TC 27 Z9 29 U1 0 U2 7 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 OCT 27 PY 2011 VL 6 AR 121 DI 10.1186/1748-5908-6-121 PG 15 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 849LX UT WOS:000297128100001 PM 22032247 ER PT J AU Kumar, MS Narla, A Nonami, A Mullally, A Dimitrova, N Ball, B McAuley, JR Poveromo, L Kutok, JL Galili, N Raza, A Attar, E Gilliland, DG Jacks, T Ebert, BL AF Kumar, Madhu S. Narla, Anupama Nonami, Atsushi Mullally, Ann Dimitrova, Nadya Ball, Brian McAuley, J. Randall Poveromo, Luke Kutok, Jeffrey L. Galili, Naomi Raza, Azra Attar, Eyal Gilliland, D. Gary Jacks, Tyler Ebert, Benjamin L. TI Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q(-) syndrome SO BLOOD LA English DT Article ID MESSENGER-RNAS; HUMAN CANCERS; STEM-CELLS; EXPRESSION; SUPPRESSOR; MIR-145; FLI-1; IDENTIFICATION; 5Q-SYNDROME; PHENOTYPE AB Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q(-) syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q(-) syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q(-) syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q(-) syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q(-) syndrome. (Blood. 2011; 118(17): 4666-4673) C1 [Narla, Anupama; Nonami, Atsushi; Mullally, Ann; Ball, Brian; McAuley, J. Randall; Poveromo, Luke; Gilliland, D. Gary; Ebert, Benjamin L.] Harvard Univ, Dept Med, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Kumar, Madhu S.; Dimitrova, Nadya; Jacks, Tyler] MIT, Dept Biol, Koch Inst Integrat Canc Res, Cambridge, MA USA. [Kumar, Madhu S.; Dimitrova, Nadya; Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA USA. [Narla, Anupama; Mullally, Ann; McAuley, J. Randall; Gilliland, D. Gary; Ebert, Benjamin L.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Narla, Anupama] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Kutok, Jeffrey L.] Harvard Univ, Dept Pathol, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Galili, Naomi; Raza, Azra] St Vincents Comprehens Canc Ctr, New York, NY USA. [Attar, Eyal] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Gilliland, D. Gary; Ebert, Benjamin L.] Harvard Stem Cell Inst, Cambridge, MA USA. [Gilliland, D. Gary] Harvard Univ, Howard Hughes Med Inst, Sch Med, Boston, MA 02115 USA. RP Ebert, BL (reprint author), Harvard Univ, Dept Med, Brigham & Womens Hosp, Sch Med, Karp Res Bldg,1 Blackfan Circle,5th Fl,CHRB 05-21, Boston, MA 02115 USA. EM benjamin_ebert@dfci.harvard.edu FU National Cancer Institute [2-PO1-CA42063]; National Cancer Institute (Cancer Center) [P30-CA14051]; National Heart, Lung, and Blood Institute [R01-HL082945]; Burroughs Wellcome Fund Career Award in the Medical Sciences FX This work was supported by the National Cancer Institute (grant 2-PO1-CA42063), in part by the National Cancer Institute (Cancer Center Support grant P30-CA14051), and in part by the National Heart, Lung, and Blood Institute (grant R01-HL082945). B. L. E. was supported by a Burroughs Wellcome Fund Career Award in the Medical Sciences. Animal research was approved by Animal Welfare Assurance (A33033-01). M. S. K. was an NSF Graduate Research Fellow. D. G. G. and T.J. are investigators of the Howard Hughes Medical Institute. T.J. is a Ludwig Scholar. NR 34 TC 42 Z9 43 U1 0 U2 8 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 OCT 27 PY 2011 VL 118 IS 17 BP 4666 EP 4673 DI 10.1182/blood-2010-12-324715 PG 8 WC Hematology SC Hematology GA 839LY UT WOS:000296368700029 PM 21873545 ER PT J AU Cheng, G Liao, S Wong, HK Lacorre, DA di Tomaso, E Au, P Fukumura, D Jain, RK Munn, LL AF Cheng, Gang Liao, Shan Wong, Hon Kit Lacorre, Delphine A. di Tomaso, Emmanuelle Au, Patrick Fukumura, Dai Jain, Rakesh K. Munn, Lance L. TI Engineered blood vessel networks connect to host vasculature via wrapping-and-tapping anastomosis SO BLOOD LA English DT Article ID IN-VIVO; ENDOTHELIAL-CELLS; PROGENITOR CELLS; CORD BLOOD; TISSUE; ANGIOGENESIS; MICROCIRCULATION; VASCULOGENESIS; GLIOBLASTOMA; PERMEABILITY AB Rapid blood perfusion is critical for postimplantation survival of thick, prevascularized bioartificial tissues. Yet the mechanism by which implanted vascular networks inosculate, or anastomose, with the host vasculature has been unknown, making it difficult to develop optimized strategies for facilitating perfusion. Here we show that implanted vascular networks anastomose with host vessels through a previously unidentified process of "wrapping and tapping" between the engrafted endothelial cells (ECs) and the host vasculature. At the host-implant interface, implanted ECs first wrap around nearby host vessels and then cause basement membrane and pericyte reorganization and localized displacement of the underlying host endothelium. In this way, the implanted ECs replace segments of host vessels to divert blood flow to the developing implanted vascular network. The process is facilitated by high levels of matrix metalloproteinase-14 and matrix metalloproteinase-9 expressed by the wrapping ECs. These findings open the door to new strategies for improving perfusion of tissue grafts and may have implications for other physiologic and pathologic processes involving postnatal vasculogenesis. (Blood. 2011; 118(17): 4740-4749) C1 [Cheng, Gang; Liao, Shan; Wong, Hon Kit; Lacorre, Delphine A.; di Tomaso, Emmanuelle; Au, Patrick; Fukumura, Dai; Jain, Rakesh K.; Munn, Lance L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Cheng, Gang; Liao, Shan; Wong, Hon Kit; Lacorre, Delphine A.; di Tomaso, Emmanuelle; Au, Patrick; Fukumura, Dai; Jain, Rakesh K.; Munn, Lance L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Munn, LL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 7, Boston, MA 02114 USA. EM munn@steele.mgh.harvard.edu RI Munn, Lance/L-3950-2016; Wong, Hon-Kit/G-3944-2014 OI Munn, Lance/0000-0003-0698-7232; Wong, Hon-Kit/0000-0003-0049-8454 FU National Institutes of Health [HL64240, PO1 CA80124, R01-CA126642]; Federal Share/National Cancer Institute [R01-CA096915] FX This work was supported by the National Institutes of Health (grant HL64240, L. L. M.; grant PO1 CA80124, R.K.J., L. L. M., and D. F.; and grant R01-CA126642, L. L. M.) and Federal Share/National Cancer Institute (Proton Beam Program Income Grants, R.K.J., L. L. M., and D. F.; and grant R01-CA096915, D.F.). NR 34 TC 45 Z9 45 U1 0 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 27 PY 2011 VL 118 IS 17 BP 4740 EP 4749 DI 10.1182/blood-2011-02-338426 PG 10 WC Hematology SC Hematology GA 839LY UT WOS:000296368700039 PM 21835951 ER PT J AU Zuber, J Shi, JW Wang, E Rappaport, AR Herrmann, H Sison, EA Magoon, D Qi, J Blatt, K Wunderlich, M Taylor, MJ Johns, C Chicas, A Mulloy, JC Kogan, SC Brown, P Valent, P Bradner, JE Lowe, SW Vakoc, CR AF Zuber, Johannes Shi, Junwei Wang, Eric Rappaport, Amy R. Herrmann, Harald Sison, Edward A. Magoon, Daniel Qi, Jun Blatt, Katharina Wunderlich, Mark Taylor, Meredith J. Johns, Christopher Chicas, Agustin Mulloy, James C. Kogan, Scott C. Brown, Patrick Valent, Peter Bradner, James E. Lowe, Scott W. Vakoc, Christopher R. TI RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia SO NATURE LA English DT Article ID TRANSCRIPTIONAL PROGRAM; H3K79 METHYLATION; STEM-CELLS; IN-VIVO; C-MYC; CLASSIFICATION; LEUKEMOGENESIS; EXPRESSION; MLL-AF9; INHIBITION AB Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs(1). Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states(2). By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. C1 [Lowe, Scott W.; Vakoc, Christopher R.] Cold Spring Harbor Lab, Howard Hughes Med Inst, Cold Spring Harbor, NY 11724 USA. [Zuber, Johannes] Res Inst Mol Pathol IMP, A-1030 Vienna, Austria. [Shi, Junwei] SUNY Stony Brook, Mol & Cellular Biol Program, Stony Brook, NY 11794 USA. [Rappaport, Amy R.; Lowe, Scott W.] Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA. [Sison, Edward A.; Magoon, Daniel; Brown, Patrick] Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Baltimore, MD 21231 USA. [Qi, Jun; Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Blatt, Katharina; Valent, Peter] Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, A-1090 Vienna, Austria. [Wunderlich, Mark; Mulloy, James C.] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Kogan, Scott C.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. RP Vakoc, CR (reprint author), Cold Spring Harbor Lab, Howard Hughes Med Inst, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. EM lowe@cshl.edu; vakoc@cshl.edu RI Clovis, Jeff/C-1020-2009; OI Vakoc, Christopher/0000-0002-1158-7180 FU Don Monti Memorial Research Foundation; Laurie Strauss Leukemia Foundation; German Research Foundation (DFG); CSHL; NIH; Barbara McClintock fellowship; Damon-Runyon Cancer Research Foundation; Smith Family Foundation; Damon Runyon-Lilly Clinical Investigator Award; Leukemia and Lymphoma Society (LLS); Leukemia and Lymphoma Society of America; National Cancer Institute; Howard Hughes Medical Institute; CSHL President's Council; SASS Foundation for Medical Research FX We thank B. Ma, S. Muller and M. Weissenboeck for technical assistance; J. Simon, E. Earl and L. Bianco for support with mouse work; C. dos Santos for assistance with LSK FACS analysis; S. Hearn for microscopy support; G. Hannon, K. Chang, and E. Hodges for shRNA technology support; A. Gordon and M. Hammell for bioinformatics support; L. Dow for assistance with mouse pathology sample preparation; and G. Blobel for comments on the manuscript. We thank the Don Monti Memorial Research Foundation and Laurie Strauss Leukemia Foundation for research support. J.Z. was supported by a research fellowship from the German Research Foundation (DFG) and by the Andrew Seligson Memorial Clinical Fellowship at CSHL; A. R. R. was supported by an NIH traineeship and the Barbara McClintock fellowship; J. E. B and J. Q. are supported by the Damon-Runyon Cancer Research Foundation and Smith Family Foundation. P. B. is supported by a Damon Runyon-Lilly Clinical Investigator Award and a Leukemia and Lymphoma Society (LLS) Translational Research Program Grant, and is an LLS Scholar in Clinical Research. S. W. L. is supported by a Specialized Center of Research (SCOR) grant from the Leukemia and Lymphoma Society of America, a Cancer Target Discovery and Development (CTD2) grant from the National Cancer Institute, and by the Howard Hughes Medical Institute; C. R. V., J. S. and E. W. are supported by the CSHL President's Council and the SASS Foundation for Medical Research. NR 42 TC 664 Z9 674 U1 16 U2 137 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 27 PY 2011 VL 478 IS 7370 BP 524 EP U124 DI 10.1038/nature10334 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837JI UT WOS:000296194200045 PM 21814200 ER PT J AU Bergwitz, C Collins, MT Kamath, RS Rosenberg, AE AF Bergwitz, Clemens Collins, Michael T. Kamath, Ravi S. Rosenberg, Andrew E. TI Case 33-2011: A 56-Year-Old Man with Hypophosphatemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TUMOR-INDUCED OSTEOMALACIA; OF-THE-LITERATURE; ONCOGENIC OSTEOMALACIA; MESENCHYMAL TUMORS; AMELOBLASTIC FIBROSARCOMA; PHOSPHATE HOMEOSTASIS; CALCIUM-METABOLISM; VITAMIN-D; FIBROBLAST-GROWTH-FACTOR-23; LOCALIZATION C1 [Bergwitz, Clemens] Massachusetts Gen Hosp, Div Endocrinol, Boston, MA 02114 USA. [Kamath, Ravi S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rosenberg, Andrew E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bergwitz, Clemens] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kamath, Ravi S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Rosenberg, Andrew E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Div Endocrinol, Boston, MA 02114 USA. FU Genzyme FX Dr. Rosenberg reports receiving consulting fees from Genzyme. No other potential conflict of interest relevant to this article was reported. NR 27 TC 8 Z9 9 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 OCT 27 PY 2011 VL 365 IS 17 BP 1625 EP 1635 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 837HI UT WOS:000296181800009 PM 22029985 ER PT J AU Szostak, JW AF Szostak, Jack W. TI An optimal degree of physical and chemical heterogeneity for the origin of life? SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Review DE origin of life; protocell; vesicle; fatty acids; genetic polymer ID FATTY-ACID VESICLES; MODEL PROTOCELL; GENETIC SYSTEM; NUCLEIC-ACID; MEMBRANES; GROWTH; LIGATION AB The accumulation of pure, concentrated chemical building blocks, from which the essential components of protocells could be assembled, has long been viewed as a necessary, but extremely difficult step on the pathway to the origin of life. However, recent experiments have shown that moderately increasing the complexity of a set of chemical inputs can in some cases lead to a dramatic simplification of the resulting reaction products. Similarly, model protocell membranes composed of certain mixtures of amphiphilic molecules have superior physical properties than membranes composed of single amphiphiles. Moreover, membrane self-assembly under simple and natural conditions gives rise to heterogeneous mixtures of large multi-lamellar vesicles, which are predisposed to a robust pathway of growth and division that simpler and more homogeneous small unilamellar vesicles cannot undergo. Might a similar relaxation of the constraints on building block purity and homogeneity actually facilitate the difficult process of nucleic acid replication? Several arguments suggest that mixtures of monomers and short oligonucleotides may enable the chemical copying of polynucleotides of sufficient length and sequence complexity to allow for the emergence of the first nucleic acid catalysts. The question of the origin of life may become less daunting once the constraints of overly well-defined laboratory experiments are appropriately relaxed. C1 [Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU NASA; NSF FX I thank Ting Zhu for help with figures, Ting Zhu and Itay Budin for helpful comments on the manuscript, and the many current and past members of my laboratory who have contributed to the development of the protocell model. This work was supported in part by grants from NASA and the NSF. The author is an Investigator of the Howard Hughes Medical Institute. NR 26 TC 32 Z9 33 U1 5 U2 39 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 OCT 27 PY 2011 VL 366 IS 1580 BP 2894 EP 2901 DI 10.1098/rstb.2011.0140 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 821RW UT WOS:000294993100006 PM 21930580 ER PT J AU Blagrove, M Fouquet, NC Henley-Einion, JA Pace-Schott, EF Davies, AC Neuschaffer, JL Turnbull, OH AF Blagrove, Mark Fouquet, Nathalie C. Henley-Einion, Josephine A. Pace-Schott, Edward F. Davies, Anna C. Neuschaffer, Jennifer L. Turnbull, Oliver H. TI Assessing the Dream-Lag Effect for REM and NREM Stage 2 Dreams SO PLOS ONE LA English DT Article ID MEMORY CONSOLIDATION; SLEEP; EVENTS; REPLICATION; MENTATION; STATES AB This study investigates evidence, from dream reports, for memory consolidation during sleep. It is well-known that events and memories from waking life can be incorporated into dreams. These incorporations can be a literal replication of what occurred in waking life, or, more often, they can be partial or indirect. Two types of temporal relationship have been found to characterize the time of occurrence of a daytime event and the reappearance or incorporation of its features in a dream. These temporal relationships are referred to as the day-residue or immediate incorporation effect, where there is the reappearance of features from events occurring on the immediately preceding day, and the dream-lag effect, where there is the reappearance of features from events occurring 5-7 days prior to the dream. Previous work on the dream-lag effect has used spontaneous home recalled dream reports, which can be from Rapid Eye Movement Sleep (REM) and from non-Rapid Eye Movement Sleep (NREM). This study addresses whether the dream-lag effect occurs only for REM sleep dreams, or for both REM and NREM stage 2 (N2) dreams. 20 participants kept a daily diary for over a week before sleeping in the sleep laboratory for 2 nights. REM and N2 dreams collected in the laboratory were transcribed and each participant rated the level of correspondence between every dream report and every diary record. The dream-lag effect was found for REM but not N2 dreams. Further analysis indicated that this result was not due to N2 dream reports being shorter, in terms of number of words, than the REM dream reports. These results provide evidence for a 7-day sleep-dependent non-linear memory consolidation process that is specific to REM sleep, and accord with proposals for the importance of REM sleep to emotional memory consolidation. C1 [Blagrove, Mark; Fouquet, Nathalie C.; Henley-Einion, Josephine A.; Davies, Anna C.; Neuschaffer, Jennifer L.] Swansea Univ, Dept Psychol, Swansea, W Glam, Wales. [Pace-Schott, Edward F.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Pace-Schott, Edward F.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Turnbull, Oliver H.] Bangor Univ, Sch Psychol, Bangor, Gwynedd, Wales. RP Blagrove, M (reprint author), Swansea Univ, Dept Psychol, Swansea, W Glam, Wales. EM m.t.blagrove@swansea.ac.uk FU Wales Institute of Cognitive Neuroscience [WBS066] FX This study was funded by the Wales Institute of Cognitive Neuroscience, grant WBS066 (http://www.wicn.ac.uk/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 15 Z9 15 U1 4 U2 9 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 OCT 26 PY 2011 VL 6 IS 10 AR e26708 DI 10.1371/journal.pone.0026708 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841NR UT WOS:000296519600046 PM 22046336 ER PT J AU McGregor, R Wu, MF Barber, G Ramanathan, L Siegel, JM AF McGregor, Ronald Wu, Ming-Fung Barber, Grace Ramanathan, Lalini Siegel, Jerome M. TI Highly Specific Role of Hypocretin (Orexin) Neurons: Differential Activation as a Function of Diurnal Phase, Operant Reinforcement versus Operant Avoidance and Light Level SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PARKINSONS-DISEASE; SLEEP-DEPRIVATION; HUMAN NARCOLEPSY; FOS EXPRESSION; KNOCKOUT MICE; MUSCLE TONE; RATS; CATAPLEXY; AROUSAL; LESIONS AB Hypocretin (Hcrt) cell loss is responsible for narcolepsy, but Hcrt's role in normal behavior is unclear. We found that Hcrt knock-out mice were unable to work for food or water reward during the light phase. However, they were unimpaired relative to wild-type (WT) mice when working for reward during the dark phase or when working to avoid shock in the light or dark phase. In WT mice, expression of Fos in Hcrt neurons occurs only in the light phase when working for positive reinforcement. Expression was seen throughout the mediolateral extent of the Hcrt field. Fos was not expressed when expected or unexpected unearned rewards were presented, when working to avoid negative reinforcement, or when given or expecting shock, even though these conditions elicit maximal electroencephalogram (EEG) arousal. Fos was not expressed in the light phase when light was removed. This may explain the lack of light-induced arousal in narcoleptics and its presence in normal individuals. This is the first demonstration of such specificity of arousal system function and has implications for understanding the motivational and circadian consequences of arousal system dysfunction. The current results also indicate that comparable and complementary specificities must exist in other arousal systems. C1 [McGregor, Ronald; Wu, Ming-Fung; Barber, Grace; Ramanathan, Lalini; Siegel, Jerome M.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [McGregor, Ronald; Wu, Ming-Fung; Barber, Grace; Ramanathan, Lalini; Siegel, Jerome M.] Vet Adm Greater Los Angeles Healthcare Syst, North Hills, CA 91343 USA. [McGregor, Ronald; Wu, Ming-Fung; Barber, Grace; Ramanathan, Lalini; Siegel, Jerome M.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. RP Siegel, JM (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. EM JSiegel@ucla.edu FU National Institutes of Health [NS14610, MH64109, NS069640]; Medical Research Service of the Department of Veteran Affairs FX This work was supported by Grants NS14610, MH64109, and NS069640 from the National Institutes of Health and the Medical Research Service of the Department of Veteran Affairs. We thank Masashi Yanagisawa for providing us with the orexin KO mice, and Lisa Boehmer and Krystal Abordo for genotyping the mice. A preliminary report of some of these data was previously presented in abstract form (McGregor et al., 2007). NR 62 TC 32 Z9 32 U1 2 U2 6 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 OCT 26 PY 2011 VL 31 IS 43 BP 15455 EP 15467 DI 10.1523/JNEUROSCI.4017-11.2011 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 840MZ UT WOS:000296446200025 PM 22031892 ER PT J AU Campanha, C Minati, L Fregni, F Boggio, PS AF Campanha, Camila Minati, Ludovico Fregni, Felipe Boggio, Paulo S. TI Responding to Unfair Offers Made by a Friend: Neuroelectrical Activity Changes in the Anterior Medial Prefrontal Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FRONTAL-CORTEX; ALTRUISTIC PUNISHMENT; DECISION-MAKING; SOCIAL COGNITION; REGRET AVERSION; FEEDBACK; BRAIN; NEGATIVITY; REWARD; CONSEQUENCES AB When receiving unfair monetary offers from another person, the most common response is punishment. Existing literature on the Ultimatum Game indicates that individuals frequently refuse unfair offers even when this results in a loss for themselves. Here, we present behavioral and neurophysiological evidence demonstrating that friendship substantially modifies this response. When the proposer was a friend rather than an unknown person, unfair offers were less frequently rejected and the medial frontal negativity (MFN) typically associated with unfair offers was reversed to positive polarity. The underlying generators were located in inferior-mesial and right inferior-and medial-lateral frontal regions (BA10 and BA11). These findings highlight the fundamental role of the anterior prefrontal cortex in interpersonal economic interaction and, particularly, present new evidence on the effects of social distance on the MFN. C1 [Campanha, Camila; Boggio, Paulo S.] Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Social & Cognit Neurosci Lab, BR-01241001 Sao Paulo, Brazil. [Campanha, Camila; Boggio, Paulo S.] Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Dev Disorders Program, BR-01241001 Sao Paulo, Brazil. [Minati, Ludovico] Fdn IRCCS Ist Neurol Carlo Besta, Dept Sci, I-20133 Milan, Italy. [Fregni, Felipe] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil,Lab Neuromodulat, Boston, MA 02114 USA. [Fregni, Felipe] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fregni, Felipe] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02115 USA. RP Boggio, PS (reprint author), Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Social & Cognit Neurosci Lab, Rua Piaui,181,10 Andar, BR-01241001 Sao Paulo, Brazil. EM boggio@mackenzie.br RI Boggio, Paulo/K-6272-2012 OI Boggio, Paulo/0000-0002-6109-0447 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2009/04694-1]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [305718/2009-6]; Mack Pesquisa FX C.C. was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (2009/04694-1). P.S.B. was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (305718/2009-6) and by Mack Pesquisa. We acknowledge Kayleen Weaver for proofreading of this manuscript, Nathalia I. Baptista for picture design, and two anonymous reviewers for insightful feedback on an earlier version. NR 35 TC 28 Z9 34 U1 2 U2 19 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 OCT 26 PY 2011 VL 31 IS 43 BP 15569 EP 15574 DI 10.1523/JNEUROSCI.1253-11.2011 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 840MZ UT WOS:000296446200035 PM 22031902 ER PT J AU Covinsky, KE Pierluissi, E Johnston, CB AF Covinsky, Kenneth E. Pierluissi, Edgar Johnston, C. Bree TI Hospitalization-Associated Disability "She Was Probably Able to Ambulate, but I'm Not Sure" SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PREDICTS FUNCTIONAL DECLINE; ACUTE MEDICAL ILLNESS; ILL OLDER PATIENTS; LONG-TERM-CARE; RANDOMIZED-TRIAL; LOW MOBILITY; MULTICOMPONENT INTERVENTION; GERIATRIC ASSESSMENT; RESTRICTED ACTIVITY; ELDERLY PATIENTS AB In older patients, acute medical illness that requires hospitalization is a sentinel event that often precipitates disability. This results in the subsequent inability to live independently and complete basic activities of daily living (ADLs). This hospitalization-associated disability occurs in approximately one-third of patients older than 70 years of age and may be triggered even when the illness that necessitated the hospitalization is successfully treated. In this article, we describe risk factors and risk stratification tools that identify older adults at highest risk of hospitalization-associated disability. We describe hospital processes that may promote hospitalization-associated disability and models of care that have been developed to prevent it. Since recognition of functional status problems is an essential prerequisite to preventing and managing disability, we also describe a pragmatic approach toward functional status assessment in the hospital focused on evaluation of ADLs, mobility, and cognition. Based on studies of acute geriatric units, we describe interventions hospitals and clinicians can consider to prevent hospitalization-associated disability in patients. Finally, we describe approaches clinicians can implement to improve the quality of life of older adults who develop hospitalization-associated disability and that of their caregivers. JAMA. 2011;306(16):1782-1793 C1 [Covinsky, Kenneth E.; Pierluissi, Edgar; Johnston, C. Bree] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94121 USA. [Covinsky, Kenneth E.; Pierluissi, Edgar; Johnston, C. Bree] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Pierluissi, Edgar] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Pierluissi, Edgar] San Francisco Gen Hosp, Div Hosp Med, San Francisco, CA 94110 USA. [Covinsky, Kenneth E.; Johnston, C. Bree] San Francisco VA Med Ctr, Sect Geriatr & Palliat Care, San Francisco, CA USA. RP Covinsky, KE (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St 181G, San Francisco, CA 94121 USA. EM ken.covinsky@ucsf.edu FU National Institute on Aging; SCAN Foundation FX This work was supported in part by a K24 midcareer investigator award from the National Institute on Aging (Covinsky). The Care of the Aging Patient series is made possible by funding from The SCAN Foundation. NR 72 TC 146 Z9 148 U1 3 U2 24 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 OCT 26 PY 2011 VL 306 IS 16 BP 1782 EP 1793 DI 10.1001/jama.2011.1556 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 837HH UT WOS:000296181600023 PM 22028354 ER PT J AU Kangovi, S Grande, D AF Kangovi, Shreya Grande, David TI Hospital Readmissions-Not Just a Measure of Quality SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID INSURANCE STATUS; FOLLOW-UP; CARE; ACCESS; IMPACT C1 [Kangovi, Shreya] Univ Penn, Robert Wood Johnson Clin Scholars Program, Philadelphia, PA 19104 USA. [Grande, David] Univ Penn, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Kangovi, Shreya; Grande, David] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Kangovi, Shreya] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Kangovi, S (reprint author), Univ Penn, Robert Wood Johnson Clin Scholars Program, 423 Guardian Dr,13th Floor,Blockley Hall, Philadelphia, PA 19104 USA. EM kangovi@mail.med.upenn.edu NR 10 TC 62 Z9 62 U1 0 U2 6 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 OCT 26 PY 2011 VL 306 IS 16 BP 1796 EP 1797 DI 10.1001/jama.2011.1562 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 837HH UT WOS:000296181600025 PM 22028356 ER PT J AU Piller, LB Baraniuk, S Simpson, LM Cushman, WC Massie, BM Einhorn, PT Oparil, S Ford, CE Graumlich, JF Dart, RA Parish, DC Retta, TM Cuyjet, AB Jafri, SZ Furberg, CD Saklayen, MG Thadani, U Probstfield, JL Davis, BR AF Piller, Linda B. Baraniuk, Sarah Simpson, Lara M. Cushman, William C. Massie, Barry M. Einhorn, Paula T. Oparil, Suzanne Ford, Charles E. Graumlich, James F. Dart, Richard A. Parish, David C. Retta, Tamrat M. Cuyjet, Aloysius B. Jafri, Syed Z. Furberg, Curt D. Saklayen, Mohammad G. Thadani, Udho Probstfield, Jeffrey L. Davis, Barry R. CA ALLHAT Collaborative Res Grp TI Long-Term Follow-Up of Participants With Heart Failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) SO CIRCULATION LA English DT Article DE heart failure; hypertension; diuretics; mortality; ejection fraction ID CONVERTING-ENZYME-INHIBITOR; CARDIOVASCULAR EVENTS; SURVIVAL; HYPERTENSION; RISK; BLOCKER; TRENDS; OLDER AB Background-In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (>= 50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. Methods and Results-With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm. Conclusions-Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. C1 [Piller, Linda B.; Baraniuk, Sarah; Simpson, Lara M.; Ford, Charles E.; Davis, Barry R.] Univ Texas Sch Publ Hlth, Houston, TX 77030 USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Massie, Barry M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Einhorn, Paula T.] NHLBI, Bethesda, MD 20892 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Birmingham, AL USA. [Graumlich, James F.] Univ Illinois, Coll Med, Peoria, IL 61656 USA. [Dart, Richard A.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Parish, David C.] Mercer Univ, Sch Med, Macon, GA 31207 USA. [Retta, Tamrat M.] Howard Univ, Coll Med, Washington, DC USA. [Cuyjet, Aloysius B.] Nassau Univ, Med Ctr, E Meadow, NY USA. [Jafri, Syed Z.] Fargo Vet Affairs Med Ctr, Fargo, ND USA. [Furberg, Curt D.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Saklayen, Mohammad G.] Vet Affairs Med Ctr, Dayton, OH USA. [Saklayen, Mohammad G.] Wright State Univ, Dayton, OH 45435 USA. [Thadani, Udho] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Thadani, Udho] Dept Vet Affairs Med Ctr, Oklahoma City, OK USA. [Probstfield, Jeffrey L.] Univ Washington, Seattle, WA 98195 USA. RP Piller, LB (reprint author), Univ Texas Sch Publ Hlth, 1200 Pressler St,W-906, Houston, TX 77030 USA. EM Linda.B.Piller@uth.tmc.edu FU National Heart, Lung, and Blood Institute [NO1-HC-35130]; Pfizer, Inc.; GlaxoSmithKline; Merck; Novartis; Corthera; Takeda; Amgen; Daiichi Sankyo; Gilead; Omron Healthcare; Pfizer; Schering Plough; Abbot Laboratories; Boehringer Ingelheim; Sanofi-aventis; Bristol-Myers Squibb; Eisai Medical Research; Eli Lilly; NIH; Schering-Plough FX This study was supported by contract NO1-HC-35130 with the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge study medications contributed by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer, Inc.; Dr Cushman has consulted for Daiichi Sankyo, Novartis, Noven, Sanofi-aventis, Takeda, and Theravance; has received honoraria from Bristol-Myers Squibb, and has received research grants from GlaxoSmithKline, Merck, and Novartis. Dr Davis has consulted for Amgen and Takeda. Dr. Massie has consulted for Averion, Bristol-Myers Squibb, Gilead, Merck, Nile Therapeutics, Novartis, and Sanofi-aventis, and has received payments for serving on the DSMB from Corthera and Takeda. Dr Oparil has consulted for Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Forest Pharmaceuticals, NicOx, and Novartis, and has received research grants from Amgen, Daiichi Sankyo, Gilead, Omron Healthcare, Pfizer, Schering Plough, and Takeda. Dr Probstfield has received research grants from Abbot Laboratories, Boehringer Ingelheim, GlaxoSmithKline, and Sanofi-aventis. Dr Thadani has consulted for Forest Laboratories, Gilead Colorado, Lilly/ICOS, and Merck; has received honoraria from Daiichi Sankyo and Eli Lilly; and has received research grants from Bristol-Myers Squibb, Eisai Medical Research, Eli Lilly, NIH, Novartis, Pfizer, and Schering-Plough. The other authors report no conflicts. NR 29 TC 17 Z9 19 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 25 PY 2011 VL 124 IS 17 BP 1811 EP U88 DI 10.1161/CIRCULATIONAHA.110.012575 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842EY UT WOS:000296576500012 PM 21969009 ER PT J AU Bangalore, S Bhatt, DL AF Bangalore, Sripal Bhatt, Deepak L. TI Right Heart Catheterization, Coronary Angiography, and Percutaneous Coronary Intervention SO CIRCULATION LA English DT Article ID ASSOCIATION TASK-FORCE; PRACTICE GUIDELINES; ACC/AHA GUIDELINES; TRIAL; GRADE; FLOW C1 [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Integrated Intervent Cardiovasc Program, Boston, MA 02132 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA 02132 USA. [Bangalore, Sripal] NYU, Sch Med, New York, NY USA. RP Bhatt, DL (reprint author), Brigham & Womens Hosp, VA Boston Healthcare Syst, Integrated Intervent Cardiovasc Program, 1400 VFW Pkwy, Boston, MA 02132 USA. EM dlbhattmd@post.harvard.edu RI Bangalore, Sripal/B-6246-2013; OI Bangalore, Sripal/0000-0001-9485-0652 NR 11 TC 5 Z9 5 U1 0 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 OCT 25 PY 2011 VL 124 IS 17 BP E428 EP E433 DI 10.1161/CIRCULATIONAHA.111.065219 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842EY UT WOS:000296576500001 PM 22025641 ER PT J AU Tsai, TT Messenger, JC Brennan, M Patel, UD Dai, D Piana, RN Anstrom, KJ Eisenstein, EL Dokholyan, RS Peterson, ED Douglas, PS AF Tsai, Thomas T. Messenger, John C. Brennan, Matthew Patel, Uptal D. Dai, David Piana, Robert N. Anstrom, Kevin J. Eisenstein, Eric L. Dokholyan, Rachel S. Peterson, Eric D. Douglas, Pamela S. TI Safety and Efficacy of Drug-Eluting Stents in Older Patients With Chronic Kidney Disease A Report From the Linked CathPCI Registry-CMS Claims Database SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE comparative effectiveness research; drug-eluting stent(s); renal insufficiency ID CHRONIC RENAL-INSUFFICIENCY; BARE-METAL STENTS; PERCUTANEOUS CORONARY REVASCULARIZATION; CARDIOVASCULAR DATA REGISTRY; LONG-TERM OUTCOMES; TAXUS-IV TRIAL; OFF-LABEL USE; AMERICAN-COLLEGE; MYOCARDIAL-INFARCTION; CLINICAL-OUTCOMES AB Objectives The purpose of this study was to determine the safety and efficacy of drug-eluting stents (DES) compared with bare-metal stents (BMS) in older patients with chronic kidney disease (CKD). Background DES may be associated with late death and myocardial infarction (MI) secondary to stent thrombosis. However, data on outcomes in older patients with CKD are limited. Methods We estimated the glomerular filtration rate (GFR) of 283,593 patients 65 years of age and older who underwent stent implantation between 2004 and 2007. In propensity-matched cohorts grouped by GFR, the association between DES and BMS and the risk of death, MI, revascularization, and major bleeding was examined. Results A total of 121,446 patients (42.8%) had CKD (GFR <60 ml/min/1.73 m(2)). The 30-month mortality rate for patients on long-term dialysis was 52.0%. In propensity-matched pairs, placement of a DES compared with a BMS in patients with normal renal function was associated with significant reductions in 30-month revascularization (hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.86 to 0.95), MI (HR: 0.77; 95% CI: 0.71 to 0.83), and death (HR: 0.73; 95% CI: 0.69 to 0.77), but no difference in bleeding (HR: 0.89; 95% CI: 0.79 to 1.00). Lower MI and mortality rates were also observed after DES compared with BMS implantation in all CKD subgroups with the exception of MI in the long-term dialysis group. Decreased rates of revascularization did not extend to any subgroup of patients with CKD. Conclusions The safety of DES compared with BMS is observed in all patients regardless of renal function and is associated with reduced rates of MI and death in some subsets of patients with CKD. (J Am Coll Cardiol 2011; 58: 1859-69) (C) 2011 by the American College of Cardiology Foundation C1 [Tsai, Thomas T.] Denver VA Med Ctr, Cardiol Sect 111B, Denver, CO 80220 USA. [Tsai, Thomas T.; Messenger, John C.] Univ Colorado, Aurora, CO USA. [Brennan, Matthew; Patel, Uptal D.; Dai, David; Anstrom, Kevin J.; Eisenstein, Eric L.; Dokholyan, Rachel S.; Peterson, Eric D.; Douglas, Pamela S.] Duke Univ Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Piana, Robert N.] Vanderbilt Univ Sch Med, Nashville, TN USA. RP Tsai, TT (reprint author), Denver VA Med Ctr, Cardiol Sect 111B, 1055 Clermont St, Denver, CO 80220 USA. EM Thomas.Tsai@va.gov FU Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) [HHSA29020050032I]; Medtronic Cardiovascular; Eli Lilly Co.; Bristol-Myers Squibb/Sanofi; Merck; Lilly; Johnson Johnson FX This project was funded under contract no. HHSA29020050032I Task Order No. 4 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services. Dr. Eisenstein has received grant support from Medtronic Cardiovascular and Eli Lilly & Co. Dr. Peterson has received research support from Bristol-Myers Squibb/Sanofi, Merck, Lilly, and Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 43 TC 42 Z9 43 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 OCT 25 PY 2011 VL 58 IS 18 BP 1859 EP 1869 DI 10.1016/j.jacc.2011.06.056 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 841UM UT WOS:000296540200005 PM 22018296 ER PT J AU Deswal, A AF Deswal, Anita TI Obesity, Leptin, and Incident Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE heart failure; leptin; obesity ID RAT VENTRICULAR MYOCYTES; ATHEROSCLEROSIS; RISK; MICE; HYPERTROPHY; APOPTOSIS; DISEASE C1 [Deswal, Anita] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Cardiol Sect, Houston, TX 77030 USA. [Deswal, Anita] Baylor Coll Med, Winters Ctr Heart Failure Res, Houston, TX 77030 USA. RP Deswal, A (reprint author), Michael E DeBakey VA Med Ctr 111B, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM adeswal@bcm.edu NR 19 TC 6 Z9 6 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 25 PY 2011 VL 58 IS 18 BP 1878 EP 1880 DI 10.1016/j.jacc.2011.07.030 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 841UM UT WOS:000296540200007 PM 22018298 ER PT J AU Januzzi, JL Rehman, SU Mohammed, AA Bhardwaj, A Barajas, L Barajas, J Kim, HN Baggish, AL Weiner, RB Chen-Tournoux, A Marshall, JE Moore, SA Carlson, WD Lewis, GD Shin, J Sullivan, D Parks, K Wang, TJ Gregory, SA Uthamalingam, S Semigran, MJ AF Januzzi, James L., Jr. Rehman, Shafiq U. Mohammed, Asim A. Bhardwaj, Anju Barajas, Linda Barajas, Justine Kim, Han-Na Baggish, Aaron L. Weiner, Rory B. Chen-Tournoux, Annabel Marshall, Jane E. Moore, Stephanie A. Carlson, William D. Lewis, Gregory D. Shin, Jordan Sullivan, Dorothy Parks, Kimberly Wang, Thomas J. Gregory, Shawn A. Uthamalingam, Shanmugam Semigran, Marc J. TI Use of Amino-Terminal Pro-B-Type Natriuretic Peptide to Guide Outpatient Therapy of Patients With Chronic Left Ventricular Systolic Dysfunction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE heart failure; natriuretic peptides; outcomes ID CHRONIC HEART-FAILURE; TRIAL; MANAGEMENT; BNP; MULTICENTER; PREDICTION; CARE; CARVEDILOL; MORTALITY; SURVIVAL AB Objectives The aim of this study was to evaluate whether chronic heart failure (HF) therapy guided by concentrations of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is superior to standard of care (SOC) management. Background It is unclear whether standard HF treatment plus a goal of reducing NT-proBNP concentrations improves outcomes compared with standard management alone. Methods In a prospective single-center trial, 151 subjects with HF due to left ventricular (LV) systolic dysfunction were randomized to receive either standard HF care plus a goal to reduce NT-proBNP concentrations <= 1,000 pg/ml or SOC management. The primary endpoint was total cardiovascular events between groups compared using generalized estimating equations. Secondary endpoints included effects of NT-proBNP-guided care on patient quality of life as well as cardiac structure and function, assessed with echocardiography. Results Through a mean follow-up period of 10 +/- 3 months, a significant reduction in the primary endpoint of total cardiovascular events was seen in the NT-proBNP arm compared with SOC (58 events vs. 100 events, p = 0.009; logistic odds for events 0.44, p = 0.02); Kaplan-Meier curves demonstrated significant differences in time to first event, favoring NT-proBNP-guided care (p = 0.03). No age interaction was found, with elderly patients bene-fitting similarly from NT-proBNP-guided care as younger subjects. Compared with SOC, NT-proBNP-guided patients had greater improvements in quality of life, demonstrated greater relative improvements in LV ejection fraction, and had more significant improvements in both LV end-systolic and -diastolic volume indexes. Conclusions In patients with HF due to LV systolic dysfunction, NT-proBNP-guided therapy was superior to SOC, with reduced event rates, improved quality of life, and favorable effects on cardiac remodeling. (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting; NCT00351390) (J Am Coll Cardiol 2011;58:1881-9) (C) 2011 by the American College of Cardiology Foundation C1 [Januzzi, James L., Jr.; Rehman, Shafiq U.; Mohammed, Asim A.; Bhardwaj, Anju; Barajas, Linda; Barajas, Justine; Kim, Han-Na; Baggish, Aaron L.; Weiner, Rory B.; Chen-Tournoux, Annabel; Marshall, Jane E.; Moore, Stephanie A.; Carlson, William D.; Lewis, Gregory D.; Shin, Jordan; Sullivan, Dorothy; Parks, Kimberly; Wang, Thomas J.; Gregory, Shawn A.; Uthamalingam, Shanmugam; Semigran, Marc J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org FU Roche Diagnostics, Inc.; Balson Cardiac Scholar Fund; Siemens Diagnostics; Critical Diagnostics; Dennis and Marilyn Barry Cardiology Fellowship FX This study was supported in part by Roche Diagnostics, Inc. Dr. Januzzi is supported in part by the Balson Cardiac Scholar Fund; has received research grants and consultancy fees from Roche Diagnostics, Inc., Siemens Diagnostics, and Critical Diagnostics; and has received speakers fees from Roche Diagnostics, Inc. and Siemens Diagnostics. Drs. Rehman, Mohammed, Bhardwaj, and Kim are supported by the Dennis and Marilyn Barry Cardiology Fellowship. Dr. Shin has served as a consultant to Acceleron Pharma. Dr. Wang has been a coinvestigator on studies that received assay support from Siemens Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 32 TC 151 Z9 154 U1 1 U2 6 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 OCT 25 PY 2011 VL 58 IS 18 BP 1881 EP 1889 DI 10.1016/j.jacc.2011.03.072 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 841UM UT WOS:000296540200008 PM 22018299 ER PT J AU Pau, VPT Smith, FJ Taylor, AB Parfenova, LV Samakai, E Callaghan, MM Abarca-Heidemann, K Hart, PJ Rothberg, BS AF Pau, Victor P. T. Smith, Frank J. Taylor, Alexander B. Parfenova, Liubov V. Samakai, Elsie Callaghan, Matthew M. Abarca-Heidemann, Karin Hart, P. John Rothberg, Brad S. TI Structure and function of multiple Ca2+-binding sites in a K+ channel regulator of K+ conductance (RCK) domain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE calcium; lipid bilayer; cooperativity ID POTASSIUM CHANNEL; GATING RING; CRYSTAL-STRUCTURES; SLO FAMILY; MTHK; MECHANISM; COMPLEX; BINDING; ACTIVATION; PROTEINS AB Regulator of K+ conductance (RCK) domains control the activity of a variety of K+ transporters and channels, including the human large conductance Ca2+-activated K+ channel that is important for blood pressure regulation and control of neuronal firing, and MthK, a prokaryotic Ca2+-gated K+ channel that has yielded structural insight toward mechanisms of RCK domain-controlled channel gating. In MthK, a gating ring of eight RCK domains regulates channel activation by Ca2+. Here, using electrophysiology and X-ray crystallography, we show that each RCK domain contributes to three different regulatory Ca2+-binding sites, two of which are located at the interfaces between adjacent RCK domains. The additional Ca2+-binding sites, resulting in a stoichiometry of 24 Ca2+ ions per channel, is consistent with the steep relation between [Ca2+] and MthK channel activity. Comparison of Ca2+-bound and unliganded RCK domains suggests a physical mechanism for Ca2+-dependent conformational changes that underlie gating in this class of channels. C1 [Pau, Victor P. T.; Smith, Frank J.; Samakai, Elsie; Callaghan, Matthew M.; Abarca-Heidemann, Karin; Rothberg, Brad S.] Temple Univ, Sch Med, Dept Biochem, Philadelphia, PA 19140 USA. [Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78240 USA. [Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78240 USA. [Parfenova, Liubov V.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78240 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Dept Vet Affairs, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78240 USA. RP Rothberg, BS (reprint author), Temple Univ, Sch Med, Dept Biochem, 3400 N Broad St, Philadelphia, PA 19140 USA. EM rothberg@temple.edu OI Rothberg, Brad/0000-0003-1982-2269 FU National Institutes of Health [GM068523]; Robert A. Welch Foundation [AQ1399]; American Heart Association FX We thank Daniel Yang and Andrew Thomson for helpful discussions, and the X-ray Core Facility of University of Texas Health Science Center at San Antonio for technical support. This research was supported by National Institutes of Health Grant GM068523 (to B. S. R) and Robert A. Welch Foundation Grant AQ1399 (to P.J.H.). V. P. P. has been supported by a postdoctoral fellowship from the American Heart Association, Great Rivers Affiliate. NR 29 TC 13 Z9 15 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 OCT 25 PY 2011 VL 108 IS 43 BP 17684 EP 17689 DI 10.1073/pnas.1107229108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839OU UT WOS:000296378100033 PM 21997217 ER PT J AU Wang, NJ Sanborn, Z Arnett, KL Bayston, LJ Liao, W Proby, CM Leigh, IM Collisson, EA Gordon, PB Jakkula, L Pennypacker, S Zou, Y Sharma, M North, JP Vemula, SS Mauro, TM Neuhaus, IM LeBoit, PE Hur, JS Park, K Huh, N Kwok, PY Arron, ST Massion, PP Bale, AE Haussler, D Cleaver, JE Gray, JW Spellman, PT South, AP Aster, JC Blacklow, SC Cho, RJ AF Wang, Nicholas J. Sanborn, Zachary Arnett, Kelly L. Bayston, Laura J. Liao, Wilson Proby, Charlotte M. Leigh, Irene M. Collisson, Eric A. Gordon, Patricia B. Jakkula, Lakshmi Pennypacker, Sally Zou, Yong Sharma, Mimansa North, Jeffrey P. Vemula, Swapna S. Mauro, Theodora M. Neuhaus, Isaac M. LeBoit, Philip E. Hur, Joe S. Park, Kyunghee Huh, Nam Kwok, Pui-Yan Arron, Sarah T. Massion, Pierre P. Bale, Allen E. Haussler, David Cleaver, James E. Gray, Joe W. Spellman, Paul T. South, Andrew P. Aster, Jon C. Blacklow, Stephen C. Cho, Raymond J. TI Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer genetics; genomic; cellular signaling ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; GROWTH-FACTOR RECEPTOR; DROSOPHILA NOTCH; LIGAND-BINDING; C-MYC; SKIN; GENE; HEAD; NECK AB Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in similar to 75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies. C1 [Liao, Wilson; Pennypacker, Sally; Mauro, Theodora M.; Neuhaus, Isaac M.; Kwok, Pui-Yan; Arron, Sarah T.; Cleaver, James E.; Cho, Raymond J.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Wang, Nicholas J.; Jakkula, Lakshmi] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. [Sanborn, Zachary; Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Arnett, Kelly L.; Bayston, Laura J.; Aster, Jon C.; Blacklow, Stephen C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Collisson, Eric A.] Univ Calif San Francisco, Dept Hematol & Oncol, San Francisco, CA 94143 USA. [Sharma, Mimansa; North, Jeffrey P.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Proby, Charlotte M.; Leigh, Irene M.; South, Andrew P.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Div Canc Res, Dundee DD1 9SY, Scotland. [Gordon, Patricia B.; Bale, Allen E.] Yale Univ, Dept Genet, New Haven, CT 06520 USA. [Zou, Yong; Massion, Pierre P.] Vanderbilt Univ, Div Allergy Pulm & Crit Care Med, Nashville, TN 37232 USA. [Vemula, Swapna S.; LeBoit, Philip E.] Univ Calif San Francisco, Serv Dermatopathol, San Francisco, CA 94115 USA. [Hur, Joe S.] Samsung Elect Headquarters, Seoul 137857, South Korea. [Park, Kyunghee; Huh, Nam] Samsung Adv Inst Technol, Emerging Technol Res Ctr, Kyonggi Do 446712, South Korea. [Gray, Joe W.] Oregon Hlth & Sci Univ, Dept Biomed Engn, Portland, OR 97239 USA. [Spellman, Paul T.] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA. [Blacklow, Stephen C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Cleaver, JE (reprint author), Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. EM jcleaver@cc.ucsf.edu; chorj@derm.ucsf.edu RI Arnett, Kelly/C-4816-2012; Kwok, Pui-Yan/F-7725-2014; OI Kwok, Pui-Yan/0000-0002-5087-3059; Arnett, Kelly/0000-0001-5117-3647; North, Jeffrey/0000-0003-3973-5314 FU Leukemia and Lymphoma Society; National Institutes of Health (NIH) [P01 CA119070, R01 CA092433]; European Research Council; Cancer Research-UK; Department of Energy [DE-AC02-05CH11231]; NIH/National Cancer Institute (NCI) [P50 CA 58207, U54 CA 112970]; National Human Genome Research Institute [U24 CA 126551]; US Army Medical Research Acquisition Activity [W81XWH-07-1-0663]; Stand Up To Cancer-American Association for Cancer Research Dream Team [SU2C-AACR-DT0409]; University of California; Dickson Emeritus Professorship; NIH/NCI [U24 CA1437991, KO8 CA137153]; Yale SPORE in Skin Cancer; National Cancer Institute [P50 CA121974]; NIH [AR051930, R01AG028492]; Department of Veterans Affairs Medical Research Service; NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases [5KO8AR057763]; Samsung Advanced Institute of Technology; Dermatology Foundation FX We thank Andrew J. Cassidy, Karin J. Purdie, Zohreh AkhavanAghdam, Catherine Chu, Sonia A. Mirza, Gad Getz, Kristian Cibulskis, and Rebecca Terrell for technical expertise and assistance. J. C. A. and S. C. B. were supported by Leukemia and Lymphoma Society grants and by National Institutes of Health (NIH) Grants P01 CA119070 and R01 CA092433. I. M. L. was supported by program grants from the European Research Council and Cancer Research-UK. J. W. G. was supported by Department of Energy Contract DE-AC02-05CH11231, NIH/National Cancer Institute (NCI) Grants P50 CA 58207 and U54 CA 112970, National Human Genome Research Institute Grant U24 CA 126551, US Army Medical Research Acquisition Activity Award W81XWH-07-1-0663, and Stand Up To Cancer-American Association for Cancer Research Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409. J. E. C. was supported by the University of California Cancer Research Campaign and the Dickson Emeritus Professorship. P. T. S. was supported by NIH/NCI Grant U24 CA1437991. A. E. B. and P. B. G. were supported by the Yale SPORE in Skin Cancer funded by the National Cancer Institute Grant P50 CA121974. T. M. M. was supported by NIH Grants AR051930 and R01AG028492 and by the Department of Veterans Affairs Medical Research Service. E. A. C. was supported by NIH/NCI Grant KO8 CA137153. W. L. was supported by NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant 5KO8AR057763. R. J. C. was supported by a Samsung Advanced Institute of Technology unrestricted gift-grant and a Career Development Award from the Dermatology Foundation. NR 55 TC 164 Z9 168 U1 3 U2 26 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 OCT 25 PY 2011 VL 108 IS 43 BP 17761 EP 17766 DI 10.1073/pnas.1114669108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839OU UT WOS:000296378100046 PM 22006338 ER PT J AU Nagao, M Feinstein, TN Ezura, Y Hayata, T Notomi, T Saita, Y Hanyu, R Hemmi, H Izu, Y Takeda, S Wang, K Rittling, S Nakamoto, T Kaneko, K Kurosawa, H Karsenty, G Denhardt, DT Vilardaga, JP Noda, M AF Nagao, Masashi Feinstein, Timothy N. Ezura, Yoichi Hayata, Tadayoshi Notomi, Takuya Saita, Yoshitomo Hanyu, Ryo Hemmi, Hiroaki Izu, Yayoi Takeda, Shu Wang, Kathryn Rittling, Susan Nakamoto, Tetsuya Kaneko, Kazuo Kurosawa, Hisashi Karsenty, Gerard Denhardt, David T. Vilardaga, Jean-Pierre Noda, Masaki TI Sympathetic control of bone mass regulated by osteopontin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE osteoporosis; G protein-coupled receptor; osteoblast ID DENDRITIC CELLS; NERVOUS-SYSTEM; RECEPTOR; CAMP; OSTEOPOROSIS; SUPPRESSION; STRESS; MICE AB The sympathetic nervous system suppresses bone mass by mechanisms that remain incompletely elucidated. Using cell-based and murine genetics approaches, we show that this activity of the sympathetic nervous systemrequires osteopontin (OPN), a cytokine and one of the major members of the noncollagenous extracellular matrix proteins of bone. In this work, we found that the stimulation of the sympathetic tone by isoproterenol increased the level of OPN expression in the plasma and bone and that mice lacking OPN (OPN-KO) suppressed the isoproterenol-induced bone loss by preventing reduced osteoblastic and enhanced osteoclastic activities. In addition, we found that OPN is necessary for changes in the expression of genes related to bone resorption and bone formation that are induced by activation of the sympathetic tone. At the cellular level, we showed that intracellular OPN modulated the capacity of the beta 2-adrenergic receptor to generate cAMP with a corresponding modulation of cAMP-response element binding (CREB) phosphorylation and associated transcriptional events inside the cell. Our results indicate that OPN plays a critical role in sympathetic tone regulation of bone mass and that this OPN regulation is taking place through modulation of the beta 2-adrenergic receptor/cAMP signaling system. C1 [Feinstein, Timothy N.; Vilardaga, Jean-Pierre] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab GPCR Biol, Pittsburgh, PA 15261 USA. [Nagao, Masashi; Ezura, Yoichi; Hayata, Tadayoshi; Notomi, Takuya; Hanyu, Ryo; Hemmi, Hiroaki; Izu, Yayoi; Nakamoto, Tetsuya; Noda, Masaki] Tokyo Med & Dent Univ, Med Res Inst, Dept Mol Pharmacol, Bunkyo Ku, Tokyo 1138510, Japan. [Nagao, Masashi; Ezura, Yoichi; Hayata, Tadayoshi; Notomi, Takuya; Hanyu, Ryo; Hemmi, Hiroaki; Takeda, Shu; Nakamoto, Tetsuya; Noda, Masaki] Tokyo Med & Dent Univ, Global Ctr Excellence Program, Int Res Ctr Mol Sci Tooth & Bone Dis, Bunkyo Ku, Tokyo 1138510, Japan. [Nagao, Masashi; Saita, Yoshitomo; Hanyu, Ryo; Kaneko, Kazuo; Kurosawa, Hisashi] Juntendo Univ, Sch Med, Dept Orthoped, Bunkyo Ku, Tokyo 1138421, Japan. [Hemmi, Hiroaki; Noda, Masaki] Tokyo Med & Dent Univ, Med Res Inst, Med Top Track Program, Bunkyo Ku, Tokyo 1138510, Japan. [Wang, Kathryn; Denhardt, David T.] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08701 USA. [Rittling, Susan] Forsyth Inst, Boston, MA 02115 USA. [Karsenty, Gerard] Columbia Univ Coll Phys & Surg, Dept Genet & Dev, New York, NY 10032 USA. [Ezura, Yoichi; Noda, Masaki] Tokyo Med & Dent Univ, Adv Bone & Joint Sci Program, Bunkyo Ku, Tokyo 1138510, Japan. [Ezura, Yoichi; Noda, Masaki] Tokyo Med & Dent Univ, Hard Tissue Genome Res Ctr, Bunkyo Ku, Tokyo 1138510, Japan. RP Vilardaga, JP (reprint author), Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab GPCR Biol, Pittsburgh, PA 15261 USA. EM jpv@pitt.edu; noda.mph@mri.tmd.ac.jp RI Ezura, Yoichi/L-9485-2016 FU Japanese Ministry of Education, International Research Center for Molecular Science in Tooth and Bone Diseases [18109011, 18659438, 18123456, 20013014]; Japan Space Forum; National Institutes of Health [R01DK087688] FX This work was supported by Grants-in-Aid 18109011, 18659438, 18123456, and 20013014 from the Japanese Ministry of Education (Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases), grants from the Japan Space Forum (to M. Noda), and National Institutes of Health Award R01DK087688 (to J.-P.V.). NR 22 TC 30 Z9 33 U1 2 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 OCT 25 PY 2011 VL 108 IS 43 BP 17767 EP 17772 DI 10.1073/pnas.1109402108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839OU UT WOS:000296378100047 PM 21990347 ER PT J AU Feige, E Yokoyama, S Levy, C Khaled, M Igras, V Lin, RJ Lee, S Widlund, HR Granter, SR Kung, AL Fisher, DE AF Feige, Erez Yokoyama, Satoru Levy, Carmit Khaled, Mehdi Igras, Vivien Lin, Richard J. Lee, Stephen Widlund, Hans R. Granter, Scott R. Kung, Andrew L. Fisher, David E. TI Hypoxia-induced transcriptional repression of the melanoma-associated oncogene MITF SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; pigmentation; signal transduction ID RENAL-CELL CARCINOMAS; INTEGRATIVE GENOMIC ANALYSES; FACTOR DEC1 STRA13; MALIGNANT-MELANOMA; GENE-EXPRESSION; PROLINE HYDROXYLATION; TFE3 GENE; MICROPHTHALMIA LOCUS; PROGNOSTIC MARKER; LINEAGE SURVIVAL AB Microphthalmia- associated transcription factor (MITF) regulates normal melanocyte development and is also a lineage-selective oncogene implicated in melanoma and clear-cell sarcoma (i.e., melanoma of soft parts). We have observed that MITF expression is potently reduced under hypoxic conditions in primary melanocytes and melanoma and clear cell sarcoma cells through hypoxia inducible factor 1 (HIF1)-mediated induction of the transcriptional repressor differentially expressed in chondrocytes protein 1 (DEC1) (BHLHE40), which subsequently binds and suppresses the promoter of M-MITF (melanocyte-restricted MITF isoform). Correspondingly, hypoxic conditions or HIF1 alpha stabilization achieved by using small-molecule prolyl-hydroxylase inhibitors reduced M-MITF expression, leading to melanoma cell growth arrest that was rescued by ectopic expression of M-MITF in vitro. Prolyl hydroxylase inhibition also potently suppressed melanoma growth in a mouse xenograft model. These studies illuminate a physiologic hypoxia response in pigment cells leading to M-MITF suppression, one that suggests a potential survival advantage mechanism for MITF amplification in metastatic melanoma and offers a small-molecule strategy for suppression of the MITF oncogene in vivo. C1 [Feige, Erez; Yokoyama, Satoru; Levy, Carmit; Khaled, Mehdi; Igras, Vivien; Lin, Richard J.; Widlund, Hans R.; Kung, Andrew L.; Fisher, David E.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Yokoyama, Satoru; Levy, Carmit; Khaled, Mehdi; Igras, Vivien; Fisher, David E.] Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. [Lee, Stephen] Univ Ottawa, Fac Med, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada. [Granter, Scott R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Fisher, DE (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM dfisher3@partners.org RI khaled, mehdi/C-4854-2012; OI Lin, Richard/0000-0002-0834-7880; Kung, Andrew/0000-0002-9091-488X FU Bonnie and Marty Tenenbaum Foundation; National Institutes of Health; Melanoma Research Alliance; Adelson Medical Research Foundation FX The authors thank Dr. William Kaelin for reagents and discussions; Dr. Ruth Halaban for providing 501mel cells; Claudine Christoforides and Abigail J. Bracha for help with early aspects of the studies; Renee Wright for superb technical assistance; and all members of the D. E. F. laboratory for useful discussions and comments. This work was supported by the Bonnie and Marty Tenenbaum Foundation, a National Institutes of Health grant, the Melanoma Research Alliance, and the Adelson Medical Research Foundation. D.E.F. is Distinguished Clinical Scholar of the Doris Duke Medical Foundation. NR 59 TC 36 Z9 36 U1 0 U2 7 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 OCT 25 PY 2011 VL 108 IS 43 BP E924 EP E933 DI 10.1073/pnas.1106351108 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839OU UT WOS:000296378100010 PM 21949374 ER PT J AU Rutemark, C Alicot, E Bergman, A Ma, MH Getahun, A Ellmerich, S Carroll, MC Heyman, B AF Rutemark, Christian Alicot, Elisabeth Bergman, Anna Ma, Minghe Getahun, Andrew Ellmerich, Stephan Carroll, Michael C. Heyman, Birgitta TI Requirement for complement in antibody responses is not explained by the classic pathway activator IgM SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE IgM mutation; natural IgM ID HUMORAL IMMUNE-RESPONSE; FOLLICULAR DENDRITIC CELLS; A-DEFICIENT MICE; MARGINAL ZONE; RECEPTORS 1; B-CELLS; MEDIATED ENHANCEMENT; TARGETED DELETION; IMMUNOGLOBULIN-M; MEMBRANE IGM AB Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen-Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, C mu 13, with a point mutation in the gene encoding the third constant domain of the mu-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in C mu 13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals. C1 [Rutemark, Christian; Bergman, Anna; Heyman, Birgitta] Uppsala Univ, Dept Med Biochem & Microbiol, BMC, SE-75123 Uppsala, Sweden. [Alicot, Elisabeth; Ma, Minghe; Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Alicot, Elisabeth; Ma, Minghe; Carroll, Michael C.] Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. [Alicot, Elisabeth; Ma, Minghe; Carroll, Michael C.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA. [Getahun, Andrew] Univ Colorado, Sch Med, Dept Immunol, Denver, CO 80206 USA. [Getahun, Andrew] Natl Jewish Hlth, Denver, CO 80206 USA. [Ellmerich, Stephan] UCL, Ctr Amyloidosis & Acute Phase Prot, Div Med, London NW3 2PF, England. RP Heyman, B (reprint author), Uppsala Univ, Dept Med Biochem & Microbiol, BMC, SE-75123 Uppsala, Sweden. EM birgitta.heyman@imbim.uu.se FU Uppsala University; Swedish Research Council; Ellen Foundation; Walter Foundation; Lennart Hesselman Foundation; Hans von Kantzow Foundation; King Gustaf V 80 Years Foundation; Ollie and Elof Ericsson Foundation; Agnes and Mac Rudberg Foundation; National Institutes of Health [RO1 AI039246] FX We thank Drs. Marina Botto, Bo Nilsson, Kristina Nilsson Ekdahl, Chae Gyu Park, Mark Pepys, Marc Shulman, Steffen Thiel, Joshua Thurman, and Raul Torres for helpful suggestions, comments, and generous gifts of reagents and mice. This work was supported by Uppsala University; the Swedish Research Council; the Ellen, Walter, and Lennart Hesselman Foundation; the Hans von Kantzow Foundation; the King Gustaf V 80 Years Foundation; the Ollie and Elof Ericsson Foundation; the Agnes and Mac Rudberg Foundation (B.H.); and National Institutes of Health Grant RO1 AI039246 (to M.C.C.). NR 65 TC 12 Z9 13 U1 0 U2 3 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 OCT 25 PY 2011 VL 108 IS 43 BP E934 EP E942 DI 10.1073/pnas.1109831108 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 839OU UT WOS:000296378100011 PM 21987785 ER PT J AU Hochedlinger, K AF Hochedlinger, Konrad TI Embryonic Stem Cells: Testing the Germ-Cell Theory SO CURRENT BIOLOGY LA English DT Editorial Material ID MOUSE; ORIGIN; DERIVATION C1 [Hochedlinger, Konrad] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Hochedlinger, Konrad] Ctr Regenerat Med, Boston, MA 02114 USA. [Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Hochedlinger, K (reprint author), Harvard Univ, Howard Hughes Med Inst, 7 Divin Ave, Cambridge, MA 02138 USA. EM khochedlinger@helix.mgh.harvard.edu NR 16 TC 2 Z9 2 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD OCT 25 PY 2011 VL 21 IS 20 BP R850 EP R852 DI 10.1016/j.cub.2011.09.024 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 838NQ UT WOS:000296299700010 PM 22032189 ER PT J AU Lee, J Srinivasan, V Radhakrishnan, H Boas, DA AF Lee, Jonghwan Srinivasan, Vivek Radhakrishnan, Harsha Boas, David A. TI Motion correction for phase-resolved dynamic optical coherence tomography imaging of rodent cerebral cortex SO OPTICS EXPRESS LA English DT Article ID TRACKING; ARTIFACT; SYSTEM; PET AB Cardiac and respiratory motions in animals are the primary source of image quality degradation in dynamic imaging studies, especially when using phase-resolved imaging modalities such as spectral-domain optical coherence tomography (SD-OCT), whose phase signal is very sensitive to movements of the sample. This study demonstrates a method with which to compensate for motion artifacts in dynamic SD-OCT imaging of the rodent cerebral cortex. We observed that respiratory and cardiac motions mainly caused, respectively, bulk image shifts (BISs) and global phase fluctuations (GPFs). A cross-correlation maximization-based shift correction algorithm was effective in suppressing BISs, while GPFs were significantly reduced by removing axial and lateral global phase variations. In addition, a non-origin-centered GPF correction algorithm was examined. Several combinations of these algorithms were tested to find an optimized approach that improved image stability from 0.5 to 0.8 in terms of the cross-correlation over 4 s of dynamic imaging, and reduced phase noise by two orders of magnitude in similar to 8% voxels. (C)2011 Optical Society of America C1 [Lee, Jonghwan; Srinivasan, Vivek; Radhakrishnan, Harsha; Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Lee, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM jonghwan@nmr.mgh.harvard.edu RI Radhakrishnan, Harsha/K-5557-2012 FU US National Institutes of Health [R01NS057476, P01NS055104, R01EB000790, R01-EB001954, K99NS067050]; AFOSR [MFELFA9550-07-1-0101] FX The authors acknowledge financial support from US National Institutes of Health grants R01NS057476, P01NS055104, R01EB000790, R01-EB001954, and K99NS067050, and the AFOSR (MFELFA9550-07-1-0101). The authors thank J. Jiang at Thorlabs for helping with the SD-OCT system. NR 19 TC 28 Z9 28 U1 1 U2 6 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 OCT 24 PY 2011 VL 19 IS 22 BP 21258 EP 21270 DI 10.1364/OE.19.021258 PG 13 WC Optics SC Optics GA 842DC UT WOS:000296568100017 PM 22108978 ER PT J AU Lim, PY Keating, JA Hoover, S Striker, R Bernard, KA AF Lim, Pei-Yin Keating, Julie A. Hoover, Spencer Striker, Rob Bernard, Kristen A. TI A Thiopurine Drug Inhibits West Nile Virus Production in Cell Culture, but Not in Mice SO PLOS ONE LA English DT Article ID DEPENDENT RNA-POLYMERASES; HEPATITIS-C VIRUS; 6-METHYLMERCAPTOPURINE RIBOSIDE; LIVER-TRANSPLANTATION; MYCOPHENOLIC-ACID; CHAIN-TERMINATORS; CRYSTAL-STRUCTURE; VIRAL LOAD; CDNA-CLONE; RIBAVIRIN AB Many viruses within the Flavivirus genus cause significant disease in humans; however, effective antivirals against these viruses are not currently available. We have previously shown that a thiopurine drug, 6-methylmercaptopurine riboside (6MMPr), inhibits replication of distantly related viruses within the Flaviviridae family in cell culture, including bovine viral diarrhea virus and hepatitis C virus replicon. Here we further examined the potential antiviral effect of 6MMPr on several diverse flaviviruses. In cell culture, 6MMPr inhibited virus production of yellow fever virus, dengue virus-2 (DENV-2) and West Nile virus (WNV) in a dose-dependent manner, and DENV-2 was significantly more sensitive to 6MMPr treatment than WNV. We then explored the use of 6MMPr as an antiviral against WNV in an immunocompetent mouse model. Once a day treatment of mice with 0.5 mg 6MMPr was just below the toxic dose in our mouse model, and this dose was used in subsequent studies. Mice were treated with 6MMPr immediately after subcutaneous inoculation with WNV for eight consecutive days. Treatment with 6MMPr exacerbated weight loss in WNV-inoculated mice and did not significantly affect mortality. We hypothesized that 6MMPr has low bioavailability in the central nervous system (CNS) and examined the effect of pre-treatment with 6MMPr on viral loads in the periphery and CNS. Pre-treatment with 6MMPr had no significant effect on viremia or viral titers in the periphery, but resulted in significantly higher viral loads in the brain, suggesting that the effect of 6MMPr is tissue-dependent. In conclusion, despite being a potent inhibitor of flaviviruses in cell culture, 6MMPr was not effective against West Nile disease in mice; however, further studies are warranted to reduce the toxicity and/or improve the bioavailability of this potential antiviral drug. C1 [Lim, Pei-Yin; Bernard, Kristen A.] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. [Lim, Pei-Yin; Bernard, Kristen A.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Striker, Rob] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Keating, Julie A.; Hoover, Spencer; Striker, Rob] Univ Wisconsin, Dept Med, Madison, WI USA. RP Lim, PY (reprint author), Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. EM kbernard@vetmed.wisc.edu FU National Institute of Allergy and Infectious Diseases; National Institutes of Health (NIH) [1U01-AI061193, 2T32AI007414]; Northeast Biodefence Center [U54-AI057158] FX This work was partially supported by federal funds from the National Institute of Allergy and Infectious Diseases, and the National Institutes of Health (NIH) under 1U01-AI061193. The BSL-3 animal core, which is funded in part by the Northeast Biodefence Center (U54-AI057158), was used for the animal studies conducted at the Wadsworth Center. JAK was supported by the NIH-funded Cellular and Molecular Parasitology Training Program (2T32AI007414). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 2 Z9 2 U1 1 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 OCT 24 PY 2011 VL 6 IS 10 AR e26697 DI 10.1371/journal.pone.0026697 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841MA UT WOS:000296515200043 PM 22039536 ER PT J AU Sullivan, C Chen, YY Shan, Y Hu, YG Peng, C Zhang, HJ Kong, LH Li, SG AF Sullivan, Con Chen, Yaoyu Shan, Yi Hu, Yiguo Peng, Cong Zhang, Haojian Kong, Linghong Li, Shaoguang TI Functional Ramifications for the Loss of P-Selectin Expression on Hematopoietic and Leukemic Stem Cells SO PLOS ONE LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; MICE; INFLAMMATION AB Hematopoiesis is a tightly regulated biological process that relies upon complicated interactions between blood cells and their microenvironment to preserve the homeostatic balance of long-term hematopoietic stem cells (LT-HSCs), short-term HSCs (ST-HSCs), multipotent progenitors (MPPs), and differentiated cells. Adhesion molecules like P-selectin (encoded by the Selp gene) are essential to hematopoiesis, and their dysregulation has been linked to leukemogenesis. Like HSCs, leukemic stem cells (LSCs) depend upon their microenvironments for survival and propagation. P-selectin plays a crucial role in Philadelphia chromosome -positive (Ph(+)) chronic myeloid leukemia (CML). In this paper, we show that cells deficient in P-selectin expression can repopulate the marrow more efficiently than wild type controls. This results from an increase in HSC self-renewal rather than alternative possibilities like increased homing velocity or cell cycle defects. We also show that P-selectin expression on LT-HSCs, but not ST-HSCs and MPPs, increases with aging. In the absence of P-selectin expression, mice at 6 months of age possess increased levels of short-term HSCs and multipotent progenitors. By 11 months of age, there is a shift towards increased levels of long-term HSCs. Recipients of BCR-ABL-transduced bone marrow cells from P-selectin-deficient donors develop a more aggressive CML, with increased percentages of LSCs and progenitors. Taken together, our data reveal that P-selectin expression on HSCs and LSCs has important functional ramifications for both hematopoiesis and leukemogenesis, which is most likely attributable to an intrinsic effect on stem cell self-renewal. C1 [Sullivan, Con] Maine Inst Human Genet & Hlth, Bangor, ME USA. [Chen, Yaoyu; Shan, Yi; Peng, Cong; Zhang, Haojian; Li, Shaoguang] Univ Massachusetts, Sch Med, Dept Med, Div Hematol Oncol, Worcester, MA USA. [Sullivan, Con; Chen, Yaoyu; Hu, Yiguo; Peng, Cong; Zhang, Haojian; Kong, Linghong; Li, Shaoguang] Jackson Lab, Bar Harbor, ME 04609 USA. [Hu, Yiguo] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sullivan, C (reprint author), Maine Inst Human Genet & Hlth, Bangor, ME USA. EM shaoguang.li@umassmed.edu RI Peng, Cong/H-2286-2011; Zhang, Haojian/H-7897-2013; Shan, Yi/E-3862-2016 FU National Institutes of Health [CA122142, CA114199] FX This work was supported by the National Institutes of Health (CA122142,CA114199). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 15 TC 8 Z9 8 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 OCT 24 PY 2011 VL 6 IS 10 AR e26246 DI 10.1371/journal.pone.0026246 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841MA UT WOS:000296515200007 PM 22039451 ER PT J AU Grady, D Berkowitz, SA AF Grady, Deborah Berkowitz, Seth A. TI Why Is a Good Clinical Prediction Rule So Hard to Find? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID IMPACT C1 [Grady, Deborah; Berkowitz, Seth A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94115 USA. [Grady, Deborah] San Francisco VA Med Ctr, San Francisco, CA USA. RP Grady, D (reprint author), Univ Calif San Francisco, Dept Med, 1635 Divisadero St,Ste 600, San Francisco, CA 94115 USA. EM Deborah.Grady@ucsf.edu NR 10 TC 16 Z9 17 U1 0 U2 8 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 OCT 24 PY 2011 VL 171 IS 19 BP 1701 EP 1702 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 837JX UT WOS:000296198200001 PM 22025427 ER PT J AU Deo, R Vittinghoff, E Lin, F Tseng, ZH Hulley, SB Shlipak, MG AF Deo, Rajat Vittinghoff, Eric Lin, Feng Tseng, Zian H. Hulley, Stephen B. Shlipak, Michael G. TI Risk Factor and Prediction Modeling for Sudden Cardiac Death in Women With Coronary Artery Disease SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; ANTIARRHYTHMIC-DRUG THERAPY; HEART-DISEASE; ESTROGEN/PROGESTIN REPLACEMENT; VENTRICULAR-ARRHYTHMIAS; POSTMENOPAUSAL WOMEN; EJECTION FRACTION; UNEXPECTED DEATH; RANDOMIZED-TRIAL; PREVENTION AB Background: To our knowledge, the risk of sudden cardiac death (SCD) and the assessment of risk factors in prediction models have not been evaluated in women with coronary artery disease (CAD). We sought to evaluate the incidence of SCD as well as its risk factors and their predictive accuracy among a population of women with CAD. Methods: The Heart and Estrogen/progestin Replacement Study evaluated the effects of hormone replacement therapy on cardiovascular events among 2763 postmenopausal women with CAD. Sudden cardiac death was defined as death resulting from a cardiac origin that occurred within 1 hour of symptom onset. The associations between candidate predictor variables and SCD were evaluated in a Cox proportional hazards model. The C-index was used to compare the predictive value of the clinical risk factors with left ventricular ejection fraction (LVEF) alone and in combination. The net reclassification improvement was also computed. Results: Over a mean follow-up of 6.8 years, SCD comprised 136 of the 254 cardiac deaths. The annual SCD event rate was 0.79% (95% confidence interval, 0.67-0.94). The following variables were independently associated with SCD in the multivariate model: myocardial infarction, heart failure, an estimated glomerular filtration rate of less than 40 mL/min/1.73 m(2), atrial fibrillation, physical inactivity, and diabetes. The incidences of SCD among women with 0 (n = 683), 1 (n = 1224), 2 (n = 610), and 3 plus (n = 246) risk factors at baseline were 0.3%, 0.5%, 1.2%, and 2.9% per year, respectively. The combination of clinical risk factors and LVEF (C-index, 0.681) were better predictors of SCD than LVEF alone (C-index, 0.600) and resulted in a net reclassification improvement of 0.20 (P < .001). Conclusions: Sudden cardiac death comprised the majority of cardiac deaths among postmenopausal women with CAD. Independent predictors of SCD, including myocardial infarction, congestive heart failure, an estimated glomerular filtration rate of less than 40 mL/min/1.73 m(2), atrial fibrillation, physical inactivity, and diabetes, improved SCD prediction when they were considered in addition to LVEF. C1 [Deo, Rajat] Univ Penn, Sect Electrophysiol, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Vittinghoff, Eric; Lin, Feng; Hulley, Stephen B.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Tseng, Zian H.] Univ Calif San Francisco, Cardiac Electrophysiol Sect, Div Cardiol, Dept Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Div Gen Internal Med, Dept Med, San Francisco, CA USA. RP Deo, R (reprint author), Univ Penn, Sect Electrophysiol, Div Cardiovasc Med, 3400 Spruce St,9 Founders Cardiol, Philadelphia, PA 19104 USA. EM Rajat.Deo@uphs.upenn.edu FU National Institutes of Health (NIH) [K23DK089118, R01 HL102090]; National Center for Research Resources, NIH [KL2 RR024132]; NIH Roadmap for Medical Research; Kynett-FOCUS Junior Faculty Investigator Award for Research in Women's Cardiovascular Health; Edna G. Kynett Memorial Foundation at the University of Pennsylvania School of Medicine FX Dr Deo was supported by grants K23DK089118 from the National Institutes of Health (NIH) and KL2 RR024132 from the National Center for Research Resources, a component of the NIH and NIH Roadmap for Medical Research. Additional grant support was obtained from a Kynett-FOCUS Junior Faculty Investigator Award for Research in Women's Cardiovascular Health funded by the Edna G. Kynett Memorial Foundation at the University of Pennsylvania School of Medicine. Dr Tseng is supported by grant R01 HL102090 from the NIH. NR 40 TC 16 Z9 16 U1 0 U2 3 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 OCT 24 PY 2011 VL 171 IS 19 BP 1703 EP 1709 DI 10.1001/archinternmed.2011.328 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 837JX UT WOS:000296198200002 PM 21788534 ER PT J AU Paynter, NP Mazer, NA Pradhan, AD Gaziano, JM Ridker, PM Cook, NR AF Paynter, Nina P. Mazer, Norman A. Pradhan, Aruna D. Gaziano, J. Michael Ridker, Paul M. Cook, Nancy R. TI Cardiovascular Risk Prediction in Diabetic Men and Women Using Hemoglobin A(1c) vs Diabetes as a High-Risk Equivalent SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; PRIMARY PREVENTION; VASCULAR-DISEASE; MELLITUS; RECLASSIFICATION; METAANALYSIS; EVENTS; STATISTICS; FRAMINGHAM; ASPIRIN AB Background: It is unclear whether models that include hemoglobin A(1c) (HbA(1c)) levels only for diabetic patients improve the ability to predict cardiovascular disease (CVD) risk compared with the currently recommended classification of diabetes as a cardiovascular risk equivalent. Methods: A total of 24 674 women (including 685 diabetic participants at baseline) and 11 280 men (including 563 diabetic participants at baseline) were followed up prospectively for cardiovascular disease (CVD). One hundred twenty-five CVD events occurred in diabetic women (666 in nondiabetic women), and 170 events occurred in diabetic men (1382 in nondiabetic men). Models for CVD risk were generated separately for men and women using the traditional CVD risk factors with the addition of a term for HbA(1c) levels only for diabetic individuals. In diabetic participants, the resulting predicted risks were compared with classification of diabetes as a cardiovascular risk equivalent (10-year CVD risk of at least 20%). Results: In women, the models including HbA(1c) levels in diabetic participants improved the C statistic by 0.177 (P < .001) over the risk equivalence model and showed improved reclassification (net reclassification improvement [NRI] of 26.7% [P = .001]). In men, the improvements were more modest but still statistically significant (C statistic change of 0.039 [P = .02]; NRI of 9.2% [P = .04]). Including HbA1c levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8% [P = .03]) but not in men. Conclusions: In both women and men with diabetes at baseline, we observed significant improvements in predictive ability of CVD risk using models incorporating HbA(1c) levels compared with classification of diabetes as a cardiovascular risk equivalent. C1 [Paynter, Nina P.; Pradhan, Aruna D.; Gaziano, J. Michael; Ridker, Paul M.; Cook, Nancy R.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Mazer, Norman A.] F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland. [Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. RP Paynter, NP (reprint author), Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave, Boston, MA 02215 USA. EM npaynter@partners.org FU F. Hoffmann-La Roche, Ltd.; Leducq Foundation; Roche Diagnostics; Amgen, Inc; AstraZeneca; Novartis; Merck; Abbott; sanofi-aventis; Schering-Plough; Isis; Siemens; Vascular Biogenics; National Heart Lung and Blood Institute [HL 043851, HL 080467, CA 047988, CA 97193, CA 34944, CA 40360, HL 26490, HL 34595]; National Cancer Institute, Bethesda, Maryland; Donald W. Reynolds Foundation, Las Vegas, Nevada FX Dr Paynter reports receiving investigator-initiated funding for this project from F. Hoffmann-La Roche, Ltd. Dr Mazer reports employment by and stock ownership in F. Hoffmann-La Roche, Ltd. Dr. Ridker reports receiving investigator-initiated funding from the Leducq Foundation, Roche Diagnostics, Amgen, Inc, AstraZeneca, Novartis, Merck, Abbott, and sanofi-aventis; consulting fees from AstraZeneca, Novartis, Merck Schering-Plough, sanofi-aventis, Isis, Siemens, and Vascular Biogenics; and is listed as a coinventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in CVD, including the use of high-sensitivity C-reactive protein in the evaluation of patients' risk of CVD. These patents have been licensed to Siemens and AstraZeneca.; This work was carried out with support from F. Hoffmann-La Roche Ltd; grants HL 043851, HL 080467, and CA 047988 for the Women's Health Study and grants CA 97193, CA 34944, CA 40360, HL 26490, and HL 34595 for the Physician's Health Study II from the National Heart Lung and Blood Institute and National Cancer Institute, Bethesda, Maryland; and the Donald W. Reynolds Foundation, Las Vegas, Nevada. NR 27 TC 23 Z9 24 U1 0 U2 3 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 OCT 24 PY 2011 VL 171 IS 19 BP 1712 EP 1718 DI 10.1001/archinternmed.2011.351 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 837JX UT WOS:000296198200004 PM 21788538 ER PT J AU Butt, AA Justice, AC Freiberg, MS AF Butt, Adeel A. Justice, Amy C. Freiberg, Matthew S. TI Risk of Heart Failure With Human Immunodeficiency Virus Is Greater Than Hypertension? Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID INFECTION; DISEASE C1 [Butt, Adeel A.; Freiberg, Matthew S.] Univ Pittsburgh, Dept Med, Sch Med, Pittsburgh, PA 15213 USA. [Butt, Adeel A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Justice, Amy C.] VA Connecticut Healthcare Syst, West Haven, CT USA. RP Butt, AA (reprint author), Univ Pittsburgh, Dept Med, Sch Med, 3601 5th Ave,Ste 3A, Pittsburgh, PA 15213 USA. EM butta@dom.pitt.edu NR 4 TC 0 Z9 0 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 OCT 24 PY 2011 VL 171 IS 19 BP 1773 EP 1774 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 837JX UT WOS:000296198200022 ER PT J AU Hilbert, A Vogele, C Tuschen-Caffier, B Hartmann, AS AF Hilbert, Anja Voegele, Claus Tuschen-Caffier, Brunna Hartmann, Andrea S. TI Psychophysiological responses to idiosyncratic stress in bulimia nervosa and binge eating disorder SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Stress; Psychophysiology; Heart rate variability; Bulimia nervosa; Binge eating disorder ID HEART-RATE-VARIABILITY; CARDIAC VAGAL TONE; MOMENTARY ASSESSMENT; EMOTION REGULATION; BLOOD-PRESSURE; OBESE WOMEN; REACTIVITY; LEPTIN; MOOD; PSYCHOPATHOLOGY AB This study examined psychophysiological stress responses to idiosyncratically relevant stress in bulimia nervosa (BN) and binge eating disorder (BED), in relation to autonomic cardiac control and nutritional status. A total of 81 women with BN, BED and healthy controls (HC) took part in an in sensu exposure to idiosyncratic stress. Psychological and peripheral physiological parameters were measured, and tonic heart rate variability, nutritional status, and types of stress were determined. In response to stress exposure, both eating disordered groups showed a stronger reactivity of sadness, and the BED group showed a stronger reactivity of insecurity than the HC group. Desire to binge was increased in the context of interpersonal stress. Stress exposure led to increased cardiovascular activity and reduced electrodermal activity that did not differ by group. The BN-specific symptomatology moderated the association between autonomic cardiac control and psychophysiological stress responses. The results suggest common and specific psychophysiological processes in symptom maintenance through life stress in EN and BED. (C) 2011 Published by Elsevier Inc. C1 [Hilbert, Anja] Univ Fribourg, Dept Psychol, CH-1700 Fribourg, Switzerland. [Voegele, Claus] Univ Luxembourg, Res Unit INSIDE, L-7201 Walferdange, Luxembourg. [Tuschen-Caffier, Brunna] Univ Freiburg, Inst Psychol, D-79085 Freiburg, Germany. [Hartmann, Andrea S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. RP Hilbert, A (reprint author), Univ Fribourg, Dept Psychol, Rue P-A de Faucigny 2, CH-1700 Fribourg, Switzerland. EM anja.hilbert@unifr.ch; Claus.Voegele@uni.lu; tuschen@psychologie.uni-freiburg.de; ahartmann1@partners.org FU German Research Foundation [TU 78/1-2] FX Funding sources for this study include grant TU 78/1-2 funded by the German Research Foundation (Dr. Tuschen-Caffier). NR 60 TC 12 Z9 12 U1 2 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD OCT 24 PY 2011 VL 104 IS 5 BP 770 EP 777 DI 10.1016/j.physbeh.2011.07.013 PG 8 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 837MP UT WOS:000296208200017 PM 21839762 ER PT J AU Torterolo, P Ramos, OV Sampogna, S Chase, MH AF Torterolo, Pablo Ramos, Oscar V. Sampogna, Sharon Chase, Michael H. TI Hypocretinergic neurons are activated in conjunction with goal-oriented survival-related motor behaviors SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Orexin; Sleep; Motivation; Reward; Hypothalamus ID MESENCEPHALIC LOCOMOTOR REGION; HYPOTHALAMIC OREXIN NEURONS; SLEEP-WAKING CYCLE; C-FOS; SEXUAL-BEHAVIOR; LATERAL HYPOTHALAMUS; CANINE NARCOLEPSY; SELF-STIMULATION; LOCUS-COERULEUS; KNOCKOUT MICE AB Hypocretinergic neurons are located in the area of the lateral hypothalamus which is responsible for mediating goal-directed, survival-related behaviors. Consequently, we hypothesize that the hypocretinergic system functions to promote these behaviors including those patterns of somatomotor activation upon which they are based. Further, we hypothesize that the hypocretinergic system is not involved with repetitive motor activities unless they occur in conjunction with the goal-oriented behaviors that are governed by the lateral hypothalamus. In order to determine the veracity of these hypotheses, we examined Fos immunoreactivity (as a marker of neuronal activity) in hypocretinergic neurons in the cat during: a) Exploratory Motor Activity; b) Locomotion without Reward; c) Locomotion with Reward; and d) Wakefulness without Motor Activity. Significantly greater numbers of hypocretinergic neurons expressed c-fos when the animals were exploring an unknown environment during Exploratory Motor Activity compared with all other paradigms. In addition, a larger number of Hcrt + Fos + neurons were activated during Locomotion with Reward than during Wakefulness without Motor Activity. Finally, very few hypocretinergic neurons were activated during Locomotion without Reward and Wakefulness without Motor Activity, wherein there was an absence of goal-directed activities. We conclude that the hypocretinergic system does not promote wakefulness per se or motor activity per se but is responsible for mediating specific goal-oriented behaviors that take place during wakefulness. Accordingly, we suggest that the hypocretinergic system is responsible for controlling the somatomotor system and coordinating its activity with other systems in order to produce successful goal-oriented survival-related behaviors that are controlled by the lateral hypothalamus. (C) 2011 Elsevier Inc. All rights reserved. C1 [Ramos, Oscar V.; Sampogna, Sharon; Chase, Michael H.] WebSci Int, Los Angeles, CA 90024 USA. [Torterolo, Pablo; Chase, Michael H.] Univ Republica, Fac Med, Dept Fisiol, Montevideo, Uruguay. [Chase, Michael H.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Chase, Michael H.] UCLA Sch Med, Dept Physiol, Los Angeles, CA USA. [Chase, Michael H.] UCLA Sch Med, Brain Res Inst, Los Angeles, CA USA. RP Chase, MH (reprint author), WebSci Int, 1251 Westwood Blvd, Los Angeles, CA 90024 USA. EM mchase@websciences.org FU USPHS [NS09999]; Brain Sciences Foundation FX This work was supported by USPHS Grant NS09999 and the Brain Sciences Foundation. NR 74 TC 10 Z9 11 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD OCT 24 PY 2011 VL 104 IS 5 BP 823 EP 830 DI 10.1016/j.physbeh.2011.07.032 PG 8 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 837MP UT WOS:000296208200024 PM 21839102 ER PT J AU Crowley, WF AF Crowley, William F. TI The developmental biology of the GnRH neurons SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Editorial Material ID GONADOTROPIN-RELEASING-HORMONE; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; OF-FUNCTION MUTATIONS; KALLMANN-SYNDROME; GENE; PROKINETICIN-2; DEFICIENCY; MOLECULES; ADHESION; PUBERTY C1 Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr Excellence, Boston, MA 02114 USA. RP Crowley, WF (reprint author), Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr Excellence, 55 Fruit St,Bartlett Hall Extens,5th Floor, Boston, MA 02114 USA. FU NICHD NIH HHS [U54 HD028138, R01 HD015788] NR 22 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD OCT 22 PY 2011 VL 346 IS 1-2 SI SI BP 1 EP 3 DI 10.1016/j.mce.2011.06.023 PG 3 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 846UQ UT WOS:000296929100001 PM 21741438 ER PT J AU Balasubramanian, R Crowley, WF AF Balasubramanian, Ravikumar Crowley, William F., Jr. TI Isolated GnRH deficiency: A disease model serving as a unique prism into the systems biology of the GnRH neuronal network SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE GnRH; GnRH deficiency; GnRH neuronal ontogeny; Puberty; Kallmann syndrome; Hypogonadotropic hypogonadism ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; GONADOTROPIN-RELEASING-HORMONE; FOLLICLE-STIMULATING-HORMONE; PULSATILE LUTEINIZING-HORMONE; LINKED KALLMANN-SYNDROME; FERTILE EUNUCH SYNDROME; MONKEY MACACA-MULATTA; HUMAN METASTIN-45-54; PROKINETICIN 2; MUTATIONS C1 [Crowley, William F., Jr.] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. RP Crowley, WF (reprint author), Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Bartlett Hall Extens,5th Floor,55 Fruit St, Boston, MA 02114 USA. EM wcrowley@partners.org FU NICHD NIH HHS [U54 HD028138-22, R01 HD015788-26, R01 HD015788, U54 HD028138] NR 77 TC 16 Z9 17 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD OCT 22 PY 2011 VL 346 IS 1-2 SI SI BP 4 EP 12 DI 10.1016/j.mce.2011.07.012 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 846UQ UT WOS:000296929100002 PM 21782888 ER PT J AU Wahab, F Quinton, R Seminara, SB AF Wahab, Fazal Quinton, Richard Seminara, Stephanie B. TI The kisspeptin signaling pathway and its role in human isolated GnRH deficiency SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE Kisspeptin; Hypogonadotropic hypogonadism; GnRH deficiency ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; GONADOTROPIN-RELEASING-HORMONE; PROTEIN-COUPLED RECEPTOR; HAMSTERS PHODOPUS-SUNGORUS; HYPOTHALAMIC KISS-1 SYSTEM; MESSENGER-RNA EXPRESSION; KALLMANN-SYNDROME; SIBERIAN HAMSTERS; REPRODUCTIVE-SYSTEM; MUTATIONS AB Amplification of the neurosecretory activity of the GnRH system is the defining neuroendocrine event for sexual maturation. The physiological mechanisms that drive GnRH secretion at puberty have been difficult to identify but the discovery in 2003 that the G protein coupled receptor KISS1R is a key regulator of pubertal development in mice and men has ushered in a new chapter in reproductive neuroendocrinology. KISS1R is activated by endogenous peptides derived from a precursor protein, kisspeptin. Despite kisspeptin's importance in driving the reproductive cascade, relatively few patients with GnRH deficient states and mutations in the kisspeptin pathway have been described. Yet, these cases, coupled with loss-of-function mouse models, provide unique and complementary information into the biological role of this signaling system in the control of GnRH secretion. This article will examine some of the subtleties in genotype-phenotype correlations in both mice and men carrying disabling mutations in the kisspeptin pathway. (C) 2011 Published by Elsevier Ireland Ltd. C1 [Wahab, Fazal; Seminara, Stephanie B.] Massachusetts Gen Hosp, Harvard Ctr Reprod Sci, Boston, MA 02114 USA. [Wahab, Fazal; Seminara, Stephanie B.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Quinton, Richard] Newcastle Univ, Inst Human Genet, Endocrinol Res Grp, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. RP Seminara, SB (reprint author), Massachusetts Gen Hosp, Harvard Ctr Reprod Sci, Fruit St, Boston, MA 02114 USA. EM sseminara@partners.org RI Wahab, Fazal/G-2478-2012 FU Eunice Kennedy Shriver NICHD/NIH [U54 HD28138-17, R01 HD43341-09] FX This research was supported by the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement [U54 HD28138-17] as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research and R01 HD43341-09. NR 71 TC 19 Z9 20 U1 2 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD OCT 22 PY 2011 VL 346 IS 1-2 SI SI BP 29 EP 36 DI 10.1016/j.mce.2011.05.043 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 846UQ UT WOS:000296929100005 PM 21704672 ER PT J AU Balasubramanian, R Plummer, L Sidis, Y Pitteloud, N Martin, C Zhou, QY Crowley, WF AF Balasubramanian, Ravikumar Plummer, Lacey Sidis, Yisrael Pitteloud, Nelly Martin, Cecilia Zhou, Qun-Yong Crowley, William F., Jr. TI The puzzles of the prokineticin 2 pathway in human reproduction SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE Prokineticin 2; Prokineticin 2 receptor; GnRH deficiency; GnRH neuronal ontogeny; Kallmann syndrome; Hypogonadotropic hypogonadism ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; PROTEIN-COUPLED RECEPTORS; KALLMANN-SYNDROME; HORMONE DEFICIENCY; PHARMACOLOGICAL CHARACTERIZATION; SUPRACHIASMATIC NUCLEUS; BIALLELIC MUTATIONS; OLFACTORY-BULB; SNAKE-VENOM; EG-VEGF AB Prokineticin, 1 (PROK1) and prokineticin 2 (PROK2), are two closely related proteins that were identified as the mammalian homologs of their two amphibian homologs, mamba intestinal toxin (MIT-1) and Bv8. MIT-1 was initially identified as a non-toxic constituent in the venom of the black mamba snake (Dendroaspis polylepis) (Joubert and Strydom, 1980) while Bv8 was identified in the skin secretion of the toad, Bombina variegate (Mollay et al., 1999). All three homologs stimulate gastrointestinal motility thus accounting for their family name "prokineticins" (Schweitz et al., 1990, 1999). However, since its initial description, both PROK1 and PROK2 have been found to regulate a dazzling array of biological functions throughout the body. In particular, PROK1 acts as a potent angiogenic mitogen on endocrine vascular epithelium, thus earning its other name, Endocrine gland-vascular endothelial factor (EG-VEGF) (LeCouter et al., 2002). In contrast, the PROK2 signaling pathway is a critical regulator of olfactory bulb morphogenesis and sexual maturation in mammals and this function is the focus of this review. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Balasubramanian, Ravikumar; Plummer, Lacey; Sidis, Yisrael; Pitteloud, Nelly; Martin, Cecilia; Crowley, William F., Jr.] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr Excellence, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Zhou, Qun-Yong] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92717 USA. RP Crowley, WF (reprint author), Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr Excellence, Reprod Endocrine Unit, Dept Med, 55 Fruit St,Bartlett Hall Extens,5th Floor, Boston, MA 02114 USA. EM wcrowley@partners.org RI PITTELOUD, Nelly/K-2709-2014 FU National Institutes of Health [5R01HD015788, 2T32HD007396, 5U54HD028138] FX This work was supported by National Institutes of Health Grants 5R01HD015788, 2T32HD007396 and 5U54HD028138, as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research. NR 47 TC 6 Z9 8 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD OCT 22 PY 2011 VL 346 IS 1-2 SI SI BP 44 EP 50 DI 10.1016/j.mce.2011.05.040 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 846UQ UT WOS:000296929100007 PM 21664414 ER PT J AU Chan, YM AF Chan, Yee-Ming TI A needle in a haystack: Mutations in GNRH1 as a rare cause of isolated GnRH deficiency SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE Gonadotropin-releasing hormone (GnRH); Luteinizing-hormone releasing hormone (LHRH, LRH); Human genetics; hypogonadal (hpg) mouse; Hypogonadotropic hypogonadism ID GONADOTROPIN-RELEASING-HORMONE; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; FOLLICLE-STIMULATING-HORMONE; LUTEINIZING-HORMONE; PROLACTIN SECRETION; GENETIC-ANALYSIS; RECEPTOR GENES; HPG MOUSE; PEPTIDE; PRECURSOR AB GNRH1, the human gene that gives rise to GnRH, has long been an obvious candidate gene for idiopathic hypogonadotropic hypogonadism, particularly because the hpg mouse, a mouse model of isolated hypogonadotropic hypogonadism, carries a deletion that disrupts Gnrh1. In 2009, 25 years after the sequence of human GNRH1 was initially determined, two groups independently reported homozygous frameshift' mutations in GNRH I in patients with idiopathic hypogonadotropic hypogonadism. In two additional families, heterozygous GNRH1 mutations segregated with reproductive disorders. In the first family, the mutation occurred alone in five female subjects with idiopathic hypogonadotropic hypogonadism, whereas in the second it co-existed with a mutation in NR0B1/DAX1 in two female subjects with delayed puberty. While hemizygous mutations the X-linked NR0B1 are a well-known cause of hypogonadotropic hypogonadism and adrenal hypoplasia in male patients, heterozygous female carriers are generally asymptomatic. Thus, mutations in GNRH1 have been associated with both mild and severe forms of GnRH deficiency, and may work in combination with other gene mutations to produce GnRH-deficient phenotypes. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Chan, Yee-Ming] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Chan, Yee-Ming] Massachusetts Gen Hosp, Harvard Reprod Sci Ctr, Boston, MA 02114 USA. [Chan, Yee-Ming] Childrens Hosp Boston, Dept Med, Div Endocrinol, Boston, MA 02115 USA. RP Chan, YM (reprint author), Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Reprod Endocrine Unit, Dept Med, 55 Fruit St,BHX 5, Boston, MA 02114 USA. EM ymchan@partners.org FU Specialized Cooperative Centers for Reproduction and Infertility Research [U54 HD028138, R01 HD043341, R01 HD015788]; Charles A. King Trust; Children's Hospital Boston FX This work was supported by U54 HD028138 as part of the Specialized Cooperative Centers for Reproduction and Infertility Research R01 HD043341 and R01 HD015788. Y.-M.C. is supported by a Charles A. King Trust Postdoctoral Fellowship and a Faculty Development Award from Children's Hospital Boston. NR 47 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD OCT 22 PY 2011 VL 346 IS 1-2 SI SI BP 51 EP 56 DI 10.1016/j.mce.2011.06.013 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 846UQ UT WOS:000296929100008 PM 21722705 ER PT J AU Au, MG Crowley, WF Buck, CL AF Au, Margaret G. Crowley, William F., Jr. Buck, Cassandra L. TI Genetic counseling for isolated GnRH deficiency SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE Genetic counseling; GnRH deficiency; Kallmann syndrome ID GONADOTROPIN-RELEASING-HORMONE; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; OF-FUNCTION MUTATIONS; FACTOR RECEPTOR 1; KALLMANN-SYNDROME; NEUROKININ B; PROKINETICIN-2; GPR54; PHENOTYPES; DELETIONS AB As our understanding of the complexities of the various etiologies and complex genetic architecture of GnRH deficiency grows, so too does the need to apply newly-developed genetic tools in a way that: (a) is meaningful to individuals and their families; (b) integrates all of the phenotypic features of this syndrome into a rationale; and (c) provides up-to-date diagnostic technologies in a cost-effective algorithm of genetic testing. Genetic counseling aims to accomplish these goals through ascertainment of detailed family histories, targeted comprehensive phenotypic evaluations, informed selection of genetic testing, interpretation of genetic test results, and the provision of highly specific risk assessments and psychological support to individuals diagnosed with this reproductive condition. This chapter offers a guide to incorporating this rapidly evolving state of knowledge of the pedigree and phenotypes into the process of selecting and prioritizing genetic testing. In addition, the provision of risk assessment that accounts for nuanced genetic concepts such as variable expressivity, incomplete penetrance, and oligogenicity, all of which are emerging features of the genetics of this clinical syndrome, is considered. Beyond translating genetic information, genetic counseling should address the psychological impact of embarrassment, shame, anxiety, and guilt that are often seen among individuals with reproductive disorders. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Buck, Cassandra L.] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. RP Buck, CL (reprint author), Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, 55 Fruit St,BHX-5, Boston, MA 02114 USA. EM clbuck@partners.org FU Eunice Kennedy Shriver NICHD/NIH [U54 HD28138, R01 HD15788] FX This research was supported by the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement U54 HD28138 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research and R01 HD15788. NR 36 TC 11 Z9 12 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD OCT 22 PY 2011 VL 346 IS 1-2 SI SI BP 102 EP 109 DI 10.1016/j.mce.2011.05.041 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 846UQ UT WOS:000296929100014 PM 21664415 ER PT J AU Pinello, L Lo Bosco, G Hanlon, B Yuan, GC AF Pinello, Luca Lo Bosco, Giosue Hanlon, Bret Yuan, Guo-Cheng TI A motif-independent metric for DNA sequence specificity SO BMC BIOINFORMATICS LA English DT Article ID HISTONE MODIFICATIONS; NUCLEOSOME OCCUPANCY; GENOMIC SEQUENCES; STEM-CELLS; IDENTIFICATION; SITES; DIFFERENTIATION; METHYLATION; PREDICTION; ENHANCERS AB Background: Genome-wide mapping of protein-DNA interactions has been widely used to investigate biological functions of the genome. An important question is to what extent such interactions are regulated at the DNA sequence level. However, current investigation is hampered by the lack of computational methods for systematic evaluating sequence specificity. Results: We present a simple, unbiased quantitative measure for DNA sequence specificity called the Motif Independent Measure (MIM). By analyzing both simulated and real experimental data, we found that the MIM measure can be used to detect sequence specificity independent of presence of transcription factor (TF) binding motifs. We also found that the level of specificity associated with H3K4me1 target sequences is highly cell-type specific and highest in embryonic stem (ES) cells. We predicted H3K4me1 target sequences by using the N-score model and found that the prediction accuracy is indeed high in ES cells. The software to compute the MIM is freely available at: https://github.com/lucapinello/mim. Conclusions: Our method provides a unified framework for quantifying DNA sequence specificity and serves as a guide for development of sequence-based prediction models. C1 [Lo Bosco, Giosue] Dipartimento Matemat & Informat, I-90123 Palermo, Italy. [Pinello, Luca; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Pinello, Luca; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Hanlon, Bret] Univ Wisconsin, Dept Stat, Madison, WI 53706 USA. RP Lo Bosco, G (reprint author), Dipartimento Matemat & Informat, Via Archirafi 34, I-90123 Palermo, Italy. EM giosue.lobosco@unipa.it; gcyuan@jimmy.harvard.edu RI Lo Bosco, Giosue/C-7644-2011 OI Lo Bosco, Giosue/0000-0002-1602-0693 FU NIH [HG005085]; Harvard School of Public Health FX We thank Zhen Shao for help with H3K4me1 data collection and initial processing. GY's research was supported by the NIH grant HG005085 and a Career Incubator Award from the Harvard School of Public Health. NR 43 TC 5 Z9 5 U1 0 U2 9 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 OCT 21 PY 2011 VL 12 AR 408 DI 10.1186/1471-2105-12-408 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 873JS UT WOS:000298879700001 PM 22017798 ER PT J AU Abdel-Motal, UM Sarkis, PTN Han, T Pudney, J Anderson, DJ Zhu, Q Marasco, WA AF Abdel-Motal, Ussama M. Sarkis, Phuong T. N. Han, Thomas Pudney, Jeffery Anderson, Deborah J. Zhu, Quan Marasco, Wayne A. TI Anti-gp120 Minibody Gene Transfer to Female Genital Epithelial Cells Protects against HIV-1 Virus Challenge In Vitro SO PLOS ONE LA English DT Article ID LEUKOCYTE PROTEASE INHIBITOR; IMMUNODEFICIENCY-VIRUS; ADENOASSOCIATED VIRUS; MONOCLONAL-ANTIBODY; VAGINAL EPITHELIUM; LONG-TERM; EXPRESSION; VECTOR; NEUTRALIZATION; TRANSDUCTION AB Background: Although cervico-vaginal epithelial cells of the female lower genital tract provide the initial defense system against HIV-1 infection, the protection is sometimes incomplete. Thus, enhancing anti-HIV-1 humoral immunity at the mucosal cell surface by local expression of anti-HIV-1 broadly neutralizing antibodies (BnAb) that block HIV-1 entry would provide an important new intervention that could slow the spread of HIV/AIDS. Methods and Findings: This study tested the hypothesis that adeno-associated virus (AAV)-BnAb gene transfer to cervico-vaginal epithelial cells will lead to protection against HIV-1. Accordingly, a recombinant AAV vector that encodes human b12 anti-HIV gp120 BnAb as a single-chain variable fragment Fc fusion (scFvFc), or "minibody'' was constructed. The secreted b12 minibody was shown to be biologically functional in binding to virus envelope protein, neutralizing HIV-1 and importantly, blocking transfer and infectivity of HIV-1(bal) in an organotypic human vaginal epithelial cell (VEC) model. Furthermore, cervico-vaginal epithelial stem cells were found to be efficiently transduced by the optimal AAV serotype mediated expression of GFP. Conclusion: This study provides the foundation for a novel microbicide strategy to protect against sexual transmission of HIV-1 by AAV transfer of broadly neutralizing antibody genes to cervico-vaginal epithelial stem cells that could replenish b12 BnAb secreting cells through multiple menstrual cycles. C1 [Abdel-Motal, Ussama M.; Sarkis, Phuong T. N.; Han, Thomas; Zhu, Quan; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Pudney, Jeffery; Anderson, Deborah J.] Boston Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA 02118 USA. RP Abdel-Motal, UM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM wayne_marasco@dfci.harvard.edu OI Han, Thang/0000-0003-2570-0938 FU National Institutes of Health (NIH) [AI079767] FX Funding: This work was supported by the National Institutes of Health (NIH) grant AI079767 to Dr. Marasco. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 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 OCT 21 PY 2011 VL 6 IS 10 AR e26473 DI 10.1371/journal.pone.0026473 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841LG UT WOS:000296513200024 PM 22031835 ER PT J AU Arjomandi, M Frelinger, J Donde, A Wong, H Yellamilli, A Raymond, W AF Arjomandi, Mehrdad Frelinger, Jessica Donde, Aneesh Wong, Hofer Yellamilli, Amritha Raymond, Wilfred TI Secreted Osteopontin Is Highly Polymerized in Human Airways and Fragmented in Asthmatic Airway Secretions SO PLOS ONE LA English DT Article ID RHEUMATOID-ARTHRITIS; POSTTRANSLATIONAL MODIFICATIONS; STRUCTURAL REQUIREMENTS; INTEGRIN ALPHA-9-BETA-1; NEUTROPHIL INFILTRATION; TISSUE TRANSGLUTAMINASE; BOVINE OSTEOPONTIN; DEFICIENT MICE; CROSS-LINKING; MURINE MODEL AB Background: Osteopontin (OPN) is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family and a cytokine with diverse biologic roles. OPN undergoes extensive post-translational modifications, including polymerization and proteolytic fragmentation, which alters its biologic activity. Recent studies suggest that OPN may contribute to the pathogenesis of asthma. Methodology: To determine whether secreted OPN (sOPN) is polymerized in human airways and whether it is qualitatively different in asthma, we used immunoblotting to examine sOPN in bronchoalveolar lavage (BAL) fluid samples from 12 healthy and 21 asthmatic subjects (and in sputum samples from 27 healthy and 21 asthmatic subjects). All asthmatic subjects had mild to moderate asthma and abstained from corticosteroids during the study. Furthermore, we examined the relationship between airway sOPN and cellular inflammation. Principal Findings: We found that sOPN in BAL fluid and sputum exists in polymeric, monomeric, and cleaved forms, with most of it in polymeric form. Compared to healthy subjects, asthmatic subjects had proportionately less polymeric sOPN and more monomeric and cleaved sOPN. Polymeric sOPN in BAL fluid was associated with increased alveolar macrophage counts in airways in all subjects. Conclusions: These results suggest that sOPN in human airways (1) undergoes extensive post-translational modification by polymerization and proteolytic fragmentation, (2) is more fragmented and less polymerized in subjects with mild to moderate asthma, and (3) may contribute to recruitment or survival of alveolar macrophages. C1 [Arjomandi, Mehrdad; Frelinger, Jessica] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Arjomandi, Mehrdad; Frelinger, Jessica; Donde, Aneesh; Wong, Hofer; Yellamilli, Amritha] Univ Calif San Francisco, Dept Med, Human Exposure Lab, San Francisco, CA USA. [Raymond, Wilfred] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Med, San Francisco, CA 94143 USA. [Arjomandi, Mehrdad; Frelinger, Jessica; Raymond, Wilfred] San Francisco VA Med Ctr, Pulm Res Grp, San Francisco, CA USA. RP Arjomandi, M (reprint author), Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. EM mehrdad.arjomandi@ucsf.edu FU National Institutes of Health (NIH) [K23 HL083099, NIH P01 HL024136]; NIH/NCRR/OD [KL2 RR024130]; Northern California Institute for Research and Education; University of California San Francisco Cardiovascular Research Institute FX Funding: This work was supported by National Institutes of Health (NIH) K23 HL083099, NIH P01 HL024136, NIH/NCRR/OD UCSF-CTSI Grant Number KL2 RR024130, Northern California Institute for Research and Education, and University of California San Francisco Cardiovascular Research Institute Faculty Development Funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 5 Z9 6 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 OCT 21 PY 2011 VL 6 IS 10 AR e25678 DI 10.1371/journal.pone.0025678 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841LG UT WOS:000296513200005 PM 22031818 ER PT J AU Grassberger, C Paganetti, H AF Grassberger, C. Paganetti, H. TI Elevated LET components in clinical proton beams SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID RELATIVE BIOLOGICAL EFFECTIVENESS; MONTE-CARLO SIMULATIONS; LOW-ENERGY PROTONS; V79 CELLS; THERAPY; RBE; INACTIVATION; PARTICLES; IONS; DISTRIBUTIONS AB This paper assesses the contribution of secondary particles to pencil and passively scattered proton beams, in particular when considering the dose-averaged linear energy transfer (LET(d)) in biological treatment planning. Proton Monte Carlo simulations are performed in water phantoms and for two patients, considering all primary and secondary particles, including recoils from inelastic nuclear interactions. Our results show that secondary protons exhibit LET(d) values up to a factor 10 higher than those of the primary protons at the same depth. Thus, secondary protons have a significant impact on the LET(d). Their contribution increases the LET(d) by similar to 50% along the central axis and even > 200% in the penumbra. Furthermore, the LET maximum after the peak changes from 12 to 15 keV mu m(-1) when adding secondary protons to the primary contribution. This is important when modeling LET(d) with analytical methods. The contribution of recoils (A > 3) is observed to be 1.2% in the entrance region considering a prostate case. The degree of biological damage inflicted by recoils remains hard to quantify, but is discussed on the basis of detailed energy spectra. The results highlight the role of secondary protons in LET-based radiobiological effectiveness calculations for proton therapy and when analyzing radiobiological experiments. Furthermore, the findings demonstrate the impact of inhomogeneities on the LET and the subtle changes between the LET distributions of passively scattered and actively scanned beams. C1 [Grassberger, C.; Paganetti, H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Grassberger, C.; Paganetti, H.] Harvard Univ, Sch Med, Boston, MA USA. [Grassberger, C.] Paul Scherrer Inst, Ctr Proton Radiotherapy, CH-5232 Villigen, Switzerland. RP Grassberger, C (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM cgrassberger@partners.org FU Federal Share of program income earned by Massachusetts General Hospital, Proton Therapy Research and Treatment Center [C06 CA059267] FX The authors thank Tony Lomax for many useful comments and suggestions, as well as AlejandroCarabe-Fernandez and Jan Schumann for various lively discussions around the topic. The project was supported by the Federal Share of program income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment Center. NR 38 TC 34 Z9 34 U1 0 U2 8 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 OCT 21 PY 2011 VL 56 IS 20 BP 6677 EP 6691 DI 10.1088/0031-9155/56/20/011 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 842MS UT WOS:000296604200014 PM 21965268 ER PT J AU Hirschey, MD Shimazu, T Jing, E Grueter, CA Collins, AM Aouizerat, B Stancakova, A Goetzman, E Lam, MM Schwer, B Stevens, RD Muehlbauer, MJ Kakar, S Bass, NM Kuusisto, J Laakso, M Alt, FW Newgard, CB Farese, RV Kahn, CR Verdin, E AF Hirschey, Matthew D. Shimazu, Tadahiro Jing, Enxuan Grueter, Carrie A. Collins, Amy M. Aouizerat, Bradley Stancakova, Alena Goetzman, Eric Lam, Maggie M. Schwer, Bjoern Stevens, Robert D. Muehlbauer, Michael J. Kakar, Sanjay Bass, Nathan M. Kuusisto, Johanna Laakso, Markku Alt, Frederick W. Newgard, Christopher B. Farese, Robert V., Jr. Kahn, C. Ronald Verdin, Eric TI SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome SO MOLECULAR CELL LA English DT Article ID FATTY-ACID OXIDATION; DIET-INDUCED OBESITY; STEAROYL-COA DESATURASE-1; HEPATIC INSULIN-RESISTANCE; HUMAN SKELETAL-MUSCLE; LYSINE ACETYLATION; DEPENDENT DEACETYLASE; C57BL/6J MOUSE; BLOOD-LIPIDS; GENE REVEALS AB Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome. C1 [Hirschey, Matthew D.; Shimazu, Tadahiro; Collins, Amy M.; Schwer, Bjoern; Verdin, Eric] Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. [Jing, Enxuan; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Cellular & Mol Physiol, Boston, MA 02215 USA. [Grueter, Carrie A.] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA. [Aouizerat, Bradley] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA 94143 USA. [Aouizerat, Bradley] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Lam, Maggie M.; Kakar, Sanjay] Univ Calif San Francisco, Dept Pathol, VA Med Ctr, San Francisco, CA 94143 USA. [Lam, Maggie M.; Kakar, Sanjay] Univ Calif San Francisco, UCSF Liver Ctr, San Francisco, CA 94143 USA. [Bass, Nathan M.; Farese, Robert V., Jr.; Verdin, Eric] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Farese, Robert V., Jr.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. [Stancakova, Alena; Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Stancakova, Alena; Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Goetzman, Eric] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15201 USA. [Stevens, Robert D.; Muehlbauer, Michael J.; Newgard, Christopher B.] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27704 USA. [Stevens, Robert D.; Muehlbauer, Michael J.; Newgard, Christopher B.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27704 USA. [Stevens, Robert D.; Muehlbauer, Michael J.; Newgard, Christopher B.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27704 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Verdin, E (reprint author), Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. EM everdin@gladstone.ucsf.edu OI Grueter, Carrie/0000-0002-1913-2527; Verdin, Eric/0000-0003-3703-3183; Hirschey, Matthew/0000-0003-4541-5376 FU MMPC [DK59637]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713]; National Institute of Child Health and Human Development (NICHD); General Clinical Research Centers [UL1RR024989, M01RR000750, M01RR00188, UL1RR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR020359, UL1RR025741]; Sandler Foundation; National Center for Research Resources (NCRR); National Institutes of Health (NIH); NIH Roadmap for Medical Research [KL2 RR024130]; Academy of Finland [124243]; Finnish Heart Foundation; Finnish Diabetes Research Foundation, TEKES [1510/31/06]; Kuopio University Hospital [5232, 5263]; Elison Medical Foundation; UCSF Liver Center though the NIDDK [P30 DK026743]; NIDDK [DK085610]; J. David Gladstone Institutes FX We thank C. Miller and J.D. Fish for histology preparation; C. Harris, L. Swift, and the MMPC (DK59637) for plasma and tissue lipid analysis; T. Tran for metabolic experiments; A. Wilson, G. Maki, and J. Carroll for figure preparation; and G. Howard and S. Ordway for editorial review. We thank the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN; a complete list of authors is located in the Supplemental Information) for providing human patient samples. NASH CRN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, and U01DK061713) and by the National Institute of Child Health and Human Development (NICHD). Several NASH CRN clinical centers use support from General Clinical Research Centers or Clinical and Translational Science Awards in conduct of NASH CRN Studies (grants UL1RR024989, M01RR000750, M01RR00188, UL1RR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR020359, and UL1RR025741). Funding for this work was supported in part by a University of California, San Francisco (UCSF) Post-doctoral Research Fellowship Award from the Sandler Foundation (M.D.H. and B.S.); from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research (KL2 RR024130) (B.A.); by grants from the Academy of Finland (contract 124243), The Finnish Heart Foundation, The Finnish Diabetes Research Foundation, TEKES (contract 1510/31/06), and Kuopio University Hospital (EVO grants 5232 and 5263), and a Senior Scholarship in Aging from the Elison Medical Foundation (F.W.A. and E.V.); the UCSF Liver Center though the NIDDK (P30 DK026743) (E.V.); an R24 grant from NIDDK (DK085610) (C.B.N., C.R.K., and E.V.); and institutional support from the J. David Gladstone Institutes (E.V.). F.W.A. is an Investigator of the Howard Hughes Medical Institute. NR 76 TC 227 Z9 240 U1 2 U2 30 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 21 PY 2011 VL 44 IS 2 BP 177 EP 190 DI 10.1016/j.molcel.2011.07.019 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837OC UT WOS:000296212100005 PM 21856199 ER PT J AU Pathania, S Nguyen, J Hill, SJ Scully, R Adelmant, GO Marto, JA Feunteun, J Livingston, DM AF Pathania, Shailja Jenna Nguyen Hill, Sarah J. Scully, Ralph Adelmant, Guillaume O. Marto, Jarrod A. Feunteun, Jean Livingston, David M. TI BRCA1 Is Required for Postreplication Repair after UV-Induced DNA Damage SO MOLECULAR CELL LA English DT Article ID STALLED REPLICATION FORKS; NUCLEOTIDE EXCISION-REPAIR; INDUCED NUCLEAR FOCI; BREAST-CANCER; POLYMERASE-ETA; HUMAN-CELLS; HOMOLOGOUS RECOMBINATION; XERODERMA-PIGMENTOSUM; GENOMIC INSTABILITY; S-PHASE AB BRCA1 contributes to the response to UV irradiation. Utilizing its BRCT motifs, it is recruited during S/G2 to UV-damaged sites in a DNA replication-dependent but nucleotide excision repair (NER)-independent manner. More specifically, at UV-stalled replication forks, it promotes photoproduct excision, suppression of translesion synthesis, and the localization and activation of replication factor C complex (RFC) subunits. The last function, in turn, triggers post-UV checkpoint activation and postreplicative repair. These BRCA1 functions differ from those required for DSBR. C1 [Pathania, Shailja; Livingston, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Scully, Ralph] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Adelmant, Guillaume O.; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Pathania, Shailja; Jenna Nguyen; Hill, Sarah J.; Adelmant, Guillaume O.; Marto, Jarrod A.; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Adelmant, Guillaume O.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Scully, Ralph] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Feunteun, Jean] Inst Gustave Roussy, UMR8200, Lab Stabilite Genet & Oncogenese, F-94805 Villejuif, France. RP Livingston, DM (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM david_livingston@dfci.harvard.edu RI Scully, Ralph/F-5008-2013 FU National Cancer Institute; Dana-Farber/Harvard Cancer Center; Breast Cancer Research Foundation; Susan B. Komen Foundation; Dana-Farber Cancer Institute; National Institutes of Health, NHGRI [P50HG004233]; NINDS [P01NS047572] FX We would like to thank Steve Elledge for helpful discussions and for ATRIP antibody, Lucian Moldovan and Alan D'Andrea for help and advice in setting up the supF assay, Alan Lehmann for the eGFP-PolH plasmid, Veronique Smits for the Rad9-GFP-HA plasmid, Zhongsheng You for the eGFP-CtIP plasmid, Richard Baer for CtIP antibody, Margaret Shipp for the HA-tagged ubiquitin plasmid, and the RNAi Consortium at the Broad Institute for shRNAs directed at BRCA1 mRNA. We also thank Daniel Silver, Hua Wang, and multiple members of the Livingston laboratory for invaluable discussions. This work was supported in part by grants to one of us (D.M.L.) from the National Cancer Institute, by a SPORE grant in breast cancer research to the Dana-Farber/Harvard Cancer Center, and by grants from the Breast Cancer Research Foundation and the Susan B. Komen Foundation for the Cure. Generous support for this work was also provided by the Dana-Farber Cancer Institute and the National Institutes of Health, NHGRI (P50HG004233), and NINDS (P01NS047572). NR 68 TC 51 Z9 52 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 21 PY 2011 VL 44 IS 2 BP 235 EP 251 DI 10.1016/j.molcel.2011.09.002 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837OC UT WOS:000296212100010 PM 21963239 ER PT J AU Egede, LE Strom, JL Fernandes, J Knapp, RG Rojugbokan, A AF Egede, Leonard E. Strom, Joni L. Fernandes, Jyotika Knapp, Rebecca G. Rojugbokan, Adebola TI Effectiveness of technology-assisted case management in low income adults with Type 2 diabetes (TACM-DM): study protocol for a randomized controlled trial SO TRIALS LA English DT Article ID NURSE CASE-MANAGEMENT; PSYCHOMETRIC PROPERTIES; GLYCEMIC CONTROL; CARE MANAGEMENT; BLOOD-PRESSURE; SCALE; INTERVENTIONS; VETERANS; VALIDITY; OUTCOMES AB Background: An estimated 1 in 3 American adults will have diabetes by the year 2050. Nationally, South Carolina ranks 10(th) in cases of diagnosed diabetes compared to other states. In adults, type 2 diabetes (T2DM) accounts for approximately 90-95% of all diagnosed cases of diabetes. Clinically, provider and health system factors account for < 10% of the variance in major diabetes outcomes including hemoglobin A1c (HbA1c), lipid control, and resource use. Use of telemonitoring systems offer new opportunities to support patients with T2DM while waiting to be seen by their health care providers at actual office visits. A variety of interventions testing the efficacy of telemedicine interventions have been conducted, but the outcomes have yielded equivocal results, emphasizing the shortage of controlled, randomized trials in this area. This study provides a unique opportunity to address this gap in the literature by optimizing two strategies that have been shown to improve glycemic control, while simultaneously implementing clinical outcomes measures, using a sufficient sample size, and offering health care delivery to rural, underserved and low income communities with T2DM who are seen at Federally Qualified Health Centers (FQHCs) in coastal South Carolina. Methods: We describe a four-year prospective, randomized clinical trial, which will test the effectiveness of technology-assisted case management in low income rural adults with T2DM. Two-hundred (200) male and female participants, 18 years of age or older and with an HbA1c >= 8%, will be randomized into one of two groups: (1) an intervention arm employing the innovative FORA system coupled with nurse case management or (2) a usual care group. Participants will be followed for 6-months to ascertain the effect of the interventions on glycemic control. Our primary hypothesis is that among indigent, rural adult patients with T2DM treated in FQHC's, participants randomized to the technology-assisted case management intervention will have significantly greater reduction in HbA1c at 6 months of follow-up compared to usual care. Discussion: Results from this study will provide important insight into the effectiveness of technology-assisted case management intervention (TACM) for optimizing diabetes care in indigent, rural adult patients with T2DM treated in FQHC's. C1 [Egede, Leonard E.; Knapp, Rebecca G.] Ralph H Johnson Vet Affairs Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC 29401 USA. [Egede, Leonard E.; Strom, Joni L.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Dept Med, Charleston, SC 29425 USA. [Egede, Leonard E.; Strom, Joni L.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Fernandes, Jyotika] Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Dept Med, Charleston, SC 29425 USA. [Knapp, Rebecca G.] Med Univ S Carolina, Div Biostat & Epidemiol, Dept Med, Charleston, SC 29425 USA. [Rojugbokan, Adebola] Franklin C Fetter Family Hlth Ctr Inc, Charleston, SC 29403 USA. RP Egede, LE (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, 109 Bee St, Charleston, SC 29401 USA. EM egedel@musc.edu FU Department of Defense [W81XWH-10-2-0057]; Telemedicine & Advanced Technology Research Center (TATRC), Fort Detrick, Maryland [W81XWH-10-2-0057] FX The study is funded by Grant # W81XWH-10-2-0057 from the Department of Defense. This research and development project was conducted by the Medical University of South Carolina and is made possible by a cooperative agreement that was awarded and administered by the U.S. Army Medical Research and Material Command (USAMRMC) and the Telemedicine & Advanced Technology Research Center (TATRC), Fort Detrick, Maryland 21702, under Contract Number: W81XWH-10-2-0057. NR 41 TC 6 Z9 6 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD OCT 20 PY 2011 VL 12 AR 231 DI 10.1186/1745-6215-12-231 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 849OF UT WOS:000297134200001 PM 22014122 ER PT J AU Sadik, CD Kim, ND Alekseeva, E Luster, AD AF Sadik, Christian D. Kim, Nancy D. Alekseeva, Elena Luster, Andrew D. TI IL-17RA Signaling Amplifies Antibody-Induced Arthritis SO PLOS ONE LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; AUTOANTIBODY-MEDIATED ARTHRITIS; RHEUMATOID-ARTHRITIS; T-CELLS; CXC CHEMOKINE; MAST-CELLS; TH17 CELLS; INTERLEUKIN-17; EXPRESSION; MICE AB Objective: To investigate the role of IL-17RA signaling in the effector phase of inflammatory arthritis using the K/BxN serum-transfer model. Methods: Wild-type and Il17ra(-/-) mice were injected with serum isolated from arthritic K/BxN mice and their clinical score was recorded daily. Mice were also harvested on days 12 and 21 and ankles were analyzed for cytokine and chemokine mRNA expression by qPCR on day 12 and for bone and cartilage erosions by histology on day 21, respectively. The induction of cytokine and chemokine expression levels by IL-17A in synovial-like fibroblasts was also analyzed using qPCR. Results: Il17ra(-/-) mice were partially protected from clinical signs of arthritis and had markedly fewer cartilage and bone erosions. The expression of several pro-inflammatory mediators, including the chemokines KC/CXCL1, MIP-2/CXCL2, LIX/CXCL5 MIP-1c/CCL9, MCP-3/CCL7, MIP-3a/CCL20, the cytokines IL-1b, IL-6, RANKL and the matrix metalloproteinases MMP2, MMP3, and MMP13 were decreased in the ankles of Il17ra(-/-) mice compared to wild-type mice. Many of these proinflammatory genes attenuated in the ankles of Il17ra(-/-) mice were shown to be directly induced by IL-17A in synovial fibroblasts in vitro. Conclusions: IL-17RA signaling plays a role as an amplifier of the effector phase of inflammatory arthritis. This effect is likely mediated by direct activation of synovial fibroblasts by IL-17RA to produce multiple inflammatory mediators, including chemokines active on neutrophils. Therefore, interrupting IL-17RA signaling maybe a promising pharmacological target for the treatment of inflammatory arthritis. C1 [Sadik, Christian D.; Kim, Nancy D.; Alekseeva, Elena; Luster, Andrew D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02115 USA. RP Sadik, CD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02115 USA. EM aluster@mgh.harvard.edu RI Sadik, Christian/E-8404-2012 FU Deutsche Forschungsgemeinschaft [Sa1960/1-1]; National Institutes of Health [R01-AI050892, K08-AR054094] FX This work was supported by grants of the Deutsche Forschungsgemeinschaft (Sa1960/1-1 to C. D. S.; www.dfg.de)) and of the National Institutes of Health (R01-AI050892 to A. D. L. and K08-AR054094 to N.D.K.; www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 18 Z9 18 U1 0 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 OCT 20 PY 2011 VL 6 IS 10 AR e26342 DI 10.1371/journal.pone.0026342 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841KI UT WOS:000296510800036 PM 22028860 ER PT J AU Kumar, SK Uno, H Jacobus, SJ Van Wier, SA Ahmann, GJ Henderson, KJ Callander, NS Haug, JL Siegel, DS Greipp, PR Fonseca, R Rajkumar, SV AF Kumar, Shaji K. Uno, Hajime Jacobus, Susanna J. Van Wier, Scott A. Ahmann, Greg J. Henderson, Kimberly J. Callander, Natalie S. Haug, Jessica L. Siegel, David S. Greipp, Philip R. Fonseca, Rafael Rajkumar, S. Vincent TI Impact of gene expression profiling-based risk stratification in patients with myeloma receiving initial therapy with lenalidomide and dexamethasone SO BLOOD LA English DT Article ID DIAGNOSED MULTIPLE-MYELOMA; MOLECULAR CLASSIFICATION; INTERGROUPE FRANCOPHONE; BORTEZOMIB; SURVIVAL; MODEL; DISEASE; TRIALS AB Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma; however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We examined the utility of 2 GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. Among 45 patients studied at baseline, 7 (16%) and 10 (22%), respectively, were high-risk using the GEP70 and GEP15 signatures. The median overall survival for the GEP70 high-risk group was 19 months versus not reached for the rest (hazard ratio = 14.1). Although the medians were not reached, the GEP15 also predicted a poor outcome among the high-risk patients. The C-statistic for the GEP70, GEP15, and FISH based risk stratification systems was 0.74, 0.7, and 0.7, respectively. Here we demonstrate the prognostic value for GEP risk stratification in a group of patients primarily treated with novel agents. This trial was registered at www.clinicaltrials.gov as #NCT00098475. (Blood. 2011; 118(16):4359-4362) C1 [Kumar, Shaji K.] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Uno, Hajime; Jacobus, Susanna J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Van Wier, Scott A.; Ahmann, Greg J.; Fonseca, Rafael] Mayo Clin Arizona, Scottsdale, AZ USA. [Callander, Natalie S.] Univ Wisconsin, Madison, WI USA. [Siegel, David S.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. RP Kumar, SK (reprint author), Mayo Clin, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA. EM kumar.shaji@mayo.edu RI Kumar, Shaji/A-9853-2008; OI Kumar, Shaji/0000-0001-5392-9284; Fonseca, Rafael/0000-0002-5938-3769; Rajkumar, S. Vincent/0000-0002-5862-1833 FU National Cancer Institute, National Institutes of Health; Department of Health and Human Services [CA23318, CA66636, CA21115, CA13650, CA93842]; National Institutes of Health [CA90628]; Celgene FX This work was coordinated by the Eastern Cooperative Oncology Group (Dr Robert L. Comis, Chair) and supported by the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services (Public Health Service grants CA23318, CA66636, CA21115, CA13650, and CA93842) and in part by the National Institutes of Health (CA90628, S.K.K.).; S.K.K. is involved with sponsored research from Celgene. The remaining authors declare no competing financial interests. NR 25 TC 16 Z9 16 U1 0 U2 1 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 OCT 20 PY 2011 VL 118 IS 16 BP 4359 EP 4362 DI 10.1182/blood-2011-03-342089 PG 4 WC Hematology SC Hematology GA 838JY UT WOS:000296286500015 PM 21860025 ER PT J AU Jacobsohn, DA Arora, M Klein, JP Hassebroek, A Flowers, ME Cutler, CS Urbano-Ispizua, A Bolwell, BJ Antin, JH Boyiadzis, M Cahn, JY Cairo, MS Herzig, RH Isola, LM Klumpp, TR Lee, SJ Petersdorf, EW Santarone, S Gale, RP Schouten, HC Spellman, SR Weisdorf, DJ Wingard, JR Horowitz, MM Pavletic, SZ AF Jacobsohn, David A. Arora, Mukta Klein, John P. Hassebroek, Anna Flowers, Mary E. Cutler, Corey S. Urbano-Ispizua, Alvaro Bolwell, Brian J. Antin, Joseph H. Boyiadzis, Michael Cahn, Jean-Yves Cairo, Mitchell S. Herzig, Roger H. Isola, Luis M. Klumpp, Thomas R. Lee, Stephanie J. Petersdorf, Effie W. Santarone, Stella Gale, Robert P. Schouten, Harry C. Spellman, Stephen R. Weisdorf, Daniel J. Wingard, John R. Horowitz, Mary M. Pavletic, Steven Z. TI Risk factors associated with increased nonrelapse mortality and with poor overall survival in children with chronic graft-versus-host disease SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; UMBILICAL-CORD BLOOD; UNRELATED DONOR TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; ACUTE-LEUKEMIA; WEIGHT-LOSS; REGISTRY; THROMBOCYTOPENIA; RECIPIENTS; DIAGNOSIS AB There is a paucity of information regarding the factors that affect nonrelapse mortality (NRM) and overall survival among children that develop chronic graft-versus-host disease (cGVHD). We performed multivariate analyses using data from the Center for International Blood and Marrow Transplant Research to identify risk factors for NRM and survival in 1117 pediatric subjects with leukemia or myelodysplastic syndrome, transplanted from related donors, unrelated donors (URD), or unrelated cord blood between 1995 and 2004. We identified 4 variables associated with higher NRM: HLA partially matched or mismatched URD, peripheral blood cell graft, Karnofsky/Lansky score < 80 at cGVHD diagnosis, and platelets < 100 x 10(9)/L at cGVHD diagnosis. Factors associated with significantly worse survival were: age > 10 years, transplantation from HLA partially matched or mismatched URD, advanced disease at transplantation, Karnofsky/Lansky < 80; and platelets < 100 x 10(9)/L. Cumulative incidence of discontinuation of systemic immune suppression at 1, 3, and 5 years after diagnosis of cGVHD were 22% (20%-25%), 34% (31%-37%), and 37% (34%-40%), respectively. This is the largest study elucidating variables affecting outcome after diagnosis of cGVHD in pediatric allograft recipients. These variables may be useful for risk stratification, development of future clinical trials, and family counseling in children with cGVHD. (Blood. 2011;118(16):4472-4479) C1 [Jacobsohn, David A.] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Arora, Mukta; Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Klein, John P.; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Hassebroek, Anna; Spellman, Stephen R.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Flowers, Mary E.; Lee, Stephanie J.; Petersdorf, Effie W.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Cutler, Corey S.; Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Urbano-Ispizua, Alvaro] Hosp Clin Barcelona, Barcelona, Spain. [Bolwell, Brian J.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Boyiadzis, Michael] Univ Pittsburgh, Ctr Canc, Pittsburgh, PA USA. [Cahn, Jean-Yves] Ctr Hosp Univ Grenoble, Hosp A Michallon, Grenoble, France. [Cairo, Mitchell S.] Morgan Stanley Childrens Hosp New York Presbyteri, New York, NY USA. [Herzig, Roger H.] Univ Louisville Hosp, James Brown Canc Ctr, Louisville, KY USA. [Isola, Luis M.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Klumpp, Thomas R.] Temple Univ, Bone Marrow Transplant Program, Philadelphia, PA 19122 USA. [Santarone, Stella] Osped Civile, BMT Ctr Pescara, Pescara, Italy. [Gale, Robert P.] Celgene Corp, Los Angeles, CA USA. [Schouten, Harry C.] Acad Ziekenhuis Maastricht, Maastricht, Netherlands. [Wingard, John R.] Shands HealthCare, Gainesville, FL USA. [Wingard, John R.] Univ Florida, Gainesville, FL USA. [Pavletic, Steven Z.] NCI, NIH, Bethesda, MD 20892 USA. RP Jacobsohn, DA (reprint author), Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Ctr Canc & Blood Disorders, 111 Michigan Ave NW, Washington, DC 20010 USA. EM dajacobs@cnmc.org RI Cahn, Jean-Yves/M-6493-2014 FU National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID), NHLBI [5U01HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Allos Inc; Amgen Inc; Medical College of Wisconsin; Astellas Pharma US Inc; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix GmbH; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Eisai Inc; Genentech Inc; Genzyme Corporation; Histogenetics Inc; HKS Medical Information Systems; Hospira Inc; Kirin Brewery Co Ltd; Leukemia & Lymphoma Society; Merck Company; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Nature Publishing Group; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc; Otsuka America Pharmaceutical Inc; Pall Life Sciences; Pfizer Inc; Schering Corporation; Sigma-Tau Pharmaceuticals; Soligenix Inc; StemCyte Inc; StemSoft Software Inc; Sysmex America Inc; THERAKOS Inc; Vidacare Corporation; ViraCor Laboratories; ViroPharma Inc; Wellpoint Inc FX CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Allos Inc; Amgen Inc; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US Inc; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix GmbH; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Eisai Inc; Genentech Inc; Genzyme Corporation; Histogenetics Inc; HKS Medical Information Systems; Hospira Inc; Kirin Brewery Co Ltd; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Nature Publishing Group; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc; Otsuka America Pharmaceutical Inc; Pall Life Sciences; Pfizer Inc; Schering Corporation; Sigma-Tau Pharmaceuticals; Soligenix Inc; StemCyte Inc; StemSoft Software Inc; Sysmex America Inc; THERAKOS Inc; Vidacare Corporation; ViraCor Laboratories; ViroPharma Inc; and Wellpoint Inc. NR 36 TC 20 Z9 21 U1 0 U2 1 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 OCT 20 PY 2011 VL 118 IS 16 BP 4472 EP 4479 DI 10.1182/blood-2011-04-349068 PG 8 WC Hematology SC Hematology GA 838JY UT WOS:000296286500030 PM 21878671 ER PT J AU Jacobs, PP Sackstein, R AF Jacobs, Pieter P. Sackstein, Robert TI CD44 and HCELL: Preventing hematogenous metastasis at step 1 SO FEBS LETTERS LA English DT Review DE CD44; Hematopoietic cell E-/L-selectin ligand; Metastasis; Glycosylation; Selectin ID COLON-CARCINOMA CELLS; L-SELECTIN LIGAND; NECROSIS-FACTOR-ALPHA; MAJOR E-SELECTIN; LEUKOCYTE ADHESION MOLECULE-1; PERIPHERAL-BLOOD MONOCYTES; HUMAN COLORECTAL-CANCER; LYMPH-NODE METASTASIS; SIALYL-LEWIS-X; P-SELECTIN AB Despite great strides in our knowledge of the genetic and epigenetic changes underlying malignancy, we have limited information on the molecular basis of metastasis. Over 90% of cancer deaths are caused by spread of tumor cells from a primary site to distant organs and tissues, highlighting the pressing need to define the molecular effectors of cancer metastasis. Mounting evidence suggests that circulating tumor cells (CTCs) home to specific tissues by hijacking the normal leukocyte trafficking mechanisms. Cancer cells characteristically express CD44, and there is increasing evidence that hematopoietic cell E-/L-selectin ligand (HCELL), a sialofucosylated glycoform of CD44, serves as the major selectin ligand on cancer cells, allowing interaction of tumor cells with endothelium, leukocytes, and platelets. Here, we review the structural biology of CD44 and of HCELL, and present current data on the function of these molecules in mediating organ-specific homing/metastasis of CTCs. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Jacobs, Pieter P.; Sackstein, Robert] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Sackstein, Robert] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Jacobs, Pieter P.; Sackstein, Robert] Harvard Univ, Sch Med, Harvard Skin Dis Res Ctr, Boston, MA 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,6th Floor,Room 647, Boston, MA 02115 USA. EM rsackstein@rics.bwh.harvard.edu FU National Institutes of Health; National Heart Lung Blood Institute; National Cancer Institute [PO1 HL107146, RO1 HL60528, RO1 HL73714, RO1 CA121335] FX This work was supported by the National Institutes of Health, in particular, the National Heart Lung Blood Institute and the National Cancer Institute (PO1 HL107146, RO1 HL60528, RO1 HL73714, and RO1 CA121335). According to National Institutes of Health policies and procedures, the Brigham and Women's Hospital has assigned intellectual property rights regarding HCELL to the inventor (R.S.). NR 176 TC 28 Z9 29 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD OCT 20 PY 2011 VL 585 IS 20 BP 3148 EP 3158 DI 10.1016/j.febslet.2011.07.039 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 841LP UT WOS:000296514100002 PM 21827751 ER PT J AU Talcott, JA Yeap, BY Clark, JA Siegel, RD Loggers, ET Lu, C Godley, PA AF Talcott, James A. Yeap, Beow Y. Clark, Jack A. Siegel, Robert D. Loggers, Elizabeth Trice Lu, Charles Godley, Paul A. TI Safety of Early Discharge for Low-Risk Patients With Febrile Neutropenia: A Multicenter Randomized Controlled Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID EARLY HOSPITAL DISCHARGE; CANCER-PATIENTS; ANTIBIOTIC-THERAPY; MULTINATIONAL-ASSOCIATION; OUTPATIENT MANAGEMENT; CLINICAL-PRACTICE; ORAL ANTIBIOTICS; PREDICTION RULE; SUPPORTIVE-CARE; FEVER AB Purpose Febrile neutropenia commonly complicates cancer chemotherapy. Outpatient treatment may reduce costs and improve patient comfort but risk progression of undetected medical problems. Patients and Methods By using our validated algorithm, we identified medically stable inpatients admitted for febrile neutropenia (neutrophils <500/mu L) after chemotherapy and randomly assigned them to continued inpatient antibiotic therapy or early discharge to receive identical antibiotic treatment at home. Our primary outcome was the occurrence of any serious medical complication, defined as evidence of medical instability requiring urgent medical attention. Results We enrolled 117 patients with 121 febrile neutropenia episodes before study termination for poor accrual. We excluded five episodes as ineligible and three because of inadequate documentation of the study outcome. Treatment groups were clinically similar, but sociodemographic imbalances occurred because of block randomization. The median presenting absolute neutrophil count was 100/mu L. Hematopoietic growth factors were used in 38% of episodes. The median neutropenia duration was 4 days (range, 1 to 15 days). Five outpatients were readmitted to the hospital. Major medical complications occurred in five episodes (8%) in the hospital arm and four (9%) in the home arm (95% CI for the difference, -10% to 13%; P = .56). No study patient died. Patient-reported quality of life was similar on both arms. Conclusion We found no evidence of adverse medical consequences from home care, despite a protocol designed to detect evidence of clinical deterioration. These results should reassure clinicians who elect to treat rigorously characterized low-risk patients with febrile neutropenia in suitable outpatient settings with appropriate surveillance for unexpected clinical deterioration. C1 [Talcott, James A.; Yeap, Beow Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Talcott, James A.] Harvard Univ, Sch Med, Boston, MA USA. [Clark, Jack A.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Clark, Jack A.] VA Med Ctr, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Siegel, Robert D.] Helen & Harry Gray Canc Ctr, Hartford, CT USA. [Loggers, Elizabeth Trice] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Loggers, Elizabeth Trice] Grp Hlth Res Inst, Seattle, WA USA. [Lu, Charles] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Godley, Paul A.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. RP Talcott, JA (reprint author), Continuum Canc Ctr New York, 325 W 15th St, New York, NY 10011 USA. EM jtalcott@chpnet.org OI Clark, Jack/0000-0002-7424-1670 FU National Cancer Institute [R01 CA71125] FX Supported by Grant No. R01 CA71125 from the National Cancer Institute. NR 35 TC 18 Z9 18 U1 0 U2 3 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 OCT 20 PY 2011 VL 29 IS 30 BP 3977 EP 3983 DI 10.1200/JCO.2011.35.0884 PG 7 WC Oncology SC Oncology GA 841YS UT WOS:000296551700012 PM 21931024 ER PT J AU Hendricks, AM Loggers, ET Talcott, JA AF Hendricks, Ann M. Loggers, Elizabeth Trice Talcott, James A. TI Costs of Home Versus Inpatient Treatment for Fever and Neutropenia: Analysis of a Multicenter Randomized Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER-PATIENTS; FEBRILE NEUTROPENIA; ECONOMIC-EVALUATION; CLINICAL-TRIALS; PREDICTION RULE; OUTPATIENT; CARE; MANAGEMENT AB Purpose For patients with cancer who have febrile neutropenia, relative costs of home versus hospital treatment, including unreimbursed costs borne by patients and families, are poorly characterized. We estimated costs from a randomized trial of patients with low-risk febrile neutropenia for whom outpatient care was feasible, comparing inpatient treatment with discharge to home care after inpatient observation. Methods We collected direct medical and self-reported indirect costs for 57 inpatient and 35 outpatient treatment episodes of patients enrolled in a randomized trial from 1996 through 2000. Charges from hospital bills were converted to costs using Medicare cost-to-charge ratios. Patients kept daily logs of out-of-pocket payments and time spent by informal caregivers providing care. Dollar amounts were standardized to June 2008. Results Mean total charges for the hospital arm were 49% higher than for the home treatment arm ($16,341 v $10,977; P < .01). Mean estimated total costs for the hospital arm were 30% higher ($10,143 v $7,830; P < .01). Inspection of sparse available data suggests that payments made were similar by treatment arm. Inpatients and their caregivers spent more out of pocket than their outpatient counterparts (mean, $201 v $74; P < .01). Informal caregivers for both treatment arms reported similar time caring and lost from work. Conclusion Home intravenous antibiotic treatment was less costly than continued inpatient care for carefully selected patients with cancer having febrile neutropenia without significantly increased indirect costs or caregiver burden. C1 [Hendricks, Ann M.] Boston Univ, VA Boston Healthcare Syst, Sch Publ Hlth, Boston, MA 02130 USA. [Talcott, James A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Talcott, James A.] Harvard Univ, Sch Med, Boston, MA USA. [Loggers, Elizabeth Trice] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Loggers, Elizabeth Trice] Grp Hlth Res Inst, Seattle, WA USA. RP Hendricks, AM (reprint author), Boston Univ, VA Boston Healthcare Syst, Sch Publ Hlth, 150 S Huntington Ave, Boston, MA 02130 USA. EM ann.hendricks@va.gov FU National Cancer Institute [CA 71125] FX Supported by National Cancer Institute Research Grant No. CA 71125. NR 21 TC 25 Z9 25 U1 0 U2 3 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 OCT 20 PY 2011 VL 29 IS 30 BP 3984 EP 3989 DI 10.1200/JCO.2011.35.1247 PG 6 WC Oncology SC Oncology GA 841YS UT WOS:000296551700013 PM 21931037 ER PT J AU Paugh, BS Broniscer, A Qu, CX Miller, CP Zhang, JY Tatevossian, RG Olson, JM Geyer, JR Chi, SN da Silva, NS Onar-Thomas, A Baker, JN Gajjar, A Ellison, DW Baker, SJ AF Paugh, Barbara S. Broniscer, Alberto Qu, Chunxu Miller, Claudia P. Zhang, Junyuan Tatevossian, Ruth G. Olson, James M. Geyer, J. Russell Chi, Susan N. da Silva, Nasjla Saba Onar-Thomas, Arzu Baker, Justin N. Gajjar, Amar Ellison, David W. Baker, Suzanne J. TI Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BRAIN-STEM GLIOMA; HIGH-GRADE GLIOMAS; PHASE-I TRIAL; PILOCYTIC ASTROCYTOMAS; GLIOBLASTOMA-MULTIFORME; MALIGNANT GLIOMAS; FUSION GENE; CHILDREN; CANCER; GROWTH AB Purpose Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. Results Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. Conclusion DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG. C1 [Baker, Suzanne J.] St Jude Childrens Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA. [Broniscer, Alberto; Gajjar, Amar] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Olson, James M.; Geyer, J. Russell] Univ Washington, Seattle, WA 98195 USA. [Chi, Susan N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [da Silva, Nasjla Saba] Univ Fed Sao Paulo, Sao Paulo, Brazil. RP Baker, SJ (reprint author), St Jude Childrens Hosp, Dept Dev Neurobiol, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM Suzanne.Baker@stjude.org RI Tatevossian, Ruth/G-6377-2016; OI Tatevossian, Ruth/0000-0002-1653-3026; Broniscer, Alberto/0000-0001-9646-0463 FU National Institutes of Health [P01 CA096832]; National Brain Tumor Society; Cure Starts Now Foundation; Smile for Sophie Forever Foundation; Tyler's Treehouse Foundation; Musicians Against Childhood Cancer; Noyes Brain Tumor Foundation; Pediatric Low Grade Astrocytoma Foundation; American Lebanese Syrian Associated Charities FX Supported by Grant No. P01 CA096832 from the National Institutes of Health and by the Sydney Schlobohm Chair of Research from the National Brain Tumor Society, Cure Starts Now Foundation, Smile for Sophie Forever Foundation, Tyler's Treehouse Foundation, Musicians Against Childhood Cancer, Noyes Brain Tumor Foundation, Pediatric Low Grade Astrocytoma Foundation, and American Lebanese Syrian Associated Charities. NR 37 TC 104 Z9 105 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 OCT 20 PY 2011 VL 29 IS 30 BP 3999 EP 4006 DI 10.1200/JCO.2011.35.5677 PG 8 WC Oncology SC Oncology GA 841YS UT WOS:000296551700015 PM 21931021 ER PT J AU Liu, YY Slotine, JJ Barabasi, AL AF Liu, Yang-Yu Slotine, Jean-Jacques Barabasi, Albert-Laszlo TI Few inputs can reprogram biological networks Reply SO NATURE LA English DT Letter C1 [Liu, Yang-Yu; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Liu, Yang-Yu; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys Comp Sci & Biol, Boston, MA 02115 USA. [Liu, Yang-Yu; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Slotine, Jean-Jacques] MIT, Nonlinear Syst Lab, Cambridge, MA 02139 USA. [Slotine, Jean-Jacques] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Slotine, Jean-Jacques] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. RP Liu, YY (reprint author), Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. EM alb@neu.edu RI Liu, Yang-Yu/G-8885-2011 OI Liu, Yang-Yu/0000-0003-2728-4907 NR 8 TC 8 Z9 8 U1 1 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 20 PY 2011 VL 478 IS 7369 BP E4 EP E5 DI 10.1038/nature10544 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 835FO UT WOS:000296021100002 ER PT J AU Blanc, FX Sok, T Laureillard, D Borand, L Rekacewicz, C Nerrienet, E Madec, Y Marcy, O Chan, S Prak, N Kim, C Lak, KK Hak, C Dim, B Sin, CI Sun, S Guillard, B Sar, B Vong, S Fernandez, M Fox, L Delfraissy, JF Goldfeld, AE AF Blanc, Francois-Xavier Sok, Thim Laureillard, Didier Borand, Laurence Rekacewicz, Claire Nerrienet, Eric Madec, Yoann Marcy, Olivier Chan, Sarin Prak, Narom Kim, Chindamony Lak, Khemarin Kim Hak, Chanroeurn Dim, Bunnet Sin, Chhun Im Sun, Sath Guillard, Bertrand Sar, Borann Vong, Sirenda Fernandez, Marcelo Fox, Lawrence Delfraissy, Jean-Francois Goldfeld, Anne E. CA CAMELIA ANRS 1295-CIPRA KH001 TI Earlier versus Later Start of Antiretroviral Therapy in HIV-Infected Adults with Tuberculosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SUB-SAHARAN AFRICA; MORTALITY; CAMBODIA; OUTCOMES; PROGRAM; PREVALENCE; DIAGNOSIS; SURVIVAL; THAILAND; IMPACT AB Background Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy. Methods We tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to antiretroviral drugs who had newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower. After beginning the standard, 6-month treatment for tuberculosis, patients were randomly assigned to either earlier treatment (2 weeks after beginning tuberculosis treatment) or later treatment (8 weeks after) with stavudine, lamivudine, and efavirenz. The primary end point was survival. Results A total of 661 patients were enrolled and were followed for a median of 25 months. The median CD4+ T-cell count was 25 per cubic millimeter, and the median viral load was 5.64 log(10) copies per milliliter. The risk of death was significantly reduced in the group that received ART earlier, with 59 deaths among 332 patients (18%), as compared with 90 deaths among 329 patients (27%) in the later-ART group (hazard ratio, 0.62; 95% confidence interval [CI]; 0.44 to 0.86; P = 0.006). The risk of tuberculosis-associated immune reconstitution inflammatory syndrome was significantly increased in the earlier-ART group (hazard ratio, 2.51; 95% CI, 1.78 to 3.59; P<0.001). Irrespective of the study group, the median gain in the CD4+ T-cell count was 114 per cubic millimeter, and the viral load was undetectable at week 50 in 96.5% of the patients. Conclusions Initiating ART 2 weeks after the start of tuberculosis treatment significantly improved survival among HIV-infected adults with CD4+ T-cell counts of 200 per cubic millimeter or lower. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institutes of Health; CAMELIA ClinicalTrials.gov number, NCT01300481.) C1 [Blanc, Francois-Xavier; Delfraissy, Jean-Francois] Hop Bicetre, AP HP, Dept Internal Med, Pneumol Unit, Le Kremlin Bicetre, France. [Delfraissy, Jean-Francois] Univ Paris 11, INSERM, U1012, Le Kremlin Bicetre, France. [Sok, Thim; Laureillard, Didier; Marcy, Olivier; Chan, Sarin; Lak, Khemarin Kim; Dim, Bunnet; Sun, Sath; Fernandez, Marcelo; Goldfeld, Anne E.] Khmer Soviet Friendship Hosp, Cambodian Hlth Comm, Phnom Penh, Cambodia. [Borand, Laurence; Nerrienet, Eric; Guillard, Bertrand; Sar, Borann; Vong, Sirenda] Khmer Soviet Friendship Hosp, Inst Pasteur Cambodia, Phnom Penh, Cambodia. [Prak, Narom] Khmer Soviet Friendship Hosp, Dept Infect Dis, Phnom Penh, Cambodia. [Sin, Chhun Im] Khmer Soviet Friendship Hosp, Dept Pneumol, Phnom Penh, Cambodia. [Kim, Chindamony; Dim, Bunnet] Med Sans Frontieres, Phnom Penh, Cambodia. [Hak, Chanroeurn] Calmette Hosp, Phnom Penh, Cambodia. [Kim, Chindamony] Donkeo Prov Hosp, Takeo, Cambodia. [Lak, Khemarin Kim; Sun, Sath] Svay Rieng Prov Hosp, Svay Rieng, Cambodia. [Dim, Bunnet] Siem Reap Prov Hosp, Siem Reap, Cambodia. [Laureillard, Didier] Georges Pompidou European Hosp, AP HP, Dept Clin Immunol, Paris, France. [Rekacewicz, Claire; Delfraissy, Jean-Francois] Agence Natl Rech Sida & Hepatites Virales, Paris, France. [Madec, Yoann] Inst Pasteur, Unite Epidemiol Malad Emergentes, Paris, France. [Fox, Lawrence] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Goldfeld, Anne E.] Harvard Univ, Sch Med, Childrens Hosp, Immune Dis Inst, Boston, MA USA. [Goldfeld, Anne E.] Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. RP Blanc, FX (reprint author), CHU Bicetre, Unite Fonct Pneumol, 78 Rue Gen Leclerc, F-94275 Le Kremlin Bicetre, France. EM xavier.blanc@bct.aphp.fr; goldfeld@idi.harvard.edu RI Blanc, Francois-Xavier/D-7425-2015 FU French National Agency for Research on AIDS and Viral Hepatitis [ANRS 1295]; National Institutes of Health; National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS [CIPRA KH001/DAID-ES ID 10425]; Annenberg Foundation; Aeras Global TB Vaccine Foundation; scientific team of the ANRS; logistic team of the ANRS; Organisation Franco-Cambodgienne de Pneumologie FX Funded by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institutes of Health; CAMELIA ClinicalTrials.gov number, NCT01300481.; Supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS 1295) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (CIPRA KH001/DAID-ES ID 10425).; Dr. Delfraissy reports serving on the international board for HIV treatment of GlaxoSmithKline, Merck Sharp & Dohme-Chibret, Gilead, and Bristol-Myers Squibb; and Dr. Goldfeld, receiving funds from the Annenberg Foundation to her laboratory and to the Cambodian Health Committee to conduct studies and serving as a consultant for the Aeras Global TB Vaccine Foundation, which provides funds to the Cambodian Health Committee to conduct studies. No other potential conflict of interest relevant to this article was reported.; We thank the patients for their participation in the trial; Franoise Barre-Sinoussi for her help with initiating the CIPRA project and the CAMELIA trial and for her support throughout the trial; H. E. Eng Huot for his early and continuing support; Philippe Glaziou for providing the initial design of the study; Charles Mayaud for his clinical mentorship; Jean-Louis Sarthou for ensuring high-quality laboratory and basic scientific support during the trial; H. E. Mean Chhivun and H. E. Mao Tan Eang for the support of the Cambodian National AIDS and Tuberculosis Programs, respectively; Takmao, Kossamak, and Kampong Trach Hospitals for referring patients to the study sites; Bart Janssens, Petros Isaakidis, and Tony Reid for the support from Medecins sans Frontieres Belgium to two of our study sites (Donkeo and Siem Reap Provincial Hospitals); the data and safety monitoring board, chaired by John Modlin, and the scientific advisory board, chaired by Charles Mayaud, for their significant contributions to the study; the scientific and logistic teams of the ANRS (Brigitte Bazin, Severine Blesson, Alpha Diallo, Annie Metro, Saphonn Vonthanak, Isabelle Fournier-Nicolle, and Michel Kazatchkine) and the National Institutes of Health (Jane E. Bupp, Ray Y. Chen, Margaret Matula, Rod Hoff, Sandra Nusinoff Lehrman, Karen Near, Barbara Laughon, Mike Ussery, Trinh Ly, Mary Fanning, and Ana Martinez) for their support and intellectual contributions; and Pierre L'Her, Etienne Leroy-Terquem, the Organisation Franco-Cambodgienne de Pneumologie, Pean Polidy, Sylvia Taylor, Josephine Braun, Vincent Guillemet, Adrienne Shapiro, Catherine Quillet, Jean-Paul Dousset, Anne-Marie Taburet, Wayne Wilson, and Vincent Deubel for their support. NR 33 TC 297 Z9 304 U1 2 U2 19 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 OCT 20 PY 2011 VL 365 IS 16 BP 1471 EP 1481 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 835BW UT WOS:000296009500001 PM 22010913 ER PT J AU Shah, U Shenoy-Bhangle, AS AF Shah, Uzma Shenoy-Bhangle, Anuradha S. TI Case 32-2011: A 19-Year-Old Man with Recurrent Pancreatitis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IDIOPATHIC CHRONIC-PANCREATITIS; HEREDITARY PANCREATITIS; CHILDREN; CHOLANGIOPANCREATOGRAPHY; GALLSTONES; INHIBITOR; RISK; GENE C1 [Shah, Uzma] Massachusetts Gen Hosp, Dept Pediat Gastroenterol, Boston, MA 02114 USA. [Shah, Uzma] Massachusetts Gen Hosp, Dept Hepatol, Boston, MA 02114 USA. [Shah, Uzma] Massachusetts Gen Hosp, Dept Nutr, Boston, MA 02114 USA. [Shenoy-Bhangle, Anuradha S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Shah, Uzma] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Shenoy-Bhangle, Anuradha S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Shah, U (reprint author), Massachusetts Gen Hosp, Dept Pediat Gastroenterol, Boston, MA 02114 USA. NR 24 TC 0 Z9 0 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 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 20 PY 2011 VL 365 IS 16 BP 1528 EP 1536 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 835BW UT WOS:000296009500009 PM 22010920 ER PT J AU Rosenbluh, J Nijhawan, D Chen, Z Wong, KK Masutomi, K Hahn, WC AF Rosenbluh, Joseph Nijhawan, Deepak Chen, Zhao Wong, Kwok-Kin Masutomi, Kenkichi Hahn, William C. TI RMRP Is a Non-Coding RNA Essential for Early Murine Development SO PLOS ONE LA English DT Article ID CARTILAGE-HAIR HYPOPLASIA; MUTATIONS AB RMRP is a non-coding RNA that is ubiquitously expressed in both humans and mice. RMRP mutations that lead to decreased RMRP levels are found in the pleiotropic syndrome Cartilage Hair Hypoplasia. To assess the effects of deleting RMRP, we engineered a targeting vector that contains loxP sequences flanking RMRP and created hemizygous mice harboring this engineered allele (RMRP conditional). We found that insertion of this cassette suppressed RMRP expression, and we failed to obtain viable mice homozygous for the RMRP conditional allele. Furthermore, we were unable to obtain viable homozygous RMRP null mice, indicating that RMRP is essential for early embryonic development. C1 [Rosenbluh, Joseph; Nijhawan, Deepak; Chen, Zhao; Wong, Kwok-Kin; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rosenbluh, Joseph; Nijhawan, Deepak; Chen, Zhao; Wong, Kwok-Kin; Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Rosenbluh, Joseph; Nijhawan, Deepak; Chen, Zhao; Wong, Kwok-Kin; Hahn, William C.] Harvard Univ, Sch Med, Boston, MA USA. [Rosenbluh, Joseph; Nijhawan, Deepak; Hahn, William C.] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA. [Masutomi, Kenkichi] Natl Canc Ctr, Res Inst, Div Canc Stem Cell, Tokyo 104, Japan. RP Rosenbluh, J (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM kmasutom@ncc.go.jp; William_Hahn@dfci.harvard.edu OI wong, kwok kin/0000-0001-6323-235X FU US National Institutes of Health [F32GM090437-01, R01 AG23145] FX This research was supported by a US National Institutes of Health postdoctoral fellowship to J.R. F32GM090437-01, and R01 AG23145 (WCH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 7 TC 12 Z9 13 U1 0 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 OCT 19 PY 2011 VL 6 IS 10 AR e26270 DI 10.1371/journal.pone.0026270 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 841JB UT WOS:000296507500047 PM 22039455 ER PT J AU Garrigues, GE Wray, WH Lindenhovius, ALC Ring, DC Ruch, DS AF Garrigues, Grant E. Wray, Walter H., III Lindenhovius, Anneluuk L. C. Ring, David C. Ruch, David S. TI Fixation of the Coronoid Process in Elbow Fracture-Dislocations SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID MEDIAL COLLATERAL LIGAMENT; TERRIBLE TRIAD INJURY; RADIAL HEAD; INSTABILITY; REPAIR AB Background: Terrible triad injuries consist of a posterior dislocation of the elbow, a coronoid fracture, and a radial head fracture. The coronoid plays a pivotal role as an anterior buttress, yet the optimal management of the coronoid fracture remains unknown. We hypothesize that suture lasso fixation of the coronoid fracture leads to fewer complications and improved outcomes compared with screw or suture anchor fixation techniques. Methods:. A retrospective chart review performed at three tertiary care centers identified forty consecutive patients treated for terrible triad injuries of the elbow with a minimum follow-up of eighteen months (mean, twenty-four months; range, eighteen to fifty-three months). All patients were managed with a standard approach consisting of: (1) repair or replacement of the radial head; (2) repair of the lateral ulnar collateral ligament (LUCL) of the elbow; and (3) repair of the coronoid fracture with one of two techniques: Group I (n = 28) consisted of the "lasso" technique and Group II (n = 12) consisted of open reduction and internal fixation (ORIF) with screws or suture anchors. Results: For the study population, the mean postoperative arc of elbow motion was 115 degrees (range, 75 degrees to 140 degrees), the average Disabilities of the Arm, Shoulder and Hand (DASH) score was 16 (range, 0 to 43), and the average Broberg-Morrey score was 90 (range, 64 to 100). For repair of the coronoid fracture, the suture lasso technique was more stable than the other techniques intraoperatively, both before (p < 0.05) and after (p < 0.05) LUCL repair, and at the final follow-up (p < 0.05). ORIF was associated with a higher prevalence of implant failure (p < 0.05), and suture anchors were associated with a higher prevalence of malunion and nonunion (p < 0.05). Conclusions: For terrible triad injuries, greater stability with fewer complications was achieved With use of the suture lasso technique for coronoid fracture fixation. C1 [Garrigues, Grant E.] Duke Univ, Dept Orthopaed Surg, Med Ctr, Durham, NC 27710 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Garrigues, GE (reprint author), Duke Univ, Dept Orthopaed Surg, Med Ctr, Box 3466, Durham, NC 27710 USA. EM d.ruch@duke.edu NR 26 TC 34 Z9 45 U1 0 U2 8 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD OCT 19 PY 2011 VL 93A IS 20 BP 1873 EP 1881 DI 10.2106/JBJS.I.01673 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 836AE UT WOS:000296077600003 PM 22012524 ER PT J AU Lu, J Liu, HS Zhang, M Wang, DH Cao, YX Ma, QF Rong, DD Wang, XY Buckner, RL Li, KC AF Lu, Jie Liu, Hesheng Zhang, Miao Wang, Danhong Cao, Yanxiang Ma, Qingfeng Rong, Dongdong Wang, Xiaoyi Buckner, Randy L. Li, Kuncheng TI Focal Pontine Lesions Provide Evidence That Intrinsic Functional Connectivity Reflects Polysynaptic Anatomical Pathways SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SPONTANEOUS FLUCTUATIONS; STRUCTURAL CONNECTIVITY; HUMAN BRAIN; STROKE; ORGANIZATION; CORTEX; MONKEY; ARCHITECTURE; PROJECTIONS; DISORDERS AB Intrinsic functional connectivity detected by functional MRI (fMRI) provides a useful but indirect approach to study the organization of human brain systems. An unresolved question is whether functional connectivity measured by resting-state fMRI reflects anatomical connections. In this study, we used the well-characterized anatomy of cerebrocerebellar circuits to directly test whether intrinsic functional connectivity is associated with an anatomic pathway. Eleven first-episode stroke patients were scanned five times during a period of 6 months, and 11 healthy control subjects were scanned three times within 1 month. In patients with right pontine strokes, the functional connectivity between the right motor cortex and the left cerebellum was selectively reduced. This connectivity pattern was reversed in patients with left pontine strokes. Although factors beyond anatomical connectivity contribute to fMRI measures of functional correlation, these results provide direct evidence that functional connectivity depends on intact connections within a specific polysynaptic pathway. C1 [Lu, Jie; Zhang, Miao; Cao, Yanxiang; Rong, Dongdong; Wang, Xiaoyi; Li, Kuncheng] Capital Med Univ, Xuanwu Hosp, Dept Radiol, Beijing 100053, Peoples R China. [Ma, Qingfeng] Capital Med Univ, Xuanwu Hosp, Dept Neurol, Beijing 100053, Peoples R China. [Liu, Hesheng; Wang, Danhong; Buckner, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Buckner, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckner, Randy L.] Howard Hughes Med Inst, Cambridge, MA 02138 USA. RP Li, KC (reprint author), Capital Med Univ, Xuanwu Hosp, Dept Radiol, Beijing 100053, Peoples R China. EM randy_buckner@harvard.edu; likuncheng1955@yahoo.com.cn RI wang, danhong/C-8353-2014; wang, danhong/M-2699-2014; OI Liu, Hesheng/0000-0002-7233-1509 FU NINDS [K25NS069805]; NIA [AG021910]; NCRR [P41RR14074]; Howard Hughes Medical Institute FX This work was supported by NINDS Grant K25NS069805, NIA Grant AG021910, NCRR Grant P41RR14074, and the Howard Hughes Medical Institute. We thank Fenna Krienen, Avram Holmes, and Jorge Sepulcre for assistance with data analysis, Judith Schaechter for discussion of behavioral assessment, Jeremy Schmahmann for discussion of anatomy, and Haderer & Muller Biomedical Art for illustration. NR 35 TC 42 Z9 42 U1 0 U2 6 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 OCT 19 PY 2011 VL 31 IS 42 BP 15065 EP 15071 DI 10.1523/JNEUROSCI.2364-11.2011 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 838FY UT WOS:000296274000026 PM 22016540 ER PT J AU Kahn, I Desai, M Knoblich, U Bernstein, J Henninger, M Graybiel, AM Boyden, ES Buckner, RL Moore, CI AF Kahn, Itamar Desai, Mitul Knoblich, Ulf Bernstein, Jacob Henninger, Michael Graybiel, Ann M. Boyden, Edward S. Buckner, Randy L. Moore, Christopher I. TI Characterization of the Functional MRI Response Temporal Linearity via Optical Control of Neocortical Pyramidal Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TRANSGENIC MICE; HUMAN BRAIN; TELL US; FMRI; CHANNELRHODOPSIN-2; ACTIVATION; CORTEX; DRIVEN AB The blood oxygenation level-dependent (BOLD) signal serves as the basis for human functional MRI(fMRI). Knowledge of the properties of the BOLD signal, such as how linear its response is to sensory stimuli, is essential for the design and interpretation of fMRI experiments. Here, we combined the cell-type and site-specific causal control provided by optogenetics and fMRI (opto-fMRI) in mice to test the linearity of BOLD signals driven by locally induced excitatory activity. We employed high-resolution mouse fMRI at 9.4 tesla to measure the BOLD response, and extracellular electrophysiological recordings to measure the effects of stimulation on single unit, multiunit, and local field potential activity. Optically driven stimulation of layer V neocortical pyramidal neurons resulted in a positive local BOLD response at the stimulated site. Consistent with a linear transform model, this locally driven BOLD response summated in response to closely spaced trains of stimulation. These properties were equivalent to responses generated through the multisynaptic method of driving neocortical activity by tactile sensory stimulation, and paralleled changes in electrophysiological measures. These results illustrate the potential of the opto-fMRI method and reinforce the critical assumption of human functional neuroimaging that-to first approximation-the BOLD response tracks local neural activity levels. C1 [Kahn, Itamar; Buckner, Randy L.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Kahn, Itamar; Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Kahn, Itamar; Buckner, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Desai, Mitul; Knoblich, Ulf; Bernstein, Jacob; Henninger, Michael; Graybiel, Ann M.; Boyden, Edward S.; Moore, Christopher I.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Bernstein, Jacob; Henninger, Michael; Boyden, Edward S.] MIT, MIT Media Lab, Synthet Neurobiol Grp, Cambridge, MA 02139 USA. [Bernstein, Jacob; Henninger, Michael; Boyden, Edward S.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Buckner, Randy L.] Massachusetts Gen Hosp, Dept Psychiat & Radiol, Boston, MA 02114 USA. RP Boyden, ES (reprint author), MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM kahn@technion.ac.il; esb@media.mit.edu; randy_buckner@harvard.edu; cim@mit.edu RI Knoblich, Ulf/A-1762-2010 OI Knoblich, Ulf/0000-0002-0756-5587 FU National Science Foundation; National Institutes of Health; Howard Hughes Medical Institute; McGovern Institute for Brain Research FX This work was supported by the National Science Foundation, National Institutes of Health, the Howard Hughes Medical Institute, and the McGovern Institute for Brain Research. We thank Jessica Cardin, Robert Haslinger, Dominique Pritchett, Jason Ritt, and Jackie Schiller for helpful discussions, Jessica Cardin for technical assistance with histology, and Harvard Center for Brain Science Optical Imaging Core and Steve Turney for assistance with fluorescence imaging. NR 26 TC 54 Z9 55 U1 2 U2 9 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 OCT 19 PY 2011 VL 31 IS 42 BP 15086 EP 15091 DI 10.1523/JNEUROSCI.0007-11.2011 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 838FY UT WOS:000296274000028 PM 22016542 ER PT J AU Behrens, CR Hooker, JM Obermeyer, AC Romanini, DW Katz, EM Francis, MB AF Behrens, Christopher R. Hooker, Jacob M. Obermeyer, Allie C. Romanini, Dante W. Katz, Elan M. Francis, Matthew B. TI Rapid Chemoselective Bioconjugation through Oxidative Coupling of Anilines and Aminophenols SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID VIRUS-LIKE PARTICLES; GENETIC-CODE; AMINO-ACIDS; SURFACE; PEPTIDES; PROTEINS; BACTERIOPHAGE-MS2; SELECTIVITY; CHEMISTRY; MOLECULE AB A highly efficient protein bioconjugation method is described involving addition of anilines to o-aminophenols in the presence of sodium periodate. The reaction takes place in aqueous buffer at pH 6.5 and can reach high conversion in 2-5 min. The major product was characterized using X-ray crystallography, which revealed that an unprecedented oxidative ring contraction occurs after the coupling step. The compatibility of the reaction with protein substrates has been demonstrated through attachment of small molecules, polymer chains, and peptides to p-aminophenylalanine residues introduced into viral capsids through amber stop codon suppression. Coupling of anilines to o-aminophenol groups derived from tyrosine residues is also described. The compatibility of this method with thiol modification chemistry is shown through attachment of a near-IR fluorescent chromophore to cysteine residues inside the viral capsid shells, followed by attachment of integrin-targeting RGD peptides to anilines on the exterior surface. C1 [Behrens, Christopher R.; Obermeyer, Allie C.; Romanini, Dante W.; Katz, Elan M.; Francis, Matthew B.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Hooker, Jacob M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Boston, MA 02129 USA. [Francis, Matthew B.] Lawrence Berkeley Natl Labs, Div Mat Sci, Berkeley, CA 94720 USA. RP Francis, MB (reprint author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. EM mbfrancis@berkeley.edu OI Hooker, Jacob/0000-0002-9394-7708 FU DOD [BC061995]; NSF; UC Berkeley [1 T32 GMO66698]; DOE California Alliance for Radiotracer Education [DESC0002061] FX These studies were supported by the DOD Breast Cancer Research Program (BC061995). C.R.B. was supported by DOE California Alliance for Radiotracer Education grant DESC0002061, and A.C.O. was supported by an NSF graduate research fellowship. The UC Berkeley Chemical Biology Graduate Program (Training Grant 1 T32 GMO66698) is also acknowledged for their support of C.RB., D.W.R, and A.C.O. NR 35 TC 31 Z9 31 U1 2 U2 51 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 19 PY 2011 VL 133 IS 41 BP 16398 EP 16401 DI 10.1021/ja2033298 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 834XJ UT WOS:000295997500021 PM 21919497 ER PT J AU Kansagara, D Englander, H Salanitro, A Kagen, D Theobald, C Freeman, M Kripalani, S AF Kansagara, Devan Englander, Honora Salanitro, Amanda Kagen, David Theobald, Cecelia Freeman, Michele Kripalani, Sunil TI Risk Prediction Models for Hospital Readmission A Systematic Review SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID QUALITY-OF-CARE; GENERAL MEDICINE PATIENTS; HEART-FAILURE; STATISTICAL-MODELS; PATIENT PREDICTORS; 30-DAY READMISSION; FOLLOW-UP; TRANSITIONS; PERFORMANCE; VALIDATION AB Context Predicting hospital readmission risk is of great interest to identify which patients would benefit most from care transition interventions, as well as to risk-adjust readmission rates for the purposes of hospital comparison. Objective To summarize validated readmission risk prediction models, describe their performance, and assess suitability for clinical or administrative use. Data Sources and Study Selection The databases of MEDLINE, CINAHL, and the Cochrane Library were searched from inception through March 2011, the EMBASE database was searched through August 2011, and hand searches were performed of the retrieved reference lists. Dual review was conducted to identify studies published in the English language of prediction models tested with medical patients in both derivation and validation cohorts. Data Extraction Data were extracted on the population, setting, sample size, follow-up interval, readmission rate, model discrimination and calibration, type of data used, and timing of data collection. Data Synthesis Of 7843 citations reviewed, 30 studies of 26 unique models met the inclusion criteria. The most common outcome used was 30-day readmission; only 1 model specifically addressed preventable readmissions. Fourteen models that relied on retrospective administrative data could be potentially used to risk-adjust readmission rates for hospital comparison; of these, 9 were tested in large US populations and had poor discriminative ability (c statistic range: 0.55-0.65). Seven models could potentially be used to identify high-risk patients for intervention early during a hospitalization (c statistic range: 0.56-0.72), and 5 could be used at hospital discharge (c statistic range: 0.68-0.83). Six studies compared different models in the same population and 2 of these found that functional and social variables improved model discrimination. Although most models incorporated variables for medical comorbidity and use of prior medical services, few examined variables associated with overall health and function, illness severity, or social determinants of health. Conclusions Most current readmission risk prediction models that were designed for either comparative or clinical purposes perform poorly. Although in certain settings such models may prove useful, efforts to improve their performance are needed as use becomes more widespread. JAMA. 2011;306(15):1688-1698 C1 [Kansagara, Devan; Freeman, Michele] Portland VA Med Ctr, VA Evidence Based Synth Program, Portland, OR 97239 USA. [Kansagara, Devan; Kagen, David] Portland VA Med Ctr, Dept Gen Internal Med, Portland, OR 97239 USA. [Kansagara, Devan; Englander, Honora; Kagen, David] Oregon Hlth & Sci Univ, Dept Internal Med, Portland, OR 97201 USA. [Salanitro, Amanda] VA Tennessee Valley Healthcare Syst, Ctr Geriatr Res Educ & Clin, Nashville, TN USA. [Salanitro, Amanda; Theobald, Cecelia; Kripalani, Sunil] Vanderbilt Univ, Dept Med, Div Gen Internal Med & Publ Hlth, Sect Hosp Med, Nashville, TN USA. RP Kansagara, D (reprint author), Portland VA Med Ctr, VA Evidence Based Synth Program, Mailcode RD71,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM kansagar@ohsu.edu FU Department of Veterans Affairs; Veterans Health Administration, Office of Research and Development, Health Services Research and Development; National Center for Research Resources, National Institutes of Health [1 UL1 RR024976] FX This report is based on research conducted by the Evidence-Based Synthesis Program Center located at the Portland VA Medical Center, and funded by the Department of Veterans Affairs and the Veterans Health Administration, Office of Research and Development, Health Services Research and Development. The research also was funded in part by Vanderbilt CTSA grant 1 UL1 RR024976 from the National Center for Research Resources, National Institutes of Health. NR 62 TC 453 Z9 454 U1 9 U2 89 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 OCT 19 PY 2011 VL 306 IS 15 BP 1688 EP 1698 DI 10.1001/jama.2011.1515 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 834MA UT WOS:000295963200028 PM 22009101 ER PT J AU Gheorghiade, M Braunwald, E AF Gheorghiade, Mihai Braunwald, Eugene TI Hospitalizations for Heart Failure in the United States-A Sign of Hope SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID VASOPRESSIN ANTAGONISM; PERFORMANCE-MEASURES; EJECTION FRACTION; OUTCOMES; ASSOCIATION; MORBIDITY; TOLVAPTAN; MORTALITY; EFFICACY; DIGOXIN C1 [Gheorghiade, Mihai] Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp,Dept Med,Med Sch, Boston, MA 02115 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, Dept Med, 645 N Michigan Ave,Ste 1006, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu NR 20 TC 19 Z9 21 U1 0 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 OCT 19 PY 2011 VL 306 IS 15 BP 1705 EP 1706 DI 10.1001/jama.2011.1510 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 834MA UT WOS:000295963200032 PM 22009103 ER PT J AU Turkbey, EB Backlund, JYC Genuth, S Jain, A Miao, CL Cleary, PA Lachin, JM Nathan, DM van der Geest, RJ Soliman, EZ Liu, CY Lima, JAC Bluemke, DA AF Turkbey, Evrim B. Backlund, Jye-Yu C. Genuth, Saul Jain, Aditya Miao, Cuilian Cleary, Patricia A. Lachin, John M. Nathan, David M. van der Geest, Rob J. Soliman, Elsayed Z. Liu, Chia-Ying Lima, Joao A. C. Bluemke, David A. CA DCCT EDIC Res Grp TI Myocardial Structure, Function, and Scar in Patients With Type 1 Diabetes Mellitus SO CIRCULATION LA English DT Article DE cardiovascular diseases; diabetes mellitus, type 1; magnetic resonance imaging; risk factors ID LEFT-VENTRICULAR MASS; CARDIAC MAGNETIC-RESONANCE; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; RISK-FACTORS; COMPLICATIONS TRIAL/EPIDEMIOLOGY; ARTERY-DISEASE; BODY-SIZE; FOLLOW-UP; INFARCTION AB Background-We report relationships between cardiovascular disease risk factors and myocardial structure, function, and scar in patients with type 1 diabetes mellitus in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods and Results-Cardiac magnetic resonance was obtained in 1017 patients with type 1 diabetes mellitus. Gadolinium cardiac magnetic resonance was also obtained in 741 patients. The mean age was 49 +/- 7 years; 52% were men; and mean duration of diabetes mellitus was 28 +/- 5 years. Associations of cardiovascular disease risk factors with cardiac magnetic resonance parameters were examined with linear and logistic regression models. History of macroalbuminuria was positively associated with left ventricular mass (by 14.8 g), leading to a significantly higher ratio of left ventricular mass to end-diastolic volume (by 8%). Mean hemoglobin A(1c) levels over the preceding 22 years were inversely associated with end-diastolic volume (-3.0 mL per unit mean hemoglobin A(1c) percent) and stroke volume (-2.3 mL per unit mean hemoglobin A(1c) percent) and positively related to the ratio of elevated left ventricular mass to end-diastolic volume (0.02 g/mL per unit). The overall prevalence of myocardial scar was 4.3% by cardiac magnetic resonance and 1.4% by clinical adjudication of myocardial infarction. Both mean hemoglobin A(1c) (odds ratio, 1.5 [95% confidence interval, 1.0-2.2] per unit) and macroalbuminuria (odds ratio, 3.5 [95% confidence interval, 1.2-9.9]) were significantly associated with myocardial scar and traditional cardiovascular disease risk factors. Conclusions-In addition to traditional cardiovascular disease risk factors, elevated mean hemoglobin A(1c) and macroalbuminuria were significantly associated with alterations in left ventricular structure and function. The prevalence of myocardial scar was 4.3% in this subcohort of DCCT/EDIC participants with relatively preserved renal function. C1 [Turkbey, Evrim B.; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Backlund, Jye-Yu C.; Cleary, Patricia A.; Lachin, John M.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Genuth, Saul] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Div Cardiol, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Miao, Cuilian] Northwestern Univ, Dept Radiol, Chicago, IL 60611 USA. [Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. [van der Geest, Rob J.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. RP Bluemke, DA (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI van der Geest, Rob/J-8193-2015; OI van der Geest, Rob/0000-0002-9084-5597; Lachin, John/0000-0001-9838-2841; Bluemke, David/0000-0002-8323-8086 FU Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute of Neurological Disorders and Stroke; General Clinical Research Centers Program; National Center for Research Resources; Genentech; National Institute of Diabetes and Digestive and Kidney Diseases; NIH FX The DCCT/EDIC project is supported by contracts with the Division of Diabetes, Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute of Neurological Disorders and Stroke; the General Clinical Research Centers Program; and the Clinical and Translation Science Centers Program, National Center for Research Resources, as well as by Genentech through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. Drs Bluemke and Turkbey are supported by the NIH Intramural research program. NR 42 TC 30 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 18 PY 2011 VL 124 IS 16 BP 1737 EP U112 DI 10.1161/CIRCULATIONAHA.111.022327 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 842BW UT WOS:000296562900018 PM 21947298 ER PT J AU Odajima, J Wills, ZP Ndassa, YM Terunuma, M Kretschmannova, K Deeb, TZ Geng, Y Gawrzak, S Quadros, IM Newman, J Das, M Jecrois, ME Yu, QY Li, N Bienvenu, F Moss, SJ Greenberg, ME Marto, JA Sicinski, P AF Odajima, Junko Wills, Zachary P. Ndassa, Yasmine M. Terunuma, Miho Kretschmannova, Karla Deeb, Tarek Z. Geng, Yan Gawrzak, Sylwia Quadros, Isabel M. Newman, Jennifer Das, Manjusri Jecrois, Marie E. Yu, Qunyan Li, Na Bienvenu, Frederic Moss, Stephen J. Greenberg, Michael E. Marto, Jarrod A. Sicinski, Piotr TI Cyclin E Constrains Cdk5 Activity to Regulate Synaptic Plasticity and Memory Formation SO DEVELOPMENTAL CELL LA English DT Article ID DEPENDENT KINASE-5; NERVOUS-SYSTEM; PROTEIN-KINASE; NMDA RECEPTORS; CELL-CYCLE; G1 CYCLIN; NEURONS; MICE; FAMILY; MOUSE AB Cyclin E is a component of the core cell cycle machinery, and it drives cell proliferation by regulating entry and progression of cells through the DNA synthesis phase. Cyclin E expression is normally restricted to proliferating cells. However, high levels of cyclin E are expressed in the adult brain. The function of cyclin E in quiescent, postmitotic nervous system remains unknown. Here we use a combination of in vivo quantitative proteomics and analyses of cyclin E knockout mice to demonstrate that in terminally differentiated neurons cyclin E forms complexes with Cdk5 and controls synapse function by restraining Cdk5 activity. Ablation of cyclin E led to a decreased number of synapses, reduced number and volume of dendritic spines, and resulted in impaired synaptic plasticity and memory formation in cyclin E-deficient animals. These results reveal a cell cycle-independent role for a core cell cycle protein, cyclin E, in synapse function and memory. C1 [Odajima, Junko; Ndassa, Yasmine M.; Geng, Yan; Gawrzak, Sylwia; Das, Manjusri; Jecrois, Marie E.; Yu, Qunyan; Li, Na; Bienvenu, Frederic; Marto, Jarrod A.; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Odajima, Junko; Geng, Yan; Gawrzak, Sylwia; Jecrois, Marie E.; Li, Na; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Wills, Zachary P.; Greenberg, Michael E.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Ndassa, Yasmine M.; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ndassa, Yasmine M.; Marto, Jarrod A.] Harvard Univ, Sch Med, Biophys Program, Boston, MA 02115 USA. [Terunuma, Miho; Kretschmannova, Karla; Deeb, Tarek Z.; Quadros, Isabel M.; Newman, Jennifer; Moss, Stephen J.] Tufts Univ, Sch Med, Dept Neurosci, Neurosci Res Ctr, Boston, MA 02111 USA. [Moss, Stephen J.] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6BT, England. RP Marto, JA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM jarrod_marto@dfci.harvard.edu; peter_sicinski@dfci.harvard.edu OI Quadros, Isabel/0000-0002-5200-2214 FU NIH [R01 CA108950] FX We thank Drs. R. Bronson, J-S Guan, M. Morabito, G. Corfas, Q. Ma, L-H. Tsai, H. Gardner, M. Ericsson, J. Wang, L. Richey, Y. Haydon, and J.C. Dodart for help and advice, Dr. L. Le Cam for cyclin E1flox construct, Y. Kim and P. Greengard for anti-phospho-S310 and -S441 and anti-total Wave1 antibodies, R. Betarbet for anti-phospho-Ser897 NR1 antibody, T. Ryan and P. De Camilli for Synapsin I cDNA. This work was supported by NIH grant R01 CA108950 (to P.S.). NR 49 TC 51 Z9 53 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD OCT 18 PY 2011 VL 21 IS 4 BP 655 EP 668 DI 10.1016/j.devcel.2011.08.009 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 839LA UT WOS:000296366000010 PM 21944720 ER PT J AU Kerlikowske, K Hubbard, RA Miglioretti, DL Geller, BM Yankaskas, BC Lehman, CD Taplin, SH Sickles, EA AF Kerlikowske, Karla Hubbard, Rebecca A. Miglioretti, Diana L. Geller, Berta M. Yankaskas, Bonnie C. Lehman, Constance D. Taplin, Stephen H. Sickles, Edward A. CA Breast Canc Surveillance Consortiu TI Comparative Effectiveness of Digital Versus Film-Screen Mammography in Community Practice in the United States A Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CANCER SURVEILLANCE CONSORTIUM; CARCINOMA IN-SITU; BREAST-CANCER; THERAPY USE; POPULATION; ACCURACY; DENSITY; PROGRAM; PERFORMANCE; WOMEN AB Background: Few studies have examined the comparative effectiveness of digital versus film-screen mammography in U. S. community practice. Objective: To determine whether the interpretive performance of digital and film-screen mammography differs. Design: Prospective cohort study. Setting: Mammography facilities in the Breast Cancer Surveillance Consortium. Participants: 329 261 women aged 40 to 79 years underwent 869 286 mammograms (231 034 digital; 638 252 film-screen). Measurements: Invasive cancer or ductal carcinoma in situ diagnosed within 12 months of a digital or film-screen examination and calculation of mammography sensitivity, specificity, cancer detection rates, and tumor outcomes. Results: Overall, cancer detection rates and tumor characteristics were similar for digital and film-screen mammography, but the sensitivity and specificity of each modality varied by age, tumor characteristics, breast density, and menopausal status. Compared with film-screen mammography, the sensitivity of digital mammography was significantly higher for women aged 60 to 69 years (89.9% vs. 83.0%; P = 0.014) and those with estrogen receptor-negative cancer (78.5% vs. 65.8%; P = 0.016); borderline significantly higher for women aged 40 to 49 years (82.4% vs. 75.6%; P = 0.071), those with extremely dense breasts (83.6% vs. 68.1%; P = 0.051), and pre- or perimenopausal women (87.1% vs. 81.7%; P = 0.057); and borderline significantly lower for women aged 50 to 59 years (80.5% vs. 85.1%; P = 0.097). The specificity of digital and film-screen mammography was similar by decade of age, except for women aged 40 to 49 years (88.0% vs. 89.7%; P < 0.001). Limitation: Statistical power for subgroup analyses was limited. Conclusion: Overall, cancer detection with digital or film-screen mammography is similar in U. S. women aged 50 to 79 years undergoing screening mammography. Women aged 40 to 49 years are more likely to have extremely dense breasts and estrogen receptor-negative tumors; if they are offered mammography screening, they may choose to undergo digital mammography to optimize cancer detection. C1 [Kerlikowske, Karla] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Washington, Sch Publ Hlth & Community Med, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98195 USA. Univ Washington, Sch Med, Seattle, WA USA. Univ Vermont, Coll Med, Burlington, VT USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Appl Res Program, Rockville, MD USA. RP Kerlikowske, K (reprint author), San Francisco VA Med Ctr, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM Karla.Kerlikowske@ucsf.edu OI Hubbard, Rebecca/0000-0003-0879-0994 FU National Cancer Institute [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, R03CA150007, RC2CA148577] FX By the National Cancer Institute-funded BCSC cooperative agreement (grants U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, and U01CA70040) and National Cancer Institute grants R03CA150007 and RC2CA148577. The collection of cancer data used in this study was supported in part by several state public health departments and cancer registries throughout the United States; for a full description of these sources, see http://breastscreening.cancer.gov/work/acknowledgement.html. NR 30 TC 93 Z9 94 U1 1 U2 14 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 OCT 18 PY 2011 VL 155 IS 8 BP 493 EP U64 DI 10.7326/0003-4819-155-8-201110180-00005 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA 835WB UT WOS:000296066300014 PM 22007043 ER PT J AU Cai, CM He, HSHS Chen, S Coleman, I Wang, HY Fang, Z Chen, SY Nelson, PS Liu, XS Brown, M Balk, SP AF Cai, Changmeng He, Housheng Hansen Chen, Sen Coleman, Ilsa Wang, Hongyun Fang, Zi Chen, Shaoyong Nelson, Peter S. Liu, X. Shirley Brown, Myles Balk, Steven P. TI Androgen Receptor Gene Expression in Prostate Cancer Is Directly Suppressed by the Androgen Receptor Through Recruitment of Lysine-Specific Demethylase 1 SO CANCER CELL LA English DT Article ID MESSENGER-RNA; TRANSCRIPTIONAL REGULATION; LSD1; PHOSPHORYLATION; PROGRESSION; ACTIVATION; MECHANISMS; CASTRATION; THERAPY; PROTEIN AB Androgen receptor (AR) is reactivated in castration-resistant prostate cancer (CRPC) through mechanisms including marked increases in AR gene expression. We identify an enhancer in the AR second intron contributing to increased AR expression at low androgen levels in CRPC. Moreover, at increased androgen levels, the AR binds this site and represses AR gene expression through recruitment of lysine-specific demethylase 1 (LSD1) and H3K4me1,2 demethylation. AR similarly represses expression of multiple genes mediating androgen synthesis, DNA synthesis, and proliferation while stimulating genes mediating lipid and protein biosynthesis. Androgen levels in CRPC appear adequate to stimulate AR activity on enhancer elements, but not suppressor elements, resulting in increased expression of AR and AR repressed genes that contribute to cellular proliferation. C1 [Cai, Changmeng; Chen, Sen; Wang, Hongyun; Fang, Zi; Chen, Shaoyong; Balk, Steven P.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Dept Med, Boston, MA 02215 USA. [Cai, Changmeng; Chen, Sen; Wang, Hongyun; Fang, Zi; Chen, Shaoyong; Balk, Steven P.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [He, Housheng Hansen; Brown, Myles] Dana Farber Canc Inst, Div Mol & Cellular Oncol, Boston, MA 02115 USA. [He, Housheng Hansen; Brown, Myles] Harvard Univ, Sch Med, Boston, MA 02115 USA. [He, Housheng Hansen; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [He, Housheng Hansen; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Coleman, Ilsa; Nelson, Peter S.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Balk, SP (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Dept Med, Boston, MA 02215 USA. EM sbalk@bidmc.harvard.edu RI He, Housheng/G-9614-2011; OI Brown, Myles/0000-0002-8213-1658; Cai, Changmeng/0000-0002-8701-2586 FU National Institutes of Health [R01 CA111803, P50 CA090381, R00 CA135592, P50 CA097186, RO1 CA146849]; Department of Defense [PC060807, PC093509]; Prostate Cancer Foundation FX We thank J. He for analyzing three AR binding sites among species; and E. A. Mostaghel, B. Marck, and A. M. Matsumoto for measuring intratumoral level of steroids. This work was supported by the National Institutes of Health (grant R01 CA111803 to S.P.B., Prostate SPORE P50 CA090381 to S.P.B. and M.B., a Career Development Award from the Prostate SPORE to C.C., grant R00 CA135592 to S.C., and grants Prostate SPORE P50 CA097186 and RO1 CA146849 to P.S.N.), Department of Defense Prostate Cancer Research Program (grant PC060807 to S.P.B., postdoctoral fellowships to C.C. and H.W., and grant PC093509 to P.S.N.), and a Challenge Grant from the Prostate Cancer Foundation. NR 38 TC 134 Z9 136 U1 2 U2 16 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 OCT 18 PY 2011 VL 20 IS 4 BP 457 EP 471 DI 10.1016/j.ccr.2011.09.001 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 836OP UT WOS:000296121300008 PM 22014572 ER PT J AU Ando, T Xuan, WJ Xu, T Dai, TH Sharma, SK Kharkwal, GB Huang, YY Wu, QH Whalen, MJ Sato, S Obara, M Hamblin, MR AF Ando, Takahiro Xuan, Weijun Xu, Tao Dai, Tianhong Sharma, Sulbha K. Kharkwal, Gitika B. Huang, Ying-Ying Wu, Qiuhe Whalen, Michael J. Sato, Shunichi Obara, Minoru Hamblin, Michael R. TI Comparison of Therapeutic Effects between Pulsed and Continuous Wave 810-nm Wavelength Laser Irradiation for Traumatic Brain Injury in Mice SO PLOS ONE LA English DT Article ID CONTROLLED CORTICAL IMPACT; HELIUM-NEON LASER; TERM NEUROLOGICAL DEFICITS; LEVEL LIGHT THERAPY; CLOSED-HEAD INJURY; SPINAL-CORD-INJURY; PROMOTES REGENERATION; FUNCTIONAL RECOVERY; MEMORY PERFORMANCE; ISCHEMIC-STROKE AB Background and Objective: Transcranial low-level laser therapy (LLLT) using near-infrared light can efficiently penetrate through the scalp and skull and could allow non-invasive treatment for traumatic brain injury (TBI). In the present study, we compared the therapeutic effect using 810-nm wavelength laser light in continuous and pulsed wave modes in a mouse model of TBI. Study Design/Materials and Methods: TBI was induced by a controlled cortical-impact device and 4-hours post-TBI 1-group received a sham treatment and 3-groups received a single exposure to transcranial LLLT, either continuous wave or pulsed at 10-Hz or 100-Hz with a 50% duty cycle. An 810-nm Ga-Al-As diode laser delivered a spot with diameter of 1-cm onto the injured head with a power density of 50-mW/cm(2) for 12-minutes giving a fluence of 36-J/cm(2). Neurological severity score (NSS) and body weight were measured up to 4 weeks. Mice were sacrificed at 2, 15 and 28 days post-TBI and the lesion size was histologically analyzed. The quantity of ATP production in the brain tissue was determined immediately after laser irradiation. We examined the role of LLLT on the psychological state of the mice at 1 day and 4 weeks after TBI using tail suspension test and forced swim test. Results: The 810-nm laser pulsed at 10-Hz was the most effective judged by improvement in NSS and body weight although the other laser regimens were also effective. The brain lesion volume of mice treated with 10-Hz pulsed-laser irradiation was significantly lower than control group at 15-days and 4-weeks post-TBI. Moreover, we found an antidepressant effect of LLLT at 4-weeks as shown by forced swim and tail suspension tests. Conclusion: The therapeutic effect of LLLT for TBI with an 810-nm laser was more effective at 10-Hz pulse frequency than at CW and 100-Hz. This finding may provide a new insight into biological mechanisms of LLLT. C1 [Ando, Takahiro; Xuan, Weijun; Xu, Tao; Dai, Tianhong; Sharma, Sulbha K.; Kharkwal, Gitika B.; Huang, Ying-Ying; Wu, Qiuhe; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Ando, Takahiro; Obara, Minoru] Keio Univ, Dept Elect & Elect Engn, Yokohama, Kanagawa 223, Japan. [Xuan, Weijun; Xu, Tao; Dai, Tianhong; Kharkwal, Gitika B.; Huang, Ying-Ying; Wu, Qiuhe; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Xuan, Weijun] Tradit Chinese Med Univ Guangxi, Dept Otolaryngol, Nanning, Peoples R China. [Xu, Tao] Shanghai Jiao Tong Univ, Lab Anesthesiol, Shanghai 200030, Peoples R China. [Huang, Ying-Ying] Guangxi Med Univ, Aesthet & Plast Ctr, Nanning, Peoples R China. [Wu, Qiuhe] Shandong Univ, Jinan Cent Hosp, Dept Burns & Plast Surg, Jinan 250100, Peoples R China. [Whalen, Michael J.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Sato, Shunichi] Natl Def Med Coll, Res Inst, Div Biomed Informat Sci, Tokorozawa, Saitama 359, Japan. [Hamblin, Michael R.] Harvard Univ, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02138 USA. RP Ando, T (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI Huang, Ying-ying/G-3153-2011; OI Huang, Ying-ying/0000-0003-3066-6981; Hamblin, Michael/0000-0001-6431-4605 FU National Institutes of Health (NIH) [R01AI050875]; Center for Integration of Medicine and Innovative Technology [DAMD17-02-2-0006]; Congressionally Directed Medical Research Program in Traumatic Brain Injury [W81XWH-09-1-0514]; Air Force Office of Scientific Research [FA9950-04-1-0079]; Ministry of Education, Culture, Sport, Science and Technology, Japan; Japan Society for the Promotion of Science (JSPS) FX This research was supported by National Institutes of Health (NIH) grant R01AI050875 (to Dr. Hamblin), Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006), Congressionally Directed Medical Research Program in Traumatic Brain Injury (W81XWH-09-1-0514) and Air Force Office of Scientific Research Military Photomedicine Program (FA9950-04-1-0079). Dr. Ando was supported in part by a Grant-in-Aid for the Global Center of Excellence for High-Level Global Cooperation for Leading-Edge Platform on Access Spaces from the Ministry of Education, Culture, Sport, Science and Technology, Japan, and a Grant-in-Aid for Research Fellows of the Japan Society for the Promotion of Science (JSPS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 43 Z9 43 U1 4 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 OCT 18 PY 2011 VL 6 IS 10 AR e26212 DI 10.1371/journal.pone.0026212 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837ID UT WOS:000296186900034 PM 22028832 ER PT J AU Becerra, L Pendse, G Chang, PC Bishop, J Borsook, D AF Becerra, Lino Pendse, Gautam Chang, Pei-Ching Bishop, James Borsook, David TI Robust Reproducible Resting State Networks in the Awake Rodent Brain SO PLOS ONE LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; BOLD SIGNAL FLUCTUATIONS; ANESTHETIZED RAT-BRAIN; FUNCTIONAL CONNECTIVITY; SPATIOTEMPORAL DYNAMICS; INSULAR CORTEX; BASAL GANGLIA; DEFAULT MODE; FREQUENCY; ORGANIZATION AB Resting state networks (RSNs) have been studied extensively with functional MRI in humans in health and disease to reflect brain function in the un-stimulated state as well as reveal how the brain is altered with disease. Rodent models of disease have been used comprehensively to understand the biology of the disease as well as in the development of new therapies. RSN reported studies in rodents, however, are few, and most studies are performed with anesthetized rodents that might alter networks and differ from their non-anesthetized state. Acquiring RSN data in the awake rodent avoids the issues of anesthesia effects on brain function. Using high field fMRI we determined RSNs in awake rats using an independent component analysis (ICA) approach, however, ICA analysis can produce a large number of components, some with biological relevance (networks). We further have applied a novel method to determine networks that are robust and reproducible among all the components found with ICA. This analysis indicates that 7 networks are robust and reproducible in the rat and their putative role is discussed. C1 [Becerra, Lino; Pendse, Gautam; Chang, Pei-Ching; Bishop, James; Borsook, David] Massachusetts Gen Hosp, Pain & Analgesia Imaging Neurosci Grp, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Becerra, L (reprint author), Massachusetts Gen Hosp, Pain & Analgesia Imaging Neurosci Grp, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM becerra@nmr.mgh.harvard.edu FU National Institute of Drug Abuse [K24NS064050-DB]; Herlands Fund for Pain Research; National Center For Research Resources [S10RR031599, 1S10RR023401, 1S10RR019307, 1S10RR023043] FX The work was supported by National Institute of Drug Abuse (grant number K24NS064050-DB) and The Herlands Fund for Pain Research (DB, LB). The project described was supported by Award Numbers S10RR031599, 1S10RR023401, 1S10RR019307, and 1S10RR023043 from the National Center For Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 40 Z9 41 U1 0 U2 13 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 OCT 18 PY 2011 VL 6 IS 10 AR e25701 DI 10.1371/journal.pone.0025701 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837ID UT WOS:000296186900016 PM 22028788 ER PT J AU Tan, KY Eminli, S Hettmer, S Hochedlinger, K Wagers, AJ AF Tan, Kah Yong Eminli, Sarah Hettmer, Simone Hochedlinger, Konrad Wagers, Amy J. TI Efficient Generation of iPS Cells from Skeletal Muscle Stem Cells SO PLOS ONE LA English DT Article ID BETA-CELLS; DIFFERENTIATION; PROGENITORS; SYSTEM; MOUSE; FAT AB Reprogramming of somatic cells into inducible pluripotent stem cells generally occurs at low efficiency, although what limits reprogramming of particular cell types is poorly understood. Recent data suggest that the differentiation status of the cell targeted for reprogramming may influence its susceptibility to reprogramming as well as the differentiation potential of the induced pluripotent stem (iPS) cells that are derived from it. To assess directly the influence of lineage commitment on iPS cell derivation and differentiation, we evaluated reprogramming in adult stem cell and mature cell populations residing in skeletal muscle. Our data using clonal assays and a second-generation inducible reprogramming system indicate that stem cells found in mouse muscle, including resident satellite cells and mesenchymal progenitors, reprogram with significantly greater efficiency than their more differentiated daughters (myoblasts and fibroblasts). However, in contrast to previous reports, we find no evidence of biased differentiation potential among iPS cells derived from myogenically committed cells. These data support the notion that adult stem cells reprogram more efficiently than terminally differentiated cells, and argue against the suggestion that "epigenetic memory" significantly influences the differentiation potential of iPS cells derived from distinct somatic cell lineages in skeletal muscle. C1 [Tan, Kah Yong; Hettmer, Simone; Wagers, Amy J.] Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. [Tan, Kah Yong; Eminli, Sarah; Hettmer, Simone; Hochedlinger, Konrad; Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Tan, Kah Yong; Eminli, Sarah; Hettmer, Simone; Hochedlinger, Konrad; Wagers, Amy J.] Harvard Stem Cell Inst, Cambridge, MA USA. [Tan, Kah Yong] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Eminli, Sarah; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Eminli, Sarah; Hochedlinger, Konrad] Ctr Regenerat Med, Boston, MA USA. [Eminli, Sarah] Free Univ Berlin, Dept Biol Chem & Pharm, D-1000 Berlin, Germany. [Hettmer, Simone] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hettmer, Simone] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Hochedlinger, Konrad; Wagers, Amy J.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Tan, KY (reprint author), Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. EM amy.wagers@joslin.harvard.edu OI Tan, Kah Yong/0000-0002-6825-2752 FU Beckman Foundation; Joslin Diabetes Center; NIH [1DP2OD003266-01]; Harvard Stem Cell Institute [DP-0003-07-03, CF-0003-08-00]; Hope Street Kids; Alex's Lemonade Stand Foundation; Bear Necessities; NIDDK [P30DK036836] FX The authors gratefully acknowledge support for this project from the Beckman Foundation (http://www.beckman-foundation.com), and Joslin Diabetes Center (www.joslinresearch.org) (to AW, no Award Number), NIH Innovator Award (to KH, Award Number 1DP2OD003266-01), the Harvard Stem Cell Institute (www.hsci.harvard.edu, to AW and KH, Award number DP-0003-07-03), and by Hope Street Kids (www.hopestreetkids.org), P. A. L. S. Bermuda/St. Baldrick's (www.stbaldricks.org), Alex's Lemonade Stand Foundation (www.alexlemonade.org) and Bear Necessities (www.bearnecessities.org) (to SH). Flow cytometry facilities were supported in by grants from the Harvard Stem Cell Institute (Award Number CF-0003-08-00) and NIDDK (Award Number P30DK036836). KY is a fellow of the Agency of Science, Technology and Research, Singapore (www.a-star.edu.sg). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies that supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 30 Z9 32 U1 0 U2 7 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 OCT 18 PY 2011 VL 6 IS 10 AR e26406 DI 10.1371/journal.pone.0026406 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 837ID UT WOS:000296186900059 PM 22028872 ER PT J AU Motivala, AA Cannon, CP Srinivas, VS Dai, D Hernandez, AF Peterson, ED Bhatt, DL Fonarow, GC AF Motivala, Apurva A. Cannon, Christopher P. Srinivas, Vankeepuram S. Dai, David Hernandez, Adrian F. Peterson, Eric D. Bhatt, Deepak L. Fonarow, Gregg C. TI Changes in Myocardial Infarction Guideline Adherence as a Function of Patient Risk An End to Paradoxical Care? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE guideline adherence; interventional; management; myocardial infarction; paradox; risk; trends ID ACUTE CORONARY SYNDROMES; AMERICAN-COLLEGE; PROGRAM; DISEASE; PREVENTION; MORTALITY; TIME AB Objectives The goals of this analysis were to determine: 1) whether guideline-based care during hospitalization for a myocardial infarction (MI) varied as a function of patients' baseline risk; and 2) whether temporal improvements in guideline adherence occurred in all risk groups. Background Guideline-based care of patients with MI improves outcomes, especially among those at higher risk. Previous studies suggest that this group is paradoxically less likely to receive guideline-based care (risk-treatment mismatch). Methods A total of 112,848 patients with MI were enrolled at 279 hospitals participating in Get With The Guidelines-Coronary Artery Disease (GWTG-CAD) between August 2000 and December 2008. We developed and validated an in-hospital mortality model (C-statistic: 0.75) to stratify patients into risk tertiles: low (0% to 3%), intermediate (3% to 6.5%), and high (>6.5%). Use of guideline-based care and temporal trends were examined. Results High-risk patients were significantly less likely to receive aspirin, beta-blockers, angiotensin-converting inhibitors/angiotensin receptor blockers, statins, diabetic treatment, smoking cessation advice, or cardiac rehabilitation referral at discharge compared with those at lower risk (all p < 0.0001). However, use of guideline-recommended therapies increased significantly in all risk groups per year (low-risk odds ratio: 1.33 [95% confidence interval (CI): 1.22 to 1.45]; intermediate-risk odds ratio: 1.30 [95% CI: 1.21 to 1.38]; and high-risk odds ratio: 1.30 [95% confidence interval: 1.23 to 1.37]). Also, there was a narrowing in the guideline adherence gap between low- and high-risk patients over time (p = 0.0002). Conclusions Although adherence to guideline-based care remains paradoxically lower in those MI patients at higher risk of mortality and most likely to benefit from treatment, care is improving for eligible patients within all risk categories, and the gaps between low- and high-risk groups seem to be narrowing. (J Am Coll Cardiol 2011;58:1760-5) (C) 2011 by the American College of Cardiology Foundation C1 [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA 90095 USA. [Motivala, Apurva A.; Srinivas, Vankeepuram S.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Cannon, Christopher P.; Bhatt, Deepak L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Dai, David; Hernandez, Adrian F.; Peterson, Eric D.] Duke Univ, Med Ctr, Durham, NC USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. RP Fonarow, GC (reprint author), Univ Calif Los Angeles, Div Cardiol, Room 247,200 Med Plaza, 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; Pfizer Inc.; Merck/Schering-Plough; Accumetrics; AstraZeneca; GlaxoSmithKline; Intekrin Therapeutics; Merck; Takeda; Bristol-Myers Squibb/Sanofi Pharmaceuticals; Novartis; Proventys; Amylin; Johnson Johnson; Bristol-Myers Squibb/Sanofi; Lilly; Bristol-Myers Squibb; Eisai; Sanofi-Aventis; The Medicines Company; Pfizer FX The Get With The Guidelines Program is funded by the American Heart Association. The program is also supported in part by unrestricted educational grants to the American Heart Association by Pfizer Inc. and the Merck/Schering-Plough Partnership, who did not participate in the design, analysis, manuscript preparation, or approval. Dr. Cannon has received research grants/support from Accumetrics, AstraZeneca, GlaxoSmithKline, Intekrin Therapeutics, Merck, and Takeda; has served on the advisory board (with funds donated to charity) of the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership and Novartis; and has acted as a clinical advisor-equity in Automedics Medical Systems. Dr. Hernandez has received research grants/support from Proventys, Amylin, Merck, Johnson & Johnson, and AstraZeneca. Dr. Peterson has received research grants/support from Bristol-Myers Squibb/Sanofi, Lilly, Johnson & Johnson, and Merck/Schering-Plough. Dr. Bhatt has received research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi-Aventis, and The Medicines Company. Dr. Fonarow has received research grants/support from Bristol-Myers Squibb/Sanofi, Merck/Schering-Plough, Pfizer, and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 14 TC 23 Z9 23 U1 0 U2 1 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 OCT 18 PY 2011 VL 58 IS 17 BP 1760 EP 1765 DI 10.1016/j.jacc.2011.06.050 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 833KL UT WOS:000295883900006 PM 21996387 ER PT J AU Noseworthy, PA Tikkanen, JT Porthan, K Salomaa, V Newton-Cheh, C Huikuri, HV AF Noseworthy, Peter A. Tikkanen, Jani T. Porthan, Kimmo Salomaa, Veikko Newton-Cheh, Christopher Huikuri, Heikki V. TI The Early Repolarization Pattern: What's in the Name? Reply SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Boston, MA 02114 USA. EM cnewtoncheh@chgr.mgh.harvard.edu NR 3 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 18 PY 2011 VL 58 IS 17 BP 1830 EP 1831 DI 10.1016/j.jacc.2011.07.027 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 833KL UT WOS:000295883900021 ER PT J AU Limmer, S Haller, S Drenkard, E Lee, J Yu, S Kocks, C Ausubel, FM Ferrandon, D AF Limmer, Stefanie Haller, Samantha Drenkard, Eliana Lee, Janice Yu, Shen Kocks, Christine Ausubel, Frederick M. Ferrandon, Dominique TI Pseudomonas aeruginosa RhlR is required to neutralize the cellular immune response in a Drosophila melanogaster oral infection model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE innate immunity; host-pathogen interactions; systemic immunity; intestinal immunity; phagocytosis ID III SECRETION SYSTEM; BACTERIAL-INFECTION; VIRULENCE FACTORS; GENE-EXPRESSION; HOST; REVEALS; PATHOGENESIS; RESISTANCE; MUTANTS; ANIMALS AB An in-depth mechanistic understanding of microbial infection necessitates a molecular dissection of host-pathogen relationships. Both Drosophila melanogaster and Pseudomonas aeruginosa have been intensively studied. Here, we analyze the infection of D. melanogaster by P. aeruginosa by using mutants in both host and pathogen. We show that orally ingested P. aeruginosa crosses the intestinal barrier and then proliferates in the hemolymph, thereby causing the infected flies to die of bacteremia. Host defenses against ingested P. aeruginosa included an immune deficiency (IMD) response in the intestinal epithelium, systemic Toll and IMD pathway responses, and a cellular immune response controlling bacteria in the hemocoel. Although the observed cellular and intestinal immune responses appeared to act throughout the course of the infection, there was a late onset of the systemic IMD and Toll responses. In this oral infection model, P. aeruginosa PA14 did not require its type III secretion system or other well-studied virulence factors such as the two-component response regulator GacA or the protease AprA for virulence. In contrast, the quorum-sensing transcription factor RhlR, but surprisingly not LasR, played a key role in counteracting the cellular immune response against PA14, possibly at an early stage when only a few bacteria are present in the hemocoel. These results illustrate the power of studying infection from the dual perspective of host and pathogen by revealing that RhlR plays a more complex role during pathogenesis than previously appreciated. C1 [Drenkard, Eliana; Lee, Janice; Yu, Shen; Kocks, Christine; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Limmer, Stefanie; Haller, Samantha; Ferrandon, Dominique] Univ Strasbourg, Inst Biol Mol & Cellulaire, CNRS, Equipe Fdn Rech Med,Unite Propre Rech 9022, F-67084 Strasbourg, France. [Lee, Janice; Kocks, Christine] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Drenkard, Eliana; Yu, Shen; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM ausubel@molbio.mgh.harvard.edu; d.ferrandon@ibmc.u-strasbg.fr OI FERRANDON, Dominique/0000-0001-7680-7773; Schirmeier, Stefanie/0000-0001-8431-9593 FU Centre National de la Recherche Scientifique; National Institutes of Health [P01 AI044220, R01 AI085581]; Fondation Recherche Medicale (Equipe Fondation pour la Recherche Medicale); French Ministry of Research FX We thank M. C. Lafarge and J. Bourdeaux for expert technical help. We are grateful to Dr. C. Makino and Dr. H. Fukuyama for a reporter fly line; to Dr. R. Feinbaum, Dr. D. K. Newman, Dr. R. Kolter, and Dr. E. Deziel for bacterial strains; and to Dr. S. Lory for plasmids. This work was funded by Centre National de la Recherche Scientifique; National Institutes of Health Grant P01 AI044220 (to F.M.A., C.K., and D.F.) and Grant R01 AI085581 (to F.M.A.); Fondation Recherche Medicale (Equipe Fondation pour la Recherche Medicale) (D.F.); and the French Ministry of Research (S.L. and S.H.). NR 40 TC 41 Z9 42 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 OCT 18 PY 2011 VL 108 IS 42 BP 17378 EP 17383 DI 10.1073/pnas.1114907108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PP UT WOS:000295975300035 PM 21987808 ER PT J AU Agam, Y Hamalainen, MS Lee, AKC Dyckman, KA Friedman, JS Isom, M Makris, N Manoach, DS AF Agam, Yigal Haemaelaeinen, Matti S. Lee, Adrian K. C. Dyckman, Kara A. Friedman, Jesse S. Isom, Marlisa Makris, Nikos Manoach, Dara S. TI Multimodal neuroimaging dissociates hemodynamic and electrophysiological correlates of error processing SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE multimodal imaging; error processing; response monitoring; action monitoring; medial frontal cortex ID ANTERIOR CINGULATE CORTEX; MEDIAL FRONTAL-CORTEX; HUMAN CEREBRAL-CORTEX; EVENT-RELATED FMRI; RESPONSE-INHIBITION; EXECUTIVE FUNCTIONS; ANTISACCADE TASK; BRAIN; PERFORMANCE; REWARD AB Recognizing errors and adjusting responses are fundamental to adaptive behavior. The error-related negativity (ERN) and error-related functional MRI (fMRI) activation of the dorsal anterior cingulate cortex (dACC) index these processes and are thought to reflect the same neural mechanism. In the present study, we evaluated this hypothesis. Although errors elicited robust dACC activation using fMRI, combined electroencephalography and magnetoencephalography data localized the ERN to the posterior cingulate cortex (PCC). ERN amplitude correlated with fMRI activation in both the PCC and dACC, and these two regions showed coordinated activity based on functional connectivity MRI. Finally, increased microstructural integrity of the posterior cingulum bundle, as measured by diffusion tensor imaging, predicted faster error correction. These findings suggest that the PCC generates the ERN and communicates with the dACC to subserve error processing. They challenge current models that view fMRI activation of the dACC as the hemodynamic reflection of the ERN. C1 [Agam, Yigal; Dyckman, Kara A.; Friedman, Jesse S.; Isom, Marlisa; Makris, Nikos; Manoach, Dara S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02215 USA. [Haemaelaeinen, Matti S.; Lee, Adrian K. C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02215 USA. [Makris, Nikos] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02215 USA. [Agam, Yigal; Haemaelaeinen, Matti S.; Lee, Adrian K. C.; Dyckman, Kara A.; Friedman, Jesse S.; Isom, Marlisa; Makris, Nikos; Manoach, Dara S.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Manoach, DS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02215 USA. EM dara@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; OI Lee, Adrian KC/0000-0002-7611-0500 FU National Institute for Mental Health [F32 MH088081, F32 MH082514, 1R21MH084041-01A1, R01 MH67720]; National Institute on Drug Abuse [1R01DA027804-01]; Massachusetts General Hospital; National Center for Research Resources [P41 RR014075-11]; National Institute of Biomedical Imaging and Bioengineering [5R01EB009048]; American Recovery and Reinvestment Act (ARRA) - National Center for Complementary and Alternative Medicine (NCCAM) FX We thank Randy Buckner, Hesheng Liu, and Mark Vangel for consultation. Support for this study was provided by National Institute for Mental Health Grants F32 MH088081 (to Y.A.), F32 MH082514 (to K.A.D.), 1R21MH084041-01A1 (to N.M.) and R01 MH67720 (to D.S.M.); National Institute on Drug Abuse Grant 1R01DA027804-01 (to N.M.); the Massachusetts General Hospital Fund for Medical Discovery (to Y.A.); National Center for Research Resources Grant P41 RR014075-11 (to M.S.H.); National Institute of Biomedical Imaging and Bioengineering Grant 5R01EB009048 (to M.S.H.); and the American Recovery and Reinvestment Act (ARRA) - National Center for Complementary and Alternative Medicine (NCCAM) (to N.M.). NR 54 TC 47 Z9 48 U1 2 U2 7 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 OCT 18 PY 2011 VL 108 IS 42 BP 17556 EP 17561 DI 10.1073/pnas.1103475108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PP UT WOS:000295975300065 PM 21969565 ER PT J AU Falskov, B Hermann, TS Raunso, J Christiansen, B Rask-Madsen, C Major-Pedersen, A Kober, L Torp-Pedersen, C Dominguez, H AF Falskov, Britt Hermann, Thomas Steffen Raunso, Jakob Christiansen, Buris Rask-Madsen, Christian Major-Pedersen, Atheline Kober, Lars Torp-Pedersen, Christian Dominguez, Helena TI Endothelial function is unaffected by changing between carvedilol and metoprolol in patients with heart failure-a randomized study SO CARDIOVASCULAR DIABETOLOGY LA English DT Article DE Heart failure; Endothelial function; Beta blocker ID CORONARY-ARTERY-DISEASE; EUROPEAN TRIAL COMET; INSULIN-RESISTANCE; DILATED CARDIOMYOPATHY; VASODILATION; DYSFUNCTION AB Background: Carvedilol has been shown to be superior to metoprolol tartrate to improve clinical outcomes in patients with heart failure (HF), yet the mechanisms responsible for these differences remain unclear. We examined if there were differences in endothelial function, insulin stimulated endothelial function, 24 hour ambulatory blood pressure and heart rate during treatment with carvedilol, metoprolol tartrate and metoprolol succinate in patients with HF. Methods: Twenty-seven patients with mild HF, all initially treated with carvedilol, were randomized to a two-month treatment with carvedilol, metoprolol tartrate or metoprolol succinate. Venous occlusion plethysmography, 24-hour blood pressure and heart rate measurements were done before and after a two-month treatment period. Results: Endothelium-dependent vasodilatation was not affected by changing from carvedilol to either metoprolol tartrate or metoprolol succinate. The relative forearm blood flow at the highest dose of serotonin was 2.42 +/- 0.33 in the carvedilol group at baseline and 2.14 +/- 0.24 after two months continuation of carvedilol (P = 0.34); 2.57 +/- 0.33 before metoprolol tartrate treatment and 2.42 +/- 0.55 after treatment (p = 0.74) and in the metoprolol succinate group 1.82 +/- 0.29 and 2.10 +/- 0.37 before and after treatment, respectively (p = 0.27). Diurnal blood pressures as well as heart rate were also unchanged by changing from carvedilol to metoprolol tartrate or metoprolol succinate. Conclusion: Endothelial function remained unchanged when switching the beta blocker treatment from carvedilol to either metoprolol tartrate or metoprolol succinate in this study, where blood pressure and heart rate also remained unchanged in patients with mild HF. C1 [Falskov, Britt; Hermann, Thomas Steffen; Raunso, Jakob; Christiansen, Buris; Major-Pedersen, Atheline; Torp-Pedersen, Christian] Gentofte Univ Hosp, Dept Cardiol, Hellerup, Denmark. [Dominguez, Helena] Herlev Hosp, Dept Cardiol, DK-2730 Herlev, Denmark. [Rask-Madsen, Christian] Joslin Diabet Ctr, Boston, MA 02215 USA. [Kober, Lars] Rigshosp, Dept Cardiol, Ctr Heart, DK-2100 Copenhagen, Denmark. RP Falskov, B (reprint author), Gentofte Univ Hosp, Dept Cardiol, Hellerup, Denmark. EM bk@heart.dk OI DOMINGUEZ, HELENA/0000-0002-7089-2636 FU Danish Heart Foundation; Bispebjerg Hospital Research Foundation FX Grant has been provided for Britt Falskov from The Danish Heart Foundation and Bispebjerg Hospital Research Foundation. NR 19 TC 5 Z9 5 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2840 J9 CARDIOVASC DIABETOL JI Cardiovasc. Diabetol. PD OCT 15 PY 2011 VL 10 AR 91 DI 10.1186/1475-2840-10-91 PG 10 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism SC Cardiovascular System & Cardiology; Endocrinology & Metabolism GA 845OT UT WOS:000296833100001 PM 21999413 ER PT J AU Chen, BB Glasser, JR Coon, TA Mallampalli, RK AF Chen, Bill B. Glasser, Jennifer R. Coon, Tiffany A. Mallampalli, Rama K. TI FBXL2 is a ubiquitin E3 ligase subunit that triggers mitotic arrest SO CELL CYCLE LA English DT Article DE F-box protein; centrosome; mitosis; cyclin D3; Aurora A ID CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE; PROTEIN-KINASE; F-BOX; CHROMOSOMAL STABILITY; REGULATORY ENZYME; CYCLIN D3; DEGRADATION; EXPRESSION; IDENTIFICATION; CYTOKINESIS AB Mitotic progression is regulated by ubiquitin E3 ligase complexes to carefully orchestrate eukaryotic cell division. Here, we show that a relatively new E3 ligase component belonging to the SCF (Skip-Cullin1-F-box protein) E3 ligase family, SCF(FBXL2), impairs cell proliferation by mediating cyclin D3 polyubiquitination and degradation. Both cyclin D3 and FBXL2 colocalize within the centrosome. FBXL2 overexpression led to G(2)/M-phase arrest in transformed epithelia, resulting in the appearance of supernumerary centrosomes, tetraploidy and nuclei where condensed chromosomes are arranged on circular monopolar spindles typical of mitotic arrest. RNAi-mediated knockdown of cyclin D3 recapitulated effects of SCF(FBXL2) expression. SCF(FBXL2) impaired the ability of cyclin D3 to associate with centrosomal assembly proteins [ Aurora A, polo-like kinase 4 (Plk4), CDK11]. Thus, these results suggest a role for SCF(FBXL2) in regulating the fidelity of cellular division. C1 [Chen, Bill B.; Glasser, Jennifer R.; Coon, Tiffany A.; Mallampalli, Rama K.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. [Chen, Bill B.; Glasser, Jennifer R.; Coon, Tiffany A.; Mallampalli, Rama K.] Univ Pittsburgh, Acute Lung Injury Ctr Excellence, Pittsburgh, PA USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. RP Chen, BB (reprint author), Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. EM chenb@upmc.edu FU US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; US Department of Veterans Affairs; National Institutes of Health [HL096376, HL097376, HL098174] FX We thank A. F. Stewart for critical review of the manuscript and helpful suggestions. This material is based upon work supported, in part, by the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. This work was supported by a Merit Review Award from the US Department of Veterans Affairs and National Institutes of Health R01 grants HL096376, HL097376 and HL098174 (to R. K. M.). The contents presented do not represent the views of the Department of Veterans Affairs or the United States Government. NR 36 TC 19 Z9 19 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2011 VL 10 IS 20 BP 3487 EP 3494 DI 10.4161/cc.10.20.17742 PG 8 WC Cell Biology SC Cell Biology GA 842DR UT WOS:000296570700026 PM 22024926 ER PT J AU Rosenthal, DT Iyer, H Escudero, S Bao, LW Wu, ZF Ventura, AC Kleer, CG Arruda, EM Garikipati, K Merajver, SD AF Rosenthal, Devin T. Iyer, Harish Escudero, Silvia Bao, Liwei Wu, Zhifen Ventura, Alejandra C. Kleer, Celina G. Arruda, Ellen M. Garikipati, Krishna Merajver, Sofia D. TI p38 gamma Promotes Breast Cancer Cell Motility and Metastasis through Regulation of RhoC GTPase, Cytoskeletal Architecture, and a Novel Leading Edge Behavior SO CANCER RESEARCH LA English DT Article ID ACTIVATED PROTEIN-KINASE; P38 MAPK; RAS TRANSFORMATION; ESTROGEN-RECEPTOR; SKELETAL-MUSCLE; IN-SITU; INVASION; PATHWAY; EXPRESSION; DEGRADATION AB Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38 gamma motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38 gamma-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38 gamma-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38 gamma is associated with lower overall survival of patients with breast cancer. Taken together, our results offer a detailed characterization of how p38 gamma contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38 gamma as a candidate therapeutic target. Cancer Res; 71(20); 6338-49. (C) 2011 AACR. C1 [Kleer, Celina G.; Merajver, Sofia D.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Rosenthal, Devin T.; Bao, Liwei; Wu, Zhifen; Merajver, Sofia D.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Iyer, Harish; Arruda, Ellen M.; Garikipati, Krishna] Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA. [Kleer, Celina G.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Rosenthal, Devin T.; Kleer, Celina G.; Merajver, Sofia D.] Univ Michigan, Cellular & Mol Biol Program, Ann Arbor, MI 48109 USA. [Escudero, Silvia] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Escudero, Silvia] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Ventura, Alejandra C.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Lab Fisiol & Biol Mol, Dept Fisiol Biol Mol & Celular,IFIBYNE CONICET, Buenos Aires, DF, Argentina. RP Merajver, SD (reprint author), Univ Michigan, Ctr Comprehens Canc, 1500 E Med Ctr Dr,Room 7217, Ann Arbor, MI 48109 USA. EM smerajve@umich.edu FU Department of Defense [BC083262]; NIH [T32-GM07315]; Burroughs Wellcome Fund; Breast Cancer Research Foundation; Department of Energy FX This work was supported by the Department of Defense Breast Cancer Research Program through a Predoctoral Traineeship award (BC083262; to D. T. Rosenthal) and a Multidisciplinary Postdoctoral award (A. C. Ventura), an NIH Cellular and Molecular Biology Training grant (T32-GM07315; D. T. Rosenthal), the Burroughs Wellcome Fund (S. D. Merajver), the Breast Cancer Research Foundation (S. D. Merajver), and a Department of Energy PECASE award (K. Garikipati). A. C. Ventura is a member of the Carrera del Investigador Cientifico (CONICET). NR 48 TC 28 Z9 30 U1 0 U2 8 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 OCT 15 PY 2011 VL 71 IS 20 BP 6338 EP 6349 DI 10.1158/0008-5472.CAN-11-1291 PG 12 WC Oncology SC Oncology GA 836WT UT WOS:000296148900006 PM 21862636 ER PT J AU Fulciniti, M Amin, S Nanjappa, P Rodig, S Prabhala, R Li, C Minvielle, S Tai, YT Tassone, P Avet-Loiseau, H Hideshima, T Anderson, KC Munshi, NC AF Fulciniti, Mariateresa Amin, Samir Nanjappa, Puru Rodig, Scott Prabhala, Rao Li, Cheng Minvielle, Stephane Tai, Yu-tzu Tassone, Pierfrancesco Avet-Loiseau, Herve Hideshima, Teru Anderson, Kenneth C. Munshi, Nikhil C. TI Significant Biological Role of Sp1 Transactivation in Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PANCREATIC-CANCER CELLS; METHYLATED NORDIHYDROGUAIARETIC ACIDS; TRANSCRIPTION FACTOR SP1; HUMAN GASTRIC-CANCER; GENE-TRANSCRIPTION; SURVIVIN GENE; ANTIVIRAL ACTIVITIES; ANTICANCER ACTIVITY; TOLFENAMIC ACID AB Purpose: The transcription factor specificity protein 1 (Sp1) controls number of cellular processes by regulating the expression of critical cell cycle, differentiation, and apoptosis-related genes containing proximal GC/GT-rich promoter elements. We here provide experimental and clinical evidence that Sp1 plays an important regulatory role in multiple myeloma (MM) cell growth and survival. Experimental Design: We have investigated the functional Sp1 activity in MM cells using a plasmid with Firefly luciferase reporter gene driven by Sp1-responsive promoter. We have also used both siRNA- and short hairpin RNA-mediated Sp1 knockdown to investigate the growth and survival effects of Sp1 on MM cells and further investigated the anti-MM activity of terameprocol (TMP), a small molecule that specifically competes with Sp1-DNA binding in vitro and in vivo. Results: We have confirmed high Sp1 activity in MM cells that is further induced by adhesion to bone marrow stromal cells (BMSC). Sp1 knockdown decreases MM cell proliferation and induces apoptosis. Sp1-DNA binding inhibition by TMP inhibits MM cell growth both in vitro and in vivo, inducing caspase-9-dependent apoptosis and overcoming the protective effects of BMSCs. Conclusions: Our results show Sp1 as an important transcription factor in myeloma that can be therapeutically targeted for clinical application by TMP. Clin Cancer Res; 17(20); 6500-9. (C) 2011 AACR. C1 [Fulciniti, Mariateresa; Amin, Samir; Nanjappa, Puru; Rodig, Scott; Li, Cheng; Tai, Yu-tzu; Hideshima, Teru; Anderson, Kenneth C.; Munshi, Nikhil C.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Fulciniti, Mariateresa; Prabhala, Rao; Munshi, Nikhil C.] Harvard Univ, VA Boston Healthcare Syst, Sch Med, Boston, MA 02115 USA. [Minvielle, Stephane; Avet-Loiseau, Herve] Ctr Hosp Univ Nantes, IRCNA, Hematol Lab, Nantes, France. [Tassone, Pierfrancesco] Magna Graecia Univ Catanzaro, Catanzaro, Italy. RP Munshi, NC (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Jerome Lipper Multiple Myeloma Ctr, 450 Brookline Ave, Boston, MA 02115 USA. EM Nikhil_Munshi@dfci.harvard.edu RI Minvielle, Stephane/K-8251-2015; OI Amin, Samir/0000-0002-3207-9505 FU DF/HCC myeloma SPORE Career Development Award; Manton Foundation; Dept. of Veterans Affairs; NIH [RO1-124929, PO1-155258, P50-100007, PO1-78378] FX This work was supported in part by DF/HCC myeloma SPORE Career Development Award to M. Fulciniti, Manton Foundation to N.C. Munshi, grants from the Dept. of Veterans Affairs Merit Review Awards, and grants from the NIH (RO1-124929 and PO1-155258 to N.C. Munshi and P50-100007 and PO1-78378 to N.C. Munshi and K.C. Anderson). NR 50 TC 23 Z9 23 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 OCT 15 PY 2011 VL 17 IS 20 BP 6500 EP 6509 DI 10.1158/1078-0432.CCR-11-1036 PG 10 WC Oncology SC Oncology GA 839IR UT WOS:000296359400016 PM 21856768 ER PT J AU Grau, DJ Chapman, BA Garlick, JD Borowsky, M Francis, NJ Kingston, RE AF Grau, Daniel J. Chapman, Brad A. Garlick, Joe D. Borowsky, Mark Francis, Nicole J. Kingston, Robert E. TI Compaction of chromatin by diverse Polycomb group proteins requires localized regions of high charge SO GENES & DEVELOPMENT LA English DT Article DE Polycomb; chromatin; transcriptional repression; intrinsic disorder ID HISTONE METHYLTRANSFERASE ACTIVITY; EMBRYONIC STEM-CELLS; POSTERIOR SEX COMBS; IN-VITRO; TRANSCRIPTIONAL ACTIVATION; DEVELOPMENTAL REGULATORS; DROSOPHILA-MELANOGASTER; GROUP-COMPLEXES; GENE; BINDING AB Polycomb group (PcG) proteins are required for the epigenetic maintenance of developmental genes in a silent state. Proteins in the Polycomb-repressive complex 1 (PRC1) class of the PcG are conserved from flies to humans and inhibit transcription. One hypothesis for PRC1 mechanism is that it compacts chromatin, based in part on electron microscopy experiments demonstrating that Drosophila PRC1 compacts nucleosomal arrays. We show that this function is conserved between Drosophila and mouse PRC1 complexes and requires a region with an overrepresentation of basic amino acids. While the active region is found in the Posterior Sex Combs (PSC) subunit in Drosophila, it is unexpectedly found in a different PRC1 subunit, a Polycomb homolog called M33, in mice. We provide experimental support for the general importance of a charged region by predicting the compacting capability of PcG proteins from species other than Drosophila and mice and by testing several of these proteins using solution assays and microscopy. We infer that the ability of PcG proteins to compact chromatin in vitro can be predicted by the presence of domains of high positive charge and that PRC1 components from a variety of species conserve this highly charged region. This supports the hypothesis that compaction is a key aspect of PcG function. C1 [Grau, Daniel J.; Chapman, Brad A.; Garlick, Joe D.; Borowsky, Mark; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Grau, Daniel J.; Chapman, Brad A.; Garlick, Joe D.; Borowsky, Mark; Kingston, Robert E.] Harvard Univ, Harvard Med Sch, Dept Genet, Cambridge, MA 02138 USA. [Francis, Nicole J.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kingston@molbio.mgh.harvard.edu OI Chapman, Brad/0000-0002-3026-1856 FU NIH [GM043901, GM078456-01] FX We thank Sarah K. Bowman, Jose M. Antao, Karim Bouazoune, and Leslie Beh for critically reading the manuscript and thoughtful discussions, and Anders Naar and C. Ting Wu for critical discussions and experimental suggestions. This work was supported by grants from the NIH (GM043901 to R. E. K., and GM078456-01 to N.J.F.). NR 65 TC 56 Z9 57 U1 0 U2 2 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 OCT 15 PY 2011 VL 25 IS 20 BP 2210 EP 2221 DI 10.1101/gad.17288211 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 841EU UT WOS:000296496100009 PM 22012622 ER PT J AU Kwok, AC Semel, ME Lipsitz, SR Bader, AM Barnato, AE Gawande, AA Jha, AK AF Kwok, Alvin C. Semel, Marcus E. Lipsitz, Stuart R. Bader, Angela M. Barnato, Amber E. Gawande, Atul A. Jha, Ashish K. TI The intensity and variation of surgical care at the end of life: a retrospective cohort study SO LANCET LA English DT Article ID MEDICARE EXPENDITURES; UNITED-STATES; CANCER; TRENDS; ICD-9-CM; OUTCOMES; QUALITY; AGE AB Background Although the extent of hospital and intensive-care use at the end of life is well known, patterns of surgical care during this period are poorly understood. We examined national patterns of surgical care in the USA among elderly fee-for-service Medicare beneficiaries in their last year of life. Methods We did a retrospective cohort study of elderly beneficiaries of fee-for-service Medicare in the USA, aged 65 years or older, who died in 2008. We identified claims for inpatient surgical procedures in the year before death and examined the relation between receipt of an inpatient procedure and both age and geographical region. We calculated an end-of-life surgical intensity (EOLSI) score for each hospital referral region defined as proportion of decedents who underwent a surgical procedure during the year before their death, adjusted for age, sex, race, and income. We compared patient characteristics with Rao-Scott chi(2) tests, resource use with generalised estimating equations, regional differences with generalised estimating equations Wald tests, and end-of-life surgical intensity scores with Spearman's partial-rank-order correlation coefficients. Findings Of 1 802 029 elderly beneficiaries of fee-for-service Medicare who died in 2008, 31.9% (95% CI 31.9-32.0; 575596 of 1802 029) underwent an inpatient surgical procedure during the year before death, 18.3% (18.2-18.4; 329 771 of 1802 029) underwent a procedure in their last month of life, and 8.0% (8.0-8.1; 144 162 of 1 802 029) underwent a procedure during their last week of life. Between the ages of 80 and 90 years, the percentage of decedents undergoing a surgical procedure in the last year of life decreased by 33% (35.3% [95% CI 34.7-35.9; 8858 of 25 094] to 23.6% [22.9-24.3; 3340 of 14 152]). EOLSI score in the highest intensity region (Munster, IN) was 34.4(95% Cl 33.7-35.1) and in the lowest intensity region (Honolulu, HI) was 11.5 (11.3-11.7). Regions with a high number of hospital beds per head had high end-of-life surgical intensity (r=0.37, 95% CI 0.27-0.46; p<0.0001), as did regions with high total Medicare spending (r=0.50, 0.41-0.58; p<0.0001). Interpretation Many elderly people in the USA undergo surgery in the year before their death. The rate at which they undergo surgery varies substantially with age and region and might suggest discretion in health-care providers' decisions to intervene surgically at the end of life. C1 [Kwok, Alvin C.; Bader, Angela M.; Gawande, Atul A.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Kwok, Alvin C.; Semel, Marcus E.; Lipsitz, Stuart R.; Bader, Angela M.; Gawande, Atul A.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Jha, Ashish K.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. [Barnato, Amber E.] Univ Pittsburgh, Med Ctr, Div Gen Med, Pittsburgh, PA 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 OI Gawande, Atul/0000-0002-1824-9176 NR 29 TC 103 Z9 104 U1 3 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 OCT 15 PY 2011 VL 378 IS 9800 BP 1408 EP 1413 DI 10.1016/S0140-6736(11)61268-3 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 838EM UT WOS:000296269600027 PM 21982520 ER PT J AU Delmonico, FL Dominguez-Gil, B Matesanz, R Noel, L AF Delmonico, Francis L. Dominguez-Gil, Beatriz Matesanz, Rafael Noel, Luc TI Organ Transplantation 1 A call for government accountability to achieve national self-sufficiency in organ donation and transplantation SO LANCET LA English DT Article ID MEDICAL GUIDELINES; EUROPEAN COUNTRIES; DEATH; DONOR; CARE; TRAFFICKING; TOURISM; FORUM AB Roughly 100 000 patients worldwide undergo organ transplantation annually, but many other patients remain on waiting lists. Transplantation rates vary substantially across countries. Affluent patients in nations with long waiting lists do not always wait for donations from within their own countries. Commercially driven transplantation, however, does not always ensure proper medical care of recipients or donors, and might lengthen waiting times for resident patients or increase the illegal and unethical purchase of organs from living donors. Governments should systematically address the needs of their countries according to a legal framework. Medical strategies to prevent end-stage organ failure must also be implemented. In view of the Madrid Resolution, the Declaration of Istanbul, and the 63rd World Health Assembly Resolution, a new paradigm of national self-sufficiency is needed. Each country or region should strive to provide a sufficient number of organs from within its own population, guided by WHO ethics principles. C1 [Delmonico, Francis L.] New England Organ Bank Inc, Waltham, MA 02451 USA. [Delmonico, Francis L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Cambridge, MA 02138 USA. [Dominguez-Gil, Beatriz; Matesanz, Rafael] Org Nacl Trasplantes, Madrid, Spain. [Noel, Luc] WHO, CH-1211 Geneva, Switzerland. RP Delmonico, FL (reprint author), New England Organ Bank Inc, 60 1st Ave, Waltham, MA 02451 USA. EM francis_delmonico@neob.org NR 20 TC 52 Z9 57 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 OCT 15 PY 2011 VL 378 IS 9800 BP 1414 EP 1418 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 838EM UT WOS:000296269600028 PM 22000137 ER PT J AU Coldren, CD Miller, YE AF Coldren, Christopher D. Miller, York E. TI Progressive Endobronchial Premalignancy: Marked by Original CIN SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID LUNG-CANCER; PRENEOPLASTIC LESIONS; CHROMOSOMAL ANEUSOMY; FLUORESCENCE; EPITHELIUM C1 [Coldren, Christopher D.; Miller, York E.] Univ Colorado, Sch Med, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA. [Miller, York E.] Eastern Colorado Hlth Care Syst, Denver Vet Affairs Med Ctr, Denver, CO USA. RP Coldren, CD (reprint author), Univ Colorado, Sch Med, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA. FU NCI NIH HHS [CA 58187, P50 CA058187] NR 15 TC 1 Z9 1 U1 0 U2 2 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 OCT 15 PY 2011 VL 184 IS 8 BP 869 EP 870 DI 10.1164/rccm.201108-1476ED PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 835PG UT WOS:000296047700005 PM 22003147 ER PT J AU Rosales, KR Singh, G Wu, K Chen, J Janes, MR Lilly, MB Peralta, ER Siskind, LJ Bennett, MJ Fruman, DA Edinger, AL AF Rosales, Kimberly Romero Singh, Gurpreet Wu, Kevin Chen, Jie Janes, Matthew R. Lilly, Michael B. Peralta, Eigen R. Siskind, Leah J. Bennett, Michael J. Fruman, David A. Edinger, Aimee L. TI Sphingolipid-based drugs selectively kill cancer cells by down-regulating nutrient transporter proteins SO BIOCHEMICAL JOURNAL LA English DT Article DE AAL-149; autophagy; bioenergetics; FTY720; leukaemia; nutrient limitation ID SPHINGOSINE 1-PHOSPHATE; AEROBIC GLYCOLYSIS; ENDOTHELIAL-CELLS; CELLULAR-ENERGY; PROSTATE-CANCER; HEART-RATE; FTY720; APOPTOSIS; KINASE; GROWTH AB Cancer cells are hypersensitive to nutrient limitation because oncogenes constitutively drive glycolytic and TCA (tricarboxylic acid) cycle intermediates into biosynthetic pathways. As the anaplerotic reactions that replace these intermediates are fueled by imported nutrients, the cancer cell's ability to generate ATP becomes compromised under nutrient-limiting conditions. In addition, most cancer cells have defects in autophagy, the catabolic process that provides nutrients from internal sources when external nutrients are unavailable. Normal cells, in contrast, can adapt to the nutrient stress that kills cancer cells by becoming quiescent and catabolic. In the present study we show that FFY720, a water-soluble sphingolipid drug that is effective in many animal cancer models, selectively starves cancer cells to death by down-regulating nutrient transporter proteins. Consistent with a bioenergetic mechanism of action, FTY720 induced homoeostatic autophagy. Cells were protected from FTY720 by cell-permeant nutrients or by reducing nutrient demand, but blocking apoptosis was ineffective. Importantly, AAL-149, a FTY720 analogue that lacks FTY720's dose-limiting toxicity, also triggered transporter loss and killed patient-derived leukaemias while sparing cells isolated from normal donors. As they target the metabolic profile of cancer cells rather than specific oncogenic mutations, FTY720 analogues such as AAL-149 should be effective against many different tumour types, particularly in combination with drugs that inhibit autophagy. C1 [Rosales, Kimberly Romero; Singh, Gurpreet; Wu, Kevin; Peralta, Eigen R.; Edinger, Aimee L.] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. [Chen, Jie; Bennett, Michael J.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Janes, Matthew R.; Fruman, David A.] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. [Janes, Matthew R.; Fruman, David A.] Univ Calif Irvine, Inst Immunol, Irvine, CA 92697 USA. [Lilly, Michael B.] Univ Calif Irvine, Dept Med, Div Hematol Oncol, Irvine, CA 92697 USA. [Siskind, Leah J.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Siskind, Leah J.] Med Univ S Carolina, Dept Med, Div Gen Internal Med Geriatr, Charleston, SC 29425 USA. RP Edinger, AL (reprint author), Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. EM aedinger@uci.edu FU National Institutes for Health [F31 CA126494, P20 RR17677, K08 CA100526, R01 GM089919]; Gabrielle's Angel Foundation; University of California; Cancer Research Coordinating Committee (UC CRCC); University of California, Irvine; Council on Research Computing and Libraries (UCI CORCL); VA [CDA-2]; VA REAP; ACS [IRG 97-219-11] FX This work was supported by the National Institutes for Health [grant numbers F31 CA126494 (to K.R.R.), P20 RR17677, K08 CA100526 and R01 GM089919], the Gabrielle's Angel Foundation, the University of California, Cancer Research Coordinating Committee (UC CRCC), a Single Investigator Innovation Grant from the University of California, Irvine, Council on Research Computing and Libraries (UCI CORCL) to A.L.E., VA CDA-2, VA REAP and ACS [grant number IRG 97-219-11 (to L.J.S.)]. NR 66 TC 17 Z9 18 U1 0 U2 13 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD OCT 15 PY 2011 VL 439 BP 299 EP 311 DI 10.1042/BJ20110853 PN 2 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 836PO UT WOS:000296123800012 ER PT J AU Brody, AL Cook, IA AF Brody, Arthur L. Cook, Ian A. TI Manipulation of Cigarette Craving with Transcranial Magnetic Stimulation SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID BRAIN C1 [Brody, Arthur L.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Greater Los Angeles Vet Affairs Smoking Cessat Pr, Los Angeles, CA 90095 USA. [Brody, Arthur L.] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. RP Brody, AL (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Greater Los Angeles Vet Affairs Smoking Cessat Pr, 300 UCLA Med Plaza,Suite 2200, Los Angeles, CA 90095 USA. EM abrody@ucla.edu FU NIDA NIH HHS [R01 DA020872, R01 DA20872] NR 10 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2011 VL 70 IS 8 BP 702 EP 703 DI 10.1016/j.biopsych.2011.08.001 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 835HG UT WOS:000296026600003 PM 21967985 ER PT J AU Touma, M Keskin, DB Shiroki, F Saito, I Koyasu, S Reinherz, EL Clayton, LK AF Touma, Maki Keskin, Derin B. Shiroki, Fumiko Saito, Ibuki Koyasu, Shigeo Reinherz, Ellis L. Clayton, Linda K. TI Impaired B Cell Development and Function in the Absence of I kappa BNS SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS-SWITCH RECOMBINATION; C-H TRANSCRIPTION; FOLLICULAR DENDRITIC CELLS; INDUCED IL-6 PRODUCTION; MARGINAL-ZONE; GERMINAL-CENTER; SELECTIVE DEFECTS; IMMUNE-RESPONSES; PLASMA-CELL; PROTEIN AB I kappa BNS has been identified as a member of the I kappa B family of NF-kappa B inhibitors, which undergoes induction upon TCR signaling. Mice carrying a targeted gene disruption of I kappa BNS demonstrate dysregulation of cytokines in T cells, macrophages, and dendritic cells. I kappa BNS mediates both positive and negative gene regulation, depending on individual cell type and/or cytokine. In this study, we demonstrate an additional role for I kappa BNS in the B cell lineage. B cells from I kappa BNS knockout ( KO) mice were impaired in proliferative responses to LPS and anti-CD40. IgM and IgG3 Igs were drastically reduced in the serum of I kappa BNS KO mice, although I kappa BNS KO B cells exhibited a higher level of surface IgM than that found in wild-type mice. Switching to IgG3 was significantly reduced in I kappa BNS KO B cells. The in vitro induction of plasma cell development demonstrated that progression to Ab-secreting cells was impaired in I kappa BNS KO B cells. In agreement with this finding, the number of Ab-secreting cells in the spleens of I kappa BNS KO mice was reduced and production of Ag-specific Igs was lower in I kappa BNS KO mice after influenza infection as compared with wild-type mice. Additionally, I kappa BNS KO mice lacked B1 B cells and exhibited a reduction in marginal zone B cells. Thus, I kappa BNS significantly impacts the development and functions of B cells and plasma cells. The Journal of Immunology, 2011, 187: 3942-3952. C1 [Clayton, Linda K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02215 USA. [Touma, Maki; Keskin, Derin B.; Reinherz, Ellis L.; Clayton, Linda K.] Dana Farber Canc Inst, Immunobiol Lab, Dept Med Oncol, Boston, MA 02115 USA. [Shiroki, Fumiko; Koyasu, Shigeo] Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, Tokyo 1608582, Japan. [Saito, Ibuki] Niigata Univ, Dept Life Sci, Grad Sch Sci & Technol, Nishi Ku, Niigata 9502181, Japan. RP Clayton, LK (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, 450 Brookline Ave, Boston, MA 02215 USA. EM linda_clayton@dfci.harvard.edu RI Koyasu, Shigeo/J-5583-2015 OI Koyasu, Shigeo/0000-0001-9585-3038 FU National Institutes of Health [AI19807, AI51779]; KAKENHI [22790457]; Uehara Memorial Foundation; Hayashi Memorial Foundation for Female Natural Scientists; Ministry of Education, Culture, Sports, Science, and Technology of Japan FX This work was supported by National Institutes of Health Grants AI19807 (to E.L.R.) and AI51779 (to L.K.C.) and by KAKENHI Grant 22790457, the Uehara Memorial Foundation, and the Hayashi Memorial Foundation for Female Natural Scientists (to M.T.). F.S. is a postdoctoral fellow of the Global Center of Excellence Program supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. NR 76 TC 14 Z9 14 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2011 VL 187 IS 8 BP 3942 EP 3952 DI 10.4049/jimmunol.1002109 PG 11 WC Immunology SC Immunology GA 829YN UT WOS:000295623100006 PM 21900180 ER PT J AU Norgaard, M Nielsen, RB Jacobsen, JB Gradus, JL Stenager, E Koch-Henriksen, N Lash, TL Sorensen, HT AF Norgaard, Mette Nielsen, Rikke Beck Jacobsen, Jacob Bonde Gradus, Jaimie L. Stenager, Egon Koch-Henriksen, Nils Lash, Timothy L. Sorensen, Henrik Toft TI Use of Penicillin and Other Antibiotics and Risk of Multiple Sclerosis: A Population-based Case-Control Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE anti-bacterial agents; case-control studies; multiple sclerosis; penicillins; risk ID DIAGNOSTIC-CRITERIA; EPIDEMIOLOGY; HISTORY; COHORT AB A 2006 study from the United Kingdom found that penicillin use may decrease the risk of multiple sclerosis (MS). To confirm this finding, the authors conducted a nationwide case-control study in Denmark, using the Danish Multiple Sclerosis Registry to identify 3,259 patients with MS onset from 1996 to 2008, and selected 10 population controls per case (n = 32,590), matched on sex and age. Through the National Prescription Database, prescriptions for antibiotics redeemed from 1995 to 2008 and before the date of first MS symptom/index date were identified. Conditional logistic regression analysis was used to compute odds ratios associating antibiotic use with MS occurrence. In total, 1,922 patients (59%) redeemed penicillin prescriptions before the index date and 2,292 (70%) redeemed any type of antibiotic prescription. Penicillin use was associated with an increased risk of MS (odds ratio = 1.21, 95% confidence interval: 1.10, 1.27). Use of any type of antibiotic was similarly associated with an increased risk of MS (odds ratio = 1.41, 95% confidence interval: 1.29, 1.53). The odds ratios for different types of antibiotics ranged between 1.08 and 1.83. Thus, this study found that penicillin use and use of other antibiotics were similarly associated with increased risk of MS, suggesting that the underlying infections may be causally associated with MS. C1 [Norgaard, Mette; Nielsen, Rikke Beck; Jacobsen, Jacob Bonde; Lash, Timothy L.; Sorensen, Henrik Toft] Aarhus Univ Hosp, Dept Clin Epidemiol, Inst Clin, DK-9000 Aalborg, Denmark. [Gradus, Jaimie L.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Gradus, Jaimie L.; Lash, Timothy L.; Sorensen, Henrik Toft] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Stenager, Egon; Koch-Henriksen, Nils] Copenhagen Univ Hosp, Danish Multiple Sclerosis Registry, Rigshosp, Copenhagen, Denmark. [Stenager, Egon] Univ So Denmark, Inst Reg Hlth Res Serv, Odense, Denmark. MS Clin So Jutland, Dept Neurol, Sonderborg, Denmark. [Koch-Henriksen, Nils] Aarhus Univ Hosp, Dept Neurol, DK-9000 Aalborg, Denmark. RP Norgaard, M (reprint author), Aarhus Univ Hosp, Dept Clin Epidemiol, Inst Clin Med, Sdr Skovvej 15, DK-9000 Aalborg, Denmark. EM m.noergaard@rn.dk OI Gradus, Jaimie/0000-0003-1459-5327 FU Clinical Epidemiology Research Foundation, Aarhus University Hospital, Aarhus, Denmark FX This work was supported by the Clinical Epidemiology Research Foundation, Aarhus University Hospital, Aarhus, Denmark. NR 17 TC 16 Z9 17 U1 2 U2 6 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 OCT 15 PY 2011 VL 174 IS 8 BP 945 EP 948 DI 10.1093/aje/kwr201 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 830TI UT WOS:000295679700009 PM 21920946 ER PT J AU Ito, H Pacold, IV Durazo-Arvizu, R Liu, K Shilipak, MG Goff, DC Tracy, RP Kramer, H AF Ito, Hiroki Pacold, Ivan V. Durazo-Arvizu, Ramon Liu, Kiang Shilipak, Michael G. Goff, David C., Jr. Tracy, Russell P. Kramer, Holly CA Multiethnic Study Atherosclerosis TI The Effect of Including Cystatin C or Creatinine in a Cardiovascular Risk Model for Asymptomatic Individuals SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cardiovascular diseases; creatinine; cystatin C; risk model ID CHRONIC KIDNEY-DISEASE; CORONARY-HEART-DISEASE; REACTIVE PROTEIN; MORTALITY; ASSOCIATION; PREDICTION; OLDER; ATHEROSCLEROSIS; STRATIFICATION; CLASSIFICATION AB The authors studied the incremental value of adding serum cystatin C or creatinine to the Framingham risk score variables (FRSVs) for the prediction of incident cardiovascular disease (CVD) among 6,653 adults without clinical CVD utilizing the Multi-Ethnic Study of Atherosclerosis (2000-2008). CVD events included coronary heart disease, heart failure, stroke, and peripheral arterial disease. Variables were transformed to yield optimal prediction of 6-year CVD events in sex-stratified models with FRSVs alone, FRSVs + cystatin C, and FRSVs + creatinine. Risk prediction in the 3 models was assessed by using the C statistic, and net reclassification improvement was calculated. The mean ages were 61.9 and 64.6 years for individuals with and without diabetes, respectively. After 6 years of follow-up, 447 (7.2%) CVD events occurred. In the total cohort, no significant change in the C statistic was noted with FRSVs + cystatin C and FRSVs + creatinine compared with FRSVs alone, and net reclassification improvement for CVD risk was extremely small and not significant with the addition of cystatin C or creatinine to FRSVs. Similar findings were noted after stratifying by baseline presence of diabetes. In conclusion, the addition of cystatin C or serum creatinine to FRSVs does not improve CVD risk prediction among adults without clinical CVD. C1 [Ito, Hiroki; Pacold, Ivan V.] Loyola Univ, Med Ctr, Div Cardiol, Dept Med, Maywood, IL 60153 USA. [Durazo-Arvizu, Ramon; Kramer, Holly] Loyola Univ, Med Ctr, Dept Prevent Med, Maywood, IL 60153 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Shilipak, Michael G.] San Francisco VA Med Ctr, Dept Epidemiol & Biostat, San Francisco, CA USA. [Goff, David C., Jr.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Lab Med, Burlington, VT USA. RP Ito, H (reprint author), Loyola Univ, Med Ctr, Div Cardiol, Dept Med, 2160 S 1st Ave, Maywood, IL 60153 USA. EM itohiroki@gmail.com OI Kramer, Holly/0000-0002-6374-837X FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-95159, N01-HC-95165, N01-HC-95167] FX This research was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95167 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. NR 29 TC 12 Z9 13 U1 1 U2 5 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 OCT 15 PY 2011 VL 174 IS 8 BP 949 EP 957 DI 10.1093/aje/kwr185 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 830TI UT WOS:000295679700010 PM 21880578 ER PT J AU O'Brien, LL Grimaldi, M Kostun, Z Wingert, RA Selleck, R Davidson, AJ AF O'Brien, Lori L. Grimaldi, Michael Kostun, Zachary Wingert, Rebecca A. Selleck, Rori Davidson, Alan J. TI Wt1a, Foxc1a, and the Notch mediator Rbpj physically interact and regulate the formation of podocytes in zebrafish SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Zebrafish; Kidney; Glomerulus; Embryo; Podocyte; Wilms' tumor suppressor-1; Notch; Foxc1a ID WILMS-TUMOR SUPPRESSOR; HELIX TRANSCRIPTION FACTORS; DEVELOPING MOUSE KIDNEY; CELL FATE; EXPRESSION ANALYSIS; PRONEPHRIC DUCT; SLIT DIAPHRAGM; GENE; NEPHRON; PROTEIN AB Podocytes help form the glomerular blood filtration barrier in the kidney and their injury or loss leads to renal disease. The Wilms' tumor suppressor-1 (Wt1) and the FoxC1/2 transcription factors, as well as Notch signaling, have been implicated as important regulators of podocyte fate. It is not known whether these factors work in parallel or sequentially on different gene targets, or as higher-order transcriptional complexes on common genes. Here, we use the zebrafish to demonstrate that embryos treated with morpholinos against wt1a, foxc1a, or the Notch transcriptional mediator rbpj develop fewer podocytes, as determined by wt1b, hey 1 and nephrin expression, while embryos deficient in any two of these factors completely lack podocytes. From GST-pull-downs and co-immunoprecipitation experiments we show that Wt1a, Foxc1a, and Rbpj can physically interact with each other, whereas only Rbpj binds to the Notch intracellular domain (NICD). In transactivation assays, combinations of Wt1. FoxC1/2, and NICD synergistically induce the Hey1 promoter, and have additive or repressive effects on the Podocalyxin promoter, depending on dosage. Taken together, these data suggest that Wt1, FoxC1/2, and Notch signaling converge on common target genes where they physically interact to regulate a podocyte-specific gene program. These findings further our understanding of the transcriptional circuitry responsible for podocyte formation and differentiation during kidney development. (C) 2011 Elsevier Inc. All rights reserved. C1 Harvard Univ, Ctr Regenerat Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Dept Med, Sch Med, Boston, MA 02114 USA. Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Davidson, AJ (reprint author), Univ Auckland, Dept Mol Med & Pathol, Auckland 1, New Zealand. EM a.davidson@auckland.ac.nz FU NIDDK NIH HHS [R01 DK077186, R01 DK077186-03] NR 86 TC 34 Z9 34 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD OCT 15 PY 2011 VL 358 IS 2 BP 318 EP 330 DI 10.1016/j.ydbio.2011.08.005 PG 13 WC Developmental Biology SC Developmental Biology GA 829SF UT WOS:000295603900005 PM 21871448 ER PT J AU Maxwell, MM Tomkinson, EM Nobles, J Wizeman, JW Amore, AM Quinti, L Chopra, V Hersch, SM Kazantsev, AG AF Maxwell, Michele M. Tomkinson, Elizabeth M. Nobles, Johnathan Wizeman, John W. Amore, Allison M. Quinti, Luisa Chopra, Vanita Hersch, Steven M. Kazantsev, Aleksey G. TI The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS SO HUMAN MOLECULAR GENETICS LA English DT Article ID FAMILIAL DYSAUTONOMIA; HUNTINGTONS-DISEASE; TUBULIN ACETYLATION; SIR2 FAMILY; IN-VIVO; TRANSPORT; LONGEVITY; HDAC6; HISTONE-DEACETYLASE-6; NEUROPROTECTION AB Sirtuin 2 (SIRT2) is one of seven known mammalian protein deacetylases homologous to the yeast master lifespan regulator Sir2. In recent years, the sirtuin protein deacetylases have emerged as candidate therapeutic targets for many human diseases, including metabolic and age-dependent neurological disorders. In non-neuronal cells, SIRT2 has been shown to function as a tubulin deacetylase and a key regulator of cell division and differentiation. However, the distribution and function of the SIRT2 microtubule (MT) deacetylase in differentiated, postmitotic neurons remain largely unknown. Here, we show abundant and preferential expression of specific isoforms of SIRT2 in the mammalian central nervous system and find that a previously uncharacterized form, SIRT2.3, exhibits age-dependent accumulation in the mouse brain and spinal cord. Further, our studies reveal that focal areas of endogenous SIRT2 expression correlate with reduced a-tubulin acetylation in primary mouse cortical neurons and suggest that the brain-enriched species of SIRT2 may function as the predominant MT deacetylases in mature neurons. Recent reports have demonstrated an association between impaired tubulin acetyltransferase activity and neurodegenerative disease; viewed in this light, our results showing age-dependent accumulation of the SIRT2 neuronal MT deacetylase in wild-type mice suggest a functional link between tubulin acetylation patterns and the aging brain. C1 [Maxwell, Michele M.; Tomkinson, Elizabeth M.; Nobles, Johnathan; Wizeman, John W.; Amore, Allison M.; Quinti, Luisa; Chopra, Vanita; Hersch, Steven M.; Kazantsev, Aleksey G.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Boston, MA 02115 USA. [Maxwell, Michele M.; Quinti, Luisa; Chopra, Vanita; Hersch, Steven M.; Kazantsev, Aleksey G.] Harvard Univ, Sch Med, Boston, MA USA. RP Maxwell, MM (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02129 USA. EM mmmaxwell@partners.org FU MassGeneral Institute for Neurodegenerative Disease; National Institutes of Health [R21-NS062189, P01-NS058793]; ALS Therapy Alliance; R.J.G. Foundation; Milton Carmen Foundation; HDSA New England Center of Excellence; HDSA Coalition for the Cure FX This work was supported by the MassGeneral Institute for Neurodegenerative Disease and by grants from the National Institutes of Health (R21-NS062189 to M.M.M.; P01-NS058793 to S.M.H.); the ALS Therapy Alliance (to M.M.M.); the R.J.G. Foundation (to A.G.K.); the Milton Carmen Foundation (to A.G.K.); the HDSA New England Center of Excellence (to S.M.H.); and the HDSA Coalition for the Cure (to S.M.H.). NR 47 TC 61 Z9 63 U1 2 U2 9 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 OCT 15 PY 2011 VL 20 IS 20 BP 3986 EP 3996 DI 10.1093/hmg/ddr326 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 824AN UT WOS:000295171200009 PM 21791548 ER PT J AU Tin, A Woodward, OM Kao, WHL Liu, CT Lu, XN Nalls, MA Shriner, D Semmo, M Akylbekova, EL Wyatt, SB Hwang, SJ Yang, Q Zonderman, AB Adeyemo, AA Palmer, C Meng, Y Reilly, M Shlipak, MG Siscovick, D Evans, MK Rotimi, CN Flessner, MF Kottgen, M Cupples, LA Fox, CS Kottgen, A AF Tin, Adrienne Woodward, Owen M. Kao, Wen Hong Linda Liu, Ching-Ti Lu, Xiaoning Nalls, Michael A. Shriner, Daniel Semmo, Mariam Akylbekova, Ermeg L. Wyatt, Sharon B. Hwang, Shih-Jen Yang, Qiong Zonderman, Alan B. Adeyemo, Adebowale A. Palmer, Cameron Meng, Yan Reilly, Muredach Shlipak, Michael G. Siscovick, David Evans, Michele K. Rotimi, Charles N. Flessner, Michael F. Koettgen, Michael Cupples, L. Adrienne Fox, Caroline S. Koettgen, Anna CA CARe & CHARGE Consortia TI Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele SO HUMAN MOLECULAR GENETICS LA English DT Article ID URIC-ACID; CARDIOVASCULAR-DISEASE; GENETIC-LOCI; POPULATION; DESIGN; TRANSPORTER; FRAMINGHAM; GLUCOSE; SLC2A9; HEART AB Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P < 5.0 x 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P = 1.0 x 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P = 3.8 x 10(-32)) and SLC22A12 (P = 2.1 x 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P = 2.7 x 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants. C1 [Koettgen, Anna] Freiburg Univ Hosp, Dept Med 4, Div Renal, D-79110 Freiburg, Germany. [Tin, Adrienne; Kao, Wen Hong Linda; Koettgen, Anna] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Woodward, Owen M.] Johns Hopkins Univ, Dept Physiol, Sch Med, Baltimore, MD 21205 USA. [Liu, Ching-Ti; Lu, Xiaoning; Cupples, L. Adrienne] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [Shriner, Daniel; Adeyemo, Adebowale A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Shriner, Daniel; Koettgen, Michael] Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Akylbekova, Ermeg L.] Jackson State Univ, Jackson, MS 39213 USA. [Wyatt, Sharon B.] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Wyatt, Sharon B.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Hwang, Shih-Jen; Cupples, L. Adrienne; Fox, Caroline S.] NHLBI Framingham Heart Study, Framingham, MA 01702 USA. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Reilly, Muredach] Univ Penn, Med Ctr, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Reilly, Muredach] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Siscovick, David] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Palmer, Cameron] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Palmer, Cameron] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Palmer, Cameron] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Palmer, Cameron; Meng, Yan] Broad Inst Harvard & MIT, Metab Dis Initiat, Cambridge, MA USA. [Flessner, Michael F.] NIDDK, KUH, NIH, Bethesda, MD 20892 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Kottgen, A (reprint author), Freiburg Univ Hosp, Dept Med 4, Div Renal, Berliner Allee 29, D-79110 Freiburg, Germany. EM akottgen@jhsph.edu RI Kottgen, Anna/D-2920-2012; Yang, Qiong/G-5438-2014; OI Cupples, L. Adrienne/0000-0003-0273-7965; Adeyemo, Adebowale/0000-0002-3105-3231; Zonderman, Alan B/0000-0002-6523-4778 FU National Heart, Lung and Blood Institute; NIH, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; National Institutes of Health [S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [Z01HG200362]; NIDDK [DK032753-25A1]; German Research Foundation FX The authors wish to acknowledge the support of the National Heart, Lung and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. We would like to thank Dr Yohannes Hagos who kindly provided the URAT1 plasmid, Dr H. Endou for the permission to use it, as well as Dr William B. Guggino for contributing experimental resources.; Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS): this research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (intramural project # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov).; Howard University Family Study (HUFS): The Howard University Family Study was supported by National Institutes of Health grants S06GM008016-320107 and S06GM008016-380111. Enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology and the Office of the Director at the National Institutes of Health (Z01HG200362). Genotyping support was provided by the Coriell Institute for Medical Research. We thank the participants of the Howard University Family Study. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health.; Individual support: O.M.W. was supported by NIDDK: DK032753-25A1, A.K. was supported by the Emmy Noether Programme of the German Research Foundation. NR 53 TC 36 Z9 42 U1 0 U2 9 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 OCT 15 PY 2011 VL 20 IS 20 BP 4056 EP 4068 DI 10.1093/hmg/ddr307 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 824AN UT WOS:000295171200015 PM 21768215 ER PT J AU Cohen, DM Mittalhenkle, A Scott, DL Young, CJ Norman, DJ AF Cohen, David M. Mittalhenkle, Anuja Scott, David L. Young, Carlton J. Norman, Douglas J. TI African American Living-Kidney Donors Should Be Screened for APOL1 Risk Alleles SO TRANSPLANTATION LA English DT Article DE Genetics; Allele; Kidney ID STAGE RENAL-DISEASE; MYH9; TRANSPLANTATION; OUTCOMES; GENE AB The adjusted rate of end-stage kidney disease (ESKD) among African Americans is markedly increased relative to European Americans. African Americans are overrepresented on the kidney transplantation waiting list and experience longer wait times. In aggregate, these pressures drive recommendations for living donor transplantation. Genovese et al. recently implicated the APOL1 gene in ESKD risk among African Americans (Genovese et al. Science 2010; 329: 841). The presence of two APOL1 risk alleles doubles the relative risk for ESKD; moreover, the alleles are prevalent among African Americans. We propose a strategy for screening for the presence of APOL1 risk alleles among African American living kidney donors and for living-related donors for African American recipients. C1 [Cohen, David M.] Portland VA Med Ctr, Nephrol Sect, Portland, OR 97239 USA. [Cohen, David M.; Mittalhenkle, Anuja; Norman, Douglas J.] Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, Portland, OR 97201 USA. [Scott, David L.] Oregon Hlth & Sci Univ, Dept Surg, Div Liver & Pancreas Transplantat, Portland, OR 97201 USA. [Young, Carlton J.] Univ Alabama, Sch Med, Dept Surg, Div Transplantat, Birmingham, AL 35294 USA. RP Cohen, DM (reprint author), Portland VA Med Ctr, Nephrol Sect, Mailcode R&D 10,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM cohend@ohsu.edu FU Department of Veterans Affairs; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health FX This work was supported by the Department of Veterans Affairs (D. M. C., A. M., and D. L. S.) and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (D.M.C.). NR 17 TC 24 Z9 24 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD OCT 15 PY 2011 VL 92 IS 7 BP 722 EP 725 DI 10.1097/TP.0b013e31822eec39 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 825YY UT WOS:000295319500006 PM 21878839 ER PT J AU Stenzel, D Lundkvist, A Sauvaget, D Busse, M Graupera, M van der Flier, A Wijelath, ES Murray, J Sobel, M Costell, M Takahashi, S Fassler, R Yamaguchi, Y Gutmann, DH Hynes, RO Gerhardt, H AF Stenzel, Denise Lundkvist, Andrea Sauvaget, Dominique Busse, Marta Graupera, Mariona van der Flier, Arjan Wijelath, Errol S. Murray, Jacqueline Sobel, Michael Costell, Mercedes Takahashi, Seiichiro Faessler, Reinhard Yamaguchi, Yu Gutmann, David H. Hynes, Richard O. Gerhardt, Holger TI Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis SO DEVELOPMENT LA English DT Article DE Angiogenesis; Tip cells; Extracellular matrix; Cell migration; Endothelial guidance ID ENDOTHELIAL-CELL MIGRATION; HEPARAN-SULFATE; EXTRACELLULAR-MATRIX; VASCULAR DEVELOPMENT; BIOLOGICAL-ACTIVITY; PRECURSOR CELLS; IN-VIVO; VEGF; EXPRESSION; GRADIENTS AB Fibronectin (FN) is a major component of the extracellular matrix and functions in cell adhesion, cell spreading and cell migration. In the retina, FN is transiently expressed and assembled on astrocytes (ACs), which guide sprouting tip cells and deposit a provisional matrix for sprouting angiogenesis. The precise function of FN in retinal angiogenesis is largely unknown. Using genetic tools, we show that astrocytes are the major source of cellular FN during angiogenesis in the mouse retina. Deletion of astrocytic FN reduces radial endothelial migration during vascular plexus formation in a gene dose-dependent manner. This effect correlates with reduced VEGF receptor 2 and PI3K/AKT signalling, and can be mimicked by selectively inhibiting VEGF-A binding to FN through intraocular injection of blocking peptides. By contrast, AC-specific replacement of the integrin-binding RGD sequence with FN-RGE or endothelial deletion of itga5 shows little effect on migration and PI3K/AKT signalling, but impairs filopodial alignment along AC processes, suggesting that FN-integrin alpha 5 beta 1 interaction is involved in filopodial adhesion to the astrocytic matrix. AC FN shares its VEGF-binding function and cell-surface distribution with heparan-sulfate (HS), and genetic deletion of both FN and HS together greatly enhances the migration defect, indicating a synergistic function of FN and HS in VEGF binding. We propose that in vivo the VEGF-binding properties of FN and HS promote directional tip cell migration, whereas FN integrin-binding functions to support filopodia adhesion to the astrocytic migration template. C1 [Stenzel, Denise; Lundkvist, Andrea; Sauvaget, Dominique; Busse, Marta; Gerhardt, Holger] London Res Inst Canc Res UK, Vasc Biol Lab, London WC2A 3PX, England. [Graupera, Mariona] Hosp Duran i Reynals 3 Planta, Oncol Mol Lab, Grp Angiogenesi, Inst Invest Biomed Bellvitge IDIBELL, Barcelona 08907, Spain. [van der Flier, Arjan; Hynes, Richard O.] MIT, Howard Hughes Med Inst, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Wijelath, Errol S.; Murray, Jacqueline; Sobel, Michael] Vet Affairs Puget Sound Hlth Care Syst, Div Vasc Surg, Dept Surg, Seattle, WA 98195 USA. [Wijelath, Errol S.; Murray, Jacqueline; Sobel, Michael] Univ Washington, Sch Med, Seattle, WA 98195 USA. [Costell, Mercedes] Univ Valencia, Dept Bioquim & Biol Mol, E-46100 Burjassot, Spain. [Takahashi, Seiichiro; Faessler, Reinhard] Max Planck Inst Biochem, Dept Mol Med, D-82152 Martinsried, Germany. [Yamaguchi, Yu] Sanford Childrens Hlth Res Ctr, Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [Gutmann, David H.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Gerhardt, Holger] VIB, Vesalius Res Ctr, Vasc Patterning Lab, B-3000 Louvain, Belgium. RP Gerhardt, H (reprint author), London Res Inst Canc Res UK, Vasc Biol Lab, London WC2A 3PX, England. EM holger.gerhardt@cancer.org.uk RI Gerhardt, Holger/G-4610-2011; OI Graupera, Mariona/0000-0003-4608-4185; Gerhardt, Holger/0000-0001-9228-7472; Gerhardt, Holger/0000-0002-3030-0384 FU Cancer Research UK; EMBO; Lister Institute of Preventive Medicine; Leducq Transatlantic Network ARTEMIS; DFG; Max-Planck Society; National Institutes of Health [RO1 HL079182, PO1-HL66105]; NIGMS Cell Migration Consortium [GC11451.126452] FX This work was funded by Cancer Research UK, EMBO Young Investigator Program, The Lister Institute of Preventive Medicine, the Leducq Transatlantic Network ARTEMIS (H. G.), DFG and Max-Planck Society. This work was further supported by grants from the National Institutes of Health (RO1 HL079182 to M. S. and E. S. W., PO1-HL66105 and the NIGMS Cell Migration Consortium, GC11451.126452; A. F. Horwitz is the P. I.) and by the Howard Hughes Medical Institute of which R.O.H. is an Investigator. Deposited in PMC for release after 6 months. NR 47 TC 53 Z9 54 U1 0 U2 9 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 OCT 15 PY 2011 VL 138 IS 20 BP 4451 EP 4463 DI 10.1242/dev.071381 PG 13 WC Developmental Biology SC Developmental Biology GA 822YD UT WOS:000295085600013 PM 21880786 ER PT J AU Zhu, C Smith, T McNulty, J Rayla, AL Lakshmanan, A Siekmann, AF Buffardi, M Meng, XD Shin, J Padmanabhan, A Cifuentes, D Giraldez, AJ Look, AT Epstein, JA Lawson, ND Wolfe, SA AF Zhu, Cong Smith, Tom McNulty, Joseph Rayla, Amy L. Lakshmanan, Abirami Siekmann, Arndt F. Buffardi, Matthew Meng, Xiangdong Shin, Jimann Padmanabhan, Arun Cifuentes, Daniel Giraldez, Antonio J. Look, A. Thomas Epstein, Jonathan A. Lawson, Nathan D. Wolfe, Scot A. TI Evaluation and application of modularly assembled zinc-finger nucleases in zebrafish SO DEVELOPMENT LA English DT Article DE gata2; Vascular development; Zebrafish; Zinc-finger nuclease ID ARTIFICIAL TRANSCRIPTION FACTORS; DNA-BINDING PROTEINS; GENE-EXPRESSION; KNOCKOUT RATS; CONSTRUCTION; RECOGNITION; SEQUENCES; SPECIFICITY; DESIGN; DROSOPHILA AB Zinc-finger nucleases (ZFNs) allow targeted gene inactivation in a wide range of model organisms. However, construction of target-specific ZFNs is technically challenging. Here, we evaluate a straightforward modular assembly-based approach for ZFN construction and gene inactivation in zebrafish. From an archive of 27 different zinc-finger modules, we assembled more than 70 different zinc-finger cassettes and evaluated their specificity using a bacterial one-hybrid assay. In parallel, we constructed ZFNs from these cassettes and tested their ability to induce lesions in zebrafish embryos. We found that the majority of zinc-finger proteins assembled from these modules have favorable specificities and nearly one-third of modular ZFNs generated lesions at their targets in the zebrafish genome. To facilitate the application of ZFNs within the zebrafish community we constructed a public database of sites in the zebrafish genome that can be targeted using this archive. Importantly, we generated new germline mutations in eight different genes, confirming that this is a viable platform for heritable gene inactivation in vertebrates. Characterization of one of these mutants, gata2a, revealed an unexpected role for this transcription factor in vascular development. This work provides a resource to allow targeted germline gene inactivation in zebrafish and highlights the benefit of a definitive reverse genetic strategy to reveal gene function. C1 [Zhu, Cong; Smith, Tom; McNulty, Joseph; Rayla, Amy L.; Lakshmanan, Abirami; Siekmann, Arndt F.; Buffardi, Matthew; Meng, Xiangdong; Lawson, Nathan D.; Wolfe, Scot A.] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. [Shin, Jimann; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Padmanabhan, Arun; Epstein, Jonathan A.] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Cifuentes, Daniel; Giraldez, Antonio J.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Wolfe, Scot A.] Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Biochem, Worcester, MA 01605 USA. RP Lawson, ND (reprint author), Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. EM nathan.lawson@umassmed.edu; scot.wolfe@umassmed.edu OI Cifuentes Buira, Daniel/0000-0001-5442-4843 FU NIH National Heart, Lung, and Blood Institute [R01 HL093766, R01 HL079266]; Department of Defense (DOD) [NF050175]; National Institute of General Medical Sciences [R01 GM081602] FX This work was funded by grants from the NIH National Heart, Lung, and Blood Institute to S. A. W. and N.D.L. (R01 HL093766) and to N.D.L. (R01 HL079266) and from the Department of Defense to A. T. L. and J.A.E. (DOD, NF050175), and from the National Institute of General Medical Sciences to A.J.G. (R01 GM081602). Deposited in PMC for release after 12 months. NR 63 TC 47 Z9 47 U1 0 U2 5 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 OCT 15 PY 2011 VL 138 IS 20 BP 4555 EP 4564 DI 10.1242/dev.066779 PG 10 WC Developmental Biology SC Developmental Biology GA 822YD UT WOS:000295085600022 PM 21937602 ER PT J AU Martins, PN AF Martins, Paulo N. TI Follicular dendritic cell sarcoma of the liver: unusual presentation of a rare tumor and literature review (vol 10, pg 443, 2011) SO HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL LA English DT Correction C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Transplantat,Dept Surg, Boston, MA 02114 USA. RP Martins, PN (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Transplantat,Dept Surg, 55 Fruit St, Boston, MA 02114 USA. EM pnmartins@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU ZHEJIANG UNIV SCH MEDICINE PI HANGZHOU PA FIRST AFFILIATED HOSPITAL, 79 QINGCHUN ROAD, HANGZHOU, 310003, PEOPLES R CHINA SN 1499-3872 J9 HEPATOB PANCREAT DIS JI Hepatob. Pancreatic. Dis. Int. PD OCT 15 PY 2011 VL 10 IS 5 BP 556 EP 556 DI 10.1016/S1499-3872(11)60094-5 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 823TH UT WOS:000295148900016 ER PT J AU Burdo, TH Lo, J Abbara, S Wei, J DeLelys, ME Preffer, F Rosenberg, ES Williams, KC Grinspoon, S AF Burdo, Tricia H. Lo, Janet Abbara, Suhny Wei, Jeffrey DeLelys, Michelle E. Preffer, Fred Rosenberg, Eric S. Williams, Kenneth C. Grinspoon, Steven TI Soluble CD163, a Novel Marker of Activated Macrophages, Is Elevated and Associated With Noncalcified Coronary Plaque in HIV-Infected Patients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID SCAVENGER RECEPTOR CD163; IMMUNE ACTIVATION; ANTIRETROVIRAL THERAPY; COMPUTED-TOMOGRAPHY; FLOW-CYTOMETRY; RISK-FACTOR; DISEASE; ATHEROSCLEROSIS; HEMOGLOBIN; CYTOMEGALOVIRUS AB Background. Pro-inflammatory monocytes/macrophages may contribute to increased atherosclerosis in human immunodeficiency virus (HIV)-infected patients. We investigated to our knowledge, for the first time-sCD163 and other markers of monocyte activation in relationship to atherosclerotic plaque in HIV-infected patients. Methods. One hundred two HIV-infected and 41 HIV-seronegative men with equivalent cardiovascular risk factors and without history of coronary artery disease were prospectively recruited and underwent computed tomography coronary angiography. Results. sCD163 levels and presence of plaque were significantly higher among antiretroviral-treated subjects with undetectable HIV RNA levels, compared with seronegative controls (1172 +/- 646 vs. 883 +/- 561 ng/mL [P = .02] for sCD163 and 61% vs. 39% [P = .03] for presence of plaque). After adjusting for age, race, lipids, blood pressure, glucose, smoking, sCD14, and HIV infection, sCD163 remained independently associated with noncalcified plaque (P = .008). Among HIV-infected patients, sCD163 was associated with coronary segments with noncalcified plaque (r = 0.21; P = .04), but not with calcium score. In contrast, markers of generalized inflammation, including C-reactive protein level, and D-dimer were not associated with sCD163 or plaque among HIV-infected patients. Conclusions. sCD163, a monocyte/macrophage activation marker, is increased in association with noncalcified coronary plaque in men with chronic HIV infection and low or undetectable viremia. These data suggest a potentially important role of chronic monocyte/macrophage activation in the development of noncalcified vulnerable plaque. Clinical Trial Registration. NCT00455793. C1 [Burdo, Tricia H.; Williams, Kenneth C.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. [Lo, Janet; Wei, Jeffrey; Grinspoon, Steven] Mass Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Abbara, Suhny] Dept Radiol, Boston, MA USA. [DeLelys, Michelle E.; Preffer, Fred] Dept Pathol, Boston, MA USA. [Rosenberg, Eric S.] Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Grinspoon, S (reprint author), Mass Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU Bristol Myers Squibb; National Institutes of Health [K23 HL092792, NS37654, NS40237, K24 DK064545, R01 HL 095123, R01 AI071915, M01 RR01066-25S1]; Mary Fisher Clinical AIDS Research and Education Fund FX This work was supported by Bristol Myers Squibb; National Institutes of Health (K23 HL092792 to J. L., NS37654 and NS40237 to K. C. W., K24 DK064545 and R01 HL 095123 to S. G., R01 AI071915 to E. S. R., and M01 RR01066-25S1); and the Mary Fisher Clinical AIDS Research and Education Fund. Funding sources had no role in the design of the study, data analysis, or the writing of the manuscript. NR 34 TC 171 Z9 172 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 OCT 15 PY 2011 VL 204 IS 8 BP 1227 EP 1236 DI 10.1093/infdis/jir520 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 821JB UT WOS:000294970100012 PM 21917896 ER PT J AU Tay, Y Kats, L Salmena, L Weiss, D Tan, SM Ala, U Karreth, F Poliseno, L Provero, P Di Cunto, F Lieberman, J Rigoutsos, I Pandolfi, PP AF Tay, Yvonne Kats, Lev Salmena, Leonardo Weiss, Dror Tan, Shen Mynn Ala, Ugo Karreth, Florian Poliseno, Laura Provero, Paolo Di Cunto, Ferdinando Lieberman, Judy Rigoutsos, Isidore Pandolfi, Pier Paolo TI Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs SO CELL LA English DT Article ID MICRORNA; EXPRESSION; IDENTIFICATION; REGIONS; GENE; MIR-17-92; TARGETS; PROTEIN; CLUSTER AB Here, we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth-and tumor-suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein-coding mRNAs. C1 [Tay, Yvonne; Kats, Lev; Salmena, Leonardo; Weiss, Dror; Ala, Ugo; Karreth, Florian; Poliseno, Laura; Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Canc Genet Program,Beth Israel Deaconess Med Ctr, Div Genet,Beth Israel Deaconess Canc Ctr,Dept Med, Boston, MA 02115 USA. [Tan, Shen Mynn; Lieberman, Judy] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Tan, Shen Mynn; Lieberman, Judy] Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Tan, Shen Mynn; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Ala, Ugo; Provero, Paolo; Di Cunto, Ferdinando] Univ Turin, Mol Biotechnol Ctr, Turin, Italy. [Ala, Ugo; Provero, Paolo; Di Cunto, Ferdinando] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Rigoutsos, Isidore] Thomas Jefferson Univ, Computat Med Ctr, Jefferson Med Coll, Philadelphia, PA 19107 USA. RP Pandolfi, PP (reprint author), Harvard Univ, Sch Med, Canc Genet Program,Beth Israel Deaconess Med Ctr, Div Genet,Beth Israel Deaconess Canc Ctr,Dept Med, Boston, MA 02115 USA. EM ppandolf@bidmc.harvard.edu RI Lieberman, Judy/A-2717-2015; Poliseno, Laura/B-5711-2012; Ala, Ugo/K-2029-2016; OI Poliseno, Laura/0000-0001-6557-955X; Ala, Ugo/0000-0001-5408-6397; Rigoutsos, Isidore/0000-0003-1529-8631; di cunto, ferdinando/0000-0001-9367-6357 FU Harvard Catalyst; The Harvard Clinical and Translational Science Center (NIH) [UL1 RR 025758]; Human Frontier Science Program; Canadian Institutes of Health Research; Fondazione per la Ricerca Biomedica ONLUS of Torino; Department of Defense (DOD); Italian Association for Cancer Research (AIRC) [IG-9408]; Jefferson Medical College of Thomas Jefferson University; NIH [R01 CA-82328-09] FX We thank Pandolfi laboratory members for critical discussions. Real-time PCR analysis was conducted through the Harvard Catalyst Laboratory for Innovative Translational Technologies with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NIH Award #UL1 RR 025758 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 National Institutes of Health. We thank B. Vogelstein for DICEREx5 cells, M. Gorospe for the pMS2 plasmids, and I. Legnini for experimental support. Y.T. was supported by a Special Fellow Award from The Leukemia & Lymphoma Society. L. K. was supported by an NHMRC Overseas Postdoctoral Fellowship. L. S. was supported by fellowships from the Human Frontier Science Program and the Canadian Institutes of Health Research. U. A. was supported by a fellowship from the Fondazione per la Ricerca Biomedica ONLUS of Torino. S. M. T. was supported by a Department of Defense (DOD) Breast Cancer Research Program (BCRP) postdoctoral fellowship award. P. P. and U. A. gratefully acknowledge support from the Italian Association for Cancer Research (AIRC) under grant IG-9408. I. R. was supported by funding from the Jefferson Medical College of Thomas Jefferson University. This work was supported, in part, by NIH grant R01 CA-82328-09 to P.P. NR 38 TC 359 Z9 399 U1 13 U2 76 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 14 PY 2011 VL 147 IS 2 BP 344 EP 357 DI 10.1016/j.cell.2011.09.029 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837KD UT WOS:000296199300013 PM 22000013 ER PT J AU Karreth, FA Tay, Y Perna, D Ala, U Tan, SM Rust, AG DeNicola, G Webster, KA Weiss, D Perez-Mancera, PA Krauthammer, M Halaban, R Provero, P Adams, DJ Tuveson, DA Pandolfi, PP AF Karreth, Florian A. Tay, Yvonne Perna, Daniele Ala, Ugo Tan, Shen Mynn Rust, Alistair G. DeNicola, Gina Webster, Kaitlyn A. Weiss, Dror Perez-Mancera, Pedro A. Krauthammer, Michael Halaban, Ruth Provero, Paolo Adams, David J. Tuveson, David A. Pandolfi, Pier Paolo TI In Vivo Identification of Tumor-Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma SO CELL LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; MIR-200 FAMILY; CLINICAL-IMPLICATIONS; MICRORNA TARGETS; REPRESSORS ZEB1; MESSENGER-RNAS; CANCER; GENE; MUTATIONS; MICE AB We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAF(V600E) to promote melanomagenesis. C1 [Karreth, Florian A.; Tay, Yvonne; Ala, Ugo; Webster, Kaitlyn A.; Weiss, Dror; Pandolfi, Pier Paolo] Harvard Univ, Beth Israel Deaconess Canc Ctr, Beth Israel Deaconess Med Ctr, Canc Genet Program,Div Genet,Dept Med & Pathol,Me, Boston, MA 02215 USA. [DeNicola, Gina] Harvard Univ, Beth Israel Deaconess Canc Ctr, Beth Israel Deaconess Med Ctr, Div Signal Transduct,Dept Med & Pathol,Med Sch, Boston, MA 02215 USA. [Perna, Daniele; Perez-Mancera, Pedro A.; Tuveson, David A.] CRUK, Li Ka Shing Ctr, Cambridge Res Inst, Cambridge CB2 0RE, England. [Ala, Ugo; Provero, Paolo] Univ Turin, Mol Biotechnol Ctr, Turin, Italy. [Ala, Ugo; Provero, Paolo] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Tan, Shen Mynn] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02215 USA. [Tan, Shen Mynn] Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp Boston, Boston, MA 02215 USA. [Tan, Shen Mynn] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02215 USA. [Rust, Alistair G.; Adams, David J.] Wellcome Trust Sanger Inst, Hinxton CB10 1HH, England. [Krauthammer, Michael] Yale Univ, Dept Pathol, New Haven, CT 06520 USA. [Halaban, Ruth] Yale Univ, Dept Dermatol, New Haven, CT 06520 USA. RP Pandolfi, PP (reprint author), Harvard Univ, Beth Israel Deaconess Canc Ctr, Beth Israel Deaconess Med Ctr, Canc Genet Program,Div Genet,Dept Med & Pathol,Me, Boston, MA 02215 USA. EM ppandolf@bidmc.harvard.edu RI Ala, Ugo/K-2029-2016; OI Ala, Ugo/0000-0001-5408-6397; Rust, Alistair/0000-0001-7287-192X FU Harvard Catalyst; The Harvard Clinical and Translational Science Center (NIH) [UL1 RR 025758]; Harvard University and its affiliated academic health care centers; University of Cambridge,; Cancer Research UK; The Li Ka Shing Foundation; Hutchison Whampoa Limited; NIHR Cambridge Biomedical Research Centre; The Wellcome Trust; The Leukemia & Lymphoma Society; Italian Association for Cancer Research (AIRC); Fundacion Ibercaja; Fondazione per la Ricerca Biomedica ONLUS of Torino; Department of Defense; AIRC [IG-9408]; Yale SPORE in Skin Cancer; National Cancer Institute [1 P50 CA121974]; NIH [R01 CA-82328-09] FX We thank Pandolfi and Tuveson laboratory members for critical discussions. qRT-PCR analysis was conducted with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NIH award #UL1 RR 025758 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 National Institutes of Health. We thank B. Vogelstein for DICER-/- cells and M. Bosenberg for TyrCreERt2 mice. We thank F. Connor and other members of the Tuveson lab for assistance and the animal care staff and histology core at CRI. Mice were maintained in compliance with the UK home office regulations. This research was supported by the University of Cambridge, Cancer Research UK, The Li Ka Shing Foundation, Hutchison Whampoa Limited, the NIHR Cambridge Biomedical Research Centre, and The Wellcome Trust. Y.T. was supported by a Special Fellow Award from The Leukemia & Lymphoma Society. D. P. received an International Fellowship in Cancer Research from the Italian Association for Cancer Research (AIRC). P.A.P.-M. was supported by the Fundacion Ibercaja. U. A. received a fellowship from the Fondazione per la Ricerca Biomedica ONLUS of Torino. S. M. T. was supported by a Department of Defense Breast Cancer Research Program fellowship. P. P. and U. A. received support from AIRC under grant IG-9408. This work was supported by the Yale SPORE in Skin Cancer funded by the National Cancer Institute grant number 1 P50 CA121974 to R. H. and by NIH grant R01 CA-82328-09 to P.P.P. NR 36 TC 274 Z9 301 U1 6 U2 53 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 14 PY 2011 VL 147 IS 2 BP 382 EP 395 DI 10.1016/j.cell.2011.09.032 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837KD UT WOS:000296199300016 PM 22000016 ER PT J AU Emanuele, MJ Elia, AEH Xu, QK Thoma, CR Izhar, L Leng, YM Guo, AL Chen, YN Rush, J Hsu, PWC Yen, HCS Elledge, SJ AF Emanuele, Michael J. Elia, Andrew E. H. Xu, Qikai Thoma, Claudio R. Izhar, Lior Leng, Yumei Guo, Ailan Chen, Yi-Ning Rush, John Hsu, Paul Wei-Che Yen, Hsueh-Chi Sherry Elledge, Stephen J. TI Global Identification of Modular Cullin-RING Ligase Substrates SO CELL LA English DT Article ID CUL3-BASED E3 LIGASE; UBIQUITIN-LIGASE; PROTEIN NETWORKS; F-BOX; SCF; COMPLEX; NEDD8; DEGRADATION; CONJUGATION; INHIBITOR AB Cullin-RING ligases (CRLs) represent the largest E3 ubiquitin ligase family in eukaryotes, and the identification of their substrates is critical to understanding regulation of the proteome. Using genetic and pharmacologic Cullin inactivation coupled with genetic (GPS) and proteomic (QUAINT) assays, we have identified hundreds of proteins whose stabilities or ubiquitylation status are regulated by CRLs. Together, these approaches yielded many known CRL substrates as well as a multitude of previously unknown putative substrates. We demonstrate that one substrate, NUSAP1, is an SCFCyclin F substrate during S and G2 phases of the cell cycle and is also degraded in response to DNA damage. This collection of regulated substrates is highly enriched for nodes in protein interaction networks, representing critical connections between regulatory pathways. This demonstrates the broad role of CRL ubiquitylation in all aspects of cellular biology and provides a set of proteins likely to be key indicators of cellular physiology. C1 [Emanuele, Michael J.; Elia, Andrew E. H.; Xu, Qikai; Thoma, Claudio R.; Izhar, Lior; Leng, Yumei; Yen, Hsueh-Chi Sherry; Elledge, Stephen J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Emanuele, Michael J.; Elia, Andrew E. H.; Xu, Qikai; Thoma, Claudio R.; Izhar, Lior; Leng, Yumei; Yen, Hsueh-Chi Sherry; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Elia, Andrew E. H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Guo, Ailan; Rush, John] Cell Signaling Technol, Danvers, MA 01923 USA. [Chen, Yi-Ning; Hsu, Paul Wei-Che; Yen, Hsueh-Chi Sherry] Acad Sinica, Inst Mol Biol, Taipei 115, Taiwan. [Emanuele, Michael J.; Elia, Andrew E. H.; Xu, Qikai; Thoma, Claudio R.; Izhar, Lior; Leng, Yumei; Yen, Hsueh-Chi Sherry; Elledge, Stephen J.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Yen, HCS (reprint author), Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM hyen@imb.sinica.edu.tw; selledge@genetics.med.harvard.edu FU The Jane Coffin Childs Foundation; The American Society for Radiation Oncology; EMBO and HFSP fellowship; American Cancer Society; NSC [NSC100-2628-B-001-014-MY3]; NIH FX We thank the members of the Elledge lab for helpful discussions. We thank W. Harper for the Cul3 and Cul4 dominant-negative clones and F box siRNA; S. Gygi for access to and assistance with MS/MS analysis software; the IMB Bioinformatics Services Core of Academia Sinica for technical support; and Michele Pagano for cyclin F plasmids. We thank Marc Vidal and David Hill for the ORFeome library. M.J.E. is the Philip O'Bryan Montgomery Jr., MD fellow of the Damon Runyon Cancer Research Foundation (DRG-1996-08). A.E.H.E. is supported by fellowships from The Jane Coffin Childs Foundation and The American Society for Radiation Oncology. C.R.T. is funded by an EMBO and HFSP fellowship. Q.X. is supported by a fellowship from the American Cancer Society. H.-C.S.Y. was supported by an NSC grant (NSC100-2628-B-001-014-MY3). This work was supported by an NIH grant to S.J.E. S.J.E. is an Investigator with the Howard Hughes Medical Institute. NR 49 TC 170 Z9 174 U1 2 U2 25 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 14 PY 2011 VL 147 IS 2 BP 459 EP 474 DI 10.1016/j.cell.2011.09.019 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 837KD UT WOS:000296199300022 PM 21963094 ER PT J AU Thorsen, K Schepeler, T Oster, B Rasmussen, MH Vang, S Wang, K Hansen, KQ Lamy, P Pedersen, JS Eller, A Mansilla, F Laurila, K Wiuf, C Laurberg, S Dyrskjot, L Orntoft, TF Andersen, CL AF Thorsen, Kasper Schepeler, Troels Oster, Bodil Rasmussen, Mads H. Vang, Soren Wang, Kai Hansen, Kristian Q. Lamy, Philippe Pedersen, Jakob Skou Eller, Asger Mansilla, Francisco Laurila, Kirsti Wiuf, Carsten Laurberg, Soren Dyrskjot, Lars Orntoft, Torben F. Andersen, Claus L. TI Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis SO BMC GENOMICS LA English DT Article ID HUMAN GENES; MESSENGER-RNA; PREDICTION; CELLS; EXPRESSION; PROMOTERS; SEQUENCE; DATABASE; COLON; CONSERVATION AB Background: Approximately half of all human genes use alternative transcription start sites (TSSs) to control mRNA levels and broaden the transcriptional output in healthy tissues. Aberrant expression patterns promoting carcinogenesis, however, may arise from alternative promoter usage. Results: By profiling 108 colorectal samples using exon arrays, we identified nine genes (TCF12, OSBPL1A, TRAK1, ANK3, CHEK1, UGP2, LMO7, ACSL5, and SCIN) showing tumor-specific alternative TSS usage in both adenoma and cancer samples relative to normal mucosa. Analysis of independent exon array data sets corroborated these findings. Additionally, we confirmed the observed patterns for selected mRNAs using quantitative real-time reverse-transcription PCR. Interestingly, for some of the genes, the tumor-specific TSS usage was not restricted to colorectal cancer. A comprehensive survey of the nine genes in lung, bladder, liver, prostate, gastric, and brain cancer revealed significantly altered mRNA isoform ratios for CHEK1, OSBPL1A, and TCF12 in a subset of these cancer types. To identify the mechanism responsible for the shift in alternative TSS usage, we antagonized the Wnt-signaling pathway in DLD1 and Ls174T colorectal cancer cell lines, which remarkably led to a shift in the preferred TSS for both OSBPL1A and TRAK1. This indicated a regulatory role of the Wnt pathway in selecting TSS, possibly also involving TP53 and SOX9, as their transcription binding sites were enriched in the promoters of the tumor preferred isoforms together with their mRNA levels being increased in tumor samples. Finally, to evaluate the prognostic impact of the altered TSS usage, immunohistochemistry was used to show deregulation of the total protein levels of both TCF12 and OSBPL1A, corresponding to the mRNA levels observed. Furthermore, the level of nuclear TCF12 had a significant correlation to progression free survival in a cohort of 248 stage II colorectal cancer samples. Conclusions: Alternative TSS usage in colorectal adenoma and cancer samples has been shown for nine genes, and OSBPL1A and TRAK1 were found to be regulated in vitro by Wnt signaling. TCF12 protein expression was upregulated in cancer samples and correlated with progression free survival. C1 [Thorsen, Kasper; Schepeler, Troels; Oster, Bodil; Rasmussen, Mads H.; Vang, Soren; Hansen, Kristian Q.; Lamy, Philippe; Pedersen, Jakob Skou; Eller, Asger; Mansilla, Francisco; Dyrskjot, Lars; Orntoft, Torben F.; Andersen, Claus L.] Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus N, Denmark. [Wang, Kai] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Wang, Kai] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Lamy, Philippe; Wiuf, Carsten] Aarhus Univ, Bioinformat Res Ctr BiRC, DK-8000 Aarhus C, Denmark. [Laurila, Kirsti] Tampere Univ Technol, Dept Signal Proc, FIN-33101 Tampere, Finland. [Laurberg, Soren] Aarhus Univ Hosp, Dept Surg P, THG, DK-8000 Aarhus C, Denmark. RP Andersen, CL (reprint author), Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus N, Denmark. EM cla@ki.au.dk RI Dyrskjot, Lars/H-4922-2012; Andersen, Claus/C-1477-2017; Pedersen, Jakob/G-3382-2012; Wiuf, Carsten/H-6320-2011; Andersen, Claus Lindbjerg/A-9217-2012 OI Andersen, Claus/0000-0002-7406-2103; Pedersen, Jakob/0000-0002-7236-4001; Wiuf, Carsten/0000-0002-1302-4445; Andersen, Claus Lindbjerg/0000-0002-7406-2103 FU John and Birthe Meyer Foundation; EU [201630]; Danish Council for Independent Research Medical Sciences; Danish Council for Strategic Research; Lundbeck Foundation; Danish Ministry of the Interior and Health FX The excellent technical assistance of Hanne Steen, Pamela Celis, Inge-Lis Thorsen Lisbet Kjeldsen, and Gitte Hoj is gratefully appreciated. We thank Dr. Hans Clevers (The Hubrecht Laboratory, The Netherlands) for the inducible Ls174T-derived and DLD1-derived cell lines. Previously described dnTCF4 gene expression profiles were kindly provided by Laurens G. van der Flier (The Hubrecht Laboratory, The Netherlands). This work was supported by The John and Birthe Meyer Foundation, the EU project GENICA Grant number 201630, The Danish Council for Independent Research Medical Sciences, The Danish Council for Strategic Research, The Lundbeck Foundation, and The Danish Ministry of the Interior and Health. NR 51 TC 23 Z9 24 U1 2 U2 16 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 OCT 14 PY 2011 VL 12 AR 505 DI 10.1186/1471-2164-12-505 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 842TC UT WOS:000296622200001 PM 21999571 ER PT J AU Liu, XH Yao, S Qiao, RF Levine, AC Kirschenbaum, A Pan, JP Wu, Y Qin, WP Bauman, WA Cardozo, CP AF Liu, Xin-Hua Yao, Shen Qiao, Rui-Fang Levine, Alice C. Kirschenbaum, Alexander Pan, Jiangping Wu, Yong Qin, Weiping Bauman, William A. Cardozo, Christopher P. TI Nandrolone reduces activation of Notch signaling in denervated muscle associated with increased Numb expression SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Anabolic steroids; Muscle atrophy; Notch; Numb; Androgens; Nandrolone ID SKELETAL-MUSCLE; SATELLITE CELLS; TESTOSTERONE SUPPLEMENTATION; POSTNATAL MYOGENESIS; FIBER HYPERTROPHY; MEN; DIFFERENTIATION; KINASE; MOUSE; MODEL AB Nandrolone, an anabolic steroid, slows denervation-atrophy in rat muscle. The molecular mechanisms responsible for this effect are not well understood. Androgens and anabolic steroids activate Notch signaling in animal models of aging and thereby mitigate sarcopenia. To explore the molecular mechanisms by which nandrolone prevents denervation-atrophy, we investigated the effects of nandrolone on Notch signaling in denervated rat gastrocnemius muscle. Denervation significantly increased Notch activity reflected by elevated levels of nuclear Notch intracellular domain (NICD) and expression of Hey1 (a Notch target gene). Activation was greatest at 7 and 35 days after denervation but remained present at 56 days after denervation. Activation of Notch in denervated muscle was prevented by nandrolone associated with upregulated expression of Numb mRNA and protein. These data demonstrate that denervation activates Notch signaling, and that nandrolone abrogates this response associated with increased expression of Numb, suggesting a potential mechanism by which nandrolone reduces denervation-atrophy. (C) 2011 Published by Elsevier Inc. C1 [Liu, Xin-Hua; Pan, Jiangping; Wu, Yong; Qin, Weiping; Bauman, William A.; Cardozo, Christopher P.] James J Peter VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Bronx, NY 10468 USA. [Liu, Xin-Hua; Yao, Shen; Qiao, Rui-Fang; Levine, Alice C.; Qin, Weiping; Bauman, William A.; Cardozo, Christopher P.] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Kirschenbaum, Alexander] Mt Sinai Sch Med, Dept Urol, New York, NY 10029 USA. RP Cardozo, CP (reprint author), James J Peter VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM chris.cardozo@mssm.edu FU Veterans Health Administration, Rehabilitation Research and Development Service [B4162C, B4616R, B3347 K] FX This work was supported by the Veterans Health Administration, Rehabilitation Research and Development Service (Grants B4162C, B4616R and B3347 K). NR 26 TC 6 Z9 8 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 14 PY 2011 VL 414 IS 1 BP 165 EP 169 DI 10.1016/j.bbrc.2011.09.048 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 837PH UT WOS:000296215200030 PM 21945932 ER PT J AU Mar, JC Matigian, NA Quackenbush, J Wells, CA AF Mar, Jessica C. Matigian, Nicholas A. Quackenbush, John Wells, Christine A. TI attract: A Method for Identifying Core Pathways That Define Cellular Phenotypes SO PLOS ONE LA English DT Article ID GENE SET ENRICHMENT; COEXPRESSION NETWORK ANALYSIS; EXPRESSION PROFILES AB attract is a knowledge-driven analytical approach for identifying and annotating the gene-sets that best discriminate between cell phenotypes. attract finds distinguishing patterns within pathways, decomposes pathways into meta-genes representative of these patterns, and then generates synexpression groups of highly correlated genes from the entire transcriptome dataset. attract can be applied to a wide range of biological systems and is freely available as a Bioconductor package and has been incorporated into the MeV software system. 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.; Quackenbush, John; Wells, Christine A.] Griffith Univ, Natl Ctr Adult Stem Cell Res, Eskitis Inst Cell & Mol Therapies, Brisbane, Qld 4111, Australia. [Quackenbush, John] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [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; johnq@jimmy.harvard.edu; c.wells@uq.edu.au RI Matigian, Nicholas/A-4935-2009; Wells, Christine/A-5071-2010 OI Matigian, Nicholas/0000-0001-7735-9415; Wells, Christine/0000-0003-3133-3628 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]; Australian Stem Cell Centre; National Health and Medical Research Council Australia [481945] 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 (www.griffith.edu.au) and a Harvard Club of Australia Foundation Fellowship (http://hcag.org.au/), and from the US National Library of Medicine (R01-LM010129). CAW is supported by the Australian Research Council (www.arc.gov.au) International linkage scheme (LX0882502), The Australian Stem Cell Centre and the National Health and Medical Research Council Australia (www.nhmrc.gov.au) CDA fellowship (481945). The funders had no role in study design, data collection and analysis, decision to publish or the preparation of the manuscript. NR 16 TC 19 Z9 19 U1 0 U2 2 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 OCT 14 PY 2011 VL 6 IS 10 AR e25445 DI 10.1371/journal.pone.0025445 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834RQ UT WOS:000295981600008 PM 22022396 ER PT J AU McCarthy, PL Owzar, K Anderson, K AF McCarthy, Philip L. Owzar, Kouros Anderson, Kenneth TI "Sowing dragon's teeth?" Myeloma and AML SO BLOOD LA English DT Editorial Material ID MYELOMONOCYTIC LEUKEMIA; MULTIPLE-MYELOMA; BALB/C MICE C1 [McCarthy, Philip L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. Dana Farber Canc Inst, Boston, MA USA. RP McCarthy, PL (reprint author), Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NR 12 TC 1 Z9 1 U1 0 U2 1 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 OCT 13 PY 2011 VL 118 IS 15 BP 4008 EP 4009 DI 10.1182/blood-2011-08-372243 PG 4 WC Hematology SC Hematology GA 838IT UT WOS:000296282200003 PM 21998330 ER PT J AU Gutierrez, A Kentsis, A Sanda, T Holmfeldt, L Chen, SC Zhang, JH Protopopov, A Chin, L Dahlberg, SE Neuberg, DS Silverman, LB Winter, SS Hunger, SP Sallan, SE Zha, S Alt, FW Downing, JR Mullighan, CG Look, AT AF Gutierrez, Alejandro Kentsis, Alex Sanda, Takaomi Holmfeldt, Linda Chen, Shann-Ching Zhang, Jianhua Protopopov, Alexei Chin, Lynda Dahlberg, Suzanne E. Neuberg, Donna S. Silverman, Lewis B. Winter, Stuart S. Hunger, Stephen P. Sallan, Stephen E. Zha, Shan Alt, Frederick W. Downing, James R. Mullighan, Charles G. Look, A. Thomas TI The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia SO BLOOD LA English DT Article ID T(5/14)(Q35,Q32); PROTEIN; MODEL; GENE; HAPLOINSUFFICIENCY; ACTIVATION; CHECKPOINT; EXPRESSION; DELETION; LINEAGE AB The BCL11B transcription factor is required for normal T-cell development, and has recently been implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) induced by TLX overexpression or Atm deficiency. To comprehensively assess the contribution of BCL11B inactivation to human T-ALL, we performed DNA copy number and sequencing analyses of T-ALL diagnostic specimens, revealing monoallelic BCL11B deletions or missense mutations in 9% (n = 10 of 117) of cases. Structural homology modeling revealed that several of the BCL11B mutations disrupted the structure of zinc finger domains required for this transcription factor to bind DNA. BCL11B haploinsufficiency occurred across each of the major molecular subtypes of T-ALL, including early T-cell precursor, HOXA-positive, LEF1-inactivated, and TAL1-positive subtypes, which have differentiation arrest at diverse stages of thymocyte development. Our findings provide compelling evidence that BCL11B is a haploinsufficient tumor suppressor that collaborates with all major T-ALL oncogenic lesions in human thymocyte transformation. (Blood. 2011; 118(15):4169-4173) C1 [Gutierrez, Alejandro; Kentsis, Alex; Sanda, Takaomi; Silverman, Lewis B.; Sallan, Stephen E.; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Gutierrez, Alejandro; Kentsis, Alex; Silverman, Lewis B.; Sallan, Stephen E.; Look, A. Thomas] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Holmfeldt, Linda; Chen, Shann-Ching; Downing, James R.; Mullighan, Charles G.] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Zhang, Jianhua; Protopopov, Alexei; Chin, Lynda] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dahlberg, Suzanne E.; Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Winter, Stuart S.] Univ New Mexico, Dept Pediat, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Hunger, Stephen P.] Univ Colorado, Sch Med, Sect Pediat Hematol Oncol, Aurora, CO USA. [Hunger, Stephen P.] Childrens Hosp, Aurora, CO USA. [Zha, Shan] Columbia Univ, Dept Pathol, Inst Canc Genet, Med Ctr, New York, NY USA. [Zha, Shan] Columbia Univ, Dept Pediat, Inst Canc Genet, Med Ctr, New York, NY 10027 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Boston, MA USA. [Alt, Frederick W.] Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst, Boston, MA 02115 USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Mayer 630,44 Binney St, Boston, MA 02215 USA. EM thomas_look@dfci.harvard.edu OI Kentsis, Alex/0000-0002-8063-9191; Gutierrez, Alejandro/0000-0002-0249-9007; Mullighan, Charles/0000-0002-1871-1850; Holmfeldt, Linda/0000-0003-4140-3423 FU National Institute of Health [2P01CA109901, 5P01CA68484, 1RO1CA158073, CA98543, CA114766, CA98413, CA30969, CA29139, 1K08CA133103]; COG 9900 cell biology study; St Jude Children's Research Hospital-Washington University FX This work was funded by National Institute of Health grants 2P01CA109901 (A. T. L. and F. W. A.), 5P01CA68484 (S. E. S. and A. T. L.), and 1RO1CA158073 (S.Z.). COG cell banking and sample distribution were supported by the COG 9900 cell biology study and grants CA98543, CA114766, CA98413, CA30969, and CA29139 from the National Institutes of Health. Sequence and analysis of St Jude, AEIOP, and COG samples was supported by the St Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project. A. G. is supported by National Institutes of Health grant 1K08CA133103 and is a scholar of the American Society of Hematology-Amos Medical Faculty Development program. L. H. is supported by the Swedish Research Council. S. S. W. is the T. John Gribble Chair of Pediatric Hematology/Oncology at the University of New Mexico. S. P. H. is the Ergen Family Chair in Pediatric Cancer at The Children's Hospital, Aurora, CO. S.Z. is supported by the Leukemia & Lymphoma Society, the St Baldrick Foundation, and the Johns M. Driscoll Jr Children's Fund. C. G. M. is a Pew Scholar in the Biomedical Sciences. The array CGH analyses were performed and supported in part by the Belfer Institute for Applied Cancer Science. NR 25 TC 59 Z9 59 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 OCT 13 PY 2011 VL 118 IS 15 BP 4169 EP 4173 DI 10.1182/blood-2010-11-318873 PG 5 WC Hematology SC Hematology GA 838IT UT WOS:000296282200025 PM 21878675 ER PT J AU Steinbicker, AU Bartnikas, TB Lohmeyer, LK Leyton, P Mayeur, C Kao, SM Pappas, AE Peterson, RT Bloch, DB Yu, PB Fleming, MD Bloch, KD AF Steinbicker, Andrea U. Bartnikas, Thomas B. Lohmeyer, Lisa K. Leyton, Patricio Mayeur, Claire Kao, Sonya M. Pappas, Alexandra E. Peterson, Randall T. Bloch, Donald B. Yu, Paul B. Fleming, Mark D. Bloch, Kenneth D. TI Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice SO BLOOD LA English DT Article ID MOUSE EMBRYOGENESIS; KNOCKOUT MICE; HEREDITARY HEMOCHROMATOSIS; JUVENILE HEMOCHROMATOSIS; GENE-EXPRESSION; RAT-LIVER; METABOLISM; GASTRULATION; FERROPORTIN; ALK2 AB Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3- than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepcidin expression. Both Alk2 and Alk3 were required for induction of hepcidin gene expression by BMP2 in cultured hepatocytes or by iron challenge in vivo. These observations demonstrate that one type I BMP receptor, Alk3, is critically responsible for basal hepcidin expression, whereas 2 type I BMP receptors, Alk2 and Alk3, are required for regulation of hepcidin gene expression in response to iron and BMP signaling. (Blood. 2011;118(15):4224-4230) C1 [Steinbicker, Andrea U.; Lohmeyer, Lisa K.; Leyton, Patricio; Mayeur, Claire; Kao, Sonya M.; Pappas, Alexandra E.; Bloch, Kenneth D.] Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Steinbicker, Andrea U.; Bartnikas, Thomas B.; Lohmeyer, Lisa K.; Leyton, Patricio; Mayeur, Claire; Kao, Sonya M.; Pappas, Alexandra E.; Bloch, Donald B.; Fleming, Mark D.; Bloch, Kenneth D.] Harvard Univ, Sch Med, Boston, MA USA. [Steinbicker, Andrea U.] Univ Munster, Dept Anesthesiol & Intens Care Med, D-48149 Munster, Germany. [Bartnikas, Thomas B.; Fleming, Mark D.; Bloch, Kenneth D.] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Peterson, Randall T.; Yu, Paul B.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bloch, Donald B.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Steinbicker, AU (reprint author), Univ Munster, Dept Anesthesia & Intens Care Med, Univ Hosp Muenster, Albert Schweitzer Campus 1, D-48149 Munster, Germany. EM andrea.steinbicker@gmail.com OI Yu, Paul/0000-0003-2145-4944 FU Deutsche Forschungsgemeinschaft (DFG) [SW 119/3-1]; National Institute of Diabetes and Digestive and Kidney Diseases [K99DK084122, R01DK082971]; Fondation LeDucq FX This work was supported by the Deutsche Forschungsgemeinschaft (DFG SW 119/3-1, A.U.S.), the National Institute of Diabetes and Digestive and Kidney Diseases (K99DK084122 to T.B.B., R01DK082971 to M.D.F., and R01DK082971 to R.T.P. and K.D.B.), and the Fondation LeDucq (P.B.Y. and K.D.B). NR 45 TC 63 Z9 64 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 OCT 13 PY 2011 VL 118 IS 15 BP 4224 EP 4230 DI 10.1182/blood-2011-03-339952 PG 7 WC Hematology SC Hematology GA 838IT UT WOS:000296282200032 PM 21841161 ER PT J AU Arai, S Jagasia, M Storer, B Chai, XY Pidala, J Cutler, C Arora, M Weisdorf, DJ Flowers, MED Martin, PJ Palmer, J Jacobsohn, D Pavletic, SZ Vogelsang, GB Lee, SJ AF Arai, Sally Jagasia, Madan Storer, Barry Chai, Xiaoyu Pidala, Joseph Cutler, Corey Arora, Mukta Weisdorf, Daniel J. Flowers, Mary E. D. Martin, Paul J. Palmer, Jeanne Jacobsohn, David Pavletic, Steven Z. Vogelsang, Georgia B. Lee, Stephanie J. TI Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria SO BLOOD LA English DT Article ID WORKING GROUP-REPORT; BONE-MARROW TRANSPLANTATION; STEM-CELL TRANSPLANTATION; DEVELOPMENT PROJECT; CLINICAL-TRIALS; CHRONIC GVHD; CLASSIFICATION; DURATION AB In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n = 32), moderate in 59% (n = 175), and severe in 31% (n = 91). Skin, lung, or eye scores determined the global severity score in the majority of cases, with the other 5 organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and nonrelapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with nonrelapse mortality (P < .0001) and survival (P < .0001); 2-year overall survival was 62% (severe), 86% (moderate), and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. This study was registered at www.clinicaltrials.gov as no. NCT00637689. (Blood. 2011;118(15):4242-4249) C1 [Storer, Barry; Chai, Xiaoyu; Flowers, Mary E. D.; Martin, Paul J.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Arai, Sally] Stanford Univ, Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Arora, Mukta; Weisdorf, Daniel J.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Palmer, Jeanne] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Jacobsohn, David] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. [Pavletic, Steven Z.] NCI, NIH, Bethesda, MD 20892 USA. [Vogelsang, Georgia B.] Johns Hopkins Univ Hosp, Dept Oncol, Baltimore, MD 21287 USA. RP Lee, SJ (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-290, Seattle, WA 98109 USA. EM sjlee@fhcrc.org FU National Institutes of Health/National Cancer Institute [CA 118953] FX This work was supported by National Institutes of Health/National Cancer Institute grant CA 118953. NR 22 TC 83 Z9 86 U1 1 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 OCT 13 PY 2011 VL 118 IS 15 BP 4242 EP 4249 DI 10.1182/blood-2011-03-344390 PG 8 WC Hematology SC Hematology GA 838IT UT WOS:000296282200035 PM 21791424 ER PT J AU Trinh, NHT Bedoya, CA Chang, TE Flaherty, K Fava, M Yeung, A AF Trinh, Nhi-Ha T. Bedoya, C. A. Chang, Trina E. Flaherty, Katherine Fava, Maurizio Yeung, Albert TI A study of a culturally focused psychiatric consultation service for Asian American and Latino American primary care patients with depression SO BMC PSYCHIATRY LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; DSM-IV; CHINESE-AMERICANS; ETHNIC-MINORITIES; MAJOR DEPRESSION; VALIDATION; INTERVENTIONS; DISPARITIES; MANAGEMENT; DISORDERS AB Background: Ethnic minorities with depression are more likely to seek mental health care through primary care providers (PCPs) than mental health specialists. However, both provider and patient-specific challenges exist. PCP-specific challenges include unfamiliarity with depressive symptom profiles in diverse patient populations, limited time to address mental health, and limited referral options for mental health care. Patient specific challenges include stigma around mental health issues and reluctance to seek mental health treatment. To address these issues, we implemented a multi-component intervention for Asian American and Latino American primary care patients with depression at Massachusetts General Hospital (MGH). Methods/Design: We propose a randomized controlled trial to evaluate a culturally appropriate intervention to improve the diagnosis and treatment of depression in our target population. Our goals are to facilitate a) primary care providers' ability to provide appropriate, culturally informed care of depression, and b) patients' knowledge of and resources for receiving treatment for depression. Our two-year long intervention targets Asian American and Latino American adult (18 years of age or older) primary care patients at MGH screening positive for symptoms of depression. All eligible patients in the intervention arm of the study who screen positive will be offered a culturally focused psychiatric (CFP) consultation. Patients will meet with a study clinician and receive toolkits that include psychoeducational booklets, worksheets and community resources. Within two weeks of the initial consultation, patients will attend a follow-up visit with the CFP clinicians. Primary outcomes will determine the feasibility and cost associated with implementation of the service, and evaluate patient and provider satisfaction with the CFP service. Exploratory aims will describe the study population at screening, recruitment, and enrollment and identify which variables influenced patient participation in the program. Discussion: The study involves an innovative yet practical intervention that builds on existing resources and strives to improve quality of care for depression for minorities. Additionally, it complements the current movement in psychiatry to enhance the treatment of depression in primary care settings. If found beneficial, the intervention will serve as a model for care of Asian American and Latino American patients. C1 [Trinh, Nhi-Ha T.; Chang, Trina E.; Fava, Maurizio; Yeung, Albert] Massachusetts Gen Hosp, Depress & Clin Res Program, Boston, MA 02114 USA. [Bedoya, C. A.] Massachusetts Gen Hosp, Behav Med Serv, Boston, MA 02114 USA. [Flaherty, Katherine] ABT Associates Inc, Cambridge, MA 02138 USA. RP Trinh, NHT (reprint author), Massachusetts Gen Hosp, Depress & Clin Res Program, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM ntrinh@partners.org FU Robert Wood Johnson Foundation (RWJF) [66709]; MGH Development Office FX This research project is funded by a grant from the Robert Wood Johnson Foundation's program, "Finding Answers: Disparities Research for Change" (RWJF grant number 66709) to Dr. Trinh, with additional support from the MGH Department of Psychiatry. The authors would like to thank the professional and support staff at the participating sites for their commitment and participation in the study: MGH Charlestown Healthcare Center, MGH Chelsea Healthcare Center, MGH Revere Healthcare Center and MGH Internal Medicine Associates. The authors would also like to thank Drs. Joseph Betancourt and Alexander Green from the MGH Disparities Solutions Center for their contributions to the conception and design of the study, Jennifer Riconda and the MGH Development Office for their support of the grant, Dr. Jerrold Rosenbaum the chief of the MGH Department of Psychiatry for his support of the study, and Charlotte Brill, Katherine Hails, Soo Jeong Yoon, Jenny Man for their technical assistance in the study. NR 35 TC 8 Z9 8 U1 8 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD OCT 13 PY 2011 VL 11 AR 166 DI 10.1186/1471-244X-11-166 PG 10 WC Psychiatry SC Psychiatry GA 843CZ UT WOS:000296651200001 PM 21995514 ER PT J AU Kovac, A Erickson, MA Banks, WA AF Kovac, Andrej Erickson, Michelle A. Banks, William A. TI Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE mouse brain pericytes; LPS; neurovascular unit; cytokines; chemokines; LRP-1; Alzheimers disease; nitric oxide ID RECEPTOR-RELATED PROTEIN-1; IL-12 P40 HOMODIMER; BLOOD-BRAIN; ALZHEIMERS-DISEASE; ENDOTHELIAL-CELLS; MICROGLIAL CELLS; CNS; BARRIER; MACROPHAGES; SURVIVAL AB Background: Brain microvascular pericytes are important constituents of the neurovascular unit. These cells are physically the closest cells to the microvascular endothelial cells in brain capillaries. They significantly contribute to the induction and maintenance of the barrier functions of the blood-brain barrier. However, very little is known about their immune activities or their roles in neuroinflammation. Here, we focused on the immunological profile of brain pericytes in culture in the quiescent and immune-challenged state by studying their production of immune mediators such as nitric oxide (NO), cytokines, and chemokines. We also examined the effects of immune challenge on pericyte expression of low density lipoprotein receptor-related protein-1 (LRP-1), a protein involved in the processing of amyloid precursor protein and the brain-to-blood efflux of amyloid-beta peptide. Methods: Supernatants were collected from primary cultures of mouse brain pericytes. Release of nitric oxide (NO) was measured by the Griess reaction and the level of S-nitrosylation of pericyte proteins measured with a modified "biotin-switch" method. Specific mitogen-activated protein kinase (MAPK) pathway inhibitors were used to determine involvement of these pathways on NO production. Cytokines and chemokines were analyzed by multianalyte technology. The expression of both subunits of LRP-1 was analyzed by western blot. Results: Lipopolysaccharide (LPS) induced release of NO by pericytes in a dose-dependent manner that was mediated through MAPK pathways. Nitrative stress resulted in S-nitrosylation of cellular proteins. Eighteen of twenty-three cytokines measured were released constitutively by pericytes or with stimulation by LPS, including interleukin (IL)-12, IL-13, IL-9, IL-10, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, eotaxin, chemokine (C-C motif) ligand (CCL)-3, and CCL-4. Pericyte expressions of both subunits of LRP-1 were upregulated by LPS. Conclusions: Our results show that cultured mouse brain microvascular pericytes secrete cytokines, chemokines, and nitric oxide and respond to the innate immune system stimulator LPS. These immune properties of pericytes are likely important in their communication within the neurovascular unit and provide a mechanism by which they participate in neuroinflammatory processes in brain infections and neurodegenerative diseases. C1 [Erickson, Michelle A.; Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Kovac, Andrej; Banks, William A.] Univ Washington, Div Gerontol & Geriatr Med, Dept Internal Med, Seattle, WA 98195 USA. [Erickson, Michelle A.; Banks, William A.] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. [Kovac, Andrej] Slovak Acad Sci, Inst Neuroimmunol, Bratislava, Slovakia. RP Banks, WA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. EM wabanks1@uw.edu FU VA Merit Review [RO1 AG029839, R01 DK083485] FX Supported by VA Merit Review, RO1 AG029839, and R01 DK083485. NR 47 TC 56 Z9 56 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD OCT 13 PY 2011 VL 8 AR 139 DI 10.1186/1742-2094-8-139 PG 9 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 841SF UT WOS:000296532700001 PM 21995440 ER PT J AU Ashktorab, H Nguza, B Fatemi, M Nouraie, M Smoot, DT Schaffer, AA Kupfer, SS Camargo, CA Brim, H AF Ashktorab, Hassan Nguza, Bijou Fatemi, Mehrnaz Nouraie, Mehdi Smoot, Duane T. Schaeffer, Alejandro A. Kupfer, Sonia S. Camargo, Carlos A., Jr. Brim, Hassan TI Case-Control Study of Vitamin D, dickkopf homolog 1 (DKK1) Gene Methylation, VDR Gene Polymorphism and the Risk of Colon Adenoma in African Americans SO PLOS ONE LA English DT Article ID D-RECEPTOR GENE; BREAST-CANCER RISK; COLORECTAL-CANCER; RECTAL-CANCER; CIRCULATING 25-HYDROXYVITAMIN-D; D DEFICIENCY; PREVENTION; POPULATION; ASSOCIATIONS; METAANALYSIS AB Background: There are sparse data on genetic, epigenetic and vitamin D exposure in African Americans (AA) with colon polyp. Consequently, we evaluated serum 25(OH) D levels, vitamin D receptor (VDR) polymorphisms and the methylation status of the tumor suppressor gene dickkopf homolog 1 (DKK1) as risk factors for colon polyp in this population. Methods: The case-control study consisted of 93 patients with colon polyp (cases) and 187 healthy individuals (controls) at Howard University Hospital. Serum levels of 25(OH)D (including D3, D2, and total) were measured by liquid chromatography-mass spectrometry. DNA analysis focused on 49 single nucleotide polymorphisms (SNPs) in the VDR gene. Promoter methylation analysis of DKK1 was also performed. The resulting data were processed in unadjusted and multivariable logistic regression analyses. Results: Cases and controls differed in vitamin D status (D-3 < 50 nmol/L: Median of 35.5 in cases vs. 36.8 in controls nmol/L; P = 0.05). Low levels of 25(OH)D-3 (< 50 nmol/L) were observed in 86% of cases and 68% of controls and it was associated with higher risks of colon polyp (odds ratio of 2.7, 95% confidence interval 1.3-3.4). The SNP analysis showed no association between 46 VDR polymorphisms and colon polyp. The promoter of the DKK1 gene was unmethylated in 96% of the samples. Conclusion: We found an inverse association between serum 25(OH)D-3 and colon polyp in AAs. VDR SNPs and DKK1 methylation were not associated with colon polyp. Vitamin D levels may in part explain the higher incidence of polyp in AAs. C1 [Ashktorab, Hassan; Nguza, Bijou; Fatemi, Mehrnaz; Smoot, Duane T.] Howard Univ, Coll Med, Dept Med, Washington, DC 20059 USA. [Ashktorab, Hassan; Nguza, Bijou; Fatemi, Mehrnaz; Smoot, Duane T.] Howard Univ, Ctr Canc, Coll Med, Washington, DC 20059 USA. [Nouraie, Mehdi] Howard Univ, Coll Med, Ctr Sickle Cell Dis, Washington, DC USA. [Brim, Hassan] Howard Univ, Coll Med, Dept Pathol, Washington, DC USA. [Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kupfer, Sonia S.] Univ Chicago, Dept Med, Gastroenterol Sect, Chicago, IL 60637 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Ashktorab, H (reprint author), Howard Univ, Coll Med, Dept Med, Washington, DC 20059 USA. EM hashktorab@howard.edu RI Schaffer, Alejandro/F-2902-2012 FU National Institutes of Health [CA102681]; Massachusetts General Hospital Center for D-receptor Activation Research; NIH, NLM FX This work was supported in part by a PHS grant from the National Institutes of Health CA102681, (H.A) and by the Massachusetts General Hospital Center for D-receptor Activation Research (C.A.C). The Cancer Research Foundation (S.S.K.) and the Digestive Disease Research Core Center (P30 DK42086). This work was also supported by the Intramural Research Program of the NIH, NLM (A.A.S.). No additional external funding 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 45 TC 9 Z9 9 U1 0 U2 4 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 OCT 13 PY 2011 VL 6 IS 10 AR e25314 DI 10.1371/journal.pone.0025314 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834QT UT WOS:000295978600012 PM 22022386 ER PT J AU Aster, JC Bodnar, N Xu, LW Karnell, F Milholland, JM Maillard, I Histen, G Nam, Y Blacklow, SC Pear, WS AF Aster, Jon C. Bodnar, Nick Xu, Lanwei Karnell, Fredrick Milholland, John M. Maillard, Ivan Histen, Gavin Nam, Yunsun Blacklow, Stephen C. Pear, Warren S. TI Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation SO PLOS ONE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; PROTEIN SECONDARY STRUCTURE; T-CELL LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; C-MYC; CIRCULAR-DICHROISM; INTRACELLULAR DOMAINS; TRANSCRIPTIONAL ACTIVATION; NEGATIVE AUTOREGULATION; CRYSTAL-STRUCTURE AB Background: The functional interchangeability of mammalian Notch receptors (Notch1-4) in normal and pathophysiologic contexts such as cancer is unsettled. We used complementary in vivo, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T-ALL), and maintain T-ALL cell growth and survival. Principal Findings: We find that the activated intracellular domains of Notch1-4 (ICN1-4) all support T cell development in mice and thymic organ culture. However, unlike ICN1-3, ICN4 fails to induce T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and is unable to rescue the growth of Notch1-dependent T-ALL cell lines. The ICN4 phenotype is mimicked by weak gain-of-function forms of Notch1, suggesting that it stems from a failure to transactivate one or more critical target genes above a necessary threshold. Experiments with chimeric receptors demonstrate that the Notch ankyrin repeat domains differ in their leukemogenic potential, and that this difference correlates with activation of Myc, a direct Notch target that has an important role in Notch-associated T-ALL. Conclusions/Significance: We conclude that the leukemogenic potentials of Notch receptors vary, and that this functional difference stems in part from divergence among the highly conserved ankyrin repeats, which influence the transactivation of specific target genes involved in leukemogenesis. C1 [Aster, Jon C.; Histen, Gavin; Blacklow, Stephen C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Xu, Lanwei; Karnell, Fredrick; Milholland, John M.; Maillard, Ivan; Pear, Warren S.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Abramson Family Canc Res Inst,Inst Med & Engn, Philadelphia, PA 19104 USA. [Bodnar, Nick; Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Bodnar, Nick; Nam, Yunsun; Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Aster, JC (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM jaster@rics.bwh.harvard.edu; wpear@mail.med.upenn.edu FU National Institutes of Health [T32 CA09140]; Leukemia and Lymphoma Society FX This work was supported by grants from the National Institutes of Health (WSP, JCA, and SCB) and the Leukemia and Lymphoma Society SCOR Program (WSP, JCA, and SCB). JMM was supported by NIH training grant T32 CA09140. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 3 Z9 3 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 OCT 13 PY 2011 VL 6 IS 10 AR e25645 DI 10.1371/journal.pone.0025645 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834QT UT WOS:000295978600025 PM 22022427 ER PT J AU Singh, T Katiyar, SK AF Singh, Tripti Katiyar, Santosh K. TI Green Tea Catechins Reduce Invasive Potential of Human Melanoma Cells by Targeting COX-2, PGE(2) Receptors and Epithelial-to-Mesenchymal Transition SO PLOS ONE LA English DT Article ID NF-KAPPA-B; GRAPE SEED PROANTHOCYANIDINS; LUNG-CANCER; INFLAMMATORY RESPONSES; GUANYLATE-CYCLASE; PROSTAGLANDIN E-2; CARCINOMA-CELLS; NITRIC-OXIDE; SKIN-CANCER; DNA-REPAIR AB Melanoma is the most serious type of skin disease and a leading cause of death from skin disease due to its highly metastatic ability. To develop more effective chemopreventive agents for the prevention of melanoma, we have determined the effect of green tea catechins on the invasive potential of human melanoma cells and the molecular mechanisms underlying these effects using A375 (BRAF-mutated) and Hs294t (Non-BRAF-mutated) melanoma cell lines as an in vitro model. Employing cell invasion assays, we found that the inhibitory effects of green tea catechins on the cell migration were in the order of (-)-epigallocatechin-3-gallate (EGCG)>(-)-epigallocatechin >(-)-epicatechin-3-gallate >(-)-gallocatechin >(-)-epicatechin. Treatment of A375 and Hs294t cells with EGCG resulted in a dose-dependent inhibition of cell migration or invasion of these cells, which was associated with a reduction in the levels of cyclooxygenase (COX)-2, prostaglandin (PG) E-2 and PGE(2) receptors (EP2 and EP4). Treatment of cells with celecoxib, a COX-2 inhibitor, also inhibited melanoma cell migration. EGCG inhibits 12-O-tetradecanoylphorbol-13-acetate-, an inducer of COX-2, and PGE(2)-induced cell migration of cells. EGCG decreased EP2 agonist (butaprost)- and EP4 agonist (Cay10580)-induced cell migration ability. Moreover, EGCG inhibited the activation of NF-kappa B/p65, an upstream regulator of COX-2, in A375 melanoma cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kappa B, also inhibited cell migration. Inhibition of melanoma cell migration by EGCG was associated with transition of mesenchymal stage to epithelial stage, which resulted in an increase in the levels of epithelial biomarkers (E-cadherin, cytokeratin and desmoglein 2) and a reduction in the levels of mesenchymal biomarkers (vimentin, fibronectin and N-cadherin) in A375 melanoma cells. Together, these results indicate that EGCG, a major green tea catechin, has the ability to inhibit melanoma cell invasion/migration, an essential step of metastasis, by targeting the endogenous expression of COX-2, PGE2 receptors and epithelial-to-mesenchymal transition. C1 [Singh, Tripti; Katiyar, Santosh K.] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama, Nutr Obes Res Ctr, Birmingham, AL USA. [Katiyar, Santosh K.] Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Singh, T (reprint author), Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU National Center for Complementary and Alternative Medicine, NCCAM/NIH [5RO1 AT002536]; Veterans Administration FX This work was supported by funds from the 5RO1 AT002536 by National Center for Complementary and Alternative Medicine, NCCAM/NIH (SKK) (http//www.cancer.gov), and Veterans Administration Merit Review Award (SKK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 39 Z9 43 U1 0 U2 22 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 OCT 13 PY 2011 VL 6 IS 10 AR e25224 DI 10.1371/journal.pone.0025224 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834QT UT WOS:000295978600011 PM 22022384 ER PT J AU Papaemmanuil, E Cazzola, M Boultwood, J Malcovati, L Vyas, P Bowen, D Pellagatti, A Wainscoat, JS Hellstrom-Lindberg, E Gambacorti-Passerini, C Godfrey, AL Rapado, I Cvejic, A Rance, R McGee, C Ellis, P Mudie, LJ Stephens, PJ McLaren, S Massie, CE Tarpey, PS Varela, I Nik-Zainal, S Davies, HR Shlien, A Jones, D Raine, K Hinton, J Butler, AP Teague, JW Baxter, EJ Score, J Galli, A Della Porta, MG Travaglino, E Groves, M Tauro, S Munshi, NC Anderson, KC El-Naggar, A Fischer, A Mustonen, V Warren, AJ Cross, NCP Green, AR Futreal, PA Stratton, MR Campbell, PJ AF Papaemmanuil, E. Cazzola, M. Boultwood, J. Malcovati, L. Vyas, P. Bowen, D. Pellagatti, A. Wainscoat, J. S. Hellstrom-Lindberg, E. Gambacorti-Passerini, C. Godfrey, A. L. Rapado, I. Cvejic, A. Rance, R. McGee, C. Ellis, P. Mudie, L. J. Stephens, P. J. McLaren, S. Massie, C. E. Tarpey, P. S. Varela, I. Nik-Zainal, S. Davies, H. R. Shlien, A. Jones, D. Raine, K. Hinton, J. Butler, A. P. Teague, J. W. Baxter, E. J. Score, J. Galli, A. Della Porta, M. G. Travaglino, E. Groves, M. Tauro, S. Munshi, N. C. Anderson, K. C. El-Naggar, A. Fischer, A. Mustonen, V. Warren, A. J. Cross, N. C. P. Green, A. R. Futreal, P. A. Stratton, M. R. Campbell, P. J. CA Int Canc Genome Consortium TI Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; DNMT3A MUTATIONS; EXPRESSION PROFILES; FREQUENT MUTATION; GENE ASXL1; CANCER; GENOME; NEOPLASMS; CELLS; CLASSIFICATION AB BACKGROUND Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODS We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTS We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONS Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.) C1 [Papaemmanuil, E.; Rapado, I.; Cvejic, A.; Rance, R.; McGee, C.; Ellis, P.; Mudie, L. J.; Stephens, P. J.; McLaren, S.; Tarpey, P. S.; Varela, I.; Nik-Zainal, S.; Davies, H. R.; Shlien, A.; Jones, D.; Raine, K.; Hinton, J.; Butler, A. P.; Teague, J. W.; Fischer, A.; Mustonen, V.; Futreal, P. A.; Stratton, M. R.; Campbell, P. J.] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. [Boultwood, J.; Pellagatti, A.] Univ Oxford, Nuffield Dept Clin Lab Sci, Oxford, England. [Vyas, P.] Univ Oxford, Weatherall Inst Mol Med, Oxford, England. [Bowen, D.] St James Hosp, St James Inst Oncol, Leeds LS9 7TF, W Yorkshire, England. [Godfrey, A. L.; Cvejic, A.; Massie, C. E.; Baxter, E. J.; Warren, A. J.; Green, A. R.; Campbell, P. J.] Univ Cambridge, Dept Haematol, Cambridge, England. [Warren, A. J.] Univ Cambridge, MRC, Mol Biol Lab, Cambridge, England. [Warren, A. J.; Green, A. R.; Campbell, P. J.] Addenbrookes Hosp, Dept Haematol, Cambridge CB2 2QQ, England. [Score, J.; Cross, N. C. P.] Univ Southampton, Sch Med, Southampton, Hants, England. [Groves, M.; Tauro, S.] Univ Dundee, Div Med Sci, Dundee, Scotland. [Cazzola, M.; Malcovati, L.; Galli, A.; Della Porta, M. G.; Travaglino, E.] Univ Pavia, Policlin San Matteo, Fdn Ist Ricovero & Cura Carattere Sci, I-27100 Pavia, Italy. [Hellstrom-Lindberg, E.] Karolinska Inst, Dept Hematol, Stockholm, Sweden. [Gambacorti-Passerini, C.] S Gerardo Hosp, Dept Hematol, Monza, Italy. [Gambacorti-Passerini, C.] Univ Milano Bicocca, Milan, Italy. [Munshi, N. C.; Anderson, K. C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Munshi, N. C.] VA Boston Healthcare Syst, Boston, MA USA. [El-Naggar, A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Fischer, A.] Univ Cologne, Inst Theoret Phys, D-5000 Cologne, Germany. RP Campbell, PJ (reprint author), Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. EM pc8@sanger.ac.uk RI Cross, Nicholas/B-4817-2009; Varela, Ignacio/G-1699-2016; OI Cross, Nicholas/0000-0001-5481-2555; Varela, Ignacio/0000-0002-0969-506X; GAMBACORTI PASSERINI, CARLO/0000-0001-6058-515X FU Wellcome Trust [077012/Z/05/Z, WT088340MA]; Kay Kendall Leukaemia Fund; Leukemia Lymphoma Research; Adenoid Cystic Carcinoma Research Foundation; Medical Research Council (MRC); Oxford National Institutes for Health Research Biomedical Research Centre; International Human Frontier Science Program Organization; Department of Veterans Affairs; National Institutes of Health [R01-124929, P01-155249, P50-100007, P01-78378]; Association for International Cancer Research; Leukemia Lymphoma Society; Associazione Italiana per la Ricerca sul Cancro; Fondazione Cariplo FX Supported by grants from the Wellcome Trust (077012/Z/05/Z, for the overall study, as well as WT088340MA, to Dr. Campbell), the Kay Kendall Leukaemia Fund, Leukemia Lymphoma Research (for the overall study and to Drs. Boultwood, Green, Vyas, and Wainscoat), the Adenoid Cystic Carcinoma Research Foundation, the Medical Research Council (MRC) (to Dr. Warren), the Oxford National Institutes for Health Research Biomedical Research Centre (to Drs. Boultwood, Vyas, and Wainscoat), the Swedish Cancer Society (to Dr. Hellstrom-Lindburg), the International Human Frontier Science Program Organization (to Dr. Varela), the Department of Veterans Affairs and the National Institutes of Health (R01-124929, P01-155249, P50-100007, and P01-78378, to Drs. Munshi and Anderson), the Association for International Cancer Research and the Leukemia Lymphoma Society (to Drs. Warren and Green), Associazione Italiana per la Ricerca sul Cancro (to the University of Pavia, the University of Milan Bicocca, and Dr. Cazzola), and Fondazione Cariplo (to the University of Pavia and the University of Milan Bicocca). NR 40 TC 428 Z9 441 U1 2 U2 33 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 OCT 13 PY 2011 VL 365 IS 15 BP 1384 EP 1395 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 832DQ UT WOS:000295782500006 PM 21995386 ER PT J AU Diller, L AF Diller, Lisa TI Adult Primary Care after Childhood Acute Lymphoblastic Leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LONG-TERM SURVIVORS; CENTRAL-NERVOUS-SYSTEM; BONE-MINERAL DENSITY; CANCER SURVIVOR; GROWTH-HORMONE; 2ND NEOPLASMS; FOLLOW-UP; SECONDARY NEOPLASMS; 5-YEAR SURVIVORS; PEDIATRIC CANCER AB A 26-year-old woman presents to an internist to establish primary care. Her medical history includes a diagnosis of acute lymphoblastic leukemia (ALL) at 3 years of age. She does not know what therapies she received, but her parents told her that she was treated for 2 years and that her leukemia never recurred. She is a high-school graduate and works as a receptionist. What are the issues to consider in the care of this long-term survivor of childhood leukemia? C1 [Diller, Lisa] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Dept Med,Childrens Hosp, Boston, MA 02215 USA. [Diller, Lisa] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02215 USA. RP Diller, L (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Dept Med,Childrens Hosp, 450 Brookline Ave, Boston, MA 02215 USA. EM lisa_diller@dfci.harvard.edu FU Hyundai FX Dr. Diller reports receiving fees for serving on the medical advisory committee for the Hope on Wheels Foundation, which is sponsored by Hyundai. No other potential conflict of interest relevant to this article was reported. NR 52 TC 21 Z9 22 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 OCT 13 PY 2011 VL 365 IS 15 BP 1417 EP 1424 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 832DQ UT WOS:000295782500009 PM 21995389 ER PT J AU Lanuti, M Sequist, LV Sharma, A Mino-Kenudson, M AF Lanuti, Michael Sequist, Lecia V. Sharma, Amita Mino-Kenudson, Mari TI Case 31-2011: A 55-Year-Old Man with Oligometastatic Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FACTOR-RECEPTOR MUTATIONS; SYNCHRONOUS BRAIN METASTASES; CHEMOTHERAPY-NAIVE PATIENTS; CLINICAL-PRACTICE GUIDELINE; SURGICAL-TREATMENT; CEREBRAL METASTASIS; EGFR MUTATIONS; GENE-MUTATIONS; PHASE-II; GEFITINIB C1 [Lanuti, Michael] Massachusetts Gen Hosp, Dept Thorac Surg, Boston, MA 02114 USA. [Sharma, Amita] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sequist, Lecia V.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Lanuti, Michael] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Sequist, Lecia V.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sharma, Amita] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Mino-Kenudson, Mari] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Lanuti, M (reprint author), Massachusetts Gen Hosp, Dept Thorac Surg, Boston, MA 02114 USA. FU Department of Continuing Education, Harvard Medical School, Boston; Boston Scientific; GlaxoSmithKline; Telik FX This case was discussed at the postgraduate course General Thoracic Surgery, directed by Douglas J. Mathisen, M.D., and Cameron Wright, M.D., of the Division of Thoracic Surgery, Massachusetts General Hospital, sponsored by the Department of Continuing Education, Harvard Medical School, Boston, and moderated by Eugene Mark, M.D.; Dr. Lanuti reports receiving consulting fees from Boston Scientific, and Dr. Sequist receiving consulting fees from GlaxoSmithKline, Telik, and Clovis Oncology and performing gratis consulting for Daiichi Sankyo and Merrimack Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. NR 35 TC 3 Z9 3 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 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 13 PY 2011 VL 365 IS 15 BP 1426 EP 1435 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 832DQ UT WOS:000295782500012 PM 21995391 ER PT J AU Singh, JA Sperling, JW Cofield, RH AF Singh, Jasvinder A. Sperling, John W. Cofield, Robert H. TI Ninety day mortality and its predictors after primary shoulder arthroplasty: an analysis of 4,019 patients from 1976-2008 SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE mortality; shoulder arthroplasty; humeral head replacement; shoulder hemiarthroplasty ID BODY-MASS INDEX; TOTAL HIP-ARTHROPLASTY; 30-DAY MORTALITY; OBESITY PARADOX; OUTCOMES; REGISTRY; SURGERY; EVENTS; RISK AB Background: Examine 90-day postoperative mortality and its predictors following shoulder arthroplasty Methods: We identified vital status of all adults who underwent primary shoulder arthroplasty (Total shoulder arthroplasty (TSA) or humeral head replacement (HHR)) at the Mayo Clinic from 1976-2008, using the prospectively collected information from Total Joint Registry. We used univariate logistic regression models to assess the association of gender, age, body mass index, American Society of Anesthesiologist (ASA) class, Deyo-Charlson comorbidity index, an underlying diagnosis and implant fixation with odds of 90-day mortality after TSA or HHR. Multivariable models additionally adjusted for the type of surgery (TSA versus HHR). Adjusted Odds ratio (OR) with 95% confidence interval (CI) were calculated. Results: Twenty-eight of the 3, 480 patient operated died within 90-days of shoulder arthroplasty (0.8%). In multivariable-adjusted analyses, the following factors were associated with significantly higher odds of 90-day mortality: higher Deyo-Charlson index (OR, 1.54; 95% CI: 1.39, 1.70; p < 0.001); a diagnosis of tumor (OR, 16.2; 95% CI: 7.1, 36.7); and ASA class III (OR, 3.57; 95% CI: 1.29, 9.91; p = 0.01) or class IV (OR, 13.4; 95% CI: 2.44, 73.86; p = 0.003). BMI >= 30 was associated with lower risk of 90-day mortality (OR, 0.25; 95% CI: 0.08, 0.78). In univariate analyses, patients undergoing TSA had significantly lower 90-day mortality of 0.4% (8/2, 580) compared to 1% in HHR (20/1, 411) (odds ratio, 0.22 (95% CI: 0.10, 0.50); p = 0.0003). Conclusions: 90-day mortality following shoulder arthroplasty was low. An underlying diagnosis of tumor, higher comorbidity and higher ASA class were risk factors for higher 90-day mortality, while higher BMI was protective. Pre-operative comorbidity management may impact 90-day mortality following shoulder arthroplasty. A higher unadjusted mortality in patients undergoing TSA versus HHR may indicate the underlying differences in patients undergoing these procedures. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Ctr Surg Med Acute Care Res & Transit C SMART, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. [Singh, Jasvinder A.; Sperling, John W.; Cofield, Robert H.] Mayo Clin, Sch Med, Dept Orthoped Surg, Rochester, MN USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. EM Jasvinder.md@gmail.com OI singh, jasvinder/0000-0003-3485-0006 FU National Institute of Health (NIH) (Mayo Clinic Center for Clinical and Translational Research) [1 KL2 RR024151-01] FX This material is the result of work supported with National Institute of Health (NIH) Clinical Translational Science Award 1 KL2 RR024151-01 (Mayo Clinic Center for Clinical and Translational Research) and the resources and the use of facilities at the Birmingham VA Medical Center, Alabama, USA. We thank Scott Harmsen, MS and Cathy Schleck, BS for performing statistical analyses and Youlonda Lochler for providing the study cohort. NR 21 TC 23 Z9 23 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD OCT 12 PY 2011 VL 12 AR 231 DI 10.1186/1471-2474-12-231 PG 7 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 839OE UT WOS:000296376400002 PM 21992475 ER PT J AU Ebrahimi-Fakhari, D Cantuti-Castelvetri, I Fan, ZY Rockenstein, E Masliah, E Hyman, BT McLean, PJ Unni, VK AF Ebrahimi-Fakhari, Darius Cantuti-Castelvetri, Ippolita Fan, Zhanyun Rockenstein, Edward Masliah, Eliezer Hyman, Bradley T. McLean, Pamela J. Unni, Vivek K. TI Distinct Roles In Vivo for the Ubiquitin-Proteasome System and the Autophagy-Lysosomal Pathway in the Degradation of alpha-Synuclein SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CHAPERONE-MEDIATED AUTOPHAGY; FAMILIAL PARKINSONS-DISEASE; INCLUSION-BODY FORMATION; PROTEIN-DEGRADATION; CELL-DEATH; NEURODEGENERATIVE DISEASE; 26S PROTEASOMES; TRANSGENIC MICE; NEURONAL CELLS; GENE-TRANSFER AB Increased intracellular levels of alpha-synuclein are implicated in Parkinson's disease and related disorders and may be caused by alterations in the ubiquitin-proteasome system (UPS) or the autophagy-lysosomal pathway (ALP). A critical question remains how alpha-synuclein is degraded by neurons in vivo. To address this, our study uses alpha-synuclein transgenic mice, expressing human alpha-synuclein or alpha-synuclein-eGFP under the (h) PDGF-beta promoter, in combination with in vivo pharmacologic and multiphoton imaging strategies to systematically test degradation pathways in the living mouse brain. We demonstrate that the UPS is the main degradation pathway for alpha-synuclein under normal conditions in vivo while with increased alpha-synuclein burden the ALP is recruited. Moreover, we report alterations of the UPS in alpha-synuclein transgenic mice and age dependence to the role of the UPS in alpha-synuclein degradation. In addition, we provide evidence that the UPS and ALP might be functionally connected such that impairment of one can upregulate the other. These results provide a novel link between the UPS, the ALP, and alpha-synuclein pathology and may have important implications for future therapeutics targeting degradation pathways. C1 [Ebrahimi-Fakhari, Darius; Cantuti-Castelvetri, Ippolita; Fan, Zhanyun; Hyman, Bradley T.; McLean, Pamela J.; Unni, Vivek K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Dept Neurol, Boston, MA 02129 USA. [Ebrahimi-Fakhari, Darius] Univ Heidelberg, Inst Anat & Cell Biol, D-69120 Heidelberg, Germany. [Rockenstein, Edward; Masliah, Eliezer] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP McLean, PJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02219 USA. EM pmclean@partners.org; unni@ohsu.edu OI Ebrahimi-Fakhari, Darius/0000-0002-0026-4714 FU National Institutes of Health [NS038372, NS063963, T32 AG000222, T32 NS048005, K08 NS069625, AG18840, AG022074, AG10435]; Michael J. Fox Foundation; German National Academic Foundation; Hamburg Foundation for International Research and Studies; Parkinson's Disease Foundation; Vector Production Core (National Institutes of Health) at Massachusetts General Hospital [P30NS045776] FX This work was supported by National Institutes of Health Grants NS038372 (B. T. H.), NS063963 (P.J.M.), T32 AG000222, T32 NS048005, K08 NS069625 (V. K. U.), and AG18840, AG022074, AG10435 (E. R., E. M.); The Michael J. Fox Foundation (I. C.-C.); the German National Academic Foundation (D.E.-F.); the Hamburg Foundation for International Research and Studies (D.E.-F.); and the Parkinson's Disease Foundation (D.E.-F.). We thank Dr. Bakhos A. Tannous and the Vector Production Core (National Institutes of Health Grant P30NS045776) at Massachusetts General Hospital. NR 83 TC 128 Z9 133 U1 2 U2 24 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 OCT 12 PY 2011 VL 31 IS 41 BP 14508 EP 14520 DI 10.1523/JNEUROSCI.1560-11.2011 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 835FB UT WOS:000296019600008 PM 21994367 ER PT J AU Sheridan, SD Theriault, KM Reis, SA Zhou, F Madison, JM Daheron, L Loring, JF Haggarty, SJ AF Sheridan, Steven D. Theriault, Kraig M. Reis, Surya A. Zhou, Fen Madison, Jon M. Daheron, Laurence Loring, Jeanne F. Haggarty, Stephen J. TI Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome SO PLOS ONE LA English DT Article ID MENTAL-RETARDATION GENE-1; REPEAT EXPANSION; MESSENGER-RNA; DIFFERENTIATION; METHYLATION; INSTABILITY; DISEASE; PROTEIN; PYROSEQUENCING(TM); INVOLVEMENT AB Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 59 untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology. C1 [Sheridan, Steven D.; Theriault, Kraig M.; Reis, Surya A.; Zhou, Fen; Madison, Jon M.; Haggarty, Stephen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02115 USA. [Sheridan, Steven D.; Reis, Surya A.; Zhou, Fen; Madison, Jon M.; Haggarty, Stephen J.] Broad Inst Harvard & Massachusetts Inst Technol, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Daheron, Laurence] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Daheron, Laurence] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Loring, Jeanne F.] Scripps Res Inst, Dept Physiol Chem, Ctr Regenerat Med, La Jolla, CA 92037 USA. RP Sheridan, SD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02115 USA. EM haggarty@chgr.mgh.harvard.edu FU FRAXA Research Foundation; Harvard Stem Cell Institute; Stanley Medical Research Institute; National Institute Of Mental Health [R33MH087896] FX This work was supported in part by the FRAXA Research Foundation, a seed grant from the Harvard Stem Cell Institute, the Stanley Medical Research Institute, and a grant (#R33MH087896) 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 120 Z9 125 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 OCT 12 PY 2011 VL 6 IS 10 AR e26203 DI 10.1371/journal.pone.0026203 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PW UT WOS:000295976000085 PM 22022567 ER PT J AU Wakabayashi-Ito, N Doherty, OM Moriyama, H Breakefield, XO Gusella, JF O'Donnell, JM Ito, N AF Wakabayashi-Ito, Noriko Doherty, Olugbenga M. Moriyama, Hideaki Breakefield, Xandra O. Gusella, James F. O'Donnell, Janis M. Ito, Naoto TI dtorsin, the Drosophila Ortholog of the Early-Onset Dystonia TOR1A (DYT1), Plays a Novel Role in Dopamine Metabolism SO PLOS ONE LA English DT Article ID TORSION DYSTONIA; TYROSINE-HYDROXYLASE; PHENOTYPIC ANALYSIS; PROTEIN TORSINA; PUNCH LOCUS; MOUSE MODEL; FRUIT-FLY; MELANOGASTER; GENE; LOCOMOTION AB Dystonia represents the third most common movement disorder in humans. At least 15 genetic loci (DYT1-15) have been identified and some of these genes have been cloned. TOR1A (formally DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. However, the function of torsinA has yet to be fully understood. Here, we have generated and characterized a complete loss-of-function mutant for dtorsin, the only Drosophila ortholog of TOR1A. Null mutation of the X-linked dtorsin was semi-lethal with most male flies dying by the pre-pupal stage and the few surviving adults being sterile and slow moving, with reduced cuticle pigmentation and thin, short bristles. Third instar male larvae exhibited locomotion defects that were rescued by feeding dopamine. Moreover, biochemical analysis revealed that the brains of third instar larvae and adults heterozygous for the loss-of-function dtorsin mutation had significantly reduced dopamine levels. The dtorsin mutant showed a very strong genetic interaction with Pu (Punch: GTP cyclohydrolase), the ortholog of the human gene underlying DYT14 dystonia. Biochemical analyses revealed a severe reduction of GTP cyclohydrolase protein and activity, suggesting that dtorsin plays a novel role in dopamine metabolism as a positive-regulator of GTP cyclohydrolase protein. This dtorsin mutant line will be valuable for understanding this relationship and potentially other novel torsin functions that could play a role in human dystonia. C1 [Wakabayashi-Ito, Noriko; Gusella, James F.; Ito, Naoto] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Doherty, Olugbenga M.; O'Donnell, Janis M.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL USA. [Moriyama, Hideaki] Univ Nebraska, Sch Biol Sci, Lincoln, NE USA. [Wakabayashi-Ito, Noriko; Breakefield, Xandra O.; Ito, Naoto] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol & Radiol, Boston, MA USA. [Wakabayashi-Ito, Noriko; Breakefield, Xandra O.; Ito, Naoto] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Wakabayashi-Ito, N (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM iton@chgr.mgh.harvard.edu FU NIH/NIDS [NS037409]; Nebraska Tobacco Settlement Biomedical Research Development Funds; Dystonia Medical Research Foundation; University of Alabama FX NIH/NIDS Grant NS037409 (JFG) (http://www.ninds.nih.gov/), Nebraska Tobacco Settlement Biomedical Research Development Funds (HM), Dystonia Medical Research Foundation (NI and JFG) (http://www.dystonia-foundation.org/) and The University of Alabama (JMO and OMD)(http://www.ua.edu/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 15 Z9 15 U1 0 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 OCT 12 PY 2011 VL 6 IS 10 AR e26183 DI 10.1371/journal.pone.0026183 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PW UT WOS:000295976000082 PM 22022556 ER PT J AU Walcott, BP Coumans, JV Mian, MK Nahed, BV Kahle, KT AF Walcott, Brian P. Coumans, Jean-Valery Mian, Matthew K. Nahed, Brian V. Kahle, Kristopher T. TI Interfacility Helicopter Ambulance Transport of Neurosurgical Patients: Observations, Utilization, and Outcomes from a Quaternary Level Care Hospital SO PLOS ONE LA English DT Article ID HEAD-INJURED PATIENTS; INTRACEREBRAL HEMORRHAGE; EXTRADURAL HEMATOMA; TRAUMA CENTERS; SERVICES; STROKE; IMPACT; MORTALITY; TRANSFERS; IMPROVE AB Background: The clinical benefit of helicopter transport over ground transportation for interfacility transport is unproven. We sought to determine actual practice patterns, utilization, and outcomes of patients undergoing interfacility transport for neurosurgical conditions. Methodology/Principal Findings: We retrospectively examined all interfacility helicopter transfers to a single trauma center during 2008. We restricted our analysis to those transfers leading either to admission to the neurosurgical service or to formal consultation upon arrival. Major exclusion criteria included transport from the scene, death during transport, and transport to any area of the hospital other than the emergency department. The primary outcome was time interval to invasive intervention. Secondary outcomes were estimated ground transportation times from the referring hospital, admitting disposition, and discharge disposition. Of 526 candidate interfacility helicopter transfers to our emergency department in 2008, we identified 167 meeting study criteria. Seventy-five (45%) of these patients underwent neurosurgical intervention. The median time to neurosurgical intervention ranged from 1.0 to 117.8 hours, varying depending on the diagnosis. For 101 (60%) of the patients, estimated driving time from the referring institution was less than one hour. Four patients (2%) expired in the emergency department, and 34 patients (20%) were admitted to a non-ICU setting. Six patients were discharged home within 24 hours. For those admitted, in-hospital mortality was 28%. Conclusions/Significance: Many patients undergoing interfacility transfer for neurosurgical evaluation are inappropriately triaged to helicopter transport, as evidenced by actual times to intervention at the accepting institution and estimated ground transportation times from the referring institution. In a time when there is growing interest in health care cost containment, practitioners must exercise discretion in the selection of patients for air ambulance transport-particularly when it may not bear influence on clinical outcome. Neurosurgical evaluation via telemedicine may be one strategy for improving air transport triage. C1 [Walcott, Brian P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. EM walcott.brian@mgh.harvard.edu FU Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Institutes of Health [UL1 RR 025758]; Harvard University; Massachusetts General Hospital, Department of Neurosurgery FX This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Institutes of Health Award #UL1 RR 025758 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 National Institutes of Health. Additional research support was provided using departmental research funds from the Massachusetts General Hospital, Department of Neurosurgery. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 12 Z9 12 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 OCT 12 PY 2011 VL 6 IS 10 AR e26216 DI 10.1371/journal.pone.0026216 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PW UT WOS:000295976000089 PM 22022572 ER PT J AU Walensky, RP Morris, BL Reichmann, WM Paltiel, AD Arbelaez, C Donnell-Fink, L Katz, JN Losina, E AF Walensky, Rochelle P. Morris, Bethany L. Reichmann, William M. Paltiel, A. David Arbelaez, Christian Donnell-Fink, Laurel Katz, Jeffrey N. Losina, Elena TI Resource Utilization and Cost-Effectiveness of Counselor-vs. Provider-Based Rapid Point-of-Care HIV Screening in the Emergency Department SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; UNITED-STATES; OPPORTUNISTIC INFECTIONS; PREVENTION; LOPINAVIR/RITONAVIR; RECOMMENDATIONS; EMTRICITABINE; ADOLESCENTS AB Background: Routine HIV screening in emergency department (ED) settings may require dedicated personnel. We evaluated the outcomes, costs and cost-effectiveness of HIV screening when offered by either a member of the ED staff or by an HIV counselor. Methods: We employed a mathematical model to extend data obtained from a randomized clinical trial of provider-vs. counselor-based HIV screening in the ED. We compared the downstream survival, costs, and cost-effectiveness of three HIV screening modalities: 1) no screening program; 2) an ED provider-based program; and 3) an HIV counselor-based program. Trial arm-specific data were used for test offer and acceptance rates (provider offer 36%, acceptance 75%; counselor offer 80%, acceptance 71%). Undiagnosed HIV prevalence (0.4%) and linkage to care rates (80%) were assumed to be equal between the screening modalities. Personnel costs were derived from trial-based resource utilization data. We examined the generalizability of results by conducting sensitivity analyses on offer and acceptance rates, undetected HIV prevalence, and costs. Results: Estimated HIV screening costs in the provider and counselor arms averaged $8.10 and $31.00 per result received. The Provider strategy (compared to no screening) had an incremental cost-effectiveness ratio of $58,700/quality-adjusted life year (QALY) and the Counselor strategy (compared to the Provider strategy) had an incremental cost-effectiveness ratio of $64,500/QALY. Results were sensitive to the relative offer and acceptance rates by strategy and the capacity of providers to target-screen, but were robust to changes in undiagnosed HIV prevalence and programmatic costs. Conclusions: The cost-effectiveness of provider-based HIV screening in an emergency department setting compares favorably to other US screening programs. Despite its additional cost, counselor-based screening delivers just as much return on investment as provider based-screening. Investment in dedicated HIV screening personnel is justified in situations where ED staff resources may be insufficient to provide comprehensive, sustainable screening services. C1 [Walensky, Rochelle P.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.; Morris, Bethany L.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Reichmann, William M.; Donnell-Fink, Laurel; Katz, Jeffrey N.; Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Arbelaez, Christian] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Walensky, Rochelle P.; Losina, Elena] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA USA. [Paltiel, A. David] Yale Univ, Sch Med, New Haven, CT USA. [Reichmann, William M.; Losina, Elena] Boston Univ Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. EM rwalensky@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU National Institute of Mental Health [R01 MH073445, R01 MH65869]; Doris Duke Charitable Foundation FX This work was funded by the National Institute of Mental Health (R01 MH073445, R01 MH65869), and the Doris Duke Charitable Foundation, Clinical Scientist Development Award to RPW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 2 Z9 2 U1 0 U2 3 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 OCT 12 PY 2011 VL 6 IS 10 AR e25575 DI 10.1371/journal.pone.0025575 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PW UT WOS:000295976000022 PM 22022415 ER PT J AU Ferraro, F Lymperi, S Mendez-Ferrer, S Saez, B Spencer, JA Yeap, BY Masselli, E Graiani, G Prezioso, L Rizzini, EL Mangoni, M Rizzoli, V Sykes, SM Lin, CP Frenette, PS Quaini, F Scadden, DT AF Ferraro, Francesca Lymperi, Stefania Mendez-Ferrer, Simon Saez, Borja Spencer, Joel A. Yeap, Beow Y. Masselli, Elena Graiani, Gallia Prezioso, Lucia Rizzini, Elisa Lodi Mangoni, Marcellina Rizzoli, Vittorio Sykes, Stephen M. Lin, Charles P. Frenette, Paul S. Quaini, Federico Scadden, David T. TI Diabetes Impairs Hematopoietic Stem Cell Mobilization by Altering Niche Function SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ENDOTHELIAL PROGENITOR CELLS; COLONY-STIMULATING FACTOR; MARROW STROMAL CELLS; BONE-MARROW; CXCR4 ANTAGONIST; G-CSF; TRANSPLANTATION; AMD3100; EXPRESSION; MELLITUS AB Success with transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) in patients depends on adequate collection of these cells after mobilization from the bone marrow niche by the cytokine granulocyte colony-stimulating factor (G-CSF). However, some patients fail to achieve sufficient HSPC mobilization. Retrospective analysis of bone marrow transplant patient records revealed that diabetes correlated with poor mobilization of CD34(+) HSPCs. In mouse models of type 1 and type 2 diabetes (streptozotocin-induced and db/db mice, respectively), we found impaired egress of murine HSPCs from the bone marrow after G-CSF treatment. Furthermore, HSPCs were aberrantly localized in the marrow niche of the diabetic mice, and abnormalities in the number and function of sympathetic nerve termini were associated with this mislocalization. Aberrant responses to beta-adrenergic stimulation of the bone marrow included an inability of marrow mesenchymal stem cells expressing the marker nestin to down-modulate the chemokine CXCL12 in response to G-CSF treatment (mesenchymal stem cells are reported to be critical for HSPC mobilization). The HSPC mobilization defect was rescued by direct pharmacological inhibition of the interaction of CXCL12 with its receptor CXCR4 using the drug AMD3100. These data suggest that there are diabetes-induced changes in bone marrow physiology and microanatomy and point to a potential intervention to overcome poor HSPC mobilization in diabetic patients. C1 [Ferraro, Francesca; Lymperi, Stefania; Saez, Borja; Sykes, Stephen M.; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Ferraro, Francesca; Lymperi, Stefania; Saez, Borja; Sykes, Stephen M.; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Mendez-Ferrer, Simon] Ctr Nacl Invest Cardiovasc, Cardiovasc Dev Biol Dept, Madrid 28029, Spain. [Spencer, Joel A.; Lin, Charles P.] Massachusetts Gen Hosp, Adv Microscopy Program, Ctr Syst Biol, Boston, MA 02114 USA. [Spencer, Joel A.; Lin, Charles P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Spencer, Joel A.] Tufts Univ, Dept Biomed Engn, Medford, MA 02155 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Masselli, Elena; Rizzini, Elisa Lodi; Mangoni, Marcellina; Rizzoli, Vittorio] Univ Parma, Dept Hematol & Bone Marrow Transplantat, I-43126 Parma, Italy. [Graiani, Gallia; Prezioso, Lucia; Quaini, Federico] Univ Parma, Dept Internal Med & Biomed Sci, I-43126 Parma, Italy. [Frenette, Paul S.] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA. [Ferraro, Francesca; Lymperi, Stefania; Saez, Borja; Sykes, Stephen M.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Quaini, F (reprint author), Univ Parma, Dept Internal Med & Biomed Sci, I-43126 Parma, Italy. EM federico.quaini@unipr.it; dscadden@mgh.harvard.edu RI Frenette, Paul/J-8272-2012; Spencer, Joel/A-4590-2013; Masselli, Elena/J-9238-2016; OI Masselli, Elena/0000-0002-4765-0428; Mendez-Ferrer, Simon/0000-0002-9805-9988 FU Collegio Ghislieri, Associazione Italiana Leucemie, Associazione Cristina Bassi; National Heart, Lung, and Blood Institute (NHLBI) [U01HL100402]; American Society of Hematology (ASH); Chamber of Industry and Commerce of the Government of Spain; NHLBI [5T32HL007623-24]; NIH [R01HL097819, R01DK056638]; Italian Ministry of Health THEAPPL; NIH NHLBI [HL097794, HL097748, HL100402, DK050234]; Ellison Foundation; Harvard Stem Cell Institute; [FP7-BIOSCENT]; [NMP-214539 2007]; [PRIN AL2YNC 2007] FX F. F. was supported by fellowships from Collegio Ghislieri, Associazione Italiana Leucemie, Associazione Cristina Bassi, and National Heart, Lung, and Blood Institute (NHLBI) U01HL100402. S.M.-F. is thankful to American Society of Hematology (ASH) for the supporting scholarship. B. S. was supported by the Chamber of Industry and Commerce of the Government of Spain. S. M. S. was supported by NHLBI 5T32HL007623-24. P. S. F. was funded by NIH grants R01HL097819 and R01DK056638. F. Q. was supported by the following grants: FP7-BIOSCENT, NMP-214539 2007, PRIN AL2YNC 2007, and Italian Ministry of Health THEAPPL 2008. D. T. S. is supported by the NIH NHLBI HL097794, HL097748, HL100402 and DK050234, the Ellison Foundation, and the Harvard Stem Cell Institute. NR 51 TC 62 Z9 63 U1 0 U2 8 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 OCT 12 PY 2011 VL 3 IS 104 AR 104ra101 DI 10.1126/scitranslmed.3002191 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 836WV UT WOS:000296149300004 PM 21998408 ER PT J AU Ochoa, CD Garg, HG Hales, CA Quinn, DA AF Ochoa, Christiaan D. Garg, Hari G. Hales, Charles A. Quinn, Deborah A. TI Low molecular weight hyaluronan, via AP-1 and NF-kappa B signalling, induces IL-8 in transformed bronchial epithelial cells SO SWISS MEDICAL WEEKLY LA English DT Article DE low molecular weight hyaluronan; IL-8; AP-1; NF-kappa B; mechanical strain; high tidal volume mechanical ventilation; bronchial epithelium ID HYPOXIC PULMONARY-HYPERTENSION; INDUCED LUNG INJURY; MOUSE MACROPHAGES; EXPRESSION; SYNTHASE; KB; INFLAMMATION; VENTILATION; INHIBITION; PRESSURE AB ANOVA: Analysis of Variance; AP-1: Activator Protein-1; BEGM: Bronchial Epithelial Cell Growth System; DNA: deoxyribonucleic acid; ELISA: Enzyme-linked Immunosorbent Assay; GAG: Glucosaminoglycans; HA: Hyaluronan; HAdase: Hyaluronydase; HAS: Hyaluronan Synthase; HMW-HA: High Molecular Weight Hyaluronan; IFN: Interferon; IL-8: Interleukin-8; JNK: c-Jun NH(2)-terminal Kinase; ERK 1/2: Extracellular Signal-regulated Kinase 1/2; JAK/STAT pathway: Janus Kinase/Signal Transducers and Activator of Transcription pathway; LDH: Lactate dehydrogenase; LMW-HA: Low Molecular Weight Hyaluronan; NF-kappa B: Nuclear Factor kappa-light-chain-enhancer of activated B cells; MAPK: Mitogen-activated Protein Kinase; TLR: Toll-like Receptors; TNF: Tumour Necrosis Factor; VALI: Ventilator-associated Lung Injury. C1 Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ochoa, CD (reprint author), Univ S Alabama, Ctr Lung Biol, Dept Pharmacol, 307 N Univ Blvd,MSB 3362, Usa Mobile, AL 36688 USA. EM cdo701@jaguar1.usouthal.edu FU Susannah Wood Fund; AHA [EIA 0440146N, 0526046H, HL007874, HL39150] FX This work was partially supported by grants from the Susannah Wood Fund and AHA EIA 0440146N (D.A.Q), AHA 0526046H (C.D.O), and HL007874, and HL39150 (C.A.H). D.A.Q. is now employed by Novartis Pharmaceuticals. Novartis did not support this work and was not involved in the planning or execution of this work. NR 37 TC 2 Z9 2 U1 0 U2 2 PU E M H SWISS MEDICAL PUBLISHERS LTD PI MUTTENZ PA FARNSBURGERSTR 8, CH-4132 MUTTENZ, SWITZERLAND SN 1424-7860 J9 SWISS MED WKLY JI Swiss Med. Wkly. PD OCT 12 PY 2011 VL 141 AR w13255 DI 10.4414/smw.2011.13255 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 834CS UT WOS:000295936800001 PM 21989944 ER PT J AU Rice, TW Wheeler, AP Thompson, BT DeBoisblanc, BP Steingrub, J Rock, P AF Rice, Todd W. Wheeler, Arthur P. Thompson, B. Taylor DeBoisblanc, Bennett P. Steingrub, Jay Rock, Peter CA NHLBI ARDS Clinical Trials Network TI Enteral Omega-3 Fatty Acid, gamma-Linolenic Acid, and Antioxidant Supplementation in Acute Lung Injury SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; MECHANICALLY VENTILATED PATIENTS; CRITICALLY-ILL PATIENTS; EICOSAPENTAENOIC ACID; FATTY-ACIDS; FISH-OIL; CLINICAL-TRIAL; PLASMA; INFLAMMATION; NUTRITION AB Context The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with gamma-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and outcomes in patients with acute lung injury. Objective To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28. Design, Setting, and Participants The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up. Interventions Twice-daily enteral supplementation of n-3 fatty acids, gamma-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement. Main Outcome Measure Ventilator-free days to study day 28. Results The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P=.02) (difference, -3.2 [95% CI, -5.8 to -0.7]) and intensive care unit-free days (14.0 vs 16.7; P=.04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P=.02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P=.054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P=.11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P=.001). Conclusions Twice-daily enteral supplementation of n-3 fatty acids, gamma-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful. C1 [Rice, Todd W.] Vanderbilt Univ, Div Allergy Pulm & Crit Care Med, Vanderbilt Med Ctr, Sch Med, Nashville, TN 37232 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [DeBoisblanc, Bennett P.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Steingrub, Jay] Baystate Med Ctr, Springfield, MA USA. [Rock, Peter] Univ Maryland, Dept Anesthesiol, Sch Med, Baltimore, MD 21201 USA. RP Rice, TW (reprint author), Vanderbilt Univ, Div Allergy Pulm & Crit Care Med, Vanderbilt Med Ctr, Sch Med, T-1218 MCN, Nashville, TN 37232 USA. EM todd.rice@vanderbilt.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268200536165C, HHSN268200536176C, HHSN268200536179C] FX This study was supported by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268200536165C, HHSN268200536176C, and HHSN268200536179C. Abbott Nutrition, Columbus, Ohio, provided the omega-3 fatty acid, gamma-linolenic acid, antioxidant, and control supplements used in the study. NR 31 TC 171 Z9 180 U1 1 U2 30 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 12 PY 2011 VL 306 IS 14 BP 1574 EP 1581 DI 10.1001/jama.2011.1435 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 831FS UT WOS:000295714700023 PM 21976613 ER PT J AU Lau, FH Deo, RC Mowrer, G Caplin, J Ahfeldt, T Kaplan, A Ptaszek, L Walker, JD Rosengard, BR Cowan, CA AF Lau, Frank H. Deo, Rahul C. Mowrer, Gregory Caplin, Joshua Ahfeldt, Tim Kaplan, Adam Ptaszek, Leon Walker, Jennifer D. Rosengard, Bruce R. Cowan, Chad A. TI Pattern Specification and Immune Response Transcriptional Signatures of Pericardial and Subcutaneous Adipose Tissue SO PLOS ONE LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; CORONARY-ARTERY-DISEASE; SMOOTH-MUSCLE-CELLS; CARDIOVASCULAR-DISEASE; RISK-FACTORS; ATHEROSCLEROTIC LESIONS; OBESE SUBJECTS; HEART-DISEASE; BODY-FAT; EXPRESSION AB Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States. Recent studies suggest that pericardial adipose tissue (PCAT) secretes inflammatory factors that contribute to the development of CVD. To better characterize the role of PCAT in the pathogenesis of disease, we performed a large-scale unbiased analysis of the transcriptional differences between PCAT and subcutaneous adipose tissue, analysing 53 microarrays across 19 individuals. As it was unknown whether PCAT-secreted factors are produced by adipocytes or cells in the supporting stromal fraction, we also sought to identify differentially expressed genes in isolated pericardial adipocytes vs. isolated subcutaneous adipocytes. Using microarray analysis, we found that: 1) pericardial adipose tissue and isolated pericardial adipocytes both overexpress atherosclerosis-promoting chemokines and 2) pericardial and subcutaneous fat depots, as well as isolated pericardial adipocytes and subcutaneous adipocytes, express specific patterns of homeobox genes. In contrast, a core set of lipid processing genes showed no significant overlap with differentially expressed transcripts. These depot-specific homeobox signatures and transcriptional profiles strongly suggest different functional roles for the pericardial and subcutaneous adipose depots. Further characterization of these inter-depot differences should be a research priority. C1 [Lau, Frank H.; Deo, Rahul C.; Mowrer, Gregory; Ahfeldt, Tim; Kaplan, Adam; Cowan, Chad A.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Lau, Frank H.; Deo, Rahul C.; Mowrer, Gregory; Ahfeldt, Tim; Kaplan, Adam; Cowan, Chad A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ahfeldt, Tim; Cowan, Chad A.] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Caplin, Joshua; Ptaszek, Leon] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. [Walker, Jennifer D.; Rosengard, Bruce R.] Massachusetts Gen Hosp, Div Cardiac Surg, Dept Surg, Boston, MA 02114 USA. RP Lau, FH (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM ccowan@fas.harvard.edu RI Ahfeldt, Tim/E-2935-2017 FU GlaxoSmithKline; Stowers Institute for Medical Research FX This work was supported by a grant from GlaxoSmithKline (http://www.gsk.com/) and by the Stowers Institute for Medical Research (http://www.stowers-institute.org/). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 3 Z9 3 U1 1 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 OCT 11 PY 2011 VL 6 IS 10 AR e26092 DI 10.1371/journal.pone.0026092 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OZ UT WOS:000295973200034 PM 22022522 ER PT J AU Sturla, LM Zinn, PO Ng, K Nitta, M Kozono, D Chen, CC Kasper, EM AF Sturla, L-M Zinn, P. O. Ng, K. Nitta, M. Kozono, D. Chen, C. C. Kasper, E. M. TI Src homology domain-containing phosphatase 2 suppresses cellular senescence in glioblastoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE glioblastoma; phosphatases; SHP2; senescence ID PROTEIN-TYROSINE-PHOSPHATASE; INTEGRATED GENOMIC ANALYSIS; GROWTH-FACTOR RECEPTOR; TELOMERASE ACTIVITY; NOONAN-SYNDROME; EGFR; MULTIFORME; RADIATION; TUMORS; SHP-2 AB BACKGROUND: Epidermal growth factor receptor (EGFR) signalling is frequently altered during glioblastoma de novo pathogenesis. An important downstream modulator of this signal cascade is SHP2 (Src homology domain-containing phosphatase 2). METHODS: We examined the The Cancer Genome Atlas (TCGA) database for SHP2 mutations. We also examined the expression of a further 191 phosphatases in the TCGA database and used principal component and comparative marker analysis available from the Broad Institute to recapitulate the TCGA-defined subgroups and identify the specific phosphatases defining each subgroup. We identified five siRNAs from two independent commercial sources that were reported by the vendor to be pre-optimised in their specificity of SHP2 silencing. The specificity and physiological effects of these siRNAs were tested using an in vitro glioma model. RESULTS: TCGA data demonstrate SHP2 to be mutated in 2% of the glioblastoma multiforme's studied. Both mutations identified in this study are likely to be activating mutations. We found that the four subgroups of GBM as defined by TCGA differ significantly with regard to the expression level of specific phosphatases as revealed by comparative marker analysis. Surprisingly, the four subgroups can be defined solely on the basis of phosphatase expression level by principal component analysis. This result suggests that critical phosphatases are responsible for the modulation of specific molecular pathways within each subgroup. Src homology domain-containing phosphatase 2 constitutes one of the 12 phosphatases that define the classical subgroup. We confirmed the biological significance by siRNA knockdown of SHP2. All five siRNAs tested reduced SHP2 expression by 70-100% and reduced glioblastoma cell line growth by up to 80%. Profiling the established molecular targets of SHP2 (ERK1/2 and STAT3) confirmed specificity of these siRNAs. The loss of cell viability induced by SHP2 silencing could not be explained by a significant increase in apoptosis alone as demonstrated by terminal deoxyribonucleotidyl transferase-mediated nick-end labelling and propidium iodide staining. Src homology domain-containing phosphatase 2 silencing, however, did induce an increase in beta-galactosidase staining. Propidium iodide staining also showed that SHP2 silencing increases the population of glioblastoma cells in the G1 phase of the cell cycle and reduces the population of such cells in the G2/M- and S-phase. CONCLUSION: Src homology domain-containing phosphatase 2 promotes the growth of glioblastoma cells by suppression of cellular senescence, a phenomenon not described previously. Selective inhibitors of SHP2 are commercially available and may be considered as a strategy for glioblastoma therapy. British Journal of Cancer (2011) 105, 1235-1243. doi:10.1038/bjc.2011.345 www.bjcancer.com Published online 20 September 2011 (C) 2011 Cancer Research UK C1 [Sturla, L-M; Zinn, P. O.; Chen, C. C.; Kasper, E. M.] Beth Israel Deaconess Med Ctr, Dept Neurosurg, Boston, MA 02215 USA. [Sturla, L-M; Zinn, P. O.; Ng, K.; Nitta, M.; Kozono, D.; Chen, C. C.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Nitta, M.] Tokyo Womens Med Univ, Dept Neurosurg, Tokyo, Japan. RP Sturla, LM (reprint author), Beth Israel Deaconess Med Ctr, Dept Neurosurg, Boston, MA 02215 USA. EM lisa.sturla@excaliburbioconsulting.com NR 34 TC 9 Z9 11 U1 1 U2 5 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 OCT 11 PY 2011 VL 105 IS 8 BP 1235 EP 1243 DI 10.1038/bjc.2011.345 PG 9 WC Oncology SC Oncology GA 836VR UT WOS:000296144900021 PM 21934682 ER PT J AU Minamishima, S Kida, K Tokuda, K Wang, HF Sips, PY Kosugi, S Mandeville, JB Buys, ES Brouckaert, P Liu, PK Liu, CH Bloch, KD Ichinose, F AF Minamishima, Shizuka Kida, Kotaro Tokuda, Kentaro Wang, Huifang Sips, Patrick Y. Kosugi, Shizuko Mandeville, Joseph B. Buys, Emmanuel S. Brouckaert, Peter Liu, Philip K. Liu, Christina H. Bloch, Kenneth D. Ichinose, Fumito TI Inhaled Nitric Oxide Improves Outcomes After Successful Cardiopulmonary Resuscitation in Mice SO CIRCULATION LA English DT Article DE cardiopulmonary resuscitation; heart arrest; magnetic resonance imaging; nitric oxide synthase; physiology ID EMERGENCY CARDIOVASCULAR CARE; ISCHEMIA-REPERFUSION INJURY; AMERICAN-HEART-ASSOCIATION; DECREASES INFARCTION SIZE; CARDIAC-ARREST; MYOCARDIAL-ISCHEMIA; SYNTHASE; MODEL; NEURODEGENERATION; DYSFUNCTION AB Background-Sudden cardiac arrest (CA) is a leading cause of death worldwide. Breathing nitric oxide (NO) reduces ischemia/reperfusion injury in animal models and in patients. The objective of this study was to learn whether inhaled NO improves outcomes after CA and cardiopulmonary resuscitation (CPR). Methods and Results-Adult male mice were subjected to potassium-induced CA for 7.5 minutes whereupon CPR was performed with chest compression and mechanical ventilation. One hour after CPR, mice were extubated and breathed air alone or air supplemented with 40 ppm NO for 23 hours. Mice that were subjected to CA/CPR and breathed air exhibited a poor 10-day survival rate (4 of 13), depressed neurological and left ventricular function, and increased caspase-3 activation and inflammatory cytokine induction in the brain. Magnetic resonance imaging revealed brain regions with marked water diffusion abnormality 24 hours after CA/CPR in mice that breathed air. Breathing air supplemented with NO for 23 hours starting 1 hour after CPR attenuated neurological and left ventricular dysfunction 4 days after CA/CPR and markedly improved 10-day survival rate (11 of 13; P=0.003 versus mice breathing air). The protective effects of inhaled NO on the outcome after CA/CPR were associated with reduced water diffusion abnormality, caspase-3 activation, and cytokine induction in the brain and increased serum nitrate/nitrite levels. Deficiency of the alpha 1 subunit of soluble guanylate cyclase, a primary target of NO, abrogated the ability of inhaled NO to improve outcomes after CA/CPR. Conclusions-These results suggest that NO inhalation after CA and successful CPR improves outcome via soluble guanylate cyclase-dependent mechanisms. (Circulation. 2011;124:1645-1653.) C1 [Minamishima, Shizuka; Kida, Kotaro; Tokuda, Kentaro; Sips, Patrick Y.; Kosugi, Shizuko; Buys, Emmanuel S.; Bloch, Kenneth D.; Ichinose, Fumito] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Charlestown, MA 02129 USA. [Wang, Huifang; Mandeville, Joseph B.; Liu, Philip K.; Liu, Christina H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Brouckaert, Peter] VIB, Dept Mol Biomed Res, Ghent, Belgium. [Brouckaert, Peter] Univ Ghent, Dept Med Mol Biol, B-9000 Ghent, Belgium. RP Ichinose, F (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, 149 13th St,4315, Charlestown, MA 02129 USA. EM fichinose@partners.org OI Sips, Patrick/0000-0001-9241-5980; Liu, Christina/0000-0002-5723-177X FU Jikei University School of Medicine; American Heart Association [09POST2220133, 10SDG2610313, GIA0855887D]; Philips [09POST2220133]; National Institutes of Health [DA26108, GM79360, HL101930]; MGH; IKARIA Inc FX This work was supported by funding from the Jikei University School of Medicine (Dr Kida); Resuscitation Fellowship Award 09POST2220133 from the American Heart Association and Philips (Dr Sips); AHA scientist development grant 10SDG2610313 (Dr Buys); AHA grant-in-aid GIA0855887D (Dr Liu); National Institutes of Health R01 grants DA26108 (Dr Liu), GM79360 (Dr Ichinose), and HL101930 (Dr Ichinose); and a sponsored research agreement between MGH and IKARIA Inc (Dr Bloch). NR 33 TC 34 Z9 39 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 11 PY 2011 VL 124 IS 15 BP 1645 EP U135 DI 10.1161/CIRCULATIONAHA.111.025395 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 835PW UT WOS:000296049300014 PM 21931083 ER PT J AU Lauer, A Cianchetti, FA Van Cott, EM Schlunk, F Schulz, E Pfeilschifter, W Steinmetz, H Schaffer, CB Lo, EH Foerch, C AF Lauer, Arne Cianchetti, Flor A. Van Cott, Elizabeth M. Schlunk, Frieder Schulz, Elena Pfeilschifter, Waltraud Steinmetz, Helmuth Schaffer, Chris B. Lo, Eng H. Foerch, Christian TI Anticoagulation With the Oral Direct Thrombin Inhibitor Dabigatran Does Not Enlarge Hematoma Volume in Experimental Intracerebral Hemorrhage SO CIRCULATION LA English DT Article DE anticoagulants; cerebral hemorrhage; intracerebral hemorrhage; warfarin; dabigatran; stroke ID DEEP-VEIN THROMBOSIS; TOTAL HIP-REPLACEMENT; VENOUS THROMBOEMBOLISM; FIBRIN POLYMERIZATION; BLEEDING-TIME; IN-VITRO; FACTOR-X; WARFARIN; COAGULATION; ETEXILATE AB Background-The direct thrombin inhibitor dabigatran etexilate (DE) may constitute a future replacement of vitamin K antagonists for long-term anticoagulation. Whereas warfarin pretreatment is associated with greater hematoma expansion after intracerebral hemorrhage (ICH), it remains unclear what effect direct thrombin inhibitors would have. Using different experimental models of ICH, this study compared hematoma volume among DE-treated mice, warfarin-treated mice, and controls. Methods and Results-CD-1 mice were fed with DE or warfarin. Sham-treated mice served as controls. At the time point of ICH induction, DE mice revealed an increased activated partial thromboplastin time compared with controls (mean +/- SD 46.1 +/- 5.0 versus 18.0 +/- 1.5 seconds; P=0.022), whereas warfarin pretreatment resulted in a prothrombin time prolongation (51.4 +/- 17.9 versus 10.4 +/- 0.3 seconds; P=0.001). Twenty-four hours after collagenase-induced ICH formation, hematoma volume was 3.8 +/- 2.9 mu L in controls, 4.8 +/- 2.7 mu L in DE mice, and 14.5 +/- 11.8 mu L in warfarin mice (n=16; Welch ANOVA between-group differences P=0.007; posthoc analysis with the Dunnett method: DE versus controls, P=0.899; warfarin versus controls, P<0.001; DE versus warfarin, P=0.001). In addition, a model of laser-induced cerebral microhemorrhage was applied, and the distances that red blood cells and blood plasma were pushed into the brain were quantified. Warfarin mice showed enlarged red blood cell and blood plasma diameters compared to controls, but no difference was found between DE mice and controls. Conclusions-In contrast with warfarin, pretreatment with DE did not increase hematoma volume in 2 different experimental models of ICH. In terms of safety, this observation may represent a potential advantage of anticoagulation with DE over warfarin. (Circulation. 2011;124:1654-1662.) C1 [Lauer, Arne; Schlunk, Frieder; Schulz, Elena; Pfeilschifter, Waltraud; Steinmetz, Helmuth; Foerch, Christian] Goethe Univ Frankfurt, Dept Neurol, D-60528 Frankfurt, Germany. [Schlunk, Frieder; Schulz, Elena; Lo, Eng H.; Foerch, Christian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab, Boston, MA USA. [Van Cott, Elizabeth M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Cianchetti, Flor A.; Schaffer, Chris B.] Cornell Univ, Dept Biomed Engn, Ithaca, NY USA. RP Foerch, C (reprint author), Goethe Univ Frankfurt, Dept Neurol, Schleusenweg 2-16, D-60528 Frankfurt, Germany. EM foerch@em.uni-frankfurt.de RI Pfeilschifter, Waltraud/K-6134-2012; Schaffer, Chris/A-7409-2008 OI Pfeilschifter, Waltraud/0000-0001-6935-8842; Schaffer, Chris/0000-0002-7800-9596 FU National Institutes of Health [EB002019, R37-NS37074, R01-NS56458, P01-NS55104] FX This work was partially supported by grants from the National Institutes of Health (EB002019 to Dr Schaffer and R37-NS37074, R01-NS56458, and P01-NS55104 to Dr Lo). The authors did not receive industrial funding for performing this study. NR 42 TC 44 Z9 45 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 11 PY 2011 VL 124 IS 15 BP 1654 EP 1662 DI 10.1161/CIRCULATIONAHA.111.035972 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 835PW UT WOS:000296049300015 PM 21911784 ER PT J AU Losina, E Freedberg, KA AF Losina, Elena Freedberg, Kenneth A. TI Life expectancy in HIV SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID AIDS; COHORT C1 [Losina, Elena] Brigham & Womens Hosp, Boston, MA 02115 USA. [Freedberg, Kenneth A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Losina, E (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM elosina@partners.org NR 12 TC 5 Z9 5 U1 0 U2 1 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 OCT 11 PY 2011 VL 343 AR d6015 DI 10.1136/bmj.d6015 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 835EJ UT WOS:000296017500003 PM 21990259 ER PT J AU Ehrlich, ME Gandy, S AF Ehrlich, Michelle E. Gandy, Sam TI Chromatin plasticity and the pathogenesis of Huntington disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID PROTEIN-1; ROLES C1 [Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, Dept Neurol, New York, NY 10029 USA. Mt Sinai Sch Med, Alzheimers Dis Res Ctr, Dept Pediat, New York, NY 10029 USA. Mt Sinai Sch Med, Alzheimers Dis Res Ctr, Dept Psychiat, New York, NY 10029 USA. James J Peters VA Med Ctr, New York, NY 10029 USA. RP Gandy, S (reprint author), Mt Sinai Sch Med, Alzheimers Dis Res Ctr, Dept Neurol, New York, NY 10029 USA. EM samuel.gandy@mssm.edu FU NINDS NIH HHS [R01 NS059936] NR 16 TC 2 Z9 2 U1 1 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 OCT 11 PY 2011 VL 108 IS 41 BP 16867 EP 16868 DI 10.1073/pnas.1113321108 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PD UT WOS:000295973800006 PM 21969556 ER PT J AU Hu, Y Chopra, V Chopra, R Locascio, JJ Liao, ZX Ding, HL Zheng, B Matson, WR Ferrante, RJ Rosas, HD Hersch, SM Scherzer, CR AF Hu, Yi Chopra, Vanita Chopra, Raman Locascio, Joseph J. Liao, Zhixiang Ding, Hongliu Zheng, Bin Matson, Wayne R. Ferrante, Robert J. Rosas, H. Diana Hersch, Steven M. Scherzer, Clemens R. TI Transcriptional modulator H2A histone family, member Y (H2AFY) marks Huntington disease activity in man and mouse SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE macroH2A; transcriptional profiling; gene expression; sodium phenylbutyrate ID GENE-EXPRESSION; PARKINSONS-DISEASE; VARIANT MACROH2A; HUMAN BLOOD; PHENYLBUTYRATE; MODEL; BIOMARKERS; BINDING; BRAIN; MICE AB Huntington disease (HD) is a progressive neurodegenerative disease that affects 30,000 individuals in North America. Treatments that slow its relentless course are not yet available, and biomarkers that can reliably measure disease activity and therapeutic response are urgently needed to facilitate their development. Here, we interrogated 119 human blood samples for transcripts associated with HD. We found that the dynamic regulator of chromatin plasticity H2A histone family, member Y (H2AFY) is specifically overexpressed in the blood and frontal cortex of patients with HD compared with controls. This association precedes the onset of clinical symptoms, was confirmed in two mouse models, and was independently replicated in cross-sectional and longitudinal clinical studies comprising 142 participants. A histone deacetylase inhibitor that suppresses neurodegeneration in animal models reduces H2AFY levels in a randomized phase II clinical trial. This study identifies the chromatin regulator H2AFY as a potential biomarker associated with disease activity and pharmacodynamic response that may become useful for enabling disease-modifying therapeutics for HD. C1 [Chopra, Vanita; Chopra, Raman; Hersch, Steven M.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Lab Neurodegenerat & Neurotherapeut, Charlestown, MA 02129 USA. [Hu, Yi; Locascio, Joseph J.; Liao, Zhixiang; Ding, Hongliu; Zheng, Bin; Scherzer, Clemens R.] Harvard Univ, Sch Med, Ctr Neurol Dis, Lab Neurogen, Cambridge, MA 02139 USA. Brigham & Womens Hosp, Cambridge, MA 02139 USA. [Rosas, H. Diana] Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, Charlestown, MA 02129 USA. [Rosas, H. Diana] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Locascio, Joseph J.; Rosas, H. Diana; Scherzer, Clemens R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Matson, Wayne R.] New England Vet Adm, Geriatr Res Educ Clin Ctr, Bedford, MA 01730 USA. [Ferrante, Robert J.] Vet Adm Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15206 USA. [Ferrante, Robert J.] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15213 USA. [Ferrante, Robert J.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Ferrante, Robert J.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Scherzer, Clemens R.] Harvard NeuroDiscovery Ctr Biomarker Program, Cambridge, MA 02139 USA. RP Hersch, SM (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Lab Neurodegenerat & Neurotherapeut, Charlestown, MA 02129 USA. EM hersch@helix.mgh.harvard.edu; cscherzer@rics.bwh.harvard.edu FU Michael J. Fox Foundation; National Institutes of Health [P01NS058793, R01NS064155, R21NS060227, P01NS045242, R01NS042861]; Maximillian E. & Marion O. Hoffman Foundation; RJG Foundation; Huntington's Disease Society of America (HDSA) Coalition for the Cure; HDSA New England Center for Excellence for Huntington Disease FX Conflict of interest statement: C. R. S. has served as a consultant to Link Medicine Corporation and was a scientific collaborator of DiaGenic in a study funded by the Michael J. Fox Foundation. He is listed as coinventor on US patent/applications held by the Brigham and Women's Hospital relating to diagnostics in neurodegenerative diseases. S. M. H. is a scientific collaborator with the Novartis Institutes for Biomedical Research. He is listed as coinventor on US patent/applications held by the Massachusetts General Hospital relating to therapeutics and diagnostics in neurodegenerative diseases.; We thank Drs. Marian DiFiglia and Antonio Valencia for 140-CAG knock-in mouse brain tissues. This study was funded by National Institutes of Health Grants P01NS058793 (to C. R. S., S. M. H., H. D. R., and R.J.F.), R01NS064155 (to C. R. S.), R21NS060227 (to C. R. S.), P01NS045242 (to S. M. H. and H. D. R.), and R01NS042861 (to H. D. R.); the Maximillian E. & Marion O. Hoffman Foundation (to C. R. S.); the RJG Foundation (to C. R. S.); the Huntington's Disease Society of America (HDSA) Coalition for the Cure (to S. M. H. and V. C.); and the HDSA New England Center for Excellence for Huntington Disease (to S. M. H. and H.D.R.). NR 44 TC 40 Z9 41 U1 0 U2 10 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 OCT 11 PY 2011 VL 108 IS 41 BP 17141 EP 17146 DI 10.1073/pnas.1104409108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834PD UT WOS:000295973800054 PM 21969577 ER PT J AU Lee, PT Kruse, GR Chan, BT Massaquoi, MBF Panjabi, RR Dahn, BT Gwenigale, WT AF Lee, Patrick T. Kruse, Gina R. Chan, Brian T. Massaquoi, Moses B. F. Panjabi, Rajesh R. Dahn, Bernice T. Gwenigale, Walter T. TI An analysis of Liberia's 2007 national health policy: lessons for health systems strengthening and chronic disease care in poor, post-conflict countries SO GLOBALIZATION AND HEALTH LA English DT Article ID SUB-SAHARAN AFRICA; MIDDLE-INCOME COUNTRIES; MENTAL-HEALTH; ANTIRETROVIRAL TREATMENT; HUMAN-RESOURCES; HEART-DISEASE; HIV TREATMENT; MEDICAL HOME; BURDEN; HYPERTENSION AB Background: Globally, chronic diseases are responsible for an enormous burden of deaths, disability, and economic loss, yet little is known about the optimal health sector response to chronic diseases in poor, post-conflict countries. Liberia's experience in strengthening health systems and health financing overall, and addressing HIV/AIDS and mental health in particular, provides a relevant case study for international stakeholders and policymakers in other poor, post-conflict countries seeking to understand and prioritize the global response to chronic diseases. Methods: We conducted a historical review of Liberia's post-conflict policies and their impact on general economic and health indicators, as well as on health systems strengthening and chronic disease care and treatment. Key sources included primary documents from Liberia's Ministry of Health and Social Welfare, published and gray literature, and personal communications from key stakeholders engaged in Liberia's Health Sector Reform. In this case study, we examine the early reconstruction of Liberia's health care system from the end of conflict in 2003 to the present time, highlight challenges and lessons learned from this initial experience, and describe future directions for health systems strengthening and chronic disease care and treatment in Liberia. Results: Six key lessons emerge from this analysis: (i) the 2007 National Health Policy's 'one size fits all' approach met aggregate planning targets but resulted in significant gaps and inefficiencies throughout the system; (ii) the innovative Health Sector Pool Fund proved to be an effective financing mechanism to recruit and align health actors with the 2007 National Health Policy; (iii) a substantial rural health delivery gap remains, but it could be bridged with a robust cadre of community health workers integrated into the primary health care system; (iv) effective strategies for HIV/AIDS care in other settings should be validated in Liberia and adapted for use in other chronic diseases; (v) mental health disorders are extremely prevalent in Liberia and should remain a top chronic disease priority; and (vi) better information systems and data management are needed at all levels of the health system. Conclusions: The way forward for chronic diseases in Liberia will require an increased emphasis on quality over quantity, better data management to inform rational health sector planning, corrective mechanisms to more efficiently align health infrastructure and personnel with existing needs, and innovative methods to improve long-term retention in care and bridge the rural health delivery gap. C1 [Lee, Patrick T.; Kruse, Gina R.; Chan, Brian T.; Panjabi, Rajesh R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lee, Patrick T.; Kruse, Gina R.; Chan, Brian T.; Panjabi, Rajesh R.] Harvard Univ, Sch Med, Boston, MA USA. [Lee, Patrick T.; Kruse, Gina R.; Chan, Brian T.; Panjabi, Rajesh R.] Tiyatien Hlth, Zwedru, Grand Gedeh Cou, Liberia. [Massaquoi, Moses B. F.] Clinton Hlth Access Initiat, Boston, MA USA. [Massaquoi, Moses B. F.; Dahn, Bernice T.; Gwenigale, Walter T.] Minist Hlth & Social Welf, Capital Bypass, Monrovia, Liberia. RP Lee, PT (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM ptlee@partners.org NR 83 TC 6 Z9 6 U1 1 U2 23 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8603 J9 GLOBALIZATION HEALTH JI Global. Health PD OCT 10 PY 2011 VL 7 AR 37 DI 10.1186/1744-8603-7-37 PG 14 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 872MT UT WOS:000298814500001 PM 21985150 ER PT J AU Tyekucheva, S Yolken, RH McCombie, WR Parla, J Kramer, M Wheelan, SJ Sabunciyan, S AF Tyekucheva, Svitlana Yolken, Robert H. McCombie, W. Richard Parla, Jennifer Kramer, Melissa Wheelan, Sarah J. Sabunciyan, Sarven TI Establishing the baseline level of repetitive element expression in the human cortex SO BMC GENOMICS LA English DT Article ID ENDOGENOUS RETROVIRAL PROMOTER; HUMAN GENOME; GENE; RETROTRANSPOSON; TRANSCRIPTOME; SEQUENCES; SCHIZOPHRENIA; METHYLATION; EVOLUTION; DISEASE AB Background: Although nearly half of the human genome is comprised of repetitive sequences, the expression profile of these elements remains largely uncharacterized. Recently developed high throughput sequencing technologies provide us with a powerful new set of tools to study repeat elements. Hence, we performed whole transcriptome sequencing to investigate the expression of repetitive elements in human frontal cortex using postmortem tissue obtained from the Stanley Medical Research Institute. Results: We found a significant amount of reads from the human frontal cortex originate from repeat elements. We also noticed that Alu elements were expressed at levels higher than expected by random or background transcription. In contrast, L1 elements were expressed at lower than expected amounts. Conclusions: Repetitive elements are expressed abundantly in the human brain. This expression pattern appears to be element specific and can not be explained by random or background transcription. These results demonstrate that our knowledge about repetitive elements is far from complete. Further characterization is required to determine the mechanism, the control, and the effects of repeat element expression. C1 [Wheelan, Sarah J.] Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Tyekucheva, Svitlana] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tyekucheva, Svitlana] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yolken, Robert H.; Sabunciyan, Sarven] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. [McCombie, W. Richard; Parla, Jennifer; Kramer, Melissa] Cold Spring Harbor Lab, Stanley Inst Cognit Genom, Cold Spring Harbor, NY 11724 USA. [Wheelan, Sarah J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. [Wheelan, Sarah J.] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Wheelan, SJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Sidney Kimmel Comprehens Canc Ctr, 550 N Broadway, Baltimore, MD 21205 USA. EM swheelan@jhmi.edu; ssabunc1@jhmi.edu OI McCombie, W. Richard/0000-0003-1899-0682 FU Stanley Medical Research Institute FX The authors would like to thank the Stanley Medical Research Institute and Dr. Fuller Torrey and Maree Webster for kindly providing the postmortem cortical tissue used in this study. The authors are grateful to The Stanley Medical Research Institute for funding this research at Johns Hopkins Stanley Division of Developmental Neurovirology and through the Stanley Institute for Cognitive Genomics at CSHL. NR 33 TC 7 Z9 8 U1 0 U2 1 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 OCT 10 PY 2011 VL 12 AR 495 DI 10.1186/1471-2164-12-495 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 842SV UT WOS:000296621400001 PM 21985647 ER PT J AU Pritchard, KI Shepherd, LE Chapman, JAW Norris, BD Cantin, J Goss, PE Dent, SF Walde, D Vandenberg, TA Findlay, B O'Reilly, SE Wilson, CF Han, L Piura, E Whelan, TJ Pollak, MN AF Pritchard, Kathleen I. Shepherd, Lois E. Chapman, Judith-Anne W. Norris, Brian D. Cantin, Jacques Goss, Paul E. Dent, Susan F. Walde, David Vandenberg, Ted A. Findlay, Brian O'Reilly, Susan E. Wilson, Carolyn F. Han, Lei Piura, Ettie Whelan, Timothy J. Pollak, Michael N. TI Randomized Trial of Tamoxifen Versus Combined Tamoxifen and Octreotide LAR Therapy in the Adjuvant Treatment of Early-Stage Breast Cancer in Postmenopausal Women: NCIC CTG MA.14 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SOMATOSTATIN ANALOGS; GROWTH-FACTOR; INSULIN; METFORMIN AB Purpose Somatostatin analogs act directly on breast cancer cells and indirectly on insulin and insulin-like growth factor 1 (IGF-1) levels. This trial was undertaken to assess whether octreotide would lower insulin and IGF-1 levels and reduce risk of breast cancer recurrence. Patients and Methods The NCIC CTG MA. 14 (NCIC Clinical Trials Group MA. 14) trial randomly assigned postmenopausal women to 5 years of tamoxifen 20 mg daily (TAM) or TAM plus 2 years of octreotide 90 mg depot intramuscular injections monthly (TAM-OCT) as adjuvant therapy. The primary end point was event-free survival (EFS). Secondary end points were relapse-free survival (RFS), overall survival (OS), toxicity, and effects of treatment on IGF physiology. Results Among 667 women with a median follow-up of 7.9 years, 220 events occurred-108 with TAM-OCT and 112 with TAM. Adjusted hazard ratios (HRs; TAM-OCT to TAM) were 0.93 for EFS (95% CI, 0.71 to 1.22; P = .62), 0.84 for RFS (95% CI, 0.59 to 1.18; P = .31), and 0.97 for OS (95% CI, 0.69 to 1.37; P = .86). Among patients with normal baseline gallbladder imaging, cholecystectomy was required in 23.0% of those receiving TAM-OCT but in only 1.4% of those receiving TAM (P < .001). At 4 months, TAM-OCT had significantly (P < .001) lowered IGF-1, IGF binding protein 3, and C-peptide levels. Older age (P = .02), tumor size (P = .001), nodal status (P = .01), high C-peptide levels (P < .001), and higher body mass index (BMI) in models excluding C-peptide (P < .001) were associated with poorer EFS in multivariate analysis. Conclusion Octreotide-related changes in circulating IGF-1 and C-peptide levels were statistically significant. Octreotide did not add significant clinical benefit. High C-peptide levels (surrogate for insulin secretion rate) and high BMI were associated with poor outcome. C1 [Pritchard, Kathleen I.] Sunnybrook Odette Canc Ctr, Toronto, ON M4N 3M5, Canada. [Pritchard, Kathleen I.] Univ Toronto, Toronto, ON M4N 3M5, Canada. [Shepherd, Lois E.; Chapman, Judith-Anne W.; Wilson, Carolyn F.; Han, Lei] Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. [Dent, Susan F.] Ottawa Hosp Canc Ctr, Ottawa, ON, Canada. [Walde, David] Sault Area Hosp, Algoma Dist Canc Program, Sault Ste Marie, ON, Canada. [Vandenberg, Ted A.] London Reg Canc Program, London, ON, Canada. [Findlay, Brian] Niagara Hlth Syst, St Catharines, ON, Canada. [Whelan, Timothy J.] McMaster Univ, Hamilton, ON, Canada. [Norris, Brian D.] British Columbia Canc Agcy, Surrey, BC, Canada. [O'Reilly, Susan E.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Cantin, Jacques] Univ Montreal, Ctr Hosp, Hotel Dieu, Montreal, PQ H3C 3J7, Canada. [Piura, Ettie; Pollak, Michael N.] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada. [Goss, Paul E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Pritchard, KI (reprint author), Sunnybrook Odette Canc Ctr, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada. EM kathy.pritchard@sunnybrook.ca RI Pollak, Michael/G-9094-2011; Whelan, Timothy/D-3185-2017; Pritchard, Kathleen/I-2184-2014 OI Pollak, Michael/0000-0003-3047-0604; Pritchard, Kathleen/0000-0003-0758-9666 FU Canadian Cancer Society Research Institute [16512]; Novartis Pharmaceuticals Canada; Israel Cancer Research Fund; Ted A. Vandenberg; GlaxoSmithKline Expert Testimony: Kathleen I. Pritchard; Novartis; AstraZeneca FX Supported by Grant No. 16512 from Canadian Cancer Society Research Institute (M.N.P); a grant from Novartis Pharmaceuticals Canada (M.N.P.); and a fellowship from the Israel Cancer Research Fund (E.P.).; Employment or Leadership Position: None Consultant or Advisory Role: Kathleen I. Pritchard, Roche (C), Novartis (C), AstraZeneca (C), Abraxis BioScience (C), Boehringer Ingelheim (C); Ted A. Vandenberg, Novartis (C), Abraxis BioScience (C), GlaxoSmithKline (C) Stock Ownership: None Honoraria: Kathleen I. Pritchard, Roche, Novartis, Abraxis BioScience, AstraZeneca, Boehringer Ingelheim; Paul E. Goss, Novartis; Ted A. Vandenberg, GlaxoSmithKline, Roche; Brian Findlay, Novartis Research Funding: Ted A. Vandenberg, GlaxoSmithKline Expert Testimony: Kathleen I. Pritchard, Novartis (U), AstraZeneca (U) Other Remuneration: None NR 29 TC 56 Z9 57 U1 0 U2 4 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 OCT 10 PY 2011 VL 29 IS 29 BP 3869 EP 3876 DI 10.1200/JCO.2010.33.7006 PG 8 WC Oncology SC Oncology GA 833LE UT WOS:000295886200010 PM 21911723 ER PT J AU Arvold, ND Taghian, AG Niemierko, A Raad, RFA Sreedhara, M Nguyen, PL Bellon, JR Wong, JS Smith, BL Harris, JR AF Arvold, Nils D. Taghian, Alphonse G. Niemierko, Andrzej Raad, Rita F. Abi Sreedhara, Meera Nguyen, Paul L. Bellon, Jennifer R. Wong, Julia S. Smith, Barbara L. Harris, Jay R. TI Age, Breast Cancer Subtype Approximation, and Local Recurrence After Breast-Conserving Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COMPARING TOTAL MASTECTOMY; SURGICAL ADJUVANT BREAST; 20-YEAR FOLLOW-UP; TUMOR RECURRENCE; STAGE-I; YOUNG-WOMEN; CONSERVATION THERAPY; RADIATION-THERAPY; RANDOMIZED-TRIAL; CLINICAL IMPLICATIONS AB Purpose Prior results of breast-conserving therapy (BCT) have shown substantial rates of local recurrence (LR) in young patients with breast cancer (BC). Patients and Methods We studied 1,434 consecutive patients with invasive BC who received BCT from December 1997 to July 2006. Ninety-one percent received adjuvant systemic therapy; no patients received trastuzumab. Five BC subtypes were approximated: estrogen receptor (ER) or progesterone receptor (PR) positive, HER2 negative, and grades 1 to 2 (ie, luminal A); ER positive or PR positive, HER2 negative, and grade 3 (ie, luminal B); ER or PR positive, and HER2 positive (ie, luminal HER2); ER negative, PR negative, and HER2 positive (ie, HER2); and ER negative, PR negative, and HER2 negative (ie, triple negative). Actuarial rates of LR were calculated by using the Kaplan-Meier method. Results Median follow-up was 85 months. Overall 5-year cumulative incidence of LR was 2.1% (95% CI, 1.4% to 3.0%). The 5-year cumulative incidence of LR was 5.0% (95% CI, 3.0% to 8.3%) for age quartile 23 to 46 years; 2.2% (95% CI, 1.0% to 4.6%) for ages 47 to 54 years; 0.9% (95% CI, 0.3% to 2.6%) for ages 55 to 63 years; and 0.6% (95% CI, 0.1% to 2.2%) for ages 64 to 88 years. The 5-year cumulative incidence of LR was 0.8% (95% CI, 0.4% to 1.8%) for luminal A; 2.3% (95% CI, 0.8% to 5.9%) for luminal B; 1.1% (95% CI, 0.2% 7.4%) for luminal HER2; 10.8% (95% CI, 4.6% to 24.4%) for HER2; and 6.7% (95% CI, 3.6% to 12.2%) for triple negative. On multivariable analysis, increasing age was associated with decreased risk of LR (adjusted hazard ratio, 0.97; 95% CI, 0.94 to 0.99; P = .009). Conclusion In the era of systemic therapy and BC subtyping, age remains an independent prognostic factor after BCT. However, the risk of LR for young women appears acceptably low. C1 [Arvold, Nils D.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. [Taghian, Alphonse G.; Niemierko, Andrzej; Raad, Rita F. Abi; Smith, Barbara L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Harris, Jay R.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Sreedhara, Meera; Nguyen, Paul L.; Bellon, Jennifer R.; Wong, Julia S.; Harris, Jay R.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Harris, JR (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Dana 1622,450 Brookline Ave, Boston, MA 02215 USA. EM jharris@lroc.harvard.edu FU National Cancer Institute [R01CA139118, P50CA089393]; Jane Mailloux Research Fund; Blanche Montesi Fund; Tim Levy Fund for breast cancer research FX Supported in part by award No. R01CA139118 (A.G.T.) and award No. P50CA089393 (A.G.T.) from the National Cancer Institute; also supported in part by the Jane Mailloux Research Fund, the Blanche Montesi Fund, and the Tim Levy Fund for breast cancer research. NR 63 TC 151 Z9 159 U1 1 U2 11 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 OCT 10 PY 2011 VL 29 IS 29 BP 3885 EP 3891 DI 10.1200/JCO.2011.36.1105 PG 7 WC Oncology SC Oncology GA 833LE UT WOS:000295886200012 PM 21900114 ER PT J AU Griggs, JJ Somerfield, MR Anderson, H Henry, NL Hudis, CA Khatcheressian, JL Partridge, AH Prestrud, AA Davidson, NE AF Griggs, Jennifer J. Somerfield, Mark R. Anderson, Holly Henry, N. Lynn Hudis, Clifford A. Khatcheressian, James L. Partridge, Ann H. Prestrud, Ann Alexis Davidson, Nancy E. TI American Society of Clinical Oncology Endorsement of the Cancer Care Ontario Practice Guideline on Adjuvant Ovarian Ablation in the Treatment of Premenopausal Women With Early-Stage Invasive Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ESTRADIOL; PLASMA AB Purpose The American Society of Clinical Oncology (ASCO) has policies and procedures for endorsing practice guidelines that have been developed by other professional organizations. Methods The Cancer Care Ontario (CCO) Guideline on Adjuvant Ovarian Ablation (OA) in the Treatment of Premenopausal Women With Early-Stage Invasive Breast Cancer was reviewed for developmental rigor by methodologists. An ad hoc review panel of experts reviewed the content. Results The ASCO ad hoc OA guideline review panel concurred that the recommendations are clear, thorough, based on the most relevant scientific evidence in this content area, and present options that will be acceptable to patients. According to the CCO guideline: one, OA should not be routinely added to systemic therapy with chemotherapy, tamoxifen, or the combination of tamoxifen and chemotherapy; two, OA alone is not recommended as an alternative to any other form of systemic therapy, except in the specific case of patients who are candidates for other forms of systemic therapy but who, for some reason, will not receive any other systemic therapy (eg, patients who cannot tolerate other forms of systemic therapy or patients who choose no other form of systemic therapy); and three, when chemical suppression using luteinizing hormone-releasing hormone agonists is the chosen method of OA, in the opinion of the Breast Cancer Disease Site Group, monthly injection is the recommended mode of administration. The mode of administration in nearly all of the available trials has been monthly administration. Conclusion The ASCO review panel agrees with the recommendations as stated in the CCO guideline, with the qualification that ongoing research studies may alter the recommendations of the panel. C1 [Griggs, Jennifer J.; Henry, N. Lynn] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Griggs, Jennifer J.; Somerfield, Mark R.; Prestrud, Ann Alexis] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Khatcheressian, James L.] Virginia Canc Inst, Richmond, VA USA. [Anderson, Holly] Breast Canc Coalit Rochester, Rochester, MN USA. [Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. RP Griggs, JJ (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org FU AstraZeneca FX Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: N. Lynn Henry, AstraZeneca Expert Testimony: None Other Remuneration: None NR 7 TC 35 Z9 36 U1 0 U2 1 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 OCT 10 PY 2011 VL 29 IS 29 BP 3939 EP 3942 DI 10.1200/JCO.2011.36.4950 PG 4 WC Oncology SC Oncology GA 833LE UT WOS:000295886200020 PM 21900112 ER PT J AU Galsky, MD Hahn, NM Rosenberg, J AF Galsky, Matthew D. Hahn, Noah M. Rosenberg, Jonathan TI Reply to O. Dizdar et al SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CHEMOTHERAPY; CISPLATIN C1 [Galsky, Matthew D.] Mt Sinai Sch Med, New York, NY USA. [Hahn, Noah M.] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Rosenberg, Jonathan] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Galsky, MD (reprint author), Mt Sinai Sch Med, New York, NY USA. NR 7 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 OCT 10 PY 2011 VL 29 IS 29 BP 3945 EP 3946 DI 10.1200/JCO.2011.37.8117 PG 2 WC Oncology SC Oncology GA 833LE UT WOS:000295886200025 ER PT J AU Arvold, ND Hsu, L Chen, WY Benzaquen, LR Weiss, SE AF Arvold, Nils D. Hsu, Liangge Chen, Wendy Y. Benzaquen, Laura R. Weiss, Stephanie E. TI Marantic Endocarditis With Cardioembolic Strokes Mimicking Leptomeningeal Metastases in Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NONBACTERIAL THROMBOTIC ENDOCARDITIS; CEREBROSPINAL-FLUID CYTOLOGY; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; CLINICOPATHOLOGIC CORRELATIONS; DIAGNOSIS; EMBOLISM; AUTOPSY; SYSTEM; ERA C1 [Arvold, Nils D.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Hsu, Liangge; Benzaquen, Laura R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Chen, Wendy Y.; Weiss, Stephanie E.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP Arvold, ND (reprint author), Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA 02115 USA. NR 24 TC 0 Z9 0 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 OCT 10 PY 2011 VL 29 IS 29 BP E743 EP E746 DI 10.1200/JCO.2011.36.4190 PG 4 WC Oncology SC Oncology GA 833LE UT WOS:000295886200001 PM 21788555 ER PT J AU O'Hare, AM Choi, AI Boscardin, WJ Clinton, WL Zawadzki, I Hebert, PL Tamura, MK Taylor, L Larson, EB AF O'Hare, Ann M. Choi, Andy I. Boscardin, W. John Clinton, Walter L. Zawadzki, Ilan Hebert, Paul L. Tamura, Manjula Kurella Taylor, Leslie Larson, Eric B. TI LESS IS MORE Trends in Timing of Initiation of Chronic Dialysis in the United States SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CHRONIC KIDNEY-DISEASE; SURVIVAL; VALIDATION; MORTALITY; HARMFUL; GFR; AGE AB Background: During the past decade, a trend has been observed in the United States toward initiation of chronic dialysis at higher levels of estimated glomerular filtration rate. This likely reflects secular trends in the composition of the dialysis population and a tendency toward initiation of dialysis earlier in the course of kidney disease. Methods: The goal of this study was to generate model-based estimates of the magnitude of changes in the timing of dialysis initiation between 1997 and 2007. We used information from a national registry for end-stage renal disease on estimated glomerular filtration rate at initiation among patients who received their first chronic dialysis treatment in 1997 or 2007. We used information regarding predialysis estimated glomerular filtration rate slope from an integrated health care system. Results: After accounting for changes in the characteristics of new US dialysis patients from 1997 to 2007, we estimate that chronic dialysis was initiated a mean of 147 days earlier (95% confidence interval, 134-160) in the later compared with the earlier year. Differences in timing were consistent across a range of patient subgroups but were most pronounced for those aged 75 years or older; the mean difference in timing in that subgroup was 233 days (95% confidence interval, 206-267). Conclusions: Chronic dialysis appears to have been initiated substantially earlier in the course of kidney disease in 2007 compared with 1997. In the absence of strong evidence to suggest that earlier initiation of chronic dialysis is beneficial, these findings call for careful evaluation of contemporary dialysis initiation practices in the United States. C1 [O'Hare, Ann M.] Univ Washington, Dept Med, Seattle, WA USA. [Hebert, Paul L.] Univ Washington, Dept Hlth Sci, Seattle, WA USA. [O'Hare, Ann M.] Vet Affairs VA Med Ctr, Seattle, WA USA. [O'Hare, Ann M.] Renal Dialysis Unit, Seattle, WA USA. [Hebert, Paul L.; Taylor, Leslie] VA Puget Sound Healthcare Syst, VA Hlth Serv, Res & Dev Ctr Excellence, Seattle, WA USA. [O'Hare, Ann M.; Clinton, Walter L.; Zawadzki, Ilan; Larson, Eric B.] Grp Hlth Cooperat Puget Sound, Seattle, WA USA. [O'Hare, Ann M.; Clinton, Walter L.; Zawadzki, Ilan; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA. [Choi, Andy I.; Boscardin, W. John] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Choi, Andy I.; Boscardin, W. John] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Tamura, Manjula Kurella] Stanford Univ, Dept Med, San Francisco, CA USA. [Tamura, Manjula Kurella] VA Palo Alto Healthcare Syst, San Francisco, CA USA. [Choi, Andy I.] VA Med Ctr, VA No Calif Healthcare Syst, San Francisco, CA USA. RP O'Hare, AM (reprint author), Vet Affairs Med Ctr, Renal Dialysis Unit, 1660 S Columbian Way, Seattle, WA 98109 USA. EM ann.ohare@va.gov RI Kurella Tamura, Manjula/C-8284-2014 OI Kurella Tamura, Manjula/0000-0001-5227-2479 FU American Federation for Aging Research [K23DK080645, K23AG028952]; National Institute on Aging; National Institutes of Health; Beeson Career Development Award [K23AG28980] FX Dr O'Hare serves as the principal investigator for an interagency agreement between the Centers for Disease Control and Prevention and the Veterans Affairs Puget Sound Healthcare System. Within the past year, she has received royalties from UpToDate, Inc. Dr Choi was supported by grant K23DK080645 and Dr Kurella Tamura was supported by grant K23AG028952 (a Paul B. Beeson Career Development Award) from the American Federation for Aging Research and the National Institute on Aging. Dr Larson has received research support from the National Institutes of Health; royalties from UpToDate, Inc; Springer Publishing Company; and Elsevier BV; and speaker honoraria from universities and other nonprofit organizations.; This study was supported by Beeson Career Development Award K23AG28980 (principal investigator: Dr O'Hare). NR 32 TC 28 Z9 28 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 OCT 10 PY 2011 VL 171 IS 18 BP 1663 EP 1669 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 830YL UT WOS:000295695600012 PM 21987197 ER PT J AU Levy, DE Kang, R Vogeli, CS Rigotti, NA AF Levy, Douglas E. Kang, Raymond Vogeli, Christine S. Rigotti, Nancy A. TI Smoking Cessation Advice Rates in US Hospitals SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Levy, Douglas E.; Vogeli, Christine S.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Levy, Douglas E.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Div Gen Med, Boston, MA 02114 USA. [Levy, Douglas E.; Vogeli, Christine S.; Rigotti, Nancy A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kang, Raymond] Northwestern Univ, Inst Healthcare Studies, Feinberg Sch Med, Chicago, IL 60611 USA. RP Levy, DE (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM dlevy3@partners.org NR 7 TC 6 Z9 6 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 OCT 10 PY 2011 VL 171 IS 18 BP 1682 EP 1684 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 830YL UT WOS:000295695600020 PM 21987201 ER PT J AU Yeh, GY Forman, DE Stevenson, LW Wood, MJ Wayne, PM McCarthy, EP Davis, RB Phillips, RS AF Yeh, Gloria Y. Forman, Daniel E. Stevenson, Lynne Warner Wood, Malissa J. Wayne, Peter Michael McCarthy, Ellen P. Davis, Roger B. Phillips, Russell S. TI Yin and Yang of Tai Chi Exercise reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Yeh, Gloria Y.; Wayne, Peter Michael; McCarthy, Ellen P.; Davis, Roger B.; Phillips, Russell S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care,Dept Med, Brookline, MA 02446 USA. [Yeh, Gloria Y.; Wayne, Peter Michael; Davis, Roger B.; Phillips, Russell S.] Harvard Univ, Sch Med, Div Res & Educ Complementary & Integrat Med Thera, Brookline, MA 02446 USA. [Forman, Daniel E.; Stevenson, Lynne Warner] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Wood, Malissa J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Yeh, GY (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care,Dept Med, 1309 Beacon St,2nd Floor, Brookline, MA 02446 USA. EM gloria_yeh@hms.harvard.edu NR 4 TC 0 Z9 0 U1 1 U2 5 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 OCT 10 PY 2011 VL 171 IS 18 BP 1685 EP 1686 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 830YL UT WOS:000295695600024 ER PT J AU Etchegaray, JP Mostoslavsky, R AF Etchegaray, Jean-Pierre Mostoslavsky, Raul TI eNERgizing Pluripotent Gene Transcription SO CELL STEM CELL LA English DT Editorial Material ID STEM-CELLS; REPAIR; TFIIH; NANOG C1 [Etchegaray, Jean-Pierre; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. RP Mostoslavsky, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. EM rmostoslavsky@mgh.harvard.edu NR 10 TC 3 Z9 3 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 7 PY 2011 VL 9 IS 4 BP 285 EP 286 DI 10.1016/j.stem.2011.09.004 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 835MT UT WOS:000296041200002 PM 21982224 ER PT J AU Arnold, K Sarkar, A Yram, MA Polo, JM Bronson, R Sengupta, S Seandel, M Geijsen, N Hochedlinger, K AF Arnold, Katrin Sarkar, Abby Yram, Mary Anna Polo, Jose M. Bronson, Rod Sengupta, Sumitra Seandel, Marco Geijsen, Niels Hochedlinger, Konrad TI Sox2(+) Adult Stem and Progenitor Cells Are Important for Tissue Regeneration and Survival of Mice SO CELL STEM CELL LA English DT Article ID SELF-RENEWAL; IN-VITRO; EXPRESSION; MARKER; DIFFERENTIATION; INDUCTION; SPERMATOGENESIS; IDENTIFICATION; PLURIPOTENCY; MULTIPOTENT AB The transcription factor Sox2 maintains the pluripotency of early embryonic cells and regulates the formation of several epithelia during fetal development. Whether Sox2 continues to play a role in adult tissues remains largely unknown. We show here that Sox2 marks adult cells in several epithelial tissues where its expression has not previously been characterized, including the stomach, cervix, anus, testes, lens, and multiple glands. Genetic lineage tracing and transplantation experiments demonstrate that Sox2-expressing cells continuously give rise to mature cell types within these tissues, documenting their self-renewal and differentiation potentials. Consistent with these findings, ablation of Sox2(+) cells in mice results in a disruption of epithelial tissue homeostasis and lethality. Developmental fate mapping reveals that Sox2(+) adult stem cells originate from fetal Sox2(+) tissue progenitors. Thus, our results identify Sox2 expression in numerous adult endodermal and ectodermal stem cell compartments, which are critical for normal tissue regeneration and survival. C1 [Arnold, Katrin; Sarkar, Abby; Yram, Mary Anna; Polo, Jose M.; Hochedlinger, Konrad] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Arnold, Katrin; Sarkar, Abby; Yram, Mary Anna; Polo, Jose M.; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Arnold, Katrin; Sarkar, Abby; Yram, Mary Anna; Polo, Jose M.; Hochedlinger, Konrad] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Arnold, Katrin; Sarkar, Abby; Yram, Mary Anna; Polo, Jose M.; Geijsen, Niels; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Arnold, Katrin; Sarkar, Abby; Yram, Mary Anna; Polo, Jose M.; Geijsen, Niels; Hochedlinger, Konrad] Ctr Regenerat Med, Boston, MA 02114 USA. [Arnold, Katrin; Sarkar, Abby; Yram, Mary Anna; Polo, Jose M.; Geijsen, Niels; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Bronson, Rod] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Sengupta, Sumitra; Seandel, Marco] Weill Cornell Med Coll, Dept Surg, New York, NY 10065 USA. RP Hochedlinger, K (reprint author), Harvard Univ, Howard Hughes Med Inst, 7 Divin Ave, Cambridge, MA 02138 USA. EM khochedlinger@helix.mgh.harvard.edu FU Harvard Stem Cell Institute; NIH [R01HD058013-01A1]; Kimmel Foundation for Cancer Research; V Foundation for Cancer Research; MGH FX We thank Laura Prickett-Rice and Kat Folz-Donahoe for assistance with FACS, and Markus Schober, Nimet Maherali, and Matthias Stadtfeld for helpful discussions and critical reading of the manuscript. K.A. and K.H. were supported by a Seed Grant from the Harvard Stem Cell Institute. Additional support to K.H. was from the NIH Director's Innovator Award R01HD058013-01A1, the Kimmel and V Foundations for Cancer Research, and MGH startup funds. NR 46 TC 211 Z9 218 U1 2 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 7 PY 2011 VL 9 IS 4 BP 317 EP 329 DI 10.1016/j.stem.2011.09.001 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 835MT UT WOS:000296041200010 PM 21982232 ER PT J AU Wilkinson, K Boyd, JD Glicksman, M Moore, KJ El Khoury, J AF Wilkinson, Kim Boyd, Justin D. Glicksman, Marcie Moore, Kathryn J. El Khoury, Joseph TI A High Content Drug Screen Identifies Ursolic Acid as an Inhibitor of Amyloid beta Protein Interactions with Its Receptor CD36 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ALZHEIMERS-DISEASE; SCAVENGER RECEPTOR; HUMAN BRAIN; CLASS-B; INFLAMMATION; MICROGLIA; ASTROCYTES; EXPRESSION; MIGRATION; FIBRILS AB A pathological hallmark of Alzheimer disease (AD) is deposition of amyloid beta (A beta) in the brain. A beta binds to microglia via a receptor complex that includes CD36 leading to production of proinflammatory cytokines and neurotoxic reactive oxygen species and subsequent neurodegeneration. Interruption of A beta binding to CD36 is a potential therapeutic strategy for AD. To identify pharmacologic inhibitors of A beta binding to CD36, we developed a 384-well plate assay for binding of fluorescently labeled A beta to Chinese hamster ovary cells stably expressing human CD36 (CHO-CD36) and screened an Food and Drug Administration-approved compound library. The assay was optimized based on the cells' tolerance to dimethyl sulfoxide, A beta concentration, time required for A beta binding, reproducibility, and signal-to-background ratio. Using this assay, we identified four compounds as potential inhibitors of A beta binding to CD36. These compounds were ursolic acid, ellipticine, zoxazolamine, and homomoschatoline. Of these compounds, only ursolic acid, a naturally occurring pentacyclic triterpenoid, successfully inhibited binding of A beta to CHO-CD36 cells in a dose-dependent manner. The ursolic acid effect reached a plateau at similar to 20 mu M, with a maximal inhibition of 64%. Ursolic acid also blocked binding of A beta to microglial cells and subsequent ROS production. Our data indicate that cell-based high-content screening of small molecule libraries for their ability to block binding of A beta to its receptors is a useful tool to identify novel inhibitors of receptors involved in AD pathogenesis. Our data also suggest that ursolic acid is a potential therapeutic agent for AD via its ability to block A beta-CD36 interactions. C1 [Wilkinson, Kim; El Khoury, Joseph] Harvard Univ, Sch Med, Ctr Immunol & Inflammatory Dis, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Boyd, Justin D.; Glicksman, Marcie] Brigham & Womens Hosp, Lab Drug Discovery Neurodegenerat, Boston, MA 02139 USA. [Moore, Kathryn J.] NYU, Leon H Charney Div Cardiol, Dept Med, Med Ctr, New York, NY 10016 USA. RP El Khoury, J (reprint author), Harvard Univ, Sch Med, Ctr Immunol & Inflammatory Dis, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM jelkhoury@partners.org OI Moore, kathryn/0000-0003-2505-2547 FU National Institutes of Health through NINDS [NS059005]; National Institutes of Health through NIAID [AI U24AI082660]; National Institutes of Health through NIA [AG032349, AG020255] FX This work was supported, in whole or in part, by National Institutes of Health Grants NS059005 through the NINDS and AI U24AI082660 through the NIAID (to J. E. K.), AG032349 through the NIA (to J. E. K. and K. J. M.), and AG020255 through the NIA (to K. J. M.). NR 24 TC 34 Z9 34 U1 0 U2 11 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 OCT 7 PY 2011 VL 286 IS 40 BP 34914 EP 34922 DI 10.1074/jbc.M111.232116 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 827DD UT WOS:000295406300045 PM 21835916 ER PT J AU Shinozaki, S Choi, CS Shimizu, N Yamada, M Kim, M Zhang, T Dong, HH Kim, YB Kaneki, M AF Shinozaki, Shohei Choi, Cheol Soo Shimizu, Nobuyuki Yamada, Marina Kim, Minhye Zhang, Ting Dong, H. Henry Kim, Young-Bum Kaneki, Masao TI Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; SKELETAL-MUSCLE CELLS; AKT/PROTEIN KINASE-B; S-NITROSYLATION; FASTING HYPERGLYCEMIA; RECEPTOR SUBSTRATE-1; POSSIBLE INVOLVEMENT; MAMMALIAN TARGET; GENE-EXPRESSION; OB/OB MICE AB Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, plays an important role in obesity-induced insulin resistance. Inhibition of iNOS by gene disruption or pharmacological inhibitors reverses or ameliorates obesity-induced insulin resistance in skeletal muscle and liver in mice. It is unknown, however, whether increased expression of iNOS is sufficient to cause insulin resistance in vivo. To address this issue, we generated liver-specific iNOS transgenic (L-iNOS-Tg) mice, where expression of the transgene, iNOS, is regulated under mouse albumin promoter. L-iNOS-Tg mice exhibited mild hyperglycemia, hyperinsulinemia, insulin resistance, and impaired insulin-induced suppression of hepatic glucose output, as compared with wild type (WT) littermates. Insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) and -2, and Akt was significantly attenuated in liver, but not in skeletal muscle, of L-iNOS-Tg mice relative to WT mice without changes in insulin receptor phosphorylation. Moreover, liver-specific iNOS expression abrogated insulin-stimulated phosphorylation of glycogen synthase kinase-3 beta, forkhead box O1, and mTOR (mammalian target of rapamycin), endogenous substrates of Akt, along with increased S-nitrosylation of Akt relative to WT mice. However, the expression of insulin receptor, IRS-1, IRS-2, Akt, glycogen synthase kinase-3 beta, forkhead box O1, protein-tyrosine phosphatase-1B, PTEN (phosphatase and tensin homolog), and p85 phosphatidylinositol 3-kinase was not altered by iNOS transgene. Hyperglycemia was associated with elevated glycogen phosphorylase activity and decreased glycogen synthase activity in the liver of L-iNOS-Tg mice, whereas phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and proliferator-activated receptor gamma coactivator-1 alpha expression were not altered. These results clearly indicate that selective expression of iNOS in liver causes hepatic insulin resistance along with deranged insulin signaling, leading to hyperglycemia and hyperinsulinemia. Our data highlight a critical role for iNOS in the development of hepatic insulin resistance and hyperglycemia. C1 [Shinozaki, Shohei; Shimizu, Nobuyuki; Yamada, Marina; Kim, Minhye; Kaneki, Masao] Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp,Shriners Hosp Children, Charlestown, MA 02129 USA. [Choi, Cheol Soo] Gachon Univ Med & Sci, Dept Internal Med, Inchon 406840, South Korea. [Choi, Cheol Soo] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Inchon 406840, South Korea. [Zhang, Ting; Dong, H. Henry] Univ Pittsburgh, Med Ctr, Div Immunogenet, Rangos Res Ctr,Childrens Hosp Pittsburgh, Pittsburgh, PA 15224 USA. [Kim, Young-Bum] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Kim, Young-Bum] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Kaneki, M (reprint author), 149 13th St,Rm 6604, Charlestown, MA 02129 USA. EM mkaneki@helix.mgh.harvard.edu RI Zhang, Ting/J-5074-2015; OI Dong, H. Henry/0000-0003-0279-5241 FU National Institutes of Health [R01DK05827, R01DK066301]; American Diabetes Association [7-08-RA-77, 109-RA-87]; Korea Healthcare Technology R&D Project, Republic of Korea [A084651] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01DK05827 (to M. K.) and R01DK066301 (to H. H. D.). This work was also supported by American Diabetes Association Grants 7-08-RA-77 (to Y.-B. K.) and 1-09-RA-87 (to H. H. D.), and Korea Healthcare Technology R&D Project, Republic of Korea Grant A084651 (to C. S. C.). NR 50 TC 27 Z9 28 U1 1 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 OCT 7 PY 2011 VL 286 IS 40 BP 34959 EP 34975 DI 10.1074/jbc.M110.187666 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 827DD UT WOS:000295406300050 PM 21846719 ER PT J AU Eng, ET Smagghe, BJ Walz, T Springer, TA AF Eng, Edward T. Smagghe, Benoit J. Walz, Thomas Springer, Timothy A. TI Intact alpha(IIb)beta(3) Integrin Is Extended after Activation as Measured by Solution X-ray Scattering and Electron Microscopy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCOPROTEIN-IIB; STRUCTURAL BASIS; CONFORMATIONAL REGULATION; CRYSTAL-STRUCTURE; CELL-ADHESION; BINDING-SITE; OUTSIDE-IN; COMPLEX; LIGAND; DOMAIN AB Integrins are bidirectional signaling molecules on the cell surface that have fundamental roles in regulating cell behavior and contribute to cell migration and adhesion. Understanding of the mechanism of integrin signaling and activation has been advanced with truncated ectodomain preparations; however, the nature of conformational change in the full-length intact integrin molecule remains an active area of research. Here we used small angle x-ray scattering and electron microscopy to study detergent-solubilized, intact platelet integrin alpha(IIb)beta(3). In the resting state, the intact alpha(IIb)beta(3) adopted a compact, bent conformation. Upon activation with Mn2+, the average integrin extension increased. Further activation by addition of ligand led to stabilization of the extended state and opening of the headpiece. The observed extension and conformational rearrangement upon activation are consistent with the extension and headpiece opening model of integrin activation. C1 [Eng, Edward T.; Smagghe, Benoit J.; Springer, Timothy A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Immune Dis Inst,CLSB, Boston, MA 02115 USA. [Eng, Edward T.; Smagghe, Benoit J.; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Immune Dis Inst,CLSB, 3 Blackfan Circle,3rd Floor, Boston, MA 02115 USA. EM springer@idi.harvard.edu FU National Institutes of Health [HL103526] FX This work was supported, in whole or in part, by National Institutes of Health Grant HL103526. NR 50 TC 27 Z9 27 U1 0 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 OCT 7 PY 2011 VL 286 IS 40 BP 35218 EP 35226 DI 10.1074/jbc.M111.275107 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 827DD UT WOS:000295406300074 PM 21832081 ER PT J AU Abu Dayyeh, BK Gupta, N Sherman, KE de Bakker, PIW Chung, RT AF Abu Dayyeh, Barham K. Gupta, Namrata Sherman, Kenneth E. de Bakker, Paul I. W. Chung, Raymond T. CA Aids Clinical Trials Grp A5178 TI IL28B Alleles Exert an Additive Dose Effect When Applied to HCV-HIV Coinfected Persons Undergoing Peginterferon and Ribavirin Therapy SO PLOS ONE LA English DT Article ID HEPATITIS-C-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; SUSTAINED VIROLOGICAL RESPONSE; INTERFERON PLUS RIBAVIRIN; AMINO-ACID SUBSTITUTIONS; COMBINATION THERAPY; INFECTED PATIENTS; GENETIC-VARIATION; LIVER-DISEASE; GENOTYPE 1B AB Background: Genetic studies have demonstrated a strong association between single nucleotide polymorphisms (SNPs) at IL28B and response to treatment with peginterferon (PEG) and ribavirin (RBV) in HCV monoinfected persons. We sought to test these associations in a prospective PEG / weight based ribavirin (WBR) treatment trial (ACTG A5178) (National Institution of Health registration number NCT00078403) in persons with HCV-HIV coinfection, and to develop a prediction score. Methods: We selected subjects enrolled in A5178 who completed at least the first 12 weeks of the trial and had DNA available, and genotyped three SNPs at IL28B (rs12979860, rs12980275, rs8099917). We used multivariate logistic regression analysis to evaluate the association between IL28B SNPs and HCV treatment outcomes and to develop the prediction score. Results: 231 HCV/HIV coinfected subjects were included. We observed a strong association between IL28B genotype and response to therapy among those with genotypes 1 or 4 (odds ratio for complete early virologic responses (cEVR) and sustained virologic response (SVR) was 2.98 [1.7-5.3] and 3.4 [1.7-6.9], respectively, for each additional copy of the C allele of rs12979860). Differences in frequency of the responder allele explained some of the discrepancy in HCV treatment outcomes between blacks and whites. A simple pretreatment prediction score that incorporates the IL28B genotype and baseline HCV viral load has a 93% negative predictive value (NPV) for SVR. Conclusions: IL28B SNPs have an additive allele dose effect in predicting HCV treatment outcomes in HCV/HIV coinfected persons and can be incorporated into a simple pretreatment prediction score that could minimize the risk of exposure to PEG/RBV therapy for persons with unfavorable scores. C1 [Abu Dayyeh, Barham K.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Abu Dayyeh, Barham K.; Chung, Raymond T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gupta, Namrata; de Bakker, Paul I. W.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Sherman, Kenneth E.] Univ Cincinnati, Dept Internal Med, Cincinnati, OH USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet,Dept Med, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr, Dept Med Genet, Div Biomed Genet, Utrecht, Netherlands. RP Abu Dayyeh, BK (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. EM rtchung@partners.org RI de Bakker, Paul/B-8730-2009 OI de Bakker, Paul/0000-0001-7735-7858 FU National Institute of Health [K27 5K24DK078772-04] FX This work was supported by the National Institute of Health [K27 5K24DK078772-04 to R.T.C.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 1 Z9 2 U1 0 U2 0 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 OCT 7 PY 2011 VL 6 IS 10 AR e25753 DI 10.1371/journal.pone.0025753 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300026 ER PT J AU Ayrapetov, MK Xu, C Sun, YL Zhu, KY Parmar, K D'Andrea, AD Price, BD AF Ayrapetov, Marina K. Xu, Chang Sun, Yingli Zhu, Kaya Parmar, Kalindi D'Andrea, Alan D. Price, Brendan D. TI Activation of Hif1 alpha by the Prolylhydroxylase Inhibitor Dimethyoxalyglycine Decreases Radiosensitivity SO PLOS ONE LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; PROLYL HYDROXYLASE INHIBITORS; GENE-EXPRESSION; DNA-DAMAGE; PROLINE HYDROXYLATION; HISTONE DEMETHYLASES; HUMAN CANCERS; JMJD2 FAMILY; TUMOR-GROWTH; GAMMA-RAYS AB Hypoxia inducible factor 1 alpha (Hif1 alpha) is a stress responsive transcription factor, which regulates the expression of genes required for adaption to hypoxia. Hif1 alpha is normally hydroxylated by an oxygen-dependent prolylhydroxylase, leading to degradation and clearance of Hif1 alpha from the cell. Under hypoxic conditions, the activity of the prolylhydroxylase is reduced and Hif1 alpha accumulates. Hif1 alpha is also constitutively expressed in tumor cells, where it is associated with resistance to ionizing radiation. Activation of the Hif1 alpha transcriptional regulatory pathway may therefore function to protect normal cells from DNA damage caused by ionizing radiation. Here, we utilized the prolylhydroxylase inhibitor dimethyloxalylglycine (DMOG) to elevate Hif1 alpha levels in mouse embryonic fibroblasts (MEFs) to determine if DMOG could function as a radioprotector. The results demonstrate that DMOG increased Hif1 alpha protein levels and decreased the sensitivity of MEFs to ionizing radiation. Further, the ability of DMOG to function as a radioprotector required Hif1 alpha, indicating a key role for Hif1 alpha's transcriptional activity. DMOG also induced the Hif1 alpha-dependent accumulation of several DNA damage response proteins, including CHD4 and MTA3 (sub-units of the NuRD deacetylase complex) and the Suv39h1 histone H3 methyltransferase. Depletion of Suv39h1, but not CHD4 or MTA3, reduced the ability of DMOG to protect cells from radiation damage, implicating increased histone H3 methylation in the radioprotection of cells. Finally, treatment of mice with DMOG prior to total body irradiation resulted in significant radioprotection of the mice, demonstrating the utility of DMOG and related prolylhydroxylase inhibitors to protect whole organisms from ionizing radiation. Activation of Hif1a through prolylhydroxylase inhibition therefore identifies a new pathway for the development of novel radiation protectors. C1 [Ayrapetov, Marina K.; Xu, Chang; Zhu, Kaya; Parmar, Kalindi; D'Andrea, Alan D.; Price, Brendan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair,Dept Radiat Oncol, Boston, MA 02115 USA. [Sun, Yingli] Chinese Acad Sci, Beijing Inst Genom, Dis Genom & Individualized Med Key Lab, Beijing, Peoples R China. RP Ayrapetov, MK (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair,Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM sunyl@big.ac.cn; kalindi_parmar@dfci.harvard.edu; brendan_price@dfci.harvard.edu FU National Cancer Institute (NCI) [CA64585, CA93602]; Associates of the Joint Center for Radiation Therapy (AJCRT) foundation; National Institute of Allergy and Infectious Diseases (NIAID) [U19 A1067751] FX This work was supported by grants from the National Cancer Institute (NCI) (CA64585 and CA93602), the Associates of the Joint Center for Radiation Therapy (AJCRT) foundation and by National Institute of Allergy and Infectious Diseases (NIAID) U19 A1067751 center grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 12 Z9 12 U1 0 U2 9 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 OCT 7 PY 2011 VL 6 IS 10 AR e26064 DI 10.1371/journal.pone.0026064 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300056 PM 22016813 ER PT J AU Stienen, BMC Tanaka, A de Gelder, B AF Stienen, Bernard M. C. Tanaka, Akihiro de Gelder, Beatrice TI Emotional Voice and Emotional Body Postures Influence Each Other Independently of Visual Awareness SO PLOS ONE LA English DT Article ID FACIAL EXPRESSIONS; INFLUENCE RECOGNITION; BODILY EXPRESSIONS; PERCEPTION; AMYGDALA; FACE; ATTENTION; MASKING; THREAT; FEAR AB Multisensory integration may occur independently of visual attention as previously shown with compound face-voice stimuli. We investigated in two experiments whether the perception of whole body expressions and the perception of voices influence each other when observers are not aware of seeing the bodily expression. In the first experiment participants categorized masked happy and angry bodily expressions while ignoring congruent or incongruent emotional voices. The onset between target and mask varied from -50 to +133 ms. Results show that the congruency between the emotion in the voice and the bodily expressions influences audiovisual perception independently of the visibility of the stimuli. In the second experiment participants categorized the emotional voices combined with masked bodily expressions as fearful or happy. This experiment showed that bodily expressions presented outside visual awareness still influence prosody perception. Our experiments show that audiovisual integration between bodily expressions and affective prosody can take place outside and independent of visual awareness. C1 [Stienen, Bernard M. C.; de Gelder, Beatrice] Tilburg Univ, Lab Cognit & Affect Neurosci, NL-5000 LE Tilburg, Netherlands. [Tanaka, Akihiro] Waseda Inst Adv Study, Tokyo, Japan. [de Gelder, Beatrice] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [de Gelder, Beatrice] Harvard Univ, Sch Med, Charlestown, MA USA. RP Stienen, BMC (reprint author), Tilburg Univ, Lab Cognit & Affect Neurosci, NL-5000 LE Tilburg, Netherlands. EM B.deGelder@uvt.nl FU Dutch Association of Scientific Research (NWO), Tango; EU [FDP6-NEST-043403]; MEXT [19001004]; European Commission, under FET-Open [249858] FX This project was funded by the Dutch Association of Scientific Research (NWO), Tango, the EU project COBOL (FDP6-NEST-043403) and by Grant-in-Aid of MEXT for Specially Promoted Research (no. 19001004). The project Tango acknowledges the financial support of the Future and Emerging Technologies (FET) programme within the Seventh Framework Programme for Research of the European Commission, under FET-Open (grant number 249858). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 12 Z9 12 U1 0 U2 11 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 OCT 7 PY 2011 VL 6 IS 10 AR e25517 DI 10.1371/journal.pone.0025517 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834OC UT WOS:000295970300017 PM 22003396 ER PT J AU Hu, XL Kim, H Stahl, E Plenge, R Daly, M Raychaudhuri, S AF Hu, Xinli Kim, Hyun Stahl, Eli Plenge, Robert Daly, Mark Raychaudhuri, Soumya TI Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; CROHNS-DISEASE; RECEPTOR GENE; B-CELLS; VARIANTS; ITGAM AB Although genome-wide association studies have implicated many individual loci in complex diseases, identifying the exact causal alleles and the cell types within which they act remains greatly challenging. To ultimately understand disease mechanism, researchers must carefully conceive functional studies in relevant pathogenic cell types to demonstrate the cellular impact of disease-associated genetic variants. This challenge is highlighted in autoimmune diseases, such as rheumatoid arthritis, where any of a broad range of immunological cell types might potentially be impacted by genetic variation to cause disease. To this end, we developed a statistical approach to identify potentially pathogenic cell types in autoimmune diseases by using a gene-expression data set of 223 murine-sorted immune cells from the Immunological Genome Consortium. We found enrichment of transitional B cell genes in systemic lupus erythematosus (p = 5.9 x 10(-6)) and epithelial-associated stimulated dendritic cell genes in Crohn disease (p = 1.6 x 10(-5)). Finally, we demonstrated enrichment of CD4+ effector memory T cell genes within rheumatoid arthritis loci (p < 10(-6)). To further validate the role of CD4+ effector memory T cells within rheumatoid arthritis, we identified 436 loci that were not yet known to be associated with the disease but that had a statistically suggestive association in a recent genome-wide association study (GWAS) meta-analysis (PG WAS < 0.001). Even among these putative loci, we noted a significant enrichment for genes specifically expressed in CD4+ effector memory T cells (p = 1.25 x 10(-4)). These cell types are primary candidates for future functional studies to reveal the role of risk alleles in autoimmunity. Our approach has application in other phenotypes, outside of autoimmunity, where many loci have been discovered and high-quality cell-type-specific gene expression is available. C1 [Hu, Xinli; Kim, Hyun; Stahl, Eli; Plenge, Robert; Raychaudhuri, Soumya] Harvard Univ, Sch Med, Div Genet, Brigham & Womens Hosp, Boston, MA 02115 USA. [Hu, Xinli; Kim, Hyun; Stahl, Eli; Plenge, Robert; Raychaudhuri, Soumya] Harvard Univ, Sch Med, Div Rheumatol Immunol & Allergy, Brigham & Womens Hosp, Boston, MA 02115 USA. [Hu, Xinli; Stahl, Eli; Plenge, Robert; Daly, Mark; Raychaudhuri, Soumya] Broad Inst, Med & Populat Genet Grp, Cambridge, MA 02142 USA. [Hu, Xinli] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA. [Hu, Xinli] MIT, Boston, MA 02115 USA. [Daly, Mark] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02214 USA. [Raychaudhuri, Soumya] Partners HealthCare Ctr Personalized Genet Med, Boston, MA 02115 USA. RP Raychaudhuri, S (reprint author), Harvard Univ, Sch Med, Div Genet, Brigham & Womens Hosp, Boston, MA 02115 USA. EM soumya@broadinstitute.org FU National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH-NIAMS) [1K08AR055688]; Harvard Health Sciences and Technology Program FX This work benefitted from data assembled by the ImmGen Consortium. This work was supported in part by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH-NIAMS) Development Award (1K08AR055688) and by the Harvard Health Sciences and Technology Program. We thank Joel Hirschorn, Michael B. Brenner, David Altshuler, and Lude Franke for helpful discussions. NR 54 TC 57 Z9 57 U1 0 U2 5 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 OCT 7 PY 2011 VL 89 IS 4 BP 496 EP 506 DI 10.1016/j.ajhg.2011.09.002 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 834HV UT WOS:000295951300004 PM 21963258 ER PT J AU Talkowski, ME Mullegama, SV Rosenfeld, JA van Bon, WM Shen, YP Repnikova, EA Gastier-Foster, J Thrush, DL Kathiresan, S Ruderfer, DM Chiang, C Hanscom, C Ernst, C Lindgren, AM Morton, CC An, Y Astbury, C Brueton, LA Lichtenbelt, KD Ades, LC Fichera, M Romano, C Innis, JW Williams, CA Bartholomew, D Van Allen, MI Parikh, A Zhang, LL Wu, BL Pyatt, RE Schwartz, S Shaffer, LG de Vries, BBA Gusella, JF Elsea, SH AF Talkowski, Michael E. Mullegama, Sureni V. Rosenfeld, Jill A. van Bon, W. M. Shen, Yiping Repnikova, Elena A. Gastier-Foster, Julie Thrush, Devon Lamb Kathiresan, Sekar Ruderfer, Douglas M. Chiang, Colby Hanscom, Carrie Ernst, Carl Lindgren, Amelia M. Morton, Cynthia C. An, Yu Astbury, Caroline Brueton, Louise A. Lichtenbelt, Klaske D. Ades, Lesley C. Fichera, Marco Romano, Corrado Innis, Jeffrey W. Williams, Charles A. Bartholomew, Dennis Van Allen, Margot I. Parikh, Aditi Zhang, Lilei Wu, Bai-Lin Pyatt, Robert E. Schwartz, Stuart Shaffer, Lisa G. de Vries, Bert B. A. Gusella, James F. Elsea, Sarah H. TI Assessment of 2q23.1 Microdeletion Syndrome Implicates MBD5 as a Single Causal Locus of Intellectual Disability, Epilepsy, and Autism Spectrum Disorder SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; SMITH-MAGENIS-SYNDROME; DNA-SEQUENCING DATA; MENTAL-RETARDATION; WIDE ASSOCIATION; CHROMOSOME REARRANGEMENTS; GENOMEWIDE ASSOCIATION; BIPOLAR DISORDER; PHENOTYPE; DELETIONS AB Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MOOS coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders. C1 [Elsea, Sarah H.] Virginia Commonwealth Univ, Sch Med, Dept Human & Mol Genet, Richmond, VA 23298 USA. [Talkowski, Michael E.; Kathiresan, Sekar; Ruderfer, Douglas M.; Chiang, Colby; Hanscom, Carrie; Ernst, Carl; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Talkowski, Michael E.; Gusella, James F.] Harvard Univ, Harvard Med Sch, Dept Genet, Cambridge, MA 02115 USA. [Talkowski, Michael E.; Gusella, James F.] Harvard Univ, Harvard Med Sch, Dept Neurol, Cambridge, MA 02115 USA. [Talkowski, Michael E.; Kathiresan, Sekar; Morton, Cynthia C.; Gusella, James F.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02143 USA. [Rosenfeld, Jill A.; Shaffer, Lisa G.] PerkinElmer Inc, Signature Genom Labs, Spokane, WA 99207 USA. [van Bon, W. M.; de Vries, Bert B. A.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands. [Shen, Yiping] Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China. [Shen, Yiping; Wu, Bai-Lin] Childrens Hosp Boston, Dept Lab Med, Boston, MA 02115 USA. [Shen, Yiping; Wu, Bai-Lin] Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA. [Kathiresan, Sekar; Wu, Bai-Lin] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Repnikova, Elena A.; Gastier-Foster, Julie; Thrush, Devon Lamb; Astbury, Caroline; Pyatt, Robert E.] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43205 USA. [Gastier-Foster, Julie; Astbury, Caroline; Pyatt, Robert E.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Gastier-Foster, Julie; Thrush, Devon Lamb] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ruderfer, Douglas M.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Ruderfer, Douglas M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ruderfer, Douglas M.] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02143 USA. [Lindgren, Amelia M.; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Lindgren, Amelia M.; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wu, Bai-Lin] Fudan Univ, Childrens Hosp, Shanghai 200032, Peoples R China. [Wu, Bai-Lin] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China. [Brueton, Louise A.] Birmingham Womens Hosp, Clin Genet Unit, W Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England. [Lichtenbelt, Klaske D.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [Ades, Lesley C.] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Fichera, Marco] Ist Ricovero & Cura, Lab Genet Diag, I-94018 Troina, Italy. [Romano, Corrado] Assoc Oasi Maria Santissima, IRCCS, I-94108 Troina, Italy. [Innis, Jeffrey W.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Innis, Jeffrey W.] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Williams, Charles A.] Univ Florida, Coll Med, Dept Pediat, Div Genet & Metab, Gainesville, FL 32611 USA. [Bartholomew, Dennis] Nationwide Childrens Hosp, Div Mol & Human Genet, Columbus, OH 43205 USA. [Van Allen, Margot I.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. [Parikh, Aditi; Zhang, Lilei] Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA. [Parikh, Aditi; Zhang, Lilei] Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. [Schwartz, Stuart] LabCorp, Res Triangle Pk, NC 27709 USA. [Elsea, Sarah H.] Virginia Commonwealth Univ, Sch Med, Dept Pediat, Richmond, VA 23298 USA. RP Elsea, SH (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Human & Mol Genet, Richmond, VA 23298 USA. EM selsea@vcu.edu RI Fichera, Marco/K-9220-2016; Ruderfer, Douglas/M-5795-2016; Astbury, Caroline/E-2665-2011; Gastier-Foster, Julie/E-3105-2011; van Bon, Bregje/D-3720-2013; Romano, Corrado/B-9695-2008; van Bon, Bregje/Q-2445-2015 OI Fichera, Marco/0000-0002-8225-6880; Ruderfer, Douglas/0000-0002-2365-386X; Romano, Corrado/0000-0003-1049-0683; FU Developmental Genome Anatomy Project [GM061354, HD065286]; National "973" project on Population and Health of China [2010CB529601]; Science and Technology Council of Shanghai [09JC1402400, 09ZR1404500]; Simons Foundation Autism Research Initiative; National Institutes of Health [F32MH087123]; "5 per mille" program FX We are thankful to all of the subjects and families involved in this study. We are grateful for the assistance of Jennifer Defant, Santhosh Girirajan, Stephen Williams, Zalak Shah, and Tracey Oh in the collection of clinical data and in the preparation of this manuscript. We thank Pamela Sklar and the International Schizophrenia Consortium for contributing control data and Nancy J. Van Vranken for patient referral. We are also grateful to Manuel Rivas for assistance with the Syzygy analysis. We thank the Fondation Jerome Lejeune (SHE.) for funding portions of this study, Developmental Genome Anatomy Project(GM061354), HD065286, National "973" project on Population and Health of China (2010CB529601), Science and Technology Council of Shanghai (09JC1402400 and 09ZR1404500), and the Simons Foundation Autism Research Initiative. M.E.T. was supported by a National Institutes of Health National Research Service Award (F32MH087123). The authors would also like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). Fichera and Romano were supported by a grant from the "5 per mille" program. NR 48 TC 90 Z9 90 U1 2 U2 16 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 OCT 7 PY 2011 VL 89 IS 4 BP 551 EP 563 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 834HV UT WOS:000295951300009 PM 21981781 ER PT J AU Jun, GG Nicolaou, M Morrison, MA Buros, J Morgan, DJ Radeke, MJ Yonekawa, Y Tsironi, EE Kotoula, MG Zacharaki, F Mollema, N Yuan, Y Miller, JW Haider, NB Hageman, GS Kim, IK Schaumberg, DA Farrer, LA DeAngelis, MM AF Jun, Gyungah Nicolaou, Michael Morrison, Margaux A. Buros, Jacqueline Morgan, Denise J. Radeke, Monte J. Yonekawa, Yoshihiro Tsironi, Evangelia E. Kotoula, Maria G. Zacharaki, Fani Mollema, Nissa Yuan, Yang Miller, Joan W. Haider, Neena B. Hageman, Gregory S. Kim, Ivana K. Schaumberg, Debra A. Farrer, Lindsay A. DeAngelis, Margaret M. TI Influence of ROBO1 and RORA on Risk of Age-Related Macular Degeneration Reveals Genetically Distinct Phenotypes in Disease Pathophysiology SO PLOS ONE LA English DT Article ID COMPLEMENT FACTOR-H; OCULAR ANGIOGENESIS; RETINAL DEVELOPMENT; GENE-EXPRESSION; AXON GUIDANCE; ASSOCIATION; SMOKING; DRUSEN; ALPHA; SUSCEPTIBILITY AB ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6x10(-4)) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P<0.05). These studies were further supported by whole transcriptome expression profile studies from 66 human donor eyes and chromatin immunoprecipitation assays from mouse retinas. These findings suggest that distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants. C1 [Jun, Gyungah; Nicolaou, Michael; Buros, Jacqueline; Farrer, Lindsay A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Morrison, Margaux A.; Yonekawa, Yoshihiro; Miller, Joan W.; Kim, Ivana K.; DeAngelis, Margaret M.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Morrison, Margaux A.; Morgan, Denise J.; Hageman, Gregory S.; DeAngelis, Margaret M.] Univ Utah, Ctr Translat Med, John Moran Eye Ctr, Salt Lake City, UT USA. [Radeke, Monte J.] Univ Calif Santa Barbara, Neurosci Res Inst, Ctr Study Macular Degenerat, Santa Barbara, CA 93106 USA. [Yonekawa, Yoshihiro] Weill Cornell Med Coll, New York, NY USA. [Tsironi, Evangelia E.; Kotoula, Maria G.; Zacharaki, Fani] Univ Thessaly, Larisa, Greece. [Mollema, Nissa; Yuan, Yang; Haider, Neena B.] Univ Nebraska Med Ctr, Omaha, NE USA. [Schaumberg, Debra A.] Brigham & Womens Hosp, Harvard Med Sch, Div Prevent Med, Boston, MA 02115 USA. [Jun, Gyungah; Nicolaou, Michael; Buros, Jacqueline; Schaumberg, Debra A.; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. RP Jun, GG (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM Margaret.DeAngelis@utah.edu RI DeAngelis, e/J-7863-2015; OI Jun, Gyungah/0000-0002-3230-8697; Farrer, Lindsay/0000-0001-5533-4225; Buros, Jacqueline/0000-0001-9588-4889 FU Thome Memorial Foundation; Bank of America N.A.; Lincy Foundation; Massachusetts Lions; Friends of the Massachusetts Eye and Ear Infirmary; Genetics of Age-related Macular Degeneration Fund; Research to Prevent Blindness; Hope for Vision; National Institutes of Health [EY014458, EY14104, EY017362, EY017404]; Massachusetts Eye and Ear Infirmary FX This work was supported by grants from the Thome Memorial Foundation; Bank of America N.A.; Lincy Foundation; the Massachusetts Lions; Friends of the Massachusetts Eye and Ear Infirmary; the Massachusetts Eye and Ear Infirmary; Genetics of Age-related Macular Degeneration Fund; Unrestricted Grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences, University of Utah; Hope for Vision; and the National Institutes of Health (EY014458, EY14104, EY017362, EY017404). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 10 Z9 10 U1 0 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 OCT 6 PY 2011 VL 6 IS 10 AR e25775 DI 10.1371/journal.pone.0025775 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834NO UT WOS:000295968700018 PM 21998696 ER PT J AU Nathan, DG AF Nathan, David G. TI Guilt by association SO BLOOD LA English DT Editorial Material ID SICKLE-CELL-DISEASE; PULMONARY-HYPERTENSION C1 [Nathan, David G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nathan, DG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 7 TC 4 Z9 4 U1 0 U2 1 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 OCT 6 PY 2011 VL 118 IS 14 BP 3758 EP 3759 DI 10.1182/blood-2011-08-370338 PG 4 WC Hematology SC Hematology GA 832LY UT WOS:000295807700003 PM 21980046 ER PT J AU Sakakibara, K Saito, N Sato, T Suzuki, A Hasegawa, Y Friedman, JM Kufe, DW VonHoff, DD Iwami, T Kawabe, T AF Sakakibara, Keiichi Saito, Naoya Sato, Takuji Suzuki, Atsushi Hasegawa, Yoko Friedman, Jonathan M. Kufe, Donald W. VonHoff, Daniel D. Iwami, Tadahiko Kawabe, Takumi TI CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity SO BLOOD LA English DT Article ID MULTIPLE-MYELOMA CELLS; ABL TYROSINE KINASE; NF-KAPPA-B; NUCLEAR EXPORT; NUCLEOCYTOPLASMIC TRANSPORT; LEPTOMYCIN-B; G(2) CHECKPOINT; LEUKEMIA-CELLS; CANCER; ACTIVATION AB CRM1 plays an important role in the nuclear export of cargo proteins bearing nuclear exporting signal sequences. Leptomycin B (LMB), a well-known CRM1 inhibitor, possesses strong antitumor properties. However, its toxicity prevents it from being clinically useful. In this study, we demonstrate that a novel compound, CBS9106, inhibits CRM1-dependent nuclear export, causing arrest of the cell cycle and inducing apoptosis in a time-and dose-dependent manner for a broad spectrum of cancer cells, including multiple myeloma cells. CBS9106 reduces CRM1 protein levels significantly without affecting CRM1 mRNA expression. This effect could be reversed by adding bortezomib or LMB. Moreover, CBS9106-biotin allows capture of CRM1 protein by streptavidin beads in a competitive manner with LMB and vice versa. Mass spectrometric analysis shows that CBS9106 reacts with a synthetic CRM1 peptide that contains Cys528 but not with a Cys528 mutant peptide. Oral administration of CBS9106 significantly suppresses tumor growth and prolongs survival in mice bearing tumor xenograft without a significant loss in body weight. A reduced level of CRM1 protein is also observed in tumor xenografts isolated from mice treated with CBS9106. Taken together, these results indicate that CBS9106 is a novel reversible CRM1 inhibitor and a promising clinical candidate. (Blood. 2011;118(14):3922-3931) C1 [Sakakibara, Keiichi; Saito, Naoya; Sato, Takuji; Suzuki, Atsushi; Hasegawa, Yoko; Friedman, Jonathan M.; Iwami, Tadahiko; Kawabe, Takumi] CanBas Co Ltd, Numazu 4100801, Japan. [Kufe, Donald W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [VonHoff, Daniel D.] Translat Genom Res Inst TGen, Phoenix, AZ USA. RP Kawabe, T (reprint author), CanBas Co Ltd, 2-2-1 Otemachi, Numazu 4100801, Japan. EM takumi@canbas.co.jp OI friedman, jonathan/0000-0001-6908-5928 NR 35 TC 58 Z9 64 U1 1 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 OCT 6 PY 2011 VL 118 IS 14 BP 3922 EP 3931 DI 10.1182/blood-2011-01-333138 PG 10 WC Hematology SC Hematology GA 832LY UT WOS:000295807700024 PM 21841164 ER PT J AU Jacquemont, S Reymond, A Zufferey, F Harewood, L Walters, RG Kutalik, Z Martinet, D Shen, YP Valsesia, A Beckmann, ND Thorleifsson, G Belfiore, M Bouquillon, S Campion, D de Leeuw, N de Vries, BBA Esko, T Fernandez, BA Fernandez-Aranda, F Fernandez-Real, JM Gratacos, M Guilmatre, A Hoyer, J Jarvelin, MR Kooy, RF Kurg, A Le Caignec, C Mannik, K Platt, OS Sanlaville, D Van Haelst, MM Gomez, SV Walha, F Wu, BL Yu, YG Aboura, A Addor, MC Alembik, Y Antonarakis, SE Arveiler, B Barth, M Bednarek, N Bena, F Bergmann, S Beri, M Bernardini, L Blaumeiser, B Bonneau, D Bottani, A Boute, O Brunner, HG Cailley, D Callier, P Chiesa, J Chrast, J Coin, L Coutton, C Cuisset, JM Cuvellier, JC David, A de Freminville, B Delobel, B Delrue, MA Demeer, B Descamps, D Didelot, G Dieterich, K Disciglio, V Doco-Fenzy, M Drunat, S Duban-Bedu, B Dubourg, C Moustafa, JSE Elliott, P Faas, BHW Faivre, L Faudet, A Fellmann, F Ferrarini, A Fisher, R Flori, E Forer, L Gaillard, D Gerard, M Gieger, C Gimelli, S Gimelli, G Grabe, HJ Guichet, A Guillin, O Hartikainen, AL Heron, D Hippolyte, L Holder, M Homuth, G Isidor, B Jaillard, S Jaros, Z Jimenez-Murcia, S Helas, GJ Jonveaux, P Kaksonen, S Keren, B Kloss-Brandstatter, A Knoers, NVAM Koolen, DA Kroisel, PM Kronenberg, F Labalme, A Landais, E Lapi, E Layet, V Legallic, S Leheup, B Leube, B Lewis, S Lucas, J MacDermot, KD Magnusson, P Marshall, C Mathieu-Dramard, M McCarthy, MI Meitinger, T Mencarelli, MA Merla, G Moerman, A Mooser, V Morice-Picard, F Mucciolo, M Nauck, M Ndiaye, NC Nordgren, A Pasquier, L Petit, F Pfundt, R Plessis, G Rajcan-Separovic, E Ramelli, GP Rauch, A Ravazzolo, R Reis, A Renieri, A Richart, C Ried, JS Rieubland, C Roberts, W Roetzer, KM Rooryck, C Rossi, M Saemundsen, E Satre, V Schurmann, C Sigurdsson, E Stavropoulos, DJ Stefansson, H Tengstrom, C Thorsteinsdottir, U Tinahones, FJ Touraine, R Vallee, L van Binsbergen, E Van der Aa, N Vincent-Delorme, C Visvikis-Siest, S Vollenweider, P Volzke, H Vulto-van Silfhout, AT Waeber, G Wallgren-Pettersson, C Witwicki, RM Zwolinksi, S Andrieux, J Estivill, X Gusella, JF Gustafsson, O Metspalu, A Scherer, SW Stefansson, K Blakemore, AIF Beckmann, JS Froguel, P AF Jacquemont, Sebastien Reymond, Alexandre Zufferey, Flore Harewood, Louise Walters, Robin G. Kutalik, Zoltan Martinet, Danielle Shen, Yiping Valsesia, Armand Beckmann, Noam D. Thorleifsson, Gudmar Belfiore, Marco Bouquillon, Sonia Campion, Dominique de Leeuw, Nicole de Vries, Bert B. A. Esko, Tonu Fernandez, Bridget A. Fernandez-Aranda, Fernando Manuel Fernandez-Real, Jose Gratacos, Monica Guilmatre, Audrey Hoyer, Juliane Jarvelin, Marjo-Riitta Kooy, R. Frank Kurg, Ants Le Caignec, Cedric Maennik, Katrin Platt, Orah S. Sanlaville, Damien Van Haelst, Mieke M. Villatoro Gomez, Sergi Walha, Faida Wu, Bai-lin Yu, Yongguo Aboura, Azzedine Addor, Marie-Claude Alembik, Yves Antonarakis, Stylianos E. Arveiler, Benoit Barth, Magalie Bednarek, Nathalie Bena, Frederique Bergmann, Sven Beri, Mylene Bernardini, Laura Blaumeiser, Bettina Bonneau, Dominique Bottani, Armand Boute, Odile Brunner, Han G. Cailley, Dorothee Callier, Patrick Chiesa, Jean Chrast, Jacqueline Coin, Lachlan Coutton, Charles Cuisset, Jean-Marie Cuvellier, Jean-Christophe David, Albert de Freminville, Benedicte Delobel, Bruno Delrue, Marie-Ange Demeer, Benedicte Descamps, Dominique Didelot, Gerard Dieterich, Klaus Disciglio, Vittoria Doco-Fenzy, Martine Drunat, Severine Duban-Bedu, Benedicte Dubourg, Christele Moustafa, Julia S. El-Sayed Elliott, Paul Faas, Brigitte H. W. Faivre, Laurence Faudet, Anne Fellmann, Florence Ferrarini, Alessandra Fisher, Richard Flori, Elisabeth Forer, Lukas Gaillard, Dominique Gerard, Marion Gieger, Christian Gimelli, Stefania Gimelli, Giorgio Grabe, Hans J. Guichet, Agnes Guillin, Olivier Hartikainen, Anna-Liisa Heron, Delphine Hippolyte, Loyse Holder, Muriel Homuth, Georg Isidor, Bertrand Jaillard, Sylvie Jaros, Zdenek Jimenez-Murcia, Susana Helas, Geraldine Joly Jonveaux, Philippe Kaksonen, Satu Keren, Boris Kloss-Brandstaetter, Anita Knoers, Nine V. A. M. Koolen, David A. Kroisel, Peter M. Kronenberg, Florian Labalme, Audrey Landais, Emilie Lapi, Elisabetta Layet, Valerie Legallic, Solenn Leheup, Bruno Leube, Barbara Lewis, Suzanne Lucas, Josette MacDermot, Kay D. Magnusson, Pall Marshall, Christian Mathieu-Dramard, Michele McCarthy, Mark I. Meitinger, Thomas Mencarelli, Maria Antonietta Merla, Giuseppe Moerman, Alexandre Mooser, Vincent Morice-Picard, Fanny Mucciolo, Mafalda Nauck, Matthias Ndiaye, Ndeye Coumba Nordgren, Ann Pasquier, Laurent Petit, Florence Pfundt, Rolph Plessis, Ghislaine Rajcan-Separovic, Evica Ramelli, Gian Paolo Rauch, Anita Ravazzolo, Roberto Reis, Andre Renieri, Alessandra Richart, Cristobal Ried, Janina S. Rieubland, Claudine Roberts, Wendy Roetzer, Katharina M. Rooryck, Caroline Rossi, Massimiliano Saemundsen, Evald Satre, Veronique Schurmann, Claudia Sigurdsson, Engilbert Stavropoulos, Dimitri J. Stefansson, Hreinn Tengstrom, Carola Thorsteinsdottir, Unnur Tinahones, Francisco J. Touraine, Renaud Vallee, Louis van Binsbergen, Ellen Van der Aa, Nathalie Vincent-Delorme, Catherine Visvikis-Siest, Sophie Vollenweider, Peter Voelzke, Henry Vulto-van Silfhout, Anneke T. Waeber, Gerard Wallgren-Pettersson, Carina Witwicki, Robert M. Zwolinksi, Simon Andrieux, Joris Estivill, Xavier Gusella, James F. Gustafsson, Omar Metspalu, Andres Scherer, Stephen W. Stefansson, Kari Blakemore, Alexandra I. F. Beckmann, Jacques S. Froguel, Philippe TI Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus SO NATURE LA English DT Article ID COPY NUMBER VARIATION; BODY-MASS INDEX; DEPENDENT PROBE AMPLIFICATION; CIRCULAR BINARY SEGMENTATION; TIME QUANTITATIVE PCR; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; FAILURE-TO-THRIVE; RELATIVE QUANTIFICATION; METABOLIC SYNDROME AB Both obesity and being underweight have been associated with increased mortality(1,2). Underweight, defined as a body mass index (BMI) <= 18.5 kg per m(2) in adults and <= -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive(3-5), feeding and eating disorder and/or anorexia nervosa(6,7). In contrast to obesity, few genetic variants underlying these clinical conditions have been reported(8,9). We previously showed that hemizygosity of a similar to 600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities(10). Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. C1 [Jacquemont, Sebastien; Zufferey, Flore; Martinet, Danielle; Beckmann, Noam D.; Belfiore, Marco; Addor, Marie-Claude; Fellmann, Florence; Ferrarini, Alessandra; Hippolyte, Loyse; Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Reymond, Alexandre; Harewood, Louise; Walha, Faida; Chrast, Jacqueline; Didelot, Gerard; Witwicki, Robert M.] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland. [Walters, Robin G.; Van Haelst, Mieke M.; Coin, Lachlan; Moustafa, Julia S. El-Sayed; Blakemore, Alexandra I. F.; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, London W12 0NN, England. 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EM Jacques.Beckmann@chuv.ch RI Koolen, D.A./L-4448-2015; Leeuw, N./L-4480-2015; Pfundt, Rolph/L-4576-2015; Meitinger, Thomas/O-1318-2015; Vulto-van Silfhout, Anneke/H-4199-2015; Nordgren, Ann/N-4057-2013; Bernardini, Laura/H-5360-2016; Kooy, Frank/F-5276-2014; Schurmann, Claudia/L-1204-2016; Coin, Lachlan/A-9001-2014; Reis, Andre/D-2309-2009; Visvikis-Siest, Sophie/H-2324-2014; Jimenez-Murcia, Susana/L-9786-2014; Walters, Robin/E-6069-2010; Beckmann, Jacques S /A-9772-2008; Estivill, Xavier/E-2957-2012; Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013; Brunner, Han/C-9928-2013; Colaus, PsyColaus/K-6607-2013; Kronenberg, Florian/B-1736-2008; Rauch, Anita/C-5568-2014; Sigurdsson, Engilbert/D-2486-2014; Fernandez-Aranda, Fernando/L-9762-2014; Arveiler, Benoit/M-3721-2014; Estivill, Xavier/A-3125-2013; ROORYCK, Caroline/M-4565-2014; MORICE-PICARD, Fanny/M-5125-2014; sanlaville, damien/M-4716-2014; Antonarakis, Stylianos/N-8866-2014; Kurg, Ants/J-2616-2015; Bonneau, Dominique/K-6110-2015; Le Caignec, Cedric/K-8467-2015; Isidor, Bertrand/L-2435-2015; Faas, B.H.W./L-4301-2015; jaillard, sylvie/L-9314-2015 OI Nordgren, Ann/0000-0003-3285-4281; Bernardini, Laura/0000-0002-3554-2817; Kooy, Frank/0000-0003-2024-0485; Schurmann, Claudia/0000-0003-4158-9192; Coin, Lachlan/0000-0002-4300-455X; Reis, Andre/0000-0002-6301-6363; Harewood, Louise/0000-0002-6398-6714; Visvikis-Siest, Sophie/0000-0001-8104-8425; Jimenez-Murcia, Susana/0000-0002-3596-8033; Walters, Robin/0000-0002-9179-0321; Beckmann, Jacques S /0000-0002-9741-1900; Scherer, Stephen /0000-0002-8326-1999; Kronenberg, Florian/0000-0003-2229-1120; Rauch, Anita/0000-0003-2930-3163; Sigurdsson, Engilbert/0000-0001-9404-7982; El-Sayed Moustafa, Julia Sarah/0000-0001-6963-6654; petit, florence/0000-0002-1368-1023; Esko, Tonu/0000-0003-1982-6569; Gieger, Christian/0000-0001-6986-9554; Stefansson, Hreinn/0000-0002-9331-6666; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; yu, yongguo/0000-0002-4472-0910; Fernandez-Real, Jose Manuel/0000-0002-7442-9323; Bergmann, Sven/0000-0002-6785-9034; Fernandez-Aranda, Fernando/0000-0002-2968-9898; Estivill, Xavier/0000-0002-0723-2256; sanlaville, damien/0000-0001-9939-2849; Antonarakis, Stylianos/0000-0001-8907-5823; Le Caignec, Cedric/0000-0002-0598-653X; Isidor, Bertrand/0000-0001-6480-126X; FU Leenaards Foundation; Jerome Lejeune Foundation; Telethon Action Suisse Foundation; Swiss National Science Foundation; European Commission [037627, QLG1-CT-2000-01643]; Ludwig Institute for Cancer Research; Swiss Institute of Bioinformatics; Imperial College Department of Medicine; Comprehensive Biomedical Research Centre; Imperial College Healthcare NHS Trust; National Institute for Health Research; Wellcome Trust; Medical Research Council; Instituto de Salud Carlos III (ISCIII)-FIS; German Mental Retardation Network; German Federal Ministry of Education and Research [NGFNplus 01GS08160]; European Union [PI081714, PS09/01778, 201413, 245536, HEALTH-2007-2.2.1-10-223423]; Belgian National Fund for Scientific Research, Flanders; Dutch Organisation for Health Research and Development (ZON-MW) [917-86-319]; Hersenstichting Nederland (B.B.A.d.V.); Chinese National Natural Science Foundation [81000346]; Simons Foundation Autism Research Initiative; Autism Speaks; NIH [GM061354, MH071425]; Oesterreichische Nationalbank (OENB) [13059]; Children's Tumor Foundation; Harvard Medical School; Fudan University; Chinese National '973' project on Population and Health [2010CB529601]; Science and Technology Council of Shanghai [09JC1402400]; Michael Smith Foundation for Health; CIHR [MOP 74502]; Estonian Government [SF0180142s08, SF0180026s09, SF0180027s10]; Helmholtz Zentrum Munich; State of Bavaria; German National Genome Research Network [01GS0823]; German Federal Ministry of Education and Research (BMBF); Munich Center of Health Sciences (MC Health, LMUinnovativ); Genome Canada; McLaughlin Centre; Academy of Finland [104781, 120315, 129269, 1114194]; University Hospital Oulu; Biocenter; University of Oulu, Finland [75617]; NHLBI [5R01HL087679-02, 1RL1MH083268-01]; NIH/NIMH [5R01MH63706:02]; ENGAGE project; Medical Research Council, UK [G0500539, G0600705]; Academy of Finland; Biocentrum Helsinki; [SAF2008-02278]; [HEALTH-F4-2007-201413] FX We thank the Vital-IT high-performance computing centre of the Swiss Institute of Bioinformatics. S.J. is recipient of a bourse de releve academique de la Faculte de Biologie et Medecine de l'Universite de Lausanne. This work was supported by the Leenaards Foundation Prize (S.J., D. M. and A. Reymond), the Jerome Lejeune Foundation (A. Reymond), the Telethon Action Suisse Foundation (A. Reymond), the Swiss National Science Foundation (A. Reymond, J.S.B., S. B. and S. E. A.), a Swiss National Science Foundation Sinergia grant (S.J., D. M., S. B., J.S.B. and A. Reymond), the European Commission an EU ploidy Integrated Project grant 037627 (A. Reymond, S. B., X. E., H. G. B. and S. E. A.), the Ludwig Institute for Cancer Research (A. V.), the Swiss Institute of Bioinformatics (S. B. and Z.K.), an Imperial College Department of Medicine PhD studentship (J.S.E.-S.M), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (P. E.), the Wellcome Trust and the Medical Research Council (A. I. F. B. and P. F.), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) (A. Reis), European Union-FEDER (PI081714, PS09/01778) (F. F. A., M. G. and X. E.), SAF2008-02278 (C. R.), the Belgian National Fund for Scientific Research, Flanders (N.V.A. and R. F. K.), the Dutch Organisation for Health Research and Development (ZON-MW grant 917-86-319) and Hersenstichting Nederland (B.B.A.d.V.), grant 81000346 from the Chinese National Natural Science Foundation (Y.G.Y.), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (J.F.G.), and Oesterreichische Nationalbank (OENB) grant 13059 (A.K.-B.). Y.S. holds a Young Investigator Award from the Children's Tumor Foundation and a Catalyst Award from Harvard Medical School. B. L. W. holds a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from the Science and Technology Council of Shanghai (09JC1402400). E. R. S. and S. L., recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. The Estonian Genome Center of the University of Tartu (EGCUT) received support from the EU Centre of Excellence in Genomics and FP7 grants 201413 and 245536, and from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (A. M., K. M. and A. K.). D. S. thanks the Direction Generale de l'Organisation des Soins from the French Ministry of Health for their support in the development of several array-CGH platforms, and the Centres Labellises Anomalies du Development in France. The Helmholtz Zentrum Munich and the State of Bavaria financed the KORA study, also supported by the German National Genome Research Network (NGFN-2 and NGFN Plus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). S. W. S. holds the GlaxoSmithKline-Canadian Institutes of Health Chair in Genetics and Genomics at the University of Toronto and the Hospital for Sick Children, and is supported by Genome Canada and the McLaughlin Centre. Funding for deCODE came in part from NIH grant MH071425 (K. S.), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds.; NFBC1966 received financial supportfrom the Academy of Finland (project grants 104781, 120315, 129269, 1114194, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the Medical Research Council, UK (G0500539, G0600705, PrevMetSyn/SALVE). The DNA extractions, sample quality controls, biobank up-keeping and aliquotting was performed in the National Public Health Institute, Biomedicum Helsinki, Finland and supported financially by the Academy of Finland and Biocentrum Helsinki. We thank M. Hass, Z. Jaros, M. Jussila, M. Koiranen, P. Rantakallio, M. C. Rudolf, V. Soo, O. Tornwall, S. Vaara, T. Ylitalo and the French DHOS national CGH network for their help, as well as all participating patients and clinicians. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 165 Z9 170 U1 2 U2 52 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 6 PY 2011 VL 478 IS 7367 BP 97 EP U111 DI 10.1038/nature10406 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829JN UT WOS:000295575400042 PM 21881559 ER PT J AU Ehret, GB Munroe, PB Rice, KM Bochud, M Johnson, AD Chasman, DI Smith, AV Tobin, MD Verwoert, GC Hwang, SJ Pihur, V Vollenweider, P O'Reilly, PF Amin, N Bragg-Gresham, JL Teumer, A Glazer, NL Launer, L Zhao, JH Aulchenko, Y Heath, S Sober, S Parsa, A Luan, JA Arora, P Dehghan, A Zhang, F Lucas, G Hicks, AA Jackson, AU Peden, JF Tanaka, T Wild, SH Rudan, I Igl, W Milaneschi, Y Parker, AN Fava, C Chambers, JC Fox, ER Kumari, M Go, MJ van der Harst, P Kao, WHL Sjogren, M Vinay, DG Alexander, M Tabara, Y Shaw-Hawkins, S Whincup, PH Liu, YM Shi, G Kuusisto, J Tayo, B Seielstad, M Sim, X Nguyen, KDH Lehtimaki, T Matullo, G Wu, Y Gaunt, TR Onland-Moret, NC Cooper, MN Platou, CGP Org, E Hardy, R Dahgam, S Palmen, J Vitart, V Braund, PS Kuznetsova, T Uiterwaal, CSPM Adeyemo, A Palmas, W Campbell, H Ludwig, B Tomaszewski, M Tzoulaki, I Palmer, ND Aspelund, T Garcia, M Chang, YPC O'Connell, JR Steinle, NI Grobbee, DE Arking, DE Kardia, SL Morrison, AC Hernandez, D Najjar, S McArdle, WL Hadley, D Brown, MJ Connell, JM Hingorani, AD Day, INM Lawlor, DA Beilby, JP Lawrence, RW Clarke, R Hopewell, JC Ongen, H Dreisbach, AW Li, YL Young, JH Bis, JC Kahonen, M Viikari, J Adair, LS Lee, NR Chen, MH Olden, M Pattaro, C Bolton, JAH Kottgen, A Bergmann, S Mooser, V Chaturvedi, N Frayling, TM Islam, M Jafar, TH Erdmann, J Kulkarni, SR Bornstein, SR Grassler, J Groop, L Voight, BF Kettunen, J Howard, P Taylor, A Guarrera, S Ricceri, F Emilsson, V Plump, A Barroso, IS Khaw, KT Weder, AB Hunt, SC Sun, YV Bergman, RN Collins, FS Bonnycastle, LL Scott, LJ Stringham, HM Peltonen, L Perola, M Vartiainen, E Brand, SM Staessen, JA Wang, TJ Burton, PR Artigas, MS Dong, YB Snieder, H Wang, XL Zhu, HD Lohman, KK Rudock, ME Heckbert, SR Smith, NL Wiggins, KL Doumatey, A Shriner, D Veldre, G Viigimaa, M Kinra, S Prabhakaran, D Tripathy, V Langefeld, CD Rosengren, A Thelle, DS Corsi, AM Singleton, A Forrester, T Hilton, G McKenzie, CA Salako, T Iwai, N Kita, Y Ogihara, T Ohkubo, T Okamura, T Ueshima, H Umemura, S Eyheramendy, S Meitinger, T Wichmann, HE Cho, YS Kim, HL Lee, JY Scott, J Sehmi, JS Zhang, WH Hedblad, B Nilsson, P Smith, GD Wong, A Narisu, N Stancakova, A Raffel, LJ Yao, J Kathiresan, S O'Donnell, CJ Schwartz, SM Ikram, MA Longstreth, WT Mosley, TH Seshadri, S Shrine, NRG Wain, LV Morken, MA Swift, AJ Laitinen, J Prokopenko, I Zitting, P Cooper, JA Humphries, SE Danesh, J Rasheed, A Goel, A Hamsten, A Watkins, H Bakker, SJL van Gilst, WH Janipalli, CS Mani, KR Yajnik, CS Hofman, A Mattace-Raso, FUS Oostra, BA Demirkan, A Isaacs, A Rivadeneira, F Lakatta, EG Orru, M Scuteri, A Ala-Korpela, M Kangas, AJ Lyytikainen, LP Soininen, P Tukiainen, T Wurtz, P Ong, RTH Dorr, M Kroemer, HK Volker, U Volzke, H Galan, P Hercberg, S Lathrop, M Zelenika, D Deloukas, P Mangino, M Spector, TD Zhai, GJ Meschia, JF Nalls, MA Sharma, P Terzic, J Kumar, MVK Denniff, M Zukowska-Szczechowska, E Wagenknecht, LE Fowkes, FGR Charchar, FJ Schwarz, PEH Hayward, C Guo, XQ Rotimi, C Bots, ML Brand, E Samani, NJ Polasek, O Talmud, PJ Nyberg, F Kuh, D Laan, M Hveem, K Palmer, LJ van der Schouw, YT Casas, JP Mohlke, KL Vineis, P Raitakari, O Ganesh, SK Wong, TY Tai, ES Cooper, RS Laakso, M Rao, DC Harris, TB Morris, RW Dominiczak, AF Kivimaki, M Marmot, MG Miki, T Saleheen, D Chandak, GR Coresh, J Navis, G Salomaa, V Han, BG Zhu, XF Kooner, JS Melander, O Ridker, PM Bandinelli, S Gyllensten, UB Wright, AF Wilson, JF Ferrucci, L Farrall, M Tuomilehto, J Pramstaller, PP Elosua, R Soranzo, N Sijbrands, EJG Altshuler, D Loos, RJF Shuldiner, AR Gieger, C Meneton, P Uitterlinden, AG Wareham, NJ Gudnason, V Rotter, JI Rettig, R Uda, M Strachan, DP Witteman, JCM Hartikainen, AL Beckmann, JS Boerwinkle, E Vasan, RS Boehnke, M Larson, MG Jarvelin, MR Psaty, BM Abecasis, GR Chakravarti, A Elliott, P van Duijn, CM Newton-Cheh, C Levy, D Caulfield, MJ Johnson, T AF Ehret, Georg B. 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Salako, Tunde Iwai, Naoharu Kita, Yoshikuni Ogihara, Toshio Ohkubo, Takayoshi Okamura, Tomonori Ueshima, Hirotsugu Umemura, Satoshi Eyheramendy, Susana Meitinger, Thomas Wichmann, H. -Erich Cho, Yoon Shin Kim, Hyung-Lae Lee, Jong-Young Scott, James Sehmi, Joban S. Zhang, Weihua Hedblad, Bo Nilsson, Peter Smith, George Davey Wong, Andrew Narisu, Narisu Stancakova, Alena Raffel, Leslie J. Yao, Jie Kathiresan, Sekar O'Donnell, Christopher J. Schwartz, Stephen M. Ikram, M. Arfan Longstreth, W. T., Jr. Mosley, Thomas H. Seshadri, Sudha Shrine, Nick R. G. Wain, Louise V. Morken, Mario A. Swift, Amy J. Laitinen, Jaana Prokopenko, Inga Zitting, Paavo Cooper, Jackie A. Humphries, Steve E. Danesh, John Rasheed, Asif Goel, Anuj Hamsten, Anders Watkins, Hugh Bakker, Stephan J. L. van Gilst, Wiek H. Janipalli, Charles S. Mani, K. Radha Yajnik, Chittaranjan S. Hofman, Albert Mattace-Raso, Francesco U. S. Oostra, Ben A. Demirkan, Ayse Isaacs, Aaron Rivadeneira, Fernando Lakatta, Edward G. Orru, Marco Scuteri, Angelo Ala-Korpela, Mika Kangas, Antti J. Lyytikainen, Leo-Pekka Soininen, Pasi Tukiainen, Taru Wurtz, Peter Ong, Rick Twee-Hee Doerr, Marcus Kroemer, Heyo K. Voelker, Uwe Voelzke, Henry Galan, Pilar Hercberg, Serge Lathrop, Mark Zelenika, Diana Deloukas, Panos Mangino, Massimo Spector, Tim D. Zhai, Guangju Meschia, James F. Nalls, Michael A. Sharma, Pankaj Terzic, Janos Kumar, M. V. Kranthi Denniff, Matthew Zukowska-Szczechowska, Ewa Wagenknecht, Lynne E. Fowkes, F. Gerald R. Charchar, Fadi J. Schwarz, Peter E. H. Hayward, Caroline Guo, Xiuqing Rotimi, Charles Bots, Michiel L. Brand, Eva Samani, Nilesh J. Polasek, Ozren Talmud, Philippa J. Nyberg, Fredrik Kuh, Diana Laan, Maris Hveem, Kristian Palmer, Lyle J. van der Schouw, Yvonne T. Casas, Juan P. Mohlke, Karen L. Vineis, Paolo Raitakari, Olli Ganesh, Santhi K. Wong, Tien Y. Tai, E. Shyong Cooper, Richard S. Laakso, Markku Rao, Dabeeru C. Harris, Tamara B. Morris, Richard W. Dominiczak, Anna F. Kivimaki, Mika Marmot, Michael G. Miki, Tetsuro Saleheen, Danish Chandak, Giriraj R. Coresh, Josef Navis, Gerjan Salomaa, Veikko Han, Bok-Ghee Zhu, Xiaofeng Kooner, Jaspal S. Melander, Olle Ridker, Paul M. Bandinelli, Stefania Gyllensten, Ulf B. Wright, Alan F. Wilson, James F. Ferrucci, Luigi Farrall, Martin Tuomilehto, Jaakko Pramstaller, Peter P. Elosua, Roberto Soranzo, Nicole Sijbrands, Eric J. G. Altshuler, David Loos, Ruth J. F. Shuldiner, Alan R. Gieger, Christian Meneton, Pierre Uitterlinden, Andre G. Wareham, Nicholas J. Gudnason, Vilmundur Rotter, Jerome I. Rettig, Rainer Uda, Manuela Strachan, David P. Witteman, Jacqueline C. M. Hartikainen, Anna-Liisa Beckmann, Jacques S. Boerwinkle, Eric Vasan, Ramachandran S. Boehnke, Michael Larson, Martin G. Jarvelin, Marjo-Riitta Psaty, Bruce M. Abecasis, Goncalo R. Chakravarti, Aravinda Elliott, Paul van Duijn, Cornelia M. Newton-Cheh, Christopher Levy, Daniel Caulfield, Mark J. Johnson, Toby CA Int Consortium Blood Pressure Geno CARDIoGRAM Consortium CKDGen Consortium KidneyGen Consortium EchoGen Consortium CHARGE-HF Consortium TI Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; COMMON VARIANTS; HYPERTENSION; METAANALYSIS; LOCI; POPULATION; RELEVANCE; RECEPTOR; CLONING; HEALTH AB Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. C1 [Ehret, Georg B.; Pihur, Vasyl; Khanh-Dung Hoang Nguyen; Arking, Dan E.; Hilton, Gina; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA. [Ehret, Georg B.; Bochud, Murielle] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1005 Lausanne, Switzerland. [Ehret, Georg B.; Bochud, Murielle] Univ Lausanne, CH-1005 Lausanne, Switzerland. [Ehret, Georg B.] Univ Hosp Geneva, Dept Specialties Internal Med, CH-1211 Geneva 14, Switzerland. [Munroe, Patricia B.; Shaw-Hawkins, Sue; Caulfield, Mark J.; Johnson, Toby] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Genome Ctr, London EC1M 6BQ, England. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Johnson, Andrew D.; Hwang, Shih-Jen; Wang, Thomas J.; Vasan, Ramachandran S.; Larson, Martin G.; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Johnson, Andrew D.; Hwang, Shih-Jen; Levy, Daniel] NHLBI, Bethesda, MD 20824 USA. [Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Smith, Albert V.; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, IS-101 Reykajvik, Iceland. [Smith, Albert V.; Aspelund, Thor; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Tobin, Martin D.; Burton, Paul R.; Artigas, Maria Soler; Shrine, Nick R. G.; Wain, Louise V.] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England. [Verwoert, Germaine C.; Amin, Najaf; Aulchenko, Yurii; Dehghan, Abbas; Ikram, M. Arfan; Hofman, Albert; Mattace-Raso, Francesco U. S.; Demirkan, Ayse; Isaacs, Aaron; Rivadeneira, Fernando; Sijbrands, Eric J. G.; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Verwoert, Germaine C.; Dehghan, Abbas; Mattace-Raso, Francesco U. S.; Rivadeneira, Fernando; Sijbrands, Eric J. G.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Verwoert, Germaine C.; Dehghan, Abbas; Ikram, M. Arfan; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] NGI, NCHA, NL-3000 CA Rotterdam, Netherlands. [Hwang, Shih-Jen; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20824 USA. [Vollenweider, Peter] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [O'Reilly, Paul F.; Chambers, John C.; Zhang, Weihua; Wurtz, Peter; Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England. [Bragg-Gresham, Jennifer L.; Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48103 USA. [Teumer, Alexander; Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, D-17487 Greifswald, Germany. [Glazer, Nicole L.; Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Glazer, Nicole L.; Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Glazer, Nicole L.; Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Launer, Lenore; Garcia, Melissa; Harris, Tamara B.] NIA, Lab Epidemiol, NIH, Bethesda, MD 20892 USA. [Zhao, Jing Hua; Luan, Jian'an; Loos, Ruth J. F.; Wareham, Nicholas J.] Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Heath, Simon; Lathrop, Mark; Zelenika, Diana] Commiss Energie Atom, Inst Genom, Ctr Natl Genotypage, F-91057 Evry, France. [Sober, Siim; Org, Elin; Veldre, Gudrun; Laan, Maris] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Parsa, Afshin; Chang, Yen-Pei C.; O'Connell, Jeffrey R.; Steinle, Nanette I.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Arora, Pankaj; Kathiresan, Sekar; O'Donnell, Christopher J.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Zhang, Feng; Mangino, Massimo; Spector, Tim D.; Zhai, Guangju; Soranzo, Nicole] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Lucas, Gavin; Elosua, Roberto] Inst Municipal Invest Med, E-08003 Barcelona, Spain. [Hicks, Andrew A.; Pattaro, Cristian; Pramstaller, Peter P.] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy. [Hicks, Andrew A.; Pattaro, Cristian; Pramstaller, Peter P.] Univ Lubeck, Affiliated Inst, Lubeck, Germany. [Jackson, Anne U.; Scott, Laura J.; Stringham, Heather M.; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Dept Biostat, Ann Arbor, MI 48109 USA. [Peden, John F.; Ongen, Halit; Goel, Anuj; Watkins, Hugh; Farrall, Martin] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford OX3 7BN, England. [Tanaka, Toshiko; Milaneschi, Yuri; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21250 USA. [Wild, Sarah H.; Rudan, Igor; Campbell, Harry; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Rudan, Igor; Campbell, Harry] Univ Edinburgh, Coll Med & Vet Med, Inst Genet & Mol Med, Edinburgh EH8 9AG, Midlothian, Scotland. [Rudan, Igor] Univ Split, Croatian Ctr Global Hlth, Split 21000, Croatia. [Igl, Wilmar; Gyllensten, Ulf B.] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, SE-75185 Uppsala, Sweden. [Parker, Alex N.] Amgen Inc, Cambridge, MA 02139 USA. [Fava, Cristiano; Sjogren, Marketa; Hedblad, Bo; Nilsson, Peter; Melander, Olle] Lund Univ, Dept Clin Sci, S-20502 Malmo, Sweden. [Fava, Cristiano] Univ Verona, Dept Med, I-37134 Verona, Italy. [Chambers, John C.; Sehmi, Joban S.; Kooner, Jaspal S.] Ealing Gen Hosp, London UB1 3HJ, England. [Fox, Ervin R.; Dreisbach, Albert W.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Kumari, Meena; Taylor, Andrew] UCL, Genet Epidemiol Grp, London WC1E 6BT, England. [Go, Min Jin; Cho, Yoon Shin; Kim, Hyung-Lae; Lee, Jong-Young; Han, Bok-Ghee] Natl Inst Hlth, Ctr Genome Sci, Seoul 122701, South Korea. [van der Harst, Pim; van Gilst, Wiek H.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands. [Kao, Wen Hong Linda; Bolton, Judith A. Hoffman; Koettgen, Anna; Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA. [Kao, Wen Hong Linda; Young, J. Hunter; Coresh, Josef] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [Vinay, D. G.; Janipalli, Charles S.; Mani, K. Radha; Kumar, M. V. Kranthi; Chandak, Giriraj R.] CSIR, CCMB, Hyderabad 500007, Andhra Pradesh, India. [Alexander, Myriam; Khaw, Kay-Tee; Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Tabara, Yasuharu; Miki, Tetsuro] Ehime Univ, Grad Sch Med, Dept Basic Med Res, Toon 7910295, Japan. [Tabara, Yasuharu; Miki, Tetsuro] Ehime Univ, Grad Sch Med, Dept Geriatr Med, Toon 7910295, Japan. [Whincup, Peter H.; Hadley, David; Strachan, David P.] St Georges Univ London, Div Community Hlth Sci, London SW17 0RE, England. [Liu, Yongmei; Rudock, Megan E.; Prokopenko, Inga] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Shi, Gang] Washington Univ St Louis, Sch Med, Div Biostat, St Louis, MO USA. [Shi, Gang] Washington Univ St Louis, Sch Med, Dept Genet, St Louis, MO USA. [Kuusisto, Johanna; Stancakova, Alena; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio 70210, Finland. [Kuusisto, Johanna; Stancakova, Alena; Laakso, Markku] Kuopio Univ Hosp, Kuopio 70210, Finland. [Tayo, Bamidele; Cooper, Richard S.] Loyola Univ, Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. [Seielstad, Mark] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Seielstad, Mark] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Seielstad, Mark; Ong, Rick Twee-Hee] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore. [Sim, Xueling; Ong, Rick Twee-Hee; Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Mol Epidemiol, Singapore 117597, Singapore. [Lehtimaki, Terho; Lyytikainen, Leo-Pekka] Univ Tampere, Dept Clin Chem, Tampere 33521, Finland. [Lehtimaki, Terho; Kahonen, Mika; Lyytikainen, Leo-Pekka] Tampere Univ Hosp, Tampere 33521, Finland. [Matullo, Giuseppe; Ricceri, Fulvio] Univ Turin, Dept Genet Biol & Biochem, I-10126 Turin, Italy. [Matullo, Giuseppe; Guarrera, Simonetta; Ricceri, Fulvio; Vineis, Paolo] Human Genet Fdn HUGEF, I-10126 Turin, Italy. [Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Gaunt, Tom R.; Day, Ian N. M.; Lawlor, Debbie A.; Smith, George Davey] Univ Bristol, MRC Ctr Causal Anal Translat Epidemiol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England. [Onland-Moret, N. Charlotte; Uiterwaal, Cuno S. P. M.; Grobbee, Diederick E.; Bots, Michiel L.; van der Schouw, Yvonne T.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3508 GA Utrecht, Netherlands. [Onland-Moret, N. Charlotte] Univ Med Ctr Utrecht, Dept Med Genet DBG, Complex Genet Sect, NL-3508 GA Utrecht, Netherlands. [Cooper, Matthew N.; Lawrence, Robert W.] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Crawley, WA 6009, Australia. [Platou, Carl G. P.; Hveem, Kristian] Norwegian Univ Sci & Technol, HUNT Res Ctr, Dept Publ Hlth & Gen Practice, N-7600 Levanger, Norway. [Hardy, Rebecca; Wong, Andrew; Kuh, Diana] MRC Unit Lifelong Hlth & Ageing, London WC1B 5JU, England. [Dahgam, Santosh; Nyberg, Fredrik] Univ Gothenburg, Dept Publ Hlth & Community Med, Inst Med, Sahlgrenska Acad, S-40530 Gothenburg, Sweden. [Palmen, Jutta; Cooper, Jackie A.; Humphries, Steve E.; Talmud, Philippa J.] UCL, Ctr Cardiovasc Genet, London WC1E 6JF, England. [Vitart, Veronique; Hayward, Caroline; Wright, Alan F.] MRC Human Genet Unit, Edinburgh EH2, Midlothian, Scotland. [Vitart, Veronique; Hayward, Caroline; Wright, Alan F.] Inst Genet & Mol Med, Edinburgh EH2, Midlothian, Scotland. [Braund, Peter S.; Tomaszewski, Maciej; Denniff, Matthew; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Braund, Peter S.; Tomaszewski, Maciej; Burton, Paul R.; Samani, Nilesh J.] Glenfield Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England. [Kuznetsova, Tatiana; Staessen, Jan A.] Univ Leuven, Studies Coordinating Ctr, Div Hypertens & Cardiac Rehabil, Dept Cardiovasc Dis, B-3000 Louvain, Belgium. [Adeyemo, Adebowale; Doumatey, Ayo; Shriner, Daniel; Rotimi, Charles] Natl Human Genome Res Inst, Ctr Res Genom & Global Hlth, New York, NY 10027 USA. [Palmas, Walter] Columbia Univ, New York, NY 10027 USA. [Ludwig, Barbara; Bornstein, Stefan R.; Graessler, Juergen] Tech Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, D-01307 Dresden, Germany. [Tzoulaki, Ioanna] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 1PG, England. [Tzoulaki, Ioanna] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. [Palmer, Nicholette D.; Langefeld, Carl D.; Wagenknecht, Lynne E.] Wake Forest Univ Hlth Sci, Winston Salem, NC 27157 USA. [Kardia, Sharon L.; Sun, Yan V.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morrison, Alanna C.] Univ Texas Houston Hlth Sci Ctr, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Hernandez, Dena; Singleton, Andrew; Nalls, Michael A.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Najjar, Samer] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Najjar, Samer] Washington Hosp Ctr, Div Cardiol, Washington, DC 20010 USA. [McArdle, Wendy L.] Univ Bristol, ALSPAC Lab, Bristol BS8 2BN, Avon, England. [Hadley, David] Univ S Florida, Pediat Epidemiol Ctr, Tampa, FL 33612 USA. [Brown, Morris J.] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England. [Connell, John M.] Univ Dundee, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Scotland. [Hingorani, Aroon D.] UCL, Genet Epidemiol Grp, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England. [Beilby, John P.] PathW Lab Med, Mol Genet, Nedlands, WA 6009, Australia. [Clarke, Robert; Hopewell, Jemma C.] Univ Oxford, Clin Trial Serv Unit, Oxford OX3 7LF, England. [Clarke, Robert; Hopewell, Jemma C.] Univ Oxford, Epidemiol Studies Unit, Oxford OX3 7LF, England. [Li, Yali; Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, Tampere 33521, Finland. [Viikari, Jorma] Univ Turku, Dept Med, Turku 20521, Finland. [Viikari, Jorma] Turku Univ Hosp, Turku 20521, Finland. [Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Lee, Nanette R.] Univ San Carlos, Off Populat Studies Fdn, Cebu 6000, Philippines. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Framingham Heart Study, Boston, MA 02118 USA. [Olden, Matthias] Univ Med Ctr Regensburg, Dept Internal Med 2, D-93053 Regensburg, Germany. [Olden, Matthias] Univ Med Ctr Regensburg, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Koettgen, Anna] Univ Hosp Freiburg, Div Renal, D-79095 Freiburg, Germany. [Bergmann, Sven; Beckmann, Jacques S.] Univ Lausanne, Dept Med Genet, CH-1015 Lausanne, Switzerland. [Bergmann, Sven] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Mooser, Vincent] GlaxoSmithKline Inc, Div Genet, Philadelphia, PA 19101 USA. [Chaturvedi, Nish] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Int Ctr Circulatory Hlth, London SW7 2AZ, England. [Frayling, Timothy M.] Univ Exeter, Peninsula Med Sch, Exeter EX4 4QJ, Devon, England. [Islam, Muhammad; Jafar, Tazeen H.] Aga Khan Univ, Dept Community Hlth Sci, Karachi 74800, Pakistan. [Islam, Muhammad; Jafar, Tazeen H.] Aga Khan Univ, Dept Med, Karachi 74800, Pakistan. [Erdmann, Jeanette] Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Kulkarni, Smita R.; Yajnik, Chittaranjan S.] KEM Hosp & Res Ctr, Diabet Unit, Pune 411011, Maharashtra, India. [Groop, Leif] Univ Hosp, Diabet & Endocrinol Res Unit, Dept Clin Sci, S-20502 Malmo, Sweden. [Groop, Leif] Lund Univ, S-20502 Malmo, Sweden. [Voight, Benjamin F.; Altshuler, David; Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02139 USA. [Kettunen, Johannes] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00251, Finland. [Kettunen, Johannes; Peltonen, Leena] Biomedicum, Inst Mol Med, FIMM, Helsinki 00251, Finland. [Howard, Philip] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England. [Emilsson, Valur; Plump, Andrew] Merck Res Lab, Rahway, NJ 07065 USA. [Barroso, Ine S.; Peltonen, Leena; Deloukas, Panos; Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, S Cambs, England. [Barroso, Ine S.] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 OQQ, England. [Weder, Alan B.] Univ Michigan, Sch Med, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Hunt, Steven C.] Univ Utah, Sch Med, Salt Lake City, UT 84132 USA. [Bergman, Richard N.] Univ So Calif, Keck Sch Med, Dept Phys & Biophys, Los Angeles, CA 90033 USA. [Collins, Francis S.; Bonnycastle, Lori L.; Narisu, Narisu; Morken, Mario A.; Swift, Amy J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Peltonen, Leena; Perola, Markus; Vartiainen, Erkki; Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki 00271, Finland. [Peltonen, Leena] Broad Inst, Cambridge, MA 02142 USA. [Brand, Stefan-Martin] Univ Munster, Dept Mol Genet Cardiovasc Dis, Leibniz Inst Arteriosclerosis Res, D-48149 Munster, Germany. [Brand, Stefan-Martin] Univ Munster, Fac Med, Dept Mol Genet Cardiovasc Dis, D-48149 Munster, Germany. [Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Dong, Yanbin; Snieder, Harold; Wang, Xiaoling; Zhu, Haidong] Med Coll Georgia, Dept Pediat, Georgia Prevent Inst, Augusta, GA 30912 USA. [Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Unit Genet Epidemiol & Bioinformat, Dept Epidemiol, NL-9713 GZ Groningen, Netherlands. [Lohman, Kurt K.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Heckbert, Susan R.; Smith, Nicholas L.; Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Smith, Nicholas L.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98124 USA. [Smith, Nicholas L.] Vet Hlth Adm Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA 98108 USA. [Wiggins, Kerri L.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Veldre, Gudrun] Univ Tartu, Dept Cardiol, EE-51014 Tartu, Estonia. [Viigimaa, Margus] Tallinn Univ Technol, Inst Biomed Engn, EE-19086 Tallinn, Estonia. [Viigimaa, Margus] N Estonia Med Ctr, Ctr Cardiol, EE-13419 Tallinn, Estonia. [Kinra, Sanjay] Univ London London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1E 7HT, England. [Prabhakaran, Dorairaj; Tripathy, Vikal] Publ Hlth Fdn India, S Asia Network Chron Dis, New Delhi 100016, India. [Rosengren, Annika] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Emergency & Cardiovasc Med, S-41685 Gothenburg, Sweden. [Thelle, Dag S.] Univ Oslo, Inst Basic Med Sci, Dept Biostat, N-0317 Oslo, Norway. [Corsi, Anna Maria] Tuscany Reg Hlth Agcy, I-50129 Florence, Italy. [Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, Res Inst Trop Med, Kingston 7, Jamaica. [Salako, Tunde] Univ Ibadan, Ibadan, Nigeria. [Iwai, Naoharu; Okamura, Tomonori] Natl Cerebral & Cardiovasc Res Ctr, Dept Genom Med, Suita, Osaka 5658565, Japan. [Iwai, Naoharu; Okamura, Tomonori] Natl Cerebral & Cardiovasc Res Ctr, Dept Prevent Cardiol, Suita, Osaka 5658565, Japan. [Kita, Yoshikuni; Ohkubo, Takayoshi; Okamura, Tomonori; Ueshima, Hirotsugu] Shiga Univ Med Sci, Dept Hlth Sci, Otsu, Shiga 5202192, Japan. [Ogihara, Toshio] Osaka Univ, Grad Sch Med, Dept Geriatr Med, Suita, Osaka 5650871, Japan. [Ohkubo, Takayoshi] Tohoku Univ, Grad Sch Pharmaceut Sci & Med, Sendai, Miyagi 9808578, Japan. [Ueshima, Hirotsugu] Shiga Univ Med Sci, Lifestyle Related Dis Prevent Ctr, Otsu, Shiga 5202192, Japan. [Umemura, Satoshi] Yokohama City Univ, Sch Med, Dept Med Sci & Cardiorenal Med, Yokohama, Kanagawa 2360004, Japan. [Eyheramendy, Susana] Pontificia Univ Catolica Chile, Dept Stat, Santiago, Chile. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munich, Inst Human Genet, D-85764 Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-81675 Munich, Germany. [Wichmann, H. -Erich; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munich, Inst Epidemiol, D-85764 Neuherberg, Germany. [Wichmann, H. -Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Wichmann, H. -Erich] Klinikum Grosshadern, D-81377 Munich, Germany. [Scott, James; Sehmi, Joban S.; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W12 0HS, England. [Raffel, Leslie J.; Yao, Jie; Guo, Xiuqing; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Kathiresan, Sekar] Broad Inst Harvard & MIT, Cambridge Ctr 5, Cambridge, MA 02142 USA. [O'Donnell, Christopher J.] NHLBI, Framingham, MA 01702 USA. [O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol & Med, Seattle, WA 98195 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Geriatr Med, Jackson, MS 39216 USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Laitinen, Jaana] Finnish Inst Occupat Hlth, Oulu 90220, Finland. [Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Zitting, Paavo] Lapland Cent Hosp, Dept Physiatr, Rovaniemi 96101, Finland. [Rasheed, Asif; Saleheen, Danish] Ctr Noncommunicable Dis, Karachi 74800, Pakistan. [Hamsten, Anders] Karolinska Inst, Dept Med, Atherosclerosis Res Unit, S-17177 Stockholm, Sweden. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Lakatta, Edward G.; Scuteri, Angelo] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Orru, Marco; Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, I-09042 Cagliari, Italy. [Orru, Marco] Presidio Osped Santa Barbara, Div Med, Unita Operat Semplice Cardiol, I-09016 Iglesias, Italy. [Ala-Korpela, Mika; Kangas, Antti J.; Soininen, Pasi; Tukiainen, Taru; Wurtz, Peter] Univ Oulu, Inst Clin Med, Computat Med Res Grp, Oulu, Finland. [Ala-Korpela, Mika] 90014 Univ Oulu, Bioctr Oulu, Clin Res Ctr, Oulu, Finland. [Ala-Korpela, Mika; Soininen, Pasi] Univ Eastern Finland, Dept Biosci, NMR Metabon Lab, Kuopio 70211, Finland. [Ala-Korpela, Mika] 90014 Univ Oulu, Dept Internal Med, Oulu, Finland. [Tukiainen, Taru; Wurtz, Peter] 00014 Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Tukiainen, Taru] Aalto Univ, Dept Biomed Engn & Computat Sci, Sch Sci & Technol, Espoo 00076, Finland. [Ong, Rick Twee-Hee] NUS Grad Sch Integrat Sci & Engn NGS, Ctr Life Sci CeLS, Singapore 117456, Singapore. [Doerr, Marcus] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med B, D-17487 Greifswald, Germany. [Kroemer, Heyo K.] Ernst Moritz Arndt Univ Greifswald, Inst Pharmacol, D-17487 Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17487 Greifswald, Germany. [Galan, Pilar; Hercberg, Serge] Univ Paris 13, Inst Natl Rech Agron U1125, Inst Natl Sante & Rech Med U557, F-93017 Bobigny, France. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, Imperial Coll Cerebrovasc Unit ICCRU, London W6 8RF, England. [Terzic, Janos] Univ Split, Fac Med, Split 21000, Croatia. [Zukowska-Szczechowska, Ewa] Med Univ Silesia, Dept Internal Med Diabetol & Nephrol, PL-41800 Zabrze, Poland. [Fowkes, F. Gerald R.] Univ Edinburgh, Sch Med, Div Community Hlth Sci, Publ Hlth Sci Sect, Edinburgh EH8 9AG, Midlothian, Scotland. [Charchar, Fadi J.] Univ Ballarat, Sch Sci & Engn, Ballarat, Vic 3353, Australia. [Schwarz, Peter E. H.] Tech Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, D-01307 Dresden, Germany. [Brand, Eva] Univ Hosp Munster, Munster, Germany. [Polasek, Ozren] Univ Zagreb, Andrija Stampar Sch Publ Hlth, Dept Med Stat Epidemiol & Med Informat, Zagreb 10000, Croatia. [Nyberg, Fredrik] AstraZeneca R&D, S-43183 Molndal, Sweden. [Palmer, Lyle J.] Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. [Palmer, Lyle J.] Univ Toronto, Samuel Lunenfeld Inst Med Res, Toronto, ON M5S 1A1, Canada. [Casas, Juan P.] Univ London London Sch Hyg & Trop Med, Fac Epidemiol & Population Hlth, London WC1E 7HT, England. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20521, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol, Turku 20521, Finland. [Ganesh, Santhi K.] Univ Michigan, Med Ctr, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Wong, Tien Y.] Singapore Eye Res Inst, Singapore 168751, Singapore. [Wong, Tien Y.] Natl Univ Singapore, Dept Ophthalmol, Singapore 119074, Singapore. [Tai, E. Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119074, Singapore. [Tai, E. Shyong] Duke Natl Univ Singapore, Grad Sch Med, Singapore 169857, Singapore. [Rao, Dabeeru C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Morris, Richard W.] UCL, Dept Primary Care & Populat Hlth, London NW3 2PF, England. [Dominiczak, Anna F.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Coresh, Josef] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, NL-9713 GZ Groningen, Netherlands. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02215 USA. [Bandinelli, Stefania] ASF, Geriatr Rehabil Unit, I-50100 Florence, Italy. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki 00271, Finland. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki 00014, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki 60220, Finland. [Tuomilehto, Jaakko] Hosp Univ La Paz, Red RECAVA Grp RD06 0014 0015, Madrid 28046, Spain. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, I-39100 Bolzano, Italy. [Elosua, Roberto] CIBER Epidemiol & Salud Publ, Barcelona 08003, Spain. [Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21201 USA. [Meneton, Pierre] Ctr Rech Cordeliers, Inst Natl Sante & Rech Med U872, F-75006 Paris, France. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, D-17487 Greifswald, Germany. [Hartikainen, Anna-Liisa] Univ Oulu, Inst Clin Med Obstet & Gynecol, Oulu 90014, Finland. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Boerwinkle, Eric] Ctr Human Genet, Houston, TX 77030 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Epidemiol & Prevent, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu 90014, Finland. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Oulu 90101, Finland. [Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC HPA Ctr Environm & Hlth, London W2 1PG, England. [van Duijn, Cornelia M.] NGI Erasmus Med Ctr, Ctr Med Syst Biol CMSB 1 2, Rotterdam, Netherlands. RP Chakravarti, A (reprint author), Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA. EM p.b.munroe@qmul.ac.uk; aravinda@jhmi.edu; cnewtoncheh@chgr.mgh.harvard.edu; levyd@nhlbi.nih.gov; m.j.caulfield@qmul.ac.uk RI Colaus, PsyColaus/K-6607-2013; Okamura, Tomonori/L-1693-2013; Aulchenko, Yurii/M-8270-2013; Altshuler, David/A-4476-2009; Grobbee, Diederick/C-7651-2014; Schnabel, Renate/F-6527-2014; Pramstaller, Peter/C-2357-2008; Cooper, Matthew/J-4420-2014; Willenborg, Christina/D-2668-2012; Palmer, Lyle/K-3196-2014; Gaunt, Tom/O-3918-2014; Kronenberg, Florian/B-1736-2008; Rudan, Igor/I-1467-2012; Hadley, David/I-6902-2012; Heath, Simon/J-4138-2012; Rice, Kenneth/A-4150-2013; Deloukas, Panos/B-2922-2013; gurrapu, gopi/A-9801-2011; Fuchsberger, Christian/C-9646-2010; Giallauria, Francesco/B-5681-2013; Cavalieri, Margherita/G-8053-2012; Johnson, Andrew/G-6520-2013; Kuznetsova, Tatiana/I-6882-2013; Gale, Daniel/D-5594-2013; Singleton, Andrew/C-3010-2009; Arora, Pankaj/F-3437-2011; Kottgen, Anna/D-2920-2012; Lucas, Gavin/D-4346-2012; Spector, Tim/F-6533-2012; Abecasis, Goncalo/B-7840-2010; Laan, Maris/A-4100-2011; Stark, Klaus/D-3813-2009; Soininen, Pasi/B-9716-2008; Aspelund, Thor/C-5983-2008; EHRET, Georg/A-9532-2009; Kivimaki, Mika/B-3607-2012; Beckmann, Jacques S /A-9772-2008; Erdmann, Jeanette/P-7513-2014; Hernandez-Fuentes, Maria/B-5011-2010; Maxwell, Patrick/C-5557-2008; Lyytikainen, Leo-Pekka/C-8544-2016; Shi, Gang/D-3301-2016; Soler Artigas, Maria/L-6529-2013; Burton, Paul/H-7527-2016; Smith, Albert/K-5150-2015; Matullo, Giuseppe/K-6383-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Schwarz, Peter/B-5127-2013; Wong, Andrew/M-8899-2016; Eggermann, Thomas/F-3807-2014; Boehm, Bernhard/F-8750-2015; Bakker, Stephan/J-4023-2015; Onland-Moret, N. Charlotte/G-9185-2011; Gudnason, Vilmundur/K-6885-2015; Staessen, Jan/A-1065-2011; Mattace- Raso, Francesco/L-2541-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Franke, Andre/B-2151-2010; Davey Smith, George/A-7407-2013; Boban, Mladen/E-2777-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; OI Okamura, Tomonori/0000-0003-0488-0351; Aulchenko, Yurii/0000-0002-7899-1575; Altshuler, David/0000-0002-7250-4107; Grobbee, Diederick/0000-0003-4472-4468; Cooper, Matthew/0000-0003-1139-3682; Willenborg, Christina/0000-0001-5217-6882; Palmer, Lyle/0000-0002-1628-3055; Gaunt, Tom/0000-0003-0924-3247; Kronenberg, Florian/0000-0003-2229-1120; Rudan, Igor/0000-0001-6993-6884; Rice, Kenneth/0000-0001-5779-4495; Deloukas, Panos/0000-0001-9251-070X; Giallauria, Francesco/0000-0003-4119-9397; Kuznetsova, Tatiana/0000-0003-3564-7405; Gale, Daniel/0000-0002-9170-1579; Arora, Pankaj/0000-0003-2420-3550; Laan, Maris/0000-0002-8519-243X; Stark, Klaus/0000-0002-7832-1942; Aspelund, Thor/0000-0002-7998-5433; EHRET, Georg/0000-0002-5730-0675; Beckmann, Jacques S /0000-0002-9741-1900; Adeyemo, Adebowale/0000-0002-3105-3231; Kumari, Meena/0000-0001-9716-1035; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Watkins, Hugh/0000-0002-5287-9016; Shrine, Nick/0000-0003-3641-4371; Zgaga, Lina/0000-0003-4089-9703; Ramachandran, Vasan/0000-0001-7357-5970; Erdmann, Jeanette/0000-0002-4486-6231; Humphries, Stephen E/0000-0002-8221-6547; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Ziegler, Andreas/0000-0002-8386-5397; Hernandez-Fuentes, Maria/0000-0002-7558-9441; Maxwell, Patrick/0000-0002-0338-2679; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Soler Artigas, Maria/0000-0002-3213-1107; Smith, Albert/0000-0003-1942-5845; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Schwarz, Peter/0000-0001-6317-7880; Wong, Andrew/0000-0003-2079-4779; Bakker, Stephan/0000-0003-3356-6791; Gudnason, Vilmundur/0000-0001-5696-0084; Staessen, Jan/0000-0002-3026-1637; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Talmud, Philippa/0000-0002-5560-1933; Fuchsberger, Christian/0000-0002-5918-8947; Monsalve, Beatriz Elena/0000-0002-5994-866X; Johnson, Toby/0000-0002-5998-3270; Ikram, Mohammad Arfan/0000-0003-0372-8585; MATULLO, Giuseppe/0000-0003-0674-7757; Felix, Janine/0000-0002-9801-5774; Org, Elin/0000-0003-1451-9375; Larson, Martin/0000-0002-9631-1254; ELOSUA, ROBERTO/0000-0001-8235-0095; Sijbrands, Eric/0000-0001-8857-7389; Magi, Reedik/0000-0002-2964-6011; Kivimaki, Mika/0000-0002-4699-5627; Whincup, Peter/0000-0002-5589-4107; Franke, Andre/0000-0003-1530-5811; Davey Smith, George/0000-0002-1407-8314; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Alexander, Myriam/0000-0002-6848-9370; Abecasis, Goncalo/0000-0003-1509-1825; Seielstad, Mark/0000-0001-5783-1401; Wurtz, Peter/0000-0002-5832-0221; Seshadri, Sudha/0000-0001-6135-2622; Sternberg, Michael/0000-0002-1884-5445; Marmot, Michael/0000-0002-2431-6419; Prabhakaran, Dorairaj/0000-0002-3172-834X; Lawlor, Debbie A/0000-0002-6793-2262; Tai, E Shyong/0000-0003-2929-8966; Johansson, Asa/0000-0002-2915-4498; Morris, Richard/0000-0001-7240-4563; Bergmann, Sven/0000-0002-6785-9034; Kleber, Marcus/0000-0003-0663-7275; Hypponen, Elina/0000-0003-3670-9399; Dehghan, Abbas/0000-0001-6403-016X; Wain, Louise/0000-0003-4951-1867 FU NIH/NHLBI FX A number of the participating studies and authors are members of the CHARGE and Global BPgen consortia. Many funding mechanisms by NIH/NHLBI, European and private funding agencies contributed to this work and a full list is provided in section 21 of the Supplementary Materials. NR 28 TC 759 Z9 777 U1 22 U2 198 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 6 PY 2011 VL 478 IS 7367 BP 103 EP 109 DI 10.1038/nature10405 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 829JN UT WOS:000295575400043 PM 21909115 ER PT J AU Jones, CU Hunt, D Shipley, WU AF Jones, Christopher U. Hunt, Daniel Shipley, William U. TI Radiotherapy and Androgen Deprivation for Prostate Cancer REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID RADIATION-THERAPY C1 [Jones, Christopher U.] Radiol Associates Sacramento, Sacramento, CA USA. [Hunt, Daniel] Radiat Therapy Oncol Grp, Philadelphia, PA USA. [Shipley, William U.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jones, CU (reprint author), Radiol Associates Sacramento, Sacramento, CA USA. EM jonesc@radiological.com 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 OCT 6 PY 2011 VL 365 IS 14 BP 1354 EP 1355 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 829KL UT WOS:000295578700025 ER PT J AU Tilson, JK Kaplan, SL Harris, JL Hutchinson, A Ilic, D Niederman, R Potomkova, J Zwolsman, SE AF Tilson, Julie K. Kaplan, Sandra L. Harris, Janet L. Hutchinson, Andy Ilic, Dragan Niederman, Richard Potomkova, Jarmila Zwolsman, Sandra E. TI Sicily statement on classification and development of evidence-based practice learning assessment tools SO BMC MEDICAL EDUCATION LA English DT Article ID EVIDENCE-BASED MEDICINE; EDUCATION; KNOWLEDGE; VALIDATION; CARE; QUESTIONNAIRE; INSTRUMENTS; STRATEGIES; BELIEFS; QUALITY AB Background: Teaching the steps of evidence-based practice (EBP) has become standard curriculum for health professions at both student and professional levels. Determining the best methods for evaluating EBP learning is hampered by a dearth of valid and practical assessment tools and by the absence of guidelines for classifying the purpose of those that exist. Conceived and developed by delegates of the Fifth International Conference of Evidence-Based Health Care Teachers and Developers, the aim of this statement is to provide guidance for purposeful classification and development of tools to assess EBP learning. Discussion: This paper identifies key principles for designing EBP learning assessment tools, recommends a common taxonomy for new and existing tools, and presents the Classification Rubric for EBP Assessment Tools in Education (CREATE) framework for classifying such tools. Recommendations are provided for developers of EBP learning assessments and priorities are suggested for the types of assessments that are needed. Examples place existing EBP assessments into the CREATE framework to demonstrate how a common taxonomy might facilitate purposeful development and use of EBP learning assessment tools. Summary: The widespread adoption of EBP into professional education requires valid and reliable measures of learning. Limited tools exist with established psychometrics. This international consensus statement strives to provide direction for developers of new EBP learning assessment tools and a framework for classifying the purposes of such tools. C1 [Tilson, Julie K.] Univ So Calif, Div Biokinesiol & Phys Therapy, Los Angeles, CA 90089 USA. [Kaplan, Sandra L.] Univ Med & Dent New Jersey, Dept Rehabil & Movement Sci, Doctoral Programs Phys Therapy, Newark, NJ 07103 USA. [Harris, Janet L.] Univ Sheffield, Sch Hlth & Related Res, Sheffield S10 2TN, S Yorkshire, England. [Hutchinson, Andy] Natl Inst Hlth & Clin Excellence, Natl Prescribing Ctr, Liverpool, Merseyside, England. [Ilic, Dragan] Monash Univ, Dept Epidemiol & Prevent Med, Sch Publ Hlth & Prevent Med, Clayton, Vic 3800, Australia. [Niederman, Richard] Forsyth Inst, Ctr Evidence Based Dent, Boston, MA USA. [Potomkova, Jarmila] Palacky Univ, Med Lib, CR-77147 Olomouc, Czech Republic. [Zwolsman, Sandra E.] Univ Amsterdam, Acad Med Ctr, Dept Gen Practice Family Med, NL-1012 WX Amsterdam, Netherlands. RP Tilson, JK (reprint author), Univ So Calif, Div Biokinesiol & Phys Therapy, Los Angeles, CA 90089 USA. EM tilson@usc.edu RI Ilic, Dragan/I-2437-2014; OI Ilic, Dragan/0000-0001-5127-9185; niederman, richard/0000-0001-6674-1774 NR 50 TC 42 Z9 43 U1 3 U2 34 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 OCT 5 PY 2011 VL 11 AR 78 DI 10.1186/1472-6920-11-78 PG 10 WC Education & Educational Research; Education, Scientific Disciplines SC Education & Educational Research GA 851XN UT WOS:000297305800001 PM 21970731 ER PT J AU Suri, P Rainville, J Fitzmaurice, GM Katz, JN Jamison, RN Martha, J Hartigan, C Limke, J Jouve, C Hunter, DJ AF Suri, Pradeep Rainville, James Fitzmaurice, Garrett M. Katz, Jeffrey N. Jamison, Robert N. Martha, Julia Hartigan, Carol Limke, Janet Jouve, Cristin Hunter, David J. TI Acute low back pain is marked by variability: An internet-based pilot study SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID PRIMARY-CARE; EPIDEMIOLOGY; DISABILITY; EPISODE; FEAR AB Background: Pain variability in acute LBP has received limited study. The objectives of this pilot study were to characterize fluctuations in pain during acute LBP, to determine whether self-reported 'flares' of pain represent discrete periods of increased pain intensity, and to examine whether the frequency of flares was associated with back-related disability outcomes. Methods: We conducted a cohort study of acute LBP patients utilizing frequent serial assessments and Internet-based data collection. Adults with acute LBP (lasting <= 3 months) completed questionnaires at the time of seeking care, and at both 3-day and 1-week intervals, for 6 weeks. Back pain was measured using a numerical pain rating scale (NPRS), and disability was measured using the Oswestry Disability Index (ODI). A pain flare was defined as 'a period of increased pain lasting at least 2 hours, when your pain intensity is distinctly worse than it has been recently'. We used mixed-effects linear regression to model longitudinal changes in pain intensity, and multivariate linear regression to model associations between flare frequency and disability outcomes. Results: 42 of 47 participants (89%) reported pain flares, and the average number of discrete flare periods per patient was 3.5 over 6 weeks of follow-up. More than half of flares were less than 4 hours in duration, and about 75% of flares were less than one day in duration. A model with a quadratic trend for time best characterized improvements in pain. Pain decreased rapidly during the first 14 days after seeking care, and leveled off after about 28 days. Patients who reported a pain flare experienced an almost 3-point greater current NPRS than those not reporting a flare (mean difference [SD] 2.70 [0.11]; p < 0.0001). Higher flare frequency was independently associated with a higher final ODI score (beta [SE} 0.28 (0.08); p = 0.002). Conclusions: Acute LBP is characterized by variability. Patients with acute LBP report multiple distinct flares of pain, which correspond to discrete increases in pain intensity. A higher flare frequency is associated with worse disability outcomes. C1 [Suri, Pradeep] VA Boston Healthcare Syst, Div PM&R, Boston, MA USA. [Suri, Pradeep] Spaulding Rehabil Hosp Network, Boston, MA USA. [Suri, Pradeep; Rainville, James; Martha, Julia; Hartigan, Carol; Limke, Janet; Jouve, Cristin; Hunter, David J.] New England Baptist Hosp, Boston, MA USA. [Suri, Pradeep; Rainville, James; Hartigan, Carol; Limke, Janet; Jouve, Cristin] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Fitzmaurice, Garrett M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy,Dept Med, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthoped Surg, Boston, MA 02115 USA. [Jamison, Robert N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol, Boston, MA 02115 USA. [Jamison, Robert N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Martha, Julia] New England Res Inst, Watertown, MA USA. [Hunter, David J.] Univ Sydney, No Clin Sch, Sydney, NSW 2006, Australia. RP Suri, P (reprint author), VA Boston Healthcare Syst, Div PM&R, Boston, MA USA. EM pradeep.suri@va.gov RI Hunter, David/A-4622-2010; OI Hunter, David/0000-0003-3197-752X; Jamison, Robert/0000-0003-1768-0906 FU Rehabilitation Medicine Scientist Training Program (RMSTP); National Institutes of Health [K12 HD001097]; Australian Research Council; NIH/NIAMS [K24 AR 02123, P60 AR 47782]; NIH/NIDA [R21 DA024298] FX Dr. Suri is funded by the Rehabilitation Medicine Scientist Training Program (RMSTP) and the National Institutes of Health (K12 HD001097). Dr Hunter is funded by an Australian Research Council Future Fellowship. Dr. Katz is funded in part by NIH/NIAMS K24 AR 02123 and NIH/NIAMS P60 AR 47782. Dr. Jamison was funded in part by NIH/NIDA R21 DA024298. The authors would like to thank the study participants for making this research possible. A portion of this material was presented at the Association of Academic Physiatrists Annual Meeting, Phoenix, AZ, USA, April 12-16, 2011. NR 25 TC 7 Z9 7 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD OCT 5 PY 2011 VL 12 AR 220 DI 10.1186/1471-2474-12-220 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 839NQ UT WOS:000296374700002 PM 21974962 ER PT J AU Lee, KY Gesta, S Boucher, J Wang, XL Kahn, CR AF Lee, Kevin Y. Gesta, Stephane Boucher, Jeremie Wang, Xiaohui L. Kahn, C. Ronald TI The Differential Role of Hif1 beta/Arnt and the Hypoxic Response in Adipose Function, Fibrosis, and Inflammation SO CELL METABOLISM LA English DT Article ID INDUCIBLE FACTOR 1-ALPHA; ARYL-HYDROCARBON RECEPTOR; MITOCHONDRIAL COMPLEX-III; KNOCK-OUT MICE; GENE-EXPRESSION; TISSUE HYPOXIA; 3T3-L1 CELLS; OBESITY; ARNT; ACTIVATION AB In obesity, adipocytes distant from vasculature become hypoxic and dysfunctional. This hypoxic response is mediated by hypoxia-inducible factors Hif1 alpha, Hif2 alpha, and Hif3 alpha) and their obligate partner, Hif1 beta (Arnt). We show that mice lacking Hif1 beta in fat (FH1 beta KO) are lean, exhibit reduced adipocyte size, and are protected from age- and diet-induced glucose intolerance. There is also reduced Vegf and vascular permeability in FH1 beta KO fat, but diet-induced inflammation and fibrosis is unchanged. Adipocytes from FH1 beta KO mice have reduced glucose uptake due to decreased Glut1 and Glut4, which is mirrored in 3T3-L1 adipocytes with Hif1 beta knockdown. Hif1 beta knockdown cells also fail to respond appropriately to hypoxia with reduced cellular respiration and reduced mitochondrial gene expression. Some, but not all, of these effects are reproduced by Hif1 alpha knockdown. Thus, Hif1 beta/Arnt regulates glucose uptake, mitochondrial gene expression, and vascular permeability to control adipose mass and function, providing a target for obesity therapy. C1 [Lee, Kevin Y.; Gesta, Stephane; Boucher, Jeremie; Wang, Xiaohui L.; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU Joslin Training Grant [T32DK007260]; NIH [DK 60837, DK 82655]; American Diabetes Association FX The authors would like to thank Dr. Frank J. Gonzalez (National Cancer Institute) for the Hif1 beta floxed mice. We are grateful to M. Rourk and G. Smyth for animal care; C. Cahill (Joslin Diabetes Research & Endocrinology Center [DERC] Advanced Microscopy Core); and A. Clermont, M. Poillucci (DERC Physiology Core), H. Li (DERC Specialized Assay Core), and J. Schroeder (DERC Genomics Core) for technical assistance. This work was supported by the Joslin Training Grant (T32DK007260), NIH grants DK 60837 and DK 82655, an American Diabetes Association mentor-based award, and the Mary K. Iacocca Professorship to C.R.K. NR 43 TC 25 Z9 26 U1 1 U2 13 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 OCT 5 PY 2011 VL 14 IS 4 BP 491 EP 503 DI 10.1016/j.cmet.2011.08.006 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 837SN UT WOS:000296223600009 PM 21982709 ER PT J AU Zhou, YF Eng, ET Nishida, N Lu, CF Walz, T Springer, TA AF Zhou, Yan-Feng Eng, Edward T. Nishida, Noritaka Lu, Chafen Walz, Thomas Springer, Timothy A. TI A pH-regulated dimeric bouquet in the structure of von Willebrand factor SO EMBO JOURNAL LA English DT Article DE biosynthesis; endothelium; platelets; shear flow; Weibel-Palade bodies ID HUMAN VONWILLEBRAND-FACTOR; WEIBEL-PALADE BODIES; PLATELET GLYCOPROTEIN IB; FACTOR A1 DOMAIN; ENDOTHELIAL-CELLS; CRYSTAL-STRUCTURE; FACTOR STORAGE; A3 DOMAIN; PROTEIN; MULTIMERIZATION AB At the acidic pH of the trans-Golgi and Weibel-Palade bodies (WPBs), but not at the alkaline pH of secretion, the C-terminal similar to 1350 residues of von Willebrand factor (VWF) zip up into an elongated, dimeric bouquet. Six small domains visualized here for the first time between the D4 and cystine-knot domains form a stem. The A2, A3, and D4 domains form a raceme with three pairs of opposed, large, flower-like domains. N-terminal VWF domains mediate helical tubule formation in WPBs and template N-terminal disulphide linkage between VWF dimers, to form ultralong VWF concatamers. The dimensions we measure in VWF at pH 6.2 and 7.4, and the distance between tubules in nascent WPB, suggest that dimeric bouquets are essential for correct VWF dimer incorporation into growing tubules and to prevent cross-linking between neighbouring tubules. Further insights into the structure of the domains and flexible segments in VWF provide an overall view of VWF structure important for understanding both the biogenesis of ultralong concatamers at acidic pH and flow-regulated changes in concatamer conformation in plasma at alkaline pH that trigger hemostasis. The EMBO Journal (2011) 30, 4098-4111. doi:10.1038/emboj.2011.297; Published online 19 August 2011 C1 [Springer, Timothy A.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Immune Dis Inst,CLSB,Childrens Hosp,Dept Pathol, Boston, MA 02115 USA. [Nishida, Noritaka] Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan. [Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Cell Biol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Program Cellular & Mol Med, Immune Dis Inst,CLSB,Childrens Hosp,Dept Pathol, 3 Blackfan Circle, Boston, MA 02115 USA. EM springer@idi.harvard.edu RI Zhou, Yanfeng/B-3792-2012 FU NIH [HL-48675] FX This work was supported by NIH Grant HL-48675. TW is an investigator in the Howard Hughes Medical Institute. NR 46 TC 36 Z9 36 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 5 PY 2011 VL 30 IS 19 BP 4098 EP 4111 DI 10.1038/emboj.2011.297 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 834ND UT WOS:000295967300021 PM 21857647 ER PT J AU Souer, JS Buijze, G Ring, D AF Souer, J. Sebastiaan Buijze, Geert Ring, David TI A Prospective Randomized Controlled Trial Comparing Occupational Therapy with Independent Exercises After Volar Plate Fixation of a Fracture of the Distal Part of the Radius SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID COLLES FRACTURES; WRIST FRACTURES; PREDICTORS; PHYSIOTHERAPY; PAIN; DISABILITY AB Background: The effect of formal occupational therapy on recovery after open reduction and volar plate fixation of a fracture of the distal part of the radius is uncertain. We hypothesized that there would be no difference in wrist function and arm-specific disability six months after open reduction and volar plate fixation of a distal radial fracture between patients who receive formal occupational therapy and those with instructions for independent exercises. Methods: Ninety-four patients with an unstable distal radial fracture treated with open reduction and volar locking plate fixation were enrolled in a prospective randomized controlled trial comparing exercises done under the supervision of an occupational therapist with surgeon-directed independent exercises. The primary study question addressed combined wrist flexion and extension six months after surgery Secondary study questions addressed wrist motion, grip strength, Gartland and Werley scores, Mayo wrist scores, and DASH (Disabilities of the Arm, Shoulder and Hand) scores at three months and six months after surgery. Results: There was a significant difference in the mean arc of wrist flexion and extension six months after surgery (118 degrees versus 129 degrees), favoring patients prescribed independent exercises. Three months after surgery, there was a significant difference in mean pinch strength (80% versus 90%), mean grip strength (66% versus 81%), and mean Gartland and Werley scores, favoring patients prescribed independent exercises. At six months, there was a.significant difference in mean wrist extension (55 degrees versus 62 degrees), ulnar deviation (82% versus 93%), mean supination (84 degrees versus 90 degrees), mean grip strength (81% versus 92%), and mean Mayo score, favoring patients prescribed independent exercises. There were no differences in arm-specific disability (DASH score) at any time point. Conclusions: Prescription of formal occupational therapy does not improve the average motion or disability score after volar locking plate fixation of a fracture of the distal part of the radius. C1 [Souer, J. Sebastiaan; Buijze, Geert; Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 17 TC 22 Z9 22 U1 0 U2 6 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD OCT 5 PY 2011 VL 93A IS 19 BP 1761 EP 1766 DI 10.2106/JBJS.J.01452 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 832OA UT WOS:000295813100001 PM 22005860 ER PT J AU Ziperstein, JC AF Ziperstein, Joshua C. TI Je Vais le Faire SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. RP Ziperstein, JC (reprint author), Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. EM jziperstein@partners.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 OCT 5 PY 2011 VL 306 IS 13 BP 1418 EP 1419 DI 10.1001/jama.2011.1411 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 828MZ UT WOS:000295506900001 PM 21972298 ER PT J AU Perrin, JM Kolls, JK Coury, DL AF Perrin, James M. Kolls, Jay K. Coury, Daniel L. TI Evidence-Based Practice and Health Advocacy Organizations SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Perrin, James M.] MassGen Hosp Children, Boston, MA USA. [Kolls, Jay K.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Coury, Daniel L.] Nationwide Childrens Hosp, Columbus, OH USA. RP Perrin, JM (reprint author), MassGen Hosp Children, Boston, MA USA. EM jperrin@partners.org RI Coury, Daniel/E-2925-2011 NR 5 TC 0 Z9 0 U1 0 U2 1 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 OCT 5 PY 2011 VL 306 IS 13 BP 1443 EP 1443 DI 10.1001/jama.2011.1404 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 828MZ UT WOS:000295506900016 PM 21972304 ER PT J AU Rao, SV Kaltenbach, LA Weintraub, WS Roe, MT Brindis, RG Rumsfeld, JS Peterson, ED AF Rao, Sunil V. Kaltenbach, Lisa A. Weintraub, William S. Roe, Matthew T. Brindis, Ralph G. Rumsfeld, John S. Peterson, Eric D. TI Prevalence and Outcomes of Same-Day Discharge After Elective Percutaneous Coronary Intervention Among Older Patients SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SINGLE-CENTER EXPERIENCE; DAY HOME DISCHARGE; STENT IMPLANTATION; ANGIOPLASTY; OUTPATIENT; FEASIBILITY; SAFETY; STAY; TRENDS; BOLUS AB Context Patients undergoing elective percutaneous coronary intervention (PCI) are generally observed overnight in the hospital. The association between same-day discharge of older patients and death or readmission is unclear. Objective To evaluate the prevalence and outcomes of same-day discharge among older patients undergoing elective PCI in the United States. Design, Setting, and Participants Multicenter cohort study. Data were from 107 018 patients 65 years or older undergoing elective PCI procedures at 903 sites participating in the CathPCI Registry between November 2004 and December 2008 and were linked with Medicare Part A claims. Patients were divided into 2 groups based on their length of stay after PCI: same-day discharge or overnight stay. Main Outcome Measures Death or rehospitalization occurring within 2 days and by 30 days after PCI. Results The prevalence of same-day discharge was 1.25% (95% CI, 1.19%-1.32%; n = 1339 patients) with significant variation across facilities. Patient characteristics were similar between the 2 groups, although same-day discharge patients underwent shorter procedures with less multivessel intervention. There were no significant differences in the rates of death or rehospitalization at 2 days (same-day discharge, 0.37% [95% CI, 0.16%-0.87%] vs overnight stay, 0.50% [95% CI, 0.46%-0.54%]; P = .51) or at 30 days (same-day discharge, 9.63% [95% CI, 8.17%-11.33%] vs overnight stay, 9.70% [95% CI, 9.52%-9.88%]; P = .94). Among patients with adverse outcomes, the median time to death or rehospitalization did not differ significantly between the groups (same-day discharge, 13 days [interquartile range, 7.0-21.0] vs overnight stay, 14 days [interquartile range, 7.0-21.0]; P = .96). After adjustment for patient and procedure characteristics, same-day discharge was not significantly associated with 30-day death or rehospitalization (adjusted odds ratio, 0.95 [95% CI, 0.78-1.16]). Conclusion Among selected low-risk Medicare patients undergoing elective PCI, same-day discharge is rarely implemented but is not associated with death or rehospitalization compared with overnight observation. JAMA. 2011;306(13):1461-1467 C1 [Rao, Sunil V.; Kaltenbach, Lisa A.; Roe, Matthew T.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC 27705 USA. [Weintraub, William S.] Christiana Care Hosp, Newark, DE USA. [Brindis, Ralph G.] No Calif Kaiser Permanente, Oakland, CA USA. [Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. RP Rao, SV (reprint author), Duke Clin Res Inst, 508 Fulton St 111A, Durham, NC 27705 USA. EM sunil.rao@duke.edu FU Terumo Medical; Medicines Company; AstraZeneca; Zoll; Ikaria; sanofi-aventis; Otsuka; Bristol-Myers Squibb; Abbott; Eli Lilly; Shionogi; Cardionet; Daiichi-Sankyo; Roche; Novartis; Merck-Schering Plough; American College of Cardiology; American Heart Association; GlaxoSmithKline; KAI Pharmaceuticals; Orexigen; Helsinn Pharmaceuticals; Regeneron; Schering Plough/Merck; Johnson Johnson; St Jude Inc; Bayer; Pfizer; American College of Cardiology Foundation National Cardiovascular Data Registry (NCDR) FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rao reported receiving consulting fees from Terumo Medical, The Medicines Company, AstraZeneca, and Zoll and research funding from Ikaria, sanofi-aventis, and Terumo Medical. Dr Weintraub reported receiving research grants from Otsuka, AstraZeneca, Bristol-Myers Squibb, sanofi-aventis, and Abbott; receiving consultant fees from Eli Lilly, Bristol-Myers Squibb, Shionogi, sanofi-aventis, Cardionet, and Daiichi-Sankyo; and providing expert testimony in cases involving Bayer and Pfizer. Dr Roe reported receiving research funding from Eli Lilly, Roche, Novartis, Merck-Schering Plough, Bristol-Myers Squibb, the American College of Cardiology, and the American Heart Association and consulting fees/honoraria from GlaxoSmithKline, KAI Pharmaceuticals, Novartis, Eli Lilly, Bristol-Myers Squibb, sanofi-aventis, Merck, Orexigen, Helsinn Pharmaceuticals, Regeneron, and AstraZeneca. Dr Rumsfeld reported being chief science officer for the National Cardiovascular Data Registry. Dr Peterson reported receiving research grants from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly, Schering Plough/Merck, Johnson & Johnson, and St Jude Inc and consultant fees from Bayer and Pfizer. No other disclosures were reported.; This analysis was funded by the American College of Cardiology. This research was supported by the American College of Cardiology Foundation National Cardiovascular Data Registry (NCDR). NR 25 TC 40 Z9 42 U1 0 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 OCT 5 PY 2011 VL 306 IS 13 BP 1461 EP 1467 DI 10.1001/jama.2011.1409 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 828MZ UT WOS:000295506900025 PM 21972308 ER PT J AU Lee, SJ Walter, LC AF Lee, Sei J. Walter, Louise C. TI Quality Indicators for Older Adults Preventing Unintended Harms SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PRACTICE GUIDELINES; OF-CARE; CANCER; PERFORMANCE; LESSONS C1 [Lee, Sei J.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. RP Lee, SJ (reprint author), Univ Calif San Francisco, Div Geriatr, 4150 Clement St,Bldg 1,Room 211A, San Francisco, CA 94121 USA. EM sei.lee@ucsf.edu FU NCI NIH HHS [R01 CA134425, 1R01CA134425]; NCRR NIH HHS [KL2 RR024130, KL2 RR024130-02]; NIA NIH HHS [K23 AG040779] NR 10 TC 19 Z9 19 U1 0 U2 4 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 OCT 5 PY 2011 VL 306 IS 13 BP 1481 EP 1482 DI 10.1001/jama.2011.1418 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 828MZ UT WOS:000295506900028 PM 21972311 ER PT J AU Foster, MC Hwang, SJ Porter, SA Massaro, JM Hoffmann, U Fox, CS AF Foster, Meredith C. Hwang, Shih-Jen Porter, Stacy A. Massaro, Joseph M. Hoffmann, Udo Fox, Caroline S. TI Development and reproducibility of a computed tomography-based measurement of renal sinus fat SO BMC NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; BODY-MASS INDEX; COMMUNITY-BASED POPULATION; IMPROVING GLOBAL OUTCOMES; CARDIOVASCULAR-DISEASE; LIPID-ACCUMULATION; METABOLIC SYNDROME; RISK-FACTORS; UNITED-STATES; OBESITY AB Background: Renal sinus fat may mediate obesity-related vascular disease, although this fat depot has not been assessed in a community-based sample. We sought to develop a protocol to quantify renal sinus fat accumulation using multi-detector computed tomography (MDCT). Methods: Protocol development was performed in participants in the Framingham Offspring cohort who underwent MDCT. Volumetric renal sinus fat was measured separately within the right and left kidneys, and renal sinus fat area within a single MDCT scan slice was measured in the right kidney. Due to the high correlation of volumetric and single-slice renal sinus fat in the right kidney (Pearson correlation [r] = 0.85, p < 0.0001), we optimized a single-slice protocol to capture renal sinus fat in the right kidney alone. Pearson correlation coefficients were used to compare to assess the correlation of volumetric and single-slice renal sinus fat in the right kidney with other measures of adiposity. Inter-and intra-reader reproducibility was assessed using intra-class correlation coefficients. Results: Single-slice measurements were obtained in 92 participants (mean age 60 years, 49% women, median renal sinus fat 0.43 cm(2)). Intra- and inter-reader intra-class correlation coefficients were 0.93 and 0.86, respectively. Single-slice renal sinus fat was correlated with body mass index (r = 0.35, p = 0.0006), waist circumference (r = 0.31, p = 0.003), and abdominal visceral fat (r = 0.48, p < 0.0001). Similar correlations were observed for volumetric renal sinus fat in the right kidney. Conclusions: Measuring renal sinus fat is feasible and reproducible using MDCT scans in a community-based sample. C1 [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Foster, Meredith C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Foster, Meredith C.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. [Porter, Stacy A.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol & Metab, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung and Blood Institute [N01-HC-25195] FX The Framingham Heart Study is supported by the National Heart, Lung and Blood Institute (N01-HC-25195). The funding body did not play a role in the study design, collection, analysis, and interpretation of data, in the writing of the manuscript, or the decision to submit the manuscript for publication. NR 43 TC 4 Z9 4 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD OCT 4 PY 2011 VL 12 AR 52 DI 10.1186/1471-2369-12-52 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 946PV UT WOS:000304366000001 PM 21970591 ER PT J AU Yeh, RW Normand, SLT Wolf, RE Jones, PG Ho, KKL Cohen, DJ Cutlip, DE Mauri, L Kugelmass, AD Amin, AP Spertus, JA AF Yeh, Robert W. Normand, Sharon-Lise T. Wolf, Robert E. Jones, Philip G. Ho, Kalon K. L. Cohen, David J. Cutlip, Donald E. Mauri, Laura Kugelmass, Aaron D. Amin, Amit P. Spertus, John A. TI Predicting the Restenosis Benefit of Drug-Eluting Versus Bare Metal Stents in Percutaneous Coronary Intervention SO CIRCULATION LA English DT Article DE coronary intervention; outcome assessment; predictors; restenosis; stents ID CARDIOVASCULAR DATA REGISTRY; ACUTE MYOCARDIAL-INFARCTION; BYPASS GRAFT-SURGERY; ANGIOGRAPHIC PREDICTORS; CLINICAL RESTENOSIS; OUTCOMES; TRIALS; RISK; IMPLANTATION; SAFETY AB Background-Drug-eluting stents (DES) for percutaneous coronary intervention decrease the risk of restenosis compared with bare metal stents. However, they are costlier, require prolonged dual antiplatelet therapy, and provide the most benefit in patients at highest risk for restenosis. To assist physicians in targeting DES use in patients at the highest risk for target vessel revascularization (TVR), we developed and validated a model to predict TVR. Methods and Results-Preprocedural clinical and angiographic data from 27 107 percutaneous coronary intervention hospitalizations between October 1, 2004, and September 30, 2007, in Massachusetts were used to develop prediction models for TVR at 1 year. Models were developed from a two-thirds random sample and validated in the remaining third. The overall rate of TVR was 7.6% (6.7% with DES, 11% with bare metal stents). Significant predictors of TVR included prior percutaneous coronary intervention, emergency or salvage percutaneous coronary intervention, prior coronary bypass surgery, peripheral vascular disease, diabetes mellitus, and angiographic characteristics. The model was superior to a 3-variable model of diabetes mellitus, stent diameter, and stent length (c statistic, 0.66 versus 0.60; P<0.001) and was well calibrated. The predicted number needed to treat with DES to prevent 1 TVR compared with bare metal stents ranged from 6 (95% confidence interval, 5.4-7.6) to 80 (95% confidence interval, 62.7-116.3), depending on patients' clinical and angiographic factors. Conclusions-A predictive model using commonly collected variables can identify patients who may derive the greatest benefit in TVR reduction from DES. Whether use of the model improves the safety and cost-effectiveness of DES use should be tested prospectively. (Circulation. 2011;124:1557-1564.) C1 [Yeh, Robert W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA 02144 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02144 USA. [Normand, Sharon-Lise T.; Wolf, Robert E.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02144 USA. [Cohen, David J.; Amin, Amit P.; Spertus, John A.] Univ Missouri, Kansas City, MO USA. [Cohen, David J.; Amin, Amit P.; Spertus, John A.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Ho, Kalon K. L.; Cutlip, Donald E.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Cardiol, Boston, MA 02144 USA. [Mauri, Laura] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA 02144 USA. [Kugelmass, Aaron D.] Baystate Med Ctr, Dept Med, Div Cardiol, Springfield, MA 01199 USA. RP Yeh, RW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, GRB 800, Boston, MA 02144 USA. EM ryeh@partners.org FU Massachusetts Data Analysis Center; Massachusetts Department of Public Health; Boston Scientific; Medtronic; Abbott Vascular; Cordis; Eli Lilly; Daiichi Sankyo; Bristol Myers Squibb; Sanofi-aventis; National Heart, Lung, and Blood Institute [HL096624]; American Heart Association [0875149N]; Lilly; BMS/Sanofi; Amgen; Evaheart FX Dr Yeh is an investigator for the Harvard Clinical Research Institute and a consultant for the Kaiser Permanente Division of Research. Dr Normand is director of the Massachusetts Data Analysis Center, contracted by the Massachusetts Department of Public Health, and is funded to collect, validate, analyze, and disseminate evidence of quality of cardiovascular care at acute care nonfederal hospitals in Massachusetts. R. E. Wolf is senior programmer for the Massachusetts Data Analysis Center and is funded to support biostatistical and programming aspects of the Center. Dr Cohen receives grant support from Boston Scientific, Medtronic, and Abbott Vascular and has served as a consultant to Medtronic, Abbott Vascular, and Cordis. Dr Mauri receives institutional research support from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly, Daiichi Sankyo, Bristol Myers Squibb, and Sanofi-aventis and has consulted for Cordis and Medtronic. Dr Spertus has received research grants from the National Heart, Lung, and Blood Institute (HL096624) and the American Heart Association (0875149N) to study the impact of prospective risk estimation on the use of DES as a function of patients' risks for restenosis. Within the past 2 years, he has also received research grant support from Lilly, BMS/Sanofi, Amgen, and Evaheart and has consulted for United Healthcare, Gilead, Quest Diagnostics, and St. Jude Medical. He has patents and an equity position in Health Outcomes Sciences, which supports the technology to deliver individualized estimates of patients' outcomes based on multivariable models. The other authors report no conflicts. NR 31 TC 30 Z9 34 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 4 PY 2011 VL 124 IS 14 BP 1557 EP U162 DI 10.1161/CIRCULATIONAHA.111.045229 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 829UG UT WOS:000295609200018 PM 21900079 ER PT J AU Tanaka, A Shimada, K Tearney, GJ Kitabata, H Taguchi, H Fukuda, S Kashiwagi, M Kubo, T Takarada, S Hirata, K Mizukoshi, M Yoshikawa, J Bouma, BE Akasaka, T AF Tanaka, Atsushi Shimada, Kenei Tearney, Guillermo J. Kitabata, Hironori Taguchi, Haruyuki Fukuda, Shota Kashiwagi, Manabu Kubo, Takashi Takarada, Shigeho Hirata, Kumiko Mizukoshi, Masato Yoshikawa, Junichi Bouma, Brett E. Akasaka, Takashi TI Conformational Change in Coronary Artery Structure Assessed by Optical Coherence Tomography in Patients With Vasospastic Angina SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary; imaging; optical coherence tomography; spasm ID SPASTIC ANGINA; INTRAVASCULAR ULTRASOUND; VARIANT ANGINA; PLAQUE; ATHEROSCLEROSIS; FEATURES; PECTORIS AB Objectives The aim of this study was to investigate the conformational change of arterial structure in the vasospastic lesion with optical coherence tomography. Background Coronary artery spasm plays an important role in the pathogenesis of ischemic heart diseases. The conformational change of each arterial layer during vasospasm has not been studied in detail. Methods We assessed 19 coronary arteries (10 spasm and 9 nonspasm lesions) with optical coherence tomography during the provocation test for coronary spasm. An intimal bump was defined as 1 or more intimal projections into the lumen that disappeared after the administration of nitroglycerine (NTG). Intimal gathering was defined as a folding/gathering of the intima, resulting in multiple kinks in the luminal contour that resolved after the administration of NTG. Results The spasm lesion more frequently showed an intimal bump at baseline and intimal gathering during spasm compared with the nonspasm lesion (spasm 80% vs. nonspasm 0%, p < 0.01, spasm 100% vs. nonspasm 0%, p < 0.01, respectively). The spasm lesion demonstrated a thicker maximum media thickness (spasm 0.24 +/- 0.04 mm vs. nonspasm 0.12 +/- 0.03 mm, p < 0.01) at baseline, whereas no differences were observed after the administration of NTG (spasm 0.13 +/- 0.03 mm vs. nonspasm 0.13 +/- 0.02 mm, p = 0.65). Conclusions Our results suggest that medial contraction occurs even in an asymptomatic state and facilitates the formation of an intimal bump in patients with vasospastic angina. Luminal narrowing during spasm is associated with intimal gathering without alteration of intimal area. (J Am Coll Cardiol 2011;58:1608-13) (C) 2011 by the American College of Cardiology Foundation C1 [Tanaka, Atsushi; Tearney, Guillermo J.; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tanaka, Atsushi; Tearney, Guillermo J.; Bouma, Brett E.] Harvard Univ, Sch Med, Boston, MA USA. [Shimada, Kenei; Taguchi, Haruyuki; Fukuda, Shota; Yoshikawa, Junichi] Osaka Ekisaikai Hosp, Dept Cardiol, Osaka, Japan. [Tearney, Guillermo J.; Bouma, Brett E.] Harvard Massachusetts Inst Technol Hlth Sci & Tec, Cambridge, MA USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kitabata, Hironori; Kashiwagi, Manabu; Kubo, Takashi; Takarada, Shigeho; Hirata, Kumiko; Mizukoshi, Masato; Akasaka, Takashi] Wakayama Med Univ, Dept Cardiovasc Med, Wakayama, Japan. RP Tanaka, A (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. EM atanaka1@partners.org FU Terumo Corp. FX Dr. Tearney is a consultant for Samsung; has performed sponsored research for the Terumo Corp.; and has received patent licensing and royalty income from the Terumo Corp. Dr. Bouma has a sponsored research agreement with and is an inventor on patents licensed to the Terumo Corp.; and is an inventor on patents licensed to LightLab Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 19 TC 24 Z9 24 U1 1 U2 4 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 OCT 4 PY 2011 VL 58 IS 15 BP 1608 EP 1613 DI 10.1016/j.jacc.2011.06.046 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 833FP UT WOS:000295868000009 PM 21958888 ER PT J AU Etcoff, NL Stock, S Haley, LE Vickery, SA House, DM AF Etcoff, Nancy L. Stock, Shannon Haley, Lauren E. Vickery, Sarah A. House, David M. TI Cosmetics as a Feature of the Extended Human Phenotype: Modulation of the Perception of Biologically Important Facial Signals SO PLOS ONE LA English DT Article ID PHYSICAL ATTRACTIVENESS; FACES; BEAUTY; COLOR; SEX; AGE; RATIONALITY; IMPRESSIONS; COMPETENCE; STEREOTYPE AB Research on the perception of faces has focused on the size, shape, and configuration of inherited features or the biological phenotype, and largely ignored the effects of adornment, or the extended phenotype. Research on the evolution of signaling has shown that animals frequently alter visual features, including color cues, to attract, intimidate or protect themselves from conspecifics. Humans engage in conscious manipulation of visual signals using cultural tools in real time rather than genetic changes over evolutionary time. Here, we investigate one tool, the use of color cosmetics. In two studies, we asked viewers to rate the same female faces with or without color cosmetics, and we varied the style of makeup from minimal (natural), to moderate (professional), to dramatic (glamorous). Each look provided increasing luminance contrast between the facial features and surrounding skin. Faces were shown for 250 ms or for unlimited inspection time, and subjects rated them for attractiveness, competence, likeability and trustworthiness. At 250 ms, cosmetics had significant positive effects on all outcomes. Length of inspection time did not change the effect for competence or attractiveness. However, with longer inspection time, the effect of cosmetics on likability and trust varied by specific makeup looks, indicating that cosmetics could impact automatic and deliberative judgments differently. The results suggest that cosmetics can create supernormal facial stimuli, and that one way they may do so is by exaggerating cues to sexual dimorphism. Our results provide evidence that judgments of facial trustworthiness and attractiveness are at least partially separable, that beauty has a significant positive effect on judgment of competence, a universal dimension of social cognition, but has a more nuanced effect on the other universal dimension of social warmth, and that the extended phenotype significantly influences perception of biologically important signals at first glance and at longer inspection. C1 [Etcoff, Nancy L.; Haley, Lauren E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Etcoff, Nancy L.; Haley, Lauren E.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Stock, Shannon] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Vickery, Sarah A.] Procter & Gamble Cosmet, Procter & Gamble Beauty & Grooming, Hunt Valley, MD USA. [House, David M.] Boston Univ, Dept Comp Sci, Boston, MA 02215 USA. RP Etcoff, NL (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM netcoff@partners.org FU P&G Beauty and Grooming FX This study was funded by P&G Beauty and Grooming, where Sarah A. Vickery is employed as a Principal Scientist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 30 Z9 30 U1 11 U2 64 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 OCT 3 PY 2011 VL 6 IS 10 AR e25656 DI 10.1371/journal.pone.0025656 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834EU UT WOS:000295943000052 PM 21991328 ER PT J AU Settles, M Etzrodt, M Kosanke, K Schiemann, M Zimmermann, A Meier, R Braren, R Huber, A Rummeny, EJ Weissleder, R Swirski, FK Wildgruber, M AF Settles, Marcus Etzrodt, Martin Kosanke, Katja Schiemann, Matthias Zimmermann, Alexander Meier, Reinhard Braren, Rickmer Huber, Armin Rummeny, Ernst J. Weissleder, Ralph Swirski, Filip K. Wildgruber, Moritz TI Different Capacity of Monocyte Subsets to Phagocytose Iron-Oxide Nanoparticles SO PLOS ONE LA English DT Article ID MR CONTRAST AGENTS; BLOOD MONOCYTES; DENDRITIC CELLS; IN-VITRO; DISEASE; USPIO; INFLAMMATION; ENDOTHELIUM; EXPRESSION; METASTASES AB Objective: To explore the capacity of human CD14(+)CD16(++) and CD14(++)CD16(-) monocytes to phagocyte iron-oxide nanoparticles in vitro. Methods: Human monocytes were labeled with four different magnetic nanoparticle preparations (Ferumoxides, SHU 555C, CLIO-680, MION-48) exhibiting distinct properties and cellular uptake was quantitatively assessed by flow cytometry, fluorescence microscopy, atomic absorption spectrometry and Magnetic Resonance Imaging (MRI). Additionally we determined whether cellular uptake of the nanoparticles resulted in phenotypic changes of cell surface markers. Results: Cellular uptake differed between the four nanoparticle preparations. However for each nanoparticle tested, CD14(++)CD16(-) monocytes displayed a significantly higher uptake compared to CD14(+)CD16(++) monocytes, this resulted in significantly lower T1 and T2 relaxation times of these cells. The uptake of iron-oxide nanoparticles further resulted in a remarkable shift of expression of cell surface proteins indicating that the labeling procedure affects the phenotype of CD14(+)CD16(++) and CD14(++)CD16(-) monocytes differently. Conclusion: Human monocyte subsets internalize different magnetic nanoparticle preparations differently, resulting in variable loading capacities, imaging phenotypes and likely biological properties. C1 [Settles, Marcus; Kosanke, Katja; Meier, Reinhard; Braren, Rickmer; Huber, Armin; Rummeny, Ernst J.; Wildgruber, Moritz] Tech Univ Munich, Klinikum Rechts Isar, Inst Radiol, D-8000 Munich, Germany. [Etzrodt, Martin; Weissleder, Ralph; Swirski, Filip K.; Wildgruber, Moritz] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Schiemann, Matthias] Tech Univ Munich, Klinikum Rechts Isar, Inst Med Mikrobiol Immunol & Hyg, D-8000 Munich, Germany. [Schiemann, Matthias] Helmholtzzentrum Munchen, Clin Cooperat Grp Antigen Specif Immunotherapy, Munich, Germany. [Zimmermann, Alexander] Tech Univ Munich, Klinikum Rechts Isar, Klin & Poliklin Gefasschirurg, D-8000 Munich, Germany. RP Settles, M (reprint author), Tech Univ Munich, Klinikum Rechts Isar, Inst Radiol, D-8000 Munich, Germany. EM moritz.wildgruber@tum.de RI Meier, Reinhard/B-2882-2014; Etzrodt, Martin/P-3325-2015; OI Etzrodt, Martin/0000-0003-1928-3904; Meier, Reinhard/0000-0002-2169-4780 FU NHLBI NIH HHS [R01 HL095612] NR 42 TC 15 Z9 15 U1 0 U2 16 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 OCT 3 PY 2011 VL 6 IS 10 AR e25197 DI 10.1371/journal.pone.0025197 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 834EU UT WOS:000295943000015 PM 21984904 ER PT J AU Nery, FG Matsuo, K Nicoletti, MA Monkul, ES Zunta-Soares, GB Hatch, JP Lafer, B Soares, JC AF Nery, Fabiano G. Matsuo, Koji Nicoletti, Mark A. Monkul, E. Serap Zunta-Soares, Giovana B. Hatch, John P. Lafer, Beny Soares, Jair C. TI Association between prior alcohol use disorders and decreased prefrontal gray matter volumes in bipolar I disorder patients SO NEUROSCIENCE LETTERS LA English DT Article DE Bipolar disorder; Alcoholism; Comorbidity; Physiopathology; Cerebral cortex; Magnetic resonance imaging ID ORBITOFRONTAL CORTEX; BRAIN; ABNORMALITIES; COMORBIDITY; DEPENDENCE; COCAINE; MRI AB Up to 50% of bipolar disorder (BD) patients present a lifetime diagnosis of alcohol use disorders (AUD). BD patients with comorbid AUD, even when in remission from the AUD, have a poorer outcome and functional impairment than patients with BD alone. The neurobiological abnormalities that potentially characterize this severe subgroup of BD patients are unknown. Our goal was to investigate gray matter (GM) volume abnormalities in BD I patients with comorbid AUD. Twenty-one BD-AUD patients, 21 BD-nonAUD BD patients, and 25 healthy controls (HC), matched by age, gender, and handedness were studied. The BD-AUD patients were in remission from AUD on average for 6.8 years. 3D SPGR MRIs (TR = 25 ms, TE = 5 ms, slice thickness = 1.5 mm) were acquired from all subjects using a 1.5 T GE Signa Imaging System. We used an optimized voxel-based morphometry protocol to compare GM volumes among the groups. BD-AUD patients presented smaller GM volumes in the left medial frontal and the right anterior cingulate gyri compared to BD-nonAUD patients. BDnon-AUD patients did not present GM volume differences compared to HC. These findings provide evidence for an effect of comorbid AUD on regional brain structure of BD I patients and warrant further research on neurobiological aspects of this prevalent and severe comorbidity. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Nery, Fabiano G.; Monkul, E. Serap; Hatch, John P.; Lafer, Beny] Univ Sao Paulo, Sch Med, Bipolar Disorder Program PROMAN, Dept Psychiat, Sao Paulo, Brazil. [Nery, Fabiano G.; Matsuo, Koji; Monkul, E. Serap] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Nery, Fabiano G.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Matsuo, Koji] Yamaguchi Univ, Div Neuropsychiat, Dept Neurosci, Grad Sch Med, Yamaguchi, Japan. [Nicoletti, Mark A.; Zunta-Soares, Giovana B.; Soares, Jair C.] Univ Texas Med Sch, Dept Psychiat & Behav Sci, Houston, TX USA. [Hatch, John P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Orthodont, San Antonio, TX 78229 USA. RP Soares, JC (reprint author), UT Houston Med Sch, Dept Psychiat & Behav Sci, 1300 Moursund St, Houston, TX 77030 USA. EM jair.c.soares@uth.tmc.edu RI Lafer, Beny/C-1055-2012; Lafer, Beny/F-9390-2015 OI Lafer, Beny/0000-0002-6132-9999; Lafer, Beny/0000-0002-6132-9999 FU UTHSCSA GCRC [M01-RR-01346]; Krus Endowed Chair in Psychiatry (UTHSCSA); Veterans Administration (VA Merit Review); KAKENHI-C [21591519]; [MH 01736]; [MH 068662]; [RR 020571] FX This research was partly supported, by grants MH 01736, MH 068662, RR 020571, UTHSCSA GCRC (M01-RR-01346), the Krus Endowed Chair in Psychiatry (UTHSCSA), the Veterans Administration (VA Merit Review), KAKENHI-C 21591519 (to K. Matsuo) and a private donation from Thompson Mottais family (to PROMAN). E. Serap Monkul is an employee of Eli Lilly Brazil. The other authors do not have any commercial associations that might pose a conflict of interest in connection with this manuscript. NR 32 TC 10 Z9 10 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 3 PY 2011 VL 503 IS 2 BP 136 EP 140 DI 10.1016/j.neulet.2011.08.026 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 836NN UT WOS:000296118500012 PM 21884753 ER PT J AU Tamura, Y Chiba, Y Tanioka, T Shimizu, N Shinozaki, S Yamada, M Kaneki, K Mori, S Araki, A Ito, H Kaneki, M AF Tamura, Yoshiaki Chiba, Yuko Tanioka, Toshihiro Shimizu, Nobuyuki Shinozaki, Shohei Yamada, Marina Kaneki, Kentaro Mori, Seijiro Araki, Atsushi Ito, Hideki Kaneki, Masao TI NO donor induces Nec-1-inhibitable, but RIP1-independent, necrotic cell death in pancreatic beta-cells SO FEBS LETTERS LA English DT Article DE Pancreatic beta-cells; Cell death; NO donor; Necroptosis; Regulated necrosis; Necrostatin-1; RIP1 ID CYTOKINE-INDUCED APOPTOSIS; NITRIC-OXIDE; KINASE-B; NECROSIS; NECROSTATIN-1; INJURY; CONTRIBUTES; MICE; INFLAMMATION; NECROPTOSIS AB Nitric oxide (NO) has been implicated in pancreatic beta-cell death in the development of diabetes. The mechanisms underlying NO-induced beta-cell death have not been clearly defined. Recently, receptor-interacting protein-1 (RIP1)-dependent necrosis, which is inhibited by necrostatin-1, an inhibitor of RIP1, has emerged as a form of regulated necrosis. Here, we show that NO donor-induced beta-cell death was inhibited by necrostatin-1. Unexpectedly, however, RIP1 knockdown neither inhibited cell death nor altered the protective effects of necrostatin-1 in NO donor-treated beta-cells. These results indicate that NO donor induces necrostatin-1-inhibitable necrotic beta-cell death independent of RIP1. Our findings raise the possibility that NO-mediated beta-cell necrosis may be a novel form of signal-regulated necrosis, which play a role in the progression of diabetes. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Tamura, Yoshiaki; Chiba, Yuko; Tanioka, Toshihiro; Shimizu, Nobuyuki; Yamada, Marina; Kaneki, Kentaro; Kaneki, Masao] Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp,Shriners Hosp Children, Charlestown, MA 02129 USA. [Tamura, Yoshiaki; Chiba, Yuko; Mori, Seijiro; Araki, Atsushi; Ito, Hideki] Tokyo Metropolitan Geriatr Inst, Itabashi Ku, Tokyo 1730015, Japan. RP Kaneki, M (reprint author), Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp,Shriners Hosp Children, 149 13th St,Rm 6604, Charlestown, MA 02129 USA. EM mkaneki@helix.mgh.harvard.edu FU National Institutes of Health [R01 DK05827]; Microscopy and Image Analysis Core of Massachusetts General Hospital [P30NS045776]; American Diabetes Association [7-08-RA-77] FX We thank Drs. C. Newgard and B. Seed for providing INS-1/832 and RIP1-deficient Jurkat cells, respectively. We also thank Dr. C. Waeber for his superb technical assistance. This work was supported by research grants from the National Institutes of Health to M. K. (R01 DK05827) and to the Microscopy and Image Analysis Core of Massachusetts General Hospital (P30NS045776), and from American Diabetes Association to M. K. (7-08-RA-77). NR 39 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD OCT 3 PY 2011 VL 585 IS 19 BP 3058 EP 3064 DI 10.1016/j.febslet.2011.08.028 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 828AW UT WOS:000295473600021 PM 21888904 ER PT J AU Patti, JA AF Patti, John A. TI The Third Rail: Engineering Safe Travel for the Physician Community SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Patti, JA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 202, Boston, MA 02114 USA. EM jpatti@partners.org NR 0 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2011 VL 8 IS 10 BP 671 EP 672 DI 10.1016/j.jacr.2011.08.017 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KE UT WOS:000306202000001 PM 21962776 ER PT J AU Earls, JP White, RD Woodard, PK Abbara, S Atalay, MK Carr, JJ Haramati, LB Hendel, RC Ho, VB Hoffman, U Khan, AR Mammen, L Martin, ET Rozenshtein, A Ryan, T Schoepf, J Steiner, RM White, CS AF Earls, James P. White, Richard D. Woodard, Pamela K. Abbara, Suhny Atalay, Michael K. Carr, J. Jeffrey Haramati, Linda B. Hendel, Robert C. Ho, Vincent B. Hoffman, Udo Khan, Arfa R. Mammen, Leena Martin, Edward T., III Rozenshtein, Anna Ryan, Thomas Schoepf, Joseph Steiner, Robert M. White, Charles S. TI ACR Appropriateness Criteria (R) Chronic Chest Pain-High Probability of Coronary Artery Disease SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Appropriateness Criteria; myocardial ischemia; coronary artery disease; cardiac magnetic resonance imaging; multidetector cardiac CT; radionuclide single photon-emission CT ID POSITRON-EMISSION-TOMOGRAPHY; ULTRAFAST COMPUTED-TOMOGRAPHY; TC-99M SESTAMIBI SPECT; CARDIOVASCULAR MAGNETIC-RESONANCE; VENTRICULAR EJECTION FRACTION; WALL-MOTION ABNORMALITIES; ELECTRON-BEAM CT; MYOCARDIAL-PERFUSION; DIAGNOSTIC-ACCURACY; STRESS ECHOCARDIOGRAPHY AB Imaging is valuable in determining the presence, extent, and severity of myocardial ischemia and the severity of obstructive coronary lesions in patients with chronic chest pain in the setting of high probability of coronary artery disease. Imaging is critical for defining patients best suited for medical therapy or intervention, and findings can be used to predict long-term prognosis and the likely benefit from various therapeutic options. Chest radiography, radionuclide single photon-emission CT, radionuclide ventriculography, and conventional coronary angiography are the imaging modalities historically used in evaluating suspected chronic myocardial ischemia. Stress echocardiography, PET, cardiac MRI, and multidetector cardiac CT have all been more recently shown to be valuable in the evaluation of ischemic heart disease. Other imaging techniques may be helpful in those patients who do not present with signs classic for angina pectoris or in those patients who do not respond as expected to standard management. The ACR Appropriateness Criteria (R) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Earls, James P.] Fairfax Radiol Consultants, Fairfax, VA USA. [White, Richard D.] Univ Florida, Coll Med Jacksonville, Jacksonville, FL USA. [Woodard, Pamela K.] Washington Univ, Sch Med, Edward Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Abbara, Suhny; Hoffman, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Atalay, Michael K.] Brown Univ, Warren Alpert Sch Med, Providence, RI 02912 USA. [Carr, J. Jeffrey] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Haramati, Linda B.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hendel, Robert C.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Hendel, Robert C.; Martin, Edward T., III; Ryan, Thomas] Amer Coll Cardiol, Bethesda, MD USA. [Ho, Vincent B.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Khan, Arfa R.] Long Isl Jewish Med Ctr, New Hyde Pk, NY 11042 USA. [Mammen, Leena] Adv Radiol Serv, Grand Rapids, MI USA. [Martin, Edward T., III] Oklahoma Heart Inst, Tulsa, OK USA. [Rozenshtein, Anna] Columbia Presbyterian Med Ctr, New York, NY 10032 USA. [Ryan, Thomas] Ohio State Univ, Heart & Vasc Ctr, Columbus, OH 43210 USA. [Schoepf, Joseph] Med Univ S Carolina, Charleston, SC 29425 USA. [Steiner, Robert M.] Temple Univ Hlth Syst, Philadelphia, PA USA. [White, Charles S.] Univ Maryland Hosp, Baltimore, MD 21201 USA. RP Earls, JP (reprint author), Amer Coll Radiol, Dept Qual & Safety, 1891 Preston White Dr, Reston, VA 20191 USA. EM jpearls@yahoo.com RI Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; White, Richard D./0000-0002-1133-7819 NR 71 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2011 VL 8 IS 10 BP 679 EP 686 DI 10.1016/j.jacr.2011.06.022 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KE UT WOS:000306202000006 PM 21962781 ER PT J AU Thrall, JH AF Thrall, James H. TI Unintended Consequences of Health Care Legislation SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Health care; legislation; Stark laws; Medicare; Medicaid; SGR AB Unintended consequences of health care legislation threaten the financial and social well-being of the United States. Examples of major legislation resulting in unintended and unforeseen consequences include the Social Security Amendments Acts of 1989 and 1993 (the Stark laws), the Balanced Budget Act of 1997, and the Social Security Amendments Act of 1965 (Medicare and Medicaid). Each of these has had unintended financial and social outcomes. Spending for Medicare and Medicaid now equals an unsustainable 23% of the federal budget. Major reasons for unintended consequences include failure to appreciate the complexity of the issues, the open-ended nature of medical advances with attendant increases in costs, the inducement of change in behaviors in response to legislation, and the moral hazard of people spending other people's money. Actions that should be considered to avoid unintended consequences include more involvement of health professionals in the design of legislation, the inclusion of triggers to target review of legislatively defined programs, and the setting of time limits for sun-setting legislation. The ACR has played an important advocacy role and should continue to offer input to legislators, federal policymakers, and other stakeholders. Many opportunities exist to address the current financial situation by reducing the amount of unnecessary care delivered. Both major US political parties need to find the political will to compromise to chart the way forward. Some level of sacrifice is likely to be necessary from patients and providers and other stakeholders. C1 [Thrall, James H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Thrall, James H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Thrall, JH (reprint author), Massachusetts Gen Hosp, Radiol FND 216,55 Fruit St, Boston, MA 02114 USA. EM jthrall@partners.org NR 15 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2011 VL 8 IS 10 BP 687 EP 691 DI 10.1016/j.jacr.2011.06.013 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KE UT WOS:000306202000007 PM 21962782 ER PT J AU Kalra, MK Singh, S Thrall, JH Mahesh, M AF Kalra, Mannudeep K. Singh, Sarabjeet Thrall, James H. Mahesh, Mahadevappa TI Pointers for Optimizing Radiation Dose in Abdominal CT Protocols SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material ID TUBE CURRENT MODULATION C1 [Mahesh, Mahadevappa] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Kalra, Mannudeep K.; Singh, Sarabjeet; Thrall, James H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Massachusetts Gen Hosp Imaging, Boston, MA USA. RP Mahesh, M (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, 601 N Caroline St, Baltimore, MD 21287 USA. EM mmahesh@jhmi.edu NR 8 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2011 VL 8 IS 10 BP 731 EP 734 DI 10.1016/j.jacr.2011.06.026 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KE UT WOS:000306202000016 PM 21962791 ER PT J AU Krishnaraj, A Hawkins, CM AF Krishnaraj, Arun Hawkins, C. Matthew TI Improving Membership Retention Rates Among New Graduates SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 [Krishnaraj, Arun] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Hawkins, C. Matthew] Univ Cincinnati, Coll Med, Dept Radiol, Cincinnati, OH 45221 USA. RP Krishnaraj, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Abdominal Imaging & Intervent, 55 Fruit St, Boston, MA 02114 USA. EM akrishnaraj@partners.org NR 2 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD OCT PY 2011 VL 8 IS 10 BP 735 EP 736 DI 10.1016/j.jacr.2011.05.013 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 971KE UT WOS:000306202000017 PM 21962792 ER PT J AU Middeldorp, CM de Moor, MHM McGrath, LM Gordon, SD Blackwood, DH Costa, PT Terracciano, A Krueger, RF de Geus, EJC Nyholt, DR Tanaka, T Esko, T Madden, PAF Derringer, J Amin, N Willemsen, G Hottenga, JJ Distel, MA Uda, M Sanna, S Spinhoven, P Hartman, CA Ripke, S Sullivan, PF Realo, A Allik, J Heath, AC Pergadia, ML Agrawal, A Lin, P Grucza, RA Widen, E Cousminer, DL Eriksson, JG Palotie, A Barnett, JH Lee, PH Luciano, M Tenesa, A Davies, G Lopez, LM Hansell, NK Medland, SE Ferrucci, L Schlessinger, D Montgomery, GW Wright, MJ Aulchenko, YS Janssens, ACJW Oostra, BA Metspalu, A Abecasis, GR Deary, IJ Raikkonen, K Bierut, LJ Martin, NG Wray, NR van Duijn, CM Smoller, JW Penninx, BWJH Boomsma, DI AF Middeldorp, C. M. de Moor, M. H. M. McGrath, L. M. Gordon, S. D. Blackwood, D. H. Costa, P. T. Terracciano, A. Krueger, R. F. de Geus, E. J. C. Nyholt, D. R. Tanaka, T. Esko, T. Madden, P. A. F. Derringer, J. Amin, N. Willemsen, G. Hottenga, J-J Distel, M. A. Uda, M. Sanna, S. Spinhoven, P. Hartman, C. A. Ripke, S. Sullivan, P. F. Realo, A. Allik, J. Heath, A. C. Pergadia, M. L. Agrawal, A. Lin, P. Grucza, R. A. Widen, E. Cousminer, D. L. Eriksson, J. G. Palotie, A. Barnett, J. H. Lee, P. H. Luciano, M. Tenesa, A. Davies, G. Lopez, L. M. Hansell, N. K. Medland, S. E. Ferrucci, L. Schlessinger, D. Montgomery, G. W. Wright, M. J. Aulchenko, Y. S. Janssens, A. C. J. W. Oostra, B. A. Metspalu, A. Abecasis, G. R. Deary, I. J. Raikkonen, K. Bierut, L. J. Martin, N. G. Wray, N. R. van Duijn, C. M. Smoller, J. W. Penninx, B. W. J. H. Boomsma, D. I. TI The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE bipolar disorder; genetic correlation; genome-wide association; polygenic score analysis; personality-major depression ID GENOTYPE IMPUTATION; ANXIETY DISORDERS; 5-FACTOR MODEL; TWIN; POPULATION; HERITABILITY; METAANALYSIS; SAMPLE; SCHIZOPHRENIA; EPIDEMIOLOGY AB The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13 835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N = 8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N = 6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, similar to 0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other. Translational Psychiatry (2011) 1, e50; doi:10.1038/tp.2011.45; published online 18 October 2011 C1 [Middeldorp, C. M.; de Moor, M. H. M.; de Geus, E. J. C.; Willemsen, G.; Hottenga, J-J; Distel, M. A.; Boomsma, D. I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Middeldorp, C. M.; de Moor, M. H. M.; de Geus, E. J. C.; Penninx, B. W. J. H.; Boomsma, D. I.] Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Middeldorp, C. M.] Univ Amsterdam, Acad Med Ctr, Dept Child & Adolescent Psychiat, NL-1105 AZ Amsterdam, Netherlands. [Middeldorp, C. M.] GGZ inGeest VU Med Ctr, Dept Child & Adolescent Psychiat, Amsterdam, Netherlands. [McGrath, L. M.; Ripke, S.; Barnett, J. H.; Lee, P. H.; Smoller, J. W.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Human Genet Res, Boston, MA 02114 USA. [McGrath, L. M.; Ripke, S.; Barnett, J. H.; Lee, P. H.; Smoller, J. W.] Massachusetts Gen Hosp, Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Gordon, S. D.; Nyholt, D. R.; Hansell, N. K.; Medland, S. E.; Montgomery, G. W.; Wright, M. J.; Martin, N. G.; Wray, N. R.] Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4006, Australia. [Blackwood, D. H.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Costa, P. T.; Terracciano, A.; Tanaka, T.; Ferrucci, L.; Schlessinger, D.] NIA, NIH, Baltimore, MD 21224 USA. [Krueger, R. F.; Derringer, J.] Univ Minnesota, Dept Psychol, Baltimore, MD USA. [Esko, T.; Metspalu, A.] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Esko, T.; Metspalu, A.] Estonian Bioctr, Tartu, Estonia. [Esko, T.; Metspalu, A.] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Madden, P. A. F.; Heath, A. C.; Pergadia, M. L.; Agrawal, A.; Lin, P.; Grucza, R. A.; Bierut, L. J.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Amin, N.; Aulchenko, Y. S.; Janssens, A. C. J. W.; van Duijn, C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Distel, M. A.; Penninx, B. W. J. H.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Uda, M.; Sanna, S.] Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Spinhoven, P.; Penninx, B. W. J. H.] Leiden Univ, Dept Clin Psychol, Leiden, Netherlands. [Spinhoven, P.; Penninx, B. W. J. H.] Leiden Univ, Dept Psychiat, Leiden, Netherlands. [Hartman, C. A.; Penninx, B. W. J. H.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 AV Groningen, Netherlands. [Ripke, S.; Palotie, A.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Realo, A.; Allik, J.] Univ Tartu, Dept Psychol, EE-50090 Tartu, Estonia. [Widen, E.; Cousminer, D. L.; Palotie, A.] Univ Helsinki, FIMM, Helsinki, Finland. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, J. G.] Vasa Cent Hosp, Vaasa, Finland. [Eriksson, J. G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, J. G.] Folkhalsan Res Ctr, Helsinki, Finland. [Palotie, A.] Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, A.] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, A.] Univ Cent Hosp, Helsinki, Finland. [Barnett, J. H.] Univ Cambridge, Dept Psychiat, Cambridge, England. [Luciano, M.; Davies, G.; Lopez, L. M.; Deary, I. J.] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Tenesa, A.] Western Gen Hosp, MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Oostra, B. A.] Erasmus Univ, Dept Clin Genet, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Abecasis, G. R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Raikkonen, K.] Univ Helsinki, Dept Psychol, SF-00100 Helsinki, Finland. [Penninx, B. W. J. H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. RP Middeldorp, CM (reprint author), Vrije Univ Amsterdam, Dept Biol Psychol, Van der Boechorststr 1, NL-1081 BT Amsterdam, Netherlands. EM cm.middeldorp@psy.vu.nl RI Lopez, Lorna/F-7265-2010; Montgomery, Grant/B-7148-2008; Hansell, Narelle/A-4553-2016; Deary, Ian/C-6297-2009; Nyholt, Dale/C-8384-2013; terracciano, antonio/B-1884-2008; Aulchenko, Yurii/M-8270-2013; Lin, P/G-7702-2014; Medland, Sarah/C-7630-2013; Wray, Naomi/C-8639-2015; Allik, Juri/D-5609-2009; de Geus, Eco/M-9318-2015; Wright, Margaret/A-4560-2016; Realo, Anu/M-9524-2016; Luciano, Michelle/F-7277-2010; OI Montgomery, Grant/0000-0002-4140-8139; Hansell, Narelle/0000-0002-8229-9741; Aulchenko, Yurii/0000-0002-7899-1575; Medland, Sarah/0000-0003-1382-380X; Wray, Naomi/0000-0001-7421-3357; Allik, Juri/0000-0002-8358-4747; de Geus, Eco/0000-0001-6022-2666; Wright, Margaret/0000-0001-7133-4970; Luciano, Michelle/0000-0003-0935-7682; Eriksson, Johan/0000-0002-2516-2060; Middeldorp, Christel/0000-0002-6218-0428; Raikkonen, Katri/0000-0003-3124-3470 FU Wellcome Trust [076113, 89061/Z/09/Z, 089062/Z/09/Z]; Netherlands Scientific Organization Centre for Medical Systems Biology (NWO Genomics) [904-61-090, 904-61-193, 480-04-004, 400-05-717, 912-100-20]; Neuroscience Campus Amsterdam (NCA); EMGO+ Institute; European Union [EU/WLRT-2001-01254]; ZonMW [10-000-1002]; NIMH [RO1 MH059160, R01 MH-079799]; NESDA; NTR; NWO-SPI [56-464-1419]; Netherlands Organization for Scientific Research (NWO) (ZonMW) [31160008, VENI-016-115-035, 916-76-125]; Australian National Health and Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613608]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health (NIH) [AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951]; National Health and Medical Research Council (NHMRC); Australian Research Council; Netherlands Organization for Scientific Research (NWO) [480-05-003]; Erasmus MC; Netherlands Genomics Initiative (NGI); NIH Genes, Environment and Health Initiative (GEI) [U01 HG004422]; Gene Environment Association Studies (GENEVA) under GEI; NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; NIH [AA13320, AA13321, DA12854, HHSN268200782096C, AA07728, AA07580, AA11998]; NIH from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U10AA008401]; National Institute on Drug Abuse (NIDA); NIH from the National Cancer Institute [P01CA89392]; NIH, National Institute on Aging [NO1-AG-1-2109]; Academy of Finland [120315, 129287, 1129457, 1216965, 120386, 125876]; European Science Foundation (EuroSTRESS); Signe and Ane Gyllenberg foundation; Research Into Ageing; Help the Aged/Age Concern (The Disconnected Mind); Biotechnology and Biological Sciences Research Council (BBSRC); Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); Medical Research Council (MRC); cross-council Lifelong Health and Wellbeing Initiative; eDIKT initiative; ECOGENE [205419]; Estonian Government [SF0180142s08]; EU; Estonian Ministry of Science and Education [SF0180029s08]; Parke-Davis Exchange Fellowship; [201413 ENGAGE]; [212111 BBMRI] FX This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the WTCCC data is available from http://www.wtccc.org.uk. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. NESDA/NTR: Funding support was provided by the Netherlands Scientific Organization (904-61-090, 904-61-193, 480-04-004, 400-05-717, 912-100-20) Centre for Medical Systems Biology (NWO Genomics), the Neuroscience Campus Amsterdam (NCA) and the EMGO+ Institute; the European Union (EU/WLRT-2001-01254), ZonMW (Geestkracht program, 10-000-1002), NIMH (RO1 MH059160) and matching funds from participating institutes in NESDA and NTR. The NTR controls in MDD2000+ were genotyped in the Genomics platform (certified service provider (CSPro(R)) for Illumina) at the LIFE and BRAIN Center, Bonn (funded by NWO-SPI 56-464-1419). Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the NWO (480-05-003). MHM de Moor and CM Middeldorp are financially supported by the Netherlands Organization for Scientific Research (NWO) (ZonMW Addiction program, grant 31160008, VENI-016-115-035 and VENI grant 916-76-125). MDD2000+/QIMR: Funding was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675,496739, 552485, 552498, 613608), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), and the US National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951). A portion of the genotyping on which this study was based (Illumina 370K scans on 4300 individuals) was carried out at the Center for Inherited Disease Research, Baltimore (CIDR), through an access award to our late colleague Dr Richard Todd (Psychiatry, Washington University School of Medicine, St Louis). GW Montgomery is supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme. NRWray and DR Nyholt are supported by the Australian Research Council Future Fellowship Scheme. The ERF study was supported by grants from The Netherlands Organization for Scientific Research (NWO), Erasmus MC and the Netherlands Genomics Initiative (NGI)-sponsored Center of Medical Systems Biology (CMSB). Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423, R01 DA019963).; Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). The Collaborative Study on the Genetics of Alcoholism (COGA) Principal Investigators: B Porjesz, V Hesselbrock, H Edenberg, L Bierut, includes 10 different centers: University of Connecticut (V Hesselbrock); Indiana University (HJ Edenberg, J Nurnberger Jr., T Foroud); University of Iowa (S Kuperman, J Kramer); SUNY Downstate (B Porjesz); Washington University in St Louis (L Bierut, A Goate, J Rice, K Bucholz); University of California at San Diego (M Schuckit); Rutgers University (J Tischfield); Southwest Foundation (L Almasy), Howard University (R Taylor) and Virginia Commonwealth University (D Dick). A Parsian and M Reilly are the NIAAA Staff Collaborators. We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, currently a consultant with COGA, P Michael Conneally, Raymond Crowe and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). The Collaborative Genetic Study of Nicotine Dependence (COGEND) project is a collaborative research group and part of the NIDA Genetics Consortium. Lead investigators directing data collection are Laura Bierut, Naomi Breslau, Dorothy Hatsukami and Eric Johnson. We thank Heidi Kromrei and Tracey Richmond for their assistance in data collection. In memory of Theodore Reich, founding Principal Investigator of COGEND, we are indebted to his leadership in the establishment and nurturing of COGEND and acknowledge with great admiration his seminal scientific contributions to the field. COGEND is supported by the NIH grant P01CA89392 from the National Cancer Institute. SardiNIA: We acknowledge support from the Intramural Research Program of the NIH, National Institute on Aging. Funding was provided by the National Institute on Aging, NIH contract NO1-AG-1-2109 to the SardiNIA ('ProgeNIA') team. HBCS: We acknowledge financial support from the Academy of Finland (grant no. 120315 and 129287 to EW, 1129457 and 1216965 to KR, 120386 and 125876 to JGE), the European Science Foundation (EuroSTRESS), the Wellcome Trust (grant no. 89061/Z/09/Z and 089062/Z/09/Z) and the Signe and Ane Gyllenberg foundation. NAG/IRPG: This study is supported by NIH grants DA12854 (to PAFM), AA07728, AA07580, AA11998, AA13320 and AA13321 (to ACH); and grants from the Australian National Health and Medical Research Council; MLP is supported by DA019951. LBC36: We thank David Liewald and Paul Redmond for technical assistance; the study Secretary Paula Davies; Alan Gow, Michelle Taylor, Janie Corley, Caroline Brett and Caroline Cameron for data collection and data entry; nurses and staff at the Wellcome Trust Clinical Research Facility, where subjects were tested and at the genotyping was performed; staff at the Lothian Health Board and staff at the SCRE Centre, University of Glasgow. The research was supported by a program grant from Research Into Ageing.; The research continues with program grants from Help the Aged/Age Concern (The Disconnected Mind). GWAS funding awarded by the Biotechnology and Biological Sciences Research Council (BBSRC) to IJD and AT. ML is a Royal Society of Edinburgh/Lloyds TSB Foundation for Scotland Personal Research Fellow. The study was conducted within the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, supported by the (BBSRC), Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and Medical Research Council (MRC), as part of the cross-council Lifelong Health and Wellbeing Initiative. This work has made use of the resources provided by the Edinburgh Compute and Data Facility (ECDF) (http://www.ecdf.ed.ac.uk/). The ECDF is partially supported by the eDIKT initiative (http://www.edikt.org.uk). BLSA: We acknowledge support from the Intramural Research Program of the NIH, National Institute on Aging. We thank Robert McCrae. EGPUT: AM and TE received support from FP7 grants (201413 ENGAGE, 212111 BBMRI, ECOGENE (no. 205419, EBC)). AM and TE also received targeted financing from Estonian Government SF0180142s08 and by EU through the European Regional Development Fund, in the frame of Centre of Excellence in Genomics. The genotyping of the Estonian Genome Project samples was performed in Estonian Biocentre Genotyping Core Facility, AM and TE thank Mari Nelis and Viljo Soo for their contributions. A Realo and J Allik are supported by a grant from the Estonian Ministry of Science and Education (SF0180029s08). STEP-BD: JH Barnett was funded by the Parke-Davis Exchange Fellowship. JW Smoller and LM McGrath were supported in part by NIMH grant R01 MH-079799 (Dr Smoller, PI). NR 62 TC 26 Z9 27 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT PY 2011 VL 1 AR e50 DI 10.1038/tp.2011.45 PG 8 WC Psychiatry SC Psychiatry GA 971PM UT WOS:000306216300007 PM 22833196 ER PT J AU Terracciano, A Esko, T Sutin, AR de Moor, MHM Meirelles, O Zhu, G Tanaka, T Giegling, I Nutile, T Realo, A Allik, J Hansell, NK Wright, MJ Montgomery, GW Willemsen, G Hottenga, JJ Friedl, M Ruggiero, D Sorice, R Sanna, S Cannas, A Raikkonen, K Widen, E Palotie, A Eriksson, JG Cucca, F Krueger, RF Lahti, J Luciano, M Smoller, JW van Duijn, CM Abecasis, GR Boomsma, DI Ciullo, M Costa, PT Ferrucci, L Martin, NG Metspalu, A Rujescu, D Schlessinger, D Uda, M AF Terracciano, A. Esko, T. Sutin, A. R. de Moor, M. H. M. Meirelles, O. Zhu, G. Tanaka, T. Giegling, I. Nutile, T. Realo, A. Allik, J. Hansell, N. K. Wright, M. J. Montgomery, G. W. Willemsen, G. Hottenga, J-J Friedl, M. Ruggiero, D. Sorice, R. Sanna, S. Cannas, A. Raikkonen, K. Widen, E. Palotie, A. Eriksson, J. G. Cucca, F. Krueger, R. F. Lahti, J. Luciano, M. Smoller, J. W. van Duijn, C. M. Abecasis, G. R. Boomsma, D. I. Ciullo, M. Costa, P. T., Jr. Ferrucci, L. Martin, N. G. Metspalu, A. Rujescu, D. Schlessinger, D. Uda, M. TI Meta-analysis of genome-wide association studies identifies common variants in CTNNA2 associated with excitement-seeking SO TRANSLATIONAL PSYCHIATRY LA English DT Article DE catenin cadherin-associated protein alpha 2 (CTNNA2); excitement-seeking; genome-wide association (GWA); impulsivity; sensation-seeking ID ALPHA-N-CATENIN; NETHERLANDS TWIN REGISTER; SENSATION SEEKING; PERSONALITY-TRAITS; BIPOLAR DISORDER; 5-FACTOR MODEL; IMPULSIVITY; RISK; GENE; SCHIZOPHRENIA AB The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N = 7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P = 2 x 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed a-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N = 5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders. Translational Psychiatry (2011) 1, e49; doi:10.1038/tp.2011.42; published online 18 October 2011 C1 [Terracciano, A.; Sutin, A. R.; Meirelles, O.; Costa, P. T., Jr.; Ferrucci, L.; Schlessinger, D.] NIA, NIH, US Dept HHS, Baltimore, MD 21224 USA. [Esko, T.; Realo, A.; Allik, J.; Metspalu, A.] Univ Tartu, EE-50090 Tartu, Estonia. [Esko, T.; Metspalu, A.] Estonian Bioctr, Tartu, Estonia. [de Moor, M. H. M.; Willemsen, G.; Hottenga, J-J; Boomsma, D. I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Zhu, G.; Hansell, N. K.; Wright, M. J.; Montgomery, G. W.; Martin, N. G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Giegling, I.; Friedl, M.; Rujescu, D.] Univ Munich, Dept Psychiat, D-8000 Munich, Germany. [Nutile, T.; Ruggiero, D.; Sorice, R.; Ciullo, M.] CNR, Inst Genet & Biophys A Buzzati Traverso, I-80125 Naples, Italy. [Sanna, S.; Cannas, A.; Cucca, F.; Uda, M.] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Raikkonen, K.; Lahti, J.] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Widen, E.; Palotie, A.] Univ Helsinki, FIMM, Helsinki, Finland. [Palotie, A.] Wellcome Trust Sanger Inst, Cambridge, England. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Krueger, R. F.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Luciano, M.] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland. [Smoller, J. W.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Human Genet Res, Boston, MA 02114 USA. [Smoller, J. W.] Massachusetts Gen Hosp, Neurodev Genet Unit, Boston, MA 02114 USA. [van Duijn, C. M.] ErasmusMC, Dept Epidemiol, Rotterdam, Netherlands. [Abecasis, G. R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Terracciano, A (reprint author), NIA, NIH, US Dept HHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM Terraccianoa@mail.nih.gov RI terracciano, antonio/B-1884-2008; Allik, Juri/D-5609-2009; Montgomery, Grant/B-7148-2008; Hansell, Narelle/A-4553-2016; Wright, Margaret/A-4560-2016; ruggiero, daniela/K-5638-2016; Realo, Anu/M-9524-2016; Luciano, Michelle/F-7277-2010; OI Allik, Juri/0000-0002-8358-4747; Montgomery, Grant/0000-0002-4140-8139; Hansell, Narelle/0000-0002-8229-9741; Wright, Margaret/0000-0001-7133-4970; ruggiero, daniela/0000-0003-3898-7827; Luciano, Michelle/0000-0003-0935-7682; sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Costa, Paul/0000-0003-4375-1712; NUTILE, TERESA/0000-0001-7062-8352; Lahti, Jari/0000-0002-4310-5297; Martin, Nicholas/0000-0003-4069-8020 FU NIH, National Institute on Aging; Estonian Ministry of Science and Education [SF0180029s08]; European Social Fund [3-8.2/60]; Estonian Government [SF0180142s08]; European Union; Beyond Blue; Borderline Personality Disorder Research Foundation; National Health and Medical Research Council [389891]; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; [201413]; [212111]; [245536] FX We thank study subjects for their participation as well as everybody involved in each of the participating studies. EGCUT authors want to acknowledge EGCUT personnel, especially Merli Hass, Viljo Soo and Mari Nelis. EGCUT data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. Cilento authors acknowledge Dr Maria Enza Amendola for the test administration and thank the personnel working in the organization of the study in the villages. QIMR thanks study participants and acknowledges Nathan Gillespie for discussion on study design related to NEO collection; Marisa Grimmer, Romana Leisser and Kim Eldridge for overseeing data collection; Anjali Henders, Megan Campbell, Lisa Bowdler, Steven Crooks and staff of the Molecular Epidemiology Laboratory for sample processing and preparation; and Harry Beeby, David Smyth and Daniel Park for IT support. We acknowledge Drs Dale R Nyholt and Scott Gordon for their substantial efforts involving the QC and preparation of the GWA data sets and Dr Sarah Medland for undertaking the imputation of the GWAS data and subsequent preparation for analyses. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Anu Realo and Juri Allik were supported by a grant from the Estonian Ministry of Science and Education (SF0180029s08) and by a Primus Grant (3-8.2/60) from the European Social Fund. TE and AM received support from FP7 Grants (201413, 212111, 245536). TE and AM also received targeted financing from Estonian Government SF0180142s08 and from the European Union through the European Regional Development Fund, in the frame of Centre of Excellence in Genomics. QIMR received support from Beyond Blue and the Borderline Personality Disorder Research Foundation. Genotyping was funded by the National Health and Medical Research Council (Medical Bioinformatics Genomics Proteomics Program, 389891). Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation and Emil Aaltonen Foundation. NR 72 TC 20 Z9 20 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD OCT PY 2011 VL 1 AR e49 DI 10.1038/tp.2011.42 PG 8 WC Psychiatry SC Psychiatry GA 971PM UT WOS:000306216300006 PM 22833195 ER PT J AU Leong, JVB Boro, MS Winter, ME AF Leong, Julie V. B. Boro, Maureen S. Winter, Michael E. TI Vancomycin clearance in overweight and obese patients SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Letter ID PHARMACOKINETICS C1 [Leong, Julie V. B.; Boro, Maureen S.] San Francisco VA Med Ctr, Pharm Informat & Pharmacokinet Program, San Francisco, CA 94121 USA. [Winter, Michael E.] Univ Calif San Francisco, Sch Pharm, San Francisco, CA 94143 USA. RP Leong, JVB (reprint author), San Francisco VA Med Ctr, Pharm Informat & Pharmacokinet Program, 4150 Clement St, San Francisco, CA 94121 USA. EM maureen.boro@va.gov NR 4 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD OCT 1 PY 2011 VL 68 IS 19 BP 1777 EP 1778 DI 10.2146/ajhp110286 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 941FG UT WOS:000303948500011 ER PT J AU Fagenholz, PJ de Moya, MA AF Fagenholz, Peter J. de Moya, Marc A. TI Laparoscopic Treatment of Bowel Obstruction Due to a Bezoar in a Meckel's Diverticulum SO JSLS-JOURNAL OF THE SOCIETY OF LAPAROENDOSCOPIC SURGEONS LA English DT Article DE Laparoscopy; Bowel obstruction; Meckel's diverticulum; Bezoar ID INTESTINAL-OBSTRUCTION; PHYTOBEZOAR AB Background and Objectives: Meckel's diverticulum is a common anomaly of the gastrointestinal tract that may result in gastrointestinal bleeding, diverticulitis, and small bowel obstruction. This report describes the use of laparoscopy to treat a rare complication of Meckel's diverticulum-small bowel obstruction due to phytobezoar impaction. More generally, it provides an example of the feasibility and utility of a laparoscopic approach to small bowel obstructions of unknown causes. Methods: A 34-year-old male presented to the emergency department complaining of episodic abdominal pain and vomiting. He had no history of abdominal surgery. His vital signs were stable, and his abdomen was distended, but only mildly tender. He had no abdominal wall hernias on examination. Imaging was consistent with small bowel obstruction. He was brought to the operating room where laparoscopy revealed a Meckel's diverticulum with an impacted phytobezoar as the source of obstruction. The diverticulum was resected and the phytobezoar removed laparoscopically. Results: The patient recovered well and was discharged home on the third postoperative day, tolerating a regular diet. Conclusions: Phytobezoar impaction in a Meckel's diverticulum causing small bowel obstruction is a rare event. It can be effectively treated laparoscopically. This case provides an example of the potential utility of laparoscopy in treating small bowel obstructions of unclear etiology. C1 [Fagenholz, Peter J.; de Moya, Marc A.] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Fagenholz, PJ (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. EM pfagenholz@partners.org NR 11 TC 4 Z9 4 U1 0 U2 1 PU SOC LAPAROENDOSCOPIC SURGEONS PI MIAMI PA 7330 SW 62 PL, STE 410, MIAMI, FL 33143-4825 USA SN 1086-8089 J9 JSLS-J SOC LAPAROEND JI JSLS-J. Soc. Laparoendosc. Surg. PD OCT-DEC PY 2011 VL 15 IS 4 BP 562 EP 564 DI 10.4293/108680811X13176785204607 PG 3 WC Surgery SC Surgery GA 936RC UT WOS:000303606700024 PM 22643518 ER PT J AU Clair, C Bitton, A Meigs, JB Rigotti, NA AF Clair, Carole Bitton, Asaf Meigs, James B. Rigotti, Nancy A. TI Relationships of Cotinine and Self-Reported Cigarette Smoking With Hemoglobin A(1c) in the US SO DIABETES CARE LA English DT Article ID BODY-MASS INDEX; GLUCOSE-TOLERANCE; DIABETES-MELLITUS; SERUM COTININE; ADIPOSE-TISSUE; EPIC-NORFOLK; POPULATION; EXPOSURE; SMOKERS; MEN AB OBJECTIVE-Whether nicotine leads to a persistent increase in blood glucose levels is not clear. Our objective was to assess the relationship between cotinine, a nicotine metabolite, and glycated hemoglobin (HbA(1c)), an index of recent glycemia. RESEARCH DESIGN AND METHODS-We used cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2008. We limited our analysis to 17,287 adults without diabetes. We created three cotinine categories: <0.05 ng/mL, 0.05-2.99 ng/mL, and >= 3 ng/mL. RESULTS-Using self-report, 25% of the sample were current smokers, 24% were former smokers, and 51% were nonsmokers. Smokers had a higher mean HbA 1, (5.36% +/- 0.01 SE) compared with never smokers (5.31% +/- 0.01) and former smokers (5.31% +/- 0.01). In a similar manner, mean HbA(1c), was higher among participants with cotinine ng/mL (5.35% +/- 0.01) and participants with cotinine 0.05-2.99 ng/mL (5.34% +/- 0.01) compared with participants with cotinine <0.05 ng/mL (5.29% +/- 0.01). In multivariable-adjusted analysis, we found that both a cotinine ng/mL and self-reported smoking were associated with higher EbA(1c), compared with a cotinine <0.05 ng/mL or not smoking. People with a cotinine level ng/mL had a relative 5% increase in HbAi, compared with people with a cotinine level <0.05 ng/mL, and smokers had a relative 7% increase in HbA(1c) compared with never smokers. CONCLUSIONS-Our study suggests that cotinine is associated with increased HbAi, in a representative sample of the U.S. population without diabetes. C1 [Clair, Carole; Rigotti, Nancy A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tobacco Res & Treatment Ctr,Div Gen Med, Boston, MA 02115 USA. [Bitton, Asaf] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gen Med, Boston, MA 02115 USA. RP Clair, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tobacco Res & Treatment Ctr,Div Gen Med, Boston, MA 02115 USA. EM carole.willi@gmail.com RI Clair, Carole/D-9786-2014 OI Clair, Carole/0000-0001-5281-0943 FU Swiss National Science Foundation [PBLAP3-127728/1]; SICPA Foundation; National Institute of Diabetes and Digestive and Kidney Diseases [K24-DK-080140]; National Heart, Lung, and Blood Institute [K24-HL-04440] FX C.C. has received grants from the Swiss National Science Foundation (PBLAP3-127728/1) and the SICPA Foundation. J.B.M. has received a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (K24-DK-080140). N.A.R. has received a grant from the National Heart, Lung, and Blood Institute (K24-HL-04440). NR 24 TC 20 Z9 20 U1 0 U2 6 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 OCT PY 2011 VL 34 IS 10 BP 2250 EP 2255 DI 10.2337/dc11-0710 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 910AG UT WOS:000301609000022 PM 21836101 ER PT J AU Ioannou, GN Boyko, EJ AF Ioannou, George N. Boyko, Edward J. TI Metformin and Colorectal Cancer Risk in Diabetic Patients SO DIABETES CARE LA English DT Editorial Material ID BREAST-CANCER; EUROPEAN ASSOCIATION; CONSENSUS ALGORITHM; MEDICAL-MANAGEMENT; METABOLIC SYNDROME; TYPE-2; THERAPY; HYPERGLYCEMIA; METAANALYSIS; ADJUSTMENT C1 [Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Div Gastroenterol, Dept Med, Seattle, WA USA. [Ioannou, George N.; Boyko, Edward J.] Univ Washington, Seattle, WA 98195 USA. [Ioannou, George N.; Boyko, Edward J.] Vet Affaiis Puget Sound Hlth Care Syst, Res Enhancement Award Program, Seattle, WA USA. [Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Div Internal Med, Dept Med, Seattle, WA USA. RP Ioannou, GN (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Div Gastroenterol, Dept Med, Seattle, WA USA. EM georgei@medicine.washington.edu NR 17 TC 7 Z9 7 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2011 VL 34 IS 10 BP 2336 EP 2337 DI 10.2337/dc11-1447 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 910AG UT WOS:000301609000040 PM 21949227 ER PT J AU Velayos-Baeza, A Holinski-Feder, E Neitzel, B Bader, B Critchley, EMR Monaco, AP Danek, A Walker, RH AF Velayos-Baeza, Antonio Holinski-Feder, Elke Neitzel, Birgit Bader, Benedikt Critchley, Edmund M. R. Monaco, Anthony P. Danek, Adrian Walker, Ruth H. TI Chorea-Acanthocytosis Genotype in the Original Critchley Kentucky Neuroacanthocytosis Kindred SO ARCHIVES OF NEUROLOGY LA English DT Article ID GENE; PROTEIN; DISEASE AB Objective: To determine the molecular nature of the neurological disease in the seminal family reported by Critchley et al in the 1960s, characterized by a hyperkinetic movement disorder and the appearance of acanthocytosis on peripheral blood smear. The eponym Levine-Critchley syndrome, subsequently termed neuroacanthocytosis, has been applied to symptomatically similar, but genetically distinct, disorders, resulting in clinical and diagnostic confusion. Design: DNA analysis. Setting: Molecular biology research laboratories. Participants: First- and second-degree relatives of the original Critchley et al proband from Kentucky. Main Outcome Measures: Mutations in the VPS13A gene. Results: A mutation was identified in the VPS13A gene, responsible for autosomal recessive chorea-acanthocytosis. Haplotype reconstruction suggested that this mutation was homozygous in the proband. Conclusion: These findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report. C1 [Walker, Ruth H.] James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY USA. [Walker, Ruth H.] Mt Sinai Sch Med, New York, NY USA. [Velayos-Baeza, Antonio; Monaco, Anthony P.] Wellcome Trust Ctr Human Genet, Oxford, England. [Critchley, Edmund M. R.] Univ Cent Lancashire, Preston PR1 2HE, Lancs, England. [Holinski-Feder, Elke; Neitzel, Birgit] Med Genet Zentrum, Munich, Germany. [Bader, Benedikt; Danek, Adrian] Univ Munich, Neurol Klin & Poliklin, Munich, Germany. RP Walker, RH (reprint author), James J Peters Vet Affairs Med Ctr, Dept Neurol 127, Bronx, NY 10468 USA. EM ruth.walker@mssm.edu RI Danek, Adrian/G-7339-2011; Monaco, Anthony/A-4495-2010 OI Danek, Adrian/0000-0001-8857-5383; Monaco, Anthony/0000-0001-7480-3197 FU Mary Kinross Charitable Trust and the Chaney family; Wellcome Trust [075491/Z/04] FX This work was supported by a grant from the Advocacy for Neuroacanthocytosis Patients (the Mary Kinross Charitable Trust and the Chaney family) (Drs Velayos-Baeza and Monaco) and grant 075491/Z/04 from the Wellcome Trust (Drs Velayos-Baeza and Monaco). NR 14 TC 1 Z9 1 U1 0 U2 1 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 OCT PY 2011 VL 68 IS 10 BP 1330 EP 1333 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 830YV UT WOS:000295696700018 PM 21987550 ER PT J AU Kinlay, S AF Kinlay, Scott TI Grasping the Nettle and Femoral Artery Stenting SO CIRCULATION-CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material DE Editorials; peripheral arterial disease; stents; drugeluting stents; revascularization; clinical trials randomized ID BARE NITINOL STENTS; BALLOON ANGIOPLASTY; INTERMITTENT CLAUDICATION; DISEASE; TRIAL; IMPLANTATION; LESIONS; RESTENOSIS; PACLITAXEL C1 [Kinlay, Scott] Harvard Univ, Brigham & Womens Hosp, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Kinlay, S (reprint author), VA Boston Healthcare Syst, Div Cardiovasc, Cardiac Catheterizat Lab, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM scott.kinlay@va.gov NR 19 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7640 J9 CIRC-CARDIOVASC INTE JI Circ.-Cardiovasc. Interv. PD OCT PY 2011 VL 4 IS 5 BP 407 EP 409 DI 10.1161/CIRCINTERVENTIONS.111.965038 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 896EV UT WOS:000300549100005 PM 22010187 ER PT J AU Dake, MD Ansel, GM Jaff, MR Ohki, T Saxon, RR Smouse, HB Zeller, T Roubin, GS Burket, MW Khatib, Y Snyder, SA Ragheb, AO White, JK Machan, LS AF Dake, Michael D. Ansel, Gary M. Jaff, Michael R. Ohki, Takao Saxon, Richard R. Smouse, H. Bob Zeller, Thomas Roubin, Gary S. Burket, Mark W. Khatib, Yazan Snyder, Scott A. Ragheb, Anthony O. White, J. King Machan, Lindsay S. CA Zilver PTX Investigators TI Paclitaxel-Eluting Stents Show Superiority to Balloon Angioplasty and Bare Metal Stents in Femoropopliteal Disease Twelve-Month Zilver PTX Randomized Study Results SO CIRCULATION-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE peripheral vascular disease; angioplasty; paclitaxel-eluting stent; drug-eluting stent ID SUPERFICIAL FEMORAL-ARTERY; NITINOL STENTS; CLINICAL-TRIALS; OCCLUSIVE DISEASE; IMPLANTATION; LESIONS; RESTENOSIS; PLACEMENT; PERFORMANCE; INHIBITION AB Background-Sustained benefits of drug-eluting stents in femoropopliteal arteries have not been demonstrated. This prospective, multinational, randomized study was designed to compare the 12-month safety and effectiveness of a polymer-free, paclitaxel-coated nitinol drug-eluting stent (DES) with percutaneous transluminal angioplasty (PTA) and provisional bare metal stent (BMS) placement in patients with femoropopliteal peripheral artery disease. Methods and Results-Patients were randomly assigned to primary DES implantation (n=236) or PTA (n=238). Demographics and lesion characteristics were similar between groups (eg, average lesion length, approximately 65 +/- 40 mm). One hundred twenty patients had acute PTA failure and underwent secondary random assignment to provisional DES (n=61) or BMS (n=59). Primary end points were the 12-month rates of event-free survival and patency in the primary DES and PTA groups. Compared with the PTA group, the primary DES group exhibited superior 12-month event-free survival (90.4% versus 82.6%; P=0.004) and primary patency (83.1% versus 32.8%; P<0.001), satisfying the primary hypotheses. In the secondary evaluations, (1) the primary DES group exhibited superior clinical benefit compared with the PTA group (88.3% versus 75.8%; P<0.001), (2) the provisional DES group exhibited superior primary patency (89.9% versus 73.0%; P=0.01) and superior clinical benefit (90.5% and 72.3%, P=0.009) compared with the provisional BMS group, and (3) the stent fracture rate (both DES and BMS) was 0.9% (4/457). Conclusions-Femoropopliteal peripheral artery disease treatment with the paclitaxel-eluting stent was associated with superior 12-month outcomes compared with PTA and provisional BMS placement. C1 [Dake, Michael D.] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Ansel, Gary M.] MidWest Cardiol Res Fdn, Columbus, OH USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ohki, Takao] Jikei Univ Hosp, Tokyo, Japan. [Saxon, Richard R.] Tri City Med Ctr, Oceanside, CA USA. [Smouse, H. Bob] OSF St Francis Med Ctr, Peoria, IL USA. [Machan, Lindsay S.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Zeller, Thomas] Herz Zentrum, Bad Krozingen, Germany. [Roubin, Gary S.] Lenox Hill Hosp, New York, NY 10021 USA. [Burket, Mark W.] Univ Toledo, Med Ctr, Toledo, OH 43606 USA. [Khatib, Yazan] First Coast Cardiovasc, Jacksonville, FL USA. [Snyder, Scott A.; Ragheb, Anthony O.] MED Inst Inc, W Lafayette, IN USA. [White, J. King] Christus St Patrick Hosp, Lake Charles, LA USA. RP Dake, MD (reprint author), Stanford Univ, Sch Med, Dept Cardiothorac Surg, Falk Cardiovasc Res Ctr, 300 Pasteur Dr, Stanford, CA 94305 USA. EM mddake@stanford.edu FU Cook Medical; Abbott Vascular; WL Gore; Bristol-Myers Squibb/Sanofi Pharmaceutical; organization and Cook Group Company FX The study was sponsored by Cook Medical.; Dr Dake received speaking honorarium and travel grants from Cook Medical and consulting fees from Abbott Vascular and WL Gore. Dr Ansel received consulting fees, travel grants, payment for review activities, lectures, and royalties for a device unrelated to this study from Cook Medical; he is an advisor for Cordis Endovascular, Boston Scientific, and Abbott Vascular. Dr Jaff is a member of VIVA Physicians, Inc, a noncompensated consultant for Boston Scientific, Abbott Vascular, Cordis Corporation, Covidien, and Medtronic Vascular, and holds equity investment in Icon Interventional, I.C. Sciences, Micell Technologies, Nexeon Medical Systems, PQ Bypass Inc, Primacea, Trireme/TMI, and Vascular Therapies. Dr Jaff has no financial relationship with Cook Medical. Dr Ohki received travel grants and payment for the development of educational materials from Cook Medical. Dr Saxon received consulting fees, travel grants, and payment for review activities from Cook Medical; he also received consulting fees from WL Gore and Atheromed and travel grants, payment for the development of educational materials, and payment for manuscript preparation from WL Gore and holds stock options in Atheromed. Dr Smouse received consulting fees from Cook Medical. Dr Machan received travel grants from Cook Medical and holds stock options in Angiotech Pharmaceuticals. Dr Zeller received consulting fees and payment for lectures from Cook Medical; he received consulting fees from Medrad Possis, eV3, CR Bard, Straub Medical, Ardian, Gore, Cordis Corporation, and Biotronik, and payment for lectures from Cordis Corporation, eV3, Medtronic Invatec, Sanofi-Aventi, Medrad Possis, WL Gore, and Pathway Medical and serves on the board for Medtronic Invatec, Angioslide, and Avidal Vascular. Dr Roubin received travel grants and royalties for a device not related to this study from Cook Medical. Dr Burket received consulting fees and travel grants from Cook Medical; he received consulting fees from Cook Medical and the IDEV DMSB and lecture fees from Bristol-Myers Squibb/Sanofi Pharmaceutical. Dr White received travel grants from Cook Medical. Drs Snyder and Ragheb are paid employees of MED Institute, a contract research organization and Cook Group Company. NR 32 TC 221 Z9 235 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7640 J9 CIRC-CARDIOVASC INTE JI Circ.-Cardiovasc. Interv. PD OCT PY 2011 VL 4 IS 5 BP 495 EP 504 DI 10.1161/CIRCINTERVENTIONS.111.962324 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 896EV UT WOS:000300549100017 PM 21953370 ER PT J AU Ananthakrishnan, A Higuchi, L Huang, E Khalili, H Richter, J Fuchs, C Chan, A AF Ananthakrishnan, Ashwin Higuchi, Leslie Huang, Edward Khalili, Hamed Richter, James Fuchs, Charles Chan, Andrew TI A Prospective Study of Aspirin, Non-steroidal Anti-inflammatory Drug Use and Risk of Crohn's Disease and Ulcerative Colitis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Ananthakrishnan, Ashwin; Huang, Edward; Khalili, Hamed; Richter, James; Chan, Andrew] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Higuchi, Leslie] Childrens Hosp Boston, Boston, MA USA. [Fuchs, Charles] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 1224 BP S462 EP S462 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772002068 ER PT J AU Bunchorntavakul, C Siripun, A Chavalitdhamrong, D AF Bunchorntavakul, Chalermrat Siripun, Aroon Chavalitdhamrong, Disaya TI Fluvastatin Monotherapy for the Treatment of Patients with Chronic Hepatitis C: A Randomized Double-Blinded Placebo-Controlled Study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Bunchorntavakul, Chalermrat; Siripun, Aroon] Rangsit Univ, Fac Med, Rajavithi Hosp, Bangkok, Thailand. [Chavalitdhamrong, Disaya] Mt Sinai Sch Med, James J Peters Vet Affairs Med Ctr, Bronx, NY USA. NR 0 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 259 BP S102 EP S103 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772000260 ER PT J AU Greenwald, B Wolfsen, H Abrams, J Lightdale, C Nishioka, N Johnston, M Zfass, A Bhatt, A Makkar, R Barthel, J Dumot, J AF Greenwald, Bruce Wolfsen, Herbert Abrams, Julian Lightdale, Charles Nishioka, Norman Johnston, Mark Zfass, Alvin Bhatt, Amit Makkar, Rohit Barthel, James Dumot, John TI Spray Cryotherapy for Esophageal Cancer: Long-term Results SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Greenwald, Bruce] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Greenwald, Bruce] Greenebaum Canc Ctr, Baltimore, MD USA. [Wolfsen, Herbert] Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. [Abrams, Julian; Lightdale, Charles] Columbia Univ, Med Ctr, New York, NY USA. [Nishioka, Norman] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nishioka, Norman] Harvard Univ, Sch Med, Boston, MA USA. [Johnston, Mark] Lancaster Gastroenterol Inc, Lancaster, PA USA. [Zfass, Alvin] Virginia Commonwealth Univ, Richmond, VA USA. [Bhatt, Amit; Makkar, Rohit] Cleveland Clin, Cleveland, OH 44106 USA. [Barthel, James] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Dumot, John] Univ Hosp Case Med Ctr, Cleveland, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 17 BP S7 EP S7 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772000018 ER PT J AU Khalili, H Higuchi, L Huang, E Ananthakrishnan, A Richter, J Fuchs, C Chan, A AF Khalili, Hamed Higuchi, Leslie Huang, Edward Ananthakrishnan, Ashwin Richter, James Fuchs, Charles Chan, Andrew TI Geographic Variations and Risk of Crohn's Disease and Ulcerative Colitis: Results from Two Large Prospective Cohorts SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Khalili, Hamed; Huang, Edward; Ananthakrishnan, Ashwin; Richter, James; Chan, Andrew] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Higuchi, Leslie] Childrens Hosp, Boston, MA 02115 USA. [Fuchs, Charles] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 1284 BP S489 EP S489 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772002128 ER PT J AU Leung, F AF Leung, Felix TI Injection Treatment for Fecal Incontinence (FI) - Review of Impact on Quality-of-life (QoL) Measures SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Leung, Felix] Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, North Hills, CA USA. [Leung, Felix] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 1319 BP S503 EP S503 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772002162 ER PT J AU Okeke, F Korsten, M Shaw, S Hunt, K Rosman, A AF Okeke, Francis Korsten, Mark Shaw, Spencer Hunt, Kristel Rosman, Alan TI Safety of Propofol Used as a Rescue Agent During Colonoscopy SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Okeke, Francis; Korsten, Mark; Shaw, Spencer; Hunt, Kristel; Rosman, Alan] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 402 BP S157 EP S158 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772000399 ER PT J AU Salazar, C Cardenas, V Reddy, R Graham, D AF Salazar, Cesar Cardenas, Victor Reddy, Rita Graham, David TI Helicobacter pylori Eradication Using a 14-day Bismuth Quadruple Therapy Among Hispanic Adults in El Paso, Texas: Preliminary Findings SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Cardenas, Victor] Univ Texas Sch Publ Hlth, El Paso, TX USA. [Reddy, Rita; Graham, David] DeBakey Vet Affairs Med Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 118 BP S47 EP S48 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772000119 ER PT J AU Spiegel, B Poysophon, P Snyder, B Agarwal, N Yen, L Hodgkins, P Cohen, E Vu, M Kurzbard, N Atia, M Sheen, V Kaneshiro, M Fuller, G Bolus, R AF Spiegel, Brennan Poysophon, Poyrung Snyder, Bradley Agarwal, Nikhil Yen, Linette Hodgkins, Paul Cohen, Erica Vu, Michelle Kurzbard, Nicole Atia, Mary Sheen, Victoria Kaneshiro, Marc Fuller, Garth Bolus, Roger TI Direct Costs and Resource Utilization for Inpatient Diverticulitis Admissions SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Spiegel, Brennan] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Snyder, Bradley; Kurzbard, Nicole] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Yen, Linette; Hodgkins, Paul] Shire Dev Inc, Global Hlth Econ Outcomes Res & Epidemiol, Los Angeles, CA USA. [Agarwal, Nikhil; Cohen, Erica; Vu, Michelle; Atia, Mary; Sheen, Victoria; Kaneshiro, Marc; Fuller, Garth; Bolus, Roger] Univ Calif Los Angeles, VA Ctr Outcomes Res & Educ CORE, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 1149 BP S428 EP S428 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772001711 ER PT J AU Wasan, S Juillerat, P Fowler, S Yajnik, V Korzenik, J Pabby, V Friedman, S Coukos, J Barto, A Pellish, R Farraye, F AF Wasan, Sharmeel Juillerat, Pascal Fowler, Sharyle Yajnik, Vijay Korzenik, Joshua Pabby, Vikas Friedman, Sonia Coukos, Jennifer Barto, Amy Pellish, Randall Farraye, Francis TI Efficacy and Safety of Natalizumab in Crohn's Disease Patients Treated at Five Academic Boston Hospitals SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 76th Annual Scientific Meeting of the American-College-of-Gastroenterology CY OCT 28-NOV 02, 2011 CL Washington, DC SP Amer Coll Gastroenterol C1 [Wasan, Sharmeel; Coukos, Jennifer; Farraye, Francis] Boston Univ, Sch Med, Boston, MA 02118 USA. [Juillerat, Pascal; Fowler, Sharyle; Yajnik, Vijay; Korzenik, Joshua] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pabby, Vikas; Friedman, Sonia] Brigham & Womens Hosp, Boston, MA 02115 USA. [Barto, Amy] Lahey Clin Fdn, Burlington, MA USA. [Pellish, Randall] Univ Massachusetts, Worcester, MA 01605 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2011 VL 106 SU 2 MA 1249 BP S473 EP S473 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 885II UT WOS:000299772002093 ER PT J AU Lin, CW Warram, JH Veng-Pedersen, P AF Lin, C. W. Warram, J. H. Veng-Pedersen, P. TI A Bayesian population analysis of the development of type 2 diabetes in the offspring of diabetic parents SO JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS LA English DT Article DE Bayesian analysis; Disease development; Type 2 diabetes; Glucose; Insulin; HOMA-IR; Body mass index ID INSULIN SECRETORY DYSFUNCTION; GLUCOSE-TOLERANCE; RISK-FACTORS; BETA-CELL; RESISTANCE; MELLITUS; NIDDM; MODEL; PROGRESSION; DISEASE AB Disease progression of type 2 diabetes (T2D) has received considerable attention, but little is known about the disease development of T2D. The purposes of this study were to identify disease development variables (DDV) for development of T2D and to compare corresponding models for disease development. All subjects included in this study were the offspring of diabetic parents and were followed up to 25 years. Repeated fasting blood samples were collected during the follow-up. Longitudinal data of four DDVs, namely fasting blood glucose (FBG), fasting serum insulin (FSI), homeostatic model assessment of insulin resistance (HOMA-IR) and body mass index (BMI) were recorded and compared. According to the diabetes status at the end of the follow-up, the data analysis involved a progressor group of 25 subjects, and a non-progressor group of 127 subjects. The temporal changes in the four DDVs over the time course of the disease development were evaluated by a single-slope and a dual-slope population-based Bayesian model. A dual-slope model based on FBG was found to be the best disease development model. For non-progressors, the FBG baseline stayed at 69.2 [66.5, 72.1] mg/dl (Bayes estimate [95% Bayesian credible set]) and increased with age by a rate of 0.227 mg/dl [0.149, 0.3] per year. For the progressors, the FBG increase with age the same rate as non-progressors and started to have an additional increase of 2.27 [0.505, 4.52] mg/dl per year, starting 8.73 [-10.8, -6.93] years before the diagnosis of T2D. No significant longitudinal increasing or decreasing temporal pattern was found for FSI, HOMA-IR and BMI by the population-based Bayesian approach. The proposed model, which enables a quantitative, time-based evaluation of the development of T2D in this higher risk population, may be used to quantify the effect of interventions/prevention strategies such as drug treatment and lifestyle changes. C1 [Lin, C. W.; Veng-Pedersen, P.] Univ Iowa, Coll Pharm, Iowa City, IA 52242 USA. [Warram, J. H.] Joslin Diabet Ctr, Sect Epidemiol & Genet, Boston, MA 02215 USA. RP Veng-Pedersen, P (reprint author), Univ Iowa, Coll Pharm, Iowa City, IA 52242 USA. EM veng@uiowa.edu NR 35 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1567-567X J9 J PHARMACOKINET PHAR JI J. Pharmacokinet. Pharmacodyn. PD OCT PY 2011 VL 38 IS 5 BP 563 EP 579 DI 10.1007/s10928-011-9208-2 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 890VB UT WOS:000300172600003 PM 21833670 ER PT J AU Alexander, KA Dovydaitis, T Beacham, B Bohinski, JM Brawner, BM Clements, CP Everett, JS Gomes, MM Harner, H McDonald, CC Pinkston, E Sommers, MS AF Alexander, Kamila A. Dovydaitis, Tiffany Beacham, Barbara Bohinski, Julia M. Brawner, Bridgette M. Clements, Carla P. Everett, Janine S. Gomes, Melissa M. Harner, Holly McDonald, Catherine C. Pinkston, Esther Sommers, Marilyn S. TI Learning Health Equity Frameworks within a Community of Scholars SO JOURNAL OF NURSING EDUCATION LA English DT Article AB Scholars in nursing science have long espoused the concept of health equity without specifically using the term or dialoguing about the social determinants of health and social justice. This article describes the development, implementation, and evaluation of a doctoral and postdoctoral seminar collective entitled "Health Equity: Conceptual, Linguistic, Methodological, and Ethical Issues." The course enabled scholars-in-training to consider the construct and its nuances and frame a personal philosophy of health equity. An example of how a group of emerging scholars can engage in the important, but difficult, discourse related to health equity is provided. The collective provided a forum for debate, intellectual growth, and increased insight for students and faculty. The lessons learned by all participants have the potential to enrich doctoral and postdoctoral scientific training in nursing science and may serve as a model for other research training programs in the health sciences. C1 [Alexander, Kamila A.; Dovydaitis, Tiffany; Beacham, Barbara; Bohinski, Julia M.; Brawner, Bridgette M.; Clements, Carla P.; Everett, Janine S.; McDonald, Catherine C.; Pinkston, Esther; Sommers, Marilyn S.] Univ Penn, Sch Nursing, Ctr Hlth Equ Res, Philadelphia, PA 19104 USA. [Harner, Holly] LaSalle Univ, MPH Program, Sch Nursing & Hlth Sci, Philadelphia, PA USA. [Gomes, Melissa M.] Virginia Commonwealth Univ, Sch Nursing, Richmond, VA USA. RP Alexander, KA (reprint author), Univ Penn, Sch Nursing, Ctr Hlth Equ Res, 418 Curie Blvd,Room 233L, Philadelphia, PA 19104 USA. EM kamilaa@nursing.upenn.edu FU National Institute of Nursing Research [T32NR007100, F31NR011524, 2R01NR005352, F31NR011106, F31NR011107]; University of Pennsylvania FX This work was supported by the Ruth L. Kirschstein NRSA Pre & Post doctoral Fellowship at the University of Pennsylvania School of Nursing, Research on Vulnerable Women, Children and Families T32NR007100 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 work was also supported by Award Number F31NR011524 (to Barbara Beacham) from the National Institute of Nursing Research; Offices of the Provost and School of Nursing Dean from the University of Pennsylvania (to Bridgette M. Brawner); Diversity Supplement to 2R01NR005352 (to Carla Clements) from the National Institute of Nursing Research; Award Number F31NR011106 (to Janine S. Everett) from the National Institute of Nursing Research; and Award Number F31NR011107 (to Catherine C. McDonald) from the National Institute of Nursing Research. NR 13 TC 2 Z9 2 U1 0 U2 4 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0148-4834 J9 J NURS EDUC JI J. Nurs. Educ. PD OCT PY 2011 VL 50 IS 10 BP 569 EP 574 DI 10.3928/01484834-20110630-05 PG 6 WC Nursing SC Nursing GA 884VK UT WOS:000299736700005 PM 21710960 ER PT J AU Mirkovic, J Lau, C McGee, S Crum, C Badizadegan, K Feld, M Stier, E AF Mirkovic, Jelena Lau, Condon McGee, Sasha Crum, Christopher Badizadegan, Kamran Feld, Michael Stier, Elizabeth TI Detecting high-grade squamous intraepithelial lesions in the cervix with quantitative spectroscopy and per-patient normalization SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID VIVO LIGHT-SCATTERING; IN-VIVO; FLUORESCENCE SPECTROSCOPY; REFLECTANCE SPECTROSCOPY; OPTICAL-DETECTION; PRECANCER; NEOPLASIA; TISSUE; PATTERNS; SPECTRA AB This study develops a spectroscopic algorithm for detection of cervical high grade squamous intraepithelial lesions (HSILs). We collected reflectance and fluorescence spectra with the quantitative spectroscopy probe to measure nine spectroscopic parameters from 43 patients undergoing standard colposcopy with directed biopsy. We found that there is improved accuracy for distinguishing HSIL from non-HSIL (low grade SIL and normal tissue) when we "normalized" spectroscopy parameters by dividing the values extracted from each clinically determined suspicious site by the corresponding value extracted from a clinically normal squamous site from the same patient. The "normalized" scattering parameter (A) at 700nm, best distinguished HSIL from non-HSIL with sensitivity and specificity of 89% and 79% suggesting that a simple, monochromatic instrument measuring only A may accurately detect HSIL. (C) 2011 Optical Society of America C1 [Mirkovic, Jelena; Lau, Condon; McGee, Sasha; Feld, Michael] MIT, George R Harrison Spect Lab, Cambridge, MA 02179 USA. [Mirkovic, Jelena; Crum, Christopher] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Badizadegan, Kamran] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stier, Elizabeth] Boston Med Ctr, Dept Obstet & Gynecol, Boston, MA 02118 USA. RP Mirkovic, J (reprint author), MIT, George R Harrison Spect Lab, 77 Massachusetts Ave, Cambridge, MA 02179 USA. EM jedza@alum.mit.edu RI Mirkovic, Jelena/A-6253-2013; OI LAU, Condon/0000-0002-6569-5814 FU National Institutes of Health [R01 CA097966]; Laser Biomedical Research Center [P41 RR02594] FX We thank Chung-Chieh Yu and Jonathan Nazemi for valuable discussions about data modeling. We thank Jonathan Nazemi and Luis Galindo for the engineering assistance, and Victoria Feng for the technical assistance. We finally thank Teresa Darragh and Antonio de las Morenas for their valuable contribution to the pathology evaluation. This research was funded by the National Institutes of Health grant R01 CA097966 and the Laser Biomedical Research Center grant P41 RR02594. NR 36 TC 4 Z9 4 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 OCT 1 PY 2011 VL 2 IS 10 BP 2917 EP 2925 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 886FN UT WOS:000299838800017 PM 22025992 ER PT J AU Westmoreland, SV Annamalai, L Lentz, MR Ratai, EM Assaf, B Boisvert, K Huynh, T Vallender, EJ Miller, GM Madras, BK Gonzalez, RG AF Westmoreland, Susan V. Annamalai, Lakshmanan Lentz, Margaret R. Ratai, Eva-Marie Assaf, Basel Boisvert, Karen Thanhthao Huynh Vallender, Eric J. Miller, Gregory M. Madras, Bertha K. Gonzalez, R. Gilberto TI Growth-associated protein-43 and ephrin B3 induction in the brain of adult SIV-infected rhesus macaques SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE Rhesus; Macaque; SIV; GAP-43; Ephrin B3; Neuronal injury; Synaptophysin; Plasticity; Microglia ID IMMUNODEFICIENCY-VIRUS ENCEPHALITIS; GLUTAMATE TRANSPORT; NEOCORTICAL DAMAGE; IN-VIVO; GAP-43; INJURY; EXPRESSION; MODEL; HIV; PLASTICITY AB Understanding the mechanisms of neuronal regeneration and repair in the adult central nervous system is a vital area of research. Using a rhesus lentiviral encephalitis model, we sought to determine whether recovery of neuronal metabolism after injury coincides with the induction of two important markers of synaptodendritic repair: growth-associated protein-43 (GAP-43) and ephrin B3. We examined whether the improvement of neuronal metabolism with combined anti-retroviral therapy (cART) after simian immunodeficiency virus (SIV) infection in rhesus macaques involved induction of GAP-43, also known as neuromodulin, and ephrin B3, both implicated in axonal pathfinding during neurodevelopment and regulation of synapse formation, neuronal plasticity, and repair in adult brain. We utilized magnetic resonance spectroscopy to demonstrate improved neuronal metabolism in vivo in adult SIV-infected cART animals compared to untreated and uninfected controls. We then assessed levels of GAP-43, ephrin B3, and synaptophysin, a presynaptic marker, in three brain regions important for cognitive function, cortex, hippocampus, and putamen, by quantitative real-time RT-PCR and immunohistochemistry. Here we demonstrate that (1) GAP-43 mRNA and protein are induced with SIV infection, (2) GAP-43 protein is higher in the hippocampus outer molecular layer in SIV-infected animals that received cART compared to those that did not, and (3) activated microglia and infiltrating SIV-infected macrophages express abundant ephrin B3, an important axonal guidance molecule. We propose a model whereby SIV infection triggers events that lead to induction of GAP-43 and ephrin B3, and that short-term cART results in increased magnitude of repair mechanisms especially in the hippocampus, a region known for high levels of adult plasticity. C1 [Westmoreland, Susan V.; Annamalai, Lakshmanan; Assaf, Basel; Boisvert, Karen] Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Div Comparat Pathol, Southborough, MA 01772 USA. [Vallender, Eric J.; Miller, Gregory M.; Madras, Bertha K.] Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Div Neurosci, Southborough, MA 01772 USA. [Thanhthao Huynh] Tufts Cummings Sch Vet Med, North Grafton, MA USA. [Lentz, Margaret R.; Ratai, Eva-Marie; Gonzalez, R. Gilberto] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Lentz, Margaret R.; Ratai, Eva-Marie; Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Neuroradiol Div, Charlestown, MA USA. RP Westmoreland, SV (reprint author), Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Div Comparat Pathol, Southborough, MA 01772 USA. EM Susan_westmoreland@hms.harvard.edu RI Vallender, Eric/A-2450-2008 OI Vallender, Eric/0000-0003-3506-0540 FU NEPRC [RR00168, R01NS050041, DA025697]; NEPRC Microscopy and Primate Genetics Cores FX We would like to thank Dr. Larry Benowitz for supplying the anti-GAP-43 antibody and protocol, Ron Desrosiers for supplying the virus inoculum SIVmac251, Keith Reimann for providing anti-CD8 cM-T807, Raymond Schinazi for supplying Racivir (RCV), and Norbert Bischofberger of Gilead Sciences for providing PMPA. In addition, we thank Elizabeth Curran, Michael O'Connell, and Doug Pauley for pathology assistance, and Drs. Prabhat Sehgal, Angela Carville, and Elisabeth Moeller for veterinary expertise. We also thank Hayley Dirscherl, Alexis Denysyk, Heather Knight, and Karen Boisvert Dalecki for their contribution with immunohistochemistry and Hong Yang for real-time PCR contribution. This work was supported by RR00168 (NEPRC Base Grant), R01NS050041 (RGG), DA025697 (GMM), and the NEPRC Microscopy and Primate Genetics Cores. NR 47 TC 1 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2011 VL 17 IS 5 BP 455 EP 468 DI 10.1007/s13365-011-0047-0 PG 14 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 876QG UT WOS:000299122000006 PM 21789725 ER PT J AU McGuire, JL Fridman, V Wuthrich, C Koralnik, IJ Jacobs, D AF McGuire, Jennifer L. Fridman, Vera Wuethrich, Christian Koralnik, Igor J. Jacobs, Dina TI Progressive multifocal leukoencephalopathy associated with isolated CD8+T-lymphocyte deficiency mimicking tumefactive MS SO JOURNAL OF NEUROVIROLOGY LA English DT Article ID JC VIRUS; CEREBROSPINAL-FLUID; MULTIPLE-SCLEROSIS; IMMUNODEFICIENCY; IMMUNOSUPPRESSION; INFECTION C1 [McGuire, Jennifer L.] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19146 USA. [McGuire, Jennifer L.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Fridman, Vera] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Wuethrich, Christian; Koralnik, Igor J.] Beth Israel Deaconess Med Ctr, Dept Med, Div Viral Pathogenesis, Boston, MA 02215 USA. [Wuethrich, Christian; Koralnik, Igor J.] Beth Israel Deaconess Med Ctr, Dept Neurol, Div Neurovirol, Boston, MA 02215 USA. [Jacobs, Dina] Hosp Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. RP McGuire, JL (reprint author), Childrens Hosp Philadelphia, Div Neurol, 34th St & Civ Ctr Blvd, Philadelphia, PA 19146 USA. EM mcguirej@email.chop.edu FU NIH [T32-NS061779, R01 NS 041198, 047029, K24 NS 060950]; Philadelphia Foundation; Biogen Idec FX Dr. McGuire received support from NIH grant T32-NS061779 and from the L. Morton Morley Funds of The Philadelphia Foundation. Dr. Koralnik has received honoraria from Bristol-Myers Squibb, Ono Pharmaceuticals, Merck Serono, Anti-sense, and Alnylam, and is supported in part by NIH grants R01 NS 041198 and 047029 and K24 NS 060950 and a research grant from Biogen Idec. Dr. Jacobs has received honoraria from Biogen Idec, Teva Pharmaceuticals, and Serono. The content is the sole responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 23 TC 3 Z9 3 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 OCT PY 2011 VL 17 IS 5 BP 500 EP 503 DI 10.1007/s13365-011-0045-2 PG 4 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 876QG UT WOS:000299122000011 PM 21786075 ER PT J AU Bailey, RR Stuckey, DR Norman, BA Duggan, AP Bacon, KM Connor, DL Lee, I Muder, RR Lee, BY AF Bailey, Rachel R. Stuckey, Dianna R. Norman, Bryan A. Duggan, Andrew P. Bacon, Kristina M. Connor, Diana L. Lee, Ingi Muder, Robert R. Lee, Bruce Y. TI Home-Based Preoperative Chlorhexidine Bathing Cloths to Prevent Surgical Site Infection Reply SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Letter C1 [Bailey, Rachel R.] Univ Pittsburgh, Publ Hlth Computat & Operat Res PHICOR, Sect Decis Sci & Clin Syst Modeling, Pittsburgh, PA 15213 USA. [Bailey, Rachel R.; Stuckey, Dianna R.; Bacon, Kristina M.; Connor, Diana L.; Lee, Bruce Y.] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA 15213 USA. [Bailey, Rachel R.; Stuckey, Dianna R.; Bacon, Kristina M.; Connor, Diana L.; Lee, Bruce Y.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Norman, Bryan A.; Duggan, Andrew P.] Univ Pittsburgh, Dept Ind Engn, Pittsburgh, PA 15213 USA. [Lee, Ingi] Univ Penn, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Lee, Ingi] Univ Penn, Sch Med, Ctr Evidence Based Practice, Philadelphia, PA 19104 USA. [Muder, Robert R.] Vet Affairs Pittsburgh Healthcare Syst, Div Infect Dis, Pittsburgh, PA USA. RP Bailey, RR (reprint author), Univ Pittsburgh, Publ Hlth Computat & Operat Res PHICOR, Sect Decis Sci & Clin Syst Modeling, 3520 Forbes Ave,1st Floor, Pittsburgh, PA 15213 USA. EM RRB16@pitt.edu NR 6 TC 0 Z9 0 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD OCT PY 2011 VL 32 IS 10 BP 1047 EP 1048 DI 10.1086/662024 PG 2 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 876BX UT WOS:000299083100016 ER PT J AU Kopeikina, KJ Carlson, GA Pitstick, R Ludvigson, AE Peters, A Luebke, JI Koffie, RM Frosch, MP Hyman, BT Spires-Jones, TL AF Kopeikina, Katherine J. Carlson, George A. Pitstick, Rose Ludvigson, Adam E. Peters, Alan Luebke, Jennifer I. Koffie, Robert M. Frosch, Matthew P. Hyman, Bradley T. Spires-Jones, Tara L. TI Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID AXONAL-TRANSPORT; NEURODEGENERATIVE DISEASES; NEUROFIBRILLARY TANGLES; AMYLOID-BETA; SYNAPTIC MITOCHONDRIA; ENDOPLASMIC-RETICULUM; OXIDATIVE STRESS; SENILE PLAQUES; DYSFUNCTION; OLIGOMERS AB Neurofibrillary tangles (NFT), intracellular inclusions of abnormal fibrillar forms of naicrotubule associated protein tau, accumulate in Alzheimer's disease (AD) and other tauopathies and are believed to cause neuronal dysfunction, but the mechanism of tau-mediated toxicity are uncertain. Tau overexpression in cell culture impairs localization and trafficking of organelles. Here we tested the hypothesis that, in the intact brain, changes in mitochondrial distribution occur secondary to pathological changes in tau. Array tomography, a high-resolution imaging technique, was used to examine mitochondria in the reversible transgenic (rTg)4510, a regulatable transgenic, mouse model and AD brain tissue. Mitochondrial distribution is progressively disrupted with age in rTg4510 brain, particularly in somata and neurites containing Alz50-positive tau aggregates. Suppression of soluble tau expression with doxycycline resulted in complete recovery of mitochondrial distribution, despite the continued presence of aggregated tau. The effect on mitochondrial distribution occurs without concomitant alterations in neuropil mitochondrial size, as assessed by both array tomography and electron microscopy. Similar mitochondrial localization alterations were also observed in human AD tissue in Alz50+ neurons, confirming the relevance of tau to mitochondrial trafficking observed in this animal model. Because abnormalities reverted to normal if soluble tau was suppressed in rTg4510 mice, even in the continued presence of fibrillar tau inclusions, we suggest that soluble tau plays an important role in mitochondrial abnormalities, which likely contribute to neuronal dysfunction in AD. (Am J Pathol 2011, 179: 2071-2082; DOI: 10.1016/j.ajpath.2011.07.004) C1 [Kopeikina, Katherine J.; Koffie, Robert M.; Frosch, Matthew P.; Hyman, Bradley T.; Spires-Jones, Tara L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA USA. [Kopeikina, Katherine J.; Ludvigson, Adam E.; Peters, Alan; Luebke, Jennifer I.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Carlson, George A.; Pitstick, Rose] McLaughlin Res Inst, Great Falls, MT USA. RP Spires-Jones, TL (reprint author), MGH Neurol, 114 16th St, Charlestown, MA 02129 USA. EM tspires@partners.org OI Luebke, Jennifer/0000-0003-1399-6073; Spires-Jones, Tara/0000-0003-2530-0598 FU National Institute of Health [AG08487, T32AG000277, AG026249, K99AG33670, P50AG05134]; Alzheimer's Association FX Supported by National Institute of Health Grants AG08487, T32AG000277, AG026249, K99AG33670, P50AG05134 and the Alzheimer's Association Zenith Award. NR 60 TC 67 Z9 71 U1 0 U2 17 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 OCT PY 2011 VL 179 IS 4 BP 2071 EP 2082 DI 10.1016/j.ajpath.2011.07.004 PG 12 WC Pathology SC Pathology GA 865JO UT WOS:000298307400046 PM 21854751 ER PT J AU Cheunsuchon, P Zhou, YL Zhang, X Lee, H Chen, WD Nakayama, Y Rice, KA Hedley-Whyte, ET Swearingen, B Klibanski, A AF Cheunsuchon, Pornsuk Zhou, Yunli Zhang, Xun Lee, Hang Chen, Wendy Nakayama, Yuki Rice, Kimberley A. Hedley-Whyte, E. Tessa Swearingen, Brooke Klibanski, Anne TI Silencing of the Imprinted DLK1-MEG3 Locus in Human Clinically Nonfunctioning Pituitary Adenomas SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TUMOR-SUPPRESSOR GENE; INHIBITS ADIPOCYTE DIFFERENTIATION; UNIPARENTAL DISOMY; CANCER CELLS; EXPRESSION; MICRORNA; PROTEIN; REGION; DLK1; HYPERMETHYLATION AB DLK1-MEG3 is an imprinted locus consisting of multiple maternally expressed noncoding RNA genes and paternally expressed protein-coding genes. The expression of maternally expressed gene 3 (MEG3) is selectively lost in clinically nonfunctioning adenomas (NFAs) of gonadotroph origin; however, expression status of other genes at this locus in human pituitary adenomas has not previously been reported. Using quantitative real-time RT-PCR, we evaluated expression of 24 genes from the DLK1-MEG3 locus in 44 human pituitary adenomas (25 NFAs, 7 ACTH-secreting, 7 GH-secreting, and 5 PRL-secreting adenomas) and 10 normal pituitaries. The effects on cell proliferation of five miRNAs whose expression was lost in NFAs were investigated by flow cytometry analysis. We found that 18 genes, including 13 miRNAs at the DLK1-MEG3 locus, were significantly down-regulated in human NFAs. In ACTH-secreting and PRL-secreting adenomas, 12 and 7 genes were significantly down-regulated, respectively; no genes were significantly down-regulated in GH-secreting tumors. One of the five miRNAs tested induced cell cycle arrest at the G2/M phase in PDFS cells derived from a human NFA. Our data indicate that the DLK1-MEG3 locus is silenced in NFAs. The growth suppression by miRNAs in PDFS cells is consistent with the hypothesis that the DLK1-MEG3 locus plays a tumor suppressor role in human NFAs. (Am J Pathol 2011, 179:2120-2130; DOI: 10.1016/j.ajpath.2011.07.002) C1 [Cheunsuchon, Pornsuk; Zhou, Yunli; Zhang, Xun; Chen, Wendy; Nakayama, Yuki; Rice, Kimberley A.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Hedley-Whyte, E. Tessa] Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Swearingen, Brooke] Massachusetts Gen Hosp, Div Neurosurg, Boston, MA 02114 USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, 55 Fruit St,Bulfinch 457, Boston, MA 02114 USA. EM aklibanski@partners.org RI Cheunsuchon, Pornsuk/O-7915-2015 OI Cheunsuchon, Pornsuk/0000-0001-8851-3553 FU NIH [R01-DK40947]; Guthart Family Foundation; Jarislowsky Foundation FX Supported by grants from the NIH (R01-DK40947 to A.K.), the Guthart Family Foundation, and the Jarislowsky Foundation. NR 51 TC 32 Z9 36 U1 0 U2 8 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 OCT PY 2011 VL 179 IS 4 BP 2120 EP 2130 DI 10.1016/j.ajpath.2011.07.002 PG 11 WC Pathology SC Pathology GA 865JO UT WOS:000298307400051 PM 21871428 ER PT J AU Jia, HB Li, N Gao, GR Wang, XD Sun, M Wu, J Liu, F Yin, L Zhang, MM Hu, SN Hou, JB Yu, B Zhang, S Zhang, SS Jang, IK AF Jia Haibo Li Ning Gao Guangren Wang Xuedong Sun Meng Wu Jian Liu Fang Yin Li Zhang Maomao Hu Sining Hou Jingbo Yu Bo Zhang Shuo Zhang Shaosong Jang Ik-kyung TI DIFFERENT VESSEL RESPONSE BETWEEN CHRONIC TOTAL OCCLUSIONS AND NON-CTO LESION AFTER SIROLIMUS-ELUTING STENT IMPLANTATION: A SERIAL OPTICAL COHERENCE TOMOGRAPHY STUDY SO HEART LA English DT Meeting Abstract CT 22nd Great Wall International Congress of Cardiology/Asia Pacific Heart Congress (GWICC and APHF) CY OCT 13-16, 2011 CL China Int Conf Ctr Sci & Technol (CICCST), Beijing, PEOPLES R CHINA SP Chinese Med Soc Cardiovasc Dis (CMSCD), Comm Cardio-Cerebral Vasc Dis GSC & CHRS, Chinese Coll Cardiovasc Phys (CCCP) HO China Int Conf Ctr Sci & Technol (CICCST) C1 [Jia Haibo; Li Ning; Gao Guangren; Wang Xuedong; Wu Jian; Liu Fang; Yin Li; Zhang Maomao; Hu Sining; Hou Jingbo; Yu Bo; Zhang Shuo] Harbin Med Coll, Affiliated Hosp 2, Dept Cardiol, Key Labs Educ Minist Myocardial Ischemia Mech & T, Harbin, Peoples R China. [Sun Meng] Harbin Med Coll, Dept Biostat, Harbin, Peoples R China. [Jang Ik-kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. 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 1355-6037 J9 HEART JI Heart PD OCT PY 2011 VL 97 SU 3 DI 10.1136/heartjnl-2011-300867.434 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 866AV UT WOS:000298352900434 ER PT J AU Tucker, JD AF Tucker, Joseph D. TI The social context of sexual HIV prevention among female sex workers in China SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID RISK C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Tucker, JD (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM jtucker4@partners.org FU FIC NIH HHS [K01 TW008200, 1K01TW008200-01A1]; NICHD NIH HHS [R24 HD056670-01] NR 11 TC 6 Z9 6 U1 1 U2 2 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 OCT PY 2011 VL 40 IS 5 BP 1421 EP 1422 DI 10.1093/ije/dyr021 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 842XK UT WOS:000296634900034 PM 21324942 ER PT J AU Folmer, RL Billings, CJ Diedesch-Rouse, AC Gallun, FJ Lew, HL AF Folmer, Robert L. Billings, Curtis J. Diedesch-Rouse, Anna C. Gallun, Frederick J. Lew, Henry L. TI Electrophysiological assessments of cognition and sensory processing in TBI: Applications for diagnosis, prognosis and rehabilitation SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Review DE Event-related potentials; Evoked potentials; EP; ERP; TBI; Traumatic brain injury ID TRAUMATIC BRAIN-INJURY; EVENT-RELATED POTENTIALS; SOMATOSENSORY-EVOKED POTENTIALS; CLOSED-HEAD-INJURY; CONTINGENT NEGATIVE VARIATION; TEMPORAL-PARIETAL LESIONS; AUDITORY ODDBALL TASK; SUBJECTS OWN NAME; MISMATCH NEGATIVITY; COMATOSE PATIENTS AB Traumatic brain injuries are often associated with damage to sensory and cognitive processing pathways. Because evoked potentials (EPs) and event-related potentials (ERPs) are generated by neuronal activity, they are useful for assessing the integrity of neural processing capabilities in patients with traumatic brain injury (TBI). This review of somatosensory, auditory and visual ERPs in assessments of TBI patients is provided with the hope that it will be of interest to clinicians and researchers who conduct or interpret electrophysiological evaluations of this population. Because this article reviews ERP studies conducted in three different sensory modalities, involving patients with a wide range of TBI severity ratings and circumstances, it is difficult to provide a coherent summary of findings. However, some general trends emerge that give rise to the following observations and recommendations: 1) bilateral absence of somatosensory evoked potentials (SEPs) is often associated with poor clinical prognosis and outcome; 2) the presence of normal ERPs does not guarantee favorable outcome; 3) ERPs evoked by a variety of sensory stimuli should be used to evaluate TBI patients, especially those with severe injuries; 4) time since onset of injury should be taken into account when conducting ERP evaluations of TBI patients or interpreting results; 5) because sensory deficits (e.g., vision impairment or hearing loss) affect ERP results, tests of peripheral sensory integrity should be conducted in conjunction with ERP recordings; and 6) patients' state of consciousness, physical and cognitive abilities to respond and follow directions should be considered when conducting or interpreting ERP evaluations. Published by Elsevier B.V. C1 [Folmer, Robert L.; Billings, Curtis J.; Diedesch-Rouse, Anna C.; Gallun, Frederick J.] Portland VA Med Ctr, NCRAR, Portland, OR 97239 USA. [Folmer, Robert L.; Billings, Curtis J.; Gallun, Frederick J.] Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97201 USA. [Lew, Henry L.] DVBIC, Rockville, MD USA. [Lew, Henry L.] VCU, Sch Med, Dept Phys Med & Rehabil, Richmond, VA USA. RP Folmer, RL (reprint author), Portland VA Med Ctr, NCRAR, 3710 SM US Vet Hosp Rd, Portland, OR 97239 USA. EM Robert.Folmer@va.gov RI Gallun, Frederick/G-3792-2012 OI Gallun, Frederick/0000-0002-4145-2199 FU VA RR&D National Center for Rehabilitative Auditory Research FX Preparation of this manuscript was supported by the VA RR&D National Center for Rehabilitative Auditory Research, located in the Portland VA Medical Center, Portland, Oregon. NR 93 TC 18 Z9 18 U1 1 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD OCT PY 2011 VL 82 IS 1 SI SI BP 4 EP 15 DI 10.1016/j.ijpsycho.2011.03.005 PG 12 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 859PZ UT WOS:000297889600002 PM 21419179 ER PT J AU Carlson, BA Yoo, MH Conrad, M Gladyshev, VN Hatfield, DL Park, JM AF Carlson, Bradley A. Yoo, Min-Hyuk Conrad, Marcus Gladyshev, Vadim N. Hatfield, Dolph L. Park, Jin Mo TI Protein kinase-regulated expression and immune function of thioredoxin reductase 1 in mouse macrophages SO MOLECULAR IMMUNOLOGY LA English DT Article DE Thioredoxin reductase; Macrophage; Lipopolysaccharide; VSIG4; Selenoprotein ID NF-KAPPA-B; GENE-EXPRESSION; SELENOPROTEINS; SELENOCYSTEINE; ACTIVATION; APOPTOSIS; RESPONSES; SELENIUM; MICE AB Macrophages exposed to lipopolysaccharide (LPS) exhibit radical changes in mRNA and protein profiles. This shift in gene expression is geared not only to activate immune effector and regulatory mechanisms, but also to adjust the immune cell's metabolism to new physiological demands. However, it remains largely unknown whether immune function and metabolic state are mutually regulatory and, if so, how they are mechanistically interrelated in macrophages. Selenium, a dietary trace element exerting pleiotropic effects on immune homeostasis, and selenium-containing proteins (selenoproteins) may play a role in such coordination. We examined the incorporation of radiolabeled selenium into protein during LPS stimulation, and identified thioredoxin reductase 1 (TR1) as the only LPS-inducible selenoprotein in macrophages. TR1 induction occurred at the transcriptional level and depended on the intracellular signaling pathways mediated by p38 MAP kinase and I kappa B kinase. Macrophage-specific ablation of TR1 in mice resulted in a drastic decrease in the expression of VSIG4, a B7 family protein known to suppress T cell activation. These results reveal TR1 as both a regulator and a regulated target in the macrophage gene expression network, and suggest a link between selenium metabolism and immune signaling. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Carlson, Bradley A.; Yoo, Min-Hyuk; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Conrad, Marcus] Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg, Germany. [Conrad, Marcus] DZNE German Ctr Neurodegenerat Dis, Munich, Germany. [Gladyshev, Vadim N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gladyshev, Vadim N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. [Park, Jin Mo] Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov; jmpark@cbrc2.mgh.harvard.edu RI Gladyshev, Vadim/A-9894-2013; OI Conrad, Marcus/0000-0003-1140-5612 FU National Institutes of Health (NIH), National Cancer Institute (NCI); Center for Cancer Research; NCI; NIH [AI074957, GM065204] FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), and Center for Cancer Research, and in addition, a specific grant from the Office of Dietary Supplements, NCI, NIH, and NIH grants AI074957 (J.M.P.) and GM065204 (V.N.G.). NR 22 TC 2 Z9 2 U1 0 U2 1 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 OCT-NOV PY 2011 VL 49 IS 1-2 BP 311 EP 316 DI 10.1016/j.molimm.2011.09.001 PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 862TU UT WOS:000298117800036 PM 21943784 ER PT J AU Declercq, E Young, R Cabral, H Ecker, J AF Declercq, Eugene Young, Robin Cabral, Howard Ecker, Jeffrey TI Is a Rising Cesarean Delivery Rate Inevitable?: Trends in Industrialized Countries, 1987 to 2007 SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material ID LABOR AB Cesarean delivery rates now exceed 30% in several industrialized countries. The substantial increase in rates of cesarean delivery in the past decade appears to be due in large part to a broadening of the indications for a primary cesarean together with an increase in scheduled repeat cesareans. This study examined current cesarean rates in industrialized countries and assessed changes over time in the trends toward increasing rates. Cesarean delivery rates per 1000 live births were followed from 1987 to 2007 in 22 industrialized countries. For comparability between countries, the inclusion criteria were 50,000 or more births annually and a per capita gross domestic product of at least 10,000 US dollars in 2007. A Poisson regression model was used to evaluate changes in cesarean delivery rates for each country over time. The investigators examined overall cesarean delivery rates, absolute changes in rates, and changes in trend lines for the rates during the study period (1987-2007). Of the 21 countries, 11 reported overall cesarean rates of more than 25% in 2007; 4 had rates more than 30%: Italy (39%), Portugal (35%), the United States (32%), and Switzerland (32%). Between 1992 and 2007, rates increased by more than 2-fold in the Czech Republic, Ireland, Austria, and Hungary. A comparison of cesarean rates across time periods showed that 14 countries (led by the United States, Canada, and Australia) experienced greater rate increases during the period 1998 to 2002 compared with the period 1993 to 1997. An analysis comparing trends from 2003 to 2007 with 1998 to 2002 showed that the rate increases slowed down in 18 countries across these 2 periods. These findings suggest that despite the continuing rise in cesarean delivery rates among industrialized countries between 1987 and 2007, the rate of increase may be slowing down. C1 [Declercq, Eugene] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. Osteoarthrit & Arthrit Ctr Outcomes Res, Boston, MA USA. Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Declercq, E (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. NR 6 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD OCT PY 2011 VL 66 IS 10 BP 603 EP 605 DI 10.1097/OGX.0b013e31823d8618 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 863EQ UT WOS:000298146000004 ER PT J AU Caronia, LM Martin, C Welt, CK Sykiotis, GP Quinton, R Thambundit, A Avbelj, M Dhruvakumar, S Plummer, L Hughes, VA Seminara, SB Boepple, PA Sidis, Y Crowley, WF Martin, KA Hall, JE Pitteloud, N AF Caronia, Lisa M. Martin, Cecilia Welt, Corrine K. Sykiotis, Gerasimos P. Quinton, Richard Thambundit, Apisadaporn Avbelj, Magdalena Dhruvakumar, Sadhana Plummer, Lacey Hughes, Virginia A. Seminara, Stephanie B. Boepple, Paul A. Sidis, Yisrael Crowley, William F., Jr. Martin, Kathryn A. Hall, Janet E. Pitteloud, Nelly TI A Genetic Basis for Functional Hypothalamic Amenorrhea SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Functional hypothalamic amenorrhea, a frequent cause of female infertility, is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency triggered by stressors, such as excessive exercise, nutritional deficits (weight loss, eating disorders), or psychological distress. These stressors suppress the hypothalamic-pituitary-gonadal axis (HPA) by inhibiting hypothalamic secretion of GnRH. Idiopathic hypogonadotropic hypogonadism is a congenital form of GnRH deficiency, with multiple genetic defects accounting for about 40% of the cases. It is unknown whether the variable susceptibility of women with hypothalamic amenorrhea to stressors reflects a genetic predisposition. This study tests the hypothesis that mutations in genes associated with idiopathic hypogonadotropic hypogonadism are causally related to the susceptibility to GnRH deficiency among women with hypothalamic amenorrhea. Genomic DNA from peripheral blood samples of 55 women with hypothalamic amenorrhea was analyzed for the presence of the known coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism. Among 7 of the 55 women with hypothalamic amenorrhea, 6 heterozygous mutations were identified: fibroblast growth factor receptor 1 gene contained 2 mutant variants (G260E and R756H), prokineticin receptor 2 gene (PROKR2) also had 2 variants (R85H and L173R), the GnRH receptor gene had 1 variant (R262Q), and the Kallmann syndrome 1 sequence gene also had 1 (V371I). A cohort of 422 control women with normal menstrual cycles contained no rare sequence variants. In vitro studies characterized the fibroblast growth factor receptor 1 gene mutants G260E and R756H, and the PROKR2 mutant R85H as loss-of-function mutations; previously, the PROKR2 mutant L173R and the GnRH receptor gene mutant R262Q had been reported as loss-of-function mutants. These findings show that genes mutated in patients with idiopathic hypogonadotropic hypogonadism are also mutated in those with hypothalamic amenorrhea. These mutations may account in part for the variable susceptibility of women to stressors leading to hypothalamic amenorrhea. C1 [Caronia, Lisa M.] Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci, Boston, MA 02114 USA. Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Royal Victoria Infirm, Dept Endocrinol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Lausanne, CHU Vaudois, Div Endocrine, Lausanne, Switzerland. RP Caronia, LM (reprint author), Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci, Boston, MA 02114 USA. RI PITTELOUD, Nelly/K-2709-2014; OI Welt, Corrine/0000-0002-8219-5504; Avbelj Stefanija, Magdalena/0000-0002-0836-5114; Sykiotis, Gerasimos/0000-0002-9565-4941 NR 2 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD OCT PY 2011 VL 66 IS 10 BP 618 EP 619 DI 10.1097/OGX.0b013e31822f94c4 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 863EQ UT WOS:000298146000011 ER PT J AU Yao, YL Danna, CH Zemp, FJ Titov, V Ciftci, ON Przybylski, R Ausubel, FM Kovalchuk, I AF Yao, Youli Danna, Cristian H. Zemp, Franz J. Titov, Viktor Ciftci, Ozan Nazim Przybylski, Roman Ausubel, Frederick M. Kovalchuk, Igor TI UV-C-Irradiated Arabidopsis and Tobacco Emit Volatiles That Trigger Genomic Instability in Neighboring Plants SO PLANT CELL LA English DT Article ID SYSTEMIC ACQUIRED-RESISTANCE; ULTRAVIOLET-B RADIATION; SALICYLIC-ACID; JASMONIC ACID; CELL-DEATH; RECOMBINATION FREQUENCY; SIGNAL-TRANSDUCTION; GENE-TRANSCRIPTION; METHYL SALICYLATE; MOSAIC-VIRUS AB We have previously shown that local exposure of plants to stress results in a systemic increase in genome instability. Here, we show that UV-C-irradiated plants produce a volatile signal that triggers an increase in genome instability in neighboring nonirradiated Arabidopsis thaliana plants. This volatile signal is interspecific, as UV-C-irradiated Arabidopsis plants transmit genome destabilization to naive tobacco (Nicotiana tabacum) plants and vice versa. We report that plants exposed to the volatile hormones methyl salicylate (MeSA) or methyl jasmonate (MeJA) exhibit a similar level of genome destabilization as UV-C-irradiated plants. We also found that irradiated Arabidopsis plants produce MeSA and MeJA. The analysis of mutants impaired in the synthesis and/or response to salicylic acid (SA) and/or jasmonic acid showed that at least one other volatile compound besides MeSA and MeJA can communicate interplant genome instability. The NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (npr1) mutant, defective in SA signaling, is impaired in both the production and the perception of the volatile signals, demonstrating a key role for NPR1 as a central regulator of genome stability. Finally, various forms of stress resulting in the formation of necrotic lesions also generate a volatile signal that leads to genomic instability. C1 [Yao, Youli; Titov, Viktor; Kovalchuk, Igor] Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada. [Danna, Cristian H.; Ausubel, Frederick M.] Univ Hartford, Dept Genet, Sch Med, Boston, MA 02114 USA. [Danna, Cristian H.; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Zemp, Franz J.] Univ Calgary, Dept Med Sci, Calgary, AB T2N 4N1, Canada. [Ciftci, Ozan Nazim; Przybylski, Roman] Univ Lethbridge, Dept Chem & Biochem, Lethbridge, AB T1K 3M4, Canada. RP Kovalchuk, I (reprint author), Univ Lethbridge, Dept Biol Sci, Lethbridge, AB T1K 3M4, Canada. EM igor.kovalchuk@uleth.ca FU Natural Sciences and Engineering Research Council of Canada; Alberta Agriculture Research Institute; Human Frontiers Scientific Program; National Institutes of Health [R37 GM48707]; National Science Foundation [MCB-0519898] FX Financial support was provided by The Natural Sciences and Engineering Research Council of Canada, Alberta Agriculture Research Institute, and Human Frontiers Scientific Program grants to I. K. and by National Institutes of Health Grant R37 GM48707 and National Science Foundation Grant MCB-0519898 awarded to F.M.A. NR 53 TC 16 Z9 16 U1 4 U2 24 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 1040-4651 J9 PLANT CELL JI Plant Cell PD OCT PY 2011 VL 23 IS 10 BP 3842 EP 3852 DI 10.1105/tpc.111.089003 PG 11 WC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology SC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology GA 863OU UT WOS:000298175900022 PM 22028460 ER PT J AU Woods, DL Phillips, LR Martin, JL AF Woods, Diana Lynn Phillips, Linda R. Martin, Jennifer L. TI Biological Basis for Sleep Disturbance and Behavioral Symptoms in Dementia A Biobehavioral Model SO RESEARCH IN GERONTOLOGICAL NURSING LA English DT Article ID NURSING-HOME RESIDENTS; MILD COGNITIVE IMPAIRMENT; APOLIPOPROTEIN-E GENOTYPE; CORTISOL SECRETORY ACTIVITY; PITUITARY-ADRENAL AXIS; LONG-TERM-CARE; ALZHEIMERS-DISEASE; SALIVARY CORTISOL; PSYCHOLOGICAL SYMPTOMS; APOE GENOTYPE AB Behavioral symptoms and sleep disturbance occur in more than 56% of older adults with mild to moderate dementia and are challenging and costly. This article proposes a biobehavioral causal model to explain sleep disturbances and behavioral symptoms in dementia (BSD) based on an integrative science perspective using the life cycle model of stress (chronic stress) integrating genetic, neuroendocrine, and personality factors. The model proposes that: (a) BSD are an outcome of sleep disturbance; (b) hypothalamic-pituitary-adrenal (HPA) axis dysregulation is key to sleep disturbances and BSD; (c) genotype influences response to stress hormones; (d) HPA is influenced by genotype; (e) trait anxiety moderates the relationship between HPA axis and BSD and/or sleep disturbances; and (f) trait anxiety is influenced by genotype. Examining these relationships simultaneously will advance our theoretical understanding of BSD and sleep disturbances, potentially providing a basis for the design of targeted interventions and prevention strategies with an understanding of risk. C1 [Woods, Diana Lynn; Phillips, Linda R.] Univ Calif Los Angeles, Sch Nursing, Ctr Adv Gerontol Nursing Sci, Los Angeles, CA 90095 USA. [Martin, Jennifer L.] Univ Calif Los Angeles, Multicampus Program Geriatr Med & Gerontol, Los Angeles, CA 90095 USA. [Martin, Jennifer L.] Vet Affairs Greater Los Angeles Healthcare Syst, Ctr Geriatr Res Educ & Clin, Los Angeles, CA USA. RP Woods, DL (reprint author), Univ Calif Los Angeles, Sch Nursing, Ctr Adv Gerontol Nursing Sci, 700 Tiverton Ave,Box 956919, Los Angeles, CA 90095 USA. EM lwoods@sonnet.ucla.edu FU University of California, Los Angeles, School of Nursing; National Institute on Aging [K23 AG028452] FX The authors disclose that they have no significant financial interests in any product or class of products discussed directly or indirectly in this activity. The authors acknowledge pilot study support from the University of California, Los Angeles, School of Nursing, Intramural Grant (D. L. Woods) and National Institute on Aging grant K23 AG028452 (L.R. Phillips). NR 125 TC 3 Z9 3 U1 3 U2 8 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1940-4921 J9 RES GERONTOL NURS JI Res. Gerontol. Nurs. PD OCT PY 2011 VL 4 IS 4 BP 281 EP 293 DI 10.3928/19404921-20110302-01 PG 13 WC Nursing SC Nursing GA 864YL UT WOS:000298276300007 PM 21417189 ER PT J AU Kehinde, JO Pope, C Amella, EJ AF Kehinde, Julius Oluwole Pope, Charlene Amella, Elaine J. TI Methodological Issues in Fall Prevention Research Involving Older Adults in Long-Term Care Facilities SO RESEARCH IN GERONTOLOGICAL NURSING LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; NURSING-HOME RESIDENTS; RISK ASSESSMENT-TOOL; TAI-CHI; STRATEGIES; PEOPLE; COSTS; INTERVENTION; PROGRAMS; CLUSTER AB The purpose of this study was to conduct a systematic review of the current fall prevention literature, examining methodological issues resulting from variations in fall definitions, methods of data collection, and standards for reporting fall rates in studies involving older adults in long-term care settings. This systematic review used the five stages of Whittemore and Knafl's review methodology to extract data from the databases, summarize, and synthesize the findings of the 10 studies included. The Critical Appraisal Skill Program checklist for randomized controlled trials criteria was used to appraise the methodological quality of the studies. Inconsistencies in fall definitions, methods of data collection, and standards for reporting fall rates were apparent across the studies reviewed. Standardized approaches to defining falls, collecting data, and reporting fall rates are necessary to interpret, make comparisons among, and disseminate the findings of studies. C1 [Kehinde, Julius Oluwole; Pope, Charlene; Amella, Elaine J.] Med Univ S Carolina, Coll Nursing, Charleston, SC 29425 USA. [Pope, Charlene] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Kehinde, JO (reprint author), Med Univ S Carolina, Coll Nursing, 99 Jonathan Lucas St, Charleston, SC 29425 USA. EM jok31@musc.edu OI Amella, Elaine/0000-0003-4114-429X NR 56 TC 1 Z9 1 U1 3 U2 14 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1940-4921 J9 RES GERONTOL NURS JI Res. Gerontol. Nurs. PD OCT PY 2011 VL 4 IS 4 BP 294 EP 304 DI 10.3928/19404921-20110503-02 PG 11 WC Nursing SC Nursing GA 864YL UT WOS:000298276300008 PM 21598864 ER PT J AU Siek, KA Khan, DU Ross, SE Haverhals, LM Meyers, J Cali, SR AF Siek, Katie A. Khan, Danish U. Ross, Stephen E. Haverhals, Leah M. Meyers, Jane Cali, Steven R. TI Designing a Personal Health Application for Older Adults to Manage Medications: A Comprehensive Case Study SO JOURNAL OF MEDICAL SYSTEMS LA English DT Article DE Older adults; Personal Health Records; Personal Health Applications; Participatory design; Medication management; Interdisciplinary design ID NONADHERENCE; CARE; HOSPITALIZATION; ADHERENCE; DISEASE; HOME AB Older adults with multiple chronic conditions often go through care transitions where they move between care facilities or providers during their treatment. These transitions are often uncoordinated and can imperil patients by omitted, duplicative, or contradictory care plans. Older adults sometimes feel overwhelmed with the new responsibility of coordinating the care plan with providers and changing their medication regimes. In response, we developed a Lesser General Public License (LGPL) open source, web-based Personal Health Application (PHA) using an iterative participatory design process that provided older adults and their caregivers the ability to manage their personal health information. In this paper, we document the PHA design process from low-fidelity prototypes to high-fidelity prototypes over the course of six user studies. Our findings establish the imperative need for interdisciplinary research and collaboration among all stakeholders to create effective PHAs. We conclude with design guidelines that encourage researchers to gradually increase functionality as users become more proficient. C1 [Siek, Katie A.; Khan, Danish U.; Meyers, Jane] Univ Colorado Boulder, Dept Comp Sci, Boulder, CO 80309 USA. [Ross, Stephen E.] Univ Colorado Denver, Div Gen Internal Med, Denver, CO 80202 USA. [Haverhals, Leah M.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. [Cali, Steven R.] Univ Colorado Denver, Denver, CO 80217 USA. RP Siek, KA (reprint author), Univ Colorado Boulder, Dept Comp Sci, 430 UCB, Boulder, CO 80309 USA. EM ksiek@cs.colorado.edu; khand@colorado.edu; Steve.Ross@ucdenver.edu; leah.haverhals@gmail.com; meyersjk@colorado.edu; stevecali@gmail.com FU Robert Wood Johnson Foundation [RWJ59880] FX We thank our participants and expert review panel for their valuable feedback. We also thank the reviewers for their insightful and constructive comments. This research was funded by the Robert Wood Johnson Foundation Project HealthDesign Grant RWJ59880 (PI Stephen E. Ross). NR 41 TC 22 Z9 22 U1 4 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0148-5598 J9 J MED SYST JI J. Med. Syst. PD OCT PY 2011 VL 35 IS 5 SI SI BP 1099 EP 1121 DI 10.1007/s10916-011-9719-9 PG 23 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 859DZ UT WOS:000297856600040 PM 21562730 ER PT J AU Sayegh, RR Madsen, KA Adler, JD Johnson, MA Mathews, MK AF Sayegh, Rony R. Madsen, Kimberly A. Adler, Jason D. Johnson, Mary A. Mathews, Michaela K. TI Diffuse retinal injury from a non-penetrating TASER dart SO DOCUMENTA OPHTHALMOLOGICA LA English DT Article DE Electrical injury; Electroretinogram; Eye; Ocular injury; Retinal detachment; TASER; Trauma ID OCULAR INJURY; CATARACT AB To describe a non-penetrating TASER gun injury resulting in a small exudative retinal detachment but significant visual acuity and retinal function loss as demonstrated by electroretinography (ERG). A 39-year-old man presented to the emergency department with a TASER barb embedded in his right lower lid. A complete clinical ophthalmologic examination and surgical extrication were performed, as well as radiologic imaging and Ganzfeld electroretinography. No scleral penetration was observed on surgical exploration. Retinal examination showed a peripheral exudative detachment. Subsequent follow-up revealed progressive resolution of the detachment and improvement in visual acuity. The ERG showed a 63-70% decrease in rod a- and b-waves, while isolated cone responses were reduced by only 10%, with a minimal increase in implicit time. This case shows that periocular TASER injuries, even if apparently superficial, may result in significant ocular damage. ERG may be useful in the diagnosis of visual loss attributed to disturbance in photoreceptor function, in the absence of anatomically evident damage. C1 [Sayegh, Rony R.; Madsen, Kimberly A.; Johnson, Mary A.; Mathews, Michaela K.] Univ Maryland, Sch Med, Dept Ophthalmol & Visual Sci, Baltimore, MD 21201 USA. [Sayegh, Rony R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Adler, Jason D.] Univ Maryland, Sch Med, Dept Emergency Med, Baltimore, MD 21201 USA. RP Mathews, MK (reprint author), Univ Maryland, Sch Med, Dept Ophthalmol & Visual Sci, Baltimore, MD 21201 USA. EM mmath002@umaryland.edu RI Sayegh, Rony/G-8777-2013 OI Sayegh, Rony/0000-0002-0119-4201 FU Research to Prevent Blindness; National Institutes of Health [1KO8EY016357-01A2] FX This work was supported in part by a grant from Research to Prevent Blindness (MAJ) and by National Institutes of Health grant #1KO8EY016357-01A2 (MKM). NR 11 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0012-4486 J9 DOC OPHTHALMOL JI Doc. Ophthalmol. PD OCT PY 2011 VL 123 IS 2 BP 135 EP 139 DI 10.1007/s10633-011-9287-9 PG 5 WC Ophthalmology SC Ophthalmology GA 859BW UT WOS:000297850200008 PM 21909993 ER PT J AU Cibulskis, K Lawrence, M Sivachenko, A Sougnez, C Nickerson, E McKenna, A Ramos, A Stojanov, P Hodis, E Zou, L Imielinski, M Saksena, G Drier, Y Bass, A Garraway, L Meyerson, M Getz, G AF Cibulskis, K. Lawrence, M. Sivachenko, A. Sougnez, C. Nickerson, E. McKenna, A. Ramos, A. Stojanov, P. Hodis, E. Zou, L. Imielinski, M. Saksena, G. Drier, Y. Bass, A. Garraway, L. Meyerson, M. Getz, G. TI Landscape of Somatic Alterations in Cancer and Their Relationship to the Environment SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Meeting Abstract CT 42nd Annual Meeting of the Environmental-Mutagen-Society on Environmental Impacts on the Genome and Epigenome - Mechanisms and Risks CY OCT 15-19, 2011 CL Montreal, CANADA SP Environm Mutagen Soc C1 [Cibulskis, K.; Lawrence, M.; Sivachenko, A.; Sougnez, C.; Nickerson, E.; McKenna, A.; Ramos, A.; Stojanov, P.; Hodis, E.; Zou, L.; Imielinski, M.; Saksena, G.; Drier, Y.; Bass, A.; Garraway, L.; Meyerson, M.; Getz, G.] Broad Inst & Harvard, Cambridge, MA USA. [Bass, A.; Garraway, L.; Meyerson, M.] Dana Farber Canc Inst, Boston, MA 02115 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 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD OCT PY 2011 VL 52 SU 1 BP S24 EP S24 PG 1 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 860DU UT WOS:000297929800047 ER PT J AU Horga, G Bernacer, J Dusi, N Entis, J Chu, KW Hazlett, EA Haznedar, MM Kemether, E Byne, W Buchsbaum, MS AF Horga, Guillermo Bernacer, Javier Dusi, Nicola Entis, Jonathan Chu, Kingwai Hazlett, Erin A. Haznedar, M. Mehmet Kemether, Eileen Byne, William Buchsbaum, Monte S. TI Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia SO EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE LA English DT Article DE Cerebral spinal fluid; Sulcal enlargement; Myelin; Fronto-thalamic connectivity ID SCHIZOTYPAL PERSONALITY-DISORDER; CORTICAL BRODMANNS AREAS; GLUCOSE METABOLIC-RATE; COMPREHENSIVE ASSESSMENT; HEALTHY-INDIVIDUALS; BRAIN; SIZE; MEDIODORSAL; PULVINAR; ABNORMALITIES AB Ventricular enlargement is one of the most consistent abnormal structural brain findings in schizophrenia and has been used to infer brain shrinkage. However, whether ventricular enlargement is related to local overlying cortex and/or adjacent subcortical structures or whether it is related to brain volume change globally has not been assessed. We systematically assessed interrelations of ventricular volumes with gray and white matter volumes of 40 Brodmann areas (BAs), the thalamus and its medial dorsal nucleus and pulvinar, the internal capsule, caudate and putamen. We acquired structural MRI (patients with schizophrenia (n = 64) and healthy controls (n = 56)) and diffusion tensor fractional anisotropy (FA) (untreated schizophrenia n = 19, controls n = 32). Volumes were assessed by manual tracing of central structures and a semi-automated parcellation of BAs. Patients with schizophrenia had increased ventricular size associated with decreased cortical gray matter volumes widely across the brain; a similar but less pronounced pattern was seen in normal controls; local correlations (e.g. temporal horn with temporal lobe volume) were not appreciably higher than non-local correlations (e.g. temporal horn with prefrontal volume). White matter regions adjacent to the ventricles similarly did not reveal strong regional relationships. FA and center of mass of the anterior limb of the internal capsule also appeared differentially influenced by ventricular volume but findings were similarly not regional. Taken together, these findings indicate that ventricular enlargement is globally interrelated with gray matter volume diminution but not directly correlated with volume loss in the immediately adjacent caudate, putamen, or internal capsule. C1 [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Psychiat, NeuroPET Ctr, San Diego, CA 92121 USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Radiol, NeuroPET Ctr, San Diego, CA 92121 USA. [Horga, Guillermo; Entis, Jonathan; Chu, Kingwai; Kemether, Eileen] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Horga, Guillermo] Hosp Clin Barcelona, Dept Psychiat, Schizophrenia Clin Program, E-08036 Barcelona, Spain. [Bernacer, Javier] Univ Navarra, Clin Univ, Lab Funct Neuromorphol, Pamplona 31008, Spain. [Dusi, Nicola] Univ Verona, Policlin Giambattista Rossi, Dept Publ Hlth & Community Med, Sect Psychiat & Clin Psychol, I-37134 Verona, Italy. [Hazlett, Erin A.; Haznedar, M. Mehmet; Byne, William] James J Peters VA Med Ctr, Dept Psychiat, Bronx, NY 10468 USA. RP Buchsbaum, MS (reprint author), Univ Calif San Diego, Dept Psychiat, NeuroPET Ctr, 11388 Sorrento Valley Rd,Suite 100, San Diego, CA 92121 USA. EM mbuchsbaum@ucsd.edu RI Bernacer, Javier/P-5810-2014; Horga, Guillermo/M-8036-2016 OI Bernacer, Javier/0000-0002-4341-9763; Horga, Guillermo/0000-0002-9049-9786 NR 47 TC 17 Z9 18 U1 0 U2 8 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0940-1334 J9 EUR ARCH PSY CLIN N JI Eur. Arch. Psych. Clin. Neurosci. PD OCT PY 2011 VL 261 IS 7 BP 467 EP 476 DI 10.1007/s00406-011-0202-x PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 856EH UT WOS:000297619700003 PM 21431919 ER PT J AU Quackenbush, J AF Quackenbush, J. TI Driving discovery through data integration and analysis SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 5th European-Organisation-for-Research-and-Treatment-of-Cancer (EORTC)/National-Cancer-Institute (NCI)/American-Society-of-Clinical-Oncology (ASCO) Annual Meeting on Molecular Markers in Cancer CY OCT 27-29, 2011 CL Brussels, BELGIUM SP European Org Res & Treatment Canc (EORTC), Natl Canc Inst (NCI), Amer Soc Clin Oncol (ASCO) C1 [Quackenbush, J.] Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD OCT PY 2011 VL 47 SU 4 BP S4 EP S4 PG 1 WC Oncology SC Oncology GA 853UT UT WOS:000297451900017 ER PT J AU DeAngelo, DJ AF DeAngelo, Daniel J. TI Chronic Myelogenous Leukemia Preface SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Editorial Material C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Adult Leukemia Program, Boston, MA 02115 USA. RP DeAngelo, DJ (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Adult Leukemia Program, 450 Brookline Ave, Boston, MA 02115 USA. EM Daniel_Deangelo@dfci.harvard.edu NR 0 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 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD OCT PY 2011 VL 25 IS 5 BP IX EP X DI 10.1016/j.hoc.2011.10.001 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 858ST UT WOS:000297823700001 PM 22054737 ER PT J AU Stolzmann, P Alkadhi, H Scheffel, H Plass, A Leschka, S Falk, V Kozerke, S Wyss, C Donati, OF AF Stolzmann, Paul Alkadhi, Hatem Scheffel, Hans Plass, Andre Leschka, Sebastian Falk, Volkmar Kozerke, Sebastian Wyss, Christophe Donati, Olivio F. TI Combining cardiac magnetic resonance and computed tomography coronary calcium scoring: added value for the assessment of morphological coronary disease? SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Coronary artery disease; Calcium scoring; Cardiac magnetic resonance imaging; Coronary catheterization ID AMERICAN-HEART-ASSOCIATION; ELECTRON-BEAM TOMOGRAPHY; ARTERY-DISEASE; CLINICAL CARDIOLOGY; NUCLEAR-CARDIOLOGY; STRESS PERFUSION; PROGNOSTIC VALUE; CT ANGIOGRAPHY; RISK-FACTORS; K-SPACE AB To investigate prospectively, in patients with suspicion of coronary artery disease (CAD), the added value of coronary calcium scoring (CS) as adjunct to cardiac magnetic resonance (CMR) for the diagnosis of morphological coronary stenosis in comparison to catheter angiography (CA). Sixty consecutive patients (8 women; 64 +/- 10 years) referred to CA underwent CMR (1.5 T) including perfusion and late gadolinium-enhancement imaging as well as CS with computed tomography. Diagnostic performance was evaluated for CMR and CS separately, and for both methods combined, with CA as reference standard. Best CS threshold combined with a specificity >90% to predict significant stenosis in patients without abnormalities on CMR was determined from receiver operator characteristics (ROC) analysis. Abnormal CMR results were considered to indicate significant stenosis regardless of CS; CS above threshold reclassified patients to have CAD regardless of CMR. CA identified 104/960 (11%) coronary segments with coronary artery stenosis >50% in 36/60 (60%) patients. ROC revealed an area-under-the-curve of 0.83 (95% CI: 0.68-0.99) with the best CS threshold of 495 Agatston score (sensitivity 50%). CMR depicted 128/960 (13%) myocardial segments with abnormalities in 31/60 (52%) patients. Sensitivity, specificity, negative (NPV) and positive predictive value (PPV) of CMR were 78, 88, 72 and 90%. When adding CS to CMR, sensitivity and NPV increased to 89 and 83%, while specificity and PPV slightly decreased to 83 and 89%. Accuracy of the combined approach (87%) was significantly (P < 0.05) higher than that of CMR (82%) alone. Adding CS to CMR improves the accuracy for the detection of morphological CAD. C1 [Stolzmann, Paul; Alkadhi, Hatem] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Stolzmann, Paul; Alkadhi, Hatem] Harvard Univ, Sch Med, Boston, MA USA. [Stolzmann, Paul; Alkadhi, Hatem; Scheffel, Hans; Leschka, Sebastian; Donati, Olivio F.] Univ Zurich Hosp, Inst Diagnost Radiol, CH-8091 Zurich, Switzerland. [Plass, Andre; Falk, Volkmar] Univ Zurich Hosp, Cardiovasc Surg Clin, CH-8091 Zurich, Switzerland. [Kozerke, Sebastian] Univ Zurich, Zurich, Switzerland. [Kozerke, Sebastian] ETH, Inst Biomed Engn, Zurich, Switzerland. [Wyss, Christophe] Univ Zurich Hosp, Dept Cardiol, CH-8091 Zurich, Switzerland. RP Stolzmann, P (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. EM pstolzmann@partners.org RI Kozerke, Sebastian/J-3209-2015 OI Kozerke, Sebastian/0000-0003-3725-8884 NR 31 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD OCT PY 2011 VL 27 IS 7 BP 969 EP 977 DI 10.1007/s10554-010-9738-5 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 858ZB UT WOS:000297841600008 PM 21052842 ER PT J AU Yoon, YE Chang, HJ Cho, I Jeon, KH Chun, EJ Choi, SI Bae, HJ Rivera, JJ Nasir, K Blumenthal, RS Lim, TH AF Yoon, Yeonyee E. Chang, Hyuk-Jae Cho, Iksung Jeon, Ki-Hyun Chun, Eun-Ju Choi, Sang-il Bae, Hee-Jun Rivera, Juan J. Nasir, Khurram Blumenthal, Roger S. Lim, Tae-Hwan TI Incidence of subclinical coronary atherosclerosis in patients with suspected embolic stroke using cardiac computed tomography SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Stroke; Coronary artery disease; Cardiac computed tomography; Diagnosis ID TRANSIENT ISCHEMIC ATTACK; HEALTH-CARE PROFESSIONALS; ARTERY-DISEASE; CEREBROVASCULAR-DISEASE; SCIENTIFIC STATEMENT; DIAGNOSTIC-ACCURACY; CLINICAL CARDIOLOGY; RISK-EVALUATION; ANGIOGRAPHY; ASSOCIATION AB The purpose of this study was to investigate the incidence of subclinical coronary artery disease (CAD) in patients with suspected acute embolic stroke or transient ischemic attack (TIA) using 64-row multi-slice computed tomography (MSCT) and to examine its association with conventional risk stratification. We consecutively enrolled 175 patients (66 +/- 13 years, 50% men) suspected to have had embolic stroke/TIA clinically or radiologically, and underwent 64-row MSCT to evaluate for a possible cardiac source of embolism. Both coronary artery calcium scoring (CACS) and coronary CT angiography (CCTA) were concurrently performed based on standard scanning protocols. Patients with a history of angina or documented CAD, and those with significant carotid stenosis were excluded. Atherosclerotic plaques were indentified in 105 (60%) individuals; 37 (21%) had occult CAD of >= 50% diameter stenosis on CCTA. Subjects with and without >= 50% occult CAD on CCTA had similar prevalence of cardiovascular risk factors. Thirty out of 175 (17%) individuals with >= 50% occult CAD would have missed further cardiac testing based on the American Heart association and the American Stroke Association guideline. However, these numbers would be reduced to 2% (4/175) using CACS. In logistic regression analysis, only CACS independently predicted the presence >= 50% occult CAD evidenced by CCTA. Subclinical CAD, including >= 50% stenotic disease, is highly prevalent in patients who had suffered a suspected embolic stroke. The current guideline for further cardiac testing may have limited value to identify patients with >= 50% CAD in this patient population, which can be improved by adopting CACS. C1 [Chang, Hyuk-Jae] Severance Cardiovasc Hosp, Div Cardiol, Seoul 120752, South Korea. [Yoon, Yeonyee E.; Cho, Iksung; Jeon, Ki-Hyun] Seoul Natl Univ, Bundang Hosp, Cardiovasc Ctr, Div Cardiol, Songnam, South Korea. [Chun, Eun-Ju; Choi, Sang-il] Seoul Natl Univ, Bundang Hosp, Dept Radiol, Songnam, South Korea. [Bae, Hee-Jun] Seoul Natl Univ, Bundang Hosp, Dept Neurol, Songnam, South Korea. [Rivera, Juan J.; Nasir, Khurram; Blumenthal, Roger S.] Johns Hopkins Ciccarone Prevent Cardiol Ctr, Baltimore, MD USA. [Rivera, Juan J.] S Beach Prevent Cardiol, Miami Beach, FL USA. [Nasir, Khurram] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac MR PET CT Program, Boston, MA USA. [Lim, Tae-Hwan] Ulsan Univ Hosp, Dept Radiol, Seoul, South Korea. RP Chang, HJ (reprint author), Severance Cardiovasc Hosp, Div Cardiol, 250 Seongsan No, Seoul 120752, South Korea. EM hjchang@yuhs.ac FU Ministry of Health, Welfare and Family Affairs, Republic of Korea [A060171] FX This study was supported by a grant (A060171) of the Korea Health 21 R&D project, Ministry of Health, Welfare and Family Affairs, Republic of Korea. NR 34 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD OCT PY 2011 VL 27 IS 7 BP 1035 EP 1044 DI 10.1007/s10554-010-9743-8 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 858ZB UT WOS:000297841600016 PM 21063781 ER PT J AU Choudhry, N Orlin, A Bilaniuk, L Maguire, AM AF Choudhry, Netan Orlin, Anton Bilaniuk, Larissa Maguire, Albert M. TI Cerebroretinal microangiopathy with occlusive telangiectasia and multisytemic manifestations SO JOURNAL OF AAPOS LA English DT Article ID CALCIFICATIONS; CYSTS AB Cerebroretinal microangiopathy with calcification and cysts is a multisystem autosomal-recessive disorder in which there is an obliterative angiopathy of small vessels, primarily in the brain, retina, and gastrointestinal tract. We present the case of a 14-year-old boy with cerebroretinal microangiopathy with calcification and cysts illustrating the classic occlusive retinal telangiectasias. His condition was diagnosed using multiple imaging modalities, including upper gastrointestinal endoscopy of the upper gastrointestinal tract, magnetic resonance imaging, optical coherence tomography, and fluorescein angiography. C1 [Choudhry, Netan] Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02141 USA. [Choudhry, Netan; Orlin, Anton; Maguire, Albert M.] Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Bilaniuk, Larissa] Childrens Hosp Philadelphia, Dept Ophthalmol, Philadelphia, PA 19104 USA. RP Choudhry, N (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 12th Floor,243 Charles St, Boston, MA 02141 USA. EM netan.choudhry@gmail.com NR 5 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 1091-8531 J9 J AAPOS JI J. AAPOS PD OCT PY 2011 VL 15 IS 5 BP 502 EP 503 DI 10.1016/j.jaapos.2011.05.014 PG 2 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 856PZ UT WOS:000297657200026 PM 22108368 ER PT J AU Baraghis, E Devor, A Fang, QQ Srinivasan, VJ Wu, WC Lesage, F Ayata, C Kasischke, KA Boas, DA Sakadzic, S AF Baraghis, Edward Devor, Anna Fang, Qianqian Srinivasan, Vivek J. Wu, Weicheng Lesage, Frederic Ayata, Cenk Kasischke, Karl A. Boas, David A. Sakadzic, Sava TI Two-photon microscopy of cortical NADH fluorescence intensity changes: correcting contamination from the hemodynamic response SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE nicotinamide adenine dinucleotide fluorescence; two-photon laser scanning microscopy; brain imaging; correction algorithms; Monte Carlo simulations; optical scattering; hemoglobin absorption ID PYRIDINE-NUCLEOTIDE FLUORESCENCE; IN-VIVO; OPTICAL-PROPERTIES; TISSUE FLUORESCENCE; INTRACELLULAR NADH; BRAIN CORTEX; BLOOD-VOLUME; SCATTERING; HEMATOCRIT; NM AB Quantification of nicotinamide adenine dinucleotide (NADH) changes during functional brain activation and pathological conditions provides critical insight into brain metabolism. Of the different imaging modalities, two-photon laser scanning microscopy (TPLSM) is becoming an important tool for cellular-resolution measurements of NADH changes associated with cellular metabolic changes. However, NADH fluorescence emission is strongly absorbed by hemoglobin. As a result, in vivo measurements are significantly affected by the hemodynamics associated with physiological and pathophysiological manipulations. We model NADH fluorescence excitation and emission in TPLSM imaging based on precise maps of cerebral microvasculature. The effects of hemoglobin optical absorption and optical scattering from red blood cells, changes in blood volume and hemoglobin oxygen saturation, vessel size, and location with respect to imaging location are explored. A simple technique for correcting the measured NADH fluorescence intensity changes is provided, with the utilization of a parallel measurement of a physiologically inert fluorophore. The model is applied to TPLSM measurements of NADH fluorescence intensity changes in rat somatosensory cortex during mild hypoxia and hyperoxia. The general approach of the correction algorithm can be extended to other TPLSM measurements, where changes in the optical properties of the tissue confound physiological measurements, such as the detection of calcium dynamics. (C) 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.3633339] C1 [Baraghis, Edward; Lesage, Frederic] Ecole Polytech, Dept Genie Elect, Montreal, PQ H3C 3A7, Canada. [Devor, Anna] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA. [Devor, Anna] Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA. [Ayata, Cenk] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Neurovasc Res Lab, Charlestown, MA 02129 USA. [Ayata, Cenk] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA 02114 USA. [Ayata, Cenk] Massachusetts Gen Hosp, Dept Neurol, Neurosci Intens Care Unit, Boston, MA 02114 USA. [Kasischke, Karl A.] Univ Rochester, Med Ctr, Dept Neurol, Ctr Neural Dev & Dis, Rochester, NY 14642 USA. RP Sakadzic, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM sava@nmr.mgh.harvard.edu FU U.S. National Institute of Health [R01-NS057476, S10-RR022428, P01-NS055104, K99NS067050]; American Heart Association [11SDG7600037, 11IRG5440002] FX We thank M. A. Yaseen and G. Boas for critically reading the manuscript and support from U.S. National Institute of Health Grants No. R01-NS057476, No. S10-RR022428, No. P01-NS055104, and No. K99NS067050, as well as American Heart Association Grants No. 11SDG7600037 and No. 11IRG5440002. NR 47 TC 8 Z9 8 U1 1 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 OCT PY 2011 VL 16 IS 10 AR 106003 DI 10.1117/1.3633339 PG 13 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 853ZV UT WOS:000297465200010 PM 22029350 ER PT J AU Wang, Q Grozdanic, SD Harper, MM Hamouche, N Kecova, H Lazic, T Yu, CX AF Wang, Qi Grozdanic, Sinisa D. Harper, Matthew M. Hamouche, Nicolas Kecova, Helga Lazic, Tatjana Yu, Chenxu TI Exploring Raman spectroscopy for the evaluation of glaucomatous retinal changes SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE glaucoma; raman spectroscopy; retinal ganglion cells; detection; support vector machine ID FLUORESCENCE; MICROSCOPY; SPECTRA; MODELS; EYE AB Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cells and subsequent loss of visual function. Early detection of glaucoma is critical for the prevention of permanent structural damage and irreversible vision loss. Raman spectroscopy is a technique that provides rapid biochemical characterization of tissues in a nondestructive and noninvasive fashion. In this study, we explored the potential of using Raman spectroscopy for detection of glaucomatous changes in vitro. Raman spectroscopic imaging was conducted on retinal tissues of dogs with hereditary glaucoma and healthy control dogs. The Raman spectra were subjected to multivariate discriminant analysis with a support vector machine algorithm, and a classification model was developed to differentiate disease tissues versus healthy tissues. Spectroscopic analysis of 105 retinal ganglion cells (RGCs) from glaucomatous dogs and 267 RGCs from healthy dogs revealed spectroscopic markers that differentiated glaucomatous specimens from healthy controls. Furthermore, the multivariate discriminant model differentiated healthy samples and glaucomatous samples with good accuracy [healthy 89.5% and glaucomatous 97.6% for the same breed (Basset Hounds); and healthy 85.0% and glaucomatous 85.5% for different breeds (Beagles versus Basset Hounds)]. Raman spectroscopic screening can be used for in vitro detection of glaucomatous changes in retinal tissue with a high specificity. (C) 2011 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.3642010] C1 [Wang, Qi; Yu, Chenxu] Iowa State Univ, Dept Agr & Biosyst Engn, Ames, IA 50011 USA. [Grozdanic, Sinisa D.; Harper, Matthew M.; Kecova, Helga; Lazic, Tatjana] US Dept Vet Affairs, Ctr Prevent & Treatment Visual Loss, Iowa City, IA 52246 USA. [Hamouche, Nicolas] McFarland Clin Eye Ctr, Ames, IA 50011 USA. RP Yu, CX (reprint author), Iowa State Univ, Dept Agr & Biosyst Engn, 3224 NSRIC, Ames, IA 50011 USA. EM chenxuyu@iastate.edu FU U.S. Department of Veterans Affairs Center for Prevention and Treatment of Visual Loss FX This study has been supported by the U.S. Department of Veterans Affairs Center for Prevention and Treatment of Visual Loss. NR 31 TC 3 Z9 3 U1 0 U2 8 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD OCT PY 2011 VL 16 IS 10 AR 107006 DI 10.1117/1.3642010 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 853ZV UT WOS:000297465200028 PM 22029368 ER PT J AU Belmatoug, N Burlina, A Giraldo, P Hendriksz, CJ Kuter, DJ Mengel, E Pastores, GM AF Belmatoug, Nadia Burlina, Alberto Giraldo, Pilar Hendriksz, Chris J. Kuter, David J. Mengel, Eugen Pastores, Gregory M. TI Gastrointestinal disturbances and their management in miglustat-treated patients SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Review ID DISEASE TYPE-C; I GAUCHER-DISEASE; N-BUTYL-DEOXYNOJIRIMYCIN; CLINICAL-EXPERIENCE; DISACCHARIDASE ACTIVITIES; BUTYLDEOXYNOJIRIMYCIN; THERAPY; TRIAL; BIOSYNTHESIS; INHIBITOR AB Miglustat (Zavesca (R)) is approved for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease (GD1) for whom enzyme replacement therapy is unsuitable, and for the treatment of progressive neurological manifestations in adult and paediatric patients with Niemann-Pick disease type C (NP-C). Gastrointestinal disturbances such as diarrhoea, flatulence and abdominal pain/discomfort have consistently been reported as the most frequent adverse events associated with miglustat during clinical trials and in real-world clinical practice settings. These adverse events are generally mild or moderate in severity, occurring mostly during the initial weeks of therapy. The mechanism underlying these gastrointestinal disturbances is the inhibition by miglustat of intestinal disaccharidase enzymes (mainly sucrase and maltase), leading to suboptimal hydrolysis of carbohydrates and subsequent osmotic diarrhoea and altered colonic fermentation. Transient decreases in body weight, which are often observed during initial miglustat therapy, are considered likely due to gastrointestinal carbohydrate malabsorption and associated negative caloric balance. While most cases of diarrhoea resolve spontaneously during continued miglustat therapy, diarrhoea also responds well to anti-propulsive medications such as loperamide. Dietary modifications such as reduced consumption of dietary sucrose, maltose and lactose have been shown to improve the gastrointestinal tolerability of miglustat and reduce the magnitude of any changes in body weight, particularly if initiated at or before the start of therapy. Miglustat dose escalation at treatment initiation may also reduce gastrointestinal disturbances. This article discusses these aspects in detail, and provides practical recommendations on how to optimize the gastrointestinal tolerability of miglustat. C1 [Pastores, Gregory M.] NYU Langone Med Ctr, Dept Neurol, Neurogenet Unit, New York, NY 10016 USA. [Belmatoug, Nadia] Beaujon Hosp, Reference Ctr Lysosomal Dis, Clichy, France. [Burlina, Alberto] Univ Hosp Padova, Div Metab Dis, Padua, Italy. [Giraldo, Pilar] CIBERER, Miguel Servet Hosp, Zaragoza, Spain. [Hendriksz, Chris J.] Birmingham Childrens Hosp NHS Fdn Trust, Birmingham, W Midlands, England. [Kuter, David J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mengel, Eugen] Johannes Gutenberg Univ Mainz, Mainz, Germany. RP Pastores, GM (reprint author), NYU Langone Med Ctr, Dept Neurol, Neurogenet Unit, 403 E 34th St,2nd Floor, New York, NY 10016 USA. EM gregory.pastores@med.nyu.edu FU Actelion Pharmaceuticals Ltd. FX Matthew Reilly, PhD, associated with InTouch Medical Ltd. provided medical writing assistance in the preparation of this manuscript, funded by Actelion Pharmaceuticals Ltd. NR 40 TC 24 Z9 25 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD OCT PY 2011 VL 34 IS 5 BP 991 EP 1001 DI 10.1007/s10545-011-9368-7 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 857UZ UT WOS:000297749500003 PM 21779792 ER PT J AU Azarova, AM Gautam, G George, RE AF Azarova, Anna M. Gautam, Gargi George, Rani E. TI Emerging importance of ALK in neuroblastoma SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE Neuroblastoma; ALK; Tyrosine kinase receptor; Targeted therapy; Crizotinib; Drug resistance; Point mutations; Small molecule inhibitors; Combination treatment ID ANAPLASTIC LYMPHOMA KINASE; RECEPTOR TYROSINE KINASE; SMALL-MOLECULE INHIBITOR; NON-HODGKINS-LYMPHOMA; LUNG-CANCER CELLS; GROWTH-FACTOR; C-MET; CRYSTAL-STRUCTURE; NEURONAL DIFFERENTIATION; DROSOPHILA-MELANOGASTER AB Since the original descriptions of gain-of function mutations in anaplastic lymphoma kinase (ALK), interest in the role of this receptor tyrosine kinase in neuroblastoma development and as a potential therapeutic target has escalated. As a group, the activating point mutations in full-length ALK, found in approximately 8% of all neuroblastoma tumors, are distributed evenly across different clinical stages. However, the most frequent somatic mutation, F1174L, is associated with amplification of the MYCN oncogene. This combination of features appears to confer a worse prognosis than MYCN amplification alone, suggesting a cooperative effect on neuroblastoma formation by these two proteins. Indeed. F1174L has shown more potent transforming activity in vivo than the second most common activating mutation. R1275Q, and is responsible for innate and acquired resistance to crizotinib, a clinically relevant ALK inhibitor that will soon be commercially available. These advances cast ALK as a bona fide oncoprotein in neuroblastoma and emphasize the need to understand ALK-mediated signaling in this tumor. This review addresses many of the current issues surrounding the role of ALK in normal development and neuroblastoma pathogenesis, and discusses the prospects for clinically effective targeted treatments based on ALK inhibition. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Azarova, Anna M.; Gautam, Gargi; George, Rani E.] Dana Farber Canc Inst, Dept Pediat Hematol & Oncol, Boston, MA 02115 USA. [Azarova, Anna M.; Gautam, Gargi; George, Rani E.] Harvard Univ, Childrens Hosp Boston, Sch Med, Boston, MA 02115 USA. [Gautam, Gargi] Karolinska Inst, Karolinska Hosp, Dept Woman & Child Hlth, Childhood Canc Res Unit, SE-17176 Stockholm, Sweden. RP George, RE (reprint author), Dana Farber Canc Inst, Dept Pediat Hematol & Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM rani_george@dfci.harvard.edu FU Sydney Kimmel Translational Research Scholar Award, Friends for Life Neuroblastoma Fund [1 R01 CA148688-01A1] FX Sydney Kimmel Translational Research Scholar Award (REG), 1 R01 CA148688-01A1 (REG), Friends for Life Neuroblastoma Fund (AA). NR 78 TC 44 Z9 51 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD OCT PY 2011 VL 21 IS 4 BP 267 EP 275 DI 10.1016/j.semcancer.2011.09.005 PG 9 WC Oncology SC Oncology GA 853RZ UT WOS:000297444700007 PM 21945349 ER PT J AU D'Adamo, DR AF D'Adamo, David R. TI Integrating Novel Therapies Into the Treatment of Sarcoma: A Multidisciplinary Approach-Introduction SO SEMINARS IN ONCOLOGY LA English DT Editorial Material C1 Dana Farber Canc Inst, Sarcoma & Bone Canc Treatment Ctr, Boston, MA 02115 USA. RP D'Adamo, DR (reprint author), Dana Farber Canc Inst, Sarcoma & Bone Canc Treatment Ctr, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2011 VL 38 IS 5 SU 3 BP S1 EP S2 DI 10.1053/j.seminoncol.2011.09.002 PG 2 WC Oncology SC Oncology GA 857LK UT WOS:000297719800001 PM 22055967 ER PT J AU D'Adamo, DR AF D'Adamo, David R. TI Appraising the Current Role of Chemotherapy for the Treatment of Sarcoma SO SEMINARS IN ONCOLOGY LA English DT Review ID SOFT-TISSUE SARCOMAS; EUROPEAN-OSTEOSARCOMA-INTERGROUP; PHASE-II TRIAL; PRIMITIVE NEUROECTODERMAL TUMOR; RANDOMIZED COOPERATIVE TRIAL; GEMCITABINE PLUS DOCETAXEL; HIGH-DOSE METHOTREXATE; ADJUVANT CHEMOTHERAPY; ONCOLOGY-GROUP; NEOADJUVANT CHEMOTHERAPY AB Sarcomas are a heterogeneous group of relatively rare mesenchymal neoplasms. They can be grouped into two general categories: soft tissue sarcoma (STS) and primary bone sarcoma, which are treated differently. Because sarcomas are relatively rare and complex with a wide variety of different histopathologic subtypes, evaluation by multidisciplinary teams who have expertise in the field is recommended. Treatment guidelines for the use of chemotherapy in patients with STS and bone sarcoma have been published by the National Comprehensive Cancer Network. The role of adjuvant chemotherapy in resected STS remains controversial. Although chemotherapy improves disease-free survival, the long-term overall survival benefit remains unproven. Chemotherapy is typically used as palliative treatment for most subtypes of metastatic STS. In contrast, chemotherapy has a proven role in the treatment of primary bone tumors and Ewing sarcoma, but it has not demonstrated efficacy in the treatment of chondrosarcoma. The standard chemotherapy regimens used in sarcoma are associated with significant toxicity, including long-term complications. Less intense and less toxic regimens are the focus of ongoing clinical research. Newer cytotoxic agents with an improved safety profile, such as trabectedin and palifosfamide, are currently in development. Future research needs to focus on identification of subpopulations of patients that are most likely to benefit from chemotherapy. Semin Oncol 38:S19-S29 (C) 2011 Elsevier Inc. All rights reserved. C1 Dana Farber Canc Inst, Sarcoma & Bone Canc Treatment Ctr, Boston, MA 02215 USA. RP D'Adamo, DR (reprint author), Dana Farber Canc Inst, Sarcoma & Bone Canc Treatment Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM david_dadamo@dfci.harvard.edu FU Novartis; Genentech; Bayer; Merck Co. Inc. FX Dr D'Adamo has received consulting fees from Novartis and Genentech. He has performed contracted research for Bayer and Genentech.; Publication of this article was supported by an educational grant from Merck & Co. Inc. NR 87 TC 36 Z9 37 U1 1 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2011 VL 38 IS 5 SU 3 BP S19 EP S29 DI 10.1053/j.seminoncol.2011.09.004 PG 11 WC Oncology SC Oncology GA 857LK UT WOS:000297719800003 PM 22055968 ER PT J AU Neuhaus, V Jupiter, JB AF Neuhaus, V. Jupiter, J. B. TI Current Concepts Review: Carpal Injuries - Fractures, Ligaments, Dislocations SO ACTA CHIRURGIAE ORTHOPAEDICAE ET TRAUMATOLOGIAE CECHOSLOVACA LA English DT Review DE carpal; concepts; current; dislocations; fractures; injuries; ligaments; review ID ACUTE SCAPHOID FRACTURES; PERILUNATE DISLOCATIONS; CONSERVATIVE TREATMENT; DISPLACED FRACTURES; OPERATIVE TREATMENT; OPEN REDUCTION; NONUNION; SCREW; RADIOGRAPHY; MANAGEMENT AB An overview about current concepts in treating carpal injuries is presented. These injuries are more commonly seen in young, active individuals after a fall on an outstretched hand. Conventional radiographs and a thorough examination are important. The scaphoid is the most affected bone. Scaphoid fractures can be classified in accordance to OTA, AO, and other classification systems, but mostly to Herbert. It can be treated non-operatively if undisplaced, however a percutaneous internal fixation can be discussed to achieve earlier return to work and shorter time to union, but hazarding the consequences of an operation. Unstable, proximal pole, or delayed diagnosed scaphoid fractures should be treated surgically. Nonunion is seen in 5 - 40% of scaphoid fractures depending mainly on displacement and localization of the fracture. The gold standard in non-osteoarthritic scaphoid nonunion is debridement of the nonunion site, bone grafting, realignment, stable fixation and rehabilitation. The treatment of scaphoid-nonunion advanced collapse is more complex. Proximal row carpectomy or arthrodesis (four-corner or complete wrist) can be mandatory. Other carpal bone fractures are rare. Perilunate dislocations are also uncommon but can be disabling. They usually originate in high-energy trauma. The Mayfield stages help to understand the injury pattern. Open reduction through both volar and dorsal approaches, repair of the volar capsule as well as volar and dorsal ligaments, and internal fixation is commonly the standard treatment. However osteoarthritis and carpal instability are often encountered. C1 [Jupiter, J. B.] Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Yawkey Ctr, Boston, MA 02114 USA. RP Jupiter, JB (reprint author), Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM jjupiter1@partners.org NR 48 TC 4 Z9 4 U1 1 U2 4 PU GALEN SRO PI PRAGUE 5 PA NA BELIDLE 34, PRAGUE 5, 150 00, CZECH REPUBLIC SN 0001-5415 J9 ACTA CHIR ORTHOP TR JI Acta Chir. Orthop. Traumatol. Cechoslov. PD OCT PY 2011 VL 78 IS 5 BP 395 EP 403 PG 9 WC Orthopedics SC Orthopedics GA 853MK UT WOS:000297430200002 PM 22094152 ER PT J AU Hanseeuw, BJ Van Leemput, K Kavec, M Grandin, C Seron, X Ivanoiu, A AF Hanseeuw, B. J. Van Leemput, K. Kavec, M. Grandin, C. Seron, X. Ivanoiu, A. TI Mild Cognitive Impairment: Differential Atrophy in the Hippocampal Subfields SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID ALZHEIMERS-DISEASE; SEGMENTATION; MRI AB BACKGROUND AND PURPOSE: Hippocampus volumetry is a useful surrogate marker for the diagnosis of Alzheimer disease, but it seems insufficiently sensitive for the aMCI stage. We postulated that some hippocampus subfields are specifically atrophic in aMCI and that measuring hippocampus subfield volumes will improve sensitivity of MR imaging to detect aMCI. MATERIALS AND METHODS: We evaluated episodic memory and hippocampus subfield volume in 15 patients with aMCI and 15 matched controls. After segmentation of the whole hippocampus from clinical MR imaging, we applied a new computational method allowing fully automated segmentation of the hippocampus subfields. This method used a Bayesian modeling approach to infer segmentations from the imaging data. RESULTS: In comparison with controls, subiculum and CA2-3 were significantly atrophic in patients with aMCI, whereas total hippocampus volume and other subfields were not. Total hippocampus volume in controls was age-related, whereas episodic memory was the main explanatory variable for both the total hippocampus volume and the subfields that were atrophic in patients with aMCI. Segmenting subfields increases sensitivity to diagnose aMCI from 40% to 73%. CONCLUSIONS: Measuring CA2-3 and subiculum volumes allows a better detection of aMCI. C1 [Hanseeuw, B. J.; Ivanoiu, A.] St Luc Univ Hosp, Dept Neurol, Brussels, Belgium. [Grandin, C.] St Luc Univ Hosp, Dept Radiol, Brussels, Belgium. [Hanseeuw, B. J.; Grandin, C.; Seron, X.; Ivanoiu, A.] Catholic Univ Louvain, Inst Neurosci, B-1200 Brussels, Belgium. [Van Leemput, K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging,Dept Radiol, Charlestown, MA USA. [Van Leemput, K.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Van Leemput, K.] Aalto Univ, Sch Sci & Technol, Espoo, Finland. [Kavec, M.] Erasmus Univ Hosp, Dept Radiol, Brussels, Belgium. RP Hanseeuw, BJ (reprint author), Clin Univ St Luc, Serv Neurol, Ave Hippocrate, B-101200 Brussels, Belgium. EM bernard.hanseeuw@uclouvain.be RI Van Leemput, Koen/A-9197-2009; OI Van Leemput, Koen/0000-0001-6466-5309; Hanseeuw, Bernard/0000-0002-3102-6778 FU Belgian Foundation for Scientific Research (FNRS); Academy of Finland [133611]; National Institutes of Health [R01NS052585, R01EB006758, R01EB009051, P41RR014075]; Massachusetts General Hospital (Executive Committee on Research Formulaic Bridge Support) [2010A055663] FX Funding for this study was provided by the Belgian Foundation for Scientific Research (FNRS). K. Van Leemput was supported in part by the Academy of Finland (grant 133611), the National Institutes of Health (R01NS052585, R01EB006758, R01EB009051, P41RR014075), and Massachusetts General Hospital (Executive Committee on Research Formulaic Bridge Support/Proposal 2010A055663). NR 17 TC 52 Z9 52 U1 1 U2 9 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD OCT PY 2011 VL 32 IS 9 BP 1658 EP 1661 DI 10.3174/ajnr.A2589 PG 4 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 849RL UT WOS:000297142700017 PM 21835940 ER PT J AU Gupta, R Mehndiratta, A Mitha, AP Grasruck, M Leidecker, C Ogilvy, C Brady, TJ AF Gupta, R. Mehndiratta, A. Mitha, A. P. Grasruck, M. Leidecker, C. Ogilvy, C. Brady, T. J. TI Temporal Resolution of Dynamic Angiography Using Flat Panel Volume CT: In Vivo Evaluation of Time-Dependent Vascular Pathologies SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID ARTERIOVENOUS-MALFORMATION MODEL; SACCULAR ANEURYSMS; SCANNER; RUPTURE; DESIGN AB BACKGROUND AND PURPOSE: Recently introduced fpVCT scanners can capture volumetric (4D) time-varying projections enabling whole-organ dynamic CTA imaging. The main objective of this study was to assess the temporal resolution of dynamic CTA in discriminating various phases of rapid and slow time-dependent neurovascular pathologies in animal models. MATERIALS AND METHODS: Animal models were created to assess phasic blood flow, subclavian steal phenomena, saccular aneurysms, and neuroperfusion under protocols approved by the SRAC. Animals with progressively increasing heart rate Macaca sylvanus (similar to 100 bpm), Oryctolagus cuniculus (NZW rabbit) (similar to 150 bpm), Rattus norvegicus (similar to 300 bpm), Mus musculus (similar to 500 bpm) were imaged to challenge the temporal resolution of the system. FpVCT, a research prototype with a 25 x 25 x 18 cm coverage, was used for dynamic imaging with the gantry rotation time varying from 3 to 5 seconds. Volumetric datasets with 50% temporal overlap were reconstructed; 4D datasets were analyzed by using the Leonardo workstation. RESULTS: Dynamic imaging by using fpVCT was capable of demonstrating the following phenomena: 1) subclavian steal in rabbits (Delta T congruent to 3-4 seconds); 2) arterial, parenchymal, and venous phases of blood flow in mice (Delta T congruent to 2 seconds), rabbits (Delta T congruent to 3-4 seconds), and Macaca sylvanus (Delta T congruent to 3-4 seconds); 3) sequential enhancement of the right and left side of the heart in Macaca sylvanus and white rabbits (Delta T congruent to 2 seconds); and 4) different times of the peak opacification of cervical and intracranial arteries, venous sinuses, and the jugular veins in these animals (smallest, Delta T congruent to 1.5-2 seconds). The perfusion imaging in all animals tested was limited due to the fast transit time through the brain and the low contrast resolution of fpVCT. CONCLUSIONS: Dynamic imaging by using fpVCT can distinguish temporal processes separated by >1.5 seconds. Neurovascular pathologies with a time constant >1.5 seconds can be evaluated noninvasively by using fpVCT. C1 [Gupta, R.; Mehndiratta, A.; Brady, T. J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mitha, A. P.; Ogilvy, C.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Mehndiratta, A.] Univ Oxford, Inst Biomed Engn, Oxford, England. [Grasruck, M.; Leidecker, C.] Siemens Med Solut, Forchheim, Germany. RP Gupta, R (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM rgupta1@partners.org FU Siemens Medical Solutions; Center for Integration of Medicine and Innovative Technology consortium; Radiological Society of North America Research and Education Foundation; Alberta Heritage Fund for Medical Research Clinical Fellowship Award; American Association of Neurological Surgeons/Congress of Neurological Surgeons Resident Research; Siemens Medical Solutions, Erlangen, Germany; Massachusetts General Hospital, Boston, Massachusetts; Siemens Healthcare; Siemens AG; Healthcare Sector; National Institutes of Health FX Financial Relationships and Grant Information: T.J.B. was partially supported by an educational grant from Siemens Medical Solutions. R.G. was funded by a grant from the Center for Integration of Medicine and Innovative Technology consortium and the Radiological Society of North America Research and Education Foundation. A.P.M. was supported by an Alberta Heritage Fund for Medical Research Clinical Fellowship Award and an American Association of Neurological Surgeons/Congress of Neurological Surgeons Resident Research Award in Cerebrovascular Disease. M.G. and C.L. are employees of Siemens Medical Solutions, Germany. The other authors did not receive any financial support in conjunction with the generation of this submission. Other than these financial relationships, the authors have no personal or institutional financial interest in drugs, materials, or devices described in this submission.; Rajiv Gupta, Research Support (including provision of equipment or materials) Siemens Medical Solutions, Erlangen, Germany, Details. The scanner was purchased from Siemens Medical Solutions. Two of the coauthors are employees of Siemens Medical Solutions. Amit Mehndiratta, Research Support (including provision of equipment or materials) Massachusetts General Hospital, Boston, Massachusetts, Details: The work submitted to the American Journal of Neuradiology was part of my research fellowship at Massachusetts General Hospital. Michael Grasruck, Research Support (including provision of equipment or materials). Employee of Siemens Healthcare, Other Financial Interests. Employee of Siemens Healthcare. Christianne Leidecker, Research Support (including provision of equipment or materials). Siemens AG, Healthcare Sector, Details Employee, Christopher S. Ogilvy, Research Support (including provision of equipment or materials) National Institutes of Health, Consultant Mizuho America, Actelion Pharmaceuticals, Toshiba, Details: Mizuho: $14 000; Actelion: $4500; Toshiba: $5000. NR 15 TC 3 Z9 3 U1 1 U2 5 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD OCT PY 2011 VL 32 IS 9 BP 1688 EP 1696 DI 10.3174/ajnr.A2586 PG 9 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 849RL UT WOS:000297142700022 PM 21835945 ER PT J AU Abdel-Bakky, MS Hammad, MA Walker, LA Ashfaq, MK AF Abdel-Bakky, Mohamed Sadek Hammad, Mohamed A. Walker, Larry A. Ashfaq, Mohammad K. TI Silencing of tissue factor by antisense deoxyoligonucleotide prevents monocrotaline/LPS renal injury in mice SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Tissue factor antisense; Monocrotaline; Lipopolysaccharide; Renal toxicity ID PYRROLIZIDINE ALKALOID MONOCROTALINE; RESPIRATORY-DISTRESS-SYNDROME; ISCHEMIA-REPERFUSION INJURY; FACTOR CYTOPLASMIC DOMAIN; TUMOR-NECROSIS-FACTOR; FACTOR VIIA; ENDOTHELIAL-CELLS; FACTOR EXPRESSION; TGF-BETA; ACTIVATION AB Tissue factor (TF) is involved in monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity. It is not known whether MCT/LPS can cause renal toxicity and whether TF is involved in this toxicity. Thus, the present study was undertaken to investigate the potential renal toxicity after MCT/LPS co-treatment and the involvement of TF in this toxicity. MCT was delivered to ND4 male mice (200 mg/kg) per os followed 4 h later by treatment with LPS ip (6 mg/kg) to investigate its effect on kidney. We injected TF antisense oligonucleotide (TF-AS) intravenously (i.v) in mice prior to LPS treatment, to block TF, and measured their blood urea nitrogen (BUN), creatinine (CRE), alkaline phosphatase (ALP), and potassium. In MCT/LPS co-treated group, fibrin was detected on the glomerular capillary lumina, distal tubules of renal cortex, and the necrotic tubules of renal medulla. An elevation of BUN, creatinine, and the BUN/creatinine ratio was seen in mice with MCT/LPS co-treatment, compared to animals receiving LPS or MCT alone. Simultaneously, an aggressive tubular necrosis was seen in the medullary tubules in the same group which may account for the oliguria observed in these animals. Fourfold inductions in the plasma TF level was detected at 10 h after MCT/LPS co-treatment which increased to 18-fold at 24 h. Increased blood level of leptin, interleukin-6 (IL-6) and downregulation of tubular chemokine (C-X-C motif) ligand 16 (CXCL16) are characteristic features in MCT/LPS co-treated animal. On the other hand, mice injected with TF-AS in the presence of MCT/LPS co-treatment showed no elevation of the blood BUN, creatinine, potassium, and normal levels of the proinflammatory molecules. TF-AS injection significantly prevented glomerular and tubular fibrin deposition, tubular necrosis, and improvement of the animal survivability. Renal toxicity involving TF can be prevented successfully by the use of TF-AS. C1 [Abdel-Bakky, Mohamed Sadek; Hammad, Mohamed A.; Walker, Larry A.; Ashfaq, Mohammad K.] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Hammad, Mohamed A.; Walker, Larry A.] Univ Mississippi, Dept Pharmacol, Sch Pharm, University, MS 38677 USA. [Abdel-Bakky, Mohamed Sadek] Al Azhar Univ, Fac Pharm, Cairo, Egypt. [Hammad, Mohamed A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. RP Ashfaq, MK (reprint author), Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. EM mkashfaq@olemiss.edu OI HAMMAD, MOHAMED/0000-0002-9684-2506 FU United States Department of Agriculture, Agricultural Research Service [58-6408-2-0009]; US Food and Drug Administration [5U01FD002071-09, 1U01FD003871-011] FX The authors wish to thank Mr. Rajnish Sahu (NCNPR, University of Mississippi) for his help in the use of fluorescent microscope. This work was supported in part by the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative agreement [58-6408-2-0009] and US Food and Drug Administration [5U01FD002071-09 and 1U01FD003871-011]. NR 54 TC 8 Z9 8 U1 0 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD OCT PY 2011 VL 85 IS 10 BP 1245 EP 1256 DI 10.1007/s00204-011-0663-8 PG 12 WC Toxicology SC Toxicology GA 852LI UT WOS:000297359000008 PM 21327618 ER PT J AU Basher, F Bunni, M Amani, Z Zhang, X Nowling, TK AF Basher, Fahmin Bunni, Marlene Amani, Zainab Zhang, Xian Nowling, Tamara K. TI Effects of Altering Fli1 Levels in Lupus T Cells on Disease Expression and T Cell Function in the MRL/Lpr Mouse Model. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Basher, Fahmin; Bunni, Marlene; Amani, Zainab; Zhang, Xian; Nowling, Tamara K.] Med Univ S Carolina, Charleston, SC 29425 USA. [Zhang, Xian; Nowling, Tamara K.] Ralph H Johnson VA Med Ctr, Charleston, SC 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2363 BP S921 EP S921 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502749 ER PT J AU Bernstein, EJ Isakova, T Sullivan, ME Chibnik, LB Bazari, H Wolf, M Kay, J AF Bernstein, Elana J. Isakova, Tamara Sullivan, Mary E. Chibnik, Lori B. Bazari, Hasan Wolf, Myles Kay, Jonathan TI Hypophosphatemia Is Associated with Nephrogenic Systemic Fibrosis: A Case-Control Study SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Bernstein, Elana J.] Hosp Special Surg, New York, NY 10021 USA. [Isakova, Tamara; Wolf, Myles] Univ Miami, Miami, FL USA. [Sullivan, Mary E.; Bazari, Hasan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chibnik, Lori B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kay, Jonathan] Univ Massachusetts, Sch Med, Worcester, 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2309 BP S902 EP S902 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502695 ER PT J AU Brown, AG Hirsch, R Laor, T Francis, KA Hannon, MJ Kwoh, CK AF Brown, Amanda G. Hirsch, Raphael Laor, Tal Francis, Kimberly A. Hannon, Michael J. Kwoh, C. Kent TI Patients with Juvenile Idiopathic Arthritis and Rheumatoid Arthritis in "Physician Determined Clinical Remission" Have Evidence of Persistent Inflammation Revealed by 3T MRI SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Brown, Amanda G.; Hirsch, Raphael; Francis, Kimberly A.] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [Laor, Tal] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Laor, Tal] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Hannon, Michael J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kwoh, C. Kent] VA Pittsburgh Healthcare, Ctr Hlth Equity Res & Promot, 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 958 BP S376 EP S376 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501153 ER PT J AU Chang, AY Ghazi, E Okawa, J Werth, VP AF Chang, Aileen Y. Ghazi, Elizabeth Okawa, Joyce Werth, Victoria P. TI Disease Activity and Quality of Life in Refractory Cutaneous Lupus Erythematosus Patients Initiated on Immunosuppressive Therapy SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Chang, Aileen Y.; Okawa, Joyce; Werth, Victoria P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Chang, Aileen Y.; Okawa, Joyce; Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Ghazi, Elizabeth] UMDNJ Robert Wood Johnson Med Sch, Piscataway, NJ 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 617 BP S239 EP S239 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500613 ER PT J AU Chung, SA Brown, EE Williams, AH Bhangale, T Ramos, PS Ziegler, JT Freedman, BI Kimberly, RP Vyse, TJ Gregersen, PK Jacob, CO Alarcon-Riquelme, ME Tsao, BP Harley, JB Behrens, TW Petri, M Kamboh, MI Demirci, FY Manzi, S Criswell, LA Moser, KL Gaffney, PM Graham, RR Langefeld, CD AF Chung, Sharon A. Brown, Elizabeth E. Williams, Adrienne H. Bhangale, Tushar Ramos, Paula S. Ziegler, Julie T. Freedman, Barry I. Kimberly, Robert P. Vyse, Timothy J. Gregersen, Peter K. Jacob, Chaim O. Alarcon-Riquelme, Marta E. Tsao, Betty P. Harley, John B. Behrens, Timothy W. Petri, M. Kamboh, M. Ilyas Demirci, F. Yesim Manzi, Susan Criswell, Lindsey A. Moser, Kathy L. Gaffney, Patrick M. Graham, Robert R. Langefeld, Carl D. TI Lupus Nephritis Susceptibility Markers in PDGRFA-GSX2, SLC5A11, ID4, and HAS2-SNTB1 Regions Identified From a Meta-Analysis of Genome Wide Association Studies of Women with Systemic Lupus Erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Chung, Sharon A.; Criswell, Lindsey A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Brown, Elizabeth E.; Kimberly, Robert P.] Univ Alabama, Birmingham, AL USA. [Williams, Adrienne H.; Ramos, Paula S.; Ziegler, Julie T.; Freedman, Barry I.; Langefeld, Carl D.] Wake Forest Sch Med, Winston Salem, NC USA. [Bhangale, Tushar; Behrens, Timothy W.; Graham, Robert R.] Genentech Inc, San Francisco, CA 94080 USA. [Vyse, Timothy J.] Kings Coll London, London WC2R 2LS, England. [Gregersen, Peter K.] Feinstein Inst Med Res, Manhasset, NY USA. [Jacob, Chaim O.] Univ So Calif, Los Angeles, CA USA. [Alarcon-Riquelme, Marta E.] Pfizer Univ Granada Junta de Andalucia, Oklahoma Med Res Fdn, Ctr Genom & Oncol Res, Oklahoma City, OK 73104 USA. [Tsao, Betty P.] Univ Calif Los Angeles, Los Angeles, CA USA. [Harley, John B.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Harley, John B.] Med Ctr, US Dept Vet Affairs, Cincinnati, OH USA. [Petri, M.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kamboh, M. Ilyas; Demirci, F. Yesim] Univ Pittsburgh, Pittsburgh, PA USA. [Manzi, Susan] Allegheny Singer Res Inst, Pittsburgh, PA 15212 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 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 OCT PY 2011 VL 63 IS 10 SU S MA 2479 BP S967 EP S967 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503050 ER PT J AU Davids, ML Do, H Tomasson, G Davis, JC Hoffman, GS McCune, WJ Specks, U St Clair, EW Stone, JH Merkel, PA Spiera, RF AF Davids, Morgana L. Do, Huong Tomasson, Gunnar Davis, John C. Hoffman, Gary S. McCune, W. Joseph Specks, Ulrich St Clair, E. William Stone, John H. Merkel, Peter A. Spiera, Robert F. TI Mental Health As a Predictor of Disease Flare in Granulomatosis with Polyangiitis (Wegener's Granulomatosis) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Davids, Morgana L.; Do, Huong; Spiera, Robert F.] Hosp Special Surg, New York, NY 10021 USA. [Tomasson, Gunnar] Boston Univ, Sch Med, Boston, MA 02118 USA. [Davis, John C.] Genentech Inc, San Francisco, CA 94080 USA. [Hoffman, Gary S.] Cleveland Clin, Cleveland, OH 44106 USA. [McCune, W. Joseph] Univ Michigan, Ann Arbor, MI 48109 USA. [Specks, Ulrich] Mayo Clin, Rochester, MN USA. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2371 BP S924 EP S925 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502757 ER PT J AU Davis, LA Pointer, LM Wolff, RK Reimold, AM Kerr, GS Mikuls, TR Cannon, GW Caplan, L AF Davis, Lisa A. Pointer, Lauren M. Wolff, Roger K. Reimold, Andreas M. Kerr, Gail S. Mikuls, Ted R. Cannon, Grant W. Caplan, Liron TI Association of Medicaons and Rheumatoid Arthritis Susceptibility Polymorphism with Lipid Profiles in Patients with Rheumatoid Arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Davis, Lisa A.] Univ Colorado, Sch Med, Aurora, CO USA. [Pointer, Lauren M.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Wolff, Roger K.] Univ Utah, Salt Lake City, UT USA. [Reimold, Andreas M.] Univ Texas SW, Dallas, TX USA. [Kerr, Gail S.] Washington DC VA, Washington, DC USA. [Kerr, Gail S.] Georgetown Univ, Washington, DC USA. [Wolff, Roger K.] Dallas VA, Dallas, TX USA. [Mikuls, Ted R.] Omaha VA, Omaha, NE USA. [Mikuls, Ted R.] Univ Nebraska, Omaha, NE 68182 USA. [Cannon, Grant W.] Salt Lake City VA, Salt Lake City, UT USA. [Cannon, Grant W.] Univ Utah, Salt Lake City, UT USA. [Caplan, Liron] Denver VA, Aurora, CO 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1181 BP S460 EP S461 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501375 ER PT J AU Davis, TE Kis-Toth, K Szanto, A Miller, LC Tsokos, GC AF Davis, Trevor E. Kis-Toth, Katalin Szanto, Attila Miller, Laurie C. Tsokos, George C. TI Methylprednisolone Modulates MicroRNA and Gene Expression in Human CD4(+) T Cells: A Novel Mechanism of Anti-Inflammatory Action SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol (ACR), Assoc Rheumatol Hlth Profess (ARHP) C1 [Davis, Trevor E.; Kis-Toth, Katalin; Tsokos, George C.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Szanto, Attila; Tsokos, George C.] Harvard Univ, Sch Med, Boston, MA USA. [Davis, Trevor E.] Tufts Med Ctr, Floating Hosp Children, Boston, MA USA. [Szanto, Attila] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Szanto, Attila/B-2198-2012 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2331 BP S910 EP S910 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502717 ER PT J AU Deng, Y Zhao, J Tan, W Kaufman, KM Brown, EE Edberg, JC Kamen, DL Gilkeson, GS Jacob, CO Scofield, RH Kimberly, RP Langefeld, CD Alarcon-Riquelme, ME Harley, JB Vyse, TJ Gaffney, PM Moser, KL James, JA Chen, JY Mikuls, TR Shadick, NA Weinblatt, ME Bridges, SL Paulus, HE Tsao, BP AF Deng, Yun Zhao, Jian Tan, Wenfeng Kaufman, Kenneth M. Brown, Elizabeth E. Edberg, Jeffrey C. Kamen, Diane L. Gilkeson, Gary S. Jacob, Chaim O. Scofield, Robert H. Kimberly, Robert P. Langefeld, Carl D. Alarcon-Riquelme, Marta E. Harley, John B. Vyse, Timothy J. Gaffney, Patrick M. Moser, Kathy L. James, Judith A. Chen, Ji-Yih Mikuls, Ted R. Shadick, Nancy A. Weinblatt, Michael E. Bridges, S. Louis, Jr. Paulus, Harold E. Tsao, Betty P. CA PROFILE Investigators BIOLUPUS GENLES TI Association of a Functional Variant in TLR7 with Systemic Lupus Erythematosus and Rheumatoid Arthritis in Multiple Ancestries SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Deng, Yun; Zhao, Jian; Tan, Wenfeng; Paulus, Harold E.; Tsao, Betty P.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Kaufman, Kenneth M.; Scofield, Robert H.; Alarcon-Riquelme, Marta E.; Gaffney, Patrick M.; Moser, Kathy L.; BIOLUPUS GENLES] US Dept Vet Affairs, Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Med Ctr, Oklahoma City, OK USA. [Brown, Elizabeth E.; Edberg, Jeffrey C.; Kimberly, Robert P.; PROFILE Investigators] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Brown, Elizabeth E.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Gilkeson, Gary S.] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Jacob, Chaim O.] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [Scofield, Robert H.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Langefeld, Carl D.] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Alarcon-Riquelme, Marta E.] Pfizer Univ Granada Junta de Andalucia, Ctr Genom & Oncol Res, Granada, Spain. [Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Vyse, Timothy J.] Kings Coll London, Div Genet, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Mol Med & Immunol, London WC2R 2LS, England. [Chen, Ji-Yih] Chang Gung Mem Hosp, Div Allergy Immunol & Rheumatol, Taipei 10591, Taiwan. [Mikuls, Ted R.] Omaha VA, Omaha, NE USA. [Mikuls, Ted R.] Univ Nebraska, Omaha, NE 68182 USA. [Shadick, Nancy A.; Weinblatt, Michael E.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Bridges, S. Louis, Jr.] Univ Alabama, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. RI Zhao, Jian/E-6292-2012 NR 0 TC 1 Z9 1 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 OCT PY 2011 VL 63 IS 10 SU S MA 634 BP S246 EP S247 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500630 ER PT J AU Dillon, SP Kao, L Kaufman, KM Ice, JA Omdal, R Mariette, X Witte, T Illei, GG Rischmueller, M Nordmark, G Jonsson, R Herlenius, MW Vyse, TJ Brennan, MT Rybicki, BA Ng, WF Segal, BM Rhodus, NL Merrill, JT Montgomery, CG Lessard, CJ Harley, JB Moser, KL Gaffney, PM Scofield, RH AF Dillon, Skyler P. Kao, Lydia Kaufman, Kenneth M. Ice, John A. Omdal, Roald Mariette, Xavier Witte, Torsten Illei, Gabor G. Rischmueller, Maureen Nordmark, Gunnel Jonsson, Roland Herlenius, Marie Wahren Vyse, Timothy J. Brennan, Michael T. Rybicki, Benjamin A. Ng, Wan-Fai Segal, Barbara M. Rhodus, Nelson L. Merrill, Joan T. Montgomery, Courtney G. Lessard, Christopher J. Harley, John B. Moser, Kathy L. Gaffney, Patrick M. Scofield, R. Hal TI Triple X Syndrome (47,XXX) Increases the Risk and Accelerates the Onset of Systemic Lupus Erythematosus and Sjogren's Syndrome: Support for a Gene-Dose Effect From the X Chromosome SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Dillon, Skyler P.; Kao, Lydia] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Mariette, Xavier] Univ Paris 11, Le Kremlin Bicetre, France. [Witte, Torsten] Hannover Med Sch, Hannover, Germany. [Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. [Rischmueller, Maureen] Queen Elizabeth Hosp, Adelaide, SA, Australia. [Nordmark, Gunnel] Uppsala Univ, Rheumatol Sect, Dept Med Sci, Uppsala, Sweden. [Herlenius, Marie Wahren] CMM L8204 Karolinska Hosp, Stockholm, Sweden. [Jonsson, Roland] Univ Bergen, Bergen, Norway. [Vyse, Timothy J.] Kings Coll London, Div Genet, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Mol Med & Immunol, London WC2R 2LS, England. [Brennan, Michael T.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Rybicki, Benjamin A.] Henry Ford Hlth Syst, Detroit, MI USA. [Ng, Wan-Fai] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Segal, Barbara M.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Rhodus, Nelson L.] Univ Minnesota, Minneapolis, MN USA. [Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Moser, Kathy L.; Gaffney, Patrick M.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK USA. RI Witte, Torsten/B-5783-2016 NR 0 TC 2 Z9 2 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 OCT PY 2011 VL 63 IS 10 SU S MA 643 BP S251 EP S251 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500639 ER PT J AU Ding, YN Hsu, HC Mountz, JD AF Ding, Yanna Hsu, Hui-Chen Mountz, John D. TI Identification of a CD62L(hi)CD44(low) T-FH Precursor Capable of Developing into An IL21(hi) IL17(hi) Mature T-FH in Autoimmune BXD2 Mice. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol (ACR), Assoc Rheumatol Hlth Profess (ARHP) C1 [Ding, Yanna; Hsu, Hui-Chen; Mountz, John D.] Univ Alabama, Birmingham, AL USA. [Mountz, John D.] Birmingham VAMC, Birmingham, AL USA. NR 0 TC 0 Z9 0 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 OCT PY 2011 VL 63 IS 10 SU S MA 2362 BP S920 EP S921 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502748 ER PT J AU Domsic, RT Lucas, M Wisniewski, SR Kwoh, CK Fine, MJ Medsger, TA AF Domsic, Robyn T. Lucas, Mary Wisniewski, Stephen R. Kwoh, C. Kent Fine, Michael J. Medsger, Thomas A. TI Development and Internal Validation of a Two-Year Mortality Risk Prediction Rule in Early Diffuse Systemic Sclerosis Patients SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Domsic, Robyn T.; Lucas, Mary; Wisniewski, Stephen R.; Kwoh, C. Kent; Fine, Michael J.; Medsger, Thomas A.] Univ Pittsburgh, Pittsburgh, PA USA. [Kwoh, C. Kent; Fine, Michael J.] VA Pittsburgh Healthcare, Ctr Hlth Equ Res & Promot, 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2485 BP S969 EP S970 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503056 ER PT J AU Drouin, EE Seward, RJ Yao, CX Katchar, K McHugh, G Strle, K Costello, CE Steere, AC AF Drouin, Elise E. Seward, Robert J. Yao, Chunxiang Katchar, Kianoosh McHugh, Gail Strle, Klemen Costello, Catherine E. Steere, Allen C. TI A Novel Human Autoantigen Induces T and B Cell Responses in Patients with Antibiotic-Refractory Lyme Arthritis. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Drouin, Elise E.; Katchar, Kianoosh; McHugh, Gail; Strle, Klemen; Steere, Allen C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Seward, Robert J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Drouin, Elise E.; Katchar, Kianoosh; McHugh, Gail; Strle, Klemen; Steere, Allen C.] Harvard Univ, Sch Med, Boston, MA USA. [Seward, Robert J.; Yao, Chunxiang; Costello, Catherine E.] Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 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 OCT PY 2011 VL 63 IS 10 SU S MA 2344 BP S914 EP S914 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502730 ER PT J AU Galasso, JA AF Galasso, Janine A. TI What Is the Health Literacy and Numeracy in a Rheumatology Veterans Population? SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Galasso, Janine A.] Philadelphia VA Med Ctr, Philadelphia, 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1551 BP S606 EP S606 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501745 ER PT J AU Ghazi, E Kling, MA Propert, K Okawa, J Werth, VP AF Ghazi, Elizabeth Kling, Mitchel A. Propert, Kathleen Okawa, Joyce Werth, Victoria P. TI Increased Depression and Anxiety Symptoms in a Group of Dermatomyositis Patients SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Ghazi, Elizabeth] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. [Kling, Mitchel A.; Okawa, Joyce; Werth, Victoria P.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Okawa, Joyce; Werth, Victoria P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. NR 0 TC 1 Z9 1 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 OCT PY 2011 VL 63 IS 10 SU S MA 249 BP S92 EP S92 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500249 ER PT J AU Gross, RL Schwartzman-Morris, JS Krathen, M Reed, G Chang, H Saunders, KC Fisher, MC Putterman, C Mease, PJ Gottlieb, AB Broder, AR AF Gross, Rachel L. Schwartzman-Morris, Julie S. Krathen, Michael Reed, George Chang, Hong Saunders, Katherine C. Fisher, Mark C. Putterman, Chaim Mease, Philip J. Gottlieb, Alice B. Broder, Anna R. TI The Risk of Malignancy in a Large Cohort of Patients with Psoriatic Arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Gross, Rachel L.; Schwartzman-Morris, Julie S.; Putterman, Chaim; Broder, Anna R.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Krathen, Michael; Chang, Hong; Gottlieb, Alice B.] Tufts Med Ctr, Boston, MA USA. [Reed, George] Univ Massachusetts, Worcester, MA 01605 USA. [Saunders, Katherine C.] CORRONA Inc, Southborough, MA USA. [Fisher, Mark C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mease, Philip J.] Seattle Rheumatol Associate, Seattle, WA USA. NR 1 TC 3 Z9 3 U1 1 U2 4 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 OCT PY 2011 VL 63 IS 10 SU S MA 509 BP S195 EP S195 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500509 ER PT J AU Hu, XL Kim, H Stahl, EA Plenge, RM Daly, M Raychaudhuri, S AF Hu, Xinli Kim, Hyun Stahl, Eli A. Plenge, Robert M. Daly, Mark Raychaudhuri, Soumya TI Integrative Analyses Demonstrate That Rheumatoid Arthritis Risk Loci Impact Genes with CD4+Effector Memory T-Cell Function SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Hu, Xinli; Kim, Hyun; Stahl, Eli A.; Plenge, Robert M.; Raychaudhuri, Soumya] Brigham & Womens Hosp, Boston, MA 02115 USA. [Daly, Mark] Massachusetts Gen Hosp, Boston, MA 02114 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2156 BP S840 EP S841 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502542 ER PT J AU Hughes, T Adler, A Merrill, JT Kelly, JA Kaufman, K Williams, A Langefeld, CD Gilkeson, GS Sanchez, E Martin, J Gaffney, PM Moser, KL Vyse, TJ Alarcon-Riquelme, ME James, JA Scofield, RH Harley, JB Richardson, BC Sawalha, AH AF Hughes, Travis Adler, Adam Merrill, J. T. Kelly, Jennifer A. Kaufman, Kenneth Williams, Adrienne Langefeld, Carl D. Gilkeson, Gary S. Sanchez, Elena Martin, Javier Gaffney, Patrick M. Moser, Kathy L. Vyse, Tomothy J. Alarcon-Riquelme, Marta E. James, Judith A. Scofield, Robert H. Harley, John B. Richardson, Bruce C. Sawalha, Amr H. CA Elizabeth E Brown PROFILE TI Sex-Specific Genetic Architecture of Systemic Lupus Erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Alarcon-Riquelme, Marta E.] Pfizer Univ Granada Junta de Andalucia, Oklahoma Med Res Fdn, Ctr Genom & Oncol Res, Oklahoma City, OK USA. [Williams, Adrienne] Wake Forest Univ, Winston Salem, NC 27109 USA. [Langefeld, Carl D.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Gilkeson, Gary S.] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Martin, Javier] Inst Parasitol & Biomed Lopez Neyra CSIC, Granada, Spain. [Elizabeth E Brown PROFILE] Univ Alabama, Birmingham, AL USA. [Vyse, Tomothy J.] Kings Coll London, Guys Hosp, London WC2R 2LS, England. [James, Judith A.; Scofield, Robert H.] Univ Oklahoma, Hlth Sci Ctr, US Dept Vet Affairs, Arthritis & Clin Immunol Res Program,Oklahoma Med, Oklahoma City, OK USA. [Scofield, Robert H.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Harley, John B.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Richardson, Bruce C.] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 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 OCT PY 2011 VL 63 IS 10 SU S MA 157 BP S57 EP S57 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500158 ER PT J AU Hwang, YG Lim, FC Wu, Q Yang, PA Fisher, G Hunter, G Hsu, HC Mountz, JD AF Hwang, Yong Gil Lim, Fei Chu Wu, Qi Yang, PingAr Fisher, Gordon Hunter, Gary Hsu, Hui-Chen Mountz, John D. TI A Novel Role for Vitamin D in Immunosenescence: Is Enough Too Much for Naive CD8 T Cells? SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Fisher, Gordon] Univ Alabama, Dept Nutr Sci, Birmingham, AL USA. [Hunter, Gary] Univ Alabama, Dept Human Studies, Birmingham, AL USA. [Mountz, John D.] Univ Alabama, Birmingham VA Med Ctr, Birmingham, AL USA. NR 0 TC 0 Z9 0 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 OCT PY 2011 VL 63 IS 10 SU S MA 2348 BP S915 EP S916 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502734 ER PT J AU Kariuki, S Franek, BS Kumar, AA Kumabe, M Kaufman, KM Anaya, JM Alarcon-Riquelme, ME Bae, SC Brown, EE Freedman, BI Gilkeson, GS Jacob, CO James, JA Kimberly, RP Martin, J Merrill, JT Pons-Estel, B Tsao, BP Vyse, TJ Langefeld, CD Harley, JB Moser, KL Gaffney, PM Skol, AD Niewold, TB AF Kariuki, Silvia Franek, Beverly S. Kumar, Akaash A. Kumabe, Marissa Kaufman, Kenneth M. Anaya, Juan-Manuel Alarcon-Riquelme, Marta E. Bae, Sang-Cheol Brown, Elizabeth E. Freedman, Barry I. Gilkeson, Gary S. Jacob, Chaim O. James, Judith A. Kimberly, Robert P. Martin, Javier Merrill, Joan T. Pons-Estel, Bernardo Tsao, Betty P. Vyse, Timothy J. Langefeld, Carl D. Harley, John B. Moser, Kathy L. Gaffney, Patrick M. Skol, Andrew D. Niewold, Timothy B. TI Genetic Associations with Serologic Autoimmunity in a Large Multi-Ancestral Systemic Lupus Erythematosus Cohort SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Kariuki, Silvia; Franek, Beverly S.; Kumar, Akaash A.; Kumabe, Marissa; Skol, Andrew D.; Niewold, Timothy B.] Univ Chicago, Chicago, IL 60637 USA. [Kaufman, Kenneth M.; Moser, Kathy L.; Gaffney, Patrick M.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Kaufman, Kenneth M.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Anaya, Juan-Manuel] Univ Rosario, Corp Invest Biol, Bogota, Colombia. [Alarcon-Riquelme, Marta E.] Oklahoma Med Res Fdn, Granada, Spain. [Alarcon-Riquelme, Marta E.] Ctr Genom & Invest Oncol Pfizer Univ Granada Junt, Granada, Spain. [Alarcon-Riquelme, Marta E.] BIOLUPUS Network, Oklahoma City, OK USA. [Alarcon-Riquelme, Marta E.] GENLES Network, Oklahoma City, OK USA. [Bae, Sang-Cheol] Hanyang Univ, Hosp Rheumat Dis, CRCRA, Seoul 133791, South Korea. [Brown, Elizabeth E.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Brown, Elizabeth E.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Freedman, Barry I.; Langefeld, Carl D.] Wake Forest Sch Med, Winston Salem, NC USA. [Gilkeson, Gary S.] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Jacob, Chaim O.] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [James, Judith A.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Martin, Javier] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain. [Tsao, Betty P.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Vyse, Timothy J.] Kings Coll London, Div Genet, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Mol Med & Immunol, London WC2R 2LS, England. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. RI Anaya, Juan-Manuel/J-1960-2016 OI Anaya, Juan-Manuel/0000-0002-6444-1249 NR 0 TC 0 Z9 0 U1 1 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 OCT PY 2011 VL 63 IS 10 SU S MA 633 BP S246 EP S246 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500629 ER PT J AU Kaufman, KM Kelly, JA Hughes, T Adler, A Sanchez, E Ojwang, JO Langefeld, CD Ziegler, JT James, JA Brown, EE Kimberly, RP Edberg, JC Criswell, LA Chang, DM Gilkeson, GS Niewold, TB Bae, SC Alarcon-Riquelme, ME Jacob, CO Moser, KL Gaffney, PM Harley, JB Sawalha, AH Tsao, BP AF Kaufman, Kenneth M. Kelly, Jennifer A. Hughes, Travis Adler, Adam Sanchez, Elena Ojwang, Joshua O. Langefeld, Carl D. Ziegler, Julie T. James, Judith A. Brown, Elizabeth E. Kimberly, Robert P. Edberg, Jeffrey C. Criswell, Lindsey A. Chang, Deh-Ming Gilkeson, Gary S. Niewold, Timothy B. Bae, Sang-Cheol Alarcon-Riquelme, Marta E. Jacob, Chaim O. Moser, Kathy L. Gaffney, Patrick M. Harley, John B. Sawalha, Amr H. Tsao, Betty P. TI Fine Mapping of Xq28: Both MECP2/IRAK1 and NAA10/RENBP Contribute to Risk for SLE in Multiple Ancestral Groups SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Kaufman, Kenneth M.; Moser, Kathy L.; Gaffney, Patrick M.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Kaufman, Kenneth M.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Langefeld, Carl D.; Ziegler, Julie T.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Brown, Elizabeth E.; Edberg, Jeffrey C.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Brown, Elizabeth E.] Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. [Criswell, Lindsey A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Chang, Deh-Ming] Natl Def Med Ctr, Taipei, Taiwan. [Gilkeson, Gary S.] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Niewold, Timothy B.] Univ Chicago, Chicago, IL 60637 USA. [Bae, Sang-Cheol] Hanyang Univ, Hosp Rheumat Dis, CRCRA, Seoul 133791, South Korea. [Alarcon-Riquelme, Marta E.] Pfizer Univ Granada Junta de Andalucia GENYO, Ctr Genom & Invest Oncol, Granada, Spain. [Alarcon-Riquelme, Marta E.] BIOLUPUS Network, Oklahoma City, OK USA. [Alarcon-Riquelme, Marta E.] GENLES Network, Oklahoma City, OK USA. [Jacob, Chaim O.] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [Harley, John B.] Cincinnato Childrens Hosp Med Ctr, Cincinnati, OH USA. [Tsao, Betty P.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 1 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 OCT PY 2011 VL 63 IS 10 SU S MA 642 BP S250 EP S251 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500638 ER PT J AU Khosroshahi, A Carruthers, M Deshpande, V Unizony, S Bloch, DB Stone, JH AF Khosroshahi, Arezou Carruthers, Mollie Deshpande, Vikram Unizony, Sebastian Bloch, Donald B. Stone, John H. TI Rituximab for the Treatment of IgG4-Related Disease: Lessons From Ten Consecutive Patients SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Khosroshahi, Arezou; Carruthers, Mollie; Deshpande, Vikram; Unizony, Sebastian; Bloch, Donald B.; Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1740 BP S683 EP S683 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502126 ER PT J AU Khosroshahi, A Hasserjian, RP Sainani, NI Deshpande, V Stone, JH AF Khosroshahi, Arezou Hasserjian, Robert P. Sainani, Nisha I. Deshpande, Vikram Stone, John H. TI A Clinicopathologic Study of Retroperitoneal Fibrosis and Its Association with Immunoglobulin G4-Related Disease SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Khosroshahi, Arezou; Hasserjian, Robert P.; Sainani, Nisha I.; Deshpande, Vikram; Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 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 OCT PY 2011 VL 63 IS 10 SU S MA 1713 BP S672 EP S672 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502099 ER PT J AU Kwoh, CK Hannon, MJ Green, SM Guermazi, A Boudreau, RM AF Kwoh, C. Kent Hannon, Michael J. Green, Stephanie M. Guermazi, Ali Boudreau, Robert M. TI A Screening Tool for Knee Osteoarthritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Hannon, Michael J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kwoh, C. Kent] VA Pittsburgh Healthcare, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Guermazi, Ali] Boston Med Ctr, Boston, MA USA. NR 0 TC 2 Z9 2 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 OCT PY 2011 VL 63 IS 10 SU S MA 2079 BP S810 EP S810 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502465 ER PT J AU Kwoh, CK Guermazi, A Hannon, MJ Boudreau, RM Green, SM Jakicic, JM Roemer, F AF Kwoh, C. Kent Guermazi, Ali Hannon, Michael J. Boudreau, Robert M. Green, Stephanie M. Jakicic, John M. Roemer, Frank TI Identification of Magnetic Resonance Imaging Morphologic Features Associated with Different Knee Pain Patterns SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Hannon, Michael J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kwoh, C. Kent] VA Pittsburgh Healthcare, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Guermazi, Ali] Boston Med Ctr, Boston, MA USA. [Roemer, Frank] Boston Univ, Boston, MA 02215 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 959 BP S376 EP S376 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501154 ER PT J AU Lessard, CJ Adrianto, I Ice, JA Kelly, JA Li, H Wiley, GB Rasmussen, A Alarcon-Riquelme, ME Anaya, JM Bae, SC Brown, EE Jacob, CO James, JA Martin, J Niewold, TB Pons-Estel, B Tsao, BP Vyse, TJ Harley, JB Wakeland, E Kaufman, KM Montgomery, C Langefeld, CD Gaffney, PM Moser, KL AF Lessard, Christopher J. Adrianto, Indra Ice, John A. Kelly, Jennifer A. Li, He Wiley, Graham B. Rasmussen, Astrid Alarcon-Riquelme, Marta E. Anaya, Juan-Manuel Bae, Sang-Cheol Brown, Elizabeth E. Jacob, Chaim O. James, Judith A. Martin, Javier Niewold, Timothy B. Pons-Estel, Bernardo Tsao, Betty P. Vyse, Timothy J. Harley, John B. Wakeland, Edward Kaufman, Kenneth M. Montgomery, Courtney Langefeld, Carl D. Gaffney, Patrick M. Moser, Kathy L. TI A Large-Scale, Multi-Racial Replication Study Identifies Novel Systemic Lupus Erythematosus Susceptibility Loci At IRF8, TMEM39A, and IKZF3/ZPBP2 SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Alarcon-Riquelme, Marta E.] Pfizer Univ Granada Junta Andalucia, Oklahoma Med Res Fdn, Ctr Genom & Oncol Res, Oklahoma City, OK USA. [Anaya, Juan-Manuel] Univ Rosario, Corp Invest Biol, Bogota, Colombia. [Bae, Sang-Cheol] Hanyang Univ, Hosp Rheumat Dis, CRCRA, Seoul 133791, South Korea. [Brown, Elizabeth E.] Univ Alabama, Birmingham, AL USA. [Jacob, Chaim O.] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Martin, Javier] Inst Parasitol & Biomed Lopez Neyra CSIC, Granada, Spain. [Niewold, Timothy B.] Univ Chicago, Chicago, IL 60637 USA. [Tsao, Betty P.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Vyse, Timothy J.] Kings Coll London, Div Genet, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Mol Med, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Immunol, London WC2R 2LS, England. [Harley, John B.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Harley, John B.] Med Ctr, US Dept Vet Affairs, Cincinnati, OH USA. [Wakeland, Edward] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Kaufman, Kenneth M.; Gaffney, Patrick M.; Moser, Kathy L.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Kaufman, Kenneth M.] Med Ctr, US Dept Vet Affairs, Oklahoma City, OK USA. [Langefeld, Carl D.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. RI Adrianto, Indra/D-4214-2013; Anaya, Juan-Manuel/J-1960-2016 OI Adrianto, Indra/0000-0002-9973-3057; Anaya, Juan-Manuel/0000-0002-6444-1249 NR 0 TC 0 Z9 0 U1 1 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 OCT PY 2011 VL 63 IS 10 SU S MA 2475 BP S965 EP S965 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621503046 ER PT J AU Lessard, CJ Adrianto, I Ice, JA Kelly, JA Jonsson, R Illei, GG Rischmueller, M Nordmark, G Mariette, X Miceli-Richard, C Herlenius, MW Witte, T Brennan, MT Omdal, R Gaffney, PM Lessard, JA Ng, WF Rhodus, NL Segal, BM Scofield, RH James, JA Anaya, JM Harley, JB Montgomery, C Moser, KL AF Lessard, Christopher J. Adrianto, Indra Ice, John A. Kelly, Jennifer A. Jonsson, Roland Illei, Gabor G. Rischmueller, Maureen Nordmark, Gunnel Mariette, Xavier Miceli-Richard, Corinne Herlenius, Marie Wahren Witte, Torsten Brennan, Michael T. Omdal, Roald Gaffney, Patrick M. Lessard, James A. Ng, Wan-Fai Rhodus, Nelson L. Segal, Barbara M. Scofield, R. Hal James, Judith A. Anaya, Juan-Manuel Harley, John B. Montgomery, Courtney Moser, Kathy L. TI Large-Scale, High-Density Genotyping Performed by the Sjogren's Genetics Network Using the ImmunoChip Identifies PRKRA as a Novel Sjogren's Syndrome Susceptibility Locus and Confirms Associations with IRF5, BLK and MHC SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Gaffney, Patrick M.; Moser, Kathy L.] Oklahoma Med Res Fdn, Arthritis & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Jonsson, Roland] Univ Bergen, Bergen, Norway. [Illei, Gabor G.] NIDCR, NIH 10 1N110, Bethesda, MD USA. [Rischmueller, Maureen] Queen Elizabeth Hosp, Adelaide, SA, Australia. [Nordmark, Gunnel] Uppsala Univ, Rheumatol Sect, Dept Med Sci, Uppsala, Sweden. [Mariette, Xavier; Miceli-Richard, Corinne] Bicetre Univ Hosp, Le Kremlin Bicetre, France. [Herlenius, Marie Wahren] Karolinska Inst, Stockholm, Sweden. [Witte, Torsten] Hannover Med Sch, Hannover, Germany. [Brennan, Michael T.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Lessard, James A.] Valley Bone& Joint Clin, Grand Forks, ND USA. [Ng, Wan-Fai] Newcastle Univ, Inst Cellular Med, Musculoskeletal Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Rhodus, Nelson L.] Univ Minnesota, Minneapolis, MN USA. [Segal, Barbara M.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Anaya, Juan-Manuel] Univ Rosario Corp Invest Biol, Bogota, Colombia. [Harley, John B.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. RI Adrianto, Indra/D-4214-2013; Witte, Torsten/B-5783-2016; Anaya, Juan-Manuel/J-1960-2016 OI Adrianto, Indra/0000-0002-9973-3057; Anaya, Juan-Manuel/0000-0002-6444-1249 NR 0 TC 0 Z9 0 U1 1 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 OCT PY 2011 VL 63 IS 10 SU S MA 773 BP S303 EP S304 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500769 ER PT J AU Lessard, CJ Ice, JA Adrianto, I Kelly, JA Jonsson, R Illei, GG Rischmueller, M Nordmark, G Mariette, X Miceli-Richard, C Herlenius, MW Witte, T Brennan, MT Omdal, R Vyse, TJ Lessard, JA Ng, WF Rhodus, NL Segal, BM Scofield, RH Anaya, JM Harley, JB Montgomery, CG Moser, KL AF Lessard, Christopher J. Ice, John A. Adrianto, Indra Kelly, Jennifer A. Jonsson, Roland Illei, Gabor G. Rischmueller, Maureen Nordmark, Gunnel Mariette, Xavier Miceli-Richard, Corinne Herlenius, Marie Wahren Witte, Torsten Brennan, Michael T. Omdal, Roald Vyse, Timothy J. Lessard, James A. Ng, Wan-Fai Rhodus, Nelson L. Segal, Barbara M. Scofield, R. Hal Anaya, Juan-Manuel Harley, John B. Montgomery, Courtney G. Moser, Kathy L. CA Benjamin A Rybicki ACCESS TI A High-Density Genome-Wide Association Study by the Sjogren's Genetics Network Identifies Five Novel Susceptibility Loci for Primary Sjogren's Syndrome and Confirms Association with MHC, IRF5, and BLK SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Lessard, Christopher J.; Ice, John A.; Adrianto, Indra; Kelly, Jennifer A.; Scofield, R. Hal; Montgomery, Courtney G.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Jonsson, Roland] Univ Bergen, Bergen, Norway. [Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. [Rischmueller, Maureen] Queen Elizabeth Hosp, Adelaide, SA, Australia. [Nordmark, Gunnel] Uppsala Univ, Rheumatol Sect, Dept Med Sci, Uppsala, Sweden. [Mariette, Xavier; Miceli-Richard, Corinne] Bicetre Univ Hosp, Le Kremlin Bicetre, France. [Herlenius, Marie Wahren] Karolinska Inst, Stockholm, Sweden. [Witte, Torsten] Hannover Med Sch, D-3000 Hannover, Germany. [Brennan, Michael T.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Vyse, Timothy J.] Kings Coll London, Div Genet, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Mol Med & Immunol, London WC2R 2LS, England. [Lessard, James A.] Valley Bone & Joint Clin, Grand Forks, ND USA. [Ng, Wan-Fai] Newcastle Univ, Inst Cellular Med, Musculoskeletal Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Rhodus, Nelson L.] Univ Minnesota, Minneapolis, MN USA. [Segal, Barbara M.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Benjamin A Rybicki ACCESS] Henry Ford Hosp, Detroit, MI 48202 USA. [Anaya, Juan-Manuel] Univ Rosario Corp Invest Biol, Bogota, Colombia. [Harley, John B.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Moser, Kathy L.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. RI Adrianto, Indra/D-4214-2013; Witte, Torsten/B-5783-2016; Anaya, Juan-Manuel/J-1960-2016 OI Adrianto, Indra/0000-0002-9973-3057; Anaya, Juan-Manuel/0000-0002-6444-1249 NR 0 TC 1 Z9 1 U1 1 U2 4 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 OCT PY 2011 VL 63 IS 10 SU S MA 481 BP S184 EP S184 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500481 ER PT J AU Li, H Hsu, HC Li, J Wu, Q Yang, PA Cua, D Mountz, JD AF Li, Hao Hsu, Hui-Chen Li, Jun Wu, Qi Yang, PingAr Cua, Daniel Mountz, John D. TI IL-23 Upregulates IRF5 and Polarizes Inflammatory M1 Macrophages to Promote Inflammation in a Mouse Model of Arthritis. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Li, Hao; Hsu, Hui-Chen; Li, Jun; Wu, Qi; Yang, PingAr; Mountz, John D.] Univ Alabama, Birmingham, AL USA. [Cua, Daniel] Merck Res Lab, Palo Alto, CA USA. [Mountz, John D.] Birmingham VAMC, Birmingham, AL 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2097 BP S816 EP S817 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502483 ER PT J AU Li, J Hsu, HC Yang, P Wu, Q Mountz, JD AF Li, Jun Hsu, Hui-Chen Yang, PingAr Wu, Qi Mountz, John D. TI Fucosylation Inhibitor, 2-D-Gal, Promotes Human Synovial Fibroblast Apoptosis and Is a Potent Suppressor of Arthritis in a TNF-alpha Tg Mouse Model In Vivo SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Li, Jun; Hsu, Hui-Chen; Yang, PingAr; Wu, Qi; Mountz, John D.] Univ Alabama, Birmingham, AL USA. [Mountz, John D.] Birmingham VAMC, Birmingham, AL 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2248 BP S879 EP S880 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502634 ER PT J AU Li, J Hsu, HC Yang, P Wu, Q Li, H Mountz, JD AF Li, Jun Hsu, Hui-Chen Yang, PingAr Wu, Qi Li, Hao Mountz, John D. TI Rebalancing the IL-23/Th17 Axis and Regulatory T Cells in Arthritis by Depleting IRF5(+) IL-23(+) M1 Macrophages Using An Anti-Human DR5 Antibody SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol (ACR), Assoc Rheumatol Hlth Profess (ARHP) C1 [Li, Jun; Hsu, Hui-Chen; Yang, PingAr; Wu, Qi; Li, Hao; Mountz, John D.] Univ Alabama, Birmingham, AL USA. [Mountz, John D.] Birmingham VAMC, Birmingham, AL 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 2246 BP S878 EP S879 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502632 ER PT J AU Liu, M Wang, LW Bongartz, T Hawse, JR Markovic, SN Schaid, DJ Goss, PE Ingle, JN Weinshilboum, RM AF Liu, Mohan Wang, Liewei Bongartz, Tim Hawse, John R. Markovic, Svetomir N. Schaid, Daniel J. Goss, Paul E. Ingle, James N. Weinshilboum, Richard M. TI Musculoskeletal Inflammation and Estrogens: T-Cell Leukemia 1A (TCL1A) Gene-Dependent Regulation of Inflammatory Cytokines SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Liu, Mohan; Wang, Liewei; Bongartz, Tim; Hawse, John R.; Markovic, Svetomir N.; Schaid, Daniel J.; Ingle, James N.; Weinshilboum, Richard M.] Mayo Clin, Rochester, MN USA. [Goss, Paul E.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1676 BP S655 EP S656 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502062 ER PT J AU Maxwell, JL Felson, DT Niu, JB Wise, B Nevitt, MC Singh, J Frey-Law, L Neogi, T AF Maxwell, Jessica L. Felson, David T. Niu, Jingbo Wise, Barton Nevitt, Michael C. Singh, Jasvinder Frey-Law, Laura Neogi, Tuhina TI Does Important Improvement in Function After Knee Replacement Guarantee Good Absolute Function SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Felson, David T.; Niu, Jingbo; Neogi, Tuhina] Boston Univ, Sch Med, Boston, MA 02118 USA. [Wise, Barton] Ctr Hlth Aging UC Davis, Sacramento, CA USA. [Nevitt, Michael C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Singh, Jasvinder] Univ Alabama, Birmingham, AL USA. [Singh, Jasvinder] Birmingham VA Med Ctr, Birmingham, AL USA. [Frey-Law, Laura] Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 0 U2 7 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 OCT PY 2011 VL 63 IS 10 SU S MA 1541 BP S602 EP S602 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501735 ER PT J AU Mohan, N Hannon, MJ Kwoh, CK AF Mohan, Niveditha Hannon, Michael J. Kwoh, C. Kent TI Correlation of Bony Enlargements with Radiological Findings in Hand Osteoarthritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Mohan, Niveditha] Univ Pittsburgh, Arth Inst, Pittsburgh, PA USA. [Hannon, Michael J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kwoh, C. Kent] VA Pittsburgh Healthcare, Ctr Hlth Equity Res & Promot, 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 962 BP S377 EP S377 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501157 ER PT J AU Mohan, N Hannon, MJ Kwoh, CK AF Mohan, Niveditha Hannon, Michael J. Kwoh, C. Kent TI Correlation of Hand Pain and Radiological Findings in Hand Osteoarthritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Mohan, Niveditha] Univ Pittsburgh, Arth Inst, Pittsburgh, PA USA. [Hannon, Michael J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kwoh, C. Kent] VA Pittsburgh Healthcare, Ctr Hlth Equity Res & Promot, 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 963 BP S377 EP S378 PG 2 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621501158 ER PT J AU Monach, PA Warner, RL Tomasson, G Specks, U Stone, JH Ding, L Fervenza, F Fessler, BJ Hoffman, GS Ikle, D Kallenberg, CGM Krischer, J Langford, CA Mueller, M Seo, P St Clair, EW Spiera, R Tchao, N Ytterberg, SR Johnson, KJ Merkel, PA AF Monach, Paul A. Warner, Roscoe L. Tomasson, Gunnar Specks, Ulrich Stone, John H. Ding, Linna Fervenza, Fernando Fessler, Barri J. Hoffman, Gary S. Ikle, David Kallenberg, Cees G. M. Krischer, Jeffrey Langford, Carol A. Mueller, Mark Seo, Philip St Clair, E. William Spiera, Robert Tchao, Nadia Ytterberg, Steven R. Johnson, Kent J. Merkel, Peter A. TI Serum Proteins Reflecting Inflammation, Injury, and Repair As Biomarkers of Disease Activity in ANCA-Associated Vasculitis. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol (ACR), Assoc Rheumatol Hlth Profess (ARHP) C1 [Tomasson, Gunnar; Merkel, Peter A.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Warner, Roscoe L.; Johnson, Kent J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Specks, Ulrich; Fervenza, Fernando; Ytterberg, Steven R.] Mayo Clin, Rochester, MN USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ding, Linna] NIAID, Bethesda, MD 20892 USA. [Fessler, Barri J.] Univ Alabama Birmingham, Birmingham, AL USA. [Hoffman, Gary S.] Cleveland Clin Found A50, Cleveland, OH USA. [Ikle, David] Rho, Chapel Hill, NC USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Krischer, Jeffrey] Univ S Florida, Tampa, FL USA. [Langford, Carol A.] Cleveland Clin, Cleveland, OH 44106 USA. [Mueller, Mark] US FDA, Bethesda, MD 20014 USA. [Seo, Philip] Johns Hopkins Vasculitis Ctr, Baltimore, MD USA. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Spiera, Robert] Hosp Special Surg, New York, NY 10021 USA. [Tchao, Nadia] Immune Tolerance Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 792 BP S312 EP S312 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500788 ER PT J AU Munroe, ME Guthridge, JM Kamen, DL Norris, JM Moser, KL Niewold, TB Gilkeson, GS Karp, DR Weisman, MH Ishimori, ML Wallace, DJ Harley, JB James, JA AF Munroe, Melissa E. Guthridge, Joel M. Kamen, Diane L. Norris, Jill M. Moser, Kathy L. Niewold, Timothy B. Gilkeson, Gary S. Karp, David R. Weisman, Michael H. Ishimori, Mariko L. Wallace, Daniel J. Harley, John B. James, Judith A. TI Altered Soluble Mediators of Inflammation At Baseline in Individuals Who Subsequently Transition to Systemic Lupus Erythematosus: Early Studies From the Lupus Autoimmunity in Relatives (LAUREL) Study SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Munroe, Melissa E.; Guthridge, Joel M.; Moser, Kathy L.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Kamen, Diane L.] Med Univ SC, Charleston, SC USA. [Norris, Jill M.] Univ Colorado Denver, Aurora, CO USA. [Niewold, Timothy B.] Univ Chicago, Chicago, IL 60637 USA. [Gilkeson, Gary S.] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Karp, David R.] UT SW Med Ctr, Dallas, TX USA. [Weisman, Michael H.; Ishimori, Mariko L.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Wallace, Daniel J.] Cedars Sinai UCLA, Los Angeles, CA USA. [Harley, John B.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 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 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD OCT PY 2011 VL 63 IS 10 SU S MA 1663 BP S650 EP S650 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621502049 ER PT J AU Neogi, T Niu, JB Felson, DT Nevitt, MC Zhang, YQ Frey-Law, L Maxwell, JL Singh, J AF Neogi, Tuhina Niu, Jingbo Felson, David T. Nevitt, Michael C. Zhang, Yuqing Frey-Law, Laura Maxwell, Jessica L. Singh, Jasvinder TI Time-Course and Extent of Pain and Function Improvements Post-Knee Replacement: The Multicenter Osteoarthritis Study SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY NOV 04-09, 2011 CL Chicago, IL SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Professionals C1 [Neogi, Tuhina; Niu, Jingbo; Felson, David T.; Zhang, Yuqing; Maxwell, Jessica L.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Nevitt, Michael C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Frey-Law, Laura] Univ Iowa, Iowa City, IA USA. [Singh, Jasvinder] Univ Alabama, Birmingham, AL USA. [Singh, Jasvinder] Birmingham VA Med Ctr, Birmingham, AL USA. NR 0 TC 0 Z9 0 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 OCT PY 2011 VL 63 IS 10 SU S MA 742 BP S289 EP S289 PG 1 WC Rheumatology SC Rheumatology GA 856EV UT WOS:000297621500738 ER EF