FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Dykxhoorn, DM Wu, YC Xie, HM Yu, FY Lal, A Petrocca, F Martinvalet, D Song, E Lim, B Lieberman, J AF Dykxhoorn, Derek M. Wu, Yichao Xie, Huangming Yu, Fengyan Lal, Ashish Petrocca, Fabio Martinvalet, Denis Song, Erwei Lim, Bing Lieberman, Judy TI miR-200 Enhances Mouse Breast Cancer Cell Colonization to Form Distant Metastases SO PLOS ONE LA English DT Article AB Background: The development of metastases involves the dissociation of cells from the primary tumor to penetrate the basement membrane, invade and then exit the vasculature to seed, and colonize distant tissues. The last step, establishment of macroscopic tumors at distant sites, is the least well understood. Four isogenic mouse breast cancer cell lines (67NR, 168FARN, 4TO7, and 4T1) that differ in their ability to metastasize when implanted into the mammary fat pad are used to model the steps of metastasis. Only 4T1 forms macroscopic lung and liver metastases. Because some miRNAs are dysregulated in cancer and affect cellular transformation, tumor formation, and metastasis, we examined whether changes in miRNA expression might explain the differences in metastasis of these cells. Methodology/Principal Findings: miRNA expression was analyzed by miRNA microarray and quantitative RT-PCR in isogenic mouse breast cancer cells with distinct metastatic capabilities. 4T1 cells that form macroscopic metastases had elevated expression of miR-200 family miRNAs compared to related cells that invade distant tissues, but are unable to colonize. Moreover, over-expressing miR-200 in 4TO7 cells enabled them to metastasize to lung and liver. These findings are surprising since the miR-200 family was previously shown to promote epithelial characteristics by inhibiting the transcriptional repressor Zeb2 and thereby enhancing E-cadherin expression. We confirmed these findings in these cells. The most metastatic 4T1 cells acquired epithelial properties (high expression of E-cadherin and cytokeratin-18) compared to the less metastatic cells. Conclusions/Significance: Expression of miR-200, which promotes a mesenchymal to epithelial cell transition (MET) by inhibiting Zeb2 expression, unexpectedly enhances macroscopic metastases in mouse breast cancer cell lines. These results suggest that for some tumors, tumor colonization at metastatic sites might be enhanced by MET. Therefore the epithelial nature of a tumor does not predict metastatic outcome. RP Dykxhoorn, DM (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM ddykxhoorn@med.miami.edu; lieberman@idi.harvard.edu RI Xie, Huangming/B-2260-2012; Lieberman, Judy/A-2717-2015; Dykxhoorn, Derek/D-1357-2015 NR 60 TC 165 Z9 170 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 29 PY 2009 VL 4 IS 9 AR e7181 DI 10.1371/journal.pone.0007181 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 500HR UT WOS:000270290100008 PM 19787069 ER PT J AU Binstadt, BA Hebert, JL Ortiz-Lopez, A Bronson, R Benoist, C Mathis, D AF Binstadt, Bryce A. Hebert, Jennifer L. Ortiz-Lopez, Adriana Bronson, Roderick Benoist, Christophe Mathis, Diane TI The same systemic autoimmune disease provokes arthritis and endocarditis via distinct mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoimmunity; complement; Fc receptor; rheumatic; lupus ID CORONARY-ARTERY ATHEROSCLEROSIS; ALTERNATIVE COMPLEMENT PATHWAY; LIBMAN-SACKS ENDOCARDITIS; RHEUMATIC HEART-DISEASE; FC-GAMMA RECEPTORS; INFLAMMATORY ARTHRITIS; LUPUS-ERYTHEMATOSUS; TRANSFER MODEL; MICE; CELLS AB The immune mechanisms that provoke concomitant inflammation of synovial joints and cardiac valves in disorders such as rheumatic fever and systemic lupus erythematosus remain poorly defined. Here, we report the discovery of spontaneous endocarditis-in addition to their well-studied autoimmune arthritis-in K/BxN T cell receptor (TCR) transgenic mice. The same adaptive immune system elements were required for initiation of arthritis and endocarditis, and both diseases were dependent on autoantibodies. In contrast, the participation of key innate immune system molecules and perhaps T cells as effectors of inflammation differed between the 2 target tissues. Arthritis in K/BxN TCR transgenic mice depended primarily on complement C5 and not FcR gamma-using receptors; conversely, endocarditis depended essentially on FcR gamma receptors and not C5. Elucidating how a single systemic autoimmune disease engages distinct immune effector pathways to damage different target tissues is essential for optimizing the treatment of such disorders. C1 [Binstadt, Bryce A.; Hebert, Jennifer L.] Univ Minnesota, Div Pediat Rheumatol, Minneapolis, MN 55455 USA. [Binstadt, Bryce A.] Harvard Univ, Sch Med, Dept Pediat, Childrens Hosp Boston, Boston, MA 02215 USA. [Binstadt, Bryce A.; Ortiz-Lopez, Adriana; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. [Ortiz-Lopez, Adriana; Bronson, Roderick; Benoist, Christophe; Mathis, Diane] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02115 USA. RP Binstadt, BA (reprint author), Univ Minnesota, Div Pediat Rheumatol, Minneapolis, MN 55455 USA. EM binstadt@umn.edu; cbdm@hms.harvard.edu RI Binstadt, Bryce/N-1305-2013 OI Binstadt, Bryce/0000-0003-3127-3856 FU National Institutes of Health [R01 AR046580, K08 AR054317]; Joslin's National Institute of Diabetes and Digestive and Kidney Diseases; Diabetes and Endocrinology Research Center; Pfizer Postdoctoral Fellowship; Arthritis Foundation Arthritis Investigator Award FX We thank Kimie Hattori and Sindhuja Rao for assistance with mice. This work was supported by grants from the National Institutes of Health (R01 AR046580) and Young Chair funds to D. Mathis and C. Benoist, and by Joslin's National Institute of Diabetes and Digestive and Kidney Diseases-funded Diabetes and Endocrinology Research Center core facilities. Bryce Binstadt was supported by a Pfizer Postdoctoral Fellowship in Rheumatology/Immunology, University of Minnesota Department of Pediatrics funding, an Arthritis Foundation Arthritis Investigator Award, and National Institutes of Health Grant K08 AR054317. NR 31 TC 17 Z9 17 U1 0 U2 1 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 SEP 29 PY 2009 VL 106 IS 39 BP 16758 EP 16763 DI 10.1073/pnas.0909132106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 500MH UT WOS:000270305800040 PM 19805369 ER PT J AU Singh, H Thomas, EJ Mani, S Sittig, D Arora, H Espadas, D Khan, MM Petersen, LA AF Singh, Hardeep Thomas, Eric J. Mani, Shrinidi Sittig, Dean Arora, Harvinder Espadas, Donna Khan, Myrna M. Petersen, Laura A. TI Timely Follow-up of Abnormal Diagnostic Imaging Test Results in an Outpatient Setting Are Electronic Medical Records Achieving Their Potential? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID DECISION-SUPPORT-SYSTEMS; INFORMATION-TECHNOLOGY; PATIENT NAVIGATION; CLINICAL-PRACTICE; COMMUNICATION; ERRORS; CARE; ALERTS; SAFETY; CONSEQUENCES AB Background: Given the fragmentation of outpatient care, timely follow-up of abnormal diagnostic imaging results remains a challenge. We hypothesized that an electronic medical record (EMR) that facilitates the transmission and availability of critical imaging results through either automated notification (alerting) or direct access to the primary report would eliminate this problem. Methods: We studied critical imaging alert notifications in the outpatient setting of a tertiary care Department of Veterans Affairs facility from November 2007 to June 2008. Tracking software determined whether the alert was acknowledged (ie, health care practitioner/provider [HCP] opened the message for viewing) within 2 weeks of transmission; acknowledged alerts were considered read. We reviewed medical records and contacted HCPs to determine timely follow-up actions (eg, ordering a follow-up test or consultation) within 4 weeks of transmission. Multivariable logistic regression models accounting for clustering effect by HCPs analyzed predictors for 2 outcomes: lack of acknowledgment and lack of timely follow-up. Results: Of 123 638 studies (including radiographs, computed tomographic scans, ultrasonograms, magnetic resonance images, and mammograms), 1196 images (0.97%) generated alerts; 217 (18.1%) of these were unacknowledged. Alerts had a higher risk of being unacknowledged when the ordering HCPs were trainees (odds ratio [ OR], 5.58; 95% confidence interval [CI], 2.86-10.89) and when dual-alert (>1 HCP alerted) as opposed to single-alert communication was used (OR, 2.02; 95% CI, 1.22-3.36). Timely follow-up was lacking in 92 (7.7% of all alerts) and was similar for acknowledged and unacknowledged alerts (7.3% vs 9.7%; P = .22). Risk for lack of timely follow-up was higher with dual-alert communication (OR, 1.99; 95% CI, 1.06-3.48) but lower when additional verbal communication was used by the radiologist (OR, 0.12; 95% CI, 0.04-0.38). Nearly all abnormal results lacking timely follow-up at 4 weeks were eventually found to have measurable clinical impact in terms of further diagnostic testing or treatment. Conclusions: Critical imaging results may not receive timely follow-up actions even when HCPs receive and read results in an advanced, integrated electronic medical record system. A multidisciplinary approach is needed to improve patient safety in this area. C1 [Singh, Hardeep; Mani, Shrinidi; Espadas, Donna; Khan, Myrna M.; Petersen, Laura A.] Baylor Coll Med, Dept Vet Affairs Hlth Serv Res & Dev Serv, Ctr Excellence, Houston, TX 77030 USA. [Singh, Hardeep; Mani, Shrinidi; Espadas, Donna; Khan, Myrna M.; Petersen, Laura A.] Baylor Coll Med, Ctr Inquiry Improve Outpatient Safety Through Eff, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Singh, Hardeep; Mani, Shrinidi; Espadas, Donna; Khan, Myrna M.; Petersen, Laura A.] Baylor Coll Med, Sect Hlth Serv Res, Dept Med, Houston, TX 77030 USA. [Thomas, Eric J.] Univ Texas Houston, Sch Med, Dept Med,Div Gen Med, Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX 77030 USA. [Sittig, Dean] Univ Texas Houston, Sch Hlth Informat Sci, Houston, TX 77030 USA. [Sittig, Dean] Univ Texas Mem Hermann Ctr Healthcare Qual & Safe, Houston, TX USA. RP Singh, H (reprint author), VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.tmc.edu FU NIH K23 [K23CA125585]; VA National Center of Patient Safety; Agency for Health Care Research and Quality; Houston VA HSR& D Center of Excellence [HFP90020] FX The study was supported by an NIH K23 career development award (K23CA125585) to Dr Singh, the VA National Center of Patient Safety, Agency for Health Care Research and Quality, and in part by the Houston VA HSR& D Center of Excellence (HFP90020). NR 43 TC 85 Z9 86 U1 9 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 28 PY 2009 VL 169 IS 17 BP 1578 EP 1586 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 499TA UT WOS:000270247400008 PM 19786677 ER PT J AU Hoffman, RM Couper, MP Zikmund-Fisher, BJ Levin, CA McNaughton-Collins, M Helitzer, DL VanHoewyk, J Barry, MJ AF Hoffman, Richard M. Couper, Mick P. Zikmund-Fisher, Brian J. Levin, Carrie A. McNaughton-Collins, Mary Helitzer, Deborah L. VanHoewyk, John Barry, Michael J. TI Prostate Cancer Screening Decisions Results From the National Survey of Medical Decisions (DECISIONS Study) SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HEALTH INTERVIEW SURVEY; UNITED-STATES; ANTIGEN; PHYSICIANS; MORTALITY; LITERACY; AIDS; CARE; MEN AB Background: Guidelines recommend informing patients about the risks and benefits of prostate cancer screening. We evaluated the medical decision-making process for prostate-specific antigen (PSA) testing. Methods: We conducted a telephone survey of a randomly selected national sample of 3010 English-speaking US adults 40 years and older. Included in the survey were 375 men who had either undergone or discussed (with health care providers [HCPs]) PSA testing in the previous 2 years. We asked subjects about socio-demographic characteristics, prostate cancer screening discussion features, prostate cancer knowledge, and the importance of various decision factors and sources of information. Results: Overall, 69.9% of subjects discussed screening before making a testing decision, including 14.4% who were not tested. Health care providers most often (64.6%) raised the idea of screening, and 73.4% recommended PSA testing. Health care providers emphasized the pros of testing in 71.4% of discussions but infrequently addressed the cons (32.0%). Although 58.0% of subjects felt well-informed about PSA testing, 47.8% failed to correctly answer any of the 3 knowledge questions. Only 54.8% of subjects reported being asked for their screening preferences. An HCP recommendation (odds ratio, 2.67; 95% confidence interval, 1.08-6.58) was the only discussion characteristic associated with testing. Valuing HCP information was also associated with testing (odds ratio, 1.26; 95% confidence interval, 1.04-1.54). Conclusions: Recommendations and information from HCPs strongly influenced testing decisions. However, most prostate cancer screening decisions did not meet criteria for shared decision making because subjects did not receive balanced discussions of decision consequences, had limited knowledge, and were not routinely asked for their preferences. C1 [Hoffman, Richard M.] New Mexico VA Hlth Care Syst, Med Serv, Albuquerque, NM USA. [Hoffman, Richard M.] Univ New Mexico, Sch Med, Dept Med, Albuquerque, NM 87131 USA. [Helitzer, Deborah L.] Univ New Mexico, Sch Med, Dept Family & Community Med, Albuquerque, NM 87131 USA. [Couper, Mick P.; Zikmund-Fisher, Brian J.; VanHoewyk, John] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA. [Zikmund-Fisher, Brian J.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Couper, Mick P.; Zikmund-Fisher, Brian J.] Univ Michigan, Ctr Behav & Decis Sci Med, Ann Arbor, MI 48109 USA. [Zikmund-Fisher, Brian J.] Ann Arbor VA Hlth Care Syst, VA Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Levin, Carrie A.] Fdn Informed Med Decis Making, Boston, MA USA. [McNaughton-Collins, Mary] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Hoffman, RM (reprint author), 1501 San Pedro Dr SE,Mail Stop 111, Albuquerque, NM 87108 USA. EM rhoffman@unm.edu RI Zikmund-Fisher, Brian/A-7677-2009; OI Zikmund-Fisher, Brian/0000-0002-1637-4176 FU FIMDM, Boston, Massachusetts; New Mexico VA Health Care System, Albuquerque; American Cancer Society [MRSG-06-130-01-CPPB] FX This study was supported by the not-for-profit FIMDM, Boston, Massachusetts, and by the New Mexico VA Health Care System, Albuquerque. Dr Zikmund-Fisher is supported by a career development award from the American Cancer Society (MRSG-06-130-01-CPPB). NR 34 TC 77 Z9 80 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9926 EI 1538-3679 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 28 PY 2009 VL 169 IS 17 BP 1611 EP 1618 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 499TA UT WOS:000270247400012 PM 19786681 ER PT J AU Weingart, SN Simchowitz, B Shiman, L Brouillard, D Cyrulik, A Davis, RB Isaac, T Massagli, M Morway, L Sands, DZ Spencer, J Weissman, JS AF Weingart, Saul N. Simchowitz, Brett Shiman, Lawrence Brouillard, Daniela Cyrulik, Adrienne Davis, Roger B. Isaac, Thomas Massagli, Michael Morway, Laurinda Sands, Daniel Z. Spencer, Justin Weissman, Joel S. TI Clinicians' Assessments of Electronic Medication Safety Alerts in Ambulatory Care SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID DRUG-INTERACTION ALERTS; TIME-SERIES EVALUATION; PRESCRIBING SAFETY; DECISION-SUPPORT; SYSTEM; IMPACT; VIEWS AB Background: While electronic prescribing (e-prescribing) systems with drug interaction and allergy alerts promise to improve medication safety in ambulatory care, clinicians often override these safety features. We undertook a study of respondents' satisfaction with e-prescribing systems, their perceptions of alerts, and their perceptions of behavior changes resulting from alerts. Methods: Random sample survey of 300 Massachusetts ambulatory care clinicians who used a commercial e-prescribing system. Results: A total of 184 respondents completed the survey (61%). Respondents indicated that e-prescribing improved the quality of care delivered (78%), prevented medical errors (83%), and enhanced patient satisfaction (71%) and clinician efficiency (75%). In addition, 35% of prescribers said that electronic alerts caused them to modify a potentially dangerous prescription in the last 30 days. They suggested that alerts also led to other changes in clinical care: counseling patients about potential reactions (49% of respondents), looking up information in medical references (44%), and changing the way a patient was monitored (33%). Altogether, 63% of clinicians reported taking action other than discontinuing or modifying an alerted prescription in the previous month in response to alerts. Despite these benefits, fewer than half of respondents were satisfied with drug interaction and allergy alerts (47%). Problems included alerts triggered by discontinued medications (58%), alerts that failed to account for appropriate drug combinations (46%), and excessive volume of alerts (37%). Conclusion: Although clinicians were critical of the quality of e-prescribing alerts, alerts may lead to clinically significant modifications in patient management not readily apparent based on "acceptance" rates. C1 [Weingart, Saul N.; Simchowitz, Brett; Shiman, Lawrence; Brouillard, Daniela; Isaac, Thomas; Morway, Laurinda; Spencer, Justin] Dana Farber Canc Inst, Ctr Patient Safety, Boston, MA 02115 USA. [Weingart, Saul N.; Davis, Roger B.; Isaac, Thomas; Sands, Daniel Z.; Weissman, Joel S.] Harvard Univ, Sch Med, Boston, MA USA. [Cyrulik, Adrienne] Blue Cross & Blue Shield Massachusetts, Boston, MA USA. [Davis, Roger B.; Isaac, Thomas; Sands, Daniel Z.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Massagli, Michael] PatientsLikeMe, Cambridge, MA USA. [Sands, Daniel Z.] Cisco, San Jose, CA USA. [Weissman, Joel S.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Weissman, Joel S.] Commonwealth Massachusetts, Execut Off Hlth & Human Serv, Boston, MA USA. [Weissman, Joel S.] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Weingart, SN (reprint author), Dana Farber Canc Inst, Ctr Patient Safety, 44 Binney St, Boston, MA 02115 USA. EM saul_weingart@dfci.harvard.edu FU Blue Cross Blue Shield of Massachusetts FX This research was supported by a grant from Blue Cross Blue Shield of Massachusetts. Role of the Sponsor: Blue Cross Blue Shield of Massachusetts was not involved in the design or conduct of the study, data collection, or data analysis. The company did not prepare or approve the final manuscript. NR 24 TC 49 Z9 50 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 28 PY 2009 VL 169 IS 17 BP 1627 EP 1632 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 499TA UT WOS:000270247400015 PM 19786683 ER PT J AU Luck, J Hagigi, F Parker, LE Yano, EM Rubenstein, LV Kirchner, JE AF Luck, Jeff Hagigi, Fred Parker, Louise E. Yano, Elizabeth M. Rubenstein, Lisa V. Kirchner, JoAnn E. TI A social marketing approach to implementing evidence-based practice in VHA QUERI: the TIDES depression collaborative care model SO IMPLEMENTATION SCIENCE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; RESEARCH INITIATIVE QUERI; LATE-LIFE DEPRESSION; QUALITY-IMPROVEMENT; PUBLIC-HEALTH; ORGANIZATIONS; EXPERIENCE; SERIES AB : Collaborative care models for depression in primary care are effective and cost-effective, but difficult to spread to new sites. Translating Initiatives for Depression into Effective Solutions (TIDES) is an initiative to promote evidence-based collaborative care in the U. S. Veterans Health Administration (VHA). Social marketing applies marketing techniques to promote positive behavior change. Described in this paper, TIDES used a social marketing approach to foster national spread of collaborative care models. TIDES social marketing approach: The approach relied on a sequential model of behavior change and explicit attention to audience segmentation. Segments included VHA national leadership, Veterans Integrated Service Network (VISN) regional leadership, facility managers, frontline providers, and veterans. TIDES communications, materials and messages targeted each segment, guided by an overall marketing plan. Results: Depression collaborative care based on the TIDES model was adopted by VHA as part of the new Primary Care Mental Health Initiative and associated policies. It is currently in use in more than 50 primary care practices across the United States, and continues to spread, suggesting success for its social marketing-based dissemination strategy. Discussion and conclusion: Development, execution and evaluation of the TIDES marketing effort shows that social marketing is a promising approach for promoting implementation of evidence-based interventions in integrated healthcare systems. C1 [Luck, Jeff; Hagigi, Fred; Parker, Louise E.; Yano, Elizabeth M.; Rubenstein, Lisa V.] VA Greater Angeles Healthcare Syst, VA Greater Angeles HSR&D Ctr Excellence, Sepulveda, CA USA. [Luck, Jeff; Hagigi, Fred; Yano, Elizabeth M.; Rubenstein, Lisa V.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Parker, Louise E.; Kirchner, JoAnn E.] Ctr Mental Healthcare & Outcomes Res, N Little Rock, AR USA. [Kirchner, JoAnn E.] S Cent Mental Illness Res Educ & Clin Ctr MIRECC, Little Rock, AR USA. [Kirchner, JoAnn E.] Univ Arkansas Med Sci Ctr, Little Rock, AR USA. RP Luck, J (reprint author), VA Greater Angeles Healthcare Syst, VA Greater Angeles HSR&D Ctr Excellence, Sepulveda, CA USA. EM jluck@ucla.edu; hagigi@ucla.edu; parkerlouise@earthlnk.net; elizabeth.yano@va.gov; lisar@rand.org; kirchnerjoanne@uams.edu FU VHA HSR D [IMA 04-161]; VHA QUERI FX This work was funded through a VHA HSR& D supplemental grant for enhancing access to implementation research expertise (Project # IMA 04-161) and a VHA QUERI service-directed project, the Cost and Value of Translating Evidence-based Practices Study (COVES) (Project # MNT 02-029). We thank Jennifer L. Magnabosco, PhD, for her coordination and project management support of the joint marketing effort across these studies. Mona Ritchie, PhD, also has provided valuable support to TIDES implementation and evaluation. John Williams, MD, Ed Chaney, PhD, Jeff Smith, PhD(c), and Susan Vivell, PhD provided valuable information about the TIDES implementation effort. Cheryl Stetler, PhD, RN and Brian Mittman, PhD provided conceptual and structural suggestions that greatly improved the manuscript. NR 47 TC 25 Z9 25 U1 2 U2 9 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 SEP 28 PY 2009 VL 4 AR 64 DI 10.1186/1748-5908-4-64 PG 13 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 507XO UT WOS:000270889300001 PM 19785754 ER PT J AU Nolting, J Daniel, C Reuter, S Stuelten, C Li, P Sucov, H Kim, BG Letterio, JJ Kretschmer, K Kim, HJ von Boehmer, H AF Nolting, Jens Daniel, Carolin Reuter, Sabine Stuelten, Christina Li, Peng Sucov, Henry Kim, Byung-Gyu Letterio, John J. Kretschmer, Karsten Kim, Hye-Jung von Boehmer, Harald TI Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; ORAL TOLERANCE; RECEPTOR; INDUCTION; GROWTH; PROMOTER; GENE; DIFFERENTIATION; BINDING; MICE AB It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor alpha (RAR alpha) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RAR alpha 1 isoform was not essential for RA-dependent enhancement of transforming growth factor beta-driven conversion, suggesting that conversion can also be mediated by RAR alpha 2. Interleukin (IL)-6 strongly reduced RAR alpha expression levels such that a deficiency of the predominant RAR alpha 1 isoform leaves too little RAR alpha 2 for RA to inhibit the generation of Th17 cells in the presence of IL-6. C1 [Nolting, Jens; Daniel, Carolin; Reuter, Sabine; Kretschmer, Karsten; Kim, Hye-Jung; von Boehmer, Harald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Stuelten, Christina] NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Li, Peng; Sucov, Henry] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90033 USA. [Kim, Byung-Gyu; Letterio, John J.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Dept Pediat, Cleveland, OH 44106 USA. RP von Boehmer, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM harald_von_boehmer@dfci.harvard.edu RI Kretschmer, Karsten/E-8174-2010; Daniel, Carolin/M-4624-2014 OI Daniel, Carolin/0000-0003-4698-7069 FU National Institutes of Health [NIH-AI53102]; Leopoldina research fellowship [BMBF-LPD 9901/8-184]; LOEWE (LiFF) program of the federal state of Hessen, Germany FX This report was supported by the National Institutes of Health (grant NIH-AI53102 to H. von Boehmer), and C. Daniel was supported by a Leopoldina research fellowship (BMBF-LPD 9901/8-184) and the LOEWE (LiFF) program of the federal state of Hessen, Germany. NR 29 TC 78 Z9 80 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 28 PY 2009 VL 206 IS 10 BP 2131 EP 2139 DI 10.1084/jem.20090639 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 500AM UT WOS:000270269300009 PM 19737861 ER PT J AU Deng, SP Markmann, JF Rickels, M Yeh, HD Kim, JI Lian, MM Gu, Y Markmann, E Palanjian, M Barker, CF Naji, A AF Deng, Shaoping Markmann, James F. Rickels, Micheal Yeh, Heidi Kim, James I. Lian, Moh-Moh Gu, Yi Markmann, Eileen Palanjian, Maral Barker, Clyde F. Naji, Ali TI Islet Alone Versus Islet After Kidney Transplantation: Metabolic Outcomes and Islet Graft Survival SO TRANSPLANTATION LA English DT Article DE Diabetes; Islet; Transplantation ID STEROID-FREE IMMUNOSUPPRESSION; PANCREATIC-ISLETS; CELL TRANSPLANTATION; PROTOCOL AB Background. Isolated islet transplantation with infusions from two to three donor pancreata and Edmonton immunosuppression consistently achieves insulin independence in patients with type 1 diabetes. The success of this protocol has been attributed to a novel combination of immunosuppressive agents and avoidance of steroids; however, the outcome of islet transplantation may differ in kidney transplant recipients who are already immunosuppressed. Methods. We compared the metabolic outcomes and graft survival of islet transplantation in our program where nine patients underwent islet transplantation alone treated with Edmonton immunosuppression and eight patients received islet after kidney (IAK) transplants under standard kidney transplant immunosuppression often including steroids. Results. Transplants in the IAK and islet transplantation alone setting demonstrated similar islet potency (islet equivalents/unit insulin reduction) and recipients from both groups routinely gained insulin independence, functional islet mass, and duration of graft survival, however, seemed superior in the IAK group. Conclusions. These results suggest that better islet graft function and survival may be attained using non-Edmonton rather than Edmonton immunosuppression and can include maintenance steroid therapy. C1 [Deng, Shaoping; Markmann, James F.; Rickels, Micheal; Yeh, Heidi; Kim, James I.; Lian, Moh-Moh; Gu, Yi; Markmann, Eileen; Palanjian, Maral; Barker, Clyde F.; Naji, Ali] Hosp Univ Penn, Dept Surg, Harrison Dept Surg Res, Philadelphia, PA 19104 USA. RP Markmann, JF (reprint author), Massachusetts Gen Hosp, Dept Surg, WHT 503,55 Fruit St, Boston, MA 02114 USA. EM jmarkmann@partners.org FU Juvenile Diabetes Research Foundation; National Institutes of Health [U42-RR-016600, UL1-RR-024134, P30-DK-19525] FX This work was supported by the Juvenile Diabetes Research Foundation and Public Health Services Research Grants U42-RR-016600 (Penn Islet Cell Resource Center), UL1-RR-024134 (Penn Clinical and Translational Research Center), and P30-DK-19525 (Penn Diabetes Endocrinology Research Center) from the National Institutes of Health. This work was supported by the NIH and the JDRF grants (A.N.). NR 19 TC 13 Z9 14 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 SEP 27 PY 2009 VL 88 IS 6 BP 820 EP 825 DI 10.1097/TP.0b013e3181b4bdbb PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 500AX UT WOS:000270270500013 PM 19920782 ER PT J AU Kegel, KB Schewkunow, V Sapp, E Masso, N Wanker, EE DiFiglia, M Goldmann, WH AF Kegel, Kimberly B. Schewkunow, Vitali Sapp, Ellen Masso, Nicholas Wanker, Erich E. DiFiglia, Marian Goldmann, Wolfgang H. TI Polyglutamine expansion in huntingtin increases its insertion into lipid bilayers SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Differential scanning calorimetry; Huntingtin; Huntington disease; Membrane; Phosphatidylethanolamine; Polyglutamine ID MEMBRANE; DISEASE; BRAIN; PHOSPHOLIPIDS; DYSFUNCTION; CHANNELS; BINDING; MODEL; ACID; HIP1 AB An expanded polyglutamine (Q) tract (>37Q) in huntingtin (htt) causes Huntington disease. Htt associates with membranes and polyglutamine expansion in htt may alter membrane function in Huntington disease through a mechanism that is not known. Here we used differential scanning calorimetry to examine the effects of polyQ expansion in htt on its insertion into lipid bilayers. We prepared synthetic lipid vesicles composed of phosphatidylcholine and phosphatidylethanolamine and tested interactions of htt amino acids 1-89 with 20Q, 32Q or 53Q with the vesicles. GST-htt1 -89 with 53Q inserted into synthetic lipid vesicles significantly more than GST-htt1-89 with 20Q or 32Q. We speculate that by inserting more into cell membranes, Mutant huntingtin could increase disorder within the lipid bilayer and thereby disturb cellular membrane function. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kegel, Kimberly B.; Sapp, Ellen; Masso, Nicholas; DiFiglia, Marian] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Schewkunow, Vitali; Goldmann, Wolfgang H.] Univ Erlangen Nurnberg, Zentrum Med Phys & Tech, D-91052 Erlangen, Germany. [Wanker, Erich E.] Max Delbruck Zentrum Mol Med MDC, Abt Neuroprote, D-13125 Berlin, Germany. RP Kegel, KB (reprint author), Massachusetts Gen Hosp E, Dept Neurol, 114 16th St,Room 2125, Charlestown, MA 02129 USA. EM kkegel@partners.org RI Goldmann, Wolfgang/H-5572-2013; OI Wanker, Erich/0000-0001-8072-1630 FU CHDI; HDSA; BFHZ; DAAD; BaCaTec FX We thank Ben Fabry for stimulating discussions. This work was funded by a Grant from CHDI to MD, Grants from the HDSA to M.D. and E.E.W, and by Grants from BFHZ, DAAD, BaCaTec to W.H.G. NR 24 TC 22 Z9 22 U1 1 U2 8 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 SEP 25 PY 2009 VL 387 IS 3 BP 472 EP 475 DI 10.1016/j.bbrc.2009.07.039 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 485QE UT WOS:000269137800011 PM 19607813 ER PT J AU Cawley, SM Buys, ES Ichinose, F Brouckaert, P Bloch, KD AF Cawley, Sharon M. Buys, Emmanuel S. Ichinose, Fumito Brouckaert, Peter Bloch, Kenneth D. TI Soluble Guanylate Cyclase alpha 1 Is Responsible for the Negative Inotropic Effects of NO and beta 3 Adrenergic Signaling SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Cawley, Sharon M.; Buys, Emmanuel S.; Ichinose, Fumito; Bloch, Kenneth D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brouckaert, Peter] Univ Ghent, B-9000 Ghent, Belgium. 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 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 25 PY 2009 VL 105 IS 7 MA P164 BP E42 EP E42 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800173 ER PT J AU Chan, SY Zhang, YY Loscalzo, J AF Chan, Stephen Y. Zhang, Ying-Yi Loscalzo, Joseph TI MicroRNA-210 Controls Mitochondrial Metabolism and Hypoxic Adaptation in Pulmonary Vascular Endothelium SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL 20-23, 2009 CL Lake Las Vegas, Henderson, NV SP Amer Heart Assoc HO Lake Las Vegas C1 [Chan, Stephen Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zhang, Ying-Yi; Loscalzo, Joseph] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 25 PY 2009 VL 105 IS 7 MA P203 BP E49 EP E49 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 498OJ UT WOS:000270150800208 ER PT J AU Hysong, SJ Sawhney, MK Wilson, L Sittig, DF Esquivel, A Watford, M Davis, T Espadas, D Singh, H AF Hysong, Sylvia J. Sawhney, Mona K. Wilson, Lindsey Sittig, Dean F. Esquivel, Adol Watford, Monica Davis, Traber Espadas, Donna Singh, Hardeep TI Improving outpatient safety through effective electronic communication: a study protocol SO IMPLEMENTATION SCIENCE LA English DT Article ID PHYSICIAN ORDER ENTRY; INFORMATION-TECHNOLOGY; MALPRACTICE CLAIMS; PRIMARY-CARE; ERRORS; SYSTEM; OUTCOMES; EVENTS AB potentially powerful systems-based interventions to facilitate diagnosis and treatment because they ensure the delivery of key new findings and other health related information to the practitioner. However, effective communication involves more than just information transfer; despite a state of the art EMR system, communication breakdowns can still occur. [1-3] In this project, we will adapt a model developed by the Systems Engineering Initiative for Patient Safety (SEIPS) to understand and improve the relationship between work systems and processes of care involved with electronic communication in EMRs. We plan to study three communication activities in the Veterans Health Administration's (VA) EMR: electronic communication of abnormal imaging and laboratory test results via automated notifications (i.e., alerts); electronic referral requests; and provider-to-pharmacy communication via computerized provider order entry (CPOE). Aim: Our specific aim is to propose a protocol to evaluate the systems and processes affecting outcomes of electronic communication in the computerized patient record system (related to diagnostic test results, electronic referral requests, and CPOE prescriptions) using a human factors engineering approach, and hence guide the development of interventions for work system redesign. Design: This research will consist of multiple qualitative methods of task analysis to identify potential sources of error related to diagnostic test result alerts, electronic referral requests, and CPOE; this will be followed by a series of focus groups to identify barriers, facilitators, and suggestions for improving the electronic communication system. Transcripts from all task analyses and focus groups will be analyzed using methods adapted from grounded theory and content analysis. C1 [Hysong, Sylvia J.; Sawhney, Mona K.; Wilson, Lindsey; Esquivel, Adol; Watford, Monica; Davis, Traber; Espadas, Donna; Singh, Hardeep] Baylor Coll Med, Houston VA HSR&D Ctr Excellence, Houston, TX 77030 USA. [Hysong, Sylvia J.; Sawhney, Mona K.; Wilson, Lindsey; Esquivel, Adol; Watford, Monica; Davis, Traber; Espadas, Donna; Singh, Hardeep] Baylor Coll Med, Ctr Inquiry Improve Outpatient Safety Effect Elec, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Hysong, Sylvia J.; Sawhney, Mona K.; Wilson, Lindsey; Esquivel, Adol; Watford, Monica; Davis, Traber; Espadas, Donna; Singh, Hardeep] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Sittig, Dean F.] Univ Texas Houston, Sch Hlth Informat Sci, Houston, TX USA. [Sittig, Dean F.] Univ Texas Houston, Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX USA. RP Hysong, SJ (reprint author), Baylor Coll Med, Houston VA HSR&D Ctr Excellence, Houston, TX 77030 USA. EM Sylvia.Hysong@med.va.gov; monak.sawhney@va.gov; lindseya.wilson@va.gov; Dean.F.Sittig@uth.tmc.edu; adol.esquivel@va.gov; monica.watford@va.gov; traber.davis@va.gov; Donna.Espadas@va.gov; hardeep.singh@va.gov RI Hysong, Sylvia/B-8420-2008; OI Hysong, Sylvia/0000-0002-9063-5207; Davis Giardina, Traber/0000-0002-9184-6524 FU Department of Veterans Affairs, Veterans Health Administration, National Center for Patient Safety; AHRQ [T32 HS017586] FX The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, National Center for Patient Safety. All authors' salaries (except for Sittig and Sawhney) were supported in part by the Department of Veterans Affairs. Mona Sawhney's salary was supported by a training fellowship from the AHRQ Training Program of the W. M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (AHRQ Grant No. T32 HS017586). The views expressed in this article are solely those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, Baylor College of Medicine, or the University of Texas. We would like to thank Dr. Laura Petersen for her support of this work and Ms. Rebecca Bryan for her assistance with technical writing. NR 33 TC 9 Z9 9 U1 1 U2 5 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 SEP 25 PY 2009 VL 4 AR 62 DI 10.1186/1748-5908-4-62 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 507XN UT WOS:000270889200001 PM 19781075 ER PT J AU Al-Akwa, AA Shaher, M Al-Akwa, S Aleryani, SL AF Al-Akwa, Ahmed A. Shaher, Monira Al-Akwa, Sameeha Aleryani, Samir L. TI Free radicals are present in human serum of Catha edulis Forsk (Khat) abusers SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Serum acetyl cholinesterase (AChE); Organophosphates (OPs); Enzyme immunoassay (EIA); Free radicals ID QAT; PEROXYNITRITE; CATHINONE; APOPTOSIS; TOXICITY; YEMEN AB Objective: Khat (Catha edulis Forsk) is a naturally occurring drug with an amphetamine-like structure and action. It has been postulated that amphetamine induces free radical formation. On this basis, we have hypothesized that Khat may promote synthesis of reactive oxygen and nitrogen species in the same way that amphetamine promotes free radical production. Materials and methods: Forty male subjects were enrolled in two groups: those with a chronic Khat chewing habit (n = 20), and those without a chewing habit (controls; n = 20). Both groups were matched with regard to age. Total antioxidant capacity and cholinesterase (AChE) activity were assayed. Results: This study showed that Khat consumption inhibited serum free radical scavenging enzymes, resulting in significant elevations in free radical loads (p = 0.01; n = 20). We also showed that serum acetyl cholinesterase (AChE) was significantly inhibited in the Khat chewing group (p = 0.002; n = 20). Conclusion: These results show for the first time that Khat may contribute to high levels of free radicals. In addition, the presence of pesticides in Khat leaves is implicated in the inhibition of AChE activity. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Al-Akwa, Ahmed A.] Sanaa Univ, Fac Med & Hlth Sci, Dept Clin Biochem & Mol Biol, Sanaa, Yemen. [Shaher, Monira; Al-Akwa, Sameeha] Minist Publ Hlth, Cent Lab, Sanaa, Yemen. [Aleryani, Samir L.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Aleryani, Samir L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Aleryani, SL (reprint author), Vanderbilt Univ, Vanderbilt Med Ctr, Sch Med, Dept Pathol,Div Lab Med, 1301 Med Ctr Dr,4605 TVC, Nashville, TN 37232 USA. EM Samir.Aleryani@Vanderbilt.edu NR 24 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD SEP 25 PY 2009 VL 125 IS 3 BP 471 EP 473 DI 10.1016/j.jep.2009.07.012 PG 3 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 506GP UT WOS:000270763100015 PM 19619634 ER PT J AU An, DD Apidianakis, Y Boechat, AL Baldini, RL Goumnerov, BC Rahme, LG AF An, Dingding Apidianakis, Yiorgos Boechat, Ana Laura Baldini, Regina L. Goumnerov, Boyan C. Rahme, Laurence G. TI The Pathogenic Properties of a Novel and Conserved Gene Product, KerV, in Proteobacteria SO PLOS ONE LA English DT Article AB Identification of novel virulence factors is essential for understanding bacterial pathogenesis and designing antibacterial strategies. In this study, we uncover such a factor, termed KerV, in Proteobacteria. Experiments carried out in a variety of eukaryotic host infection models revealed that the virulence of a Pseudomonas aeruginosa kerV null mutant was compromised when it interacted with amoebae, plants, flies, and mice. Bioinformatics analyses indicated that KerV is a hypothetical methyltransferase and is well-conserved across numerous Proteobacteria, including both well-known and emerging pathogens (e.g., virulent Burkholderia, Escherichia, Shigella, Vibrio, Salmonella, Yersinia and Brucella species). Furthermore, among the 197 kerV orthologs analyzed in this study, about 89% reside in a defined genomic neighborhood, which also possesses essential DNA replication and repair genes and detoxification gene. Finally, infection of Drosophila melanogaster with null mutants demonstrated that KerV orthologs are also crucial in Vibrio cholerae and Yersinia pseudotuberculosis pathogenesis. Our findings suggested that KerV has a novel and broad significance as a virulence factor in pathogenic Proteobacteria and it might serve as a new target for antibiotic drug design. RP An, DD (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM rahme@molbio.mgh.harvard.edu RI Baldini, Regina/C-4035-2012; OI Baldini, Regina/0000-0003-4349-6352; Apidianakis, Yiorgos/0000-0002-7465-3560 NR 48 TC 4 Z9 4 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 SEP 25 PY 2009 VL 4 IS 9 AR e7167 DI 10.1371/journal.pone.0007167 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 498WL UT WOS:000270176200010 PM 19779606 ER PT J AU Omer, AD Janas, MM Novina, CD AF Omer, Arina D. Janas, Maja M. Novina, Carl D. TI The Chicken or the Egg: MicroRNA-Mediated Regulation of mRNA Translation or mRNA Stability SO MOLECULAR CELL LA English DT Editorial Material ID CAENORHABDITIS-ELEGANS; INITIATION-FACTOR; IN-VITRO; PROTEIN; MECHANISMS; COMPLEX AB In this issue of Molecular Cell, Fabian et al. (2009) demonstrate that in cell-free extracts from mouse Krebs-2 ascites, microRNA-mediated translational repression precedes target mRNA deadenylation, and identify GW182, PABP, and deadenylase subunits CAR and CCR4 as factors required for deadenylation. C1 [Omer, Arina D.; Janas, Maja M.; Novina, Carl D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Omer, Arina D.; Janas, Maja M.; Novina, Carl D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Omer, Arina D.; Janas, Maja M.; Novina, Carl D.] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. RP Novina, CD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM carl_novina@dfci.harvard.edu NR 12 TC 16 Z9 16 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 24 PY 2009 VL 35 IS 6 BP 739 EP 740 DI 10.1016/j.molcel.2009.09.003 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 503SE UT WOS:000270559100008 PM 19782024 ER PT J AU Dutta-Simmons, J Zhang, YY Gorgun, G Gatt, M Mani, M Hideshima, T Takada, K Carlson, NE Carrasco, DE Tai, YT Raje, N Letai, AG Anderson, KC Carrasco, DR AF Dutta-Simmons, Jui Zhang, Yunyu Gorgun, Gullu Gatt, Moshe Mani, Mala Hideshima, Teru Takada, Kohichi Carlson, Nicole E. Carrasco, Daniel E. Tai, Yu-Tzu Raje, Noopur Letai, Anthony G. Anderson, Kenneth C. Carrasco, Daniel R. TI Aurora kinase A is a target of Wnt/beta-catenin involved in multiple myeloma disease progression SO BLOOD LA English DT Article ID SMALL-MOLECULE INHIBITION; CELL-CYCLE; THERAPEUTIC TARGETS; BETA-CATENIN; C-MYC; CANCER; PATHWAY; PHOSPHORYLATION; PROLIFERATION; TRANSITION AB Multiple myeloma (MM) is a cancer of plasma cells with complex molecular characteristics that evolves from monoclonal gammopathy of undetermined significance, a highly prevalent premalignant condition. MM is the second most frequent hematologic cancer in the United States, and it remains incurable, thereby highlighting the need for new therapeutic approaches, particularly those targeting common molecular pathways involved in disease progression and maintenance, shared across different MM subtypes. Here we report that Wnt/beta-catenin is one such pathway. We document the involvement of beta-catenin in cell-cycle regulation, proliferation, and invasion contributing to enhanced proliferative and metastatic properties of MM. The pleiotropic effects of beta-catenin in MM correlate with its transcriptional function, and we demonstrate regulation of a novel target gene, Aurora kinase A, implicating beta-catenin in G2/M regulation. beta-catenin and Aurora kinase A are present in most MM but not in normal plasma cells and are expressed in a pattern that parallels progression from monoclonal gammopathy of undetermined significance to MM. Our data provide evidence for a novel functional link between beta-catenin and Aurora kinase A, underscoring a critical role of these pathways in MM disease progression. (Blood. 2009; 114: 2699-2708) C1 [Dutta-Simmons, Jui; Zhang, Yunyu; Gorgun, Gullu; Gatt, Moshe; Mani, Mala; Hideshima, Teru; Takada, Kohichi; Carlson, Nicole E.; Carrasco, Daniel E.; Tai, Yu-Tzu; Raje, Noopur; Letai, Anthony G.; Anderson, Kenneth C.; Carrasco, Daniel R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gorgun, Gullu; Hideshima, Teru; Tai, Yu-Tzu; Raje, Noopur; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Carrasco, Daniel R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Carrasco, DR (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM ruben_carrasco@dfci.harvard.edu FU Multiple Myeloma Research Foundation (MMRF); LeBow Family Fund FX D. R. C. is supported by the Multiple Myeloma Research Foundation (MMRF) Senior Award; K. C. A. is supported by the LeBow Family Fund to Cure Myeloma. NR 40 TC 52 Z9 53 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 SEP 24 PY 2009 VL 114 IS 13 BP 2699 EP 2708 DI 10.1182/blood-2008-12-194290 PG 10 WC Hematology SC Hematology GA 498KK UT WOS:000270138600022 PM 19652203 ER PT J AU Kulkarni, H Marconi, VC He, WJ Landrum, ML Okulicz, JF Delmar, J Kazandjian, D Castiblanco, J Ahuja, SS Wright, EJ Weiss, RA Clark, RA Dolan, MJ Ahuja, SK AF Kulkarni, Hemant Marconi, Vincent C. He, Weijing Landrum, Michael L. Okulicz, Jason F. Delmar, Judith Kazandjian, Dickran Castiblanco, John Ahuja, Seema S. Wright, Edwina J. Weiss, Robin A. Clark, Robert A. Dolan, Matthew J. Ahuja, Sunil K. TI The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; ETHNIC NEUTROPENIA; BLOOD-GROUP; AIDS SUSCEPTIBILITY; PLASMA-LEVELS; MALARIA; ANTIGEN; PATHOGENESIS; CHEMOKINES AB Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects, we show that, although leukopenia (< 4000 WBC/mm(3) during infection) was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The African-specific -46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AAs). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4(+) T-cell counts, such that leukopenic but not nonleukopenic HIV+ AAs with DARC -46C/C had a survival advantage compared with all Duffy-positive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIV-infected AAs, despite immunodeficiency. (Blood. 2009;114:2783-2792) C1 [Kulkarni, Hemant; He, Weijing; Castiblanco, John; Ahuja, Seema S.; Clark, Robert A.; Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Kulkarni, Hemant; He, Weijing; Castiblanco, John; Ahuja, Seema S.; Clark, Robert A.; Ahuja, Sunil K.] S Texas Vet Hlth Care Syst, Vet Adm Res Ctr AIDS & HIV Infect 1, San Antonio, TX USA. [Marconi, Vincent C.; Landrum, Michael L.; Okulicz, Jason F.; Delmar, Judith] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Marconi, Vincent C.; Landrum, Michael L.; Okulicz, Jason F.; Delmar, Judith; Dolan, Matthew J.] Brooke Army Med Ctr, San Antonio Mil Med Ctr, Infect Dis Serv, Ft Sam Houston, TX 78234 USA. [Landrum, Michael L.; Dolan, Matthew J.] Henry M Jackson Fdn, Lackland AFB, TX USA. [Kazandjian, Dickran] Wilford Hall USAF Med Ctr, Dept Med, Lackland AFB, TX 78236 USA. [Wright, Edwina J.] Monash Univ, Fac Med Nursing & Hlth Sci, Melbourne, Vic 3004, Australia. [Wright, Edwina J.] Alfred Hosp, Burnet Inst, Melbourne, Vic, Australia. [Weiss, Robin A.] UCL, Div Infect & Immun, London, England. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol, San Antonio, TX 78229 USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Immunol, San Antonio, TX 78229 USA. RP Ahuja, SK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM ahujas@uthscsa.edu RI CASTIBLANCO, JOHN/B-6599-2009; Marconi, Vincent/N-3210-2014; OI CASTIBLANCO, JOHN/0000-0002-7965-9822; Marconi, Vincent/0000-0001-8409-4689; CASTIBLANCO, JOHN/0000-0003-2556-3697 FU Veterans Administration Center on AIDS and HIV infection of the South Texas Veterans Health Care System; MERIT [R37046326]; National Institutes of Health [AI043279, MH069270]; Veterans Administration MERIT; Elizabeth Glaser Scientist Award; Burroughs Wellcome Clinical Scientist Award in Translational Research; Doris Duke Distinguished Clinical Scientist Award; Department of Defense HIV Natural History Study cohort; Infectious Disease Clinical Research Program of the Uniformed Services University of the Health Sciences; Uniformed Services University of the Health Sciences; Henry M. Jackson Foundation for the Advancement of Military Medicine; Human Services/National Institutes of Health/National Institute of Allergy and Infectious Diseases/Division of Clinical Research [Y1-AI-5072] FX The authors thank Duane Hospenthal, Brian Agan, and the anonymous reviewers for their critical feedback. This work was supported by the Veterans Administration Center on AIDS and HIV infection of the South Texas Veterans Health Care System, and a MERIT (R37046326) and other awards (AI043279 and MH069270) from the National Institutes of Health (S.K.A.). S. K. A. is also supported by a Veterans Administration MERIT award and is a recipient of the Elizabeth Glaser Scientist Award, the Burroughs Wellcome Clinical Scientist Award in Translational Research, and the Doris Duke Distinguished Clinical Scientist Award. Support for the Department of Defense HIV Natural History Study cohort and staff involved in this work was provided by the Infectious Disease Clinical Research Program of the Uniformed Services University of the Health Sciences, of which the HIV Natural History Study is a component. The Infectious Disease Clinical Research Program is a Department of Defense tri-service program executed through Uniformed Services University of the Health Sciences and the Henry M. Jackson Foundation for the Advancement of Military Medicine, in collaboration with Department of Health and Human Services/National Institutes of Health/National Institute of Allergy and Infectious Diseases/Division of Clinical Research through Interagency Agreement Y1-AI-5072.; The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the National Institutes of Health or the Department of Health and Human Services, the Department of Defense or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government. NR 49 TC 21 Z9 21 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 24 PY 2009 VL 114 IS 13 BP 2783 EP 2792 DI 10.1182/blood-2009-04-215186 PG 10 WC Hematology SC Hematology GA 498KK UT WOS:000270138600031 PM 19620399 ER PT J AU Li, HW Liu, H Corrales, CE Risner, JR Forrester, J Holt, JR Heller, S Edge, ASB AF Li, Huawei Liu, Hong Corrales, C. Eduardo Risner, Jessica R. Forrester, Jeff Holt, Jeffrey R. Heller, Stefan Edge, Albert S. B. TI Differentiation of neurons from neural precursors generated in floating spheres from embryonic stem cells SO BMC NEUROSCIENCE LA English DT Article ID DOPAMINE NEURONS; HAIR-CELLS; MICE; DERIVATION; CULTURE; REINNERVATION; SPECIFICATION; PROGENITORS; INDUCTION; MIDBRAIN AB Background: Neural differentiation of embryonic stem (ES) cells is usually achieved by induction of ectoderm in embryoid bodies followed by the enrichment of neuronal progenitors using a variety of factors. Obtaining reproducible percentages of neural cells is difficult and the methods are time consuming. Results: Neural progenitors were produced from murine ES cells by a combination of nonadherent conditions and serum starvation. Conversion to neural progenitors was accompanied by downregulation of Oct4 and NANOG and increased expression of nestin. ES cells containing a GFP gene under the control of the Sox1 regulatory regions became fluorescent upon differentiation to neural progenitors, and ES cells with a tau-GFP fusion protein became fluorescent upon further differentiation to neurons. Neurons produced from these cells upregulated mature neuronal markers, or differentiated to glial and oligodendrocyte fates. The neurons gave rise to action potentials that could be recorded after application of fixed currents. Conclusion: Neural progenitors were produced from murine ES cells by a novel method that induced neuroectoderm cells by a combination of nonadherent conditions and serum starvation, in contrast to the embryoid body method in which neuroectoderm cells must be selected after formation of all three germ layers. C1 [Li, Huawei; Liu, Hong] Fudan Univ, Inst Biomed Sci, Dept Otolarygol, EENT Hosp,Shanghai Med Coll, Shanghai 200031, Peoples R China. [Corrales, C. Eduardo; Heller, Stefan] Stanford Univ, Sch Med, Dept Otolaryngol HNS, Stanford, CA 94305 USA. [Corrales, C. Eduardo; Heller, Stefan] Stanford Univ, Sch Med, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA. [Forrester, Jeff; Edge, Albert S. B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Forrester, Jeff; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Edge, Albert S. B.] Harvard & MIT, Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Risner, Jessica R.; Holt, Jeffrey R.] Univ Virginia, Dept Neurosci, Charlottesville, VA 22908 USA. [Holt, Jeffrey R.] Univ Virginia, Dept Otolaryngol, Charlottesville, VA 22908 USA. RP Li, HW (reprint author), Fudan Univ, Inst Biomed Sci, Dept Otolarygol, EENT Hosp,Shanghai Med Coll, Shanghai 200031, Peoples R China. EM hwli@shmu.edu.cn; hliu@meei.harvard.edu; edcor@stanford.edu; jrr3p@virginia.edu; jeff_forrester@meei.harvard.edu; jh5am@Virginia.Edu; hellers@stanford.edu; albert_edge@meei.harvard.edu FU National Institute on Deafness and other Communicative Disorders (NIDCD) [DC007174, DC006167, DC005209]; National Nature Science Foundation of China [30525038, 30672300]; National Basic Research Program of China [2006CB943701] FX Supported by grants DC007174, DC006167 and DC005209 from the National Institute on Deafness and other Communicative Disorders (NIDCD), grants 30525038, 30672300 from the National Nature Science Foundation of China, and grant 2006CB943701 from the National Basic Research Program of China. NR 27 TC 11 Z9 14 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD SEP 24 PY 2009 VL 10 AR 122 DI 10.1186/1471-2202-10-122 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 513LF UT WOS:000271323100002 PM 19778451 ER PT J AU Stark, JR Mucci, L Rothman, KJ Adami, HO AF Stark, Jennifer R. Mucci, Lorelei Rothman, Kenneth J. Adami, Hans-Olov TI Screening for prostate cancer remains controversial SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID SOJOURN TIME; MORTALITY; ANTIGEN; TRENDS; OVERDIAGNOSIS; TRIAL; MEN C1 [Mucci, Lorelei; Adami, Hans-Olov] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mucci, Lorelei] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, Boston, MA 02115 USA. [Rothman, Kenneth J.] Res Triangle Inst, RTI Hlth Solut, Res Triangle Pk, NC 27709 USA. [Rothman, Kenneth J.] Boston Univ, Med Ctr, Dept Epidemiol, Boston, MA USA. [Rothman, Kenneth J.] Boston Univ, Med Ctr, Dept Med, Boston, MA USA. [Mucci, Lorelei; Adami, Hans-Olov] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM stark@hsph.harvard.edu RI Rider, Jennifer/A-5371-2011; OI Rider, Jennifer/0000-0002-2637-6036; Rothman, Kenneth/0000-0003-2398-1705 NR 22 TC 23 Z9 24 U1 0 U2 0 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 SEP 24 PY 2009 VL 339 AR b3601 DI 10.1136/bmj.b3601 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 499OG UT WOS:000270231800004 PM 19778971 ER PT J AU Fernandez, HF Sun, ZX Yao, XP Litzow, MR Luger, SM Paietta, EM Racevskis, J Dewald, GW Ketterling, RP Bennett, JM Rowe, JM Lazarus, HM Tallman, MS AF Fernandez, Hugo F. Sun, Zhuoxin Yao, Xiaopan Litzow, Mark R. Luger, Selina M. Paietta, Elisabeth M. Racevskis, Janis Dewald, Gordon W. Ketterling, Rhett P. Bennett, John M. Rowe, Jacob M. Lazarus, Hillard M. Tallman, Martin S. TI Anthracycline Dose Intensification in Acute Myeloid Leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; ACUTE NONLYMPHOCYTIC LEUKEMIA; ACUTE MYELOCYTIC-LEUKEMIA; UNTREATED ADULT PATIENTS; ONCOLOGY-GROUP; CYTOSINE-ARABINOSIDE; GROUP-B; INDUCTION CHEMOTHERAPY; REMISSION INDUCTION; DAUNORUBICIN AB Background In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival. Methods In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival. Results In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P = 0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months. Conclusions In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.) C1 [Fernandez, Hugo F.] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL 33612 USA. [Sun, Zhuoxin; Yao, Xiaopan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Litzow, Mark R.; Dewald, Gordon W.; Ketterling, Rhett P.] Mayo Clin, Rochester, MN USA. [Luger, Selina M.] Univ Penn, Philadelphia, PA 19104 USA. [Paietta, Elisabeth M.; Racevskis, Janis] Montefiore Med Ctr, North Div, Bronx, NY 10467 USA. [Bennett, John M.] Univ Rochester, Rochester, NY USA. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Tallman, Martin S.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Fernandez, HF (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, 12902 Magnolia Dr,Rm 3116, Tampa, FL 33612 USA. EM hugo.fernandez@moffitt.org FU Public Health Service [CA23318, CA66636, CA21115, CA13650, CA15488, CA17145, CA14548]; National Cancer Institute and the Department of Health and Human Services; Wyeth Pharmaceuticals and Immunex FX Supported in part by grants from the Public Health Service (CA23318, CA66636, CA21115, CA13650, CA15488, CA17145, and CA14548) and from the National Cancer Institute and the Department of Health and Human Services. Funding for laboratory correlative studies was provided by Wyeth Pharmaceuticals and Immunex through a grant to the ECOG. NR 26 TC 375 Z9 386 U1 1 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 24 PY 2009 VL 361 IS 13 BP 1249 EP 1259 DI 10.1056/NEJMoa0904544 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 497RN UT WOS:000270078700006 PM 19776406 ER PT J AU Kaufman, DS McDougal, WS Harisinghani, MG Wu, CL AF Kaufman, Donald S. McDougal, W. Scott Harisinghani, Mukesh G. Wu, Chin-Lee TI A Man with Recurrent Transitional-Cell Carcinoma of the Ureter Transitional-cell carcinoma of the right renal pelvis and ureter (AJCC TNM pathological stage pT3NxMx). Transitional-cell carcinoma of the left ureter (AJCC TNM pathological stage pT1N0Mx). SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT Conference on Genitourinary Oncology CY NOV 06, 2008 CL Massachusetts Gen Hosp, Boston, MA HO Massachusetts Gen Hosp ID UPPER URINARY-TRACT; PROGNOSTIC-FACTORS; UROTHELIAL TUMORS; SURVIVAL; EXPERIENCE; MANAGEMENT; THERAPY; KIDNEY C1 [Kaufman, Donald S.] Massachusetts Gen Hosp, Div Hematol Oncol, Dept Med, Boston, MA 02114 USA. [McDougal, W. Scott] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kaufman, Donald S.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [McDougal, W. Scott] Harvard Univ, Sch Med, Dept Urol, Cambridge, MA 02138 USA. [Harisinghani, Mukesh G.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Wu, Chin-Lee] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Kaufman, DS (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Dept Med, Boston, MA 02114 USA. NR 19 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 SEP 24 PY 2009 VL 361 IS 13 BP 1292 EP 1299 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 497RN UT WOS:000270078700012 PM 19776411 ER PT J AU Asch, DA Nicholson, S Srinivas, S Herrin, J Epstein, AJ AF Asch, David A. Nicholson, Sean Srinivas, Sindhu Herrin, Jeph Epstein, Andrew J. TI Evaluating Obstetrical Residency Programs Using Patient Outcomes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MORTALITY-RATES; TRAINING-PROGRAMS; PROVIDER VOLUME; CARE; POLICY; HOSPITALS; SURGEONS; QUALITY AB Context Patient outcomes have been used to assess the performance of hospitals and physicians; in contrast, residency programs have been compared based on non-clinical measures. Objective To assess whether obstetrics and gynecology residency programs can be evaluated by the quality of care their alumni deliver. Design, Setting, and Patients A retrospective analysis of all Florida and New York obstetrical hospital discharges between 1992 and 2007, representing 4 906 169 deliveries performed by 4124 obstetricians from 107 US residency programs. Main Outcome Measures Nine measures of maternal complications from vaginal and cesarean births reflecting laceration, hemorrhage, and all other complications after vaginal delivery; hemorrhage, infection, and all other complications after cesarean delivery; and composites for vaginal and cesarean deliveries and for all deliveries regardless of mode. Results Obstetricians' residency program was associated with substantial variation in maternal complication rates. Women treated by obstetricians trained in residency programs in the bottom quintile for risk-standardized major maternal complication rates had an adjusted complication rate of 13.6%, approximately one-third higher than the 10.3% adjusted rate for women treated by obstetricians from programs in the top quintile (absolute difference, 3.3%; 95% confidence interval, 2.8%-3.8%). The rankings of residency programs based on each of the 9 measures were similar. Adjustment for medical licensure examination scores did not substantially alter the program ranking. Conclusions Obstetrics and gynecology training programs can be ranked by the maternal complication rates of their graduates' patients. These rankings are stable across individual types of complications and are not associated with residents' licensing examination scores. JAMA. 2009;302(12):1277-1283 C1 [Asch, David A.; Nicholson, Sean; Srinivas, Sindhu; Epstein, Andrew J.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Srinivas, Sindhu] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Nicholson, Sean] Cornell Univ, Ithaca, NY USA. [Herrin, Jeph; Epstein, Andrew J.] Yale Univ, New Haven, CT USA. RP Asch, DA (reprint author), Univ Penn, Leonard Davis Inst Hlth Econ, 3641 Locust Walk, Philadelphia, PA 19104 USA. EM asch@wharton.upenn.edu RI Sandall, Jane/D-4146-2009 OI Sandall, Jane/0000-0003-2000-743X FU National Board of Medical Examiners FX This work was supported by a grant from the Stemmler Fund of the National Board of Medical Examiners (Drs Asch, Nicholson, and Epstein). NR 19 TC 84 Z9 84 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 23 PY 2009 VL 302 IS 12 BP 1277 EP 1283 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 497AR UT WOS:000270026000009 PM 19773562 ER PT J AU Stanley, SA Hung, DT AF Stanley, Sarah A. Hung, Deborah T. TI Chemical Tools for Dissecting Bacterial Physiology and Virulence SO BIOCHEMISTRY LA English DT Article ID SMALL-MOLECULE INHIBITORS; III SECRETION; PSEUDOMONAS-AERUGINOSA; CHLAMYDIA-PNEUMONIAE; CELL-DIVISION; MYCOBACTERIUM-TUBERCULOSIS; ESCHERICHIA-COLI; INDUCED HAPLOINSUFFICIENCY; ANTIBACTERIAL DISCOVERY; METHICILLIN-RESISTANT AB Increasingly, chemical biology is being used in the context of bacterial virulence and the host-pathogen interaction, as small molecule inhibitors provide a number of unique advantages or the study of bacterial pathogens that complement powerful, existing classical genetic approaches. Small molecules have the potential to inhibit targets rapidly and reversibly, with a high degree of specificity. They are therefore well suited for studying the role of essential genes in bacterial physiology and virulence in both genetically tractable and intractable organisms, with the capacity to reveal novel phenotypes and insights into the function of essential factors during infection. The use of small molecule inhibitors during infection is also deepening our understanding of the role that host factors play in bacterial pathogenesis. In the future, the utility of chemical biology will grow as technologies for rapid identification of targets of interesting bioactive small molecules are developed. In this review, we highlight recent work in which small Molecule inhibitors are used to study essential genes and genetically intractable organisms, to reveal novel phenotypes related to bacterial physiology, and to probe the role of bacterial and host factors during infection. In addition, we review recent advances in biochemical, genetic, and genomic techniques for target identification. C1 [Hung, Deborah T.] Broad Inst, Infect Dis Initiat, Cambridge, MA 02142 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Hung, DT (reprint author), Broad Inst, Infect Dis Initiat, NE30-2013,7 Cambridge Ctr, Cambridge, MA 02142 USA. EM dhung@broadinstitute.org FU Foundation for Biomedical Research [2006-000116]; Helen Hay Whitney Foundation FX This work was supported by a flew Foundation for Biomedical Research grant to D.T.H. (2006-000116). We thank the Helen Hay Whitney Foundation for S.A.S.'s funding. NR 87 TC 10 Z9 10 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 22 PY 2009 VL 48 IS 37 BP 8776 EP 8786 DI 10.1021/bi9009083 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 492ZN UT WOS:000269702200005 PM 19653697 ER PT J AU Hivert, MF Grant, RW Shrader, P Meigs, JB AF Hivert, Marie-France Grant, Richard W. Shrader, Peter Meigs, James B. TI Identifying primary care patients at risk for future diabetes and cardiovascular disease using electronic health records SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID METABOLIC SYNDROME; CONTROLLED-TRIAL; UNITED-STATES; MELLITUS; HEART; PREVALENCE; MANAGEMENT; US AB Background: Prevention of diabetes and coronary heart disease (CHD) is possible but identification of at-risk patients for targeting interventions is a challenge in primary care. Methods: We analyzed electronic health record (EHR) data for 122,715 patients from 12 primary care practices. We defined patients with risk factor clustering using metabolic syndrome (MetS) characteristics defined by NCEP-ATPIII criteria; if missing, we used surrogate characteristics, and validated this approach by directly measuring risk factors in a subset of 154 patients. For subjects with at least 3 of 5 MetS criteria measured at baseline (2003-2004), we defined 3 categories: No MetS (0 criteria); At-risk-for MetS (1-2 criteria); and MetS (>= 3 criteria). We examined new diabetes and CHD incidence, and resource utilization over the subsequent 3-year period (2005-2007) using age-sex-adjusted regression models to compare outcomes by MetS category. Results: After excluding patients with diabetes/CHD at baseline, 78,293 patients were eligible for analysis. EHR-defined MetS had 73% sensitivity and 91% specificity for directly measured MetS. Diabetes incidence was 1.4% in No MetS; 4.0% in At-risk-for MetS; and 11.0% in MetS (p < 0.0001 for trend; adjusted OR MetS vs No MetS = 6.86 [6.06-7.76]); CHD incidence was 3.2%, 5.3%, and 6.4% respectively (p < 0.0001 for trend; adjusted OR = 1.42 [1.25-1.62]). Costs and resource utilization increased across categories (p < 0.0001 for trends). Results were similar analyzing individuals with all five criteria not missing, or defining MetS as >= 2 criteria present. Conclusion: Risk factor clustering in EHR data identifies primary care patients at increased risk for new diabetes, CHD and higher resource utilization. C1 [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. EM marie-france.hivert@usherbrooke.ca; rgrant@partners.org; pshrader@partners.org; jmeigs@partners.org OI Grant, Richard/0000-0002-6164-8025 FU Massachusetts General Hospital Clinical Research Program; American Diabetes Association Career Development Award; NIDDK [K24 DK080140, K23 DK067452]; Centre de Recherche Medicale de l'Universite de Sherbrooke (CRMUS); Canadian Institute of Health Research (CHIR) FX Funding sources: Massachusetts General Hospital Clinical Research Program, American Diabetes Association Career Development Award (JBM), and NIDDK K24 DK080140 (JBM). MFH was supported by the Centre de Recherche Medicale de l'Universite de Sherbrooke (CRMUS) and a Canadian Institute of Health Research (CHIR) Fellowships Health Professional Award. RWG was supported NIDDK K23 DK067452. NR 19 TC 34 Z9 34 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD SEP 22 PY 2009 VL 9 AR 170 DI 10.1186/1472-6963-9-170 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 501VA UT WOS:000270409800001 PM 19772639 ER PT J AU Latourelle, JC Pankratz, N Dumitriu, A Wilk, JB Goldwurm, S Pezzoli, G Mariani, CB DeStefano, AL Halter, C Gusella, JF Nichols, WC Myers, RH Foroud, T AF Latourelle, Jeanne C. Pankratz, Nathan Dumitriu, Alexandra Wilk, Jemma B. Goldwurm, Stefano Pezzoli, Gianni Mariani, Claudio B. DeStefano, Anita L. Halter, Cheryl Gusella, James F. Nichols, William C. Myers, Richard H. Foroud, Tatiana CA PSG -PROGENI GenePD Investigators TI Genomewide association study for onset age in Parkinson disease SO BMC MEDICAL GENETICS LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; HUMAN EYE-COLOR; ALPHA-SYNUCLEIN; SEGREGATION ANALYSIS; WIDE ASSOCIATION; NEURODEGENERATIVE DISEASES; SUSCEPTIBILITY GENES; VENEZUELAN KINDREDS; PIGMENTATION GENES AB Background: Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age. Methods: Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy. Results: Meta-analysis across the three studies detected consistent association (p < 1 x 10(-5)) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 x 10(-7)) lies between the genes QSER1 and PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 x 10(-6)) which lies in an intron of the AAK1 gene. This gene is closely related to GAK, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases. Conclusion: Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis. C1 [Latourelle, Jeanne C.; Dumitriu, Alexandra; Wilk, Jemma B.; DeStefano, Anita L.; Myers, Richard H.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Pankratz, Nathan; Halter, Cheryl; Foroud, Tatiana] Indiana Univ, Sch Med, Indianapolis, IN USA. [Goldwurm, Stefano; Pezzoli, Gianni; Mariani, Claudio B.] Parkinson Inst, Ist Clin Perfezionamento, Milan, Italy. [DeStefano, Anita L.] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Gusella, James F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gusella, James F.] Harvard Univ, Sch Med, Boston, MA USA. [Nichols, William C.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Nichols, William C.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. RP Myers, RH (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. EM jlatoure@bu.edu; npankrat@iupui.edu; adumitri@bu.edu; jwilk@bu.edu; goldwurm@parkinson.it; Pezzoli@parkinson.it; mariani@parkinson.it; adestef@bu.edu; chalter@iupui.edu; gusella@helix.mgh.harvard.edu; Bill.Nichols@cchmc.org; rmyers@bu.edu; tforoud@iupui.edu RI Goldwurm, Stefano/Q-8978-2016; OI Goldwurm, Stefano/0000-0002-1651-567X; Latourelle, Jeanne/0000-0002-4218-9572; Dumitriu, Alexandra/0000-0002-4467-4803; Myers, Richard/0000-0002-8365-2674 FU Robert P. & Judith N. Goldberg Foundation; Bumpus Foundation; Harvard NeuroDiscovery Center; [R01 NS37167]; [R01 NS036711]; Fondazione Telethon FX This project was supported by R01 NS37167, R01 NS036711, the Robert P. & Judith N. Goldberg Foundation, the Bumpus Foundation and the Harvard NeuroDiscovery Center. This study used samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository http://ccr.coriell.org/ninds, as well as clinical data. NR 75 TC 42 Z9 42 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD SEP 22 PY 2009 VL 10 AR 98 DI 10.1186/1471-2350-10-98 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 502VF UT WOS:000270487700002 PM 19772629 ER PT J AU Jensen, BC Swigart, PM Laden, ME DeMarco, T Hoopes, C Simpson, PC AF Jensen, Brian C. Swigart, Philip M. Laden, Marie-Eve DeMarco, Teresa Hoopes, Charles Simpson, Paul C. TI The Alpha-1D Is the Predominant Alpha-1-Adrenergic Receptor Subtype in Human Epicardial Coronary Arteries SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE adrenergic; alpha and beta; arteries; coronary disease; receptors ID BENIGN PROSTATIC HYPERPLASIA; CARDIAC MYOCYTES; ALPHA(1)-ADRENERGIC RECEPTORS; KNOCKOUT MOUSE; MESSENGER-RNAS; SMOOTH-MUSCLE; ALPHA(1B); HEART; ALPHA(1B)-ADRENOCEPTOR; CONSTRICTION AB Objectives The goal was to identify alpha-1-adrenergic receptor (AR) subtypes in human coronary arteries. Background The alpha 1-ARs regulate human coronary blood flow. The alpha 1-ARs exist as 3 molecular subtypes, alpha 1A, alpha 1B,and alpha 1D, and the alpha 1D subtype mediates coronary vasoconstriction in the mouse. However, the alpha 1A is thought to be the only subtype in human coronary arteries. Methods We obtained human epicardial coronary arteries and left ventricular (LV) myocardium from 19 transplant recipients and 6 unused donors (age 19 to 70 years; 68% male; 32% with coronary artery disease). We cultured coronary rings and human coronary smooth muscle cells. We assayed alpha 1-and alpha-AR subtype messenger ribonucleic acid (mRNA) by quantitative real-time reverse transcription polymerase chain reaction and subtype proteins by radioligand binding and extracellular signal-regulated kinase (ERK) activation. Results The alpha 1D subtype was 85% of total coronary alpha 1-AR mRNA and 75% of total alpha 1-AR protein, and alpha 1D stimulation activated ERK. In contrast, the alpha 1D was low in LV myocardium. Total coronary alpha 1-AR levels were one-third of beta-ARs, which were 99% the beta 2 subtype. Conclusions The alpha 1D subtype is predominant and functional in human epicardial coronary arteries, whereas the alpha 1A and alpha 1B are present at very low levels. This distribution is similar to the mouse, where myocardial alpha 1A-and alpha 1B-ARs mediate beneficial functional responses and coronary alpha 1Ds mediate vasoconstriction. Thus, alpha 1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of nonselective alpha 1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial alpha 1A-and/or alpha 1B-AR signaling without causing coronary vasoconstriction. (J Am Coll Cardiol 2009; 54: 1137-45) (C) 2009 by the American College of Cardiology Foundation C1 [Jensen, Brian C.; Swigart, Philip M.; Laden, Marie-Eve; Simpson, Paul C.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA. [Jensen, Brian C.; DeMarco, Teresa; Simpson, Paul C.] Univ Calif San Francisco, Div Cardiol, San Francisco, CA 94143 USA. [Hoopes, Charles] Univ Calif San Francisco, Div Cardiothorac, San Francisco, CA 94143 USA. RP Simpson, PC (reprint author), San Francisco VA Med Ctr, Cardiol Sect, 111-C-8,4150 Clement St, San Francisco, CA 94121 USA. EM paul.simpson@ucsf.edu FU Sarnoff Cardiovascular Research Foundation; Duke University, Durham, North Carolina; Department of General Surgery; Stanford University, Stanford, California FX From the *Cardiology Section, San Francisco VA Medical Center, San Francisco, California; and the Divisions of dagger Cardiology and Cardiothoracic Surgery, University of California, San Francisco, San Francisco, California. Dr. Simpson received funding from the Veterans Administration and the National Institutes of Health. Dr. Jensen was the recipient of a Young Investigators Award from the GlaxoSmithKline Research and Education Foundation for Cardiovascular Disease and has received support from the University of California, San Francisco Foundation for Cardiac Research. Dr. Laden received a fellowship from the Sarnoff Cardiovascular Research Foundation, and was a medical student at Duke University, Durham, North Carolina, when this work was done. Dr. DeMarco has served as a speaker/consultant for Actelion, Gilead, Boston Scientific, Cardiokinetics, and Medtronic. Dr. Jensen is currently affiliated with the Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Dr. Laden is currently affiliated with the Department of General Surgery, Stanford University, Stanford, California. NR 33 TC 26 Z9 28 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 SEP 22 PY 2009 VL 54 IS 13 BP 1137 EP 1145 DI 10.1016/j.jacc.2009.05.056 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 494OO UT WOS:000269823300003 PM 19761933 ER PT J AU Ix, JH Katz, R De Boer, IH Kestenbaum, BR Allison, MA Siscovick, DS Newman, AB Sarnak, MJ Shlipak, MG Criqui, MH AF Ix, Joachim H. Katz, Ronit De Boer, Ian H. Kestenbaum, Brian R. Allison, Matthew A. Siscovick, David S. Newman, Anne B. Sarnak, Mark J. Shlipak, Michael G. Criqui, Michael H. TI Association of Chronic Kidney Disease With the Spectrum of Ankle Brachial Index The CHS (Cardiovascular Health Study) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE kidney disease; chronic; atherosclerosis; calcium; cardiovascular disease; arterial stiffness ID PERIPHERAL ARTERIAL-DISEASE; STAGE RENAL-DISEASE; SERUM CYSTATIN-C; ISOLATED SYSTOLIC HYPERTENSION; ARM INDEX; ELDERLY PERSONS; DIABETIC-PATIENTS; VASCULAR-DISEASE; BLOOD-PRESSURE; UNITED-STATES AB Objectives This study sought to determine the association of chronic kidney disease (CKD) with high ankle brachial index (ABI) measurement and to compare its strength with that of CKD with a low ABI. Background CKD is an important risk factor for cardiovascular disease (CVD) events. A high ABI, a marker of lower extremity arterial stiffness, is associated with CVD events and mortality. The association between CKD and high ABI is unknown. Methods The CHS (Cardiovascular Health Study) enrolled community-living people >65 years of age and measured kidney function and ABI. Glomerular filtration rate (GFR) was estimated using equations that incorporated either cystatin C or creatinine, and CKD was defined by estimated GFR <60 ml/min/1.73 m(2). The ABI was categorized as low (<0.90), low-normal (0.90 to 1.09), normal (1.10 to 1.40), and high (>1.40 or incompressible). Multinomial logistic regression was used to evaluate the associations of CKD with ABI categories. Results Among 4,513 participants, 23% had CKD, 13% had a low ABI, and 3% had a high ABI. In models adjusted for age, sex, race, hypertension, diabetes, smoking, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and C-reactive protein, cystatin C-based CKD was associated with both low ABI (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.6 to 2.5; p <0.001) and high ABI (RR: 1.6; 95% CI: 1.0 to 2.3; p = 0.03). Results were similar when CKD was defined by creatinine. Conclusions CKD is associated with both the high and the low extremes of ABI in community-living older people. Future studies should evaluate whether arterial stiffness is an important mechanism leading to CVD in people with CKD. (J Am Coll Cardiol 2009; 54: 1176-84) (C) 2009 by the American College of Cardiology Foundation C1 [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol, La Jolla, CA 92161 USA. [Ix, Joachim H.; Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, Div Prevent Med, La Jolla, CA 92161 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Med, Div Cardiol, La Jolla, CA 92161 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA 92161 USA. [Katz, Ronit; Siscovick, David S.] Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA. [De Boer, Ian H.; Kestenbaum, Brian R.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [De Boer, Ian H.] Vet Affairs Puget Sound Healthcare Syst, Nephrol Sect, Seattle, WA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Sarnak, Mark J.] Tufts Univ New England Med Ctr, Dept Med, Div Nephrol, Boston, MA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Gen Med Sect, San Francisco, CA USA. RP Ix, JH (reprint author), Univ Calif San Diego, Dept Med, Div Nephrol & Hypertens, 3350 La Jolla Village Dr,Mail Code 111-H, La Jolla, CA 92161 USA. EM joeix@ucsd.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Allison, Matthew/0000-0003-0777-8272 FU NHLBI NIH HHS [N01-HC-85082, N01 HC-55222, N01 HC015103, N01 HC035129, N01 HC045133, N01 HC055222, N01 HC075150, N01 HC085079, N01-HC-75150, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01HC55222, N01HC75150, N01HC85079, N01HC85086, U01 HL080295, U01 HL080295-01]; NIA NIH HHS [R01 AG027002, R01 AG027002-01, R01AG027002] NR 61 TC 41 Z9 44 U1 1 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 SEP 22 PY 2009 VL 54 IS 13 BP 1176 EP 1184 DI 10.1016/j.jacc.2009.06.017 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 494OO UT WOS:000269823300010 PM 19761940 ER PT J AU Mainero, C Benner, T Radding, A van der Kouwe, A Jensen, R Rosen, BR Kinkel, RP AF Mainero, C. Benner, T. Radding, A. van der Kouwe, A. Jensen, R. Rosen, B. R. Kinkel, R. P. TI In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI SO NEUROLOGY LA English DT Article ID INVERSION-RECOVERY; LESIONS; BRAIN; PHASE; DEMYELINATION; INFLAMMATION; DISEASE; PLAQUES; IMAGES; IRON AB Objective: We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data. Methods: We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 x 033 x 1 mm(3)), and a 3-dimensional magnetization-prepared rapid gradient echo. Results: Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing-remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p < 0.02 by Spearman test) and older age (p < 0.04 by Spearman test). Conclusions: Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability. Neurology (R) 2009;73:941-948 C1 [Mainero, C.; Benner, T.; Radding, A.; van der Kouwe, A.; Rosen, B. R.] Massachusetts Gen Hosp, A Athinoula Martinos Ctr Biomed Imaging, IIMS MIT, Charlestown, MA 02129 USA. [Jensen, R.; Kinkel, R. P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Mainero, C (reprint author), Massachusetts Gen Hosp, A Athinoula Martinos Ctr Biomed Imaging, IIMS MIT, 149 13th St, Charlestown, MA 02129 USA. EM caterina@nmr.mgh.harvard.edu FU A. A. Martinos Center internal funds; NIH [5P41 RR14075 08] FX The study was sponsored by A. A. Martinos Center internal funds and by the NIH (5P41 RR14075 08). NR 35 TC 108 Z9 110 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 22 PY 2009 VL 73 IS 12 BP 941 EP 948 DI 10.1212/WNL.0b013e3181b64bf7 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 497DN UT WOS:000270035000006 PM 19641168 ER PT J AU Qi, LY Xiu, MH Chen, DC Wang, F Kosten, TA Kosten, TR Zhang, XY AF Qi, Ling Yan Xiu, Mei Hong Chen, Da Chun Wang, Fan Kosten, Therese A. Kosten, Thomas R. Zhang, Xiang Yang TI Increased serum S100B levels in chronic schizophrenic patients on long-term clozapine or typical antipsychotics SO NEUROSCIENCE LETTERS LA English DT Article DE Schizophrenia; S100B; Psychopathology; Antipsychotics; Serum; Neurotrophin ID S-100B PROTEIN; BLOOD; BRAIN; ASTROCYTES; SYMPTOMS; BARRIER; CSF AB S100B is a calcium-binding protein, mainly produced and secreted by astrocytes, and it mediates the interaction among glial cells and between glial cells and neurons. Recently, several studies have shown increased serum 100B levels in patients with schizophrenia, suggesting that S100B might be relevant to the pathophysiology of schizophrenia. To examine the potentially differential effect of clozapine compared to typical antipsychotics on serum S100B and the relationship between S100B levels and psychopathology in patients with schizophrenia, 63 physically healthy patients with schizophrenia were compared with 50 age-, sex-matched normal controls. The psychopathology of patients was assessed by the Positive and Negative SyndromeScale (PANSS). Serum S100B levels were measured by sandwich ELISA. The results showed that S100B levels were significantly elevated in chronic patients with schizophrenia than in healthy controls (p < 0.0001). As compared with healthy controls, there was a significant increase in S100B levels in patients treated with both clozapine and typical antipsychotics (both p < 0.0001). However, no significant difference in S100B was found between patients treated with clozapine and typical antipsychotic subgroups (p > 0.05). Furthermore, there was no significant correlation between S100B and standardized drug doses or the duration of taking neuroleptic medications (both p > 0.05). In addition, no significant correlation was observed between S100B and PANSS total score and its subscale scores (all >0.05). These findings suggest that serum S100B levels in chronic schizophrenia under antipsychotic medication may be increased, suggesting that a dysfunction of astrocytes and/or oligodendrocytes may play a role in the pathogenesis of schizophrenia. Long term treatment with both typical and atypical antipsychotics may produce similar effects on the S100B serum levels, which however remains to be characterized in a large sample of first-episode, medication-naive patients with schizophrenia using a longitudinal design. (c) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Qi, Ling Yan; Xiu, Mei Hong; Chen, Da Chun; Wang, Fan; Zhang, Xiang Yang] Beijing HuiLongGuan Hosp, Ctr Biol Psychiat, Beijing, Peoples R China. [Kosten, Therese A.; Kosten, Thomas R.; Zhang, Xiang Yang] Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. RP Kosten, TR (reprint author), VA Med Ctr, Res Bldg 110,Room 229,2002 Holcombe Blvd, Houston, TX 77030 USA. EM kosten@bcm.edu; xyzhang@bcm.edu NR 34 TC 18 Z9 20 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 22 PY 2009 VL 462 IS 2 BP 113 EP 117 DI 10.1016/j.neulet.2009.06.019 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 484SR UT WOS:000269068300004 PM 19539717 ER PT J AU Dubach, JM Das, S Rosenzweig, A Clark, HA AF Dubach, J. Matthew Das, Saumya Rosenzweig, Anthony Clark, Heather A. TI Visualizing sodium dynamics in isolated cardiomyocytes using fluorescent nanosensors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cellular imaging; ion channels; sodium sparks ID CARDIAC MYOCYTES; VENTRICULAR MYOCYTES; CHANNELS; CELLS; RECEPTOR; SCN9A; RAT; NA+; STIMULATION; INHIBITION AB Regulation of sodium flux across the cell membrane plays a vital role in the generation of action potentials and regulation of membrane excitability in cells such as cardiomyocytes and neurons. Alteration of sodium channel function has been implicated in diseases such as epilepsy, long QT syndrome, and heart failure. However, single cell imaging of sodium dynamics has been limited due to the narrow selection of fluorescent sodium indicators available to researchers. Here we report, the detection of spatially defined sodium activity during action potentials. Fluorescent nanosensors that measure sodium in real-time, are reversible and are completely selective over other cations such as potassium that were used to image sodium. The use of the nanosensors in vitro was validated by determining drug-induced activation in heterologous cells transfected with the voltage-gated sodium channel Na(V)1.7. Spatial information of sodium concentrations during action potentials will provide insight at the cellular level on the role of sodium and how slight changes in sodium channel function can affect the entirety of an action potential. C1 [Dubach, J. Matthew; Clark, Heather A.] Charles Stark Draper Lab, Biomed Engn Grp, Cambridge, MA 02139 USA. [Das, Saumya; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [Das, Saumya] Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02114 USA. RP Clark, HA (reprint author), Charles Stark Draper Lab, Biomed Engn Grp, 555 Technol Sq, Cambridge, MA 02139 USA. EM hclark@draper.com RI Clark, Heather/D-5247-2013 FU National Institutes of Health National Institute of General Medical Sciences [R01 GM084366]; Draper Internal Research and Development; Leducq Foundation Network of Research Excellence; David Ganz; Maxwell Hurston Charitable Foundation; Harvard MIT Health Sciences and Technology Clinical Investigation Training Program; National Institutes of Health/National Heart, Lung, and Blood Institute [K08 HL081319] FX We thank Dr. Owen Mcmanus of Merck and Prof. Norbert Klugbauer of Albert-Ludwigs-Universitat Freiburg for providing the HEK PN1 cells; Drs. Jeremy Ruskin and Patrick Ellinor for their thoughtful suggestions; and Drs. Ling LiandChunyangXiao for technical help with myocyte preparations. This work was supported by National Institutes of Health National Institute of General Medical Sciences Grant R01 GM084366; Draper Internal Research and Development; a Leducq Foundation Network of Research Excellence, Judith and David Ganz, and the Maxwell Hurston Charitable Foundation (to A. R.); and the Harvard MIT Health Sciences and Technology Clinical Investigation Training Program grant and National Institutes of Health/National Heart, Lung, and Blood Institute Grant K08 HL081319 ( to S. D.). NR 33 TC 32 Z9 33 U1 2 U2 21 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 22 PY 2009 VL 106 IS 38 BP 16145 EP 16150 DI 10.1073/pnas.0905909106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 497PF UT WOS:000270071600029 PM 19805271 ER PT J AU Shi, DD Pop, MS Kulikov, R Love, IM Kung, A Grossman, SR AF Shi, Dingding Pop, Marius S. Kulikov, Roman Love, Ian M. Kung, Andrew Grossman, Steven R. TI CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID UBIQUITIN LIGASE; NEGATIVE REGULATOR; ONCOPROTEIN HDM2; PROTEIN P300; MDM2; PHOSPHORYLATION; DEGRADATION; CBP/P300; DOMAIN; ACETYLATION AB p300 and CREB-binding protein (CBP) act as multifunctional regulators of p53 via acetylase and polyubiquitin ligase (E4) activities. Prior work in vitro has shown that the N-terminal 595 aa of p300 encode both generic ubiquitin ligase (E3) and p53-directed E4 functions. Analysis of p300 or CBP-deficient cells revealed that both coactivators were required for endogenous p53 polyubiquitination and the normally rapid turnover of p53 in unstressed cells. Unexpectedly, p300/CBP ubiquitin ligase activities were absent in nuclear extracts and exclusively cytoplasmic. Consistent with the cytoplasmic localization of its E3/E4 activity, CBP deficiency specifically stabilized cytoplasmic, but not nuclear p53. The N-terminal 616 aa of CBP, which includes the conserved Zn(2+)-binding C/H1-TAZ1 domain, was the minimal domain sufficient to destabilize p53 in vivo, and it included within an intrinsic E3 autoubiquitination activity and, in a two-step E4 assay, exhibited robust E4 activity for p53. Cytoplasmic compartmentalization of p300/CBP's ubiquitination function reconciles seemingly opposed functions and explains how a futile cycle is avoided-cytoplasmic p300/CBP E4 activities ubiquitinate and destabilize p53, while physically separate nuclear p300/CBP activities, such as p53 acetylation, activate p53. C1 [Shi, Dingding; Pop, Marius S.; Kulikov, Roman; Love, Ian M.; Grossman, Steven R.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. [Grossman, Steven R.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. [Grossman, Steven R.] Univ Massachusetts, Sch Med, Gastrointestinal Canc Program, Worcester, MA 01605 USA. [Shi, Dingding; Pop, Marius S.; Kulikov, Roman; Love, Ian M.; Grossman, Steven R.] Univ Massachusetts, Mem Canc Ctr, Dept Canc Biol, Worcester, MA 01605 USA. [Grossman, Steven R.] Univ Massachusetts, Mem Canc Ctr, Dept Med, Worcester, MA 01605 USA. [Grossman, Steven R.] Univ Massachusetts, Mem Canc Ctr, Gastrointestinal Canc Program, Worcester, MA 01605 USA. [Kung, Andrew] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Grossman, SR (reprint author), Univ Massachusetts, Sch Med, Dept Canc Biol, 364 Plantat St, Worcester, MA 01605 USA. EM steven.grossman@umassmed.edu OI Kung, Andrew/0000-0002-9091-488X FU National Cancer Institute (NCI) [R01CA107532] FX We thank C. M. Chiang (UT Southwestern, Dallas, TX) for generously providing FLAG-CBP baculovirus, C. Blattner (Forschungszentrum Karlsruhe, Karlsruhe, Germany) for providing pCDNA3. p53-UbF, and members of the Altieri and Grossman labs for helpful discussions. S. G. was supported by a Kimmel Scholar Award, and R01CA107532 from the National Cancer Institute (NCI). NR 35 TC 73 Z9 73 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 22 PY 2009 VL 106 IS 38 BP 16275 EP 16280 DI 10.1073/pnas.0904305106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 497PF UT WOS:000270071600051 PM 19805293 ER PT J AU Li, QS Brass, AL Ng, A Hu, ZY Xavier, RJ Liang, TJ Elledge, SJ AF Li, Qisheng Brass, Abraham L. Ng, Aylwin Hu, Zongyi Xavier, Ramnik J. Liang, T. Jake Elledge, Stephen J. TI A genome-wide genetic screen for host factors required for hepatitis C virus propagation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HCV; RNA interference; viral host factors; functional genomics; viral lifecycle ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELLULAR COFACTORS; IN-VITRO; REPLICATION; INFECTION; IDENTIFICATION; CULTURE; PROTEINS AB Hepatitis C virus (HCV) infection is a major cause of end-stage liver disease and a leading indication for liver transplantation. Current therapy fails in many instances and is associated with significant side effects. HCV encodes only a few proteins and depends heavily on host factors for propagation. Each of these host dependencies is a potential therapeutic target. To find host factors required by HCV, we completed a genome-wide small interfering RNA (siRNA) screen using an infectious HCV cell culture system. We applied a two-part screening protocol to allow identification of host factors involved in the complete viral lifecycle. The candidate genes found included known or previously identified factors, and also implicate many additional host cell proteins in HCV infection. To create a more comprehensive view of HCV and host cell interactions, we performed a bioinformatic meta-analysis that integrates our data with those of previous functional and proteomic studies. The identification of host factors participating in the complete HCV lifecycle will both advance our understanding of HCV pathogenesis and illuminate therapeutic targets. C1 [Brass, Abraham L.; Elledge, Stephen J.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Brigham & Womens Hosp,Dept Genet,Div Genet, Boston, MA 02115 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Li, Qisheng; Hu, Zongyi; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Brass, Abraham L.] Massachusetts Gen Hosp, Ragon Inst, MIT, Charlestown, MA 02129 USA. [Brass, Abraham L.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Brigham & Womens Hosp,Dept Genet,Div Genet, Boston, MA 02115 USA. EM jakel@bdg10.niddk.nih.gov; selledge@genetics.med.harvard.edu RI Li, Qisheng/K-1909-2013 FU Center for the Study of Inflammatory Bowel Disease Genetics and Genomics Core and National Institutes of Health [DK043351]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health [U54 AI057159]; New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases; Howard Hughes Medical Institute FX We thank the ICCB-Longwood: C. Shamu, S. Chang, S. Rudnicki, S. Johnston, K. Rudnicki, D. Wrobel, and Z. Cooper. Funding support: A. L. B. (Harvard Center for AIDS Research), A. N. (Crohns and Colitis Foundation of America), R. J. X. (Center for the Study of Inflammatory Bowel Disease Genetics and Genomics Core and National Institutes of Health Grant DK043351). The ICCB-Longwood is in part supported by a grant to T. Mitchison (National Cancer Institute). This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (National Institutes of Health Grant U54 AI057159 to Dennis Kasper). S. J. E. is an Investigator with the Howard Hughes Medical Institute. NR 37 TC 220 Z9 225 U1 1 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 SEP 22 PY 2009 VL 106 IS 38 BP 16410 EP 16415 DI 10.1073/pnas.0907439106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 497PF UT WOS:000270071600074 PM 19717417 ER PT J AU Azadani, AN Joussaud, N Matthews, PB Ge, L Guy, TS Chuter, TA Tseng, EE AF Azadani, Ali N. Joussaud, Nicolas Matthews, Peter B. Ge, Liang Guy, T. Sloane Chuter, Timothy A. Tseng, Elaine E. TI Can Degenerated Bioprostheses Be Treated Effectively Using Transcatheter Aortic Valves? SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Meeting Abstract CT 21st Annual Transcatheter Cardiovascular Therapeutics Conference CY SEP 21-25, 2009 CL San Francisco, CA C1 UCSF Med Ctr, San Francisco, CA USA. San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 21 PY 2009 VL 104 IS 6A BP 45D EP 45D PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 496NP UT WOS:000269981600128 ER PT J AU Don, C Witzke, C Cubeddu, R Palacios, I AF Don, Creighton Witzke, Christian Cubeddu, Roberto Palacios, Igor TI Rapid Ventricular Pacing During Aortic Valvuloplasty Is Safe But Associated With Lower Procedural Success SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Meeting Abstract CT 21st Annual Transcatheter Cardiovascular Therapeutics Conference CY SEP 21-25, 2009 CL San Francisco, CA C1 [Don, Creighton; Witzke, Christian; Cubeddu, Roberto; Palacios, Igor] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 21 PY 2009 VL 104 IS 6A BP 50D EP 51D PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 496NP UT WOS:000269981600144 ER PT J AU Gonzalo, N Tearney, GJ Serruys, PW van Soest, G Okamura, T van Geuns, RJ Garcia-Garcia, HM Ligthart, J Bouma, B Regar, E AF Gonzalo, Nieves Tearney, Guillermo J. Serruys, Patrick W. van Soest, Gijs Okamura, Takayuki van Geuns, Robert J. Garcia-Garcia, Hector M. Ligthart, Jurgen Bouma, Brett Regar, Evelyn TI New Generation Optical Coherence Tomography In Clinical Practice SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Meeting Abstract CT 21st Annual Transcatheter Cardiovascular Therapeutics Conference CY SEP 21-25, 2009 CL San Francisco, CA C1 [Gonzalo, Nieves; Serruys, Patrick W.; van Soest, Gijs; Okamura, Takayuki; van Geuns, Robert J.; Garcia-Garcia, Hector M.; Ligthart, Jurgen; Regar, Evelyn] Erasmus Univ, Thoraxctr, Erasmus MC, NL-3000 DR Rotterdam, Netherlands. [Tearney, Guillermo J.; Bouma, Brett] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RI van Soest, Gijs/B-4881-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 21 PY 2009 VL 104 IS 6A BP 58D EP 58D PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 496NP UT WOS:000269981600163 ER PT J AU Ebrahimi, R Ahmadi, N AF Ebrahimi, Ramin Ahmadi, Naser TI Clinical Outcomes of Individuals with Discordance Between the Framingham Risk Score and the Coronary Artery Calcification Score SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Meeting Abstract CT 21st Annual Transcatheter Cardiovascular Therapeutics Conference CY SEP 21-25, 2009 CL San Francisco, CA C1 [Ebrahimi, Ramin; Ahmadi, Naser] Univ Calif Los Angeles, Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 21 PY 2009 VL 104 IS 6A BP 67D EP 68D PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 496NP UT WOS:000269981600190 ER PT J AU Ebrahimi, R Ahmadi, N Babaei, H AF Ebrahimi, Ramin Ahmadi, Naser Babaei, Hormoz TI Association of Post-traumatic Stress Disorder and the Severity of Coronary Artery Disease Diagnosed by Computed Tomography Angiography SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Meeting Abstract CT 21st Annual Transcatheter Cardiovascular Therapeutics Conference CY SEP 21-25, 2009 CL San Francisco, CA C1 [Ebrahimi, Ramin; Ahmadi, Naser; Babaei, Hormoz] Univ Calif Los Angeles, Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 21 PY 2009 VL 104 IS 6A BP 69D EP 69D PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 496NP UT WOS:000269981600193 ER PT J AU Chan, ST Tam, Y Lai, CY Wu, HY Lam, YK Wong, PN Kwong, KK AF Chan, Suk-tak Tam, Yan Lai, Chun-yip Wu, How-yee Lam, Yan-kei Wong, Pok-ning Kwong, Kenneth K. TI Transcranial Doppler study of cerebrovascular reactivity: Are migraineurs more sensitive. to breath-hold challenge? SO BRAIN RESEARCH LA English DT Article DE Migraine; Transcranial Doppler; Cerebral hemodynamics; Ultrasound ID MIDDLE CEREBRAL-ARTERY; NEAR-INFRARED SPECTROSCOPY; HEART-RATE-VARIABILITY; BLOOD-FLOW; VISUAL-STIMULATION; SIGNAL CHANGES; AURA; HUMANS; AUTOREGULATION; MECHANISMS AB Transcranial Doppler sonography (TCD) of cerebrovascular reactivity has been used to study migraine interictally. However, the previous TCD findings had been quite varied at the post breath-hold period. Autonomic responses were usually studied with cardiac information. The aim of this study was to use TCD as a tool to examine difference in cerebrovascular reactivity between migraineurs and non-headache controls by measuring interictally the whole time course of cerebral blood flow velocity (CBFV) during and after a breath-hold challenge. The percentage change of CBFV was derived in the left and light middle cerebral arteries in 10 migraineurs and 10 controls during and after a 20 s breath-hold. Three phases of CBFV change were identified with an initial positive phase above baseline, a middle negative phase during breath-hold, and a late positive phase which started before the cessation of breath-hold and continued for a period after. In addition to CBFV, we also extracted and utilized the information of the cardiac cycle duration (CC) derived from the time course of CBFV. The percentage change of CC was derived from time intervals between every two points of inflexion in CBFV. Two undershoots of CC change were shown at the transitions of breathing motions. We found evidence that migraineurs had significant difference of CBFV change at the middle negative phase during breath-hold and the pronounced undershoots of CC change compared to non-headache controls. (C) 2009 Elsevier B.V. All rights reserved. C1 [Chan, Suk-tak; Tam, Yan; Lai, Chun-yip; Wu, How-yee; Lam, Yan-kei; Wong, Pok-ning] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Kowloon, Hong Kong, Peoples R China. [Kwong, Kenneth K.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Chan, ST (reprint author), Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Kowloon, Hong Kong, Peoples R China. EM htphoebe@inet.polyu.edu.hk RI Chan, Suk-tak/G-5846-2015 FU Department of Health Technology and Informatics, The Hong Kong Polytechnic University FX This research was supported by the Department of Health Technology and Informatics, The Hong Kong Polytechnic University. NR 45 TC 5 Z9 7 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 21 PY 2009 VL 1291 BP 53 EP 59 DI 10.1016/j.brainres.2009.07.057 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 497GF UT WOS:000270045200006 PM 19635466 ER PT J AU Wetterling, F Liehr, M Schimpf, P Liu, H Haueisen, J AF Wetterling, F. Liehr, M. Schimpf, P. Liu, H. Haueisen, J. TI The localization of focal heart activity via body surface potential measurements: tests in a heterogeneous torso phantom SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID HUMAN SKULL PHANTOM; VOLUME CURRENTS; MEG; MUSIC; EEG AB The non-invasive localization of focal heart activity via body surface potential measurements (BSPM) could greatly benefit the understanding and treatment of arrhythmic heart diseases. However, the in vivo validation of source localization algorithms is rather difficult with currently available measurement techniques. In this study, we used a physical torso phantom composed of different conductive compartments and seven dipoles, which were placed in the anatomical position of the human heart in order to assess the performance of the Recursively Applied and Projected Multiple Signal Classification (RAP-MUSIC) algorithm. Electric potentials were measured on the torso surface for single dipoles with and without further uncorrelated or correlated dipole activity. The localization error averaged 11 +/- 5 mm over 22 dipoles, which shows the ability of RAP-MUSIC to distinguish an uncorrelated dipole from surrounding sources activity. For the first time, real computational modelling errors could be included within the validation procedure due to the physically modelled heterogeneities. In conclusion, the introduced heterogeneous torso phantom can be used to validate state-of-the-art algorithms under nearly realistic measurement conditions. C1 [Wetterling, F.; Liehr, M.; Haueisen, J.] Univ Jena, Biomagnet Ctr, Dept Neurol, Jena, Germany. [Wetterling, F.; Haueisen, J.] Tech Univ Ilmenau, Inst Biomed Engn & Informat, Ilmenau, Germany. [Wetterling, F.] Trinity Coll Dublin, Sch Phys, Dublin, Ireland. [Schimpf, P.] Eastern Washington Univ, Dept Comp Sci, Cheney, WA 99004 USA. [Liu, H.] MIT, Massachusetts Gen Hosp, Boston, MA USA. [Liu, H.] Harvard Univ, Sch Med, Boston, MA USA. [Liu, H.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Wetterling, F (reprint author), Univ Jena, Biomagnet Ctr, Dept Neurol, Jena, Germany. EM wetterlf@tcd.ie RI Haueisen, Jens/B-7183-2011; OI Haueisen, Jens/0000-0003-3871-2890; Liu, Hesheng/0000-0002-7233-1509 FU German Research Foundation (DFG) [Ha 2899/6-1, 8-1]; Thuringian Ministry of Education [2008FE9005] FX This work was in part supported by the German Research Foundation (DFG Ha 2899/6-1 & 8-1) and the Thuringian Ministry of Education (2008FE9005). NR 22 TC 5 Z9 5 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 21 PY 2009 VL 54 IS 18 BP 5395 EP 5409 DI 10.1088/0031-9155/54/18/003 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 523QG UT WOS:000272088800002 PM 19700819 ER PT J AU Jain, A Munn, LL AF Jain, Abhishek Munn, Lance L. TI Determinants of Leukocyte Margination in Rectangular Microchannels SO PLOS ONE LA English DT Article AB Microfabrication of polydimethylsiloxane (PDMS) devices has provided a new set of tools for studying fluid dynamics of blood at the scale of real microvessels. However, we are only starting to understand the power and limitations of this technology. To determine the applicability of PDMS microchannels for blood flow analysis, we studied white blood cell (WBC) margination in channels of various geometries and blood compositions. We found that WBCs prefer to marginate downstream of sudden expansions, and that red blood cell (RBC) aggregation facilitates the process. In contrast to tubes, WBC margination was restricted to the sidewalls in our low aspect ratio, pseudo-2D rectangular channels and consequently, margination efficiencies of more than 95% were achieved in a variety of channel geometries. In these pseudo-2D channels blood rheology and cell integrity were preserved over a range of flow rates, with the upper range limited by the shear in the vertical direction. We conclude that, with certain limitations, rectangular PDMS microfluidic channels are useful tools for quantitative studies of blood rheology. RP Jain, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Steele Lab Tumor Biol, Charlestown, MA USA. EM lance@steele.mgh.harvard.edu RI Munn, Lance/L-3950-2016; OI Munn, Lance/0000-0003-0698-7232; Jain, Abhishek/0000-0003-2235-5139 FU NCI NIH HHS [R21 CA126761] NR 66 TC 44 Z9 44 U1 4 U2 17 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 SEP 21 PY 2009 VL 4 IS 9 AR e7104 DI 10.1371/journal.pone.0007104 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 498PJ UT WOS:000270154000008 PM 19768109 ER PT J AU Haddad, RI Tishler, RB Norris, C Goguen, L Balboni, TA Costello, R Wirth, L Lorch, J Andreozzi, B Annino, D Posner, MR AF Haddad, Robert I. Tishler, Roy B. Norris, Charles Goguen, Laura Balboni, Tracy A. Costello, Rosemary Wirth, Lori Lorch, Jochen Andreozzi, Britta Annino, Donald Posner, Marshall R. TI Phase I Study of C-TPF in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 30-JUN 03, 2008 CL Chicago, IL SP Amer Soc Clin Oncol ID ADVANCED LARYNGEAL-CANCER; INDUCTION CHEMOTHERAPY; ORGAN PRESERVATION; RADIATION-THERAPY; PLUS CETUXIMAB; DOCETAXEL; CISPLATIN; FLUOROURACIL; CHEMORADIOTHERAPY; TRIAL AB Purpose Phase I study to determine the maximum tolerated dose (MTD) of fluorouracil (FU) in the docetaxel/cisplatin/FU (TPF) regimen when combined with cetuximab (C) for induction treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients with previously untreated SCCHN were enrolled. FU cohorts were 700, 850, and 1,000 mg/m(2)/d for 4 days via continuous infusion. TPF given every 3 weeks for three cycles and C was given weekly for a total of 9 weeks, starting on day 1 of TPF. All patients received chemoradiotherapy after C-TPF. Results A total of 30 patients were enrolled and 28 were assessable. The median age was 57 years, 92% had stage 4 disease, 71% were oropharynx, and 100% had a performance status of 0. No dose-limiting toxicity (DLT) was encountered on dose levels 1 and 2. At dose level 3 of 1000 mg/m(2), one DLT was encountered and three more patients were enrolled with no DLTs. In the expansion cohort at the MTD, three DLT's were encountered. The decision was made to decrease the FU from 1,000 mg/m(2) to dose level 2 of 850 mg/m(2). A total of 13 patients were enrolled at the MTD of 850 mg/m(2). The number of average weeks that C was delivered was seven of nine planned. Conclusion C-TPF appears to be safe and feasible as given in this study. GI toxicity (mucositis, enteritis, and diarrhea) appears to be the major combined DLT. Reducing the FU in TPF to 850 mg/m2 reduces GI toxicity and is the recommended phase II dose. J Clin Oncol 27:4448-4453. (C) 2009 by American Society of Clinical Oncology C1 [Haddad, Robert I.] Dana Farber Canc Inst, Dept Med & Radiat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Head & Neck Surg, Boston, MA 02115 USA. RP Haddad, RI (reprint author), Dana Farber Canc Inst, Dept Med & Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM robert_haddad@dfci.harvard.edu NR 20 TC 33 Z9 34 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 SEP 20 PY 2009 VL 27 IS 27 BP 4448 EP 4453 DI 10.1200/JCO.2009.22.1333 PG 6 WC Oncology SC Oncology GA 496ZO UT WOS:000270019900004 PM 19704061 ER PT J AU Avet-Loiseau, H Li, C Magrangeas, F Gouraud, W Charbonnel, C Harousseau, JL Attal, M Marit, G Mathiot, C Facon, T Moreau, P Anderson, KC Campion, L Munshi, NC Minvielle, S AF Avet-Loiseau, Herve Li, Cheng Magrangeas, Florence Gouraud, Wilfried Charbonnel, Catherine Harousseau, Jean-Luc Attal, Michel Marit, Gerald Mathiot, Claire Facon, Thierry Moreau, Philippe Anderson, Kenneth C. Campion, Loic Munshi, Nikhil C. Minvielle, Stephane TI Prognostic Significance of Copy-Number Alterations in Multiple Myeloma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID IN-SITU HYBRIDIZATION; COMPARATIVE GENOMIC HYBRIDIZATION; DOUBLE-STRANDED-RNA; STEM-CELL TRANSPLANTATION; LOSS-OF-HETEROZYGOSITY; LOW CD27 EXPRESSION; P53 GENE DELETION; HIGH-RISK DISEASE; INTERGROUPE FRANCOPHONE; ABNORMALITIES AB Purpose Chromosomal aberrations are a hallmark of multiple myeloma but their global prognostic impact is largely unknown. Patients and Methods We performed a genome-wide analysis of malignant plasma cells from 192 newly diagnosed patients with myeloma using high-density, single-nucleotide polymorphism (SNP) arrays to identify genetic lesions associated with prognosis. Results Our analyses revealed deletions and amplifications in 98% of patients. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were the most frequent lesions associated with adverse prognosis, whereas recurrent amplifications of chromosomes 5, 9, 11, 15, and 19 conferred a favorable prognosis. Multivariate analysis retained three independent lesions: amp(1q23.3), amp(5q31.3), and del(12p13.31). When adjusted to the established prognostic variables (ie, t(4; 14), del(17p), and serum beta(2)-microglobulin [S beta(2)M]), del(12p13.31) remained the most powerful independent adverse marker (P < .0001; hazard ratio [HR], 3.17) followed by S beta(2)M (P < .0001; HR, 2.78) and the favorable marker amp(5q31.3) (P = .0005; HR, 0.37). Patients with amp(5q31.3) alone and low S beta(2)M had an excellent prognosis (5-year overall survival, 87%); conversely, patients with del(12p13.31) alone or amp(5q31.3) and del(12p13.31) and high S beta(2)M had a very poor outcome (5-year overall survival, 20%). This prognostic model was validated in an independent validation cohort of 273 patients with myeloma. Conclusion These findings demonstrate the power and accessibility of molecular karyotyping to predict outcome in myeloma. In addition, integration of expression of genes residing in the lesions of interest revealed putative features of the disease driving short survival. J Clin Oncol 27:4585-4590. (C) 2009 by American Society of Clinical Oncology C1 Univ Nantes, INSERM, U892, Inst Reg Canc Nantes Atlantique, F-44093 Nantes, France. CHU Nantes, Inst Reg Canc Nantes Atlantique, Hematol Lab, F-44035 Nantes 01, France. CHU Nantes, Inst Reg Canc Nantes Atlantique, Serv Hematol Clin, F-44035 Nantes 01, France. Ctr Lutte Canc Nantes Atlantique, Inst Reg Canc Nantes Atlantique, Nantes, France. CHU Toulouse, Serv Hematol Clin, Toulouse, France. CHU Bordeaux, Serv Hematol Clin, Bordeaux, France. Inst Curie, Hematol Lab, Paris, France. CHU Lille, Serv Hematol Clin, F-59037 Lille, France. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dept Biostat & Computat Biol, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Adult Onc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston Vet Affairs Healthcare Syst, Boston, MA USA. RP Minvielle, S (reprint author), Univ Nantes, INSERM, U892, Inst Biol, 9 Quai Moncousu, F-44093 Nantes, France. EM sminvielle@chu-nantes.fr RI FACON, THIERRY/M-9736-2014; Magrangeas, Florence/L-3080-2015; Minvielle, Stephane/K-8251-2015; Campion, Loic/K-4726-2015; richard, chrystelle/K-8595-2015 OI FACON, THIERRY/0000-0001-7705-8460; Campion, Loic/0000-0003-4903-0908; FU Ligue contre le Cancer [SPORE P50 CA100707-04]; National Cancer Institute; Department of Veterans Affairs merit review award; National Institutes of Health. [RO1-129295, PO1-78378, RO1-50947] FX Supported in part by grants from the Ligue contre le Cancer (Equipe Labellise see); Grant No. SPORE P50 CA100707-04 (H. A. L., K. C. A., N. C. M.) from the National Cancer Institute; by the Department of Veterans Affairs merit review award; and Grants No. RO1-129295 (N. C. M.), PO1-78378 (K. C. A., N. C. M.), and RO1-50947 (K. C. A.) from the National Institutes of Health. NR 43 TC 131 Z9 133 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 SEP 20 PY 2009 VL 27 IS 27 BP 4585 EP 4590 DI 10.1200/JCO.2008.20.6136 PG 6 WC Oncology SC Oncology GA 496ZO UT WOS:000270019900024 PM 19687334 ER PT J AU Ogino, S Nosho, K Irahara, N Shima, K Baba, Y Kirkner, GJ Meyerhardt, JA Fuchs, CS AF Ogino, Shuji Nosho, Katsuhiko Irahara, Natsumi Shima, Kaori Baba, Yoshifumi Kirkner, Gregory J. Meyerhardt, Jeffrey A. Fuchs, Charles S. TI Prognostic Significance and Molecular Associations of 18q Loss of Heterozygosity: A Cohort Study of Microsatellite Stable Colorectal Cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; COLON-CANCER; CHROMOSOME 18Q; ALLELIC LOSS; LINE-1 HYPOMETHYLATION; DNA DEMETHYLATION; PIK3CA MUTATION; POOR-PROGNOSIS; BRAF MUTATION; JC VIRUS AB Purpose Loss of heterozygosity (LOH) at chromosome 18q frequently occurs late during colon cancer development and is inversely associated with microsatellite instability (MSI). 18q LOH has been reported to predict shorter survival in patients with colorectal cancer, whereas MSI-high status has been associated with superior prognosis. However, it is unclear whether 18q LOH in colorectal cancer has any prognostic implication independent of MSI status and other potential predictors of clinical outcome. Patients and Methods Among 555 non-MSI-high colorectal cancers (stage I to IV) in two independent prospective cohort studies, we examined 18q LOH in relation to other molecular events and patient survival. Cox proportional hazard models computed hazard ratio of death, adjusted for clinical and tumoral characteristics, including KRAS, BRAF, PIK3CA, beta-catenin, p53, CpG island methylator phenotype, LINE-1 methylation, and John Cunningham (JC) virus T antigen. Results In multivariate logistic regression, 18q LOH was independently associated with JC virus T antigen (odds ratio [OR] = 1.93; P = .0077), body mass index >= 30 kg/m(2) (obesity; OR = 2.01; P = .014), high tumor grade (OR = 0.40; P = .018), KRAS mutation (OR = 0.66; P = .40), and LINE-1 hypomethylation (for a 30% decrease; OR = 1.92; P = .045). Five-year colorectal cancer-specific survival was 75% among patients with 18q LOH-positive tumors and 74% among those with 18q LOH-negative tumors (log-rank P = .80). Five-year overall survival was 70% among patients with 18q LOH-positive tumors and 68% among those with 18q LOH-negative tumors (log-rank P = .54). Multivariate analysis did not show prognostic significance of 18q LOH. Conclusion In our large prospective study of patients with non-MSI-high colorectal cancer, 18q LOH or allelic imbalance was not associated with patient survival. J Clin Oncol 27:4591-4598. (C) 2009 by American Society of Clinical Oncology C1 [Ogino, Shuji] Harvard Univ, Ctr Mol Oncol Pathol, Dana Farber Canc Inst, Brigham & Womens Hosp,Sch Med,Dept Med Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Ctr Mol Oncol Pathol, Dana Farber Canc Inst, Brigham & Womens Hosp,Sch Med,Dept Med Oncol, 44 Binney St,Room JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU National Institutes of Health [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826, K07 CA97992]; Bennett Family Fund; Entertainment Industry Foundation National Colorectal Cancer Research Alliance; Japan Society for Promotion of Science FX Supported by the National Institutes of Health (Grants No. P01 CA87969 to S. Hankinson, P01 CA55075 to W. Willett, P50 CA127003 to C. S. F., K07 CA122826 to S. O., and K07 CA97992 to J. A. M.), the Bennett Family Fund, and the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. K. N. was supported by a fellowship grant from the Japan Society for Promotion of Science. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript. NR 49 TC 59 Z9 60 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 SEP 20 PY 2009 VL 27 IS 27 BP 4591 EP 4598 DI 10.1200/JCO.2009.22.8858 PG 8 WC Oncology SC Oncology GA 496ZO UT WOS:000270019900025 PM 19704056 ER PT J AU O'Donoghue, ML Braunwald, E Antman, EM Murphy, SA Bates, ER Rozenman, Y Michelson, AD Hautvast, RW Lee, PNV Close, SL Shen, L Mega, JL Sabatine, MS Wiviott, SD AF O'Donoghue, Michelle L. Braunwald, Eugene Antman, Elliott M. Murphy, Sabina A. Bates, Eric R. Rozenman, Yoseph Michelson, Alan D. Hautvast, Raymond W. Lee, Peter N. Ver Close, Sandra L. Shen, Lei Mega, Jessica L. Sabatine, Marc S. Wiviott, Stephen D. TI Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials SO LANCET LA English DT Article ID ACUTE CORONARY SYNDROMES; OF-FUNCTION POLYMORPHISM; PLATELET-AGGREGATION; ANTIPLATELET ACTION; STENT THROMBOSIS; ATORVASTATIN; OUTCOMES; ASPIRIN; THROMBOLYSIS; INTERVENTION AB Background Proton-pump inhibitors (PPIs) are often prescribed in combination with thienopyridines. Conflicting data exist as to whether PPIs diminish the efficacy of clopiclogrel. We assessed the association between PPI use, measures of platelet function, and clinical outcomes for patients treated with clopidogrel or prasugrel. Methods In the PRINCIPLE-TIMI 44 trial, the primary outcome was inhibition of platelet aggregation at 6 h assessed by light-transmission aggregometry. In the TRITON-TIMI 38 trial, the primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. In both studies, PPI use was at physician's discretion. We used a multivariable Cox model with propensity score to assess the association of PPI use with clinical outcomes. Findings In the PRINCIPLE-TIMI 44 trial, 201 patients undergoing elective percutaneous coronary intervention were randomly assigned to prasugrel (n=102) or high-dose clopidogrel (n=99). Mean inhibition of platelet aggregation was significantly lower for patients on a PPI than for those not on a PPI at 6 h after a 600 mg clopiclogrel loading dose (23.2 +/- 19.5% vs 35.2 +/- 20.9%, p=0.02), whereas a more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel (69.6 +/- 13.5% vs 76.7 +/- 12.4%, p=0.054). In the TRITON-TIMI 38 trial, 13 608 patients with an acute coronary syndrome were randomly assigned to prasugrel (n=6813) or clopidogrel (n=6795). In this study, 33% (n=4529) of patients were on a PPI at randomisation. No association existed between PPI use and risk of the primary endpoint for patients treated with clopiclogrel (adjusted hazard ratio [HR] 0.94, 95% CI 0.80-1.11) or prasugrel (1.00, 0.84-1.20). Interpretation The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel. Funding Daiichi Sankyo Company Limited and Eli Lilly and Company sponsored the trials. This analysis had no funding. C1 [O'Donoghue, Michelle L.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Bates, Eric R.] Univ Michigan, Ann Arbor, MI 48109 USA. [Rozenman, Yoseph] Tel Aviv Univ, Edith Wolfson Med Ctr, Holon, Israel. [Michelson, Alan D.] Childrens Hosp, Boston, MA 02115 USA. [Hautvast, Raymond W.] Med Ctr Alkmaar, Alkmaar, Netherlands. [Lee, Peter N. Ver] NE Cardiol Associates, Bangor, ME USA. [Close, Sandra L.; Shen, Lei] Eli Lilly Res Labs, Indianapolis, IN USA. RP O'Donoghue, ML (reprint author), Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. EM modonoghue@partners.org FU Eli Lilly; Daiichi Sankyo; Sanofi Aventis; Johnson Johnson; Bayer Healthcare; Astra Zeneca; Bristol-Myers Squibb; Schering Plough FX EB received research grants and honoraria from Eli Lilly and Daiichi Sankyo. EMA received research grants from Eli Lilly, Daiichi Sankyo, and Sanofi Aventis; and consulting fees or paid advisory board fees from Sanofi Aventis and lecture fees from Eli Lilly and Sanofi Aventis. SAM received research grants front Eli Lilly and Daiichi Sankyo, and consulting fees from Eli Lilly. ERB received honoraria from Eli Lilly, Daiichi Sankyo, Sanofi Aventis, and Bristol-Myers Squibb. YR received consulting or lecture fees from Eli Lilly, Sanofi Aventis, Medtronic, Boston Scientific, Pfizer, and Schering-Plough. ADM is a consultant to Eli Lilly, Daiichi Sankyo, Sanofi Aventis, and Bristol-Myers Squibb. S LC and LS are employees and stockholders of Eli Lilly. JLM received research grants from Eli Lilly, Daiichi Sankyo, and Johnson & Johnson, and honoraria from Bayer Healthcare. MSS received research grants from Sanofi Aventis and Astra Zeneca, and honoraria and/or consulting fees from Sanofi Aventis, Bristol-Myers Squibb, Astra Zeneca, and Eli Lilly. SDW received research grants from Eli Lilly, Daiichi Sankyo, Sanofi Aventis, and Schering Plough; consulting fees or paid advisory fees from Astra Zeneca, and Sanofi Aventis; and honoraria from Eli Lilly, Daiichi Sankyo, Astra Zeneca, and Schering Plough. MO'D, RWH, PVL declare that they have no conflicts of interest. NR 28 TC 419 Z9 451 U1 2 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 SEP 19 PY 2009 VL 374 IS 9694 BP 989 EP 997 DI 10.1016/S0140-6736(09)61525-7 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 498PK UT WOS:000270154100029 PM 19726078 ER PT J AU McNeill, LH Coeling, M Puleo, E Suarez, EG Bennett, GG Emmons, KM AF McNeill, Lorna H. Coeling, Molly Puleo, Elaine Suarez, Elizabeth Gonzalez Bennett, Gary G. Emmons, Karen M. TI Colorectal cancer prevention for low-income, sociodemographically-diverse adults in public housing: baseline findings of a randomized controlled trial SO BMC PUBLIC HEALTH LA English DT Article ID CHRONIC DISEASE PREVENTION; BODY-MASS INDEX; PHYSICAL-ACTIVITY; UNITED-STATES; WORKING-CLASS; SOCIETY GUIDELINES; HEALTHY DIRECTIONS; MULTIVITAMIN USE; SUPPLEMENT USE; WOMEN AB Background: This paper presents the study design, intervention components, and baseline data from Open Doors to Health, a study designed to address social contextual factors in colorectal cancer (CRC) prevention for low-income, racial/ethnic minority populations. Methods: A cluster randomized design with 12 housing sites as the primary sampling units was used: 6 sites were assigned to a "Peer-led plus Screening Access" (PL) condition, and 6 were assigned to "Screening Access only" (SCR) condition. Study-related outcomes were CRC screening, physical activity (measured as mean steps/day), and multivitamin use. Results: At baseline (unweighted sample size = 1554), two-thirds self-reported that they were current with screening recommendations for CRC (corrected for medical records validation, prevalence was 52%), with half having received a colonoscopy (54%); 96% had health insurance. Mean steps per day was 5648 (se mean = 224), and on average 28% of the sample reported regular multivitamin use. Residents reported high levels of social support [mean = 4.40 (se = .03)] and moderately extensive social networks [mean = 2.66 (se = .02)]. Conclusion: Few studies have conducted community-based studies in public housing communities; these data suggest areas for improvement and future opportunities for intervention development and dissemination. Findings from the randomized trial will determine the effectiveness of the intervention on our health-related outcomes as well as inform future avenues of research. C1 [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Houston, TX 77030 USA. [Coeling, Molly; Suarez, Elizabeth Gonzalez; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Center Community Based Res, Boston, MA 02115 USA. [Puleo, Elaine] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC 27706 USA. RP McNeill, LH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Houston, TX 77030 USA. EM lmcneill@mdanderson.org; Molly_Coeling@dfci.harvard.edu; epuleo@schoolph.umass.edu; elizabeth_gonzalez_suarez@dfci.harvard.edu; gary.bennett@duke.edu; karen_m_emmons@dfci.harvard.edu FU National Cancer Institute [5R01CA098864-02, 3R01CA098864-02S1]; Liberty Mutual, National Grid; Patterson Fellowship Fund FX This research was supported by grant 5R01CA098864-02 from the National Cancer Institute and support to the Dana-Farber Cancer Institute by Liberty Mutual, National Grid, and the Patterson Fellowship Fund. At the time of this study, Lorna H. McNeill was supported by the Alonzo Yerby Postdoctoral Fellowship at the Harvard School of Public Health. Gary G. Bennett is supported by an award from the Dana-Farber/Harvard Cancer Center and by grant 3R01CA098864-02S1 from the National Cancer Institute. NR 62 TC 21 Z9 21 U1 3 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD SEP 18 PY 2009 VL 9 AR 353 DI 10.1186/1471-2458-9-353 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 505FQ UT WOS:000270676400001 PM 19765309 ER PT J AU Treon, SP AF Treon, Steven P. TI How I treat Waldenstrom macroglobulinemia SO BLOOD LA English DT Review ID CONSENSUS PANEL RECOMMENDATIONS; 2ND INTERNATIONAL WORKSHOP; COLD-REACTING AUTOANTIBODIES; COOPERATIVE-ONCOLOGY-GROUP; IMMUNOGLOBULIN-M FLARE; LYMPHOMA STUDY-GROUP; RITUXIMAB THERAPY; WAIDENSTROMS MACROGLOBULINEMIA; MONOCLONAL IMMUNOGLOBULINS; BIOLOGIC ACTIVITY AB Waldenstrom macroglobulinemia (WM) is a distinct B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related IgM-secreting lymphoplasmacytic cells. Genetic factors play an important role, with 20% of patients demonstrating a familial predisposition. Asymptomatic patients should be observed. Patients with a disease-related hemoglobin level less than 10 g/L, platelet count less than 100 x 10(9)/L, bulky adenopathy or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or evidence of disease transformation should be considered for therapy. Plasmapheresis should be considered for symptomatic hyperviscosity and for prophylaxis in patients in whom rituximab therapy is contemplated. The use of rituximab as mono-therapy or in combination with cyclophosphamide, nucleoside analog, bortezomib, or thalidomide-based regimens can be considered for the first-line therapy of WM and should take into account specific treatment goals, future autologous stem cell transplantation eligibility, and long-term risks of secondary malignancies. In the salvage setting, the reuse or use of an alternative frontline regimen can be considered as well as bortezomib, alemtuzumab, and stem cell transplantation. Newer agents, such as bendamustine and everolimus, can also be considered in the treatment of WM. (Blood. 2009; 114: 2375-2385) C1 Harvard Univ, Bing Ctr Waldenstroms Macroglobulinemia, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. RP Treon, SP (reprint author), Harvard Univ, Bing Ctr Waldenstroms Macroglobulinemia, Dana Farber Canc Inst, Sch Med, M548,44 Binney St, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu FU Peter and Helen Bing Fund for Waldenstrom Macroglobulinemia; Linda and Edward Nelson Fund; Bailey Family Fund for Waldenstrom Macroglobulinemia; International Waldenstrom Macroglobulinemia Foundation FX The author thanks the staff of the Bing Center for Waldenstrom Macroglobulinemia and, in particular, Robert J. Manning, Christopher J. Patterson, and Lefkothea Ioakimidis for the data collection used in this manuscript.; This work was supported by the Peter and Helen Bing Fund for Waldenstrom Macroglobulinemia, the Linda and Edward Nelson Fund, the Bailey Family Fund for Waldenstrom Macroglobulinemia, and the International Waldenstrom Macroglobulinemia Foundation. NR 92 TC 99 Z9 107 U1 0 U2 5 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 SEP 17 PY 2009 VL 114 IS 12 BP 2375 EP 2385 DI 10.1182/blood-2009-05-174359 PG 11 WC Hematology SC Hematology GA 495WD UT WOS:000269925000005 PM 19617573 ER PT J AU Greenberg, PL Sun, ZX Miller, KB Bennett, JM Tallman, MS Dewald, G Paietta, E van der Jagt, R Houston, J Thomas, ML Cella, D Rowe, JM AF Greenberg, Peter L. Sun, Zhuoxin Miller, Kenneth B. Bennett, John M. Tallman, Martin S. Dewald, Gordon Paietta, Elisabeth van der Jagt, Richard Houston, Jessie Thomas, Mary L. Cella, David Rowe, Jacob M. TI Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996) SO BLOOD LA English DT Article ID QUALITY-OF-LIFE; RECOMBINANT-HUMAN-ERYTHROPOIETIN; INTERNATIONAL WORKING GROUP; ACUTE MYELOID-LEUKEMIA; CELL LUNG-CANCER; DARBEPOETIN-ALPHA; DOUBLE-BLIND; G-CSF; FUNCTIONAL ASSESSMENT; RESPONSE CRITERIA AB This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels < 200 mU/mL vs > 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein(+) CD34(+) marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation. (Blood. 2009; 114: 2393-2400) C1 [Greenberg, Peter L.] Stanford Univ, Ctr Canc, Stanford, CA 94305 USA. [Sun, Zhuoxin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Miller, Kenneth B.] Tufts Univ New England Med Ctr, Boston, MA USA. [Bennett, John M.] Univ Rochester, Med Ctr, Wilmot Canc Ctr, Rochester, NY 14627 USA. [Tallman, Martin S.; Cella, David] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Dewald, Gordon; Houston, Jessie] Mayo Clin, Rochester, MN USA. [Paietta, Elisabeth] Montefiore Med Ctr, Bronx, NY 10467 USA. [van der Jagt, Richard] Ottawa Hosp, Ottawa, ON, Canada. [Houston, Jessie] Carle Clin Assoc, Urbana, IL USA. [Thomas, Mary L.] Vet Adm Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. [Rowe, Jacob M.] Technion Israel Inst Technol, Haifa, Israel. RP Greenberg, PL (reprint author), Stanford Univ, Med Ctr, Div Hematol, 875 Blake Wilbur Dr,Rm 2335, Stanford, CA 94305 USA. EM peterg@stanford.edu FU National Cancer Institute, National Institutes of Health [CA23318, CA66636, CA21115, CA80775, CA07190, CA11083, CA17145, CA13650]; Department of Health and Human Services FX Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or of the Department of Veterans Affairs. NR 50 TC 85 Z9 88 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 17 PY 2009 VL 114 IS 12 BP 2393 EP 2400 DI 10.1182/blood-2009-03-211797 PG 8 WC Hematology SC Hematology GA 495WD UT WOS:000269925000007 PM 19564636 ER PT J AU Pyne, S Gutman, R Kim, CS Futcher, B AF Pyne, Saumyadipta Gutman, Roee Kim, Chang Sik Futcher, Bruce TI Phase Coupled Meta-analysis: sensitive detection of oscillations in cell cycle gene expression, as applied to fission yeast SO BMC GENOMICS LA English DT Article ID REGULATED GENES; IDENTIFICATION; PROTEIN; MICROARRAY; ORTHOLOGS; DATABASE AB Background: Many genes oscillate in their level of expression through the cell division cycle. Previous studies have identified such genes by applying Fourier analysis to cell cycle time course experiments. Typically, such analyses generate p-values; i.e., an oscillating gene has a small p-value, and the observed oscillation is unlikely due to chance. When multiple time course experiments are integrated, p-values from the individual experiments are combined using classical meta-analysis techniques. However, this approach sacrifices information inherent in the individual experiments, because the hypothesis that a gene is regulated according to the time in the cell cycle makes two independent predictions: first, that an oscillation in expression will be observed; and second, that gene expression will always peak in the same phase of the cell cycle, such as S-phase. Approaches that simply combine p-values ignore the second prediction. Results: Here, we improve the detection of cell cycle oscillating genes by systematically taking into account the phase of peak gene expression. We design a novel meta-analysis measure based on vector addition: when a gene peaks or troughs in all experiments in the same phase of the cell cycle, the representative vectors add to produce a large final vector. Conversely, when the peaks in different experiments are in various phases of the cycle, vector addition produces a small final vector. We apply the measure to ten genome-wide cell cycle time course experiments from the fission yeast Schizosaccharomyces pombe, and detect many new, weakly oscillating genes. Conclusion: A very large fraction of all genes in S. pombe, perhaps one-quarter to one-half, show some cell cycle oscillation, although in many cases these oscillations may be incidental rather than adaptive. C1 [Pyne, Saumyadipta] MIT, Broad Inst, Cambridge, MA 02142 USA. [Pyne, Saumyadipta] Harvard Univ, Cambridge, MA 02142 USA. [Gutman, Roee] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Kim, Chang Sik] Sookmyung Womens Univ, RCWD, Dept Biol Sci, Seoul, South Korea. [Futcher, Bruce] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. RP Pyne, S (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM saumyadipta_pyne@dfci.harvard.edu; rgutman@fas.harvard.edu; cskim@kangwon.ac.kr; bfutcher@ms.cc.sunysb.edu RI Gutman, Roee/J-2355-2014 OI Gutman, Roee/0000-0001-7095-3016 FU NIH [RO1 GM 064813, RO1 GM 039978] FX We would like to thank Steven Skiena for extensive discussions, ideas, and suggestions during the early part of this work. We would like to thank Thomas Skot Jensen and Lars Juhl Jensen for useful discussions of statistical approaches, and Chris Penkett for sharing orthology data. This work was funded by NIH RO1 GM 064813 and 039978 to BF. NR 37 TC 2 Z9 2 U1 0 U2 3 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 SEP 17 PY 2009 VL 10 AR 440 DI 10.1186/1471-2164-10-440 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 501QE UT WOS:000270395600001 PM 19761608 ER PT J AU Haas, BJ Kamoun, S Zody, MC Jiang, RHY Handsaker, RE Cano, LM Grabherr, M Kodira, CD Raffaele, S Torto-Alalibo, T Bozkurt, TO Ah-Fong, AMV Alvarado, L Anderson, VL Armstrong, MR Avrova, A Baxter, L Beynon, J Boevink, PC Bollmann, SR Bos, JIB Bulone, V Cai, GH Cakir, C Carrington, JC Chawner, M Conti, L Costanzo, S Ewan, R Fahlgren, N Fischbach, MA Fugelstad, J Gilroy, EM Gnerre, S Green, PJ Grenville-Briggs, LJ Griffith, J Grunwald, NJ Horn, K Horner, NR Hu, CH Huitema, E Jeong, DH Jones, AME Jones, JDG Jones, RW Karlsson, EK Kunjeti, SG Lamour, K Liu, ZY Ma, LJ MacLean, D Chibucos, MC McDonald, H McWalters, J Meijer, HJG Morgan, W Morris, PF Munro, CA O'Neill, K Ospina-Giraldo, M Pinzon, A Pritchard, L Ramsahoye, B Ren, QH Restrepo, S Roy, S Sadanandom, A Savidor, A Schornack, S Schwartz, DC Schumann, UD Schwessinger, B Seyer, L Sharpe, T Silvar, C Song, J Studholme, DJ Sykes, S Thines, M van de Vondervoort, PJI Phuntumart, V Wawra, S Weide, R Win, J Young, C Zhou, SG Fry, W Meyers, BC van West, P Ristaino, J Govers, F Birch, PRJ Whisson, SC Judelson, HS Nusbaum, C AF Haas, Brian J. Kamoun, Sophien Zody, Michael C. Jiang, Rays H. Y. Handsaker, Robert E. Cano, Liliana M. Grabherr, Manfred Kodira, Chinnappa D. Raffaele, Sylvain Torto-Alalibo, Trudy Bozkurt, Tolga O. Ah-Fong, Audrey M. V. Alvarado, Lucia Anderson, Vicky L. Armstrong, Miles R. Avrova, Anna Baxter, Laura Beynon, Jim Boevink, Petra C. Bollmann, Stephanie R. Bos, Jorunn I. B. Bulone, Vincent Cai, Guohong Cakir, Cahid Carrington, James C. Chawner, Megan Conti, Lucio Costanzo, Stefano Ewan, Richard Fahlgren, Noah Fischbach, Michael A. Fugelstad, Johanna Gilroy, Eleanor M. Gnerre, Sante Green, Pamela J. Grenville-Briggs, Laura J. Griffith, John Gruenwald, Niklaus J. Horn, Karolyn Horner, Neil R. Hu, Chia-Hui Huitema, Edgar Jeong, Dong-Hoon Jones, Alexandra M. E. Jones, Jonathan D. G. Jones, Richard W. Karlsson, Elinor K. Kunjeti, Sridhara G. Lamour, Kurt Liu, Zhenyu Ma, LiJun MacLean, Daniel Chibucos, Marcus C. McDonald, Hayes McWalters, Jessica Meijer, Harold J. G. Morgan, William Morris, Paul F. Munro, Carol A. O'Neill, Keith Ospina-Giraldo, Manuel Pinzon, Andres Pritchard, Leighton Ramsahoye, Bernard Ren, Qinghu Restrepo, Silvia Roy, Sourav Sadanandom, Ari Savidor, Alon Schornack, Sebastian Schwartz, David C. Schumann, Ulrike D. Schwessinger, Ben Seyer, Lauren Sharpe, Ted Silvar, Cristina Song, Jing Studholme, David J. Sykes, Sean Thines, Marco van de Vondervoort, Peter J. I. Phuntumart, Vipaporn Wawra, Stephan Weide, Rob Win, Joe Young, Carolyn Zhou, Shiguo Fry, William Meyers, Blake C. van West, Pieter Ristaino, Jean Govers, Francine Birch, Paul R. J. Whisson, Stephen C. Judelson, Howard S. Nusbaum, Chad TI Genome sequence and analysis of the Irish potato famine pathogen Phytophthora infestans SO NATURE LA English DT Article ID EFFECTOR PROTEINS; RXLR EFFECTORS; CELL-DEATH; PLANT; AVIRULENCE; AVR3A; RESISTANCE; INFECTION; GENES AB Phytophthora infestans is the most destructive pathogen of potato and a model organism for the oomycetes, a distinct lineage of fungus-like eukaryotes that are related to organisms such as brown algae and diatoms. As the agent of the Irish potato famine in the mid-nineteenth century, P. infestans has had a tremendous effect on human history, resulting in famine and population displacement(1). To this day, it affects world agriculture by causing the most destructive disease of potato, the fourth largest food crop and a critical alternative to the major cereal crops for feeding the world's population(1). Current annual worldwide potato crop losses due to late blight are conservatively estimated at $6.7 billion(2). Management of this devastating pathogen is challenged by its remarkable speed of adaptation to control strategies such as genetically resistant cultivars(3,4). Here we report the sequence of the P. infestans genome, which at similar to 240 megabases (Mb) is by far the largest and most complex genome sequenced so far in the chromalveolates. Its expansion results from a proliferation of repetitive DNA accounting for similar to 74% of the genome. Comparison with two other Phytophthora genomes showed rapid turnover and extensive expansion of specific families of secreted disease effector proteins, including many genes that are induced during infection or are predicted to have activities that alter host physiology. These fast-evolving effector genes are localized to highly dynamic and expanded regions of the P. infestans genome. This probably plays a crucial part in the rapid adaptability of the pathogen to host plants and underpins its evolutionary potential. C1 [Kamoun, Sophien; Cano, Liliana M.; Raffaele, Sylvain; Bozkurt, Tolga O.; Jones, Alexandra M. E.; Jones, Jonathan D. G.; MacLean, Daniel; Schornack, Sebastian; Schwessinger, Ben; Silvar, Cristina; Studholme, David J.; Thines, Marco; Win, Joe] Sainsbury Lab, Norwich NR4 7UH, Norfolk, England. [Haas, Brian J.; Zody, Michael C.; Handsaker, Robert E.; Grabherr, Manfred; Kodira, Chinnappa D.; Alvarado, Lucia; Gnerre, Sante; Karlsson, Elinor K.; Ma, LiJun; O'Neill, Keith; Sharpe, Ted; Sykes, Sean; Nusbaum, Chad] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. [Kamoun, Sophien; Torto-Alalibo, Trudy; Bos, Jorunn I. B.; Cakir, Cahid; Huitema, Edgar; Liu, Zhenyu; Song, Jing; Young, Carolyn] Ohio State Univ, Ohio Agr Res & Dev Ctr, Dept Plant Pathol, Wooster, OH 44691 USA. [Zody, Michael C.] Uppsala Univ, Dept Med Biochem & Microbiol, SE-75124 Uppsala, Sweden. [Jiang, Rays H. Y.; Meijer, Harold J. G.; van de Vondervoort, Peter J. I.; Weide, Rob; Govers, Francine] Univ Wageningen & Res Ctr, Phytopathol Lab, NL-6708 PB Wageningen, Netherlands. [Ah-Fong, Audrey M. V.; Roy, Sourav; Judelson, Howard S.] Univ Calif Riverside, Dept Plant Pathol & Microbiol, Riverside, CA 92521 USA. [Anderson, Vicky L.; Grenville-Briggs, Laura J.; Horner, Neil R.; Schumann, Ulrike D.; Wawra, Stephan; van West, Pieter] Univ Aberdeen, Aberdeen Oomycete Lab, Coll Life Sci & Med, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Armstrong, Miles R.; Avrova, Anna; Boevink, Petra C.; Gilroy, Eleanor M.; Pritchard, Leighton; Whisson, Stephen C.] Scottish Crop Res Inst, Plant Pathol Programme, Dundee DD2 5DA, Scotland. [Baxter, Laura; Beynon, Jim] Univ Warwick, Warwick CV35 9EF, England. [Bollmann, Stephanie R.; Gruenwald, Niklaus J.] ARS, USDA, Hort Crops Res Lab, Corvallis, OR 97330 USA. [Bulone, Vincent; Fugelstad, Johanna] AlbaNova Univ Ctr, Sch Biotechnol, Royal Inst Technol KTH, SE-10691 Stockholm, Sweden. [Cai, Guohong; Fry, William] Cornell Univ, Dept Plant Pathol & Plant Microbe Biol, Ithaca, NY 14853 USA. [Carrington, James C.; Fahlgren, Noah] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Carrington, James C.; Fahlgren, Noah] Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA. [Chawner, Megan; Griffith, John; Horn, Karolyn; McWalters, Jessica; Ospina-Giraldo, Manuel; Seyer, Lauren] Lafayette Coll, Dept Biol, Easton, PA 18042 USA. [Conti, Lucio; Ewan, Richard; Sadanandom, Ari] Univ Glasgow, Plant Mol Sci Fac Biomed & Life Sci, Glasgow G12 8QQ, Lanark, Scotland. [Costanzo, Stefano] ARS, USDA, Dale Bumpers Natl Rice Res Ctr, Stuttgart, AR 72160 USA. [Fischbach, Michael A.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Green, Pamela J.; Jeong, Dong-Hoon; Meyers, Blake C.] Univ Delaware, Delaware Biotechnol Inst, Newark, DE 19711 USA. [Hu, Chia-Hui; Ristaino, Jean] N Carolina State Univ, Dept Plant Pathol, Raleigh, NC 27695 USA. [Jones, Richard W.] ARS, USDA, Beltsville, MD 20705 USA. [Kunjeti, Sridhara G.] Univ Delaware, Dept Plant & Soil Sci, Newark, DE 19716 USA. [Lamour, Kurt] Univ Tennessee, Dept Entomol & Plant Pathol, Knoxville, TN 37996 USA. [Chibucos, Marcus C.] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [McDonald, Hayes] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA. [Morgan, William] Coll Wooster, Dept Biol, Wooster, OH 44691 USA. [Morris, Paul F.; Phuntumart, Vipaporn] Bowling Green State Univ, Dept Biol Sci, Bowling Green, OH 43403 USA. [Munro, Carol A.] Univ Aberdeen, Sch Med Sci, Coll Life Sci & Med, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Pinzon, Andres; Restrepo, Silvia] Univ Los Andes, Mycol & Phytopathol Lab, Bogota, Colombia. [Ramsahoye, Bernard] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Canc Res Ctr, Edinburgh EH4 2XU, Midlothian, Scotland. [Schwartz, David C.; Zhou, Shiguo] Univ Wisconsin, Dept Chem, Genet Lab, Ctr Biotechnol,Lab Mol & Computat Genom, Madison, WI 53706 USA. [Thines, Marco] Univ Hohenheim, Inst Bot 210, D-70593 Stuttgart, Germany. [Birch, Paul R. J.] Univ Dundee, SCRI, Coll Life Sci, Div Plant Sci, Dundee DD2 5DA, Scotland. [Ren, Qinghu] J Craig Venter Inst, Rockville, MD 20850 USA. [Savidor, Alon] Tel Aviv Univ, Dept Plant Sci, IL-69978 Tel Aviv, Israel. RP Kamoun, S (reprint author), Sainsbury Lab, Norwich NR4 7UH, Norfolk, England. EM sophien.kamoun@tsl.ac.uk; chad@broad.mit.edu RI Roy, Sourav/A-5330-2013; Grenville-Briggs, Laura/B-3386-2013; MacLean, Dan/C-7046-2013; Bulone, Vincent/D-7469-2013; Zhou, Shiguo/B-3832-2011; Grunwald, Niklaus/K-6041-2013; Conti, Lucio/M-7982-2013; Cai, Guohong/N-1274-2013; Liu, Zhenyu/C-1369-2014; Grenville-Briggs, Laura/C-3419-2014; Song, Jing/F-7567-2014; Win, Joe/H-2557-2014; Liu, Zhenyu /C-9814-2012; Raffaele, Sylvain/F-7187-2012; Birch, Paul/F-7681-2012; Meijer, Harold/G-5703-2012; Kamoun, Sophien/B-3529-2009; Restrepo, Silvia/G-1297-2010; Schornack, Sebastian/A-3650-2011; Jones, Alexandra/B-5227-2009; Munro, Carol/A-5175-2011; Govers, Francine/A-5616-2009; Bos, Jorunn/E-4703-2011; Schumann, Ulrike/F-3987-2011; Huitema, Edgar/G-3760-2011; Thines, Marco/H-1685-2011; Pritchard, Leighton/A-7331-2008; Meyers, Blake/B-6535-2012; Wawra, Stephan/D-2781-2013; Cano, Liliana/O-7041-2016; Carrington, James/A-4656-2012; Fahlgren, Noah/D-4404-2011; OI Roy, Sourav/0000-0002-0359-994X; MacLean, Dan/0000-0003-1032-0887; Zhou, Shiguo/0000-0001-7421-2506; Grunwald, Niklaus/0000-0003-1656-7602; Conti, Lucio/0000-0002-7837-4227; Grenville-Briggs, Laura/0000-0001-5910-3651; Win, Joe/0000-0002-9851-2404; Studholme, David/0000-0002-3010-6637; Karlsson, Elinor/0000-0002-4343-3776; Birch, Paul/0000-0002-6559-3746; Schwessinger, Benjamin/0000-0002-7194-2922; Young, Carolyn/0000-0003-0406-8398; Restrepo, Silvia/0000-0001-9016-1040; Silvar, Cristina/0000-0002-1782-8045; Ristaino, Jean/0000-0002-9458-0514; Kamoun, Sophien/0000-0002-0290-0315; Schornack, Sebastian/0000-0002-7836-5881; Jones, Alexandra/0000-0003-2571-8708; Govers, Francine/0000-0001-5311-929X; Bos, Jorunn/0000-0003-3222-8643; Huitema, Edgar/0000-0002-5766-0830; Pritchard, Leighton/0000-0002-8392-2822; Meyers, Blake/0000-0003-3436-6097; Wawra, Stephan/0000-0001-8555-1618; Cano, Liliana/0000-0002-7996-4181; Carrington, James/0000-0003-3572-129X; Fahlgren, Noah/0000-0002-5597-4537; Munro, Carol/0000-0003-0761-1755; Ma, Li-Jun/0000-0002-2733-3708; Horner, Neil/0000-0002-0550-4537; Chibucos, Marcus/0000-0001-9586-0780 FU National Research Initiative of the USDA Cooperative State Research, Education and Extension Service [2004-35600-15024, 2006-35600-16623]; National Science Foundation [EF-0333274, EF-0523670]; Gatsby Charitable Foundation FX Acknowledgements We thank L. Gaffney for help with figures and tables, E. Blanco and R. Guigo for training the GeneID gene prediction software, J. Crabtree for providing a Sybil (http://sybil.sf.net) software component used to render genome comparison illustrations, the Broad Institute Genome Sequencing Platform for sequence data generation, and C. Cuomo and D. Neafsey for comments on the manuscript. The project was supported by the National Research Initiative of the USDA Cooperative State Research, Education and Extension Service, grant numbers 2004-35600-15024 and 2006-35600-16623, and the National Science Foundation grants EF-0333274 and EF-0523670, and the Gatsby Charitable Foundation. NR 24 TC 516 Z9 566 U1 26 U2 268 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 17 PY 2009 VL 461 IS 7262 BP 393 EP 398 DI 10.1038/nature08358 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494QB UT WOS:000269828100039 PM 19741609 ER PT J AU Frank, RG Zeckhauser, RJ AF Frank, Richard G. Zeckhauser, Richard J. TI Health Care 2009: Health Insurance Exchanges -- Making the Markets Work. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CHOICE C1 [Frank, Richard G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Zeckhauser, Richard J.] Harvard Univ, Harvard Kennedy Sch, Cambridge, MA 02138 USA. [Frank, Richard G.; Zeckhauser, Richard J.] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Frank, RG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. NR 5 TC 9 Z9 9 U1 0 U2 3 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 SEP 17 PY 2009 VL 361 IS 12 BP 1135 EP 1137 DI 10.1056/NEJMp0906246 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 494QA UT WOS:000269828000004 PM 19625711 ER PT J AU Ding, EL Song, YQ Manson, JE Hunter, DJ Lee, CC Rifai, N Buring, JE Gaziano, JM Liu, SM AF Ding, Eric L. Song, Yiqing Manson, JoAnn E. Hunter, David J. Lee, Cathy C. Rifai, Nader Buring, Julie E. Gaziano, J. Michael Liu, Simin TI Sex Hormone-Binding Globulin and Risk of Type 2 Diabetes in Women and Men. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; POSTMENOPAUSAL WOMEN; BREAST-CANCER; SHBG GENE; MENDELIAN RANDOMIZATION; REPLACEMENT THERAPY; ESTROGEN; HEALTH; CELLS; POLYMORPHISM AB Background: Circulating sex hormone-binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain. Methods: We performed a nested case-control study of postmenopausal women in the Women's Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone-binding globulin were measured; two polymorphisms of the gene encoding sex hormone-binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians' Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls). Results: Among women, higher plasma levels of sex hormone-binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone-binding globulin levels (P=0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P=0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone-binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone-binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone-binding globulin may have a causal role in the risk of type 2 diabetes. Conclusions: Low circulating levels of sex hormone-binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination. N Engl J Med 2009;361:1152-63. C1 [Lee, Cathy C.; Liu, Simin] Univ Calif Los Angeles, Sch Publ Hlth, Ctr Metab Dis Prevent, Los Angeles, CA 90095 USA. [Lee, Cathy C.; Liu, Simin] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Program Genom & Nutr, Los Angeles, CA 90095 USA. [Lee, Cathy C.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Lee, Cathy C.; Liu, Simin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Liu, Simin] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Ding, Eric L.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ding, Eric L.; Manson, JoAnn E.; Hunter, David J.; Buring, Julie E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ding, Eric L.; Song, Yiqing; Manson, JoAnn E.; Buring, Julie E.; Gaziano, J. Michael] Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA 02115 USA. [Ding, Eric L.; Manson, JoAnn E.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Dept Med, Boston, MA 02115 USA. [Rifai, Nader] Harvard Univ, Sch Med, Boston, MA USA. [Rifai, Nader] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. RP Liu, SM (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Ctr Metab Dis Prevent, CHS 73-265,Box 951772,650 Charles E Young Dr, Los Angeles, CA 90095 USA. EM siminliu@ucla.edu RI Perez , Claudio Alejandro/F-8310-2010; Liu, Simin/I-3689-2014; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Liu, Simin/0000-0003-2098-3844; Ding, Eric/0000-0002-5881-8097 FU National Institutes of Health [DK066401, HL043851, HL080467, CA047988]; Burroughs Wellcome Fund; National Cancer Institute [CA34944, CA40360, CA097193]; National Heart, Lung, and Blood Institute [HL26490, HL34595]; American Diabetes Association fellowship; Paul and Daisy Soros fellowship; National Institute of Diabetes and Digestive and Kidney Diseases [K01-DK078846] FX Supported by grants from the National Institutes of Health (DK066401, to Dr. Liu; HL043851, HL080467, and CA047988, to the Women's Health Study); the Burroughs Wellcome Fund (to Dr. Liu, for development of a metabolic disease research and training program at UCLA); the National Cancer Institute CA34944, CA40360, and CA097193, to the Physicians' Health Study II); the National Heart, Lung, and Blood Institute (HL26490 and HL34595); the American Diabetes Association fellowship (to Dr. Ding); the Paul and Daisy Soros fellowship (to Dr. Ding); and the National Institute of Diabetes and Digestive and Kidney Diseases (K01-DK078846, to Dr. Song). NR 40 TC 275 Z9 288 U1 2 U2 15 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 SEP 17 PY 2009 VL 361 IS 12 BP 1152 EP 1163 DI 10.1056/NEJMoa0804381 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 494QA UT WOS:000269828000006 PM 19657112 ER PT J AU Stone, VE Bounds, BC Muse, VV Ferry, JA AF Stone, Valerie E. Bounds, Brenna C. Muse, Victorine V. Ferry, Judith A. TI Case 29-2009: An 81-Year-Old Man with Weight Loss, Odynophagia, and Failure to Thrive Diffuse large-B-cell lymphoma, consistent with primary hepatic lymphoma, occurring in a patient with HIV infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NON-HODGKINS-LYMPHOMA; ACTIVE ANTIRETROVIRAL THERAPY; EXTRAPULMONARY TUBERCULOSIS; UNITED-STATES; PROGNOSTIC-FACTORS; PULMONARY-DISEASE; ORAL CANDIDIASIS; PATIENTS OLDER; AIDS C1 [Stone, Valerie E.; Bounds, Brenna C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Bounds, Brenna C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Muse, Victorine V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ferry, Judith A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stone, Valerie E.; Bounds, Brenna C.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Muse, Victorine V.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Ferry, Judith A.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Stone, VE (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 54 TC 2 Z9 3 U1 1 U2 3 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 SEP 17 PY 2009 VL 361 IS 12 BP 1189 EP 1198 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 494QA UT WOS:000269828000012 PM 19759382 ER PT J AU Bushel, PR Heard, NA Gutman, R Liu, LW Peddada, SD Pyne, S AF Bushel, Pierre R. Heard, Nicholas A. Gutman, Roee Liu, Liwen Peddada, Shyamal D. Pyne, Saumyadipta TI Dissecting the fission yeast regulatory network reveals phase-specific control elements of its cell cycle SO BMC SYSTEMS BIOLOGY LA English DT Article ID MESSENGER-RNA STABILITY; SCHIZOSACCHAROMYCES-POMBE; TRANSCRIPTION FACTOR; GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; RIBOSOME BIOGENESIS; DIVISION CYCLE; GENOMIC SCALE; TIME-SERIES; PROTEIN AB Background: Fission yeast Schizosaccharomyces pombe and budding yeast Saccharomyces cerevisiae are among the original model organisms in the study of the cell-division cycle. Unlike budding yeast, no large-scale regulatory network has been constructed for fission yeast. It has only been partially characterized. As a result, important regulatory cascades in budding yeast have no known or complete counterpart in fission yeast. Results: By integrating genome-wide data from multiple time course cell cycle microarray experiments we reconstructed a gene regulatory network. Based on the network, we discovered in addition to previously known regulatory hubs in M phase, a new putative regulatory hub in the form of the HMG box transcription factor SPBC19G7.04. Further, we inferred periodic activities of several less known transcription factors over the course of the cell cycle, identified over 500 putative regulatory targets and detected many new phase-specific and conserved cis-regulatory motifs. In particular, we show that SPBC19G7.04 has highly significant periodic activity that peaks in early M phase, which is coordinated with the late G2 activity of the forkhead transcription factor fkh2. Finally, using an enhanced Bayesian algorithm to co-cluster the expression data, we obtained 31 clusters of co-regulated genes 1) which constitute regulatory modules from different phases of the cell cycle, 2) whose phase order is coherent across the 10 time course experiments, and 3) which lead to identification of phase-specific control elements at both the transcriptional and post-transcriptional levels in S. pombe. In particular, the ribosome biogenesis clusters expressed in G2 phase reveal new, highly conserved RNA motifs. Conclusion: Using a systems-level analysis of the phase-specific nature of the S. pombe cell cycle gene regulation, we have provided new testable evidence for post-transcriptional regulation in the G2 phase of the fission yeast cell cycle. Based on this comprehensive gene regulatory network, we demonstrated how one can generate and investigate plausible hypotheses on fission yeast cell cycle regulation which can potentially be explored experimentally. C1 [Bushel, Pierre R.; Liu, Liwen; Peddada, Shyamal D.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Heard, Nicholas A.] Univ London Imperial Coll Sci Technol & Med, Dept Math, London, England. [Gutman, Roee] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Pyne, Saumyadipta] Harvard Univ, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Pyne, Saumyadipta] MIT, Broad Inst, Cambridge, MA 02142 USA. [Bushel, Pierre R.] Harvard Univ, Sch Publ Hlth, Dept Stat, Boston, MA 02115 USA. [Bushel, Pierre R.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Pyne, Saumyadipta] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Bushel, PR (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. EM bushel@niehs.nih.gov; n.heard@imperial.ac.uk; rgutman@fas.harvard.edu; liuliw@niehs.nih.gov; peddada@niehs.nih.gov; Saumyadipta_Pyne@DFCI.HARVARD.EDU RI Peddada, Shyamal/D-1278-2012; Gutman, Roee/J-2355-2014 OI Gutman, Roee/0000-0001-7095-3016 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04] FX Research of PRB, LL and SDP was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES101744-04]. We thank Jonathan H. Freedman and Reuben Thomas for their review of the manuscript. SP thanks Aviv Regev and Ana Paula Leite for programs on module network analysis. We also dearly thank James C. Liao for his personal communication regarding NCA. NR 65 TC 10 Z9 10 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD SEP 16 PY 2009 VL 3 AR 93 DI 10.1186/1752-0509-3-93 PG 21 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 506EE UT WOS:000270755700001 PM 19758441 ER PT J AU Lu-Yao, GL Albertsen, PC Moore, DF Shih, WC Lin, Y DiPaola, RS Barry, MJ Zietman, A O'Leary, M Walker-Corkery, E Yao, SL AF Lu-Yao, Grace L. Albertsen, Peter C. Moore, Dirk F. Shih, Weichung Lin, Yong DiPaola, Robert S. Barry, Michael J. Zietman, Anthony O'Leary, Michael Walker-Corkery, Elizabeth Yao, Siu-Long TI Outcomes of Localized Prostate Cancer Following Conservative Management SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RESEARCH ENDEAVOR CAPSURE; ACTIVE SURVEILLANCE; RADICAL PROSTATECTOMY; ANDROGEN-DEPRIVATION; CURATIVE INTENT; SURVIVAL; MEN; TRENDS; RISK; INTERVENTION AB Context Most newly diagnosed prostate cancers are clinically localized, and major treatment options include surgery, radiation, or conservative management. Although conservative management can be a reasonable choice, there is little contemporary prostate-specific antigen (PSA)-era data on outcomes with this approach. Objective To evaluate the outcomes of clinically localized prostate cancer managed without initial attempted curative therapy in the PSA era. Design, Setting, and Participants A population-based cohort study of men aged 65 years or older when they were diagnosed (1992-2002) with stage T1 or T2 prostate cancer and whose cases were managed without surgery or radiation for 6 months after diagnosis. Living in areas covered by the Surveillance, Epidemiology, and End Results (SEER) program, the men were followed up for a median of 8.3 years (through December 31, 2007). Competing risk analyses were performed to assess outcomes. Main Outcome Measures Ten-year overall survival, cancer-specific survival, and major cancer related interventions. Results Among men who were a median age of 78 years at cancer diagnosis, 10-year prostate cancer-specific mortality was 8.3%(95% confidence interval [CI], 4.2%-12.8%) formen with well-differentiated tumors; 9.1%(95% CI, 8.3%-10.1%) for those with moderately differentiated tumors, and 25.6% (95% CI, 23.7%-28.3%) for those with poorly differentiated tumors. The corresponding 10-year risks of dying of competing causes were 59.8%(95% CI, 53.2%-67.8%), 57.2%(95% CI, 52.6%-63.9%), and 56.5%(95% CI, 53.6%-58.8%), respectively. Ten-year disease-specific mortality for men aged 66 to 74 years diagnosed with moderately differentiated disease was 60% to 74% lower than earlier studies: 6%(95% CI, 4%-8%) in the contemporary PSA era (1992-2002) compared with results of previous studies(15%-23%) in earlier eras (1949-1992). Improved survival was also observed in poorly differentiated disease. The use of chemotherapy (1.6%) or major interventions for spinal cord compression (0.9%) was uncommon. Conclusions Results following conservative management of clinically localized prostate cancer diagnosed from 1992 through 2002 are better than outcomes among patients diagnosed in the 1970s and 1980s. This may be due, in part, to additional lead time, overdiagnosis related to PSA testing, grade migration, or advances in medical care. JAMA. 2009; 302(11): 1202-1209 C1 [Lu-Yao, Grace L.; Moore, Dirk F.; Shih, Weichung; Lin, Yong; DiPaola, Robert S.; Yao, Siu-Long] Univ Med & Dent New Jersey, Canc Inst New Jersey, Piscataway, NJ 08854 USA. [Lu-Yao, Grace L.; DiPaola, Robert S.; Yao, Siu-Long] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, Piscataway, NJ 08854 USA. [Moore, Dirk F.; Shih, Weichung; Lin, Yong] Univ Med & Dent New Jersey, Sch Publ Hlth, Dept Biostat, Piscataway, NJ 08854 USA. [Albertsen, Peter C.] Univ Connecticut, Dept Surg Oncol, Farmington, CT USA. [Lu-Yao, Grace L.; DiPaola, Robert S.] Massachusetts Gen Hosp, Dean & Betty Gallo Prostate Canc Ctr, Boston, MA 02114 USA. [Barry, Michael J.; Walker-Corkery, Elizabeth] Massachusetts Gen Hosp, Med Practices Evaluat Ctr, Boston, MA 02114 USA. [Zietman, Anthony] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [O'Leary, Michael] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Yao, Siu-Long] Schering Plough Res Inst, Kenilworth, NJ USA. RP Lu-Yao, GL (reprint author), 195 Little Albany St,Room 5534, New Brunswick, NJ USA. EM luyaogr@umdnj.edu FU US Army Medical Research Acquisition Activity, Fort Detrick, MD [DAMD17-01-10755]; Department of Defense award [W81XWG-05-1-0235]; Ohl Foundation [R01 CA116399]; National Cancer Institute [CA-72720-10] FX Funding/Support: The study was supported by the following grants and awards: award DAMD17-01-10755 from the US Army Medical Research Acquisition Activity, Fort Detrick, MD, Department of Defense award W81XWG-05-1-0235, Ohl Foundation, and grants R01 CA116399 and CINJ core grant CA-72720-10 from the National Cancer Institute. NR 40 TC 225 Z9 233 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 16 PY 2009 VL 302 IS 11 BP 1202 EP 1209 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 494FR UT WOS:000269797600030 PM 19755699 ER PT J AU Covington, HE Maze, I LaPlant, QC Vialou, VF Ohnishi, YN Berton, O Fass, DM Renthal, W Rush, AJ Wu, EY Ghose, S Krishnan, V Russo, SJ Tamminga, C Haggarty, SJ Nestler, EJ AF Covington, Herbert E., III Maze, Ian LaPlant, Quincey C. Vialou, Vincent F. Ohnishi, Yoshinori N. Berton, Olivier Fass, Dan M. Renthal, William Rush, Augustus J., III Wu, Emma Y. Ghose, Subroto Krishnan, Vaishnav Russo, Scott J. Tamminga, Carol Haggarty, Stephen J. Nestler, Eric J. TI Antidepressant Actions of Histone Deacetylase Inhibitors SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GENE-EXPRESSION; SYNAPTIC PLASTICITY; INDUCED ANHEDONIA; SOCIAL DEFEAT; DEPRESSION; STRESS; DOPAMINE; MOUSE; FAMILY; MODEL AB Persistent symptoms of depression suggest the involvement of stable molecular adaptations in brain, which may be reflected at the level of chromatin remodeling. We find that chronic social defeat stress in mice causes a transient decrease, followed by a persistent increase, in levels of acetylated histone H3 in the nucleus accumbens, an important limbic brain region. This persistent increase in H3 acetylation is associated with decreased levels of histone deacetylase 2 (HDAC2) in the nucleus accumbens. Similar effects were observed in the nucleus accumbens of depressed humans studied postmortem. These changes in H3 acetylation and HDAC2 expression mediate long-lasting positive neuronal adaptations, since infusion of HDAC inhibitors into the nucleus accumbens, which increases histone acetylation, exerts robust antidepressant-like effects in the social defeat paradigm and other behavioral assays. HDAC inhibitor [N-(2-aminophenyl)-4-[N-( pyridine-3-ylmethoxy-carbonyl) aminomethyl] benzamide (MS-275)] infusion also reverses the effects of chronic defeat stress on global patterns of gene expression in the nucleus accumbens, as determined by microarray analysis, with striking similarities to the effects of the standard antidepressant fluoxetine. Stress-regulated genes whose expression is normalized selectively by MS-275 may provide promising targets for the future development of novel antidepressant treatments. Together, these findings provide new insight into the underlying molecular mechanisms of depression and antidepressant action, and support the antidepressant potential of HDAC inhibitors and perhaps other agents that act at the level of chromatin structure. C1 [Covington, Herbert E., III; Maze, Ian; LaPlant, Quincey C.; Vialou, Vincent F.; Ohnishi, Yoshinori N.; Russo, Scott J.; Nestler, Eric J.] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY 10029 USA. [Berton, Olivier] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Fass, Dan M.; Haggarty, Stephen J.] MIT, Boston, MA 02142 USA. [Fass, Dan M.; Haggarty, Stephen J.] Broad Inst Harvard, Stanley Ctr Psychiat Res, Boston, MA 02142 USA. [Renthal, William; Rush, Augustus J., III; Wu, Emma Y.; Ghose, Subroto; Krishnan, Vaishnav; Tamminga, Carol; Nestler, Eric J.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Nestler, EJ (reprint author), Mt Sinai Sch Med, Fishberg Dept Neurosci, 1 Gustave L Levy Pl,Box 1065, New York, NY 10029 USA. EM eric.nestler@mssm.edu RI vialou, vincent/F-2968-2013; Ghose, Subroto/J-6732-2016; OI vialou, vincent/0000-0002-8212-751X; Maze, Ian/0000-0003-1490-7781; Dowd, Emma Wu/0000-0003-0219-8527; Krishnan, Vaishnav/0000-0002-2847-0069; Rush, Augustus/0000-0003-2004-2382; Haggarty, Stephen J./0000-0002-7872-168X FU National Institute of Mental Health; AstraZeneca FX This work was supported by grants from the National Institute of Mental Health and a research alliance with AstraZeneca. NR 55 TC 265 Z9 272 U1 4 U2 18 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 SEP 16 PY 2009 VL 29 IS 37 BP 11451 EP 11460 DI 10.1523/JNEUROSCI.1758-09.2009 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 494RW UT WOS:000269834100007 PM 19759294 ER PT J AU Ernst, MB Wunderlich, CM Hess, S Paehler, M Mesaros, A Koralov, SB Kleinridders, A Husch, A Munzberg, H Hampel, B Alber, J Kloppenburg, P Bruning, JC Wunderlich, FT AF Ernst, Marianne B. Wunderlich, Claudia M. Hess, Simon Paehler, Moritz Mesaros, Andrea Koralov, Sergei B. Kleinridders, Andre Husch, Andreas Muenzberg, Heike Hampel, Brigitte Alber, Jens Kloppenburg, Peter Bruening, Jens C. Wunderlich, F. Thomas TI Enhanced Stat3 Activation in POMC Neurons Provokes Negative Feedback Inhibition of Leptin and Insulin Signaling in Obesity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DIET-INDUCED OBESITY; GLUCOSE-HOMEOSTASIS; ARCUATE NUCLEUS; AGRP NEURONS; BODY-WEIGHT; CYTOKINE SIGNALING-3; ENERGY HOMEOSTASIS; EXPRESSING NEURONS; MICE; RECEPTOR AB Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in maintenance of energy homeostasis. While Stat3 activation in POMC neurons is required for POMC expression, the role of elevated basal Stat3 activation as present in the development of obesity has not been directly addressed. Here, we have generated and characterized mice expressing a constitutively active version of Stat3 (Stat3-C) in POMC neurons (Stat3-C-POMC mice). On normal chow diet, these animals develop obesity as a result of hyperphagia and decreased POMC expression accompanied by central leptin and insulin resistance. This unexpected finding coincides with POMC-cell-specific, Stat3-mediated upregulation of SOCS3 expression inhibiting both leptin and insulin signaling as insulin-stimulated PIP3 (phosphatidylinositol-3,4,5 triphosphate) formation and protein kinase B (AKT) activation in POMC neurons as well as with the fact that insulin's ability to hyperpolarize POMC neurons is largely reduced in POMC cells of Stat3-C-POMC mice. These data indicate that constitutive Stat3 activation is not sufficient to promote POMC expression but requires simultaneous PI3K (phosphoinositide 3-kinase)-dependent release of FOXO1 repression. In contrast, upon exposure to a high-fat diet, food intake and body weight were unaltered in Stat3-C-POMC mice compared with control mice. Taken together, these experiments directly demonstrate that enhanced basal Stat3 activation in POMC neurons as present in control mice upon high-fat feeding contributes to the development of hypothalamic leptin and insulin resistance. C1 [Ernst, Marianne B.; Wunderlich, Claudia M.; Mesaros, Andrea; Kleinridders, Andre; Hampel, Brigitte; Alber, Jens; Bruening, Jens C.; Wunderlich, F. Thomas] Univ Cologne, Inst Genet, Cologne Excellence Cluster Cellular Stress Respon, Ctr Mol Med Cologne, D-50674 Cologne, Germany. [Bruening, Jens C.] Univ Hosp Cologne, Dept Internal Med 2, D-50674 Cologne, Germany. [Hess, Simon; Paehler, Moritz; Husch, Andreas; Kloppenburg, Peter] Univ Cologne, CECAD, Inst Zool & Physiol, D-50674 Cologne, Germany. [Koralov, Sergei B.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Muenzberg, Heike] Louisiana State Univ Syst, Pennington Biomed Res Inst, Baton Rouge, LA 70808 USA. [Bruening, Jens C.] Max Planck Inst Biol Ageing, D-50931 Cologne, Germany. RP Bruning, JC (reprint author), Univ Cologne, Inst Genet, Cologne Excellence Cluster Cellular Stress Respon, Ctr Mol Med Cologne, Zulpicher Str 47, D-50674 Cologne, Germany. EM jens.bruening@uni-koeln.de; Thomas.Wunderlich@uni-koeln.de FU Zentrum fur Molekulare Medizin der Universitat zu Koln; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases; Deutsche Forschungsgemeinschaft [1492-7] FX This work was supported by grants from Zentrum fur Molekulare Medizin der Universitat zu Koln ( to J. C. B.), the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases ( to F. T. W. and J. C. B.), and the Deutsche Forschungsgemeinschaft (1492-7) ( to J. C. B.). We thank Gisela Schmall and Tanja Rayle for excellent secretarial assistance. We thank Klaus Rajewsky and Tomoo Okamura for experimental assistance and discussions. NR 59 TC 64 Z9 65 U1 0 U2 11 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 SEP 16 PY 2009 VL 29 IS 37 BP 11582 EP 11593 DI 10.1523/JNEUROSCI.5712-08.2009 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 494RW UT WOS:000269834100018 PM 19759305 ER PT J AU Kozell, LB Walter, NAR Milner, LC Wickman, K Buck, KJ AF Kozell, Laura B. Walter, Nicole A. R. Milner, Lauren C. Wickman, Kevin Buck, Kari J. TI Mapping a Barbiturate Withdrawal Locus to a 0.44 Mb Interval and Analysis of a Novel Null Mutant Identify a Role for Kcnj9 (GIRK3) in Withdrawal from Pentobarbital, Zolpidem, and Ethanol SO JOURNAL OF NEUROSCIENCE LA English DT Review ID QUANTITATIVE TRAIT LOCI; CENTRAL-NERVOUS-SYSTEM; CONDITIONED TASTE-AVERSION; GATED POTASSIUM CHANNELS; RECOMBINANT INBRED MICE; VENTRAL TEGMENTAL AREA; RECTIFYING K+ CHANNELS; ALCOHOL-WITHDRAWAL; SEIZURE SUSCEPTIBILITY; DENDRITE ARBORIZATION AB Here, we map a quantitative trait locus (QTL) with a large effect on predisposition to barbiturate (pentobarbital) withdrawal to a 0.44 Mb interval of mouse chromosome 1 syntenic with human 1q23.2. We report a detailed analysis of the genes within this interval and show that it contains 15 known and predicted genes, 12 of which demonstrate validated genotype-dependent transcript expression and/or nonsynonymous coding sequence variation that may underlie the influence of the QTL on withdrawal. These candidates are involved in diverse cellular functions including intracellular trafficking, potassium conductance and spatial buffering, and multimolecular complex dynamics, and indicate both established and novel aspects of neurobiological response to sedative-hypnotics. This work represents a substantial advancement toward identification of the gene(s) that underlie the phenotypic effects of the QTL. We identify Kcnj9 as a particularly promising candidate and report the development of a Kcnj9-null mutant model that exhibits significantly less severe withdrawal from pentobarbital as well as other sedative-hypnotics (zolpidem and ethanol) versus wild-type littermates. Reduced expression of Kcnj9, which encodes GIRK3 (Kir3.3), is associated with less severe sedative-hypnotic withdrawal. A multitude of QTLs for a variety of complex traits, including diverse responses to sedative-hypnotics, have been detected on distal chromosome 1 in mice, and as many as four QTLs on human chromosome 1q have been implicated in human studies of alcohol dependence. Thus, our results will be primary to additional efforts to identify genes involved in a wide variety of behavioral responses to sedative-hypnotics and may directly facilitate progress in human genetics. C1 [Kozell, Laura B.; Walter, Nicole A. R.; Milner, Lauren C.; Buck, Kari J.] Vet Affairs Med Ctr, Dept Behav Neurosci, Portland, OR 97239 USA. [Kozell, Laura B.; Walter, Nicole A. R.; Milner, Lauren C.; Buck, Kari J.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Wickman, Kevin] Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA. RP Buck, KJ (reprint author), Portland VA Med Ctr, Mail Code R&D40,3710 Vet Hosp Rd, Portland, OR 97239 USA. EM buckk@ohsu.edu OI Wickman, Kevin/0000-0002-5179-9540; Kozell, Laura/0000-0003-3059-2046 FU Public Health Service [DA05228, AA011114, DA011806, AA01731, AA10760, MH61933] FX This work was supported by Public Health Service Grants DA05228, AA011114, DA011806, AA01731, AA10760, and MH61933, and a Veterans Affairs Merit Award. We gratefully acknowledge Drs. Aimee Mayeda and John Hofstetter for providing some breeder stock; Drs. John Belknap, John Crabbe, and Pamela Metten for helpful discussions on this project; and Gregory Auger for his technical assistance. NR 103 TC 31 Z9 31 U1 1 U2 1 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 SEP 16 PY 2009 VL 29 IS 37 BP 11662 EP 11673 DI 10.1523/JNEUROSCI.1413-09.2009 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 494RW UT WOS:000269834100026 PM 19759313 ER PT J AU Dries, AM Richardson, P Cavazos, J Abraham, NS AF Dries, A. M. Richardson, P. Cavazos, J. Abraham, N. S. TI Therapeutic intent of proton pump inhibitor prescription among elderly nonsteroidal anti-inflammatory drug users SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID GASTROESOPHAGEAL-REFLUX DISEASE; BLEEDING PEPTIC-ULCERS; HELICOBACTER-PYLORI; RANDOMIZED-TRIAL; APPROPRIATE USE; PRIMARY-CARE; RISK-FACTORS; HEALTH-CARE; OMEPRAZOLE; GUIDELINES AB P>Background Prescription of proton pump inhibitors (PPIs) has increased dramatically. Aim To assess therapeutic intent of PPI prescription among elderly veterans prescribed nonsteroidal anti-inflammatory drugs. Methods Medical-record abstraction identified therapeutic intent of PPI prescription. An 'appropriate therapeutic intent' was defined as symptomatic gastro-oesophageal reflux disease or endoscopic oesophagitis, Zollinger-Ellison disease, dyspepsia, upper gastrointestinal event, Helicobacter pylori infection or nonsteroidal anti-inflammatory drug gastroprotection. Logistic regression predicted the outcome while adjusting for clinical characteristics. Results Of 1491 patients [mean 73 years (s.d. 5.6), 73% white and 99.8% men], among those charts which did document a therapeutic indication, 88.8% were appropriate. Prior gastroscopy was predictive of an appropriate therapeutic intent (OR 2.7; 95% CI: 1.9-3.7). Prescription to patients who used VA pharmacy services only, to in-patients, or by a cardiologist or an otolaryngologist were less likely to be appropriate. Gastroprotection was poorly recognized as an indication for PPI prescription, except by rheumatologists (OR 46.7; 95% CI: 15.9-136.9), or among highly co-morbid patients (OR 1.8; 95% CI: 1.1-2.9). Among in-patients, 45% of PPI prescriptions were initiated for unknown or inappropriate reasons. Conclusions Type of provider predicts appropriate PPI use. In-patient prescription is associated with poor recognition of necessary gastroprotection and unknown therapeutic intent. C1 [Richardson, P.; Cavazos, J.; Abraham, N. S.] Michael E DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Geriatr GI Outcomes Res Unit, Houston, TX 77030 USA. [Dries, A. M.] Baylor Coll Med, Dept Med, Div Gastroenterol, Houston, TX 77030 USA. RP Abraham, NS (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Geriatr GI Outcomes Res Unit, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM nabraham@bcm.edu FU American Gastroenterological Association (AGA) Foundation-Sucampo-ASP Geriatrics Research Career Development Award; Department of Veterans Affairs [IIR 115-05] FX Declaration of personal interests: Dr Abraham is the guarantor of the paper. Each author's contribution to the paper: Dr Abraham conceived, designed and conducted the study; acquired necessary funding; interpreted the data; assisted in preparation of the manuscript and had final approval of this research. Dr Dries performed chart abstraction, participated in data analysis and participated in preparation of the manuscript. Dr Cavazos participated in preparation of the manuscript. Dr Richardson participated in data analysis, interpretation and preparation of the manuscript. This material is the result of work supported with resources and the use of facilities at Houston VA HSR&D Center of Excellence (HFP90-020). The views expressed in this study are those of the authors and do not necessarily reflect those of the Department of Veterans Affairs (Baylor College of Medicine). Declaration of Funding interests: Dr Abraham is supported by the American Gastroenterological Association (AGA) Foundation-Sucampo-ASP Geriatrics Research Career Development Award, and a Merit Review Award from the Department of Veterans Affairs (VA) (IIR 115-05). None of the funding agencies played a role in the design and conduct of the study, analysis and interpretation of the data, or preparation and approval of the manuscript. This material is based upon the work supported (wholly or in part) by the Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. NR 49 TC 9 Z9 9 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD SEP 15 PY 2009 VL 30 IS 6 BP 652 EP 661 DI 10.1111/j.1365-2036.2009.04085.x PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 484YG UT WOS:000269086100013 PM 19573167 ER PT J AU Thakkar, K Chen, L Tatevian, N Shulman, RJ McDuffie, A Tsou, M Gilger, MA El-Serag, HB AF Thakkar, K. Chen, L. Tatevian, N. Shulman, R. J. McDuffie, A. Tsou, M. Gilger, M. A. El-Serag, H. B. TI Diagnostic yield of oesophagogastroduodenoscopy in children with abdominal pain SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID FUNCTIONAL GASTROINTESTINAL DISORDERS; IRRITABLE-BOWEL-SYNDROME; EOSINOPHILIC ESOPHAGITIS; HELICOBACTER-PYLORI; PEDIATRIC-GASTROENTEROLOGY; GASTROESOPHAGEAL REFLUX; DYSPEPSIA; NUTRITION; SYMPTOMS; RECOMMENDATIONS AB P>Background Abdominal pain is the most common indication for oesophagogastroduodenoscopy (OGD) in children. However, existing studies examining the diagnostic outcomes of OGD in children with abdominal pain are limited. Aim To examine the diagnostic yield of OGD with biopsy in the evaluation of abdominal pain and to describe the endoscopic and histological findings in patients undergoing OGD for abdominal pain of unclear aetiology. Methods We performed a retrospective cross-sectional cohort study in children under 18 years of age who had OGD for the primary indication of abdominal pain, at Texas Children's Hospital and Children's Hospital of The King's Daughters from 1 January 2002 to 30 June 2005. Results Overall, OGD was diagnostic in 454 (38.1%) of the 1191 procedures, including reflux oesophagitis (23%, n = 271), Helicobacter pylori infections (5%, n = 55), peptic ulcers (3%, n = 32), eosinophilic oesophagitis (2%, n = 25), celiac disease (1%, n = 9) and Crohn's disease (0.5%, n = 7). Male gender, older age, elevated C-reactive protein and vomiting were associated with increased diagnostic yield. Conclusions Our findings suggest that OGD is valuable for the evaluation of chronic abdominal pain in children, with a diagnostic yield of 38%. The majority of alarm symptoms and routine laboratory tests are not significantly associated with diagnostic yield. C1 [Thakkar, K.; Chen, L.; Tatevian, N.; Shulman, R. J.; Gilger, M. A.] Baylor Coll Med, Sect Pediat Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. [McDuffie, A.; Tsou, M.] Childrens Hosp Kings Daughters, Sect Pediat Gastroenterol, Norfolk, VA USA. [El-Serag, H. B.] Michael E Debakey Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX USA. [El-Serag, H. B.] Michael E Debakey Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX USA. [El-Serag, H. B.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Thakkar, K (reprint author), Baylor Coll Med, Sect Pediat Gastroenterol Hepatol & Nutr, 6621 Fannin St CCC 1010, Houston, TX 77030 USA. EM kthakkar@bcm.tmc.edu FU TAP Pharmaceutical Products, Inc. FX No conflicts of interest exist. We thank Renu Ouseph, MD, Nicole Baranowski and Rebbecca Olsak, MD, for assistance with data collection; and Maria Aguiar, MD, for review of biopsy reports. Declaration of funding interests: This study was funded in full by TAP Pharmaceutical Products, Inc., as an investigator-initiated research project. The funding source (TAP) had no role in the study design, data collection, analysis or interpretation of the data for this manuscript. NR 40 TC 14 Z9 14 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD SEP 15 PY 2009 VL 30 IS 6 BP 662 EP 669 DI 10.1111/j.1365-2036.2009.04084.x PG 8 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 484YG UT WOS:000269086100014 PM 19573168 ER PT J AU Revicki, DA Camilleri, M Kuo, B Norton, NJ Murray, L Palsgrove, A Parkman, HP AF Revicki, D. A. Camilleri, M. Kuo, B. Norton, N. J. Murray, L. Palsgrove, A. Parkman, H. P. TI Development and content validity of a gastroparesis cardinal symptom index daily diary SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID GASTRIC-EMPTYING SCINTIGRAPHY; PATIENT-REPORTED OUTCOMES; BOTULINUM-TOXIN; CLINICAL-TRIAL; SEVERITY; PAIN; STIMULATION; ASSOCIATION; VALIDATION; DIAGNOSIS AB P>Background The Gastroparesis Cardinal Symptom Index (GCSI) is a patient-reported outcome for gastroparesis using a two-week recall period. To minimize potential patient recall effects, a daily diary version of the GCSI (GCSI-DD) was developed. Aims To evaluate the content validity of GCSI-DD for the symptoms in patients with documented gastroparesis, to capture symptom variability over time and to compare responses of this GCSI-DD to the original GCSI. Methods In gastroparesis adults with delayed gastric emptying, cognitive debriefing interviews were conducted to elicit their perspective on relevant symptoms of gastroparesis and relevant recall periods and to evaluate patient understanding of GCSI-DD. Patients completed the GCSI-DD daily over a 2-week period and completed the GCSI at baseline and the 2-week follow-up visit. Results Twelve gastroparesis patients, of whom five were diabetic and nine women, reported nausea (100%), vomiting (100%), stomach fullness (75%), bloating (58%) and loss of appetite (50%) were important symptoms. All patients understood diary instructions and item content and reported that the diary captured their gastroparesis symptom experience; 83% considered response scales adequate. There was significant daily variability in GCSI-DD scores. Mean GCSI-DD subscale and total scores over 2 weeks correlated strongly (all r > 0.90) with GCSI scores at 2-week follow-up. Conclusions The GCSI-DD includes symptoms relevant to patients with gastroparesis, captures daily variability of those symptoms and has psychometric properties consistent with a good patient-reported outcome endpoint for gastroparesis clinical trials. C1 [Revicki, D. A.; Murray, L.; Palsgrove, A.] United BioSource Corp, Ctr Hlth Outcomes Res, Bethesda, MD USA. [Camilleri, M.] Mayo Clin, Ctr Program, Rochester, MN USA. [Kuo, B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Gastroenterol, Boston, MA USA. [Norton, N. J.] Int Fdn Funct Gastrointestinal Disorders, Milwaukee, WI USA. [Parkman, H. P.] Temple Univ, Sch Med, Dept Med, Philadelphia, PA 19122 USA. RP Parkman, HP (reprint author), Temple Univ Hosp & Med Sch, Dept Med, Gastroenterol Sect, 3401 N Broad St, Philadelphia, PA 19140 USA. FU American Neurogastroenterology and Motility Society; Evoke; GSK; Movetis; SmartPill; Salix FX Declaration of personal interests: Dennis Revicki has served as a speaker, a consultant and an advisory board member for Evoke Pharma and has received research funding from Evoke Pharma. Michael Camilleri has served as a consultant for Albireo Pharma, SK Bio-Pharmaceuticals, Takeda, Theravance, ARYx Therapeutics, SmartPill. Michael Camilleri has research grants from Wyeth Research and Tsumura. Braden Kuo, MD has served as a consultant and is on the Advisory Board for SmartPill and Evoke. Braden Kuo is a speaker for Takeda Pharmaceuticals. Nancy Norton has served as an advisory board member for Takeda Pharmaceuticals North America, Degge Group, Inc and Salix Pharmaceuticals, Inc. Henry Parkman serves on advisory board for SmartPill and has consulted with Evoke, Theravance, ARYx Pharmaceuticals. Henry Parkman has research grants from SmartPill, Medtronic. Declaration of funding interests: This study was funded in part by the American Neurogastroenterology and Motility Society with help from Evoke, GSK, Movetis, SmartPill, and Salix. NR 22 TC 39 Z9 39 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD SEP 15 PY 2009 VL 30 IS 6 BP 670 EP 680 DI 10.1111/j.1365-2036.2009.04078.x PG 11 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 484YG UT WOS:000269086100015 PM 19558608 ER PT J AU Thurston, RC Sowers, MR Sternfeld, B Gold, EB Bromberger, J Chang, YF Joffe, H Crandall, CJ Waetjen, LE Matthews, KA AF Thurston, Rebecca C. Sowers, MaryFran R. Sternfeld, Barbara Gold, Ellen B. Bromberger, Joyce Chang, Yuefang Joffe, Hadine Crandall, Carolyn J. Waetjen, L. Elaine Matthews, Karen A. TI Gains in Body Fat and Vasomotor Symptom Reporting Over the Menopausal Transition SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adipose tissue; adiposity; body composition; body fat distribution; climacteric; hot flashes; menopause ID HOT FLASHES; MIDLIFE WOMEN; RISK-FACTORS; REPRODUCTIVE HORMONES; POSTMENOPAUSAL WOMEN; HEALTH; MASS; ASSOCIATION; ETHNICITY; ESTRADIOL AB Although most women report vasomotor symptoms (hot flashes, night sweats) during midlife, their etiology and risk factors are incompletely understood. Body fat is positively associated with vasomotor symptoms cross-sectionally, but the longitudinal relation between changes in body fat and vasomotor symptoms is uncharacterized. The study aim was to examine whether gains in body fat were related to vasomotor symptom reporting over time. Measures of bioelectrical impedance for body fat, reproductive hormones, and reported vasomotor symptoms were assessed annually over 4 years from 2002 to 2006 among 1,659 women aged 47-59 years participating in the Study of Women's Health Across the Nation. Body fat change was examined in relation to vasomotor symptoms by using generalized estimating equations. Body fat gains were associated with greater odds of reporting hot flashes in models adjusted for age, site, race/ethnicity, education, smoking, parity, anxiety, and menopausal status (relative to stable body fat, gain: odds ratio = 1.23, 95% confidence interval: 1.02, 1.48; P = 0.03; loss: odds ratio = 1.07, 95% confidence interval: 0.89, 1.29; P = 0.45). Findings persisted controlling for estradiol, the free estradiol index, or follicle-stimulating hormone concentrations. The relations between body fat changes and night sweats were not statistically significant. Body fat gains are associated with greater hot flash reporting during the menopausal transition. C1 [Thurston, Rebecca C.; Matthews, Karen A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Thurston, Rebecca C.; Bromberger, Joyce; Matthews, Karen A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Sowers, MaryFran R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Sternfeld, Barbara] Kaiser Permanente, Div Res, Oakland, CA USA. [Gold, Ellen B.] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Chang, Yuefang] Univ Pittsburgh, Sch Med, Dept Neurosurg, Pittsburgh, PA 15213 USA. [Joffe, Hadine] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Crandall, Carolyn J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Waetjen, L. Elaine] Univ Calif Davis, Dept Obstet & Gynecol, Davis, CA 95616 USA. RP Thurston, RC (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. EM thurstonrc@upmc.edu FU Pfizer/Society for the Advancement of Women's Health Research Scholars Award; Abbott Laboratories; Astra-Zeneca Pharmaceuticals; Bayer HealthCare Pharmaceuticals; Eli Lilly and Company; Forest Laboratries, Inc.; GlaxoSmithKline; Pfizer, Inc.; Janssen Pharmaceutical, Organon Biosciences; Sanofi-Aventis; Sepracor, Inc.; Wyeth-Ayerst Pharmaceuticals FX Conflict of interest statement: Dr. Joffe has received research support from Pfizer/Society for the Advancement of Women's Health Research Scholars Award, Abbott Laboratories, Astra-Zeneca Pharmaceuticals, Bayer HealthCare Pharmaceuticals, Eli Lilly and Company, Forest Laboratries, Inc., GlaxoSmithKline, Pfizer, Inc., Janssen Pharmaceutical, Organon Biosciences, Sanofi-Aventis (product support only), Sepracor, Inc., and Wyeth-Ayerst Pharmaceuticals. She has received speaking/honoraria from Eli Lilly and Company and GlaxoSmithKline and served as an advisor/consultant to Abbott Laboratories, Eli Lilly and Company, JDS-Noven Pharmaceuticals, Sanofi-Aventis, Sepracor, Inc., and Wyeth-Ayerst Pharmaceuticals. No other authors have any conflicts to report. NR 42 TC 50 Z9 50 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2009 VL 170 IS 6 BP 766 EP 774 DI 10.1093/aje/kwp203 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 491UX UT WOS:000269606900012 PM 19675142 ER PT J AU Schunemann, HJ Osborne, M Moss, J Manthous, C Wagner, G Sicilian, L Ohar, J McDermott, S Lucas, L Jaeschke, R AF Schuenemann, Holger J. Osborne, Molly Moss, Joel Manthous, Constantine Wagner, Gregory Sicilian, Leonard Ohar, Jill McDermott, Shane Lucas, Lance Jaeschke, Roman CA ATS Ethics Conflict Interest Comm Documents Dev Implementation Comm TI An Official American Thoracic Society Policy Statement: Managing Conflict of Interest in Professional Societies SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID PHYSICIAN-INDUSTRY RELATIONSHIPS AB Background. Competing interests occur frequently in health care. This results in the potential for conflict of interest (COI). COI can lead to biased generation or assessment of evidence and misinform healthcare decision makers. Declaration of COI is insufficient to neutralize potentially harmful effects. Medical professional societies are obliged to develop robust mechanisms to "manage" COI, particularly in the development of official guidance documents that affect health care. Purpose: This document describes the background, methods, and content of the new "American Thoracic Society (ATS) Policy on Management of COI in Official ATS Documents, Projects, and Conferences." Methods: We used existing reviews on COI policies that were prepared for the World Health Organization and for an ATS guideline methodology workshop as the evidence base for this work. We reviewed existing policies of selected organizations and other relevant literature. Members of the ATS Documents Development and Implementation Committee and the ATS Ethics and COI Committee collaborated to draft a COI policy. We used face-to-face meetings, electronic correspondence, and teleconferences to finalize the draft. The policy then underwent review and ultimate approval by the ATS Board of Directors. Results: The ATS developed a new policy and procedures for declaration and management of COL These procedures include: (1) self declaration of COI, (2) review of potential participants' COI, (3) disclosure of COI to project participants, (4) recusal or excusal from certain decisions or recommendations when appropriate, (5) disclosure of COI to users of documents or attendees of conferences, (6) handling disputes in COI resolution. This policy includes a tool that may be useful for supporting decision makers in management of COIs as they assess the value and relevance of conflicts. Conclusions: The ATS Policy on Management of COI in Official ATS Documents, Projects, and Conferences, in effect since March 2008, promises greater organizational transparency. Application and ongoing evaluation of the policy will give the ATS the opportunity to determine its usefulness in specific settings. C1 [Schuenemann, Holger J.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Schuenemann, Holger J.] SUNY Buffalo, Dept Med, Buffalo, NY 14260 USA. [Schuenemann, Holger J.; Jaeschke, Roman] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Osborne, Molly] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Osborne, Molly] Portland VA Med Ctr, Portland, OR USA. [Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Manthous, Constantine] Yale Univ, Sch Med, Bridgeport Hosp, New Haven, CT USA. [Wagner, Gregory] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Sicilian, Leonard] Massachusetts Gen Hosp, Dept Med, Adult Cyst Fibrosis Program, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Ohar, Jill] Wake Forest Univ, Bowman Gray Sch Med, Sect Pulm Crit Care Allergy & Immunol Dis, Winston Salem, NC USA. [McDermott, Shane] Off Eth & Conflict Interest Policies, New York, NY USA. [Lucas, Lance] Amer Thorac Soc, Off Documents, New York, NY USA. [Lucas, Lance] Amer Thorac Soc, Ad Hoc Projects, New York, NY USA. RP Schunemann, HJ (reprint author), McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. NR 15 TC 34 Z9 35 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 15 PY 2009 VL 180 IS 6 BP 564 EP 580 DI 10.1164/rccm.200901-0126ST PG 17 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 496TV UT WOS:000270002600013 PM 19734351 ER PT J AU Whellan, DJ Ellis, SJ Kraus, WE Hawthorne, K Pina, IL Keteyian, SJ Kitzman, DW Cooper, L Lee, K O'Connor, CM AF Whellan, David J. Ellis, Stephen J. Kraus, William E. Hawthorne, Katie Pina, Ileana L. Keteyian, Steven J. Kitzman, Dalane W. Cooper, Lawton Lee, Kerry O'Connor, Christopher M. TI Method for Establishing Authorship in a Multicenter Clinical Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HEART-FAILURE; HF-ACTION; GUIDELINES; TIME AB With the emergence of large multicenter trials over the past 20 years, the numbers of investigators involved and publications resulting from each study have grown exponentially. An efficient, fair, and effective way to establish authorship on study-related manuscripts could diminish conflict among the investigators and help ensure robust and timely dissemination of study results. This article describes a process developed by the investigators in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial (ClinicalTrials. gov registration number: NCT00047437) to establish authorship of the manuscripts describing the baseline characteristics, study design, and trial outcomes in an equitable and transparent manner based on objective, quantifiable contributions to the study as a whole. The HF-ACTION investigators developed a scoring system that assigned points to investigators by using the criteria established for enrollment, adherence to the exercise program, data completion, committee service, and other trial efforts. The scoring system has been successfully implemented for baseline manuscripts and has allowed many investigators to participate in the HF-ACTION publication process. C1 Duke Univ, Med Ctr, Durham, NC USA. Duke Clin Res Inst, Durham, NC USA. Wake Forest Univ, Sch Med, Winston Salem, NC USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Henry Ford Hosp, Detroit, MI 48202 USA. NHLBI, NIH, Bethesda, MD 20892 USA. [Whellan, David J.] Jefferson Med Coll, Dept Cardiol, Philadelphia, PA 19107 USA. RP Whellan, DJ (reprint author), Jefferson Med Coll, Dept Cardiol, 1015 Chestnut St,Suite 317, Philadelphia, PA 19107 USA. OI Kraus, William E/0000-0003-1930-9684 FU National Heart, Lung, and Blood Institute, National Institutes of Health [NIH/NHLBI U01HL063747] FX By the National Heart, Lung, and Blood Institute, National Institutes of Health, for the HF-ACTION trial (NIH/NHLBI U01HL063747). NR 9 TC 12 Z9 13 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 15 PY 2009 VL 151 IS 6 BP 414 EP W133 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 501OB UT WOS:000270390100006 PM 19755366 ER PT J AU Matulonis, U AF Matulonis, Ursula TI Review: Erythropoiesis-stimulating agents increase mortality in patients with cancer SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Matulonis, U (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 15 PY 2009 VL 151 IS 6 AR JC3-7 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 501OB UT WOS:000270390100024 PM 19755353 ER PT J AU Eckstein, F Benichou, O Wirth, W Nelson, DR Maschek, S Hudelmaier, M Kwoh, CK Guermazi, A Hunter, D AF Eckstein, Felix Benichou, Olivier Wirth, Wolfgang Nelson, David R. Maschek, Susanne Hudelmaier, Martin Kwoh, C. Kent Guermazi, Ali Hunter, David CA Osteoarthritis Initiative Investig TI Magnetic Resonance Imaging-Based Cartilage Loss in Painful Contralateral Knees With and Without Radiographic Joint Space Narrowing: Data From the Osteoarthritis Initiative SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID ARTICULAR-CARTILAGE; DISEASE PROGRESSION; RISK-FACTORS; 3 TESLA; PRECISION; VOLUME; MORPHOMETRY; MORPHOLOGY; SYMPTOMS; PROTOCOL AB Objective. To determine by magnetic resonance imaging (MRI), whether knees with advanced radiographic disease (medial joint space narrowing [mJSN]) encounter greater longitudinal cartilage loss than contralateral knees with earlier disease (no or less mJSN). Methods. Participants were selected from 2,678 cases in the Osteoarthritis Initiative, based on exhibition of bilateral pain, body mass index >25 (kg/m(2)), mJSN in 1 knee, no or less mJSN in the contralateral knee, and no lateral JSN in both knees. Eighty participants (mean +/- SD age 60.6 +/- 9.1 years) fulfilled these criteria. Medial tibial and femoral cartilage morphology was analyzed from the baseline and the 1-year followup MRI (sagittal double echo at steady state by 3.0T) of both knees by experienced readers blinded to the time point and mJSN status. Results. Knees with more radiographic mJSN displayed greater medial cartilage loss (-80 mu m) assessed by MRI than contralateral knees with less mJSN (-57 mu m). The difference reached statistical significance in participants with an mJSN grade of 2 or 3 (P = 0.005-0.08), but not in participants with an mJSN grade of 1 (P = 0.28-0.98). In knees with more mJSN, cartilage loss increased with higher grades of mJSN (P = 0.003 in the medial femur). Knees with an mJSN grade of 2 or 3 displayed greater cartilage loss in the weight-bearing medial femur than in the posterior femur or in the medial tibia (P = 0.048). Conclusion. Knees with advanced mJSN displayed greater cartilage loss than contralateral knees with less mJSN. These data suggest that radiography can be used to stratify fast structural progressors, and that MRI cartilage thickness loss is more pronounced at advanced radiographic disease stage. C1 [Eckstein, Felix; Hudelmaier, Martin] Paracelsus Med Univ, Inst Anat & Musculoskeletal Res, A-5020 Salzburg, Austria. [Eckstein, Felix; Wirth, Wolfgang; Maschek, Susanne; Hudelmaier, Martin] Chondrometrics, Ainring, Germany. [Benichou, Olivier; Nelson, David R.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Kwoh, C. Kent] Univ Pittsburgh, Pittsburgh, PA USA. [Kwoh, C. Kent] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Guermazi, Ali] Boston Univ, Med Ctr, Boston, MA USA. [Hunter, David] New England Baptist Hosp, Boston, MA USA. RP Eckstein, F (reprint author), Paracelsus Med Univ, Inst Anat & Musculoskeletal Res, Strubergasse 21, A-5020 Salzburg, Austria. EM felix.eckstein@pmu.ac.at RI Hudelmaier, Martin/C-8712-2011; Eckstein, Felix/E-1585-2011; Hunter, David/A-4622-2010; Wirth, Wolfgang/C-8724-2011 OI Hunter, David/0000-0003-3197-752X; Wirth, Wolfgang/0000-0002-2297-8283 FU Osteoarthritis Initiative [N01-AR-2-2258, N01-AR2-2259, N01-AR-2-2260, N01-AR-2-2261, N01-AR-22262]; Merck; Novartis; GlaxoSmithKline; Pfizer; Eli Lilly; Indianapolis; Indiana FX The study and image acquisition were supported by the Osteoarthritis Initiative (contracts N01-AR-2-2258, N01-AR2-2259, N01-AR-2-2260, N01-AR-2-2261, and N01-AR-22262). The Osteoarthritis Initiative receives support from Merck, Novartis, GlaxoSmithKline, and Pfizer. The image analysis was supported by Eli Lilly, Indianapolis, Indiana. NR 24 TC 41 Z9 41 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD SEP 15 PY 2009 VL 61 IS 9 BP 1218 EP 1225 DI 10.1002/art.24791 PG 8 WC Rheumatology SC Rheumatology GA 497KP UT WOS:000270058400010 PM 19714595 ER PT J AU Gratton, SB Scalapino, KJ Fye, KH AF Gratton, Sarah B. Scalapino, Kenneth J. Fye, Kenneth H. TI Case of Anakinra as a Steroid-Sparing Agent for Gout Inflammation SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID IL-1 C1 [Gratton, Sarah B.; Scalapino, Kenneth J.; Fye, Kenneth H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Scalapino, Kenneth J.] San Francisco VA Med Ctr, Arthritis Sect, San Francisco, CA USA. RP Gratton, SB (reprint author), San Francisco VAMC 111R, 4150 Clement St, San Francisco, CA 94121 USA. EM sarah.gratton@ucsf.edu FU Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; Biomedical Laboratory Research and Development FX Dr. Scalapino's work was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. His contribution is the result of work supported with the resources and the use of facilities at the San Francisco VA Medical Center. NR 6 TC 26 Z9 28 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD SEP 15 PY 2009 VL 61 IS 9 BP 1268 EP 1270 DI 10.1002/art.24694 PG 3 WC Rheumatology SC Rheumatology GA 497KP UT WOS:000270058400017 PM 19714614 ER PT J AU Levay, M Settleman, J Ligeti, E AF Levay, Magdolna Settleman, Jeffrey Ligeti, Erzsebet TI Regulation of the Substrate Preference of p190RhoGAP by Protein Kinase C-Mediated Phosphorylation of a Phospholipid Binding Site SO BIOCHEMISTRY LA English DT Article ID GTPASE-ACTIVATING PROTEIN; SURFACE-CHARGE; PLASMA-MEMBRANE; RHOGAP; ADHESION; ARF; PHAGOCYTOSIS; CONVERGENCE; MIGRATION; INTEGRIN AB The Rho family GTPases are stringently regulated through the action of a large family of GTPase activating proteins (GAPs) that stimulate their relatively weak intrinsic GTP hydrolyzing activity. The p190RhoGAPs, which include the p190A and p190B proteins, are potent and widely expressed GAPs acting on both Rho and Rac GTPases. We have observed that several acidic phospholipids inhibit the RhoGAP activity and promote the RacGAP activity of p190 proteins. In liposome binding assays we have demonstrated that binding of p190A to phospholipids is controlled by electrostatic interactions. Using mapping techniques, we determined that a small polybasic peptide stretch within p190A is a common site for both the phospholipid binding and PKC phosphorylation. Moreover, PKC-mediated phosphorylation of two amino acids (serine-1221 and threonine-1226) within this region of p190A prevents the binding and substrate specificity regulation by phospholipids. Transfection of COS-7 cells with mutant forms of p190A either unable to bind to phospholipids or unable to become phosphorylated induced distinct morphological changes. Together, these findings reveal a novel GAP regulatory mechanism in which phosphorylation indirectly alters GTPase substrate preference by affecting the interaction with acidic phospholipids. Our observations provide a potential mechanism of Rac/Rho antagonism described in several cellular functions. C1 [Levay, Magdolna; Ligeti, Erzsebet] Semmelweis Univ, Dept Physiol, H-1094 Budapest, Hungary. [Settleman, Jeffrey] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Settleman, Jeffrey] Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Ligeti, E (reprint author), Semmelweis Univ, Dept Physiol, Tuzolto U 37-47, H-1094 Budapest, Hungary. EM ligeti@puskin.sote.hu FU FIRCA [1 R03 TW006421-01A1]; Hungarian Research Fund [NK62221, K75084]; NIH [RO1 CA62142] FX Experimental work has been supported by grants from FIRCA (1 R03 TW006421-01A1), the Hungarian Research Fund (OTKA NK62221 and K75084), and the NIH (RO1 CA62142 to J.S.). NR 26 TC 18 Z9 18 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 15 PY 2009 VL 48 IS 36 BP 8615 EP 8623 DI 10.1021/bi900667y PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 490FV UT WOS:000269485500014 PM 19673492 ER PT J AU Wang, ZH Birch, CM Sagotsky, J Deisboeck, TS AF Wang, Zhihui Birch, Christina M. Sagotsky, Jonathan Deisboeck, Thomas S. TI Cross-scale, cross-pathway evaluation using an agent-based non-small cell lung cancer model SO BIOINFORMATICS LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; TGF-BETA; FACTOR-RECEPTOR; TUMOR-GROWTH; IN-VITRO; SIGNALING PATHWAYS; MATRIX ADHESION; INVASION; DYNAMICS; MIGRATION AB We present a multiscale agent-based non-small cell lung cancer model that consists of a 3D environment with which cancer cells interact while processing phenotypic changes. At the molecular level, transforming growth factor beta (TGF beta) has been integrated into our previously developed in silico model as a second extrinsic input in addition to epidermal growth factor (EGF). The main aim of this study is to investigate how the effects of individual and combinatorial change in EGF and TGF beta concentrations at the molecular level alter tumor growth dynamics on the multi-cellular level, specifically tumor volume and expansion rate. Our simulation results show that separate EGF and TGF beta fluctuations trigger competing multicellular phenotypes, yet synchronous EGF and TGF beta signaling yields a spatially more aggressive tumor that overall exhibits an EGF-driven phenotype. By altering EGF and TGF beta concentration levels simultaneously and asynchronously, we discovered a particular region of EGF-TGF beta profiles that ensures phenotypic stability of the tumor system. Within this region, concentration changes in EGF and TGF beta do not impact the resulting multi-cellular response substantially, while outside these concentration ranges, a change at the molecular level will substantially alter either tumor volume or tumor expansion rate, or both. By evaluating tumor growth dynamics across different scales, we show that, under certain conditions, therapeutic targeting of only one signaling pathway may be insufficient. Potential implications of these in silico results for future clinico-pharmacological applications are discussed. C1 [Wang, Zhihui; Sagotsky, Jonathan; Deisboeck, Thomas S.] Massachusetts Gen Hosp, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Charlestown, MA 02129 USA. [Birch, Christina M.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. RP Deisboeck, TS (reprint author), Massachusetts Gen Hosp, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Charlestown, MA 02129 USA. EM deisboec@helix.mgh.harvard.edu FU NIH [113004]; Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging and the Department of Radiology at Massachusetts General Hospital FX NIH grant CA 113004; Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging and the Department of Radiology at Massachusetts General Hospital. NR 53 TC 29 Z9 29 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD SEP 15 PY 2009 VL 25 IS 18 BP 2389 EP 2396 DI 10.1093/bioinformatics/btp416 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 491VC UT WOS:000269607700015 PM 19578172 ER PT J AU DeLuca, DS Eiz-Vesper, B Ladas, N Khattab, BAM Blasczyk, R AF DeLuca, David S. Eiz-Vesper, Britta Ladas, Nektarios Khattab, Barbara Anna-Maria Blasczyk, Rainer TI High-throughput minor histocompatibility antigen prediction SO BIOINFORMATICS LA English DT Article ID ARTIFICIAL NEURAL-NETWORK; EPITOPE PREDICTION; T-CELLS; PEPTIDES; BINDING; GENE; DATABASE; IMMUNOTHERAPY; EXPRESSION; SYFPEITHI AB Motivation: Minor histocompatibility antigens (mHags) are a diverse collection of MHC-bound peptides that have immunological implications in the context of allogeneic transplantation because of their differential presence in donor and host, and thus play a critical role in the induction of the detrimental graft-versus-host disease (GvHD) or in the development of the beneficial graft-versus-leukemia (GvL) effect. Therefore, the search for mHags has implications not only for preventing GvHD, but also for therapeutic applications involving leukemia-specific T cells. We have created a web-based system, named PeptideCheck, which aims to augment the experimental discovery of mHags using bioinformatic means. Analyzing peptide elution data to search for mHags and predicting mHags from polymorphism and protein databases are the core features. Results: Comparison with known mHag data reveals that some but not all of the previously known mHags can be reproduced. By applying a system of filtering and ranking, we were able to produce an ordered list of potential mHag candidates in which HA-1, HA-3 and HA-8 occur in the best 0.25%. By combining single nucleotide polymorphism, protein, tissue expression and genotypic frequency data, together with antigen presentation prediction algorithms, we propose a list of the best peptide candidates which could potentially induce the GvL effect without causing GvFD. C1 [DeLuca, David S.; Eiz-Vesper, Britta; Ladas, Nektarios; Khattab, Barbara Anna-Maria; Blasczyk, Rainer] Hannover Med Sch, Inst Transfus Med, D-3000 Hannover, Germany. [DeLuca, David S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. RP Blasczyk, R (reprint author), Hannover Med Sch, Inst Transfus Med, D-3000 Hannover, Germany. EM blasczyk.rainer@mh-hannover.de FU Federal Ministry of Education and Research, Germany [01DS001C] FX Federal Ministry of Education and Research, Germany ( funding number 01DS001C). NR 30 TC 6 Z9 6 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD SEP 15 PY 2009 VL 25 IS 18 BP 2411 EP 2417 DI 10.1093/bioinformatics/btp404 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 491VC UT WOS:000269607700018 PM 19570803 ER PT J AU Rue, M Vilaprinyo, E Lee, S Martinez-Alonso, M Carles, M Marcos-Gragera, R Pla, R Espinas, JA AF Rue, Montserrat Vilaprinyo, Ester Lee, Sandra Martinez-Alonso, Montserrat Carles, Misericordia Marcos-Gragera, Rafael Pla, Roger Espinas, Josep-Alfons TI Effectiveness of early detection on breast cancer mortality reduction in Catalonia (Spain) SO BMC CANCER LA English DT Article ID SCREENING MAMMOGRAPHY; PROGRAM; DISEASE; COHORT; RATES; RISK; AGE AB Background: At present, it is complicated to use screening trials to determine the optimal age intervals and periodicities of breast cancer early detection. Mathematical models are an alternative that has been widely used. The aim of this study was to estimate the effect of different breast cancer early detection strategies in Catalonia (Spain), in terms of breast cancer mortality reduction (MR) and years of life gained (YLG), using the stochastic models developed by Lee and Zelen (LZ). Methods: We used the LZ model to estimate the cumulative probability of death for a cohort exposed to different screening strategies after T years of follow-up. We also obtained the cumulative probability of death for a cohort with no screening. These probabilities were used to estimate the possible breast cancer MR and YLG by age, period and cohort of birth. The inputs of the model were: incidence of, mortality from and survival after breast cancer, mortality from other causes, distribution of breast cancer stages at diagnosis and sensitivity of mammography. The outputs were relative breast cancer MR and YLG. Results: Relative breast cancer MR varied from 20% for biennial exams in the 50 to 69 age interval to 30% for annual exams in the 40 to 74 age interval. When strategies differ in periodicity but not in the age interval of exams, biennial screening achieved almost 80% of the annual screening MR. In contrast to MR, the effect on YLG of extending screening from 69 to 74 years of age was smaller than the effect of extending the screening from 50 to 45 or 40 years. Conclusion: In this study we have obtained a measure of the effect of breast cancer screening in terms of mortality and years of life gained. The Lee and Zelen mathematical models have been very useful for assessing the impact of different modalities of early detection on MR and YLG in Catalonia (Spain). C1 [Rue, Montserrat; Martinez-Alonso, Montserrat] Biomed Res Inst Lleida IRBLLEIDA, Lleida, Catalonia, Spain. [Rue, Montserrat] Univ Lleida, Lleida, Catalonia, Spain. [Vilaprinyo, Ester] Hosp Tortosa, Fdn Dr Ferran, Catalonia, Spain. [Lee, Sandra] Dana Farber Canc Inst, Boston, MA 02115 USA. [Carles, Misericordia] Univ Rovira & Virgili, E-43201 Reus, Catalonia, Spain. [Marcos-Gragera, Rafael] Girona Canc Registry, Girona, Catalonia, Spain. [Marcos-Gragera, Rafael; Espinas, Josep-Alfons] Catalan Canc Plan Dept Hlth, Catalonia, Spain. [Pla, Roger] Catalan Inst Hlth, Terres De Lebre Region, Catalonia, Spain. RP Rue, M (reprint author), Biomed Res Inst Lleida IRBLLEIDA, Lleida, Catalonia, Spain. EM montse.rue@cmb.udl.cat; evilaprinyo@cmb.udl.cat; sjlee@jimmy.harvard.edu; montserrat.martinez@cmb.udl.cat; misericordia.carles@urv.cat; rmarcos@iconcologia.net; rpla.ebre.ics@gencat.cat; ja.espinas@iconcologia.net RI Vilaprinyo, Ester/A-6702-2010; Rue, Montserrat/B-5663-2009; Martinez-Alonso, Montserrat/B-5582-2009; OI Vilaprinyo, Ester/0000-0002-5787-5890; Rue, Montserrat/0000-0002-7862-9365; Martinez-Alonso, Montserrat/0000-0003-1504-8552; Marcos-Gragera, Rafael/0000-0001-9824-3657 FU Spanish Ministry of Health [PI06/1649, PI06/90355]; Catalan Agency for Health Technology Assessment (Agencia d'Avaluacio de Tecnologia i Recerca Mediques) [068/27/06] FX To Marvin Zelen for encouraging us to study the impact of early detection and for providing his time and support. To Hui Huang who provided the code and spent many hours sharing her knowledge with us. This study has been funded by grants PI06/1649 and PI06/90355 from the Health Research Fund (Fondo de Investigacion Sanitaria) of the Spanish Ministry of Health and by grant 068/27/06 of the Catalan Agency for Health Technology Assessment (Agencia d'Avaluacio de Tecnologia i Recerca Mediques). NR 34 TC 13 Z9 13 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD SEP 15 PY 2009 VL 9 AR 326 DI 10.1186/1471-2407-9-326 PG 10 WC Oncology SC Oncology GA 510WE UT WOS:000271123200001 PM 19754959 ER PT J AU Ma, CHE Palmer, A Taylor, JSH AF Ma, Chi Him Eddie Palmer, Antony Taylor, Jeremy S. H. TI Synergistic effects of osteonectin and NGF in promoting survival and neurite outgrowth of superior cervical ganglion neurons SO BRAIN RESEARCH LA English DT Article DE Sympathetic neuron; Schwann cell; Secreted factor; Survival; Neuritogenesis; Synergistic ID NERVE GROWTH-FACTOR; EXTRACELLULAR-MATRIX GLYCOPROTEIN; RAT SYMPATHETIC NEURONS; SCHWANN-CELLS; MATRICELLULAR PROTEIN; ENDOTHELIAL-CELLS; SENSORY NEURONS; TYROSINE PHOSPHORYLATION; AUTOCRINE REGULATION; PERIPHERAL-NERVE AB Schwann cells (SCs) play a major role in the successful regeneration of peripheral nerves regeneration. Here we examined the effects of osteonectin (ON), a major factor secreted by SCs, on survival and neuritogenesis of mouse superior cervical ganglion (SCG) neurons. SC conditioned medium (SCCM) not only promoted the survival and neuritogenesis of SCG neurons at a level comparable to nerve growth factor (NGF) but also doubled the neurite length of NGF-treated SCG neurons. SCCM neuritogenic effects were not blocked by the tyrosine kinase receptor (Trk) inhibitor K252a demonstrating that these are not due solely to classical neurotrophic factors. Anti-ON neutralizing antibody diminished the SCCM-induced survival and neuritogenesis significantly. In the presence of K252a, the SCCM neuritogenic effects were blocked completely by anti-ON which suggests synergistic effects of ON with Trk-mediated growth factors. ON alone increased the survival and neurite outgrowth of SCG neurons significantly at high density cultures. ON at low concentration acts synergistically with NGF which induced maximum survival and neurite outgrowth (>50% increase). However, ON at high concentration was detrimental to survival (64% decrease) and neurite outgrowth (87% decrease) even in the presence of NGF. The well documented counter-adhesive effect of ON may account for this observation. Nevertheless, the growth promoting effects of ON became more pronounced as the cell density increased which suggests a possible interaction of ON with growth factors secreted by SCG neurons (autocrine or paracrine effects). Taken together, our study indicates that ON plays important roles in nervous system repair through its synergistic effects with growth factors. (C) 2009 Elsevier B.V. All rights reserved. C1 [Ma, Chi Him Eddie; Palmer, Antony; Taylor, Jeremy S. H.] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. RP Ma, CHE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 149 Bldg,13th St,Room 4309, Charlestown, MA 02129 USA. EM chi.ma@mgh.harvard.edu OI MA, Chi Him Eddie/0000-0003-2054-0445 FU Wellcome Trust; Croucher Foundation; Hong Kong Croucher Foundation Scholarship FX We thank members of the Taylor Lab for many stimulating discussions and Dr. Edward Bampton for his insightful comments on the manuscript. This work was funded by the Wellcome Trust and Croucher Foundation. Dr. Chi Ma is a recipient of a Hong Kong Croucher Foundation Scholarship. NR 75 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 15 PY 2009 VL 1289 BP 1 EP 13 DI 10.1016/j.brainres.2009.06.093 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 493YP UT WOS:000269776000001 PM 19596278 ER PT J AU Mery, CM George, S Bertagnolli, MM Raut, CP AF Mery, Carlos M. George, Suzanne Bertagnolli, Monica M. Raut, Chandrajit P. TI Secondary Sarcomas After Radiotherapy for Breast Cancer Sustained Risk and Poor Survival SO CANCER LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 01-05, 2007 CL Chicago, IL SP Amer Soc Clin Oncol DE sarcoma; angiosarcoma; lymphangiosarcoma; radiotherapy; breast neoplasms; malignant fibrous histiocytomas; partial mastectomy; breast conservation therapy ID SOFT-TISSUE SARCOMA; ANGIOSARCOMA; THERAPY; CARCINOMA; RADIATION; SURGERY; BONE AB BACKGROUND: Radiotherapy (RT) has been a risk factor for development of soft tissue sarcomas (STS). The objective of the current study was to quantify the risk of STS after RT and surgery for breast cancer (BCa), assess time trends, and compare long-term survival of patients with RT-associated and non-RT-associated angiosarcoma (AS) using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Women with BCa reported to SEER in 1973 to 2003 were included. Kaplan-Meier curves and proportional hazards models, reported as hazards ratios (HR) with 95% confidence intervals (95% CI), were used. Survival of patients who developed RT-associated AS was compared with that of patients with primary AS of the thorax and upper extremities. RESULTS: The cohort of 563,155 BCa patients was divided into 2 groups: those who received RT (37%) and those who received no RT. RT use increased with time (P < .0001). A total of 948 patients developed STS 1 to 29 years after BCa diagnosis. RT patients had a higher incidence of all STS (31 vs 22 per 100,000 person-years; HR, 1.5 [95%CI, 1.3-1.8]), AS (HR, 7.6; 95% Cl, 4.9-11.9), and malignant fibrous histiocytomas (MFH) (HR, 2.5; 95% Cl, 1.6-3.9). RT remained a significant predictor after adjustment for covariates (HR, 1.4; 95% Cl, 1.2-1.7). Partial mastectomies (HR, 7.1; 95% Cl, 3.2-16), RT (HR, 2.2; 95% Cl, 1.1-4.3), and lymph node dissections (HR, 2.6; 95% Cl, 1.3-5) were found to be independent risk factors for AS. The hazard of STS after RT peaked at 10 years, reaching the non-RT hazard at approximately 23 years. The 5-year survival for STS was 38%. There was no difference in survival noted between RT-induced and non-RT-induced AS. CONCLUSIONS: RT was found to increase the risk for STS, in particular AS and MFH. Patients who received RT for BCa should be followed closely for >20 years, Cancer 2009;115:4055-63. (C) 2009 American Cancer Society. C1 [Mery, Carlos M.; Bertagnolli, Monica M.; Raut, Chandrajit P.] Harvard Univ, Dept Surg, Sch Med, Brigham & Womens Hosp,Dana Farber Canc Inst, Boston, MA 02115 USA. [George, Suzanne] Harvard Univ, Dept Med Oncol, Sch Med, Brigham & Womens Hosp,Dana Farber Canc Inst, Boston, MA 02115 USA. RP Raut, CP (reprint author), Harvard Univ, Dept Surg, Sch Med, Brigham & Womens Hosp,Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM craut@partners.org NR 20 TC 31 Z9 31 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4055 EP 4063 DI 10.1002/cncr.24462 PG 9 WC Oncology SC Oncology GA 493BY UT WOS:000269709300006 PM 19526590 ER PT J AU Dreicer, R Li, HL Stein, M DiPaola, R Eleff, M Roth, BJ Wilding, G AF Dreicer, Robert Li, Hailun Stein, Mark DiPaola, Robert Eleff, Michael Roth, Bruce J. Wilding, George TI Phase 2 Trial of Sorafenib in Patients With Advanced Urothelial Cancer A Trial of the Eastern Cooperative Oncology Group SO CANCER LA English DT Article DE cisplatin; sorafenib; tyrosine kinase inhibitors; urothelial cancer ID TRANSITIONAL-CELL CARCINOMA; GROWTH-FACTOR RECEPTOR; LONG-TERM-SURVIVAL; BLADDER-CANCER; PROGNOSTIC-FACTORS; RANDOMIZED-TRIAL; II TRIAL; CISPLATIN; METHOTREXATE; VINBLASTINE AB BACKGROUND: There is no effective second-line systemic chemotherapy for patients with disease progression after cisplatin-based chemotherapy. A phase 2 trial of sorafenib was performed to determine the activity and toxicity of this agent in a multi-institutional setting in patients previously treated with 1 prior chemotherapy regimen. METHODS: Twenty-seven patients with advanced urothelial carcinoma were treated with sorafenib 400 mg orally twice daily continuously until progression or unacceptable toxicity. RESULTS: There were no objective responses observed. The 4-month progression-free survival (PFS) rate was 9.5%; median overall survival of the group was 6.8 months. There were no therapy-related deaths, and common grade 3 toxicities included fatigue and hand-foot syndrome. CONCLUSIONS: Although sorafenib as a single agent has minimal activity in patients with advanced urothelial cancer in the second-line setting, further investigation of tyrosine kinase inhibitors using different trial designs with PFS endpoints is warranted. Cancer 2009;115:4090-5. (C) 2009 American Cancer Society. C1 [Dreicer, Robert] Cleveland Clin, Dept Solid Tumor Oncol, Taussig Canc Inst, Cleveland, OH 44195 USA. [Li, Hailun] Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. [Stein, Mark; DiPaola, Robert; Eleff, Michael] Canc Inst New Jersey, New Brunswick, NJ USA. [Roth, Bruce J.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Wilding, George] Univ Wisconsin, Paul P Carbone Canc Ctr, Madison, WI USA. RP Dreicer, R (reprint author), Cleveland Clin, Dept Solid Tumor Oncol, Taussig Canc Inst, 9500 Euclid Ave R35, Cleveland, OH 44195 USA. EM dreicer@ccf.org FU Public Health Service [CA23318, CA66636, CA21115, CA49957, CA21076]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX This study was supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, and CA21076 and by the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. NR 24 TC 92 Z9 93 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4090 EP 4095 DI 10.1002/cncr.24467 PG 6 WC Oncology SC Oncology GA 493BY UT WOS:000269709300010 PM 19536901 ER PT J AU Caglar, HB Baldini, EH Othus, M Rabin, MS Bueno, R Sugarbaker, DJ Mentzer, SJ Janne, PA Johnson, BE Allen, AM AF Caglar, Hale B. Baldini, Elizabeth H. Othus, Megan Rabin, Michael S. Bueno, Raphael Sugarbaker, David J. Mentzer, Steven J. Janne, Pasi A. Johnson, Bruce E. Allen, Aaron M. TI Outcomes of Patients With Stage III Nonsmall Cell Lung Cancer Treated With Chemotherapy and Radiation With and Without Surgery SO CANCER LA English DT Article DE carcinoma; nonsmall cell; lung neoplasm; radiation; local recurrence ID SOUTHWEST-ONCOLOGY-GROUP; ELECTIVE NODAL IRRADIATION; HIGH-DOSE RADIATION; LEUKEMIA GROUP-B; GROUP PHASE-II; CONCURRENT CHEMOTHERAPY; NEOADJUVANT THERAPY; PULMONARY RESECTION; CHEST RADIOTHERAPY; SURVIVAL AB BACKGROUND: The objective of this study was to identify the factors associated with improved outcome after treatment for stage III nonsmall cell lung cancer (NSCLC). METHODS: A retrospective review of stage III NSCLC patients treated at who were treated at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center was done with institutional review board approval. Patients were followed for toxicity, local and distant failure, and overall survival. Multivariate Cox logistic regression analysis was used to determine the factors associated with treatment outcome. RESULTS: Between August 2000 and November 2006,144 patients received concurrent chemoradiation (CRT) for stage III NSCLC. Eighty of 144 patients were men (56%), and the median age was 61 years (range, 33-81 years). Sixty-two patients (43%) had stage IIIA NSCLC, and 82 patients (57%) had stage IIIB NSCLC. Radiotherapy (RT) was given concurrently with chemotherapy to all patients; 100 patients (69%) received CRT without surgery, and 44 patients (31%) received with neoadjuvant CRT followed by surgical resection. The median RT dose was 60 grays (Gy) (range, 46-70 Gy). The median follow-up was 15 months (range, 3-64 months), the median potential follow-up was 37 months (range, 12-84 months), and the median overall survival was 22 months (95% confidence interval, 15-28 months). The 1-year and 2-year survival rates were 68% and 47%, respectively. Among the 44 patients who underwent resection, the median survival was 61 months, and the 2-year survival rate was 73%. On multivariate analysis, stage at the time of treatment (stage IIIA vs stage 11113) and use of surgery were the only factors associated with improved outcome (P=.01 and P=.001, respectively). CONCLUSIONS: In this retrospective series, those patients who were able to undergo resection appeared to have improved outcome after induction CRT. Cancer 2009;115:4156-66. (C) 2009 American Cancer Society. C1 [Caglar, Hale B.; Baldini, Elizabeth H.; Allen, Aaron M.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Othus, Megan] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Rabin, Michael S.; Janne, Pasi A.; Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bueno, Raphael; Sugarbaker, David J.; Mentzer, Steven J.] Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02215 USA. RP Allen, AM (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02215 USA. EM aallen@lroc.harvard.edu NR 40 TC 23 Z9 24 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4156 EP 4166 DI 10.1002/cncr.24492 PG 11 WC Oncology SC Oncology GA 493BY UT WOS:000269709300018 PM 19551884 ER PT J AU Bober, SL Recklitis, CJ Campbell, EG Park, ER Kutner, JS Najita, JS Diller, L AF Bober, Sharon L. Recklitis, Christopher J. Campbell, Eric G. Park, Elyse R. Kutner, Jean S. Najita, Julie S. Diller, Lisa TI Caring for Cancer Survivors A Survey of Primary Care Physicians SO CANCER LA English DT Article; Proceedings Paper CT 4th Biennial Cancer Survivorship Research Conference CY JUN 18-20, 2008 CL Atlanta, GA SP Amer Canc Soc, NCI, Lance Armstrong Fdn DE long-term cancer survivor; multidimensional survivorship care; survivorship care plans; primary care physicians; physician survey ID FOLLOW-UP; CHALLENGE; HEALTH; TRIAL; FAIL AB BACKGROUND: The number of long-term US cancer survivors is expected to double by the year 2050. Although primary care physicians (PCPs) provide the majority of care for long-term cancer survivors, to the authors' knowledge, few data to date have detailed PCP practice patterns, attitudes, and challenges in caring for long-term cancer survivors. METHODS: Self-administered surveys were mailed to 406 community-and academic-based general internal medicine physicians in Denver, Colorado. Survey development included in-depth physician interviews and pretesting. Of the 299 responses, 72 were ineligible; an analysis of the data from 227 surveys is presented. RESULTS: The response rate was 76%. Community-based PCPs comprised 70% of completed surveys. Reported care patterns were assessed to create a multidimensional care score reflecting levels of attention to 4 areas of survivorship care: monitoring for cancer recurrence, management of late effects, sexual functioning, and mental health. Only 24% of PCPs met criteria for routinely providing more multidimensional survivorship care. More recent medical school graduates reported providing less multidimensional survivorship care when compared with their more experienced colleagues. Approximately 82% of PCPs believed that primary care guidelines for adult cancer survivors are not well defined, and 47% of PCPs cited inadequate preparation and lack of formal training in cancer survivorship as a problem when delivering care to long-term survivors. CONCLUSIONS: Although PCPs provide the bulk of care for long-term survivors within the survivorship phase of the cancer trajectory, only a small subset have reported providing multidimensional survivorship care. Results underscore a need for substantially increased training in survivorship care to support the delivery of multidimensional primary care for long-term survivors. Cancer 2009;115(18 suppl):4409-18. (C) 2009 American Cancer Society. C1 [Bober, Sharon L.; Recklitis, Christopher J.; Diller, Lisa] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Campbell, Eric G.; Park, Elyse R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Hlth Policy, Boston, MA 02115 USA. [Kutner, Jean S.] Univ Colorado, Sch Med, Dept Med, Div Gen Internal Med, Denver, CO USA. [Najita, Julie S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Bober, SL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Dana 321,44 Binney St, Boston, MA 02115 USA. EM sharon_bober@dfci.harvard.edu NR 25 TC 78 Z9 79 U1 0 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 15 PY 2009 VL 115 IS 18 BP 4409 EP 4418 DI 10.1002/cncr.24590 PG 10 WC Oncology SC Oncology GA 493CA UT WOS:000269709500013 PM 19731354 ER PT J AU Hoshida, Y Nijman, SMB Kobayashi, M Chan, JA Brunet, JP Chiang, DY Villanueva, A Newell, P Ikeda, K Hashimoto, M Watanabe, G Gabriel, S Friedman, SL Kumada, H Llovet, JM Golub, TR AF Hoshida, Yujin Nijman, Sebastian M. B. Kobayashi, Masahiro Chan, Jennifer A. Brunet, Jean-Philippe Chiang, Derek Y. Villanueva, Augusto Newell, Philippa Ikeda, Kenji Hashimoto, Masaji Watanabe, Goro Gabriel, Stacey Friedman, Scott L. Kumada, Hiromitsu Llovet, Josep M. Golub, Todd R. TI Integrative Transcriptome Analysis Reveals Common Molecular Subclasses of Human Hepatocellular Carcinoma SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; BETA-CATENIN; INTRAHEPATIC RECURRENCE; FUNCTIONAL GENOMICS; HUMAN CANCER; TGF-BETA; CLASSIFICATION; DEFINES; PROGRESSION; INTERFERON AB Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of St tumors was not simply the result of beta-catenin mutation but rather was the result of transforming growth factor-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease. [Cancer Res 2009;69(18):7385-92] C1 [Hoshida, Yujin; Nijman, Sebastian M. B.; Chan, Jennifer A.; Brunet, Jean-Philippe; Chiang, Derek Y.; Gabriel, Stacey; Golub, Todd R.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Hoshida, Yujin; Nijman, Sebastian M. B.; Chan, Jennifer A.; Brunet, Jean-Philippe; Chiang, Derek Y.; Gabriel, Stacey; Golub, Todd R.] Harvard Univ, Cambridge, MA 02138 USA. [Hoshida, Yujin; Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Golub, Todd R.] Harvard Univ, Childrens Hosp Boston, Sch Med, Boston, MA 02115 USA. [Golub, Todd R.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Nijman, Sebastian M. B.] Austrian Acad Sci, Ctr Mol Med, A-1010 Vienna, Austria. [Kobayashi, Masahiro; Ikeda, Kenji; Hashimoto, Masaji; Watanabe, Goro; Kumada, Hiromitsu] Toranomon Gen Hosp, Tokyo, Japan. [Chan, Jennifer A.] Univ Calgary, Calgary, AB, Canada. [Villanueva, Augusto; Llovet, Josep M.] IDIBAPS, Hosp Clin, CIBERehd, Barcelona Clin Liver Canc Grp,Liver Unit, Barcelona, Spain. [Llovet, Josep M.] Inst Catalana Recerca Estudis Avancats, Barcelona, Spain. [Newell, Philippa; Friedman, Scott L.; Llovet, Josep M.] Mt Sinai Sch Med, Liver Canc Program, New York, NY USA. RP Golub, TR (reprint author), Harvard Univ, Broad Inst, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM golub@broad.mit.edu RI Augusto, Villanueva/F-9378-2012; Llovet, Josep M /D-4340-2014; OI Augusto, Villanueva/0000-0003-3585-3727; Llovet, Josep M /0000-0003-0547-2667; Chiang, Derek/0000-0002-1131-6065 FU NIH/National Cancer Institute [5U54 CA112962-03]; NIH/National Institutes of Diabetes, Digestive and Kidney Diseases [1R01DK076986]; NIH (Spain) [SAF-2007-61898]; Samuel Waxman Cancer Research Foundation; Charles A. King Trust fellowship; Netherlands Organisation for Scientific Research (Rubicon); Dutch Cancer Society fellowships FX Grant support: NIH/National Cancer Institute grant 5U54 CA112962-03 (T.R. Golub), NIH/National Institutes of Diabetes, Digestive and Kidney Diseases grant 1R01DK076986 (J.M. Llovet), NIH (Spain) grant I+D Program SAF-2007-61898 (J.M. Llovet), and Samuel Waxman Cancer Research Foundation. Y. Hoshida is supported by Charles A. King Trust fellowship. S.M.B. Nijman was supported by the Netherlands Organisation for Scientific Research (Rubicon) and Dutch Cancer Society fellowships.; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.; We thank Menno Creyghton for reagents and helpful suggestion; So Young Kim, Ron Firestein, William Hahn. and David Root for the shRNA constructs; Megan Hanna for technical help; Weijia Zhang for critical reading of the manuscript; and Jadwiga. Grabarek and Mariko Kobayashi for general support. NR 38 TC 266 Z9 272 U1 3 U2 24 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2009 VL 69 IS 18 BP 7385 EP 7392 DI 10.1158/0008-5472.CAN-09-1089 PG 8 WC Oncology SC Oncology GA 496FC UT WOS:000269954000033 PM 19723656 ER PT J AU Kim, WY Jin, Q Oh, SH Kim, ES Yang, YJ Lee, DH Feng, L Behrens, C Prudkin, L Millers, YE Lee, JJ Lippman, SM Hong, WK Wistuba, II Lee, HY AF Kim, Woo-Young Jin, Quanri Oh, Seung-Hyun Kim, Edward S. Yang, Youn Joo Lee, Dong Hoon Feng, Lei Behrens, Carmen Prudkin, Ludmila Millers, York E. Lee, J. Jack Lippman, Scott M. Hong, Waun Ki Wistuba, Ignacio I. Lee, Ho-Young TI Elevated Epithelial Insulin-like Growth Factor Expression Is a Risk Factor for Lung Cancer Development SO CANCER RESEARCH LA English DT Article ID FACTOR-I RECEPTOR; BINDING PROTEIN-3 EXPRESSION; TRANSGENIC MICE; PROGNOSTIC ROLE; NEVER SMOKERS; CELL-LINES; IGF; GENE; MUTATIONS; APOPTOSIS AB Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has been implicated in several human neoplasms. However, the role of serum levels of IGFs in lung cancer risk is controversial. We assessed the role of tissue-derived IGFs in lung carcinogenesis. We found that IGF-I and IGF-II levels in bronchial tissue specimens containing high-grade dysplasia were significantly higher than in those containing normal epithelium, hyperplasia, and squamous metaplasia. Derivatives of human bronchial epithelial cell lines with activation mutation in KRAS(V12) or loss of p53 overexpressed IGF-I and IGF-II. The transformed characteristics of these cells were significantly suppressed by inactivation of IGF-IR or inhibition of IGF-I or IGF-II expression but enhanced by overexpression of IGF-IR or exposure to the tobacco carcinogens (TC) 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone and benzo(a)pyrene. We further determined the role of IGF-IR signaling in lung tumorigenesis by determining the antitumor activities of the selective IGF-IR tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine using an in vitro progressive cell system and an in vivo mouse model with a lung-specific IGF-I transgene after exposure to TCs, including 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone plus benzo(a)pyrene. Our results show that airway epithelial cells produce IGFs in an autocrine or paracrine manner, and these IGFs act jointly with TCs to enhance lung carcinogenesis. Furthermore, the use of selective IGF-IR inhibitors may be a rational approach to controlling lung cancer. [Cancer Res 2009;69(18):7439-48] C1 [Kim, Woo-Young; Jin, Quanri; Oh, Seung-Hyun; Kim, Edward S.; Yang, Youn Joo; Lee, Dong Hoon; Behrens, Carmen; Prudkin, Ludmila; Lippman, Scott M.; Hong, Waun Ki; Wistuba, Ignacio I.; Lee, Ho-Young] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA. [Feng, Lei; Lee, J. Jack] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Behrens, Carmen; Wistuba, Ignacio I.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Lee, J. Jack; Lee, Ho-Young] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX USA. [Millers, York E.] Univ Colorado, Denver Vet Affairs Med Ctr, Dept Med, Denver, CO 80202 USA. RP Lee, HY (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM hlee@mdanderson.org FU NIH [R01 CA109520, CA100816-01A1, P50 CA58187]; DOD [W81XWH-04-1-0142-01-VITAL]; Department of Veterans Affairs FX Grant support: NIH grants R01 CA109520 and CA100816-01A1 (H-Y. Lee), and in part by DOD grant W81XWH-04-1-0142-01-VITAL (W.K. Hong), NIH grant P50 CA58187 (Y.E. Miller), and a Department of Veterans Affairs Merit Review grant (Y.E. Miller).; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.; We thank OSI Pharmaceuticals for providing PQIP. NR 49 TC 31 Z9 31 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2009 VL 69 IS 18 BP 7439 EP 7448 DI 10.1158/0008-5472.CAN-08-3792 PG 10 WC Oncology SC Oncology GA 496FC UT WOS:000269954000039 PM 19738076 ER PT J AU Chaput, M Handschumacher, MD Guerrero, JL Holmvang, G Dal-Bianco, JP Sullivan, S Vlahakes, GJ Hung, J Levine, RA AF Chaput, Miguel Handschumacher, Mark D. Guerrero, J. Luis Holmvang, Godtfred Dal-Bianco, Jacob P. Sullivan, Suzanne Vlahakes, Gus J. Hung, Judy Levine, Robert A. CA Leducq Fdn MITRAL Transatlantic Ne TI Mitral Leaflet Adaptation to Ventricular Remodeling Prospective Changes in a Model of Ischemic Mitral Regurgitation SO CIRCULATION LA English DT Article; Proceedings Paper CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc DE mitral regurgitation; mitral valve leaflets; left ventricular remodeling ID ACUTE MYOCARDIAL-INFARCTION; DOPPLER-ECHOCARDIOGRAPHY; PAPILLARY-MUSCLE; VALVE LEAFLETS; HEART; PATHOGENESIS; DYSFUNCTION; SEVERITY; PROLAPSE AB Background-Ischemic mitral regurgitation is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about how chronic tethering affects leaflet area, in part because it cannot be measured repeatedly in situ. Recently, a new method for 3D echocardiographic measurement of mitral leaflet area was developed and validated in vivo against sheep valves, later excised. Clinical studies (n=80) showed that mitral leaflet area increased by >30% in patients with inferior myocardial infarction and dilated cardiomyopathy versus normal; greater adaptation independently predicted less mitral regurgitation. This study explored whether mitral valve area changes over time within the same heart with ischemic mitral regurgitation. Methods and Results-Twelve sheep were studied at baseline and 3 months after inferior myocardial infarction by 3D echocardiography; 6 were untreated and 6 were treated initially with an epicardial patch to limit left ventricular dilation and mitral regurgitation. Untreated sheep developed left ventricular dilation at 3 months, with global dysfunction (mean +/- SD ejection fraction, 24 +/- 10% versus 44 +/- 10% with patching, P=0.02) and moderate mitral regurgitation (vena contracta, 5.0 +/- 1.0 versus 0.8 +/- 1.0 mm, P<0.0002). In untreated sheep, total diastolic leaflet area increased from 13.1 +/- 1.3 to 18.1 +/- 2.5 cm(2) (P=0.0001). In patched sheep, leaflet area at 3 months was not significantly different from baseline sheep values (13.0 +/- 1.1 versus baseline, 12.1 +/- 1.8 cm(2), P=0.31). Conclusions-Mitral valve area, independent of systolic stretch, increases over time as the left ventricular remodels after inferior myocardial infarction. This increase, however, fails to compensate adequately for tethering to prevent mitral regurgitation. Understanding the mechanism of valve adaptation can potentially suggest new biological and surgical therapeutic targets. (Circulation. 2009; 120[suppl 1]: S99-S103.) C1 [Levine, Robert A.] Harvard Univ, Cardiac Ultrasound Lab, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, Div Cardiothorac Surg, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Levine, RA (reprint author), Harvard Univ, Cardiac Ultrasound Lab, Massachusetts Gen Hosp, Sch Med, YAWKEY 5068,55 Fruit St, Boston, MA 02115 USA. EM rlevine@partners.org FU NHLBI NIH HHS [K24 HL067434-08, K24 HL67434, R01 HL038176, R01 HL038176-14, R01 HL38176, R01 HL72265, K24 HL067434]; NIBIB NIH HHS [R21 EB05294] NR 24 TC 43 Z9 44 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 15 PY 2009 VL 120 IS 11 BP S99 EP S103 DI 10.1161/CIRCULATIONAHA.109.844019 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 493XQ UT WOS:000269773000015 PM 19752393 ER PT J AU Dixon, JA Gorman, RC Stroud, RE Bouges, S Hirotsugu, H Gorman, JH Martens, TP Itescu, S Schuster, MD Plappert, T St John-Sutton, MG Spinale, FG AF Dixon, Jennifer A. Gorman, Robert C. Stroud, Robert E. Bouges, Shenikqua Hirotsugu, Hamamoto Gorman, Joseph H., III Martens, Timothy P. Itescu, Silviu Schuster, Michael D. Plappert, Theodore St John-Sutton, Martin G. Spinale, Francis G. TI Mesenchymal Cell Transplantation and Myocardial Remodeling After Myocardial Infarction SO CIRCULATION LA English DT Article; Proceedings Paper CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc DE infarct expansion; stem cells; matrix metalloproteinase; tissue inhibitor of matrix metalloproteinase; fibrosis ID BONE-MARROW-CELLS; STEM-CELLS; MATRIX METALLOPROTEINASES; INTRAMYOCARDIAL INJECTION; CARDIAC REPAIR; HEART-FAILURE; MODEL; INHIBITORS; PRESSURE; OVERLOAD AB Background-Targeted delivery of mesenchymal precursor cells (MPCs) can modify left ventricular (LV) cellular and extracellular remodeling after myocardial infarction (MI). However, whether and to what degree LV remodeling may be affected by MPC injection post-MI, and whether these effects are concentration-dependent, remain unknown. Methods and Results-Allogeneic MPCs were expanded from sheep bone marrow, and direct intramyocardial injection was performed within the borderzone region 1 hour after MI induction (coronary ligation) in sheep at the following concentrations: 25 X 10(6) (25 M, n=7), 75 X 10(6) (75 M, n=7), 225 X 10(6) (225 M, n=10), 450 X 10(6) (450 M, n=8), and MPC free media only (MI Only, n=14). LV end diastolic volume increased in all groups but was attenuated in the 25 and 75 M groups. Collagen content within the borderzone region was increased in the MI Only, 225, and 450 M groups, whereas plasma ICTP, an index of collagen degradation, was highest in the 25 M group. Within the borderzone region matrix metalloproteinases (MMPs) and MMP tissue inhibitors (TIMPs) also changed in a MPC concentration-dependent manner. For example, borderzone levels of MMP-9 were highest in the 25 M group when compared to the MI Only and other MPC treatment group values. Conclusions-MPC injection altered collagen dynamics, MMP, and TIMP levels in a concentration-dependent manner, and thereby influenced indices of post-MI LV remodeling. However, the greatest effects with respect to post-MI remodeling were identified at lower MPC concentrations, thus suggesting a therapeutic threshold exists for this particular cell therapy. (Circulation. 2009; 120[suppl 1]: S220-S229.) C1 [Dixon, Jennifer A.; Stroud, Robert E.; Bouges, Shenikqua; Spinale, Francis G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. [Gorman, Robert C.; Hirotsugu, Hamamoto; Gorman, Joseph H., III; Plappert, Theodore; St John-Sutton, Martin G.] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Gorman, Robert C.; Hirotsugu, Hamamoto; Gorman, Joseph H., III; Plappert, Theodore; St John-Sutton, Martin G.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Martens, Timothy P.; Itescu, Silviu; Schuster, Michael D.] Columbia Univ, Dept Surg, New York, NY USA. [Dixon, Jennifer A.; Stroud, Robert E.; Bouges, Shenikqua; Spinale, Francis G.] Med Univ S Carolina, Div Cardiothorac Surg, 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 NHLBI NIH HHS [R01 HL059165, R01 HL063954-08, R01 HL071137-04, HL59165, HL73021, R01 HL073021, R01 HL059165-10, HL71137, R01 HL071137, HL63954, R01 HL073021-04, R01 HL063954] NR 30 TC 62 Z9 66 U1 1 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 SEP 15 PY 2009 VL 120 IS 11 BP S220 EP S229 DI 10.1161/CIRCULATIONAHA.108.842302 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 493XQ UT WOS:000269773000032 PM 19752372 ER PT J AU Ruddy, JM Jones, JA Stroud, RE Mukherjee, R Spinale, FG Ikonomidis, JS AF Ruddy, Jean Marie Jones, Jeffrey A. Stroud, Robert E. Mukherjee, Rupak Spinale, Francis G. Ikonomidis, John S. TI Differential Effects of Mechanical and Biological Stimuli on Matrix Metalloproteinase Promoter Activation in the Thoracic Aorta SO CIRCULATION LA English DT Article; Proceedings Paper CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc DE metalloproteinases; aorta; wall stress; angiotensin ID VASCULAR SMOOTH-MUSCLE; C-DEPENDENT ACTIVATION; FOCAL ADHESION KINASE; FACTOR-KAPPA-B; ANGIOTENSIN-II; SUPEROXIDE-PRODUCTION; PROTEIN-KINASES; NAD(P)H OXIDASE; MMP-2 ACTIVITY; KNOCKOUT MICE AB Background-The effect of multiple integrated stimuli on vascular wall expression of matrix metalloproteinases (MMPs) remains unknown. Accordingly, this study examined the influence of the vasoactive peptide angiotensin II (Ang II) on wall tension-induced promoter activation of MMP-2, MMP-9, and membrane type-1 MMP (MT1-MMP). Methods and Results-Thoracic aortic rings harvested from transgenic reporter mice containing the MMP-2, MMP-9, or MT1-MMP promoter sequence fused to a reporter gene were subjected to 3 hours of wall tension at 70, 85, or 100 mm Hg, with or without 100 nM Ang II. Total RNA was harvested from the aortic rings, and reporter gene transcripts were quantified by quantitative real-time polymerase chain reaction to measure MMP promoter activity. MT1-MMP promoter activity was increased at both 85 and 100 mm Hg, compared with baseline tension of 70 mm Hg, whereas treatment with Ang II stimulated MT1-MMP promoter activity to the same degree at all tension levels (P<0.05). Elevated tension and Ang II displayed a potential synergistic enhancement of MMP-2 promoter activation at 85 and 100 mm Hg, whereas the same stimuli caused a decrease in MMP-9 promoter activity (P<0.05) at 100 mm Hg. Conclusions-This study demonstrated that exposure to a relevant biological stimulus (Ang II) in the presence of elevated tension modulated MMP promoter activation. Furthermore, these data suggest that a mechanical-molecular set point exists for the induction of MMP promoter activation and that this set point can be adjusted up or down by a secondary biological stimulus. Together, these results may have significant clinical implications toward the regulation of hypertensive vascular remodeling. (Circulation. 2009; 120[suppl 1]: S262-S268.) C1 [Ikonomidis, John S.] Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Ikonomidis, JS (reprint author), Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg, 25 Courtenay Dr,POB MSC 295, Charleston, SC 29425 USA. EM ikonomij@musc.edu FU NHLBI NIH HHS [R01 HL075488-05, R01 HL102121, R01 HL075488]; NIA NIH HHS [R01 AG036954] NR 50 TC 21 Z9 21 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 SEP 15 PY 2009 VL 120 IS 11 BP S262 EP S268 DI 10.1161/CIRCULATIONAHA.108.843581 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 493XQ UT WOS:000269773000037 PM 19752377 ER PT J AU Hirata, H Hinoda, Y Nakajima, K Kawamoto, K Kikuno, N Kawakami, K Yamamura, S Ueno, K Majid, S Saini, S Ishii, N Dahiya, R AF Hirata, Hiroshi Hinoda, Yuji Nakajima, Koichi Kawamoto, Ken Kikuno, Nobuyuki Kawakami, Kazumori Yamamura, Soichiro Ueno, Koji Majid, Shahana Saini, Sharanjot Ishii, Nobuhisa Dahiya, Rajvir TI Wnt Antagonist Gene DKK2 Is Epigenetically Silenced and Inhibits Renal Cancer Progression through Apoptotic and Cell Cycle Pathways SO CLINICAL CANCER RESEARCH LA English DT Article ID SIGNALING PATHWAY; FAMILY GENES; PROMOTER-HYPERMETHYLATION; DICKKOPF FAMILY; PROSTATE-CANCER; SUPPRESSOR GENE; CERVICAL-CANCER; DOWN-REGULATION; BREAST-CANCER; CARCINOMA AB Purpose: Wnt/beta-catenin signaling is involved in renal cancer. DKK2, a Wnt antagonist, is silenced in some cancers, although its function has not been investigated. We hypothesized that DKK2 may be epigenetically silenced and inhibits progression of renal cell carcinoma (RCC). Experimental Design: RCC cell lines and a normal kidney cell line were used for methylation and chromatin immunoprecipitation assays. To assess various functions of DKK2, we established stable DKK2-transfected cells and examined them with regard to cell viability, colony formation, apoptosis, cell cycle, and invasive capability. A total of 52 patients with confirmed conventional RCC were enrolled in this study. Results: RCC cell lines had decreased levels of DKK2, which were significantly increased after treatment with 5-Aza-2'-deoxycytidine alone or 5-Aza-2'-deoxycytidine and trichostatin A. In chromatin immunoprecipitation assay, the levels of acetyl H3, acetyl H4, and dimethylated H3K4 were decreased, whereas the level of dimethylated H3K9 was increased in RCC cell lines compared with HK2 cells. Increased methylation in RCC tissues was associated with higher grades, pathologic stages, and pathologic tumor in RCC. Functional analysis showed that the numbers of viable A498 cells were significantly decreased in DKK2-transfected cells compared with mock cells. The number of apoptotic cells and S/G(2)-M phase cells was significantly increased and decreased after DKK2 transfection, respectively. Corresponding to these results, Bc12 and cyclin D1 expression were also decreased in DKK2-overexpressing cells. Conclusion: DKK2 is epigenetically silenced by methylation in higher grades and stages of RCC. These results suggest that DKK2 inhibits renal cancer progression through apoptotic and cell cycle pathways. (Clin Cancer Res 2009;15(18):5678-87) C1 [Hirata, Hiroshi; Kawamoto, Ken; Kikuno, Nobuyuki; Kawakami, Kazumori; Yamamura, Soichiro; Ueno, Koji; Majid, Shahana; Saini, Sharanjot; Dahiya, Rajvir] San Francisco VA Med Ctr, Dept Urol, San Francisco, CA USA. [Hirata, Hiroshi; Kawamoto, Ken; Kikuno, Nobuyuki; Kawakami, Kazumori; Yamamura, Soichiro; Ueno, Koji; Majid, Shahana; Saini, Sharanjot; Dahiya, Rajvir] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hinoda, Yuji] Yamaguchi Univ, Grad Sch Med, Dept Oncol & Lab Med, Yamaguchi, Japan. [Nakajima, Koichi; Ishii, Nobuhisa] Toho Univ, Fac Med, Dept Urol, Tokyo, Japan. RP Dahiya, R (reprint author), Vet Affairs Med Ctr, Urol Res Ctr 112F, 4150 Clement St, San Francisco, CA 94121 USA. EM rdahiya@urology.ucsf.edu FU NCI NIH HHS [R01CA108612, R01CA111470, R01CA130860]; NIDDK NIH HHS [T32-DK07790] NR 35 TC 40 Z9 43 U1 1 U2 3 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 SEP 15 PY 2009 VL 15 IS 18 BP 5678 EP 5687 DI 10.1158/1078-0432.CCR-09-0558 PG 10 WC Oncology SC Oncology GA 496OA UT WOS:000269982800011 PM 19755393 ER PT J AU Krishnaswamy, S Kanteti, R Duke-Cohan, JS Loganathan, S Liu, WQ Ma, PC Sattler, M Singleton, PA Ramnath, N Innocenti, F Nicolae, DL Ouyang, Z Liang, J Minna, J Kozloff, MF Ferguson, MK Natarajan, V Wang, YC Garcia, JGN Vokes, EE Salgia, R AF Krishnaswamy, Soundararajan Kanteti, Rajani Duke-Cohan, Jonathan S. Loganathan, Sivakumar Liu, Wanqing Ma, Patrick C. Sattler, Martin Singleton, Patrick A. Ramnath, Nithya Innocenti, Federico Nicolae, Dan L. Ouyang, Zheng Liang, Jie Minna, John Kozloff, Mark F. Ferguson, Mark K. Natarajan, Viswanathan Wang, Yi-Ching Garcia, Joe G. N. Vokes, Everett E. Salgia, Ravi TI Ethnic Differences and Functional Analysis of MET Mutations in Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID C-MET; TYROSINE KINASE; EGFR MUTATIONS; ACTIVATING MUTATIONS; RECEPTOR; GEFITINIB; CARCINOMA; INHIBITION; RESISTANCE; THERAPY AB Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding. (Clin Cancer Res 2009;15(18):5714-23) C1 [Salgia, Ravi] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Ferguson, Mark K.] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [Ouyang, Zheng; Liang, Jie] Univ Illinois, Dept Bioengn, SEO, Chicago, IL USA. [Duke-Cohan, Jonathan S.; Sattler, Martin] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Ma, Patrick C.] Case Western Reserve Univ, Dept Med, Div Hematol Oncol, Univ Hosp,Case Med Ctr,Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Ramnath, Nithya] Univ Michigan, Dept Internal Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Minna, John] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Kozloff, Mark F.] Ingalls Mem Hosp, Harvey, IL USA. [Wang, Yi-Ching] Natl Cheng Kung Univ, Coll Med, Dept Pharmacol, Tainan 70101, Taiwan. RP Salgia, R (reprint author), Univ Chicago, Med Ctr, Dept Med, 5841 S Maryland Ave,MC2115,M255A, Chicago, IL 60637 USA. EM rsalgia@medicine.bsd.uchicago.edu RI Garcia, Joe/E-8862-2010; OI Duke-Cohan, Jonathan/0000-0002-9478-9609 FU NIH/National Cancer Institute [CA100750-04, CA129501-01A1, CA-125541-01] FX NIH/National Cancer Institute R01 grants, CA100750-04, CA129501-01A1, and CA-125541-01; V-Foundation/Guy Geleerd Memorial; MARF/Jeffrey P. Hayes Memorial Grant; Cancer Research Foundation/Goldblatt Award (R. Salgia); Lung Cancer Specialized Programs ofFlesearch Excellence P50CA70907 (J. Minna); and P01 HLO58064-13 (J. Garcia). NR 31 TC 72 Z9 76 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 SEP 15 PY 2009 VL 15 IS 18 BP 5714 EP 5723 DI 10.1158/1078-0432.CCR-09-0070 PG 10 WC Oncology SC Oncology GA 496OA UT WOS:000269982800015 PM 19723643 ER PT J AU Pozzi, S Vallet, S Mukherjee, S Cirstea, D Vaghela, N Santo, L Rosen, E Ikeda, H Okawa, Y Kiziltepe, T Schoonmaker, J Xie, WL Hideshima, T Weller, E Bouxsein, ML Munshi, NC Anderson, KC Raje, N AF Pozzi, Samantha Vallet, Sonia Mukherjee, Siddhartha Cirstea, Diana Vaghela, Nileshwari Santo, Loredana Rosen, Eyal Ikeda, Hiroshi Okawa, Yutaka Kiziltepe, Tanyel Schoonmaker, Jesse Xie, Wanling Hideshima, Teru Weller, Edie Bouxsein, Mary L. Munshi, Nikhil C. Anderson, Kenneth C. Raje, Noopur TI High-Dose Zoledronic Acid Impacts Bone Remodeling with Effects on Osteoblastic Lineage and Bone Mechanical Properties SO CLINICAL CANCER RESEARCH LA English DT Article ID NITROGEN-CONTAINING BISPHOSPHONATES; CLINIC CONSENSUS STATEMENT; MULTIPLE-MYELOMA; AMERICAN-SOCIETY; IN-VITRO; TRABECULAR BONE; ALENDRONATE; OSTEONECROSIS; APOPTOSIS; MICE AB Purpose: The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling. Experimental Design: Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays. Results: We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice. Conclusions: High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease. (Clin Cancer Res 2009;15(18):5829-39) C1 [Raje, Noopur] Massachusetts Gen Hosp, Div Hematol & Oncol, Ctr Canc, Boston, MA 02114 USA. [Pozzi, Samantha; Vallet, Sonia; Cirstea, Diana; Santo, Loredana; Ikeda, Hiroshi; Okawa, Yutaka; Kiziltepe, Tanyel; Xie, Wanling; Hideshima, Teru; Munshi, Nikhil C.; Anderson, Kenneth C.; Raje, Noopur] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rosen, Eyal; Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Rosen, Eyal; Bouxsein, Mary L.] Harvard Univ, Sch Med, Boston, MA USA. RP Raje, N (reprint author), Massachusetts Gen Hosp, Div Hematol & Oncol, Ctr Canc, POB 216,55 Fruit St, Boston, MA 02114 USA. EM nraje@partners.org RI Pozzi, Samantha/A-7617-2012 OI Pozzi, Samantha/0000-0001-7917-1774 FU International Myeloma Foundation; American Society of Clinical Oncology; Multiple Myeloma Research Foundation FX Grant support: S. Pozzi and S. Vallet are research fellows supported by the International Myeloma Foundation, and N. Raie has a career development award from American Society of Clinical Oncology and grant support from the Multiple Myeloma Research Foundation. NR 51 TC 37 Z9 38 U1 0 U2 5 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 SEP 15 PY 2009 VL 15 IS 18 BP 5829 EP 5839 DI 10.1158/1078-0432.CCR-09-0426 PG 11 WC Oncology SC Oncology GA 496OA UT WOS:000269982800027 PM 19737962 ER PT J AU DePrimo, SE Huang, X Blackstein, ME Garrett, CR Harmon, CS Schoffski, P Shah, MH Verweij, J Baum, CM Demetri, GD AF DePrimo, Samuel E. Huang, Xin Blackstein, Martin E. Garrett, Christopher R. Harmon, Charles S. Schoffski, Patrick Shah, Manisha H. Verweij, Jaap Baum, Charles M. Demetri, George D. TI Circulating Levels of Soluble KIT Serve as a Biomarker for Clinical Outcome in Gastrointestinal Stromal Tumor Patients Receiving Sunitinib following Imatinib Failure SO CLINICAL CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITOR; SURROGATE END-POINTS; RENAL-CELL CARCINOMA; C-KIT; GROWTH-FACTOR; LUNG-CANCER; PHASE-II; IN-VIVO; SU11248; RECEPTOR AB Purpose: To evaluate changes in circulating levels of soluble KIT (SKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study. Experimental Design: Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma SKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis. Results: From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in SKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in SKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in SKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% Cl, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% Cl, 0.39-3.40). Conclusions: The results suggest that circulating plasma SKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings. (Clin Cancer Res 2009;15(18):5869-77) C1 [DePrimo, Samuel E.; Huang, Xin; Harmon, Charles S.; Baum, Charles M.] Pfizer Oncol, San Diego, CA USA. [Blackstein, Martin E.] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Blackstein, Martin E.] Univ Toronto, Toronto, ON, Canada. [Garrett, Christopher R.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Schoffski, Patrick] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Shah, Manisha H.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Verweij, Jaap] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Demetri, George D.] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA USA. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Ludwig Ctr Canc Res, Dana Farber Harvard Canc Ctr, D1212,44 Binney St, Boston, MA 02115 USA. EM gdemetri@partners.org FU Pfizer, Inc. (New York, NY); Virginia and Daniel K. Ludwig Trust for Cancer Research; Rubenstein Foundation; Katz Foundation; Quick Family Fund for Cancer Research; Ronald O. Perelman Fund for Cancer Research at Dana-Farber; Stutman GIST Cancer Research Fund FX Grant support: Pfizer, Inc. (New York, NY); the Virginia and Daniel K. Ludwig Trust for Cancer Research, the Rubenstein Foundation, the Katz Foundation, the Quick Family Fund for Cancer Research, the Ronald O. Perelman Fund for Cancer Research at Dana-Farber, the Stutman GIST Cancer Research Fund, Paul's Posse, and Leslie's Links (G.D. Demetri). NR 44 TC 30 Z9 31 U1 0 U2 1 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 SEP 15 PY 2009 VL 15 IS 18 BP 5869 EP 5877 DI 10.1158/1078-0432.CCR-08-2480 PG 9 WC Oncology SC Oncology GA 496OA UT WOS:000269982800031 PM 19737953 ER PT J AU Demetri, GD Heinrich, MC Fletcher, JA Fletcher, CDM Van den Abbeele, AD Corless, CL Antonescu, CR George, S Morgan, JA Chen, MH Bello, CL Huang, X Cohen, DP Baum, CM Maki, RG AF Demetri, George D. Heinrich, Michael C. Fletcher, Jonathan A. Fletcher, Christopher D. M. Van den Abbeele, Annick D. Corless, Christopher L. Antonescu, Cristina R. George, Suzanne Morgan, Jeffrey A. Chen, Ming Hui Bello, Carlo L. Huang, Xin Cohen, Darrel P. Baum, Charles M. Maki, Robert G. TI Molecular Target Modulation, Imaging, and Clinical Evaluation of Gastrointestinal Stromal Tumor Patients Treated with Sunitinib Malate after Imatinib Failure SO CLINICAL CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITOR; GROWTH-FACTOR; EMISSION-TOMOGRAPHY; ANTITUMOR-ACTIVITY; IN-VIVO; SU11248; CANCER; HYPOTHYROIDISM; RESISTANCE; KIT AB Purpose: To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor (GIST) patients after imatinib failure, in addition to assessing the safety and pharmacokinetics (PK) of different dose schedules. Experimental Design: In this open-label, dose-ranging, phase I/II study, 97 patients with metastatic imatinib-resistant/intolerant GIST received sunitinib at doses of 25, 50, or 75 mg/d on one of three schedules. Serial tumor imaging was done using computed tomography and [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography scanning. PK and cell proliferation and KIT phosphorylation status in tumor biopsies were also analyzed. Results: Clinical benefit was observed in 52 patients (54%: 7 objective partial responses, 45 stable disease >= 6 months). Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography. Sunitinib treatment was associated with reduced tumor cell proliferation by > 25% in 52% of cases analyzed and reduced levels of phospho-KIT in tumor biopsies (indicating target modulation). The recommended dose schedule was 50 mg/d for 4 weeks followed by 2 weeks off treatment. On the 50-mg dose across all schedules, 79% of PK-evaluable patients achieved total drug trough concentrations above the target concentration (50 ng/mL) within 14 days of dosing. In addition, adverse events were generally mild to moderate in severity. Conclusion: Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of KIT in GIST following imatinib failure, illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy. (Clin Cancer Res 2009;15(18):5902-9) C1 [Demetri, George D.] Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr, Ludwig Ctr, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Demetri, George D.; Fletcher, Jonathan A.; Fletcher, Christopher D. M.; Van den Abbeele, Annick D.; George, Suzanne; Morgan, Jeffrey A.; Chen, Ming Hui] Harvard Univ, Sch Med, Boston, MA USA. [Fletcher, Jonathan A.; Fletcher, Christopher D. M.; Van den Abbeele, Annick D.; Chen, Ming Hui] Brigham & Womens Hosp, Boston, MA 02115 USA. [Fletcher, Jonathan A.; Chen, Ming Hui] Childrens Hosp, Boston, MA 02115 USA. [Heinrich, Michael C.] Portland VA Med Ctr, Portland, OR USA. [Heinrich, Michael C.; Corless, Christopher L.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Antonescu, Cristina R.; Maki, Robert G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Bello, Carlo L.; Huang, Xin; Cohen, Darrel P.; Baum, Charles M.] Pfizer Oncol, La Jolla, CA USA. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr, Ludwig Ctr, Ctr Sarcoma & Bone Oncol, 44 Binney St,Dana 1212, Boston, MA 02115 USA. EM gdemetri@partners.org FU Pfizer, Inc.; National Cancer Institute [CA 47179, 1P50CA127003-02]; Veterans Affairs Merit Review; Life Raft Group; Translational Fund for Research in Cardiology and Oncology; Department of Cardiology; Children's Hospital Boston; Trust for Cancer Research; Rubenstein Foundation; Quick Family Fund for Cancer Research; Ronald O. Perelman Fund for Cancer Research at Dana-Farber; Leslie's Links; Stutman GIST Cancer Research Fund; Shuman Family Fund for GIST Research FX Grant support: Pfizer, Inc., National Cancer Institute grant CA 47179 (R.G. Maki and C.R. Antonescu); National Cancer Institute grant 1P50CA127003-02 (J.A. Fletcher); Veterans Affairs Merit Review Grant (M.C. Heinrich); Life Raft Group (M.C. Heinrich and J.A. Fletcher); Translational Fund for Research in Cardiology and Oncology, Department of Cardiology, Children's Hospital Boston (M.H. Chen); and philanthropic support by the following sources: The Virginia and Daniel K. Ludwig Trust for Cancer Research, the Rubenstein Foundation, the Quick Family Fund for Cancer Research, the Ronald O. Perelman Fund for Cancer Research at Dana-Farber, and Leslie's Links (G.D. Demetri); the Stutman GIST Cancer Research Fund (M.C. Heinrich, J.A. Fletcher, and G.D. Demetri); an anonymous donor (J.A. Fletcher); and Cycle for Survival and the Shuman Family Fund for GIST Research (R.G. Maki). NR 35 TC 57 Z9 59 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2009 VL 15 IS 18 BP 5902 EP 5909 DI 10.1158/1078-0432.CCR-09-0482 PG 8 WC Oncology SC Oncology GA 496OA UT WOS:000269982800035 PM 19737946 ER PT J AU Demetri, GD Casali, PG Blay, JY von Mehren, M Morgan, JA Bertulli, R Ray-Coquard, I Cassier, P Davey, M Borghaei, H Pink, D Debiec-Rychter, M Cheung, W Bailey, SM Veronese, ML Reichardt, A Fumagalli, E Reichardt, P AF Demetri, George D. Casali, Paolo G. Blay, Jean-Yves von Mehren, Margaret Morgan, Jeffrey A. Bertulli, Rossella Ray-Coquard, Isabelle Cassier, Philippe Davey, Monica Borghaei, Hossein Pink, Daniel Debiec-Rychter, Maria Cheung, Wing Bailey, Stuart M. Veronese, Maria Luisa Reichardt, Annette Fumagalli, Elena Reichardt, Peter TI A Phase I Study of Single-Agent Nilotinib or in Combination with Imatinib in Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID KINASE INHIBITORS; TYROSINE KINASE; ACQUIRED-RESISTANCE; KIT MUTATIONS; MESYLATE; BIOLOGY; SUNITINIB; LEUKEMIA; TRIALS; AMN107 AB Purpose: To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors. Experimental Design: A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done. Results: Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group. Conclusions: Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation. (Clin Cancer Res 2009;15(18):5910-6) C1 [Demetri, George D.; Morgan, Jeffrey A.] Dana Farber Canc Inst, Ludwig Ctr, Boston, MA 02115 USA. [Demetri, George D.; Morgan, Jeffrey A.] Harvard Univ, Sch Med, Boston, MA USA. [Casali, Paolo G.; Bertulli, Rossella; Fumagalli, Elena] Fdn Ist Ricovero & Cura Carattere Sci, Ist Nazl Tumori, Milan, Italy. [Blay, Jean-Yves; Ray-Coquard, Isabelle; Cassier, Philippe] Ctr Leon Berard, Dept Med, F-69373 Lyon, France. [von Mehren, Margaret; Davey, Monica; Borghaei, Hossein] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Pink, Daniel; Reichardt, Peter] Helios Klinikum Bad Saarow, Dept Hematol Oncol & Palliat Med, Bad Saarow Pieskow, Germany. [Debiec-Rychter, Maria] Catholic Univ Louvain, Ctr Human Genet, B-3000 Louvain, Belgium. [Cheung, Wing; Bailey, Stuart M.; Veronese, Maria Luisa] Novartis Pharmaceut AG, Basel, Switzerland. [Reichardt, Annette] Helios Klinikum Berlin Buch, Sarcoma Ctr, Berlin, Germany. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Ludwig Ctr, Dana 1212,44 Binney St, Boston, MA 02115 USA. EM gdemetri@partners.org RI Blay, Jean-Yves/N-3966-2016; casali, Paolo Giovanni/D-1524-2017; Fumagalli, Elena Rosa/E-2065-2017 OI Blay, Jean-Yves/0000-0001-7190-120X; casali, Paolo Giovanni/0000-0003-4056-8023; Fumagalli, Elena Rosa/0000-0003-4814-7637 FU Novartis Pharmaceuticals Corporation, Oncology Business Unit, Florham Park, NJ; Virginia and Daniel K. Ludwig Trust for Cancer Research; Stutman GIST Cancer Research Fund; National Cancer Institute [P30 CA006927, CA106588]; Pfizer, Inc. FX Grant support: Novartis Pharmaceuticals Corporation, Oncology Business Unit, Florham Park, NJ. G. Demetri received additional philanthropic support for this work from the following sources: The Virginia and Daniel K. Ludwig Trust for Cancer Research and the Stutman GIST Cancer Research Fund. M. von Mehren was supported by grant number P30 CA006927 and CA106588 from the National Cancer Institute. The following authors received funding from Novartis Pharmaceuticals: G. Demetri, E. Fumagalli, P.G. Casali, P. Reichardt, M. von Mehren, and J.Y. Blay. The following authors received funding from Pfizer, Inc., for other projects: G. Demetri, E. Fumagalli, and P.G. Casali. NR 31 TC 71 Z9 70 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 SEP 15 PY 2009 VL 15 IS 18 BP 5910 EP 5916 DI 10.1158/1078-0432.CCR-09-0542 PG 7 WC Oncology SC Oncology GA 496OA UT WOS:000269982800036 PM 19723647 ER PT J AU Meyerhardt, JA Ogino, S Kirkner, GJ Chan, AT Wolpin, B Ng, K Nosho, K Shima, K Giovannucci, EL Loda, M Fuchs, CS AF Meyerhardt, Jeffrey A. Ogino, Shuji Kirkner, Gregory J. Chan, Andrew T. Wolpin, Brian Ng, Kimmie Nosho, Katsuhiko Shima, Kaori Giovannucci, Edward L. Loda, Massimo Fuchs, Charles S. TI Interaction of Molecular Markers and Physical Activity on Mortality in Patients with Colon Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; NATIONAL DEATH INDEX; GROWTH-FACTOR-I; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; ENERGY RESTRICTION; RISK-FACTORS; MAMMARY CARCINOGENESIS; ACTIVITY QUESTIONNAIRE; DOWN-REGULATION AB Purpose: Physical activity in colon cancer survivors has been associated with lower cancer recurrences and improved survival. Whether molecular features of the tumor portend more or less likelihood for benefit from exercise is unknown. Experimental Design: Using two large prospective cohort studies with physical activity assessments after colon cancer diagnosis, we examined expression of fatty acid synthase, p53, p21, and p27 and mutational status of K-ras and phosphatidylinositol 3-kinase(PI3KCA). We calculated hazard ratios (HR) of colon cancer-specific mortality, adjusted for tumor and patient characteristics, and tested for molecular interactions with exercise. Results: In a cohort of 484 men and women with stage I to III colon cancer, patients who engaged in at least 18 metabolic equivalent task (MET)-hours per week after diagnosis had an adjusted HR for colon cancer-specific mortality of 0.64 [95% confidence interval (95% CI), 0.33-1.23] and for overall mortality of 0.60 (95% Cl, 0.41-0.86). A statistically significant interaction was detected based on p27 expression (P = 0.03). For tumors with loss of p27 (n = 195), physical activity of >= 18 MET-hours/week led to a HR for colon cancer mortality of 1.40 (95% Cl, 0.41-4.72), compared with those with < 18 MET-hours/week. However, for tumors with expression of p27 (n = 251), the adjusted HR was 0.33 (95% Cl, 0.12-0.85). Molecular status of fatty acid synthase, K-ras, p53, p21, and PI3KCA did not influence the association between exercise and colon cancer-specific or overall mortality. Conclusion: The benefit of physical activity on outcomes in patients with stage I to III colon cancer may be influenced by p27 status. Further studies are warranted to confirm these findings. (Clin Cancer Res 2009;15(18):5931-6) C1 [Meyerhardt, Jeffrey A.; Ogino, Shuji; Wolpin, Brian; Ng, Kimmie; Nosho, Katsuhiko; Shima, Kaori; Loda, Massimo; Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ogino, Shuji; Kirkner, Gregory J.; Chan, Andrew T.; Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ogino, Shuji; Kirkner, Gregory J.; Chan, Andrew T.; Giovannucci, Edward L.; Loda, Massimo; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji; Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM jmeyerhardt@partners.org FU US NIH [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826]; Bennett Family Fund; Entertainment Industry Foundation FX Grant support: US NIH grants P01 CA87969 (principal investigator: Hankinson), P01 CA55075 (principal investigator: Willett), P50 CA127003 (principal investigator: Fuchs), K07 CA097992 (principal investigator: Meyerhardt), K07 CA122826 (principal investigator: Ogino), and in part by the Bennett Family Fund for Targeted Therapies Research and the Entertainment Industry Foundation through the EIF National Colorectal Cancer Research Alliance. None of these funding agencies has not had any role in design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. NR 44 TC 40 Z9 41 U1 1 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 SEP 15 PY 2009 VL 15 IS 18 BP 5931 EP 5936 DI 10.1158/1078-0432.CCR-09-0496 PG 6 WC Oncology SC Oncology GA 496OA UT WOS:000269982800039 PM 19723652 ER PT J AU Pallin, DJ Espinola, JA Leung, DY Hooper, DC Camargo, CA AF Pallin, Daniel J. Espinola, Janice A. Leung, Donald Y. Hooper, David C. Camargo, Carlos A., Jr. TI Epidemiology of Dermatitis and Skin Infections in United States Physicians' Offices, 1993-2005 SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; SOFT-TISSUE INFECTIONS; EMERGENCY-DEPARTMENT; VISITS AB Background. Since the discovery of community-associated methicillin-resistant Staphylococcus aureus (MRSA), the number of emergency department visits for skin and soft-tissue infection (SSTI) has increased, and one report suggested an increase in the much larger setting of physicians' offices. Dermatitis compromises the cutaneous barrier to microorganisms and may predispose to SSTI. Our objectives were to determine whether office visits for dermatitis or SSTI have become more frequent since the emergence of community-associated MRSA, to describe the age-specific frequency of visits for dermatitis and SSTI, and to determine whether dermatitis is associated with SSTI and whether the association strengthened over time. Methods. We analyzed visits for the diagnoses of dermatitis and SSTI by means of codes from the International Classification of Diseases, Ninth Revision recorded in the National Ambulatory Medical Care Survey, 1993-2005. We calculated population estimates by year and age group, with 95% confidence intervals (CIs), and examined trends over time. Multivariate logistic regression quantified the association between dermatitis and SSTI and assessed for interaction between dermatitis and year in the prediction of SSTI. Results. Dermatitis was diagnosed at 13 million office visits per year (95% CI, 12-14 million office visits per year) over the study period, and SSTI was diagnosed at 6.3 million office visits per year (95% CI, 5.8 million-6.8 million office visits per year). The frequency did not change for either diagnosis over time when expressed as a percentage of all visits (both, P> .60). Dermatitis was most common among infants (256 visits per 1,000 population per year; 95% CI, 216-293 visits per 1,000 population per year). The rate of diagnosis of SSTI did not vary importantly by age. Dermatitis was associated with SSTI (odds ratio, 2.54; 95% CI, 1.92-3.35). The association did not strengthen over time. Conclusions. The rate of office visits for dermatitis or SSTI did not increase from 1993 through 2005. Dermatitis was associated with SSTI. This association did not strengthen as community-associated MRSA became prevalent. C1 [Pallin, Daniel J.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Pallin, Daniel J.] Childrens Hosp Boston, Div Emergency Med, Boston, MA USA. [Espinola, Janice A.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Hooper, David C.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Leung, Donald Y.] Natl Jewish Med Hlth, Dept Pediat, Denver, CO USA. RP Pallin, DJ (reprint author), 75 Francis St, Boston, MA 02115 USA. EM dpallin@partners.org RI Pallin, Daniel/H-6382-2013 OI Pallin, Daniel/0000-0002-8517-9702 FU Pfizer [GA595241] FX Pfizer (investigator-initiated unrestricted research grant GA595241). NR 13 TC 24 Z9 24 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2009 VL 49 IS 6 BP 901 EP 907 DI 10.1086/605434 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 485ST UT WOS:000269145100011 PM 19663690 ER PT J AU Bradford, RD Pettit, AC Wright, PW Mulligan, MJ Moreland, LW McLain, DA Gnann, JW Bloch, KC AF Bradford, Russell D. Pettit, April C. Wright, Patty W. Mulligan, Mark J. Moreland, Larry W. McLain, David A. Gnann, John W. Bloch, Karen C. TI Herpes Simplex Encephalitis during Treatment with Tumor Necrosis Factor-alpha Inhibitors SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID POLYMERASE-CHAIN-REACTION; RHEUMATOID-ARTHRITIS; CEREBROSPINAL-FLUID; VIRUS ENCEPHALITIS; INFECTIONS; MANAGEMENT; DIAGNOSIS; THERAPY; RISK AB We report 3 cases of herpes simplex virus encephalitis in patients receiving tumor necrosis factor-alpha (TNF-alpha) inhibitors for rheumatologic disorders. Although TNF-alpha inhibitors have been reported to increase the risk of other infectious diseases, to our knowledge, an association between anti-TNF-alpha drugs and herpes simplex virus encephalitis has not been previously described. C1 [Bradford, Russell D.; Gnann, John W.] Univ Alabama, Dept Pediat, Div Infect Dis, Birmingham, AL 35233 USA. [Gnann, John W.] Univ Alabama, Dept Med, Div Infect Dis, Birmingham, AL 35233 USA. [Gnann, John W.] Birmingham VA Med Ctr, Birmingham, AL USA. [Pettit, April C.; Wright, Patty W.; Bloch, Karen C.] Vanderbilt Univ, Sch Med, Div Infect Dis, Dept Med, Nashville, TN 37212 USA. [Bloch, Karen C.] Vanderbilt Univ, Sch Med, Dept Prevent Med, Nashville, TN 37212 USA. [Mulligan, Mark J.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA. [Moreland, Larry W.] Univ Pittsburgh, Dept Med, Div Clin Immunol & Rheumatol, Pittsburgh, PA 15260 USA. RP Bradford, RD (reprint author), Univ Alabama, Dept Pediat, Div Infect Dis, 1600 7th Ave S,CHB 308, Birmingham, AL 35233 USA. EM rbradford@peds.uab.edu FU National Institutes of Health [N0-1-AI-30025]; University of Alabama at Birmingham; Centers for Disease Control and Prevention [U50/CCU416123-09]; Emory Vaccine and Treatment Evaluation Unit [N01 AI80005]; Merck; Sanofi Pasteur; Amgen FX Potential conflicts of interest. M.J.M. has received research funding from Merck and Sanofi Pasteur. D. A. M. is a shareholder in Amgen and Wyeth and has received grant support from Amgen. All other authors: no conflicts. NR 16 TC 28 Z9 29 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2009 VL 49 IS 6 BP 924 EP 927 DI 10.1086/605498 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 485ST UT WOS:000269145100015 PM 19681709 ER PT J AU Brumme, Z Wang, BX Nair, K Brumme, C de Pierres, C Reddy, S Julg, B Moodley, E Thobakgale, C Lu, Z van der Stok, M Bishop, K Mncube, Z Chonco, F Yuki, Y Frahm, N Brander, C Carrington, M Freedberg, K Kiepiela, P Goulder, P Walker, B Ndung'u, T Losina, E AF Brumme, Zabrina Wang, Bingxia Nair, Kriebashne Brumme, Chanson de Pierres, Chantal Reddy, Shabashini Julg, Boris Moodley, Eshia Thobakgale, Christina Lu, Zhigang van der Stok, Mary Bishop, Karen Mncube, Zenele Chonco, Fundisiwe Yuki, Yuko Frahm, Nicole Brander, Christian Carrington, Mary Freedberg, Kenneth Kiepiela, Photini Goulder, Philip Walker, Bruce Ndung'u, Thumbi Losina, Elena TI Impact of Select Immunologic and Virologic Biomarkers on CD4 Cell Count Decrease in Patients with Chronic HIV-1 Subtype C Infection: Results from Sinikithemba Cohort, Durban, South Africa SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD8(+) T-CELLS; PLASMA VIRAL LOAD; CLASS-I ALLELES; SET-POINT; LYMPHOCYTE RESPONSES; DISEASE PROGRESSION; GAG; AIDS; HLA AB Background. The extent to which immunologic and clinical biomarkers influence human immunodeficiency virus type 1 (HIV-1) infection outcomes remains incompletely characterized, particularly for non-B subtypes. On the basis of data supporting in vitro HIV-1 protein-specific CD8 T lymphocyte responses as correlates of immune control in cross-sectional studies, we assessed the relationship of these responses, along with established HIV-1 biomarkers, with rates of CD4 cell count decrease in individuals infected with HIV-1 subtype C. Methods. Bivariate and multivariate mixed-effects models were used to assess the relationship of baseline CD4 cell count, plasma viral load, human leukocyte antigen (HLA) class I alleles, and HIV-1 protein-specific CD8 T cell responses with the rate of CD4 cell count decrease in a longitudinal population-based cohort of 300 therapy-naive, chronically infected adults with baseline CD4 cell counts >200 cells/mm(3) and plasma viral loads > 500 copies/mL over a median of 25 months of follow-up. Results. In bivariate analyses, baseline CD4 cell count, plasma viral load, and possession of a protective HLA allele correlated significantly with the rate of CD4 cell count decrease. No relationship was observed between HIV-1 protein - specific CD8 T cell responses and CD4 cell count decrease. Results from multivariate models incorporating baseline CD4 cell counts (201-350 vs >350 cells/mm(3)), plasma viral load (<= 100,000 vs >100,000 copies/mL), and HLA (protective vs not protective) yielded the ability to discriminate CD4 cell count decreases over a 10- fold range. The fastest decrease was observed among individuals with CD4 cell counts >350 cells/mm(3) and plasma viral loads >100,000 copies/mL with no protective HLA alleles (-59 cells/mm(3) per year), whereas the slowest decrease was observed among individuals with CD4 cell counts 201-350 cells/mm(3), plasma viral loads <= 100,000 copies/ mL, and a protective HLA allele (-6 cells/mm(3) per year). Conclusions. The combination of plasma viral load and HLA class I type, but not in vitro HIV-1 protein specific CD8 T cell responses, differentiates rates of CD4 cell count decrease in patients with chronic subtype-C infection better than either marker alone. C1 [Wang, Bingxia; Lu, Zhigang; Freedberg, Kenneth; Losina, Elena] Massachusetts Gen Hosp, Program HIV Outcomes Res, Boston, MA 02114 USA. [Brumme, Zabrina; Brumme, Chanson; Julg, Boris; Frahm, Nicole; Brander, Christian; Goulder, Philip; Walker, Bruce; Ndung'u, Thumbi] Harvard Univ, Boston, MA 02115 USA. [Brumme, Zabrina; Brumme, Chanson; Julg, Boris; Frahm, Nicole; Brander, Christian; Goulder, Philip; Walker, Bruce; Ndung'u, Thumbi] Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Nair, Kriebashne; de Pierres, Chantal; Reddy, Shabashini; Julg, Boris; Moodley, Eshia; Thobakgale, Christina; van der Stok, Mary; Bishop, Karen; Mncube, Zenele; Chonco, Fundisiwe; Kiepiela, Photini; Goulder, Philip; Walker, Bruce; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Durban, South Africa. [Goulder, Philip] Nuffield Dept Med, Dept Paediat, Oxford, England. [Yuki, Yuko; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21701 USA. [Walker, Bruce] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Losina, E (reprint author), Massachusetts Gen Hosp, Program HIV Epidemiol & Outcomes Res, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM elosina@partners.org OI Brander, Christian/0000-0002-0548-5778; Ndung'u, Thumbi/0000-0003-2962-3992; Brumme, Chanson/0000-0003-2722-5288 FU Canadian Institutes of Health Research; South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS; Bill and Melinda Gates Foundation; International AIDS Vaccine Initiative; South African AIDS Vaccine Initiative; Center for AIDS Research at Harvard University; National Institutes of Health [R01-AI067073, N01-AI-15422, R01-AI46995]; Wellcome Trust; National Cancer Institute and National Institutes of Health [HHSN261200800001E]; Intramural Research Program FX Canadian Institutes of Health Research (postdoctoral fellowship to Z.L.B.); the South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS (T.N.); Bill and Melinda Gates Foundation; the International AIDS Vaccine Initiative; the South African AIDS Vaccine Initiative; Center for AIDS Research at Harvard University; National Institutes of Health (grant R01-AI067073 and contract N01-AI-15422 to B. D. W. and grant R01-AI46995 to P. G.); the Wellcome Trust (P. G.); National Cancer Institute and National Institutes of Health (contract HHSN261200800001E and the Intramural Research Program). NR 39 TC 14 Z9 14 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2009 VL 49 IS 6 BP 956 EP 964 DI 10.1086/605503 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 485ST UT WOS:000269145100021 PM 19663693 ER PT J AU Conen, KL Nishimori, S Provot, S Kronenberg, HM AF Conen, K. L. Nishimori, S. Provot, S. Kronenberg, H. M. TI The transcriptional cofactor Lbh regulates angiogenesis and endochondral bone formation during fetal bone development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Endochondral bone formation; Runx2; Lbh; VEGF ID ENDOTHELIAL GROWTH-FACTOR; TRISOMY 2P SYNDROME; CHONDROCYTE DIFFERENTIATION; OSTEOBLAST DIFFERENTIATION; SKELETAL DEVELOPMENT; VEGF; CBFA1; MICE; EXPRESSION; PLATE AB Lbh is thought to act as a transcriptional cofactor and is highly conserved among species. Here we show that Lbh is expressed in chondrocytes, cells of the perichondrium, and the primary spongiosa in fetal growth plates of mice and chickens. Lbh overexpression in chick wings, using the RCAS-retroviral vector strategy, results in shortened skeletal elements and delayed hypertrophic chondrocyte maturation and bone formation. Additionally, osteoclast and endothelial cell invasion are delayed in the Lbh-overexpressing bones. Finally, we find a dramatic suppression of Runx2 and VEGF mRNAs in chondrocytes and osteoblasts that overexpress Lbh. Strikingly, this abnormal bone development in infected limbs can be rescued by concurrent overexpression of Runx2. These results suggest that during endochondral bone formation, Lbh may negatively regulate vascular invasion and formation of the early ossification center at least in part by interfering with Runx2 and/or VEGF expression. (C) 2009 Elsevier Inc. All rights reserved. C1 [Conen, K. L.; Nishimori, S.; Kronenberg, H. M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02115 USA. [Conen, K. L.] Univ Basel Bruderholz, Kantonsspital Bruderholz, Dept Med, Basel, Switzerland. [Provot, S.] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. RP Kronenberg, HM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02115 USA. EM kronenberg.henry@mgh.harvard.edu FU NIH [DK056246]; Swiss National Foundation [PBSKB-114291]; Freiwillige Akademische Gesellschaft Basel, Switzerland FX We thank Clifford Tabin and Patrick Allard for assistance in using the chicken system and related experiments and for providing reagents. We thank Ernestina Schipani, JoyWu and Tatsuya Kobayashi for technical advice and critical discussions. We thank Gregory Nachtrab and Abhishek Gole for technical assistance. This work was supported by NIH grant DK056246, by Swiss National Foundation grant PBSKB-114291 and by the Freiwillige Akademische Gesellschaft Basel, Switzerland. NR 31 TC 12 Z9 13 U1 1 U2 7 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 SEP 15 PY 2009 VL 333 IS 2 BP 348 EP 358 DI 10.1016/j.ydbio.2009.07.003 PG 11 WC Developmental Biology SC Developmental Biology GA 526AQ UT WOS:000272260300011 PM 19607824 ER PT J AU del Castillo-Olivares, A Kulkarni, M Smith, HE AF del Castillo-Olivares, Antonio Kulkarni, Madhura Smith, Harold E. TI Regulation of sperm gene expression by the GATA factor ELT-1 SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Germ line; Spermatogenesis; GATA factor; Gene expression ID SEX-DETERMINING GENE; TRANSCRIPTION FACTOR GATA-1; NEMATODE CAENORHABDITIS-ELEGANS; ZINC-FINGER PROTEINS; ONE-HYBRID SYSTEM; C-ELEGANS; DNA-BINDING; DIFFERENTIATION GENE; MOUSE TESTIS; CELL FATE AB Cell fate specification is mediated primarily through the expression of cell-type-specific genes. The regulatory pathway that governs the sperm/egg decision in the hermaphrodite germ line of Caenorhabditis elegans has been well characterized, but the transcription factors that drive these developmental programs remain unknown. We report the identification of ELT-1, a GATA transcription factor that specifies hypodermal fate in the embryo, as a regulator of sperm-specific transcription in the germ line. Computational analysis identified a conserved bipartite sequence element that is found almost exclusively in the promoters of a number of sperm genes. ELT-1 was recovered in a yeast one-hybrid screen for factors that bind to that sperm consensus site. In vitro assays defined the sperm consensus sequence as an optimal binding site for ELT-1. We determined that expression of elt-1 is elevated in the sperm-producing germ line, and that ELT-1 is required for sperm function. Deletion of the ELT-1 binding site from a sperm promoter abrogates sperm-specific expression of a reporter transgene. This work demonstrates a role for the ELT-1 transcription factor in sperm, and provides a critical link between the germ line sex determination program and gamete-specific gene expression. (C) 2009 Elsevier Inc. All rights reserved. C1 [del Castillo-Olivares, Antonio; Smith, Harold E.] Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. [Kulkarni, Madhura] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Kulkarni, Madhura] Harvard Univ, Sch Med, Dept Cell Biol, Charlestown, MA 02129 USA. [Kulkarni, Madhura] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02129 USA. [Smith, Harold E.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Smith, HE (reprint author), 8 Ctr Dr, Bethesda, MD 20892 USA. EM smithhe2@niddk.nih.gov FU National Science Foundation [0445684] FX We wish to thank the Caenorhabditis Genetics Center and the C. elegans Gene Knockout Consortium for providing strains and plasmids, Bronessa Fernandes for assistance with the yeast one-hybrid assays, one anonymous reviewer for suggesting the mosaic/GFP experiment, and members of the lab and the Baltimore/Washington worm community for fruitful discussions. This work was supported in part by National Science Foundation grant number 0445684 to H. E. S. NR 79 TC 10 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 15 PY 2009 VL 333 IS 2 BP 397 EP 408 DI 10.1016/j.ydbio.2009.06.044 PG 12 WC Developmental Biology SC Developmental Biology GA 526AQ UT WOS:000272260300015 PM 19591818 ER PT J AU Cotsapas, C Speliotes, EK Hatoum, IJ Greenawalt, DM Dobrin, R Lum, PY Suver, C Chudin, E Kemp, D Reitman, M Voight, BF Neale, BM Schadt, EE Hirschhorn, JN Kaplan, LM Daly, MJ AF Cotsapas, Chris Speliotes, Elizabeth K. Hatoum, Ida J. Greenawalt, Danielle M. Dobrin, Radu Lum, Pek Y. Suver, Christine Chudin, Eugene Kemp, Daniel Reitman, Marc Voight, Benjamin F. Neale, Benjamin M. Schadt, Eric E. Hirschhorn, Joel N. Kaplan, Lee M. Daly, Mark J. CA GIANT Consortium TI Common body mass index-associated variants confer risk of extreme obesity SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ADULT OBESITY; FTO GENE; STRATIFICATION; CHILDHOOD; SNPS; LOCI; MAP AB To investigate the genetic architecture of severe obesity, we performed a genome-wide association study of 775 cases and 3197 unascertained controls at similar to 550 000 markers across the autosomal genome. We found convincing association to the previously described locus including the FTO gene. We also found evidence of association at a further six of 12 other loci previously reported to influence body mass index (BMI) in the general population and one of three associations to severe childhood and adult obesity and that cases have a higher proportion of risk-conferring alleles than controls. We found no evidence of homozygosity at any locus due to identity-by-descent associating with phenotype which would be indicative of rare, penetrant alleles, nor was there excess genome-wide homozygosity in cases relative to controls. Our results suggest that variants influencing BMI also contribute to severe obesity, a condition at the extreme of the phenotypic spectrum rather than a distinct condition. C1 [Cotsapas, Chris; Speliotes, Elizabeth K.; Voight, Benjamin F.; Neale, Benjamin M.; Hirschhorn, Joel N.; Daly, Mark J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hatoum, Ida J.; Kaplan, Lee M.] Massachusetts Gen Hosp, MGH Weight Ctr, Boston, MA 02114 USA. [Cotsapas, Chris; Voight, Benjamin F.; Neale, Benjamin M.; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Cotsapas, Chris; Voight, Benjamin F.; Neale, Benjamin M.; Daly, Mark J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Speliotes, Elizabeth K.; Hatoum, Ida J.; Kaplan, Lee M.] MIT & Harvard, Broad Inst, Metab Initiat, Cambridge, MA USA. [Speliotes, Elizabeth K.; Hirschhorn, Joel N.] MIT & Harvard, Broad Inst, Med & Populat Genet Program, Cambridge, MA USA. [Greenawalt, Danielle M.; Dobrin, Radu; Lum, Pek Y.; Suver, Christine] Genet Rosetta Inpharmat LLC, Seattle, WA 98109 USA. [Kemp, Daniel; Reitman, Marc] Merck Res Labs, Dept Metab Disorders, Rahway, NJ 07065 USA. [Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. RP Kaplan, LM (reprint author), Massachusetts Gen Hosp, MGH Weight Ctr, Blake 4,55 Fruit St, Boston, MA 02114 USA. EM kaplan@helix.mgh.harvard.edu; mjdaly@chgr.mgh.harvard.edu RI Voight, Benjamin/F-1775-2011; Reitman, Marc/B-4448-2013; OI Reitman, Marc/0000-0002-0426-9475; Suver, Christine/0000-0002-2986-385X; Dobrin, Radu/0000-0002-3336-0091; Cotsapas, Chris/0000-0002-7772-5910 FU Merck Research Laboratories; National Institutes of Health [DK046200, DK043351, DK057478, DK07191-32, DK079466-01, DK080145-01]; MGH ECOR/FMD fellowship FX This work was supported by grants to L. M. K. from Merck Research Laboratories and the National Institutes of Health [grant numbers DK046200, DK043351 and DK057478]. C. C. is supported by an MGH ECOR/FMD fellowship. E. K. S. was supported by the National Institutes of Health [grant numbers DK07191-32, DK079466-01 and DK080145-01]. NR 19 TC 57 Z9 62 U1 0 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 SEP 15 PY 2009 VL 18 IS 18 BP 3502 EP 3507 DI 10.1093/hmg/ddp292 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 486NF UT WOS:000269203000015 PM 19553259 ER PT J AU McLaughlin, KA Chitnis, T Newcombe, J Franz, B Kennedy, J McArdel, S Kuhle, J Kappos, L Rostasy, K Pohl, D Gagne, D Ness, JM Tenembaum, S O'Connor, KC Viglietta, V Wong, SJ Tavakoli, NP de Seze, J Idrissova, Z Khoury, SJ Bar-Or, A Hafler, DA Banwell, B Wucherpfennig, KW AF McLaughlin, Katherine A. Chitnis, Tanuja Newcombe, Jia Franz, Bettina Kennedy, Julia McArdel, Shannon Kuhle, Jens Kappos, Ludwig Rostasy, Kevin Pohl, Daniela Gagne, Donald Ness, Jayne M. Tenembaum, Silvia O'Connor, Kevin C. Viglietta, Vissia Wong, Susan J. Tavakoli, Norma P. de Seze, Jerome Idrissova, Zhannat Khoury, Samia J. Bar-Or, Amit Hafler, David A. Banwell, Brenda Wucherpfennig, Kai W. TI Age-Dependent B Cell Autoimmunity to a Myelin Surface Antigen in Pediatric Multiple Sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACUTE DISSEMINATED ENCEPHALOMYELITIS; OLIGODENDROCYTE GLYCOPROTEIN; DIAGNOSTIC-CRITERIA; T-CELLS; MYELIN/OLIGODENDROCYTE GLYCOPROTEIN; NEUROMYELITIS-OPTICA; CLINICAL-FEATURES; MILK PROTEIN; CHILDREN; ANTIBODIES AB Multiple sclerosis (MS) typically manifests in early to mid adulthood, but there is increasing recognition of pediatric-onset MS, aided by improvements in imaging techniques. The immunological mechanisms of disease are largely unexplored in pediatric-onset MS, in part because studies have historically focused on adult-onset disease. We investigated autoantibodies to myelin surface Ags in a large cohort of pediatric MS cases by flow cytometric labeling of transfectants that expressed different myelin proteins. Although Abs to native myelin oligodendrocyte glycoprotein (MOG) were uncommon among adult-onset patients, a subset of pediatric patients had serum Abs that brightly labeled the MOG transfectant. Abs to two other myelin surface Ags were largely absent. Affinity purification of MOG Abs as well as competition of binding with soluble MOG documented their binding specificity. Such affinity purified Abs labeled myelin and glial cells in human CNS white matter as well as myelinated axons in gray matter. The prevalence of such autoantibodies was highest among patients with a very early onset of MS: 38.7% of patients less than 10 years of age at disease onset had MOG Abs, compared with 14.7% of patients in the 10- to 18-year age group. B cell autoimmunity to this myelin surface Ag is therefore most common in patients with a very early onset of MS. The Journal of Immunology, 2009,183: 4067-4076. C1 [McLaughlin, Katherine A.; Franz, Bettina; Wucherpfennig, Kai W.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [McLaughlin, Katherine A.; McArdel, Shannon; Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Program Immunol, Boston, MA 02115 USA. [Chitnis, Tanuja; O'Connor, Kevin C.; Viglietta, Vissia; Khoury, Samia J.; Hafler, David A.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Chitnis, Tanuja; O'Connor, Kevin C.; Viglietta, Vissia; Khoury, Samia J.; Hafler, David A.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Chitnis, Tanuja] Massachusetts Gen Hosp Children, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. [Newcombe, Jia] UCL, Inst Neurol, London, England. [Kennedy, Julia; Banwell, Brenda] Hosp Sick Children, Dept Pediat, Div Neurol, Inst Neurol, Toronto, ON M5G 1X8, Canada. [Kuhle, Jens; Kappos, Ludwig] Univ Basel Hosp, Dept Res, CH-4031 Basel, Switzerland. [Kuhle, Jens; Kappos, Ludwig] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Rostasy, Kevin] Univ Gottingen, Dept Pediat & Pediat Neurol, Gottingen, Germany. [Pohl, Daniela] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada. [Gagne, Donald; Bar-Or, Amit] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. [Ness, Jayne M.] Childrens Hosp Alabama, Birmingham, AL 35233 USA. [Tenembaum, Silvia] Natl Pediat Hosp Dr JP Garrahan, Dept Pediat Neurol, Buenos Aires, DF, Argentina. [Wong, Susan J.; Tavakoli, Norma P.] New York State Dept Hlth, Wadsworth Ctr, Diagnost Immunol Lab, Albany, NY 12207 USA. [de Seze, Jerome] Strasbourg Univ, Dept Neurol, Alsace, France. [Idrissova, Zhannat] Kazak State Med Univ, Dept Neurol, Alma Ata, Kazakhstan. RP Wucherpfennig, KW (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,Room D1410, Boston, MA 02115 USA. EM Kai_Wucherpfennig@dfci.harvard.edu RI Bar-Or, Amit/C-4213-2011; De Seze, Jerome/M-8316-2016; OI De Seze, Jerome/0000-0002-7197-7578; khoury, samia/0000-0003-3198-6063 FU National Institutes of Health [POI A1045757]; National Multiple Sclerosis Society [RG 4122-A-6]; Wadsworth Foundation FX This work was supported by Grant POI A1045757 from the National Institutes of Health (to K.W.W.), Grant RG 4122-A-6 from the National Multiple Sclerosis Society (to K.W.W,), and Grant A B-O from the Wadsworth Foundation (to B.B.). NR 58 TC 89 Z9 91 U1 1 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2009 VL 183 IS 6 BP 4067 EP 4076 DI 10.4049/jimmunol.0801888 PG 10 WC Immunology SC Immunology GA 498XR UT WOS:000270179700061 PM 19687098 ER PT J AU McGovern, BH Nagami, EH Birch, CE Bowen, MJ Reyor, LL Chung, RT Kim, AY AF McGovern, Barbara H. Nagami, Ellen H. Birch, Christopher E. Bowen, Melinda J. Reyor, Laura L. Chung, Raymond T. Kim, Arthur Y. TI Rate of Sustained Virologic Response in Relation to Baseline Hepatitis C Virus (HCV) RNA Level and Rapid Virologic Clearance in Persons with Acute HCV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 59th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases CY OCT 31-NOV 04, 2008 CL San Francisco, CA SP Amer Assoc Study Liver Dis, Moscone West Convent Ctr ID ALPHA-2A (40 KD)/RIBAVIRIN; RIBAVIRIN; THERAPY AB Treatment of acute hepatitis C virus (HCV) infection leads to a sustained virologic response (SVR) in the vast majority of patients, although the clinical predictors of these favorable responses are not well understood. In chronic infection, the most potent predictor of a SVR is complete viral suppression after 4 weeks of treatment, also known as a rapid virologic response (RVR). However, few patients with HCV genotype 1 infection and high-level viremia ever achieve this benchmark. In 2 separate cohorts of patients with acute HCV infection, we demonstrate that rapid virologic clearance and low-level viremia (HCV RNA level, <400,000 IU/mL) are highly prevalent, regardless of HCV genotype. C1 [McGovern, Barbara H.] Lemuel Shattuck Hosp, Div Infect Dis, Boston, MA 02130 USA. [McGovern, Barbara H.] Massachusetts Gen Hosp, Tufts Med Sch, Boston, MA 02114 USA. [Reyor, Laura L.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chung, Raymond T.; Kim, Arthur Y.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Nagami, Ellen H.; Birch, Christopher E.; Kim, Arthur Y.] Harvard Univ, Ctr AIDS Res, Boston, MA 02115 USA. [Nagami, Ellen H.; Birch, Christopher E.; Bowen, Melinda J.; Reyor, Laura L.; Kim, Arthur Y.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Nagami, Ellen H.; Birch, Christopher E.; Bowen, Melinda J.; Reyor, Laura L.; Kim, Arthur Y.] Harvard Univ, Charlestown, MA USA. [Bowen, Melinda J.] Univ Massachusetts, Sch Med, Worcester, MA USA. RP McGovern, BH (reprint author), Lemuel Shattuck Hosp, Div Infect Dis, 170 Morton St Jamaica Plain, Boston, MA 02130 USA. EM bmcgovern@tuftsmedicalcenter.org FU NIAID NIH HHS [P30 AI 060354, U19 AI066345-030002, P30 AI060354-01, K23 AI 054379, U19 AI 066345, U19 AI066345, U19 AI066345-010002, K23 AI054379-05, U19 AI066345-020002, K23 AI054379, U19 AI066345-040002, P30 AI060354]; NIMHD NIH HHS [L32 MD000727-02A1, L32 MD000727] NR 16 TC 15 Z9 15 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2009 VL 200 IS 6 BP 877 EP 881 DI 10.1086/605444 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 484HF UT WOS:000269034200007 PM 19673649 ER PT J AU Rodger, AJ Fox, Z Lundgren, JD Kuller, LH Boesecke, C Gey, D Skoutelis, A Goetz, MB Phillips, AN AF Rodger, Alison J. Fox, Zoe Lundgren, Jens D. Kuller, Lewis H. Boesecke, Christoph Gey, Daniela Skoutelis, Athanassios Goetz, Matthew Bidwell Phillips, Andrew N. CA INSIGHT Strategies Management TI Activation and Coagulation Biomarkers Are Independent Predictors of the Development of Opportunistic Disease in Patients with HIV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 16th Conference on Retroviruses and Opportunistic Infections CY FEB 08-11, 2009 CL Montreal, CANADA ID C-REACTIVE PROTEIN; CD4(+) CELL COUNT; IMMUNE ACTIVATION; CARDIOVASCULAR-DISEASE; ANTIRETROVIRAL TREATMENT; GENE-EXPRESSION; VIRAL LOAD; MARKERS; AIDS; INTERLEUKIN-6 AB Activation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human immunodeficiency virus (HIV)-positive patients were examined. Methods. Inflammatory (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], amyloid-A, and amyloid-P) and coagulation (D-dimer and prothrombin-fragment 1+2) markers were determined. Conditional logistic regression analyses were used to assess associations between these biomarkers and risk of OD. Results. The 91 patients who developed an OD were matched to 182 control subjects. Patients with an hsCRP level >= 5 mu g/mL at baseline had a 3.5 higher odds of OD (95% confidence interval [CI], 1.5-8.1) than did those with an hsCRP level <1 mu g/mL (P = .003, by test for trend) and patients with an IL-6 level >= 3 pg/mL at baseline had a 2.4 higher odds of OD (95% CI, 1.0-5.4) than did those with an IL-6 level <1.5 pg/mL (P = .02, by test for trend). No other baseline biomarkers predicted development of an OD. Latest follow-up hsCRP level for those with an hsCRP level >= 5 mu g/mL (compared with a level <1 mu g/mL; odds ratio [OR], 7.6; 95% CI, 2.0-28.5; P = .002, by test for trend), latest amyloid-A level for those with an amyloid-A level >= 6 mg/L (compared with a leve <2 mg/L; OR, 3.8; 95% CI, 1.1-13.4; P = .03, by test for trend), and latest IL-6 level for those with an IL-6 level >= 3 pg/mL (compared with a level <1.5 pg/mL; OR 2.4; 95% CI, 0.7-8.8; P = .04, by test for trend) were also associated with development of an OD. Conclusions. Higher IL-6 and hsCRP levels independently predicted development of OD. These biomarkers could provide additional prognostic information for predicting the risk of OD. Clinical trials registration. Clinical Trials.gov number NCT00027352. C1 [Rodger, Alison J.] UCL, HIV Epidemiol & Biostat Grp, Res Dept Infect & Populat Hlth, Sch Med, London NW3 2PF, England. [Fox, Zoe; Lundgren, Jens D.; Gey, Daniela] Univ Copenhagen, Copenhagen, Denmark. [Fox, Zoe; Lundgren, Jens D.; Gey, Daniela] Rigshosp, DK-2100 Copenhagen, Denmark. [Skoutelis, Athanassios] Gen Hosp, Athens, Greece. [Kuller, Lewis H.] Univ Pittsburgh, Pittsburgh, PA USA. [Goetz, Matthew Bidwell] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Boesecke, Christoph] Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. RP Rodger, AJ (reprint author), UCL, HIV Epidemiol & Biostat Grp, Res Dept Infect & Populat Hlth, Sch Med, Royal Free Campus,Rowland Hill St, London NW3 2PF, England. EM a.rodger@pcps.ucl.ac.uk RI Phillips, Andrew/B-4427-2008; SHCS, int. coll. B/G-4090-2011; SHCS, all/G-4072-2011; Pulido, Federico/B-8417-2009; Brites, Carlos/D-1353-2013; OI Phillips, Andrew/0000-0003-2384-4807; Lundgren, Jens/0000-0001-8901-7850; Goetz, Matthew/0000-0003-4542-992X; Pulido, Federico/0000-0002-7414-8812; Koirala, Janak/0000-0002-3608-474X; Brites, Carlos/0000-0002-4673-6991; Okhuysen, Pablo/0000-0002-1596-3411; Gayet-Ageron, Angele/0000-0002-6164-9693; Magenta, Lorenzo/0000-0002-7644-3647 FU Medical Research Council [MC_U122886352]; NIAID NIH HHS [U01 AI 042170, U01 AI 46362, U01 AI042170, U01 AI042170-07, U01 AI046362] NR 31 TC 86 Z9 88 U1 2 U2 13 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2009 VL 200 IS 6 BP 973 EP 983 DI 10.1086/605447 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 484HF UT WOS:000269034200018 PM 19678756 ER PT J AU Pereyra, F Palmer, S Miura, T Block, BL Wiegand, A Rothchild, AC Baker, B Rosenberg, R Cutrell, E Seaman, MS Coffin, JM Walker, BD AF Pereyra, Florencia Palmer, Sarah Miura, Toshiyuki Block, Brian L. Wiegand, Ann Rothchild, Alissa C. Baker, Brett Rosenberg, Rachel Cutrell, Emily Seaman, Michael S. Coffin, John M. Walker, Bruce D. TI Persistent Low-Level Viremia in HIV-1 Elite Controllers and Relationship to Immunologic Parameters SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 15th Conference on Retroviruses and Opportunistic Infections CY FEB 03-06, 2008 CL Boston, MA ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL-ACTIVATION; ANTIRETROVIRAL THERAPY; VIRAL REPLICATION; INFECTION; TYPE-1; ABSENCE; INDIVIDUALS; PLASMA; RNA AB Background. Human immunodeficiency virus type 1 (HIV-1) elite controllers are able to control virus replication to levels below the limits of detection by commercial assays, but the actual level of viremia in these individuals is not well defined. Here, we quantify plasma HIV-1 RNA in elite controllers and correlate this with specific immunologic parameters. Methods. Plasma HIV-1 RNA levels were quantified in 90 elite controllers with use of a real time reverse-transcriptase polymerase chain reaction assay with a sensitivity of 0.2 copies/mL. HIV-1-specific immune responses and longitudinal CD4(+) T cell counts were examined. Results. The median plasma HIV-1 RNA level was 2 copies/mL (interquartile range, 0.2-14 copies/mL). A longitudinal analysis of 31 elite controllers demonstrated 2-5-fold fluctuations in viremia in the majority of individuals; 6 had persistent levels below 1 copy/mL. Viremia correlated directly with HIV-1-specific neutralizing antibodies and Western blot reactivity but not with CD8(+) T cell responses. Absolute CD4(+) T cell decrease was more common among individuals with detectable viremia (P = .04). Conclusions. Low-level viremia is present in the majority of elite controllers and is associated with higher HIV-1-specific antibody responses. Absolute CD4(+) T cell loss is more common among viremic individuals, suggesting that even very low-level viremia has negative consequences over time. C1 [Pereyra, Florencia; Miura, Toshiyuki; Block, Brian L.; Rothchild, Alissa C.; Baker, Brett; Rosenberg, Rachel; Cutrell, Emily; Walker, Bruce D.] Massachusetts Gen Hosp, Ragon Inst, MIT, Charlestown, MA 02129 USA. [Pereyra, Florencia] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Palmer, Sarah; Wiegand, Ann] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Miura, Toshiyuki; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Palmer, Sarah] Swedish Inst Infect Dis Control, Dept Virol, Solna, Sweden. [Palmer, Sarah] Karolinska Inst, Solna, Sweden. RP Pereyra, F (reprint author), Massachusetts Gen Hosp, Ragon Inst, MIT, 149 13th St, Charlestown, MA 02129 USA. EM fpereyra@partners.org OI Rothchild, Alissa/0000-0001-7484-1193 FU NIAID NIH HHS [AI30914, P30 AI060354, AI28568, R37 AI028568, R01 AI028568, R01 AI030914] NR 27 TC 108 Z9 110 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2009 VL 200 IS 6 BP 984 EP 990 DI 10.1086/605446 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 484HF UT WOS:000269034200019 PM 19656066 ER PT J AU Singh, N Aguado, JM Bonatti, H Forrest, G Gupta, KL Safdar, N John, GT Pursell, KJ Munoz, P Patel, R Fortun, J Martin-Davila, P Philippe, B Philit, F Tabah, A Terzi, N Chatelet, V Kusne, S Clark, N Blumberg, E Julia, MB Humar, A Houston, S Lass-Florl, C Johnson, L Dubberke, ER Barron, MA Lortholary, O AF Singh, Nina Aguado, Jose M. Bonatti, Hugo Forrest, Graeme Gupta, Krishan L. Safdar, Nasia John, George T. Pursell, Kenneth J. Munoz, Patricia Patel, Robin Fortun, Jesus Martin-Davila, Pilar Philippe, Bruno Philit, Francois Tabah, Alexis Terzi, Nicolas Chatelet, Valerie Kusne, Shimon Clark, Nina Blumberg, Emily Blanes Julia, Marino Humar, Abhi Houston, Sally Lass-Floerl, Cornelia Johnson, Leonard Dubberke, Erik R. Barron, Michelle A. Lortholary, Olivier TI Zygomycosis in Solid Organ Transplant Recipients: A Prospective, Matched Case-Control Study to Assess Risks for Disease and Outcome SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RECEIVING VORICONAZOLE PROPHYLAXIS; INVASIVE FUNGAL-INFECTIONS; CARE CANCER CENTER; IRON OVERLOAD; CRYPTOCOCCUS-NEOFORMANS; KIDNEY-TRANSPLANTATION; COMBINATION THERAPY; SALVAGE THERAPY; LIVER; POSACONAZOLE AB Background. Clinical characteristics, risks, and outcomes in solid organ transplant (SOT) recipients with zygomycosis in the era of modern immunosuppressive and newer antifungal agent use have not been defined. Methods. In a matched case-controlled study, SOT recipients with zygomycosis were prospectively studied. The primary outcome measure was success (complete or partial response) at 90 days. Results. Renal failure (odds ratio [OR], 3.17; P = .010), diabetes mellitus (OR, 8.11; P<.001), and prior voriconazole and/or caspofungin use (OR, 4.41; P = .033) were associated with a higher risk of zygomycosis, whereas tacrolimus (OR, 0.23; P = .002) was associated with a lower risk of zygomycosis. Liver transplant recipients were more likely to have disseminated disease (OR, 5.48; P = .021) and developed zygomycosis earlier after transplantation than did other SOT recipients (median, 0.8 vs 5.7 months; P<.001). Overall the treatment success rate was 60%. Renal failure (OR, 11.3; P = 0.23) and disseminated disease (OR, 14.6; P = .027) were independently predictive of treatment failure, whereas surgical resection was associated with treatment success (OR, 33.3; P = .003). The success rate with liposomal amphotericin B was 4-fold higher even when controlling for the afore-mentioned variables. Conclusions. The risks identified for zygomycosis and for disseminated disease, including those that were previously unrecognized, have implications for further elucidating the biologic basis and for optimizing outcomes in SOT recipients with zygomycosis C1 [Singh, Nina] VA Pittsburgh Healthcare Syst, Infect Dis Sect, VA Med Ctr, Pittsburgh, PA 15240 USA. [Singh, Nina] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Blumberg, Emily] Univ Penn, Philadelphia, PA 19104 USA. [Munoz, Patricia] Univ Gregario Maranon, Gen Hosp, Madrid, Spain. [Fortun, Jesus; Martin-Davila, Pilar] Hosp Univ Ramon & Cajal, Madrid, Spain. [Blanes Julia, Marino] Hosp Univ La Fe, Valencia, Spain. [Bonatti, Hugo] Univ Virginia, Charlottesville, VA USA. [Forrest, Graeme] Univ Maryland, Baltimore, MD 21201 USA. [Gupta, Krishan L.] Postgrad Inst Med Educ & Res, Chandigarh 160012, India. [John, George T.] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Safdar, Nasia] Univ Wisconsin, Madison, WI 53706 USA. [Pursell, Kenneth J.] Univ Chicago, Chicago, IL 60637 USA. [Clark, Nina] Univ Illinois, Chicago, IL USA. [Patel, Robin] Mayo Clin, Rochester, MN USA. [Humar, Abhi] Univ Minnesota, Minneapolis, MN USA. [Philippe, Bruno] Hop CMC Foch, Suresnes, France. [Philit, Francois] Hop Louis Pradel, Lyon, France. [Tabah, Alexis] Univ Hosp Albert Michallon, Grenoble, France. [Terzi, Nicolas; Chatelet, Valerie] CHU Caen, F-14000 Caen, France. [Lortholary, Olivier] Univ Paris 05, Hop Necker Enfants Malad, Ctr Infectiol Necker Pasteur, Paris, France. [Lortholary, Olivier] Inst Pasteur, Ctr Natl Reference Mycol & Antifong, Paris, France. [Kusne, Shimon] Mayo Clin, Scottsdale, AZ USA. [Houston, Sally] Univ S Florida, Tampa, FL USA. [Lass-Floerl, Cornelia] Innsbruck Med Univ, Innsbruck, Austria. [Johnson, Leonard] St John Hosp & Med Ctr, Detroit, MI USA. [Dubberke, Erik R.] Washington Univ, Sch Med, St Louis, MO USA. [Barron, Michelle A.] Univ Colorado, Denver, CO 80202 USA. RP Singh, N (reprint author), VA Pittsburgh Healthcare Syst, Infect Dis Sect, VA Med Ctr, Univ Dr, Pittsburgh, PA 15240 USA. EM nis5@pitt.edu RI Tabah, Alexis/B-6982-2014; OI Tabah, Alexis/0000-0003-3513-2778; Munoz Garcia, Patricia Carmen/0000-0001-5706-5583; Clark, Nina/0000-0001-5670-4443 NR 48 TC 87 Z9 87 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2009 VL 200 IS 6 BP 1002 EP 1011 DI 10.1086/605445 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 484HF UT WOS:000269034200021 PM 19659439 ER PT J AU Blankstein, R Shturman, LD Rogers, IS Rocha, JA Okada, DR Sarwar, A Soni, AV Bezerra, H Ghoshhajra, BB Petranovic, M Loureiro, R Feuchtner, G Gewirtz, H Hoffmann, U Mamuya, WS Brady, TJ Cury, RC AF Blankstein, Ron Shturman, Leon D. Rogers, Ian S. Rocha-Filho, Jose A. Okada, David R. Sarwar, Ammar Soni, Anand V. Bezerra, Hiram Ghoshhajra, Brian B. Petranovic, Milena Loureiro, Ricardo Feuchtner, Gudrun Gewirtz, Henry Hoffmann, Udo Mamuya, Wilfred S. Brady, Thomas J. Cury, Ricardo C. TI Adenosine-Induced Stress Myocardial Perfusion Imaging Using Dual-Source Cardiac Computed Tomography SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE infarction; ischemia; imaging; coronary disease; computed tomography ID CORONARY-ARTERY-DISEASE; SYNDROME EVALUATION WISE; COMPREHENSIVE ASSESSMENT; MAGNETIC-RESONANCE; STABLE ANGINA; INFARCTION; CT; ANGIOGRAPHY; ISCHEMIA; HEART AB Objectives This study sought to determine the feasibility of performing a comprehensive cardiac computed tomographic (CT) examination incorporating stress and rest myocardial perfusion imaging together with coronary computed tomography angiography (CTA). Background Although cardiac CT can identify coronary stenosis, very little data exist on the ability to detect stress-induced myocardial perfusion defects in humans. Methods Thirty-four patients who had a nuclear stress test and invasive angiography were included in the study. Dual-source computed tomography (DSCT) was performed as follows: 1) stress CT: contrast-enhanced scan during adenosine infusion; 2) rest CT: contrast-enhanced scan using prospective triggering; and 3) delayed scan: acquired 7 min after rest CT. Images for CTA, computed tomography perfusion (CTP), and single-photon emission computed tomography (SPECT) were each read by 2 independent blinded readers. Results The DSCT protocol was successfully completed for 33 of 34 subjects (average age 61.4 +/- 10.7 years; 82% male; body mass index 30.4 +/- 5 kg/m(2)) with an average radiation dose of 12.7 mSv. On a per-vessel basis, CTP alone had a sensitivity of 79% and a specificity of 80% for the detection of stenosis >= 50%, whereas SPECT myocardial perfusion imaging had a sensitivity of 67% and a specificity of 83%. For the detection of vessels with >= 50% stenosis with a corresponding SPECT perfusion abnormality, CTP had a sensitivity of 93% and a specificity of 74%. The CTA during adenosine infusion had a per-vessel sensitivity of 96%, specificity of 73%, and negative predictive value of 98% for the detection of stenosis > 70%. Conclusions Adenosine stress CT can identify stress-induced myocardial perfusion defects with diagnostic accuracy comparable to SPECT, with similar radiation dose and with the advantage of providing information on coronary stenosis. (J Am Coll Cardiol 2009; 54: 1072-84) (C) 2009 by the American College of Cardiology Foundation C1 [Blankstein, Ron; Shturman, Leon D.; Rogers, Ian S.; Rocha-Filho, Jose A.; Okada, David R.; Sarwar, Ammar; Soni, Anand V.; Bezerra, Hiram; Ghoshhajra, Brian B.; Petranovic, Milena; Loureiro, Ricardo; Feuchtner, Gudrun; Gewirtz, Henry; Hoffmann, Udo; Mamuya, Wilfred S.; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Blankstein, Ron; Shturman, Leon D.; Rogers, Ian S.; Rocha-Filho, Jose A.; Okada, David R.; Sarwar, Ammar; Soni, Anand V.; Bezerra, Hiram; Ghoshhajra, Brian B.; Petranovic, Milena; Loureiro, Ricardo; Feuchtner, Gudrun; Gewirtz, Henry; Hoffmann, Udo; Mamuya, Wilfred S.; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Blankstein, Ron; Shturman, Leon D.; Rogers, Ian S.; Rocha-Filho, Jose A.; Okada, David R.; Sarwar, Ammar; Soni, Anand V.; Bezerra, Hiram; Ghoshhajra, Brian B.; Petranovic, Milena; Loureiro, Ricardo; Feuchtner, Gudrun; Gewirtz, Henry; Hoffmann, Udo; Mamuya, Wilfred S.; Brady, Thomas J.; Cury, Ricardo C.] Harvard Univ, Sch Med, Boston, MA USA. [Blankstein, Ron] Brigham & Womens Hosp, Dept Med & Radiol, Noninvas Cardiovasc Imaging Program, Boston, MA 02115 USA. [Bezerra, Hiram] Case Western Reserve Univ, Harrington McLaughlin Heart & Vasc Inst, Cleveland, OH 44106 USA. [Feuchtner, Gudrun] Innsbruck Med Univ, Dept Radiol, Innsbruck, Austria. [Mamuya, Wilfred S.] Lown Cardiovasc Grp, Brookline, MA USA. [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Cardiovasc MR & CT Program, Miami, FL USA. RP Blankstein, R (reprint author), Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM rblankstein@partners.org FU National Institutes of Health [1T32 HL076136]; GE Healthcare; Bracco Diagnostics; Bayer Healthcare; Astellas Pharma, Inc. FX From the Cardiac MR PET CT Program, Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Noninvasive Cardiovascular Imaging Program, Department of Medicine and Radiology, Brigham and Women's Hospital, Boston, Massachusetts; Harrington McLaughlin Heart and Vascular Institute, Case Western Reserve University, Cleveland, Ohio; Department of Radiology, Innsbruck Medical University, Innsbruck, Austria; Lown Cardiovascular Group, Brookline, Massachusetts; and the Cardiovascular MR and CT Program, Baptist Cardiac and Vascular Institute, Miami, Florida. This study was supported in part by a grant from Astellas, Inc. Drs. Blankstein, Shturman, Rogers, and Soni have received support from National Institutes of Health grant 1T32 HL076136. Dr. Hoffmann has received research grants from GE Healthcare, Bracco Diagnostics, and Bayer Healthcare. Dr. Cury has received research grant support from Astellas Pharma, Inc. NR 26 TC 234 Z9 253 U1 0 U2 15 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 SEP 15 PY 2009 VL 54 IS 12 BP 1072 EP 1084 DI 10.1016/j.jacc.2009.06.014 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 491ZV UT WOS:000269624000004 PM 19744616 ER PT J AU Sauce, D Larsen, M Abbott, RJM Hislop, AD Leese, AM Khan, N Papagno, L Freeman, GJ Rickinson, AB AF Sauce, Delphine Larsen, Martin Abbott, Rachel J. M. Hislop, Andrew D. Leese, Alison M. Khan, Naeem Papagno, Laura Freeman, Gordon J. Rickinson, Alan B. TI Upregulation of Interleukin 7 Receptor Alpha and Programmed Death 1 Marks an Epitope-Specific CD8(+) T-Cell Response That Disappears following Primary Epstein-Barr Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CHRONIC VIRAL-INFECTION; PD-1 EXPRESSION; IN-VIVO; IL-7 RECEPTOR; MEMORY CELLS; EXHAUSTION; ANTIGEN; DIFFERENTIATION; IMMUNODOMINANCE; EVOLUTION AB In immunocompetent individuals, the stability of the herpesvirus-host balance limits opportunities to study the disappearance of a virus-specific CD8(+) T-cell response. However, we noticed that in HLA-A*0201-positive infectious mononucleosis (IM) patients undergoing primary Epstein-Barr virus (EBV) infection, the initial CD8 response targets three EBV lytic antigen-derived epitopes, YVLDHLIVV (YVL), GLCTLVAML (GLC), and TLDYKPLSV (TLD), but only the YVL and GLC reactivities persist long-term; the TLD response disappears within 10 to 27 months. While present, TLD-specific cells remained largely indistinguishable from YVL and GLC reactivities in many phenotypic and functional respects but showed unique temporal changes in two markers of T-cell fate, interleukin 7 receptor alpha (IL-7R alpha; CD127) and programmed death 1 (PD-1). Thus, following the antigen-driven downregulation of IL-7R alpha seen on all populations in acute IM, in every case, the TLD-specific population recovered expression unusually quickly post-IM. As well, in four of six patients studied, TLD-specific cells showed very strong PD-1 upregulation in the last blood sample obtained before the cells' disappearance. Our data suggest that the disappearance of this individual epitope reactivity from an otherwise stable EBV-specific response (i) reflects a selective loss of cognate antigen restimulation (rather than of IL-7-dependent signals) and (ii) is immediately preceded, and perhaps mediated, by PD-1 upregulation to unprecedented levels. C1 [Sauce, Delphine; Larsen, Martin; Abbott, Rachel J. M.; Hislop, Andrew D.; Leese, Alison M.; Khan, Naeem; Rickinson, Alan B.] Univ Birmingham, CRUK, Inst Canc Studies, Birmingham B15 2TT, W Midlands, England. [Sauce, Delphine; Larsen, Martin; Abbott, Rachel J. M.; Hislop, Andrew D.; Leese, Alison M.; Khan, Naeem; Rickinson, Alan B.] Univ Birmingham, MRC, Ctr Immune Regulat, Birmingham B15 2TT, W Midlands, England. [Sauce, Delphine; Papagno, Laura] Univ Paris 06, INSERM, U543, Hop Pitie Salpetriere, Paris, France. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Dept Med, Boston, MA 02115 USA. RP Rickinson, AB (reprint author), Univ Birmingham, CRUK, Inst Canc Studies, Birmingham B15 2TT, W Midlands, England. EM A.B.Rickinson@bham.ac.uk RI sauce, delphine/H-1990-2014; Larsen, Martin/A-7316-2014; OI sauce, delphine/0000-0003-4596-7373; Larsen, Martin/0000-0003-1375-4816; Abbott, Rachel/0000-0003-1902-1429 FU United Kingdom Medical Research Council; NIH [AI56299] FX This study was supported by the United Kingdom Medical Research Council and NIH grant AI56299 ( Gordon Freeman). D. S. benefited from a Lavoisier grant from the Ministere des Affaires Etrangeres, France.; We declare no financial conflict of interest. NR 49 TC 13 Z9 13 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD SEP 15 PY 2009 VL 83 IS 18 BP 9068 EP 9078 DI 10.1128/JVI.00141-09 PG 11 WC Virology SC Virology GA 485MI UT WOS:000269127000005 PM 19605492 ER PT J AU Bhattacharya, D Mayuri, R Best, SM Perera, R Kuhn, RJ Striker, R AF Bhattacharya, Dipankar Mayuri, R. Best, S. M. Perera, R. Kuhn, R. J. Striker, Rob TI Protein Kinase G Phosphorylates Mosquito-Borne Flavivirus NS5 SO JOURNAL OF VIROLOGY LA English DT Article ID C VIRUS NS5A; RNA-SYNTHESIS; POLYMERASE; SITE; HYPERPHOSPHORYLATION; SUBSTRATE; SEQUENCE; BEHAVIOR AB Serine/threonine phosphorylation of the nonstructural protein 5 (NS5) is a conserved feature of flaviviruses, but the kinase(s) responsible and function(s) remain unknown. Mass spectrometry was used to compare the phosphorylation sites of the NS5 proteins of yellow fever virus (YFV) and dengue virus (DENV), two flaviviruses transmitted by mosquitoes. Seven DENV phosphopeptides were identified, but only one conserved phosphoacceptor site (threonine 449 in DENV) was identified in both viruses. This site is predicted to be a protein kinase G (PKG) recognition site and is a strictly conserved serine/threonine phosphoacceptor site in mosquito-borne flaviviruses. In contrast, in tick-borne flaviviruses, this residue is typically a histidine. A DENV replicon engineered to have the tick-specific histidine residue at this position is replication defective. We show that DENV NS5 purified from Escherichia coli is a substrate for PKG in vitro and facilitates the autophosphorylation of PKG as seen with cellular substrates. Phosphorylation in vitro by PKG also occurs at threonine 449. Activators and inhibitors of PKG modulate DENV replication in cell culture but not replication of the tick-borne langat virus. Collectively, these data argue that PKG mediates a conserved serine/threonine phosphorylation event specifically for flaviviruses spread by mosquitoes. C1 [Bhattacharya, Dipankar; Striker, Rob] Univ Wisconsin, Dept Med, Madison, WI 53706 USA. [Mayuri, R.; Perera, R.; Kuhn, R. J.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Striker, Rob] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53706 USA. [Best, S. M.] NIAID, Virol Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Striker, R (reprint author), Univ Wisconsin, Dept Med, Madison, WI 53706 USA. EM rtstriker@wisc.edu RI Perera, Rushika/E-7183-2017 OI Perera, Rushika/0000-0001-6798-2537 FU NIH/NIAID; NIH [1-U54AI-057153]; National Institute of Allergy and Infectious Diseases [AI55672]; University of Wisconsin Madison FX We also thank James Wolfinbarger for the doing the LGTV focus-forming assays. NR 24 TC 18 Z9 18 U1 1 U2 2 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 SEP 15 PY 2009 VL 83 IS 18 BP 9195 EP 9205 DI 10.1128/JVI.00271-09 PG 11 WC Virology SC Virology GA 485MI UT WOS:000269127000017 PM 19587048 ER PT J AU Huang, Z Dore, LC Li, Z Orkin, SH Feng, G Lin, S Crispino, JD AF Huang, Zan Dore, Louis C. Li, Zhe Orkin, Stuart H. Feng, Gang Lin, Simon Crispino, John D. TI GATA-2 Reinforces Megakaryocyte Development in the Absence of GATA-1 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; HOMEOBOX GENE HEX; HEMATOPOIETIC-CELLS; MEGAKARYOBLASTIC LEUKEMIA; ERYTHROID-DIFFERENTIATION; PROGENITOR CELLS; DOWN-SYNDROME; STEM-CELLS; EXPRESSION; LINEAGE AB GATA-2 is an essential transcription factor that regulates multiple aspects of hematopoiesis. Dysregulation of GATA-2 is a hallmark of acute megakaryoblastic leukemia in children with Down syndrome, a malignancy that is defined by the combination of trisomy 21 and a GATA1 mutation. Here, we show that GATA-2 is required for normal megakaryocyte development as well as aberrant megakaryopoiesis in Gata1 mutant cells. Furthermore, we demonstrate that GATA-2 indirectly controls cell cycle progression in GATA-1-deficient megakaryocytes. Genome-wide microarray analysis and chromatin immunoprecipitation studies revealed that GATA-2 regulates a wide set of genes, including cell cycle regulators and megakaryocyte-specific genes. Surprisingly, GATA-2 also negatively regulates the expression of crucial myeloid transcription factors, such as Sfpi1 and Cebpa. In the absence of GATA-1, GATA-2 prevents induction of a latent myeloid gene expression program. Thus, GATA-2 contributes to cell cycle progression and the maintenance of megakaryocyte identity of GATA-1-deficient cells, including GATA-1s-expressing fetal megakaryocyte progenitors. Moreover, our data reveal that overexpression of GATA-2 facilitates aberrant megakaryopoiesis. C1 [Huang, Zan; Crispino, John D.] Northwestern Univ, Div Hematol Oncol, Dept Med, Chicago, IL 60611 USA. [Dore, Louis C.] Northwestern Univ, Integrated Grad Program, Chicago, IL 60611 USA. [Li, Zhe] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Harvard Stem Cell Inst, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Feng, Gang; Lin, Simon] Northwestern Univ, Bioinformat Program, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. RP Crispino, JD (reprint author), Northwestern Univ, Div Hematol & Oncol, 303 Super St,Lurie Res Bldg 5-113, Chicago, IL 60611 USA. EM j-crispino@northwestern.edu RI Dore, Louis/A-5689-2009; OI Dore, Louis/0000-0002-7837-5887; Crispino, John/0000-0002-8182-8306 FU National Cancer Institute [R01 CA101774]; Chicago Center for Systems Biology [P50 GM081892]; Searle Funds at the Chicago Community Trust; Leukemia and Lymphoma Society FX This research was funded by a grant from the National Cancer Institute (R01 CA101774), by the Chicago Center for Systems Biology (P50 GM081892), and by the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. J.D.C. is a Scholar of the Leukemia and Lymphoma Society. NR 43 TC 50 Z9 51 U1 2 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 SEP 15 PY 2009 VL 29 IS 18 BP 5168 EP 5180 DI 10.1128/MCB.00482-09 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 487ZK UT WOS:000269318000026 PM 19620289 ER PT J AU Purev, E Neff, L Horne, WC Baron, R AF Purev, Enkhtsetseg Neff, Lynn Horne, William C. Baron, Roland TI c-Cbl and Cbl-b Act Redundantly to Protect Osteoclasts from Apoptosis and to Displace HDAC6 from beta-Tubulin, Stabilizing Microtubules and Podosomes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GROWTH-FACTOR RECEPTOR; NEGATIVE REGULATION; SRC KINASE; CELL-DEATH; EXTRACELLULAR-MATRIX; SIGNALING PATHWAY; TYROSINE KINASE; DOWN-REGULATION; IN-VIVO; ACTIVATION AB c-Cbl and Cbl-b are highly conserved adaptor proteins that participate in integrin signaling, regulating cytoskeletal organization, motility, and bone resorption. Deletion of both c-Cbl and Cbl-b in mice leads to embryonic lethality, indicating that the two proteins perform essential redundant functions. To examine the redundant actions of c-Cbl and Cbl-b in osteoclasts, we depleted c-Cbl in Cbl-b(-/-) osteoclasts by using a short hairpin RNA. Depleting both Cbl proteins disrupted both the podosome belt and the microtubule network and decreased bone-resorbing activity. Stabilizing the microtubules with paclitaxel or inhibiting histone deacetylase 6 (HDAC6), which destabilizes microtubules by deacetylating beta-tubulin, protected both the microtubule network and the podosome belt. Examination of the mechanism involved demonstrated that the conserved four-helix bundle of c-Cbl's tyrosine kinase binding domain bound to beta-tubulin, and both c-Cbl and Cbl-b displaced HDAC6. In addition to the effects on microtubules and the podosome belt, depleting both Cbls significantly increased the levels of the proapoptotic protein Bim and apoptosis relative to the levels induced by eliminating either protein alone. Thus, both c-Cbl and Cbl-b promote bone resorption via the stabilization of microtubules, allowing the formation of the podosome belt in osteoclasts, and by promoting osteoclast survival. C1 [Purev, Enkhtsetseg; Neff, Lynn; Horne, William C.; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Baron, Roland] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Baron, Roland] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Baron, R (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. EM roland_baron@hsdm.harvard.edu FU National Institutes of Health [DE-04724, AR-42927]; James Hudson Brown-Alexander Brown Coxe Postdoctoral Fellowship in the Medical Sciences FX We thank the Harvard NeuroDiscovery Optical Imaging Center for assistance with quantification of confocal images, Peter Renehan fr assistance in generating GST fusion proteins, Karen Ford for assistance with animal care, and Cecile Itzstein for helpful discussions. This study was supported by National Institutes of Health grants DE-04724 and AR-42927 (to R. B.) and the James Hudson Brown-Alexander Brown Coxe Postdoctoral Fellowship in the Medical Sciences (to E. P.). NR 62 TC 33 Z9 35 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP 15 PY 2009 VL 20 IS 18 BP 4021 EP 4030 DI 10.1091/mbc.E09-03-0248 PG 10 WC Cell Biology SC Cell Biology GA 493YU UT WOS:000269776500004 PM 19641021 ER PT J AU Schmahmann, JD Gardner, R MacMore, J Vangel, MG AF Schmahmann, Jeremy D. Gardner, Raquel MacMore, Jason Vangel, Mark G. TI Development of a Brief Ataxia Rating Scale (BARS) Based on a Modified Form of the ICARS SO MOVEMENT DISORDERS LA English DT Article DE ataxia; dysmetria; rating scale; assessment; cerebellum ID FUNCTIONAL LOCALIZATION; HUMAN CEREBELLUM; SOMATOTOPIC ORGANIZATION; CLINICAL-SCALE; BASIS PONTIS; RELIABILITY; VALIDITY; SYSTEM; MRI AB To develop a brief ataxia rating scale (BARS) for use by movement disorder specialists and general neurologists. Current ataxia rating scales are cumbersome and not designed for clinical practice. We first modified the International Cooperative Ataxia Rating Scale (ICARS) by adding seven ataxia tests (modified ICARS, or MICARS), and observed only minimally increased scores. We then used the statistics package R to find a five-test subset in MICARS that would correlate best with the total MICARS score. This was accomplished first without constraints and then with the clinical constraint requiring one test each of Gait, Kinetic Function-Arm, Kinetic Function-Leg, Speech, and Eye Movements. We validated these clinical constraints by factor analysis. We then validated the results in a second cohort of patients; evaluated inter-rater reliability in a third cohort; and used the same data set to compare BARS with the Scale for the Assessment and Rating of Ataxia (SARA). Correlation of ICARS with the seven additional tests that when added to ICARS form MICARS was 0.88. There were 31,481 five-test subtests (48% of possible combinations) that had a correlation with total MICARS score of >= 0.90. The strongest correlation of an unconstrained five-test subset was 0.963. The clinically constrained subtest validated by factor analysis, BARS, had a correlation with MICARS-minus-BARS of 0.952. Cronbach alpha for BARS and SARA was 0.90 and 0.92 respectively; and inter-rater reliability (intraclass correlation coefficient) was 0.91 and 0.93 respectively. BARS is valid, reliable, and sufficiently fast and accurate for clinical purposes. (C) 2009 Movement Disorder Society C1 [Schmahmann, Jeremy D.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Schmahmann, JD (reprint author), Massachusetts Gen Hosp, Dept Neurol, Suite 340,Charles River Plaza S,55 Fruit St, Boston, MA 02114 USA. EM jschmahmann@partners.org FU Birmingham Foundation [RO1 MH067980] FX Supported in part by RO1 MH067980, and the Birmingham Foundation. Presented in part to the 59th annual meeting of the American Academy of Neurology, Boston, March 2007. The statistical analysis was performed principally by Mark Vangel, PhD. NR 27 TC 59 Z9 59 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2009 VL 24 IS 12 BP 1820 EP 1828 DI 10.1002/mds.22681 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 509EG UT WOS:000270996500014 PM 19562773 ER PT J AU Zhao, X Rosenke, R Kronemann, D Brim, B Das, SR Dunah, AW Magnusson, KR AF Zhao, X. Rosenke, R. Kronemann, D. Brim, B. Das, S. R. Dunah, A. W. Magnusson, K. R. TI THE EFFECTS OF AGING ON N-METHYL-D-ASPARTATE RECEPTOR SUBUNITS IN THE SYNAPTIC MEMBRANE AND RELATIONSHIPS TO LONG-TERM SPATIAL MEMORY SO NEUROSCIENCE LA English DT Review DE prefrontal cortex; hippocampus; NR2B; NR1; spatial; learning ID NR2B-CONTAINING NMDA-RECEPTORS; MESSENGER-RNA EXPRESSION; AGE-RELATED DEFICITS; GLUTAMATE RECEPTORS; WATER MAZE; ELDERLY ADULTS; HIPPOCAMPAL SYNAPSES; POSTSYNAPTIC DENSITY; SELECTIVE IMPAIRMENT; MOLECULAR DIVERSITY AB There are declines in the protein expression of the NR2B (mouse epsilon 2) and NR1 (mouse zeta 1) subunits of the N-methyl-D-aspartate (NMDA) receptor in the cerebral cortex and hippocampus during aging in C57BL/6 mice. This study was designed to determine if there is a greater effect of aging on subunit expression and a stronger relationship between long-term spatial memory and subunit expression within the synaptic membrane than in the cell as a whole. Male, C57BL/6JNIA mice (4, 11 and 26 months old) were tested for long-term spatial memory in the Morris water maze. Frontal cortex, including prefrontal regions, and hippocampus were homogenized and fractionated into light and synaptosomal membrane fractions. Western blots were used to analyze protein expression of NR2B and NR1 subunits of the NMDA receptor. Old mice performed significantly worse than other ages in the spatial task. In the frontal cortex, the protein levels of the NR2B! subunit showed a greater decline with aging in the synaptic membrane fraction than in the whole homogenate, while in the hippocampus a similar age-related decline was observed in both fractions. There were no significant effects of aging on the expression of the NR1 subunit. Within the middle-aged mouse group, higher expression of both NR2B and NR1 subunits in the synaptic membrane of the hippocampus was associated with better memory. In the aged mice, however, higher expression of both subunits was associated with poorer memory. These results indicate that aging could be altering the localization of the NR2B subunit to the synaptic membrane within the frontal cortex. The correlational results suggest that NMDA receptor functions, receptor subunit composition, and/or the environment in which the receptor interacted in the hippocampus were not the same in the old animals as in younger mice and this may have contributed to memory declines during aging. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Zhao, X.; Brim, B.; Das, S. R.; Magnusson, K. R.] Oregon State Univ, Coll Vet Med, Dept Biomed Sci, Program Mol & Cellular Biol,Ctr Healthy Aging, Corvallis, OR 97331 USA. [Zhao, X.; Rosenke, R.; Kronemann, D.; Das, S. R.; Magnusson, K. R.] Univ Idaho, Moscow, ID 83844 USA. [Rosenke, R.] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. [Kronemann, D.] Univ Minnesota, Minneapolis, MN 55455 USA. [Dunah, A. W.] Massachusetts Gen Hosp, Charlestown, MA 02114 USA. [Dunah, A. W.] Harvard Univ, Sch Med, Charlestown, MA 02114 USA. RP Magnusson, KR (reprint author), Oregon State Univ, Coll Vet Med, Dept Biomed Sci, Program Mol & Cellular Biol,Ctr Healthy Aging, 105 Magruder Hall, Corvallis, OR 97331 USA. EM Kathy.Magnusson@oregonstate.edu FU NIH [AG16322] FX This work was supported by NIH grant AG16322 to K.R.M. We would also like to thank David G. Standaert for his advice on the subfractionation protocol. NR 107 TC 43 Z9 44 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD SEP 15 PY 2009 VL 162 IS 4 BP 933 EP 945 DI 10.1016/j.neuroscience.2009.05.018 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 483LS UT WOS:000268968900008 PM 19446010 ER PT J AU Kidambi, S Yarmush, RS Novik, E Chao, P Yarmush, ML Nahmias, Y AF Kidambi, Srivatsan Yarmush, Rubin S. Novik, Eric Chao, Piyun Yarmush, Martin L. Nahmias, Yaakov TI Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug discovery; liver metabolism; tissue engineering ID CULTURED RAT HEPATOCYTES; SANDWICH CONFIGURATION; NONPARENCHYMAL CELLS; EXTRACELLULAR-MATRIX; COLLAGEN SANDWICH; ENDOTHELIAL-CELLS; TERM CULTURE; LIVER CELLS; VITRO; HEPATOTOXICITY AB The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R(2) of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures. C1 [Kidambi, Srivatsan; Yarmush, Rubin S.; Yarmush, Martin L.; Nahmias, Yaakov] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02111 USA. [Novik, Eric; Chao, Piyun] H REL Corp, Beverly Hills, CA 90211 USA. [Nahmias, Yaakov] Hebrew Univ Jerusalem, Selim & Rachel Benin Sch Comp Sci & Engn, IL-91904 Jerusalem, Israel. RP Nahmias, Y (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02111 USA. EM ynahmias@partners.org RI Nahmias, Yaakov/H-4725-2013; KIDAMBI, SRIVATSAN/A-5689-2015; OI KIDAMBI, SRIVATSAN/0000-0002-0282-0411; Nahmias, Yaakov/0000-0002-6051-616X FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [K01DK080241]; National Institutes of Health BioMEMS Resource Center [P41 EB-002503]; Shriners Hospital FX We thank Carley J. Shulman and Chris Pohun Chen for technical support. This work was supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grant K01DK080241, National Institutes of Health BioMEMS Resource Center Grant P41 EB-002503, and the Shriners Hospital. NR 44 TC 78 Z9 78 U1 0 U2 11 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 SEP 15 PY 2009 VL 106 IS 37 BP 15714 EP 15719 DI 10.1073/pnas.0906820106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494IS UT WOS:000269806600039 PM 19720996 ER PT J AU Blundell, MP Bouma, G Metelo, J Worth, A Calle, Y Cowell, LA Westerberg, LS Moulding, DA Mirando, S Kinnon, C Cory, GO Jones, GE Snapper, SB Burns, SO Thrasher, AJ AF Blundell, Michael P. Bouma, Gerben Metelo, Joao Worth, Austen Calle, Yolanda Cowell, Lucy A. Westerberg, Lisa S. Moulding, Dale A. Mirando, Samuel Kinnon, Christine Cory, Giles O. Jones, Gareth E. Snapper, Scott B. Burns, Siobhan O. Thrasher, Adrian J. TI Phosphorylation of WASp is a key regulator of activity and stability in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE actin polymerization; immune deficiency; Wiskott-Aldrich syndrome ID WISKOTT-ALDRICH-SYNDROME; INTERFERENCE REFLECTION MICROSCOPY; SYNDROME PROTEIN WASP; X-LINKED NEUTROPENIA; B-CELL ACTIVATION; N-WASP; T-CELL; CONGENITAL NEUTROPENIA; IMMUNOLOGICAL SYNAPSE; ACTIN POLYMERIZATION AB The Wiskott-Aldrich syndrome protein (WASp) is a key cytoskeletal regulator in hematopoietic cells. Covalent modification of a conserved tyrosine by phosphorylation has emerged as an important potential determinant of activity, although the physiological significance remains uncertain. In a murine knockin model, mutation resulting in inability to phosphorylate Y293 (Y293F) mimicked many features of complete WASp-deficiency. Although a phosphomimicking mutant Y293E conferred enhanced actin-polymerization, the cellular phenotype was similar due to functional dysregulation. Furthermore, steady-state levels of Y293E-WASp were markedly reduced compared to wild-type WASp and Y293F-WASp, although partially recoverable by treatment of cells with proteasome inhibitors. Consequently, tyrosine phosphorylation plays a critical role in normal activation of WASp in vivo, and is indispensible for multiple tasks including proliferation, phagocytosis, chemotaxis, and assembly of adhesion structures. Furthermore, it may target WASp for proteasome-mediated degradation, thereby providing a default mechanism for self-limiting stimulation of the Arp2/3 complex. C1 [Blundell, Michael P.; Bouma, Gerben; Metelo, Joao; Worth, Austen; Cowell, Lucy A.; Moulding, Dale A.; Mirando, Samuel; Kinnon, Christine; Burns, Siobhan O.; Thrasher, Adrian J.] UCL Inst Child Hlth, Mol Immunol Unit, Wolfson Ctr Gene Therapy Childhood Dis, London WC1N 1EH, England. [Blundell, Michael P.; Bouma, Gerben; Metelo, Joao; Worth, Austen; Cowell, Lucy A.; Moulding, Dale A.; Mirando, Samuel; Kinnon, Christine; Burns, Siobhan O.; Thrasher, Adrian J.] UCL Inst Child Hlth, Ctr Immunodeficiency, London WC1N 1EH, England. [Blundell, Michael P.; Bouma, Gerben; Metelo, Joao; Worth, Austen; Cowell, Lucy A.; Moulding, Dale A.; Mirando, Samuel; Kinnon, Christine; Burns, Siobhan O.; Thrasher, Adrian J.] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Calle, Yolanda] Kings Coll London, Dept Haematol Med, Rayne Inst, London SE5 9NU, England. [Westerberg, Lisa S.; Snapper, Scott B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,GI Unit, Boston, MA 02114 USA. [Cory, Giles O.] Peninsula Coll Med & Dent, Peninsula Med Sch, Exeter EX1 2LU, Devon, England. [Jones, Gareth E.] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England. RP Thrasher, AJ (reprint author), UCL Inst Child Hlth, Mol Immunol Unit, Wolfson Ctr Gene Therapy Childhood Dis, London WC1N 1EH, England. EM a.thrasher@ich.ucl.ac.uk RI Bouma, Gerben/C-1554-2008; Kinnon, Christine/A-1585-2010; Jones, Gareth/H-2282-2012; OI Jones, Gareth/0000-0001-5879-3048; Bouma, Gerben/0000-0002-1465-9178; Westerberg, Lisa/0000-0003-2943-2192; Moulding, Dale/0000-0002-1431-7047 FU European Union; Burton Myeloma Program; Wellcome Trust; MRC FX We thank Guillaume Charras ( University College London Centre for Nanotechnology) for his gift of LifeAct Ruby. This work was supported by the European Union ( M. P. B., G. B., and A.J.T.), the Burton Myeloma Program (Y.C.), the Wellcome Trust (A.J.T., G. B., and G. E. J.), and the MRC ( G. E. J.). NR 41 TC 37 Z9 38 U1 0 U2 0 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 SEP 15 PY 2009 VL 106 IS 37 BP 15738 EP 15743 DI 10.1073/pnas.0904346106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494IS UT WOS:000269806600043 PM 19805221 ER PT J AU Petnicki-Ocwieja, T Hrncir, T Liu, YJ Biswas, A Hudcovic, T Tlaskalova-Hogenova, H Kobayashi, KS AF Petnicki-Ocwieja, Tanja Hrncir, Tomas Liu, Yuen-Joyce Biswas, Amlan Hudcovic, Tomas Tlaskalova-Hogenova, Helena Kobayashi, Koichi S. TI Nod2 is required for the regulation of commensal microbiota in the intestine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE commensal bacteria; Crohn's disease; mouse; NLR ID INFLAMMATORY-BOWEL-DISEASE; ILEAL CROHNS-DISEASE; EPITHELIAL-CELLS; PANETH CELLS; HELICOBACTER-HEPATICUS; DEFENSIN EXPRESSION; ALPHA-DEFENSINS; INNATE; GENE; INDUCE AB Mutations in the Nod2 gene are among the strongest genetic risk factors in the pathogenesis of ileal Crohn's disease, but the exact contributions of Nod2 to intestinal mucosal homeostasis are not understood. Here we show that Nod2 plays an essential role in controlling commensal bacterial flora in the intestine. Analysis of intestinal bacteria from the terminal ilea of Nod2-deficient mice showed that they harbor an increased load of commensal resident bacteria. Furthermore, Nod2-deficient mice had a diminished ability to prevent intestinal colonization of pathogenic bacteria. In vitro, intestinal crypts isolated from terminal ilea of Nod2-deficient mice were unable to kill bacteria effectively, suggesting an important role of Nod2 signaling in crypt function. Interestingly, the expression of Nod2 is dependent on the presence of commensal bacteria, because mice re-derived into germ-free conditions expressed significantly less Nod2 in their terminal ilea, and complementation of commensal bacteria into germ-free mice induced Nod2 expression. Therefore, Nod2 and intestinal commensal bacterial flora maintain a balance by regulating each other through a feedback mechanism. Dysfunction of Nod2 results in a break-down of this homeostasis. C1 [Petnicki-Ocwieja, Tanja; Liu, Yuen-Joyce; Biswas, Amlan; Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Petnicki-Ocwieja, Tanja; Biswas, Amlan; Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Tlaskalova-Hogenova, Helena] Charles Univ Prague, Fac Med 1, Inst Microbiol & Immunol, CR-11636 Prague, Czech Republic. [Hrncir, Tomas; Hudcovic, Tomas; Tlaskalova-Hogenova, Helena] Acad Sci Czech Republic, Inst Microbiol, Dept Immunol & Gnotobiol, Prague 11720 1, Czech Republic. RP Kobayashi, KS (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM Koichi_Kobayashi@dfci.harvard.edu RI Hrncir, Tomas/H-6733-2014; Tlaskalova-Hogenova, Helena/J-8008-2014; Hudcovic, Tomas/H-7917-2014 OI Hudcovic, Tomas/0000-0002-4761-5040 FU National Institutes of Health [R01DK074738, R03TW6833, P30DK034854]; Crohn's and Colitis Foundation of America; Czech Science Foundation [303/06/0974]; Cancer Research Institute; Claudia Adams Barr Award; Benacerraf Memorial Fellowship FX The authors thank T. B. Meissner and M. Delhase for helpful discussions and R. S. Blumberg for critical reading of the manuscript. This work was supported by Grants R01DK074738, R03TW6833, and P30DK034854 from the National Institutes of Health (to K. S. K.), the Crohn's and Colitis Foundation of America (K. S. K.), and by Grant 303/06/0974 from the Czech Science Foundation (to H. T.-H.). K. S. K. is a recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award, and T. P.-O. is a recipient of the Benacerraf Memorial Fellowship. NR 41 TC 262 Z9 269 U1 6 U2 33 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 SEP 15 PY 2009 VL 106 IS 37 BP 15813 EP 15818 DI 10.1073/pnas.0907722106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494IS UT WOS:000269806600056 PM 19805227 ER PT J AU Ho, VT Vanneman, M Kim, H Sasada, T Kang, YJ Pasek, M Cutler, C Koreth, J Alyea, E Sarantopoulos, S Antin, JH Ritz, J Canning, C Kutok, J Mihm, MC Dranoff, G Soiffer, R AF Ho, Vincent T. Vanneman, Matthew Kim, Haesook Sasada, Tetsuro Kang, Yoon Joong Pasek, Mildred Cutler, Corey Koreth, John Alyea, Edwin Sarantopoulos, Stefanie Antin, Joseph H. Ritz, Jerome Canning, Christine Kutok, Jeffery Mihm, Martin C. Dranoff, Glenn Soiffer, Robert TI Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bone marrow transplant; GVL; MICA; NKG2D; tumor immunity ID BONE-MARROW-TRANSPLANTATION; COLONY-STIMULATING FACTOR; AUGMENTS ANTITUMOR IMMUNITY; GRAFT-VERSUS-LEUKEMIA; REGULATORY T-CELLS; METASTATIC MELANOMA; PEPTIDE VACCINATION; TUMOR-IMMUNITY; THERAPY; CANCER AB Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12-43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial immunotherapy might potentiate graft-versus-leukemia in patients. C1 [Ho, Vincent T.; Vanneman, Matthew; Sasada, Tetsuro; Kang, Yoon Joong; Pasek, Mildred; Cutler, Corey; Koreth, John; Alyea, Edwin; Sarantopoulos, Stefanie; Antin, Joseph H.; Ritz, Jerome; Canning, Christine; Dranoff, Glenn; Soiffer, Robert] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ho, Vincent T.; Vanneman, Matthew; Sasada, Tetsuro; Kang, Yoon Joong; Pasek, Mildred; Cutler, Corey; Koreth, John; Alyea, Edwin; Sarantopoulos, Stefanie; Antin, Joseph H.; Ritz, Jerome; Canning, Christine; Dranoff, Glenn; Soiffer, Robert] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Ho, Vincent T.; Vanneman, Matthew; Sasada, Tetsuro; Kang, Yoon Joong; Pasek, Mildred; Cutler, Corey; Koreth, John; Alyea, Edwin; Sarantopoulos, Stefanie; Antin, Joseph H.; Ritz, Jerome; Canning, Christine; Dranoff, Glenn; Soiffer, Robert] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Ho, Vincent T.; Vanneman, Matthew; Kim, Haesook; Sasada, Tetsuro; Kang, Yoon Joong; Pasek, Mildred; Cutler, Corey; Koreth, John; Alyea, Edwin; Sarantopoulos, Stefanie; Antin, Joseph H.; Ritz, Jerome; Canning, Christine; Kutok, Jeffery; Dranoff, Glenn; Soiffer, Robert] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kutok, Jeffery] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kim, Haesook] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Mihm, Martin C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mihm, Martin C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Dranoff, G (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM glenn_dranoff@dfci.harvard.edu; robert_soiffer@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU National Institutes of Health [AI29530]; National Cancer Institute [CA78378, CA111506]; Leukemia and Lymphoma Society; Ted and Eileen Pasquarello Research Fund; Bayer Pharmaceuticals FX We thank the staff of The Dana-Farber Cancer Institute Cell Manipulation Core Facility for outstanding work on vaccine manufacture and cell processing, and Stephen Conley at Massachusetts General Hospital for help with photography. This work was supported by National Institutes of Health Grant AI29530 (to R. S. and G. D.), National Cancer Institute Grants CA78378 (to G. D.) and CA111506 (to G. D.), the Leukemia and Lymphoma Society (G. D.), the Ted and Eileen Pasquarello Research Fund, and Bayer Pharmaceuticals. NR 35 TC 57 Z9 57 U1 0 U2 1 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 SEP 15 PY 2009 VL 106 IS 37 BP 15825 EP 15830 DI 10.1073/pnas.0908358106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494IS UT WOS:000269806600058 PM 19717467 ER PT J AU Seixas, E Gozzelino, R Chora, A Ferreira, A Silva, G Larsen, R Rebelo, S Penido, C Smith, NR Coutinho, A Soares, MP AF Seixas, Elsa Gozzelino, Raffaella Chora, Angelo Ferreira, Ana Silva, Gabriela Larsen, Rasmus Rebelo, Sofia Penido, Carmen Smith, Neal R. Coutinho, Antonio Soares, Miguel P. TI Heme oxygenase-1 affords protection against noncerebral forms of severe malaria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE heme; heme-oxygenase-1; cell death; infection ID CARBON-MONOXIDE SUPPRESS; INFECTIOUS-DISEASES; FALCIPARUM-MALARIA; T-CELLS; PATHOGENESIS; ACTIVATION; RESISTANCE; TOLERANCE; DAMAGE; LIVER AB Infection by Plasmodium, the causative agent of malaria, is associated with hemolysis and therefore with release of hemoglobin from RBC. Under inflammatory conditions, cell-free hemoglobin can be oxidized, releasing its heme prosthetic groups and producing deleterious free heme. Here we demonstrate that survival of a Plasmodium-infected host relies strictly on its ability to prevent the cytotoxic effects of free heme via the expression of the heme-catabolyzing enzyme heme oxygenase-1 (HO-1; encoded by the Hmox1 gene). When infected with Plasmodium chabaudi chabaudi (Pcc), wild-type (Hmox1(+/+)) BALB/c mice resolved infection and restored homeostasis thereafter (0% lethality). In contrast, HO-1 deficient (Hmox1(-/-)) BALB/c mice developed a lethal form of hepatic failure (100% lethality), similar to the one occurring in Pcc-infected DBA/2 mice (75% lethality). Expression of HO-1 suppresses the pro-oxidant effects of free heme, preventing it from sensitizing hepatocytes to undergo TNF-mediated programmed cell death by apoptosis. This cytoprotective effect, which inhibits the development of hepatic failure in Pcc-infected mice without interfering with pathogen burden, is mimicked by pharmacological antioxidants such as N-acetylcysteine (NAC). When administered therapeutically, i.e., after Pcc infection, NAC suppressed the development of hepatic failure in Pcc-infected DBA/2 mice (0% lethality), without interfering with pathogen burden. In conclusion, we describe a mechanism of host defense against Plasmodium infection, based on tissue cytoprotection against free heme and limiting disease severity irrespectively of parasite burden. C1 [Seixas, Elsa; Gozzelino, Raffaella; Chora, Angelo; Ferreira, Ana; Silva, Gabriela; Larsen, Rasmus; Rebelo, Sofia; Penido, Carmen; Coutinho, Antonio; Soares, Miguel P.] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Smith, Neal R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Soares, MP (reprint author), Inst Gulbenkian Ciencias, Oeiras, Portugal. EM mpsoares@igc.gulbenkian.pt RI Larsen, Rasmus/I-9204-2012; Gozzelino, Raffaella/J-4524-2013; OI Gozzelino, Raffaella/0000-0002-1195-8527; Ferreira, Ana/0000-0002-9171-6068; Ferreira Chora, Angelo/0000-0002-7941-7196; Soares, Miguel/0000-0002-9314-4833 NR 27 TC 123 Z9 124 U1 4 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 15 PY 2009 VL 106 IS 37 BP 15837 EP 15842 DI 10.1073/pnas.0903419106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494IS UT WOS:000269806600060 PM 19706490 ER PT J AU Monach, PA Hueber, W Kessler, B Tomooka, BH BenBarak, M Simmons, BP Wright, J Thornhill, TS Monestier, M Ploegh, H Robinson, WH Mathis, D Benoist, C AF Monach, Paul A. Hueber, Wolfgang Kessler, Benedikt Tomooka, Beren H. BenBarak, Maya Simmons, Barry P. Wright, John Thornhill, Thomas S. Monestier, Marc Ploegh, Hidde Robinson, William H. Mathis, Diane Benoist, Christophe TI A broad screen for targets of immune complexes decorating arthritic joints highlights deposition of nucleosomes in rheumatoid arthritis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoantibodies; histones; mass spectrometry; proteomics ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ARTICULAR-CARTILAGE; SYNOVIAL-FLUID; GLUCOSE-6-PHOSPHATE ISOMERASE; AUTOIMMUNE-DISEASE; MATRIX PROTEIN; ANTIBODIES; AUTOANTIBODIES; IGG; COMPLEMENT AB Deposits of Ig and complement are abundant in affected joints of patients with rheumatoid arthritis (RA) and in animal models of RA in which antibodies are demonstrably pathogenic. To identify molecular targets of the Igs deposited in arthritic joints, which may activate local inflammation, we used a combination of mass spectrometry (MS) and protein microarrays. Immune complexes were affinity-purified from surgically removed joint tissues of 26 RA and osteoarthritis (OA) patients. Proteins complexed with IgG were identified by proteomic analysis using tandem MS. A striking diversity of components of the extracellular matrix, and some intracellular components, copurified specifically with IgG from RA and OA tissues. A smaller set of autoantigens was observed only in RA eluates. In complementary experiments, IgG fractions purified from joint immune complexes were tested on protein microarrays against a range of candidate autoantigens. These Igs bound a diverse subset of proteins and peptides from synovium and cartilage, different from that bound by normal serum Ig. One type of intracellular protein detected specifically in RA joints (histones H2A/B) was validated by immunohistology and found to be deposited on the cartilage surface of RA but not OA joints. Thus, autoantibodies to many determinants (whether deposited as "neoantigens'' or normal constituents of the extracellular matrix) have the potential to contribute to arthritic inflammation. C1 [Monach, Paul A.; Mathis, Diane; Benoist, Christophe] Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. [Monach, Paul A.; Mathis, Diane; Benoist, Christophe] Brigham & Womens Hosp, Div Rheumatol, Boston, MA 02115 USA. [Hueber, Wolfgang; Tomooka, Beren H.; BenBarak, Maya; Robinson, William H.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Hueber, Wolfgang; Tomooka, Beren H.; BenBarak, Maya; Robinson, William H.] Vet Affairs Palo Alto Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Palo Alto, CA USA. [Kessler, Benedikt; Ploegh, Hidde] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Simmons, Barry P.; Wright, John; Thornhill, Thomas S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 USA. [Monestier, Marc] Temple Univ, Sch Med, Dept Microbiol & Immunol, Philadelphia, PA 19122 USA. RP Mathis, D (reprint author), Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. EM dm@hms.harvard.edu; cb@hms.harvard.edu OI Kessler, Benedikt/0000-0002-8160-2446 FU NHLBI NIH HHS [N01 HV028183]; NIAID NIH HHS [T32 AI007290, AI069160, R21 AI069160]; NIAMS NIH HHS [R01-AR-46580, R01 AR046580]; NIGMS NIH HHS [R01 GM062502, GM62502] NR 41 TC 38 Z9 38 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 15 PY 2009 VL 106 IS 37 BP 15867 EP 15872 DI 10.1073/pnas.0908032106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494IS UT WOS:000269806600065 PM 19720992 ER PT J AU Li, G Passias, P Kozanek, M Fu, E Wang, SB Xia, Q Li, GA Rand, FE Wood, KB AF Li, Gang Passias, Peter Kozanek, Michal Fu, Eric Wang, Shaobai Xia, Qun Li, Guoan Rand, Frank E. Wood, Kirkham B. TI Adult Scoliosis in Patients Over Sixty-Five Years of Age Outcomes of Operative Versus Nonoperative Treatment at a Minimum Two-Year Follow-up SO SPINE LA English DT Article DE adult scoliosis; operative versus nonoperative treatment; outcomes; age over 65 ID FORM HEALTH SURVEY; THORACOLUMBAR DEFORMITY ARTHRODESIS; DEGENERATIVE LUMBAR SCOLIOSIS; LOW-BACK-PAIN; IDIOPATHIC SCOLIOSIS; SURGICAL-TREATMENT; SPINAL DEFORMITY; SURVEY SF-36; PERIOPERATIVE COMPLICATIONS; PRIMARY FUSIONS AB Study Design. Retrospective case-control study. Objective. The purpose of this study was to compare the self-reported outcomes between operatively and nonoperatively treated patients over the age of 65 with adult scoliosis, using 4 distinct self-assessment questionnaires (SRS-22, SF-12, EQ5D, and Oswestry disability index [ODI]) and standard radiographic measurement parameters. Summary of Background Data. The current spine literature contains no studies that directly compare the self-reported and radiographic outcomes of operatively and nonoperatively treated patients over the age of 65 years with adult scoliosis. Methods. We retrospectively analyzed the self-reported outcomes of 83 adult scoliosis in patients over the age of 65 years. A total of 34 patients were treated operatively, whereas 49 patients were managed nonoperatively. For each of these patients, standard radiographic measurements were recorded both before and after treatment, and each patient received 4 questionnaires (SRS-22, SF-12, EQ5D, and ODI) that were completed with a minimum of 2-year follow-up from the time the treatment was initiated. The outcomes of both groups were then statistically compared. Results. As compared to the nonoperative group, the operative group reported significantly better self-assessment scores for the EQ5D index, EQ5D Visual Analogue Score, and SRS-22 questionnaires. However, no statistically significant difference between the groups was detected for the ODI, SF-12 Mental Health Component Summary, and SF-12 PCS. Furthermore, the operative group also had a significant improvement in radiographic measurements. Conclusion. Adult scoliosis patients over the age of 65 years treated operatively had significantly less pain, a better health-related quality of life, self image, mental health, and were more satisfied with their treatment than patients treated conservatively. However, we found no statistically significant differences in their degree of disability as measured by the ODI as well as physical and mental health by the SF-12 instrument. Preoperative radiographic deformity was not determined to be a significant factor for predicting whether an operative or nonoperative treatment course was chosen. C1 [Li, Gang; Passias, Peter; Kozanek, Michal; Fu, Eric; Wang, Shaobai; Xia, Qun; Li, Guoan; Wood, Kirkham B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Li, Gang; Passias, Peter; Kozanek, Michal; Fu, Eric; Wang, Shaobai; Xia, Qun; Li, Guoan; Wood, Kirkham B.] Harvard Univ, Sch Med, Boston, MA USA. [Rand, Frank E.] New England Baptist Hosp, Dept Orthopaed, Boston, MA USA. RP Wood, KB (reprint author), MA Gen Hosp, Dept Orthopaed, Brigham & Womens Hosp, Spine Surg Program, 55 Fruit St,Yawkey 3A, Boston, MA 02114 USA. EM kbwood@partners.org NR 37 TC 35 Z9 36 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD SEP 15 PY 2009 VL 34 IS 20 BP 2165 EP 2170 DI 10.1097/BRS.0b013e3181b3ff0c PG 6 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 495OJ UT WOS:000269902800016 PM 19713875 ER PT J AU Bess, S Boachie-Adjei, O Burton, D Cunningham, M Shaffrey, C Shelokov, A Hostin, R Schwab, F Wood, K Akbarnia, B AF Bess, Shay Boachie-Adjei, Oheneba Burton, Doug Cunningham, Matthew Shaffrey, Chris Shelokov, Alexis Hostin, Richard Schwab, Frank Wood, Kirkham Akbarnia, Behrooz CA Int Spine Study Grp TI Pain and Disability Determine Treatment Modality for Older Patients With Adult Scoliosis, While Deformity Guides Treatment for Younger Patients SO SPINE LA English DT Article DE adult scoliosis; operative treatment; nonoperative treatment ID SPINAL DEFORMITY; SURGICAL-TREATMENT; COMPLICATIONS; SURGERY; OUTCOMES; INSTRUMENTATION; MANAGEMENT; IMPACT AB Study Design. Multi-center, retrospective review. Objective. Identify age associated clinical and radiographic features correlating with AS treatment. Summary of Background Data. Little information exists about factors determining treatment for adult scoliosis (AS). Existing studies have not evaluated age stratified differences. Methods. Multicenter, retrospective review of 290 patients treated for AS. Patients divided into operative (OP) or nonoperative (NON), and age stratified into 3 groups (G1 = < 50 years, G2 = 50-65 years, G3 = >65 years). Demographic and spinopelvic radiographic parameters evaluated. Health-related quality of life (HRQL) measures included SRS-22, Oswestry Disability Index (ODI), visual analog pain scale. Results. Treatment groups (OP, n = 137; NON, n = 153) demonstrated similar age (OP = 52.7 years; NON = 55.5 years; P > 0.05) and cormorbidities. OP had larger thoracic curves than NON (OP = 51 degrees, NON = 45 degrees; P < 0.05). OP had worse HRQL scores than NON (SRS = 2.95 vs. 3.12, P < 0.05; ODI = 33.4 vs. 28.7, P < 0.05; visual analog pain scale = 6.9 vs. 5.6, P < 0.05, respectively). Age stratification of OP demonstrated larger curves in G1 and G2 versus G3, progressively worsening sagittal imbalance in older age groups, and worse HRQL scores in G3 versus G1 and G2. Age stratification of NON demonstrated worsening sagittal imbalance with age, however, other radiographic values and HRQL scores were similar between all NON age groups. Treatment stratification of age groups demonstrated G1-OP had greater deformity than G1-NON (mean thoracic curve: G1-OP = 53 degrees, G1-NON = 43 degrees; P < 0.05) but similar HRQL values. Whereas G2 and G3-OP had similar radiographic coronal and sagittal values as G2 and G3-NON, but worse HRQL scores. Conclusion. Counter to previous reports, age, cormorbidities, and sagittal balance did not influence treatment modality for AS. Operative treatment for younger patients was driven by increased coronal plane deformity. Conversely, pain and disability mandated treatment for olderpatients, independent of radiographic measures. These findings suggest that AS patients do not become uniformly disabled with age, and that disability can not be solely predicted by radiographic findings. These data should be considered when considering treatment for AS. C1 [Bess, Shay] Rocky Mt Hosp Children, Dept Orthopaed Surg, Denver, CO 80218 USA. [Boachie-Adjei, Oheneba; Cunningham, Matthew] Hosp Special Surg, New York, NY 10021 USA. [Burton, Doug] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Shaffrey, Chris] Univ Virginia, Charlottesville, VA USA. [Hostin, Richard] Baylor Scoliosis Ctr, Plano, TX USA. [Schwab, Frank] NYU, Hosp Joint Dis, New York, NY USA. [Wood, Kirkham] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Akbarnia, Behrooz] San Diego Ctr Spinal Disorders, La Jolla, CA USA. RP Bess, S (reprint author), Rocky Mt Hosp Children, Dept Orthopaed Surg, 1721 E 19th Ave,Suite 244, Denver, CO 80218 USA. EM shay_bess@hotmail.com OI Cunningham, Matthew/0000-0003-3723-062X; bess, shay/0000-0002-9697-8999 NR 17 TC 48 Z9 56 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD SEP 15 PY 2009 VL 34 IS 20 BP 2186 EP 2190 DI 10.1097/BRS.0b013e3181b05146 PG 5 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 495OJ UT WOS:000269902800020 PM 19752704 ER PT J AU Reese, PP Feldman, HI Asch, DA Thomasson, A Shults, J Bloom, RD AF Reese, Peter P. Feldman, Harold I. Asch, David A. Thomasson, Arwin Shults, Justine Bloom, Roy D. TI Short-Term Outcomes for Obese Live Kidney Donors and Their Recipients SO TRANSPLANTATION LA English DT Article DE Live donor; Obesity; Kidney transplantation ID BODY-MASS INDEX; GLOMERULAR-FILTRATION-RATE; FOLLOW-UP; RENAL-FUNCTION; CARDIOVASCULAR EVENTS; TRANSPLANT CENTERS; SERUM CREATININE; LIVING DONORS; HEALTHY-MEN; NEPHRECTOMY AB Background. Given the association between obesity and kidney disease, transplant professionals have debated the appropriateness of accepting obese live kidney donors. We hypothesized that compared with normal weight donors, donors with elevated body mass index (BMI) would have (1) more perioperative readmissions and reoperations and (2) a greater rise in blood pressure, greater percent rise in serum creatinine, and a greater loss of estimated glomerular filtration rate after nephrectomy. Methods. Retrospective cohort study using Organ Procurement and Transplantation Network data on live donors who donated kidneys from July 1, 2004, to December 31, 2005. Results. Nine thousand three hundred nineteen live donor kidney transplants were performed. After eliminating donors with missing BMI data, 5304 donors were analyzed, among whom 2108 (40.0%) were overweight (25 <= BMI<30), 944 (17.8%) were obese (30 <= BMI<35), and 250 (4.7%) were very obese (BMI>=35). Readmission and reoperation rates did not differ across donor BMI categories. At baseline and at 6 months after nephrectomy, higher BMI was associated with higher blood pressure (P<0.01), but changes in systolic blood pressure from baseline were similar across BMI categories (P=0.40). At 6 months, decline in estimated glomerular filtration rate from baseline (P=0.63) and percent change in creatinine (P=0.11) did not differ significantly across groups. Delayed graft function was more common among recipients of kidneys from very obese donors (odds ratio 2.16, confidence interval 1.20-3.89, P=0.01), but the rates of recipient allograft failure and recipient mortality across donor BMI groups were similar. Conclusion. Short-term follow-up data show good outcomes for donors with elevated BMI and their recipients. C1 [Reese, Peter P.; Feldman, Harold I.; Bloom, Roy D.] Univ Penn, Dept Med, Div Renal, Philadelphia, PA 19104 USA. [Reese, Peter P.; Feldman, Harold I.; Asch, David A.; Thomasson, Arwin; Shults, Justine] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Reese, Peter P.; Feldman, Harold I.; Asch, David A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Reese, PP (reprint author), Hosp Univ Penn, Div Renal, 1 Founders Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM peter.reese@uphs.upenn.edu OI Asch, David/0000-0002-7970-286X FU NIH Career Development Award [K23-DK078688-01]; NIH Midcareer Award [K24-DK002651]; Health Resources and Services Administration [234-2005-370011C] FX This study was supported by the NIH Career Development Award K23-DK078688-01 (P.P.R), an NIH Midcareer Award (Patient Oriented Research) K24-DK002651 (H.I.F.), and the Health Resources and Services Administration contract 234-2005-370011C (in part). NR 40 TC 29 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD SEP 15 PY 2009 VL 88 IS 5 BP 662 EP 671 DI 10.1097/TP.0b013e3181b27a17 PG 10 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 493MO UT WOS:000269741200010 PM 19741463 ER PT J AU Zhang, P Cantiello, HF AF Zhang, Peng Cantiello, Horacio F. TI Electrical mapping of microtubular structures by surface potential microscopy SO APPLIED PHYSICS LETTERS LA English DT Article ID ELECTROSTATIC FORCE MICROSCOPY AB Microtubules (MTs) are important cytoskeletal polymers that play an essential role in cell division and transport in all eukaryotes and information processing in neurons. MTs are highly charged polyelectrolytes, composed of hollow cylindrical arrangements of alpha beta-tubulin dimers. To date, there is little information about electrical properties of MTs. Here, we deposited and dried MTs onto a gold-plated surface to image their topology by atomic force microscopy (AFM), and determined their electrical mapping with surface potential microscopy (SPM). We found a strong linear correlation between the magnitude of relative surface potential and MT parameters, including diameter and height. AFM images confirmed the cylindrical topology of microtubular structures, and the presence of topological discontinuities along their surface, which may contribute to their unique electrical properties. (C) 2009 American Institute of Physics. [doi: 10.1063/1.3212147] C1 [Zhang, Peng] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Zhang, P (reprint author), Massachusetts Gen Hosp, Div Nephrol, 149 13th St, Charlestown, MA 02129 USA. EM cantiello@helix.mgh.harvard.edu NR 18 TC 5 Z9 5 U1 0 U2 9 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD SEP 14 PY 2009 VL 95 IS 11 AR 113703 DI 10.1063/1.3212147 PG 3 WC Physics, Applied SC Physics GA 497XC UT WOS:000270096900093 ER PT J AU Weingart, SN Simchowitz, B Padolsky, H Isaac, T Seger, AC Massagli, M Davis, RB Weissman, JS AF Weingart, Saul N. Simchowitz, Brett Padolsky, Harper Isaac, Thomas Seger, Andrew C. Massagli, Michael Davis, Roger B. Weissman, Joel S. TI An Empirical Model to Estimate the Potential Impact of Medication Safety Alerts on Patient Safety, Health Care Utilization, and Cost in Ambulatory Care SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID DRUG-INTERACTION ALERTS; PHYSICIAN ORDER ENTRY; EVENTS; ERRORS; PREVENTION; BENEFITS; ILLNESS; VIEWS AB Background: Because ambulatory care clinicians override as many as 91% of drug interaction alerts, the potential benefit of electronic prescribing (e-prescribing) with decision support is uncertain. Methods: We studied 279 476 alerted prescriptions written by 2321 Massachusetts ambulatory care clinicians using a single commercial e-prescribing system from January 1 through June 30, 2006. An expert panel reviewed a sample of common drug interaction alerts, estimating the likelihood and severity of adverse drug events (ADEs) associated with each alert, the likely injury to the patient, and the health care utilization required to address each ADE. We estimated the cost savings due to e-prescribing by using third-party-payer and publicly available information. Results: Based on the expert panel's estimates, electronic drug alerts likely prevented 402 (interquartile range [IQR], 133-846) ADEs in 2006, including 49 (14-130) potentially serious, 125 (34-307) significant, and 228 (85409) minor ADEs. Accepted alerts may have prevented a death in 3 (IQR, 2-13) cases, permanent disability in 14 (3-18), and temporary disability in 31 (10-97). Alerts potentially resulted in 39 (IQR, 14-100) fewer hospitalizations, 34 (6-74) fewer emergency department visits, and 267 (105-541) fewer office visits, for a cost savings of $402 619 (IQR, $141 012-$1 012 386). Based on the panel's estimates, 331 alerts were required to prevent 1 ADE, and a few alerts (10%) likely accounted for 60% of ADEs and 78% of cost savings. Conclusions: Electronic prescribing alerts in ambulatory care may prevent a substantial number of injuries and reduce health care costs in Massachusetts. Because a few alerts account for most of the benefit, e-prescribing systems should suppress low-value alerts. C1 [Weingart, Saul N.; Simchowitz, Brett; Padolsky, Harper; Isaac, Thomas; Seger, Andrew C.] Dana Farber Canc Inst, Ctr Patient Safety, Boston, MA 02115 USA. [Padolsky, Harper] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Weingart, Saul N.; Isaac, Thomas; Davis, Roger B.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Seger, Andrew C.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Seger, Andrew C.] Massachusetts Coll Pharm & Hlth Sci, Boston, MA USA. [Weissman, Joel S.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Weissman, Joel S.] Commonwealth Massachusetts, Execut Off Hlth & Human Serv, Boston, MA USA. [Massagli, Michael] PatientsLikeMe, Cambridge, MA USA. [Weissman, Joel S.] Univ Massachusetts, Sch Med, Dept Community & Family Med, Worcester, MA USA. RP Weingart, SN (reprint author), Dana Farber Canc Inst, Ctr Patient Safety, 44 Binney St, Boston, MA 02115 USA. EM saul_weingart@dfci.harvard.edu FU Weingart; Weissman; Blue Cross Blue Shield of Massachusetts FX Funding/Support: This study was supported by a grant from Blue Cross Blue Shield of Massachusetts. NR 31 TC 39 Z9 39 U1 3 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 14 PY 2009 VL 169 IS 16 BP 1465 EP 1473 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 493VB UT WOS:000269765300003 PM 19752403 ER PT J AU McCabe, C Kirchner, C Zhang, HL Daley, J Fisman, DN AF McCabe, Caitlin Kirchner, Cheryl Zhang, Huiling Daley, Jennifer Fisman, David N. TI Guideline-Concordant Therapy and Reduced Mortality and Length of Stay in Adults With Community-Acquired Pneumonia Playing by the Rules SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ANTIMICROBIAL THERAPY; ETIOLOGY; DISEASES; MULTICENTER; VACCINATION; POPULATION; MANAGEMENT; ADHERENCE; OUTCOMES; RISK AB Background: Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Clinical practice guidelines for empirical CAP treatment, formulated jointly by the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS), remain controversial and inconsistently applied. We evaluated the impact of guideline-concordant therapy on in-hospital survival and other outcomes using a large database including adults treated for CAP in both community and tertiary care hospitals. Methods: We evaluated the association between in-hospital survival and guideline-concordant therapy using logistic regression models. Time until discharge from hospital and discontinuation of parenteral therapy were evaluated using survival analysis. Results: Of 54 619 non-intensive care unit inpatients with CAP hospitalized at 113 community hospitals and tertiary care centers, 35 477 (65%) received initial guideline-concordant therapy. After adjustment for severity of illness and other confounders, guideline-concordant therapy was associated with decreased in-hospital mortality (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.63-0.77), sepsis (OR, 0.83; 95% CI, 0.72-0.96), and renal failure (OR, 0.79; 95% CI, 0.67-0.94), and reduced both length of stay and duration of parenteral therapy by approximately 0.6 days (P < .001 for both comparisons). These findings were robust with alternate definitions of "concordance" and were linked to treatment with fluoroquinolone or macrolide agents. Conclusions: Guideline-concordant therapy for CAP is associated with improved health outcomes and diminished resource use in adults. The mechanisms underlying this finding remain speculative and warrant further study, but our findings nonetheless support compliance with CAP clinical practice guidelines as a benchmark of quality of care. C1 [McCabe, Caitlin; Fisman, David N.] Hosp Sick Children, Res Inst, Toronto, ON M5G 1E2, Canada. [Kirchner, Cheryl; Zhang, Huiling] Tenet Healthcare, Div Clin Qual, Dallas, TX USA. [Daley, Jennifer] Partners Community Healthcare Inc, Boston, MA USA. [Daley, Jennifer] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Daley, Jennifer] Harvard Univ, Sch Med, Boston, MA USA. [Fisman, David N.] Univ Toronto, Dalla Lana Sch Publ Hlth, Dept Epidemiol, Toronto, ON, Canada. [Fisman, David N.] Univ Toronto, Dept Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Fisman, David N.] Ontario Agcy Hlth Protect & Promot, Toronto, ON, Canada. RP Fisman, DN (reprint author), Hosp Sick Children, Res Inst, 123 Edward St,Room 428, Toronto, ON M5G 1E2, Canada. EM david.fisman@gmail.com FU Ontario Ministry of Research and Innovation FX Funding/Support: Dr Fisman is supported by an Early Researcher Award from the Ontario Ministry of Research and Innovation. NR 42 TC 97 Z9 100 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 14 PY 2009 VL 169 IS 16 BP 1525 EP 1531 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 493VB UT WOS:000269765300012 PM 19752411 ER PT J AU Goldberg, BD Vakoc, BJ Oh, WY Suter, MJ Waxman, S Freilich, MI Bouma, BE Tearney, GJ AF Goldberg, Brian D. Vakoc, Benjamin J. Oh, Wang-Yuhl Suter, Melissa J. Waxman, Sergio Freilich, Mark I. Bouma, Brett E. Tearney, Guillermo J. TI Performance of reduced bit-depth acquisition for optical frequency domain imaging SO OPTICS EXPRESS LA English DT Article ID SWEPT SEMICONDUCTOR-LASER; COHERENCE TOMOGRAPHY; MODE-LOCKING; SPEED; WAVELENGTH; SENSITIVITY; MICROSCOPY AB High-speed optical frequency domain imaging (OFDI) has enabled practical wide-field microscopic imaging in the biological laboratory and clinical medicine. The imaging speed of OFDI, and therefore the field of view, of current systems is limited by the rate at which data can be digitized and archived rather than the system sensitivity or laser performance. One solution to this bottleneck is to natively digitize OFDI signals at reduced bit depths, e. g., at 8-bit depth rather than the conventional 12-14 bit depth, thereby reducing overall bandwidth. However, the implications of reduced bit-depth acquisition on image quality have not been studied. In this paper, we use simulations and empirical studies to evaluate the effects of reduced depth acquisition on OFDI image quality. We show that image acquisition at 8-bit depth allows high system sensitivity with only a minimal drop in the signal-to-noise ratio compared to higher bit-depth systems. Images of a human coronary artery acquired in vivo at 8-bit depth are presented and compared with images at higher bit-depth acquisition. (C) 2009 Optical Society of America C1 [Goldberg, Brian D.; Vakoc, Benjamin J.; Oh, Wang-Yuhl; Suter, Melissa J.; Bouma, Brett E.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Goldberg, Brian D.; Vakoc, Benjamin J.; Bouma, Brett E.; Tearney, Guillermo J.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Waxman, Sergio; Freilich, Mark I.] Lahey Clin Fdn, Dept Cardiol, Burlington, MA USA. RP Goldberg, BD (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. EM gtearney@partners.org RI Oh, Wang-Yuhl/C-2055-2011 FU NIH [1 F31 EB005141-01]; Terumo Medical Corporation [NIH R01HL076398]; DOD [FA9550-04-1-0079] FX Funding for this work was provided in part by the NIH (1 F31 EB005141-01), Terumo Medical Corporation, NIH R01HL076398, and DOD, the AFOSR MFEL Program (FA9550-04-1-0079). NR 27 TC 17 Z9 17 U1 0 U2 4 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 SEP 14 PY 2009 VL 17 IS 19 BP 16957 EP 16968 DI 10.1364/OE.17.016957 PG 12 WC Optics SC Optics GA 493KS UT WOS:000269736100066 PM 19770914 ER PT J AU Okoli, I Coleman, JJ Tempakakis, E An, WF Holson, E Wagner, F Conery, AL Larkins-Ford, J Wu, G Stern, A Ausubel, FM Mylonakis, E AF Okoli, Ikechukwu Coleman, Jeffrey J. Tempakakis, Emmanouil An, W. Frank Holson, Edward Wagner, Florence Conery, Annie L. Larkins-Ford, Jonah Wu, Gang Stern, Andy Ausubel, Frederick M. Mylonakis, Eleftherios TI Identification of Antifungal Compounds Active against Candida albicans Using an Improved High-Throughput Caenorhabditis elegans Assay SO PLOS ONE LA English DT Article AB Candida albicans, the most common human pathogenic fungus, can establish a persistent lethal infection in the intestine of the microscopic nematode Caenorhabditis elegans. The C. elegans-C. albicans infection model was previously adapted to screen for antifungal compounds. Modifications to this screen have been made to facilitate a high-throughput assay including co-inoculation of nematodes with C. albicans and instrumentation allowing precise dispensing of worms into assay wells, eliminating two labor-intensive steps. This high-throughput method was utilized to screen a library of 3,228 compounds represented by 1,948 bioactive compounds and 1,280 small molecules derived via diversity-oriented synthesis. Nineteen compounds were identified that conferred an increase in C. elegans survival, including most known antifungal compounds within the chemical library. In addition to seven clinically used antifungal compounds, twelve compounds were identified which are not primarily used as antifungal agents, including three immunosuppressive drugs. This assay also allowed the assessment of the relative minimal inhibitory concentration, the effective concentration in vivo, and the toxicity of the compound in a single assay. RP Okoli, I (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM emylonakis@partners.org RI Coleman, Jeffrey/E-2981-2015; OI Coleman, Jeffrey/0000-0001-8579-1996 FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [R01 AI075286, T32 AI007061, R01 AI072508]; NIDDK NIH HHS [P30 DK040561-14, P30 DK040561] NR 68 TC 47 Z9 51 U1 1 U2 8 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 SEP 14 PY 2009 VL 4 IS 9 AR e7025 DI 10.1371/journal.pone.0007025 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 494FN UT WOS:000269796300019 PM 19750012 ER PT J AU Peterson, RT AF Peterson, Randall T. TI In vivo small molecule discovery in zebrafish SO TOXICOLOGY LETTERS LA English DT Meeting Abstract CT 46th Congress of the European-Societies-of-Toxicology CY SEP 13-16, 2009 CL Dreden, GERMANY SP European Soc Toxicol C1 [Peterson, Randall T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Peterson, Randall T.] Harvard Univ, Sch Med, Boston, MA USA. [Peterson, Randall T.] Broad Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 13 PY 2009 VL 189 BP S50 EP S50 DI 10.1016/j.toxlet.2009.06.101 PG 1 WC Toxicology SC Toxicology GA 493ZM UT WOS:000269778800143 ER PT J AU Lee, J Ryu, H Kowall, NW AF Lee, Junghee Ryu, Hoon Kowall, Neil W. TI Differential regulation of neuronal and inducible nitric oxide synthase (NOS) in the spinal cord of mutant SOD1 (G93A) ALS mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Amyotrophic lateral sclerosis (ALS); Nitric oxide synthase (NOS); Nitric oxide; Astrocytes; Motor neuron; L-Arginine ID AMYOTROPHIC-LATERAL-SCLEROSIS; PROLONGS SURVIVAL; ROOT AVULSION; ARGININE; EXPRESSION; INFLAMMATION; MOTONEURONS; MOUSE; DEATH AB Amyotrophic lateral Sclerosis (ALS) is a fatal neurological disorder characterized by degeneration of motor neurons throughout the central nervous system. Mutations of the free radical scavenging enzyme superoxide dismutase-1 (SOD1) are a cause of familial ALS but it is not known how Mutations lead to cell death. Free radicals such as nitric oxide (NO) are thought to play a key pathogenic role. NO is synthesized by NO synthases (NOSs) from arginine, which is a rate-limiting factor for NO production. We found that neuronal NOS (nNOS)-positive motor neurons were depleted while inducible NOS (iNOS)-positive activated glial cells were increased in transgenic mtSOD1 (G93A) ALS mice. iNOS expression was up regulated consistent with the increases of motor neuron loss and glial activation and citrulline and NO levels while nNOS expression was decreased in G93A ALS mice. Administration Of L-arginine to G93A mice reduced the severity of motor neuron depletion and glial activation. In treated animals, nNOS expression was preserved while citrulline and NO were reduced, possibly due to reduced activation of glia expressing iNOS. Our findings show that high concentrations of NO correlate with iNOS expression rather than nNOS expression in G93A ALS mice. This suggests that therapy focused on iNOS inhibition might be a fruitful direction for future ALS therapeutic trials. Published by Elsevier Inc. C1 [Lee, Junghee; Ryu, Hoon; Kowall, Neil W.] VA Boston Healthcare Syst, Neurol Serv, Boston, MA 02130 USA. [Lee, Junghee; Ryu, Hoon; Kowall, Neil W.] VA Boston Healthcare Syst, Geriatr Res & Educ & Clin Ctr, Boston, MA 02130 USA. [Lee, Junghee; Ryu, Hoon; Kowall, Neil W.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Kowall, Neil W.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. RP Lee, J (reprint author), VA Boston Healthcare Syst, Neurol Serv, 150 S Huntington Ave, Boston, MA 02130 USA. EM junghee@bu.edu; nkowall@bu.edu RI Kowall, Neil/G-6364-2012 OI Kowall, Neil/0000-0002-6624-0213 FU Les Turner ALS Foundation; NIH [P30 AG13846, NS52724]; KOSEF [800-20080848] FX J.L. is an awardee of Les Turner ALS Foundation Grant. NIH P30 AG13846 (J.L.), NIH NS52724 (H.R.), and the Merit Review Grant from the Department of Veterans Affairs (J.L., N.W.K.) supported this work. The WCU Neurocytomics Program Grant (800-20080848) through SNU from KOSEF (H.R.) supported this work, in part. NR 26 TC 10 Z9 10 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 11 PY 2009 VL 387 IS 1 BP 202 EP 206 DI 10.1016/j.bbrc.2009.07.007 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 480LL UT WOS:000268736100037 PM 19580782 ER PT J AU Tamehiro, N Mujawar, Z Zhou, SP Zhuang, DZ Hornemann, T von Eckardstein, A Fitzgerald, ML AF Tamehiro, Norimasa Mujawar, Zahedi Zhou, Suiping Zhuang, Debbie Z. Hornemann, Thorsten von Eckardstein, Arnold Fitzgerald, Michael L. TI Cell Polarity Factor Par3 Binds SPTLC1 and Modulates Monocyte Serine Palmitoyltransferase Activity and Chemotaxis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; APOE-DEFICIENT MICE; E-KNOCKOUT MICE; CHOLESTEROL EFFLUX; SPHINGOLIPID METABOLISM; SPHINGOMYELIN SYNTHESIS; PERMEABILITY BARRIER; PLASMA SPHINGOMYELIN; INHIBITOR MYRIOCIN; ATHEROSCLEROSIS AB Elevated sphingolipids have been associated with increased cardiovascular disease. Conversely, atherosclerosis is reduced in mice by blocking de novo synthesis of sphingolipids catalyzed by serine palmitoyltransferase (SPT). The SPT enzyme is composed of the SPTLC1 and -2 subunits, and here we describe a novel protein-protein interaction between SPTLC1 and the PDZ protein Par3 (partitioning defective protein 3). Mammalian SPTLC1 orthologs have a highly conserved C terminus that conforms to a type II PDZ protein interaction motif, and by screening PDZ domain protein arrays with an SPTLC1 C-terminal peptide, we found it bound the third PDZ domain of Par3. Overlay and immuno-precipitation assays confirmed this interaction and indicate Par3 is able to associate with the SPTLC1/2 holoenzyme by binding the C-terminal SPTLC1 PDZ motif. The physiologic existence of the SPTLC1/2-Par3 complex was detected in mouse liver and macrophages, and short interfering RNA inhibition of Par3 in human THP-1 monocytes significantly reduced SPT activity and de novo ceramide synthesis by nearly 40%. Given monocyte recruitment into inflamed vessels is thought to promote atherosclerosis, and because Par3 and sphingolipids have been associated with polarized cell migration, we tested whether the ability of THP-1 monocytes to migrate toward MCP- 1 (monocyte chemoattractant protein 1) depended upon Par3 and SPTLC1 expression. Knockdown of Par3 significantly reduced MCP1-induced chemotaxis of THP-1 monocytes, as did knockdown of SPTLC1, and this Par3 effect depended upon SPT activity and was blunted by ceramide treatment. In conclusion, protein arrays were used to identify a novel SPTLC1-Par3 interaction that associates with increased monocyte serine palmitoyltransferase activity and chemotaxis toward inflammatory signals. C1 [Fitzgerald, Michael L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lipid Metab Unit,Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Hornemann, Thorsten; von Eckardstein, Arnold] Univ Zurich Hosp, Inst Clin Chem, CH-8091 Zurich, Switzerland. RP Fitzgerald, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lipid Metab Unit,Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA. EM mfitzgerald@ccib.mgh.harvard.edu FU NHLBI [HL074136]; American Heart Association [09GRNT2260352]; Uehara Memorial Foundation; Nagai Foundation of Tokyo; Japan Heart Foundation; American Heart Association; Massachusetts Biomedical Research Corporation FX This work was supported, in part, by National Institutes of Health Grant HL074136 from NHLBI (to M.L.F.). This work was also supported by an American Heart Association Grant-in-Aid 09GRNT2260352 to M.L.F.) and by fellowship training grants from the Uehara Memorial Foundation, the Nagai Foundation of Tokyo, and the Japan Heart Foundation (to N.T.), the American Heart Association (to Z.M.), and the Massachusetts Biomedical Research Corporation (to S.Z.). NR 45 TC 9 Z9 9 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 SEP 11 PY 2009 VL 284 IS 37 BP 24881 EP 24890 DI 10.1074/jbc.M109.014365 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 493JZ UT WOS:000269734000022 PM 19592499 ER PT J AU Cao, ZX Wara, AK Icli, B Sun, XH Packard, RRS Esen, F Stapleton, CJ Subramaniam, M Kretschmer, K Apostolou, I von Boehmer, H Hansson, GK Spelsberg, TC Libby, P Feinberg, MW AF Cao, Zhuoxiao Wara, Akm Khyrul Icli, Basak Sun, Xinghui Packard, Rene R. S. Esen, Fehim Stapleton, Christopher J. Subramaniam, Malayannan Kretschmer, Karsten Apostolou, Irina von Boehmer, Harald Hansson, Goran K. Spelsberg, Thomas C. Libby, Peter Feinberg, Mark W. TI Kruppel-like Factor KLF10 Targets Transforming Growth Factor-beta 1 to Regulate CD4(+)CD25(-) T Cells and T Regulatory Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-BETA; TRANSCRIPTION FACTOR FOXP3; TGF-BETA; CUTTING EDGE; TRANSPLANT ARTERIOSCLEROSIS; ACCELERATES ATHEROSCLEROSIS; AGGRAVATES ATHEROSCLEROSIS; VASCULAR INFLAMMATION; PERIPHERAL TOLERANCE; FACTOR EKLF AB CD4(+)CD25(+) regulatory T cells (T regs) play a major role in the maintenance of self-tolerance and immune suppression, although the mechanisms controlling T reg development and suppressor function remain incompletely understood. Herein, we provide evidence that Kruppel-like factor 10 (KLF10/TIEG1) constitutes an important regulator of T regulatory cell suppressor function and CD4(+)CD25(-) T cell activation through distinct mechanisms involving transforming growth factor (TGF)-beta 1 and Foxp3. KLF10 overexpressing CD4(+)CD25(-) T cells induced both TGF-beta 1 and Foxp3 expression, an effect associated with reduced T-Bet (Th1 marker) and Gata3 (Th2 marker) mRNA expression. Consistently, KLF10(-/-) CD4(+)CD25(-) T cells have enhanced differentiation along both Th1 and Th2 pathways and elaborate higher levels of Th1 and Th2 cytokines. Furthermore, KLF10(-/-) CD4(+)CD25(-) T cell effectors cannot be appropriately suppressed by wild-type T regs. Surprisingly, KLF10(-/-) T reg cells have reduced suppressor function, independent of Foxp3 expression, with decreased expression and elaboration of TGF-beta 1, an effect completely rescued by exogenous treatment with TGF-beta 1. Mechanistic studies demonstrate that in response to TGF-beta 1, KLF10 can transactivate both TGF-beta 1 and Foxp3 promoters, implicating KLF10 in a positive feedback loop that may promote cell-intrinsic control of T cell activation. Finally, KLF10(-/-) CD4(+)CD25(-) T cells promoted atherosclerosis by similar to 2-fold in ApoE(-/-)/scid/scid mice with increased leukocyte accumulation and peripheral pro-inflammatory cytokines. Thus, KLF10 is a critical regulator in the transcriptional network controlling TGF-beta 1 in both CD4(+)CD25(-) T cells and T regs and plays an important role in regulating atherosclerotic lesion formation in mice. C1 [Cao, Zhuoxiao; Wara, Akm Khyrul; Icli, Basak; Sun, Xinghui; Packard, Rene R. S.; Esen, Fehim; Stapleton, Christopher J.; Libby, Peter; Feinberg, Mark W.] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp,Cardiovasc Div, Boston, MA 02115 USA. [Subramaniam, Malayannan; Spelsberg, Thomas C.] Mayo Clin, Dept Biochem & Mol Biol, Coll Med, Rochester, MN 55905 USA. [Kretschmer, Karsten; Apostolou, Irina; von Boehmer, Harald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Hansson, Goran K.] Karolinska Inst, Ctr Mol Med, SE-17176 Stockholm, Sweden. [Hansson, Goran K.] Karolinska Inst, Dept Med, SE-17176 Stockholm, Sweden. [Stapleton, Christopher J.] Harvard Univ, Sch Med, Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Boston, MA 02115 USA. RP Feinberg, MW (reprint author), 77 Ave Louis Pasteur,NRB 742F, Boston, MA 02115 USA. EM mfeinberg@rics.bwh.harvard.edu RI Hansson, Goran/B-7423-2012; Kretschmer, Karsten/E-8174-2010; OI Packard, Rene/0000-0002-8520-5843 FU National Institutes of Health [HL080174, HL091076, F32HL086157, F32HL088819, DE14036]; American Cancer Society Research Scholar Grant [RSG0719501-LIB]; Leducq Transatlantic Network on Atherothrombosis; Swedish Research Council FX This work was supported, in whole or in part, by National Institutes of Health Grants HL080174 and HL091076 (to M.W.F.), F32HL086157 (to Z.C.), F32HL088819 (to A.K.W.), and DE14036 (to T.C.S. and M.S.). This work was also supported by American Cancer Society Research Scholar Grant RSG0719501-LIB (to M. W. F.), the Leducq Transatlantic Network on Atherothrombosis (to R.R.S.P., G.K.H., and P.L.), and the Swedish Research Council (to G.K.H.). NR 62 TC 39 Z9 39 U1 0 U2 12 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 SEP 11 PY 2009 VL 284 IS 37 BP 24914 EP 24924 DI 10.1074/jbc.M109.000059 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 493JZ UT WOS:000269734000025 PM 19602726 ER PT J AU Lal, A Navarro, F Maher, CA Maliszewski, LE Yan, N O'Day, E Chowdhury, D Dykxhoorn, DM Tsai, P Hofmann, O Becker, KG Gorospe, M Hide, W Lieberman, J AF Lal, Ashish Navarro, Francisco Maher, Christopher A. Maliszewski, Laura E. Yan, Nan O'Day, Elizabeth Chowdhury, Dipanjan Dykxhoorn, Derek M. Tsai, Perry Hofmann, Oliver Becker, Kevin G. Gorospe, Myriam Hide, Winston Lieberman, Judy TI miR-24 Inhibits Cell Proliferation by Targeting E2F2, MYC, and Other Cell-Cycle Genes via Binding to "Seedless" 3 ' UTR MicroRNA Recognition Elements SO MOLECULAR CELL LA English DT Article ID C-MYC; PROTEIN-SYNTHESIS; EXPRESSION; IDENTIFICATION; MIRNA; DIFFERENTIATION; APOPTOSIS; ELEGANS; GROWTH; TRANSLATION AB miR-24, upregulated during terminal differentiation of multiple lineages, inhibits cell-cycle progression. Antagonizing miR-24 restores postmitotic cell proliferation and enhances fibroblast proliferation, whereas overexpressing miR-24 increases the G1 compartment. The 248 mRNAs downregulated upon miR-24 overexpression are highly enriched for DNA repair and cell-cycle regulatory genes that form a direct interaction network with prominent nodes at genes that enhance (MYC, E2F2, CCNB1, and CDC2) or inhibit (p27Kip1 and VHL) cell-cycle progression. miR-24 directly regulates MYC and E2F2 and some genes that they transactivate. Enhanced proliferation from antagonizing miR-24 is abrogated by knocking down E2F2, but not MYC, and cell proliferation, inhibited by miR-24 overexpression, is rescued by miR-24-insensitive E2F2. Therefore, E2F2 is a critical miR-24 target. The E2F2 3'UTR lacks a predicted miR-24 recognition element. In fact, miR-24 regulates expression of E2F2, MYC, AURKB, CCNA2, CDC2, CDK4, and FEN1 by recognizing seedless but highly complementary sequences. C1 [Lal, Ashish; Navarro, Francisco; Maliszewski, Laura E.; Yan, Nan; O'Day, Elizabeth; Chowdhury, Dipanjan; Dykxhoorn, Derek M.; Tsai, Perry; Lieberman, Judy] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med,Immune Dis Inst, Boston, MA 02115 USA. [Lal, Ashish; Navarro, Francisco; Maliszewski, Laura E.; Yan, Nan; O'Day, Elizabeth; Chowdhury, Dipanjan; Dykxhoorn, Derek M.; Tsai, Perry; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Maher, Christopher A.] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA. [Becker, Kevin G.; Gorospe, Myriam] NIA, Res Resources Branch, IRP, NIH, Baltimore, MD 21224 USA. [Becker, Kevin G.; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, IRP, NIH, Baltimore, MD 21224 USA. [Hide, Winston] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hide, Winston] Univ Western Cape, S African Natl Bioinformat Inst, ZA-7535 Bellville, South Africa. [Dykxhoorn, Derek M.] Univ Miami, Miller Sch Med, John T Macdonald Fdn, Dept Human Genet, Miami, FL 33136 USA. [Dykxhoorn, Derek M.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. RP Lal, A (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med,Immune Dis Inst, Boston, MA 02115 USA. EM alal@idi.harvard.edu; lieberman@idi.harvard.edu RI Hide, Winston Hide/C-7217-2009; Hofmann, Oliver/F-1800-2013; Lieberman, Judy/A-2717-2015; Dykxhoorn, Derek/D-1357-2015; OI Hide, Winston Hide/0000-0002-8621-3271; Hofmann, Oliver/0000-0002-7738-1513; Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health (NIH) [A1070302]; GSK-IDI Alliance; the NIA-IRP; NIH; the Harry Oppenheimer Memorial Trust; GSK-IDI Alliance fellowship; Harvard Center for AIDS Research FX This work was supported, in part, by National Institutes of Health (NIH) A1070302 and a GSK-IDI Alliance grant (J.L.); the NIA-IRP, NIH (K.G.B., M.G.); the Harry Oppenheimer Memorial Trust (W.H.); a GSK-IDI Alliance fellowship (F.N.); and the Harvard Center for AIDS Research (N.Y.). We thank N. Dyson (Harvard Medical School) for the HA-E2F2 expression plasmid, Ray McGovern for programming support, and Lieberman laboratory members for useful discussions. NR 41 TC 327 Z9 343 U1 2 U2 17 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 SEP 11 PY 2009 VL 35 IS 5 BP 610 EP 625 DI 10.1016/j.molcel.2009.08.020 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 495QP UT WOS:000269909400010 PM 19748357 ER PT J AU Dutta, C Rhind, N AF Dutta, Chaitali Rhind, Nicholas TI The Role of Specific Checkpoint-Induced S-Phase Transcripts in Resistance to Replicative Stress SO PLOS ONE LA English DT Article AB Checkpoint activation during S phase modulates transcription. In response to replication arrest, the fission yeast Cds1 checkpoint kinase maintains the normal S-phase transcriptional program by regulating MBF, the S-phase transcription factor. We show that similar regulation occurs in response to DNA damage during S-phase. We test the relative contributions to replication-stress resistance of transcriptional regulation and the two other major checkpoint functions: cell-cycle arrest and fork stabilization. We show that, although transcriptional regulation provides only modest resistance relative to fork stabilization, it contributes significantly to cell survival. Finally, we investigate the roles of two specific transcripts: mik1 and mrc1. These results demonstrate the general importance of checkpoint regulation of G1/S transcription in response to replicative stress and elucidate the specific roles of Mik1 and Mrc1 in the checkpoint. RP Dutta, C (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM nick.rhind@umassmed.edu OI Rhind, Nicholas/0000-0003-1758-7736 FU NIGMS NIH HHS [GM069957, R01 GM069957, R01 GM069957-05] NR 27 TC 6 Z9 6 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 11 PY 2009 VL 4 IS 9 AR e6944 DI 10.1371/journal.pone.0006944 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 492XS UT WOS:000269696600004 PM 19750219 ER PT J AU Tso, FY Hoffmann, FG Tully, DC Lemey, P Rasmussen, RA Zhang, H Ruprecht, RA Wood, C AF Tso, For Yue Hoffmann, Federico G. Tully, Damien C. Lemey, Philippe Rasmussen, Robert A. Zhang, Hong Ruprecht, Ruth A. Wood, Charles TI A comparative study of HIV-1 clade C env evolution in a Zambian infant with an infected rhesus macaque during disease progression SO AIDS LA English DT Article DE disease progression; evolution; HIV-1; rhesus macaque; simian HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECOMBINANT GLYCOPROTEIN-120 VACCINE; NEUTRALIZING ANTIBODIES; TYPE-1 GP120; MOLECULAR EVOLUTION; V3 LOOP; ENVELOPE; MONKEYS; REGION; GLYCOSYLATION AB Objective: To evaluate whether HIV-1 clade C (HIV-C) envelope variations that arise during disease progression in rhesus macaque model reflect changes that occur naturally in human infection. Design: An infant macaque was infected with SHIV-1157i, an R5 tropic clade C SHIV, that expresses a primary HIV-C envelope derived from an infected human infant and monitored over a 5-year period. Genetic variation of the V1-V5 envelope region, which is the main target for humoral immune responses, derived from the infected macaque and infant was examined. Methods: The V1-V5 envelope region was cloned and sequenced from longitudinal peripheral blood mononuclear cell samples collected from the infected macaque and infant. Phylogenetic analysis [phylogenetic tree, diversity, divergence, ratio of non-synonymous (dN) and synonymous substitution (dS) and dN distribution] was performed. Plasma RNA viral load, CD4(+) T-cell count, changes in the length of V1-V5 region, putative N-linked glycosylation site number and distribution were also measured. Results: Phylogenetic analysis revealed that changes in the macaque closely reflected those of the infant during disease progression. Similar distribution patterns of dN and hot spots were observed between the macaque and infant. Analysis of putative N-linked glycosylation sites revealed several common variations between the virus populations in the two host species. These variations correlate with decline of CD4 T-cell count in the macaque and might be linked with disease progression. Conclusion: SHIV-C infection of macaque is a relevant animal model for studying variation of primary HIV-C envelope during disease progression and could be used to analyze the selection pressures that are associated with those changes. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Wood, Charles] Univ Nebraska, Sch Biol Sci, Morrison Ctr, Nebraska Ctr Virol, Lincoln, NE 68583 USA. [Rasmussen, Robert A.; Ruprecht, Ruth A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rasmussen, Robert A.; Ruprecht, Ruth A.] Harvard Univ, Sch Med, Boston, MA USA. [Lemey, Philippe] Katholieke Univ Leuven, Rega Inst Med Res, Leuven, Belgium. RP Wood, C (reprint author), Univ Nebraska, Sch Biol Sci, Morrison Ctr, Nebraska Ctr Virol, POB 830666, Lincoln, NE 68583 USA. EM cwood@unlnotes.unl.edu FU PHS [CA75903, TW001429]; NCRR COBRE [RR15635, P01AI48240, R01 DE12937, R01 DE0160354, R37AI34266]; FWO postdoctoral research fund FX This work was supported by PHS grants, CA75903, TW001429 and NCRR COBRE grant RR15635 to C.W; P01AI48240 to R.M.R., C.W and R.A.R.; R01 DE12937, R01 DE0160354 and R37AI34266 to R.M.R.; P.L. was supported by an FWO postdoctoral research fund. NR 58 TC 6 Z9 6 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 2009 VL 23 IS 14 BP 1817 EP 1828 DI 10.1097/QAD.0b013e32832f3da6 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 495QJ UT WOS:000269908800004 PM 19609201 ER PT J AU Bihl, F Berger, C Chisholm, JV Henry, LM Bertisch, B Trojan, A Nadal, D Speck, RF Flepp, M Brander, C Mueller, NJ AF Bihl, Florian Berger, Christoph Chisholm, John V., III Henry, Leah M. Bertisch, Barbara Trojan, Andreas Nadal, David Speck, Roberto F. Flepp, Markus Brander, Christian Mueller, Nicolas J. CA Swiss HIV Cohort Study TI Cellular immune responses and disease control in acute AIDS-associated Kaposi's sarcoma SO AIDS LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CD8(+) T-CELLS; HERPESVIRUS; HHV8 AB Kaposi's sarcoma-associated herpesvirus (KSHV) specific T cell responses and KSHV viremia were analyzed in seven HIV-infected patients with active Kaposi's sarcoma lesions who initiated highly active antiretroviral therapy, and were compared between patients with improved Kaposi's sarcoma and those with progressive Kaposi's sarcoma requiring further systemic chemotherapy. Patients with controlled Kaposi's sarcoma disease demonstrated undetectable Kaposi's sarcoma viremia together with KSHV-specific CD8(+) T cells secreting interferon-gamma and tumor necrosis factor-alpha, whereas progressors showed increasing viremia with weak or no T-cell responses. These data point toward a potential role of KSHV-specific immunity in the control of AIDS-associated Kaposi's sarcoma. C1 [Bihl, Florian] Univ Hosp Geneva, Dept Gastroenterol & Hepatol, Geneva, Switzerland. [Berger, Christoph; Nadal, David] Uni Childrens Hosp Zurich, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland. [Chisholm, John V., III; Henry, Leah M.; Brander, Christian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA USA. [Bertisch, Barbara; Speck, Roberto F.; Mueller, Nicolas J.] Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland. [Trojan, Andreas] Univ Zurich Hosp, Clin Oncol, Zurich, Switzerland. [Flepp, Markus] Ctr Infect Dis, Zurich, Switzerland. [Brander, Christian] Hosp Badalona Germans Trias & Pujol, Fundacio IrsiCaixa, Barcelona, Spain. [Brander, Christian] ICREA, Barcelona, Spain. RP Bihl, F (reprint author), Univ Hosp Geneva, Dept Gastroenterol & Hepatol, Geneva, Switzerland. RI Infektiologie, USZ/A-6921-2011; SHCS, all/G-4072-2011; SHCS, ch/G-4077-2011; SHCS, only/G-4080-2011; Mueller, Nicolas/B-6864-2013; Pantaleo, Giuseppe/K-6163-2016; Speck, Roberto/O-2433-2016; OI Mueller, Nicolas/0000-0002-1059-3191; Brander, Christian/0000-0002-0548-5778 NR 13 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 10 PY 2009 VL 23 IS 14 BP 1918 EP 1922 DI 10.1097/QAD.0b013e3283300a91 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 495QJ UT WOS:000269908800019 PM 19609199 ER PT J AU Shaw, AT Yeap, BY Mino-Kenudson, M Digumarthy, SR Costa, DB Heist, RS Solomon, B Stubbs, H Admane, S McDermott, U Settleman, J Kobayashi, S Mark, EJ Rodig, SJ Chirieac, LR Kwak, EL Lynch, TJ Iafrate, AJ AF Shaw, Alice T. Yeap, Beow Y. Mino-Kenudson, Mari Digumarthy, Subba R. Costa, Daniel B. Heist, Rebecca S. Solomon, Benjamin Stubbs, Hannah Admane, Sonal McDermott, Ultan Settleman, Jeffrey Kobayashi, Susumu Mark, Eugene J. Rodig, Scott J. Chirieac, Lucian R. Kwak, Eunice L. Lynch, Thomas J. Iafrate, A. John TI Clinical Features and Outcome of Patients With Non-Small-Cell Lung Cancer Who Harbor EML4-ALK SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol ID GROWTH-FACTOR-RECEPTOR; ANAPLASTIC LYMPHOMA KINASE; FUSION GENE; EGFR MUTATIONS; PHASE-II; GEFITINIB; KRAS; CHEMOTHERAPY; ERLOTINIB; TUMORS AB Purpose The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients and Methods Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Results Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P < .005) and were more likely to be men (P < .036 and P < .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. Conclusion EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents. C1 [Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Peter MacCallum Canc Ctr, Dept Haematol & Med Oncol, Melbourne, Vic, Australia. RP Iafrate, AJ (reprint author), Massachusetts Gen Hosp, Dept Pathol, Ctr Canc, Warren 501C,55 Fruit St, Boston, MA 02114 USA. EM aiafrate@partners.org OI Costa, Daniel/0000-0002-0689-395X; McDermott, Ultan/0000-0001-9032-4700 FU NCI NIH HHS [P20 CA090578, P50 CA090578, CA090578] NR 29 TC 814 Z9 901 U1 6 U2 43 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 SEP 10 PY 2009 VL 27 IS 26 BP 4247 EP 4253 DI 10.1200/JCO.2009.22.6993 PG 7 WC Oncology SC Oncology GA 492JU UT WOS:000269652200005 PM 19667264 ER PT J AU Mai, A Valente, S Meade, S Carafa, V Tardugno, M Nebbioso, A Galmozzi, A Mitro, N De Fabiani, E Altucci, L Kazantsev, A AF Mai, Antonello Valente, Sergio Meade, Sarah Carafa, Vincenzo Tardugno, Maria Nebbioso, Angela Galmozzi, Andrea Mitro, Nico De Fabiani, Emma Altucci, Lucia Kazantsev, Aleksey TI Study of 1,4-Dihydropyridine Structural Scaffold: Discovery of Novel Sirtuin Activators and Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SILENT INFORMATION REGULATOR; BIOLOGICAL EVALUATION; CELLULAR SENESCENCE; METABOLIC DISEASE; LEUKEMIA-CELLS; IN-VIVO; DEACETYLASE; SURVIVAL; CANCER; SIR2 AB NAD(+)-dependent sirtuin deacetylases have emerged as potential therapeutic targets for treatment of human illnesses such as cancer, metabolic, cardiovascular, and neurodegenerative diseases. The benefits of sirtuin modulation by small molecules have been demonstrated for these diseases. In contrast to the discovery of inhibitors of SIRT1, -2,and -3, only activators for SIRT1 are known. Here, we rationalized the potential of the previously unexplored dihydropyridine scaffold in developing sirtuin ligands, thus we prepared a series of 1,4-dihydropyridine-based derivatives 1-3. Assessment of their SIRT1-3 deacetylase activities revealed the importance of the substituent at the NI position of the dihydropyridine structure on sirtuin activity. Placement of cyclopropyl, phenyl, or phenylethyl groups at NI conferred nonselective SIRT1 and SIRT2 inhibition activity, while a benzyl group at N1 conferred potent SIRT1, -2, and -3 activation. Senescence assays performed on hMSC and mitochondrial function studies conducted with murine C2C12 myoblasts confirmed the compounds' novel and unique SIRT-activating properties. C1 [Mai, Antonello; Valente, Sergio; Tardugno, Maria] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Fdn Cenci Bolognetti, Ist Pasteur, I-00185 Rome, Italy. [Meade, Sarah; Kazantsev, Aleksey] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. [Carafa, Vincenzo; Nebbioso, Angela; Altucci, Lucia] Univ Naples 2, Dipartimento Patol Gen, I-80138 Naples, Italy. [Galmozzi, Andrea; Mitro, Nico; De Fabiani, Emma] Univ Milan, Dipartimento Sci Farmacol, I-20133 Milan, Italy. [Mitro, Nico] Giovanni Armenise Harvard Fdn Lab, Boston, MA USA. RP Mai, A (reprint author), Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Fdn Cenci Bolognetti, Ist Pasteur, Ple A Moro 5, I-00185 Rome, Italy. EM antonello.mai@uniroma1.it RI De Fabiani, Emma/B-6936-2015; Valente, Sergio/K-2198-2016; NEBBIOSO, Angela/C-3566-2016; OI De Fabiani, Emma/0000-0003-2406-1468; Valente, Sergio/0000-0002-2241-607X; NEBBIOSO, Angela/0000-0001-5374-3527; altucci, lucia/0000-0002-7312-5387; Mai, Antonello/0000-0001-9176-2382; Mitro, Nico/0000-0002-5000-3619 FU AIRC; RETI FIRB; European Union (APOSYS, ATLAS); Fondazione Luigi Califano ONLUS; Fondazione Roma; RJG; Carmen's Foundations FX This work was supported by grants from AIRC, RETI FIRB, European Union (APOSYS, ATLAS), Fondazione Luigi Califano ONLUS, Fondazione Roma, and RJG and Carmen's Foundations. NR 53 TC 70 Z9 72 U1 2 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 10 PY 2009 VL 52 IS 17 BP 5496 EP 5504 DI 10.1021/jm9008289 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 492KU UT WOS:000269655500022 PM 19663498 ER PT J AU Maida, Y Yasukawa, M Furuuchi, M Lassmann, T Possemato, R Okamoto, N Kasim, V Hayashizaki, Y Hahn, WC Masutomi, K AF Maida, Yoshiko Yasukawa, Mami Furuuchi, Miho Lassmann, Timo Possemato, Richard Okamoto, Naoko Kasim, Vivi Hayashizaki, Yoshihide Hahn, William C. Masutomi, Kenkichi TI An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA SO NATURE LA English DT Article ID SMALL INTERFERING RNAS; CARTILAGE-HAIR-HYPOPLASIA; HEPATITIS-C VIRUS; HUMAN TELOMERASE; CATALYTIC SUBUNIT; HUMAN-CELLS; GENETIC ELEMENTS; MARROW FAILURE; IMMORTAL CELLS; MOUSE OOCYTES AB Constitutive expression of telomerase in human cells prevents the onset of senescence and crisis by maintaining telomere homeostasis. However, accumulating evidence suggests that the human telomerase reverse transcriptase catalytic subunit ( TERT) contributes to cell physiology independently of its ability to elongate telomeres. Here we show that TERT interacts with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), a gene that is mutated in the inherited pleiotropic syndrome cartilage-hair hypoplasia. Human TERT and RMRP form a distinct ribonucleoprotein complex that has RNA-dependent RNA polymerase (RdRP) activity and produces double- stranded RNAs that can be processed into small interfering RNA in a Dicer ( also known as DICER1)-dependent manner. These observations identify a mammalian RdRP composed of TERT in complex with RMRP. C1 [Possemato, Richard; Hahn, William C.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Possemato, Richard; Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Possemato, Richard; Hahn, William C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Masutomi, Kenkichi] Japan Sci & Technol Agcy, PREST, Kawaguchi, Saitama 3320012, Japan. [Maida, Yoshiko; Yasukawa, Mami; Furuuchi, Miho; Okamoto, Naoko; Kasim, Vivi; Masutomi, Kenkichi] Natl Canc Ctr, Canc Stem Cell Project, Chuo Ku, Tokyo 1040045, Japan. [Lassmann, Timo; Hayashizaki, Yoshihide] RIKEN, Yokohama Inst, RIKEN Om Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. RP Hahn, WC (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM william_hahn@dfci.harvard.edu; kmasutom@ncc.go.jp RI Lassmann, Timo/A-8271-2008; OI Lassmann, Timo/0000-0002-0138-2691; Possemato, Richard/0000-0002-2401-0030; Kasim, Vivi/0000-0001-9182-8230 FU NIA NIH HHS [R01 AG023145-05, R01 AG23145, R01 AG023145] NR 49 TC 186 Z9 193 U1 3 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 10 PY 2009 VL 461 IS 7261 BP 230 EP U104 DI 10.1038/nature08283 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 492KN UT WOS:000269654600037 PM 19701182 ER PT J AU Gruber-Olipitz, M Segal, RA AF Gruber-Olipitz, Mariella Segal, Rosalind A. TI Live or Let Die: CCM2 Provides the Link SO NEURON LA English DT Editorial Material ID CEREBRAL CAVERNOUS MALFORMATIONS; TRK NEUROTROPHIN RECEPTORS; MEDULLOBLASTOMA; PATHOGENESIS AB TrkA receptors are well known for promoting neuronal cell survival. However, in some neuroblastic tumors, TrkA activation can instead induce apoptosis. In this issue of Neuron, Harel et al. identify CCM2 as a mediator of TrkA-dependent cell death, suggesting that CCM2 is a distinctive type of tumor suppressor that modulates tyrosine kinase signaling. C1 [Gruber-Olipitz, Mariella; Segal, Rosalind A.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Gruber-Olipitz, Mariella; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Canc Biol & Pediat Oncol, Boston, MA 02115 USA. RP Segal, RA (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 44 Binney St, Boston, MA 02115 USA. EM rosalind_segal@dfci.harvard.edu FU NINDS NIH HHS [R01 NS037757] NR 12 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 10 PY 2009 VL 63 IS 5 BP 559 EP 560 DI 10.1016/j.neuron.2009.08.030 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 494XH UT WOS:000269852300001 PM 19755097 ER PT J AU Glykys, J Dzhala, VI Kuchiblhotla, KV Feng, GP Kuner, T Augustine, G Bacskai, BJ Staley, KJ AF Glykys, Joseph Dzhala, Volodymyr I. Kuchiblhotla, Kishore V. Feng, Guoping Kuner, Thomas Augustine, George Bacskai, Brian J. Staley, Kevin J. TI Differences in Cortical versus Subcortical GABAergic Signaling: A Candidate Mechanism of Electroclinical Uncoupling of Neonatal Seizures SO NEURON LA English DT Article ID GRAMICIDIN-PERFORATED-PATCH; HIGH-FREQUENCY OSCILLATIONS; CATION-CHLORIDE COTRANSPORTERS; IMAGING SYNAPTIC INHIBITION; GABA(A) RECEPTOR FUNCTION; RAT NEOCORTICAL NEURONS; TEMPORAL-LOBE EPILEPSY; K+-CL-COTRANSPORTER; RHYTHMS IN-VITRO; INTRACELLULAR CHLORIDE AB Electroclinical uncoupling of neonatal seizures refers to electrographic seizure activity that is not clinically manifest. Uncoupling increases after treatment with Phenobarbital, which enhances the GABA(A) receptor (GABA(A)R) conductance. The effects of GABAAR activation depend on the intracellular Cl(-) concentration ([Cl(-)](i)) that is determined by the inward Cl(-) transporter NKCC1 and the outward Cl(-) transporter KCC2. Differential maturation of Cl(-) transport observed in cortical versus subcortical regions should alter the efficacy of GABA-mediated inhibition. In perinatal rat pups, most thalamic neurons maintained low [Cl(-)](i) and were inhibited by GABA. Phenobarbital suppressed thalamic seizure activity. Most neocortical neurons maintained higher [Cl(-)](i), and were excited by GABAAR activation. Phenobarbital had insignificant anticonvulsant responses in the neocortex until NKCC1 was blocked. Regional differences in the ontogeny of Cl(-) transport may thus explain why seizure activity in the cortex is not suppressed by anticonvulsants that block the transmission of seizure activity through subcortical networks. C1 [Glykys, Joseph; Dzhala, Volodymyr I.; Kuchiblhotla, Kishore V.; Bacskai, Brian J.; Staley, Kevin J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02144 USA. [Feng, Guoping; Augustine, George] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. [Augustine, George] Duke Natl Univ Singapore, Grad Sch Med, Program Neurosci & Behav Disorders, Singapore 169547, Singapore. [Kuner, Thomas] Univ Heidelberg, Inst Anat & Cell Biol, D-69120 Heidelberg, Germany. [Kuchiblhotla, Kishore V.] Harvard Univ, Program Biophys, Boston, MA 02115 USA. RP Staley, KJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02144 USA. EM kstaley@partners.org FU American Epilepsy Society; NIH [NS580752, NS040109, EB000768]; DFG [KU1983/1-2] FX We give our thanks to the Staley lab for helpful discussion. This work was supported by the American Epilepsy Society (J.G.), NIH NS580752 (K.V.K.), NIH NS040109 (K.J.S.), NIH EB000768 (B.J.B.), and DFG grant KU1983/1-2 (T.K.). J.G. was responsible for the design, electrophysiology, two-photon imaging, analysis, and writing; K.K. and D.V., for two-photon imaging and analysis; G.F., T.K., and G.A., for mice generation; BJB., for two-photon imaging; and K.J.S., for design and writing. NR 102 TC 66 Z9 67 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 10 PY 2009 VL 63 IS 5 BP 657 EP 672 DI 10.1016/j.neuron.2009.08.022 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 494XH UT WOS:000269852300012 PM 19755108 ER PT J AU Dey, BR Spitzer, TR Hasserjian, RP AF Dey, Bimalangshu R. Spitzer, Thomas R. Hasserjian, Robert P. TI A Man with Fatigue, Cough, and Peripheral-Blood Monocytosis Acute myeloid leukemia, not otherwise specified (acute monocytic leukemia), with FLT3-ITD SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT Clinicopathological Conference 2009 CY MAR 26, 2009 CL MA SP Gen Hosp Canc Ctr Grand Rounds ID STEM-CELL TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; HOST DISEASE; OLDER; INDUCTION; GRAFT; NUCLEOPHOSMIN; CHEMOTHERAPY; OUTCOMES; ADULTS C1 [Dey, Bimalangshu R.; Spitzer, Thomas R.] Massachusetts Gen Hosp, Hematol Oncol Unit, Boston, MA 02114 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Dey, Bimalangshu R.; Spitzer, Thomas R.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Hasserjian, Robert P.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Dey, BR (reprint author), Massachusetts Gen Hosp, Hematol Oncol Unit, Boston, MA 02114 USA. NR 22 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 SEP 10 PY 2009 VL 361 IS 11 BP 1099 EP 1106 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 492LP UT WOS:000269659400015 PM 19741232 ER PT J AU Charles, RC Harris, JB Chase, MR Lebrun, LM Sheikh, A LaRocque, RC Logvinenko, T Rollins, SM Tarique, A Hohmann, EL Rosenberg, I Krastins, B Sarracino, DA Qadri, F Calderwood, SB Ryan, ET AF Charles, Richelle C. Harris, Jason B. Chase, Michael R. Lebrun, Lauren M. Sheikh, Alaullah LaRocque, Regina C. Logvinenko, Tanya Rollins, Sean M. Tarique, Abdullah Hohmann, Elizabeth L. Rosenberg, Ian Krastins, Bryan Sarracino, David A. Qadri, Firdausi Calderwood, Stephen B. Ryan, Edward T. TI Comparative Proteomic Analysis of the PhoP Regulon in Salmonella enterica Serovar Typhi Versus Typhimurium SO PLOS ONE LA English DT Article AB Background: S. Typhi, a human-restricted Salmonella enterica serovar, causes a systemic intracellular infection in humans (typhoid fever). In comparison, S. Typhimurium causes gastroenteritis in humans, but causes a systemic typhoidal illness in mice. The PhoP regulon is a well studied two component (PhoP/Q) coordinately regulated network of genes whose expression is required for intracellular survival of S. enterica. Methodology/Principal Findings: Using high performance liquid chromatography mass spectrometry (HPLC-MS/MS), we examined the protein expression profiles of three sequenced S. enterica strains: S. Typhimurium LT2, S. Typhi CT18, and S. Typhi Ty2 in PhoP-inducing and non-inducing conditions in vitro and compared these results to profiles of phoP(-)/Q(-) mutants derived from S. Typhimurium LT2 and S. Typhi Ty2. Our analysis identified 53 proteins in S. Typhimurium LT2 and 56 proteins in S. Typhi that were regulated in a PhoP-dependent manner. As expected, many proteins identified in S. Typhi demonstrated concordant differential expression with a homologous protein in S. Typhimurium. However, three proteins (HlyE, STY1499, and CdtB) had no homolog in S. Typhimurium. HlyE is a pore-forming toxin. STY1499 encodes a stably expressed protein of unknown function transcribed in the same operon as HlyE. CdtB is a cytolethal distending toxin associated with DNA damage, cell cycle arrest, and cellular distension. Gene expression studies confirmed up-regulation of mRNA of HlyE, STY1499, and CdtB in S. Typhi in PhoP-inducing conditions. Conclusions/Significance: This study is the first protein expression study of the PhoP virulence associated regulon using strains of Salmonella mutant in PhoP, has identified three Typhi-unique proteins (CdtB, HlyE and STY1499) that are not present in the genome of the wide host-range Typhimurium, and includes the first protein expression profiling of a live attenuated bacterial vaccine studied in humans (Ty800). RP Charles, RC (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM rccharles@partners.org RI Tarique, Abdullah/M-2860-2013; OI Tarique, Abdullah/0000-0003-3782-345X; Rollins, Sean/0000-0002-3724-1989 FU FIC NIH HHS [D43 TW005572, K01 TW007144, K01 TW007409, K01 TW07144, TW05572]; NIAID NIH HHS [AI058935, AI072599, AI67103, K08 AI089721, R01 AI067103, R21 AI072599, U01 AI058935, U54 AI057159]; NINDS NIH HHS [NS059429, R21 NS059429] NR 60 TC 31 Z9 33 U1 0 U2 8 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 SEP 10 PY 2009 VL 4 IS 9 AR e6994 DI 10.1371/journal.pone.0006994 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 492XR UT WOS:000269696500007 PM 19746165 ER PT J AU D'Avolio, LW AF D'Avolio, Leonard W. TI Electronic Medical Records at a Crossroads Impetus for Change or Missed Opportunity? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID HEALTH-CARE-SYSTEM; QUALITY-OF-CARE C1 [D'Avolio, Leonard W.] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Cooperat Studies Program Coordinating Ctr, Jamaica Plain, MA 02130 USA. [D'Avolio, Leonard W.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. RP D'Avolio, LW (reprint author), Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr 15, 150 S Huntington Ave, Jamaica Plain, MA 02130 USA. EM leonard.davolio@va.gov NR 6 TC 15 Z9 17 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 9 PY 2009 VL 302 IS 10 BP 1109 EP 1111 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 491XH UT WOS:000269616200031 PM 19738097 ER PT J AU Sittig, DF Singh, H AF Sittig, Dean F. Singh, Hardeep TI Eight Rights of Safe Electronic Health Record Use SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID UNEXPECTED INCREASED MORTALITY; ORDER ENTRY SYSTEM; IMPLEMENTATION C1 [Sittig, Dean F.] UT Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX 77030 USA. [Sittig, Dean F.] Univ Texas Houston, Sch Hlth Informat Sci, Houston, TX USA. [Singh, Hardeep] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Ctr Inquiry Improve Outpatient Safety Effect Elec, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Houston VA Hlth Serv, Res & Dev Ctr Excellence, Houston, TX 77030 USA. RP Sittig, DF (reprint author), UT Mem Hermann Ctr Healthcare Qual & Safety, 6410 Fannin St,UTPB 1100-43, Houston, TX 77030 USA. EM dean.f.sittig@uth.tmc.edu FU NCI NIH HHS [K23CA125585]; NLM NIH HHS [R01-LM006942] NR 10 TC 38 Z9 38 U1 0 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 9 PY 2009 VL 302 IS 10 BP 1111 EP 1113 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 491XH UT WOS:000269616200032 PM 19738098 ER PT J AU Yealy, DM Fine, MJ AF Yealy, Donald M. Fine, Michael J. TI Measurement of Serum Procalcitonin A Step Closer to Tailored Care for Respiratory Infections? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID COMMUNITY-ACQUIRED PNEUMONIA; ANTIBIOTIC USE; PRACTICE GUIDELINES; CLINICAL-PRACTICE; RANDOMIZED-TRIAL; TRACT INFECTIONS; IMPLEMENTATION; INTERVENTIONS; THERAPY C1 [Yealy, Donald M.] Univ Pittsburgh, Sch Med, Dept Emergency Med, Pittsburgh, PA 15260 USA. [Fine, Michael J.] Univ Pittsburgh, Sch Med, Ctr Hlth Equ Res & Promot, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Fine, Michael J.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA 15260 USA. RP Yealy, DM (reprint author), Univ Pittsburgh, Sch Med, Dept Emergency Med, 3600 Meyran Ave,Forbes Tower Ste 10028, Pittsburgh, PA 15260 USA. EM yealydm@upmc.edu NR 22 TC 8 Z9 8 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 9 PY 2009 VL 302 IS 10 BP 1115 EP 1116 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 491XH UT WOS:000269616200034 PM 19738100 ER PT J AU Rajimehr, R Tootell, RBH AF Rajimehr, Reza Tootell, Roger B. H. TI Does Retinotopy Influence Cortical Folding in Primate Visual Cortex? SO JOURNAL OF NEUROSCIENCE LA English DT Article ID BRAIN; MAPS; MONKEYS AB In humans and other Old World primates, much of visual cortex comprises a set of retinotopic maps, embedded in a cortical sheet with well known, identifiable folding patterns. However, the relationship between these two prominent cortical variables has not been comprehensively studied. Here, we quantitatively tested this relationship using functional and structural magnetic resonance imaging in monkeys and humans. We found that the vertical meridian of the visual field tends to be represented on gyri (convex folds), whereas the horizontal meridian is preferentially represented in sulci (concave folds), throughout visual cortex in both primate species. This relationship suggests that the retinotopic maps may constrain the pattern of cortical folding during development. C1 [Rajimehr, Reza; Tootell, Roger B. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Martinos Ctr, Charlestown, MA 02129 USA. [Rajimehr, Reza] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. RP Rajimehr, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Martinos Ctr, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM reza@nmr.mgh.harvard.edu FU National Institutes of Health [R01 MH67529, R01 EY017081]; Martinos Center for Biomedical Imaging; National Center for Research Resources; MIND Institute FX This research was supported by the National Institutes of Health (Grants R01 MH67529 and R01 EY017081 to R. B. H. T.), the Martinos Center for Biomedical Imaging, the National Center for Research Resources, and the MIND Institute. We thank John Maunsell and two anonymous reviewers for helpful comments on this manuscript. NR 12 TC 25 Z9 26 U1 1 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 9 PY 2009 VL 29 IS 36 BP 11149 EP 11152 DI 10.1523/JNEUROSCI.1835-09.2009 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 492QS UT WOS:000269674700009 PM 19741121 ER PT J AU Weiss, AP Ellis, CB Roffman, JL Stufflebeam, S Hamalainen, MS Duff, M Goff, DC Schacter, DL AF Weiss, Anthony P. Ellis, Cameron B. Roffman, Joshua L. Stufflebeam, Steven Hamalainen, Matti S. Duff, Margaret Goff, Donald C. Schacter, Daniel L. TI Aberrant Frontoparietal Function during Recognition Memory in Schizophrenia: A Multimodal Neuroimaging Investigation SO JOURNAL OF NEUROSCIENCE LA English DT Article ID EVENT-RELATED POTENTIALS; SURFACE-BASED ANALYSIS; EPISODIC MEMORY; CORTICAL SURFACE; BRAIN POTENTIALS; PARIETAL CORTEX; ELECTROPHYSIOLOGICAL EVIDENCE; COORDINATE SYSTEM; RETRIEVAL SUCCESS; WORKING-MEMORY AB Prefrontal-parietal networks are essential to many cognitive processes, including the ability to differentiate new from previously presented items. As patients with schizophrenia exhibit structural abnormalities in these areas along with well documented decrements in recognition memory, we hypothesized that these patients would demonstrate memory-related abnormalities in prefrontal and parietal physiology as measured by both functional magnetic resonance imaging and magnetoencephalography (MEG). Medicated outpatients with schizophrenia (n = 18) and age-matched healthy control subjects (n = 18) performed an old-new recognition memory task while physiological data were obtained. Whereas controls exhibited strong, bilateral activation of prefrontal and posterior parietal regions during successful identification of old versus new items, patients exhibited greatly attenuated activation of the right prefrontal and parietal cortices. However, within the patient group, there was strong correlation between memory performance and activation of these right-sided regions as well as a tight correlation between old-new effect-related activations in frontal and parietal regions, a pattern not seen in control subjects. Using MEG, control subjects-but not patients-exhibited a sequential pattern of old > new activity in the left posterior parietal cortex and then right prefrontal cortex; however, patients uniquely exhibited old > new activity in right temporal cortex. Collectively, these findings point to markedly different distributions of regional specialization necessary to complete the old-new item recognition task in patients versus controls. Inefficient utilization of prefrontal-parietal networks, with compensatory activation in temporal regions, may thus contribute to deficient old-new item recognition in schizophrenia. C1 [Weiss, Anthony P.; Ellis, Cameron B.; Roffman, Joshua L.; Duff, Margaret; Goff, Donald C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Weiss, Anthony P.; Ellis, Cameron B.; Roffman, Joshua L.; Stufflebeam, Steven; Hamalainen, Matti S.; Duff, Margaret] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Schacter, Daniel L.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Weiss, AP (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq, Boston, MA 02114 USA. EM aweiss@partners.org RI Hamalainen, Matti/C-8507-2013; OI Schacter, Daniel/0000-0002-2460-6061 FU National Institutes of Health (NIH) [K23-MH06019, R01-MH060941]; Howard Hughes Medical Institute Physician-Scientist Early Career Award; MIND Institute; National Center for Research Resources Regional Resources [P41RR14075] FX This work was supported by National Institutes of Health (NIH) Grant K23-MH06019 (A. P. W.), NIH Grant R01-MH060941 (D.L.S.), Howard Hughes Medical Institute Physician-Scientist Early Career Award (J.L.R.), the MIND Institute, and National Center for Research Resources Regional Resources Grant P41RR14075 (Martinos Center). We thank Tali Ditman and Michael Zussman for assistance with the paradigm development, and Dr. Lindsay Jubelt, Deidre von Pechmann, and Kaila Norman for assistance with data acquisition. NR 85 TC 6 Z9 6 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 SEP 9 PY 2009 VL 29 IS 36 BP 11347 EP 11359 DI 10.1523/JNEUROSCI.0617-09.2009 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 492QS UT WOS:000269674700029 PM 19741141 ER PT J AU Fu, H Cai, J Clevers, H Fast, E Gray, S Greenberg, R Jain, MK Ma, QF Qiu, MS Rowitch, DH Taylor, CM Stiles, CD AF Fu, Hui Cai, Jun Clevers, Hans Fast, Eva Gray, Susan Greenberg, Rachel Jain, Mukesh K. Ma, Qiufu Qiu, Mengsheng Rowitch, David H. Taylor, Christopher M. Stiles, Charles D. TI A Genome-Wide Screen for Spatially Restricted Expression Patterns Identifies Transcription Factors That Regulate Glial Development SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DEVELOPING SPINAL-CORD; CENTRAL-NERVOUS-SYSTEM; OLIGODENDROCYTE DIFFERENTIATION; GENE-EXPRESSION; BETA-CATENIN; FACTOR OLIG2; LINEAGE COMMITMENT; MOUSE EMBRYO; DATABASE; FAMILY AB Forward genetic screens in genetically accessible invertebrate organisms such as Drosophila melanogaster have shed light on transcription factors that specify formation of neurons in the vertebrate CNS. However, invertebrate models have, to date, been uninformative with respect to genes that specify formation of the vertebrate glial lineages. All recent insights into specification of vertebrate glia have come via monitoring the spatial and temporal expression patterns of individual transcription factors during development. In studies described here, we have taken this approach to the genome scale with an in silico screen of the Mahoney pictorial atlas of transcription factor expression in the developing CNS. From the population of 1445 known or probable transcription factors encoded in the mouse genome, we identify 12 novel transcription factors that are expressed in glial lineage progenitor cells. Entry-level screens for biological function establish one of these transcription factors, Klf15, as sufficient for genesis of precocious GFAP-positive astrocytes in spinal cord explants. Another transcription factor, Tcf4, plays an important role in maturation of oligodendrocyte progenitors. C1 [Fu, Hui; Ma, Qiufu; Taylor, Christopher M.; Stiles, Charles D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ma, Qiufu] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Taylor, Christopher M.; Stiles, Charles D.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Gray, Susan] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Cai, Jun] Univ Louisville, Kosair Childrens Hosp, Res Inst, Dept Pediat, Louisville, KY 40202 USA. [Cai, Jun; Qiu, Mengsheng] Univ Louisville, Sch Med, Dept Anat Sci & Neurobiol, Louisville, KY 40202 USA. [Clevers, Hans] Hubrecht Lab, NL-3584 CT Utrecht, Netherlands. [Fast, Eva] Boston Univ, Dept Biol, Boston, MA 02215 USA. [Greenberg, Rachel] Columbia Univ, Columbia Coll, Dept Biol Sci, New York, NY 10027 USA. [Jain, Mukesh K.] Case Western Reserve Univ, Sch Med, Case Cardiovasc Res Inst, Cleveland, OH 44106 USA. [Rowitch, David H.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Rowitch, David H.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Rowitch, David H.] Univ Calif San Francisco, Inst Regenerat Med, San Francisco, CA 94143 USA. [Fu, Hui] Nanchang Univ, Basic Med Coll, Dept Physiol, Nanchang 330006, Jiangxi, Peoples R China. RP Stiles, CD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM Charles_stiles@dfci.harvard.edu RI Fu, Hui/C-2881-2011 OI Fu, Hui/0000-0003-0252-6009 FU National Institutes of Health [NS059893]; National Natural Science Foundation of China [N030860131] FX This research was supported by National Institutes of Health Grant NS059893 and National Natural Science Foundation of China Grant N030860131. Wethank Dr. William Stallcup for NG2 antibody and Dr. David Anderson for Sox10 antibody. We also thank Xuemei Hu for technical support. NR 52 TC 65 Z9 66 U1 0 U2 11 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 SEP 9 PY 2009 VL 29 IS 36 BP 11399 EP 11408 DI 10.1523/JNEUROSCI.0160-09.2009 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 492QS UT WOS:000269674700034 PM 19741146 ER PT J AU Duan, ZF Choy, E Harmon, D Yang, C Ryu, K Schwab, J Mankin, H Hornicek, FJ AF Duan, Zhenfeng Choy, Edwin Harmon, David Yang, Cao Ryu, Keinosuke Schwab, Joseph Mankin, Henry Hornicek, Francis J. TI ZNF93 Increases Resistance to ET-743 (Trabectedin; Yondelis (R)) and PM00104 (Zalypsis (R)) in Human Cancer Cell Lines SO PLOS ONE LA English DT Article AB Background: ET-743 (trabectedin, Yondelis (R)) and PM00104 (Zalypsis (R)) are marine derived compounds that have antitumor activity. ET-743 and PM00104 exposure over sustained periods of treatment will result in the development of drug resistance, but the mechanisms which lead to resistance are not yet understood. Methodology/Principal Findings: Human chondrosarcoma cell lines resistant to ET-743 (CS-1/ER) or PM00104 (CS-1/PR) were established in this study. The CS-1/ER and CS-1/PR exhibited cross resistance to cisplatin and methotrexate but not to doxorubicin. Human Affymetrix Gene Chip arrays were used to examine relative gene expression in these cell lines. We found that a large number of genes have altered expression levels in CS-1/ER and CS-1/PR when compared to the parental cell line. 595 CS-1/ER and 498 CS-1/PR genes were identified as overexpressing; 856 CS-1/ER and 874 CS-1/PR transcripts were identified as underexpressing. Three zinc finger protein (ZNF) genes were on the top 10 overexpressed genes list. These genes have not been previously associated with drug resistance in tumor cells. Differential expressions of ZNF93 and ZNF43 genes were confirmed in both CS-1/ER and CS-1/PR resistant cell lines by real-time RT-PCR. ZNF93 was overexpressed in two ET-743 resistant Ewing sarcoma cell lines as well as in a cisplatin resistant ovarian cancer cell line, but was not overexpressed in paclitaxel resistant cell lines. ZNF93 knockdown by siRNA in CS-1/ER and CS-1/PR caused increased sensitivity for ET-743, PM00104, and cisplatin. Furthermore, ZNF93 transfected CS-1 cells are relatively resistant to ET-743, PM00104 and cisplatin. Conclusions/Significance: This study suggests that zinc finger proteins, and ZNF93 in particular, are involved in resistance to ET-743 and PM00104. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. EM zduan@partners.org OI Choy, Edwin/0000-0001-9896-8084 FU NCI NIH HHS [R01-CA119617, R01 CA119617] NR 27 TC 8 Z9 9 U1 0 U2 6 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 SEP 9 PY 2009 VL 4 IS 9 AR e6967 DI 10.1371/journal.pone.0006967 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 491ZI UT WOS:000269622500025 PM 19742314 ER PT J AU Wang, SX Zhang, L Lim, G Sung, B Tian, YH Chou, CW Hernstadt, H Rusanescu, G Ma, YX Mao, JR AF Wang, Shuxing Zhang, Lin Lim, Grewo Sung, Backil Tian, Yinghong Chou, Chiu-Wen Hernstadt, Hayley Rusanescu, Gabriel Ma, Yuxin Mao, Jianren TI A combined effect of dextromethorphan and melatonin on neuropathic pain behavior in rats SO BRAIN RESEARCH LA English DT Article DE Melatonin; Dextromethorphan; Neuropathic pain; Depression ID LOW-BACK-PAIN; ASPARTATE RECEPTOR ANTAGONIST; CHRONIC MUSCULOSKELETAL PAIN; INTRAVENOUS KETAMINE TEST; DIABETIC-NEUROPATHY; DOUBLE-BLIND; POSTHERPETIC NEURALGIA; MECHANICAL ALLODYNIA; MORPHINE-TOLERANCE; CLUSTER HEADACHE AB Previous study has shown that administration of melatonin into the anterior cingulate cortex contralateral to peripheral nerve injury prevented exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats. In the present study, we examined the effect of the individual versus combined treatment of melatonin and/or dextromethorphan (DM), a clinically available N-methyl-D-aspartate (NMDA) receptor antagonist, on pain behaviors in WKY rats with chronic constriction sciatic nerve injury (CCI). Pain behaviors (thermal hyperalgesia and mechanical allodynia) were established at one week after CCI. WKY rats were then treated intraperitoneally with various doses of melatonin, DM or their combination once daily for the following week. At the end of this one-week treatment, behavioral tests were repeated in these same rats. While DM alone was effective in reducing thermal hyperalgesia at three tested doses (15, 30 or 60 mg/kg), it reduced mechanical allodynia only at high doses (30 or 60 mg/kg). By comparison, administration of melatonin alone was effective in reducing thermal hyperalgesia only at the highest dose (120 mg/kg, but not 30 or 60 mg/kg) tested in this experiment. Melatonin alone failed to reverse allodynia at all three tested doses (30, 60 and 120 mg/kg). However, the combined intraperitoneal administration of melatonin (30 mg/kg) and DM (15 mg/kg) effectively reversed both thermal hyperalgesia and mechanical allodynia although each individual dose alone did not reduce pain behaviors. These results suggest that a combination of melatonin with a clinically available NMDA receptor antagonist might be more effective than either drug alone for the treatment of neuropathic pain. (C) 2009 Elsevier B.V. All rights reserved. C1 [Wang, Shuxing; Zhang, Lin; Lim, Grewo; Sung, Backil; Tian, Yinghong; Chou, Chiu-Wen; Hernstadt, Hayley; Rusanescu, Gabriel; Ma, Yuxin; Mao, Jianren] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH Ctr Translat Pain Res,Dept Anesthesia & Crit, Boston, MA 02114 USA. RP Mao, JR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH Ctr Translat Pain Res,Dept Anesthesia & Crit, WACC 324, Boston, MA 02114 USA. EM jmao@partners.org FU NIH [DE18214, DE18S38, NS45681] FX This study is supported by NIH RO1 grants DE18214, DE18S38, and NS45681. NR 99 TC 14 Z9 17 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 8 PY 2009 VL 1288 BP 42 EP 49 DI 10.1016/j.brainres.2009.06.094 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 497ZK UT WOS:000270104200005 PM 19595681 ER PT J AU Ng, K Wolpin, BM Meyerhardt, JA Wu, K Chan, AT Hollis, BW Giovannucci, EL Stampfer, MJ Willett, WC Fuchs, CS AF Ng, K. Wolpin, B. M. Meyerhardt, J. A. Wu, K. Chan, A. T. Hollis, B. W. Giovannucci, E. L. Stampfer, M. J. Willett, W. C. Fuchs, C. S. TI Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE vitamin D; colorectal cancer; epidemiology; diet and nutrition ID NATIONAL DEATH INDEX; III COLON-CANCER; 1,25-DIHYDROXYVITAMIN D-3; PHYSICAL-ACTIVITY; CARCINOMA-CELLS; DAIRY-PRODUCTS; NURSES HEALTH; UNITED-STATES; RISK; CALCIUM AB BACKGROUND: In an earlier study, a 25-hydroxyvitamin D(3) (25(OH) D) score calculated from known predictors of vitamin D status significantly predicted plasma levels of 25(OH) D and the risk of colorectal cancer, but the influence of the 25(OH) D score on survival after diagnosis is unknown. MATERIALS AND METHODS: We prospectively examined the influence of post-diagnosis predicted 25(OH) D levels on mortality among 1017 participants in the Nurses' Health Study and Health Professionals Follow-Up Study who were diagnosed with colorectal cancer from 1986 to 2004. Colorectal cancer-specific and overall mortality according to quintiles of predicted 25(OH) D levels were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) adjusted for other risk factors of survival. RESULTS: Higher predicted 25(OH) D levels were associated with a significant reduction in colorectal cancer-specific (P trend = 0.02) and overall mortality (P trend = 0.002). Compared with levels in the lowest quintile, participants with predicted 25(OH) D levels in the highest quintile had an adjusted HR of 0.50 (95% CI, 0.26-0.95) for cancer-specific mortality and 0.62 (95% CI, 0.42-0.93) for overall mortality. CONCLUSION: Higher predicted 25(OH) D levels after a diagnosis of colorectal cancer may be associated with improved survival. Further study of the vitamin D pathway in colorectal cancer is warranted. British Journal of Cancer (2009) 101, 916-923. doi:10.1038/sj.bjc.6605262 www.bjcancer.com Published online 18 August 2009 (C) 2009 Cancer Research UK C1 [Ng, K.; Wolpin, B. M.; Meyerhardt, J. A.; Fuchs, C. S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wu, K.; Giovannucci, E. L.; Stampfer, M. J.; Willett, W. C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chan, A. T.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Hollis, B. W.] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Giovannucci, E. L.; Stampfer, M. J.; Fuchs, C. S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Giovannucci, E. L.; Stampfer, M. J.; Fuchs, C. S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Giovannucci, E. L.; Stampfer, M. J.; Willett, W. C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Ng, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM Kimmie_Ng@dfci.harvard.edu FU NCI NIH HHS [CA055075, CA87969, P50CA127003, R01 CA137178] NR 40 TC 64 Z9 65 U1 0 U2 4 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 SEP 8 PY 2009 VL 101 IS 6 BP 916 EP 923 DI 10.1038/sj.bjc.6605262 PG 8 WC Oncology SC Oncology GA 491XO UT WOS:000269617200008 PM 19690551 ER PT J AU Kaelin, WG AF Kaelin, William G., Jr. TI SDH5 Mutations and Familial Paraganglioma: Somewhere Warburg is Smiling SO CANCER CELL LA English DT Editorial Material ID FUMARATE HYDRATASE; RENAL-CANCER; HYPOXIA; PHENOTYPE; CELLS AB Paragangliomas have been linked to mutations affecting the succinate dehydrogenase complex. In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function. Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma. C1 [Kaelin, William G., Jr.] Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA. [Kaelin, William G., Jr.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Howard Hughes Med Inst, 44 Binney St, Boston, MA 02115 USA. EM william_kaelin@dfci.harvard.edu FU Howard Hughes Medical Institute NR 12 TC 36 Z9 37 U1 0 U2 2 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 SEP 8 PY 2009 VL 16 IS 3 BP 180 EP 182 DI 10.1016/j.ccr.2009.08.013 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 493CS UT WOS:000269711500005 PM 19732718 ER PT J AU Garrett, WS Punit, S Gallini, CA Michaud, M Zhang, D Sigrist, KS Lord, GM Glickman, JN Glimcher, LH AF Garrett, Wendy S. Punit, Shivesh Gallini, Carey A. Michaud, Monia Zhang, Dorothy Sigrist, Kirsten S. Lord, Graham M. Glickman, Jonathan N. Glimcher, Laurie H. TI Colitis-Associated Colorectal Cancer Driven by T-bet Deficiency in Dendritic Cells SO CANCER CELL LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; TOLL-LIKE RECEPTORS; DNA-PLOIDY PATTERN; ULCERATIVE-COLITIS; COLON CARCINOGENESIS; IMMUNE-SYSTEM; MICE; METASTASIS; DYSPLASIA; ALPHA AB We previously described a mouse model of ulcerative colitis linked to T-bet deficiency in the innate immune system. Here, we report that the majority of T-bet(-/-) RAG2(-/-) ulcerative colitis (TRUC) mice spontaneously progress to colonic dysplasia and rectal adenocarcinoma solely as a consequence of MyD88-independent intestinal inflammation. Dendritic cells (DCs) are necessary cellular effectors for a proinflammatory program that is carcinogenic. Whereas these malignancies arise in the setting of a complex inflammatory environment, restoration of T-bet selectively in DCs was sufficient to reduce colonic inflammation and prevent the development of neoplasia. TRUC colitis-associated colorectal cancer resembles the human disease and provides ample opportunity to probe how inflammation drives colorectal cancer development and to test preventative and therapeutic strategies preclinically. C1 [Garrett, Wendy S.; Punit, Shivesh; Gallini, Carey A.; Michaud, Monia; Zhang, Dorothy; Sigrist, Kirsten S.; Lord, Graham M.; Glimcher, Laurie H.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Garrett, Wendy S.; Glimcher, Laurie H.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Glickman, Jonathan N.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Garrett, WS (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. EM wendy_garrett@dfci.harvard.edu; lglimche@hsph.harvard.edu RI Lord, Graham/B-3797-2011 FU National Institutes of Health [CA112663]; Ellison Scholar; Damon Runyon Cancer Research Foundation; Burroughs Wellcome Career in Medical Sciences; V Foundation; DF/HCC [GI SPORE 1P50CA127003-02]; Irving Janock; HDDC Pilot FX We thank Jacobo Ramirez and Diana Pascual for outstanding care of our mice; Landy Kangaloo and members of the Glimcher laboratory for helpful discussion; Drs. Vanja Lazarevic, Marc Wein, Fabio Martinon, and Tracy Staton for critical review of the manuscript; and Drs. Tyler Jacks, Ji-Hye Paik, and Alfred Zullo for advice. This work was supported by grants from the National Institutes of Health (CA112663) and an Ellison Scholar Award to L.H.G. W.S.G. is a recipient of a Damon Runyon Cancer Research Foundation fellowship, a Burroughs Wellcome Career in Medical Sciences Award, and funding from the V Foundation, DF/HCC GI SPORE 1P50CA127003-02, Irving Janock Fellowship, and HDDC Pilot Award. L.H.G. holds equity and is on the Board of Directors of Bristol-Myers Squibb. Dedicated in memory of R.B., L.K., and N.H., whose battles with CRC were an inspiration for this study. NR 50 TC 95 Z9 98 U1 0 U2 9 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 SEP 8 PY 2009 VL 16 IS 3 BP 208 EP 219 DI 10.1016/j.ccr.2009.07.015 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 493CS UT WOS:000269711500008 PM 19732721 ER PT J AU Mukohara, T Shimada, H Ogasawara, N Wanikawa, R Shimomura, M Nakatsura, T Ishii, G Park, JO Janne, PA Saijo, N Minami, H AF Mukohara, Toru Shimada, Hiroyuki Ogasawara, Naomi Wanikawa, Ryoko Shimomura, Manami Nakatsura, Tetsuya Ishii, Genichiro Park, Joon Oh Jaenne, Pasi A. Saijo, Nagahiro Minami, Hironobu TI Sensitivity of breast cancer cell lines to the novel insulin-like growth factor-1 receptor (IGF-1R) inhibitor NVP-AEW541 is dependent on the level of IRS-1 expression SO CANCER LETTERS LA English DT Article DE Breast cancer; IGF-1R; IRS-1; Tyrosine kinase inhibitor ID TRASTUZUMAB RESISTANCE; ADJUVANT CHEMOTHERAPY; NEUROBLASTOMA-CELLS; ANTITUMOR-ACTIVITY; PIK3CA MUTATIONS; KINASE; SUBSTRATE-1; ACTIVATION; TUMORS; VIVO AB To investigate the potential value of targeting insulin-like growth factor-1 receptor (IGF-1R) in breast cancer, we examined the effects of NVP-AEW541, a selective small-molecule inhibitor of the IGF-1R tyrosine kinase, in a panel of 16 breast cancer cell lines. All cell lines expressed IGF-1R, but MCF-7 expressed much higher levels of insulin receptor substrate-1 (IRS-1) than the others. NVP-AEW541 was more potent at inhibiting growth of MCF-7 cells as compared to the others (IC(50), 1 mu M vs. approximate to 7 mu M). Comparing MCF-7 to T47D cells, which express IGF-1R at a level identical to MCF-7 but have less than 1/30 the amount of IRS-1, NVP-AEW541 caused cell-cycle arrest at the G1-S boundary, reduced in vitro cell migration, and enhanced the cytotoxic effects of vinorelbine and paclitaxel in MCF-7, but not in T47D. While NVP-AEW541 decreased the phosphorylation of IGF-1R in both cell lines, it inhibited phosphorylation of Akt and disrupted the IRS-1/PI3 K complex only in MCF-7. These findings suggest that inhibiting IGF-1R may be an effective therapeutic strategy for breast cancers that co-express IGF-1R and IRS-1 at high levels. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Mukohara, Toru; Minami, Hironobu] Natl Canc Ctr Hosp E, Div Hematol & Oncol, Kashiwa, Chiba 2778577, Japan. [Mukohara, Toru; Shimada, Hiroyuki; Ogasawara, Naomi; Wanikawa, Ryoko; Shimomura, Manami; Nakatsura, Tetsuya; Ishii, Genichiro; Saijo, Nagahiro; Minami, Hironobu] Natl Canc Ctr Hosp E, Res Ctr Innovat Oncol, Kashiwa, Chiba 2778577, Japan. [Saijo, Nagahiro] Natl Canc Ctr Hosp E, Div Thorac Oncol, Kashiwa, Chiba 2778577, Japan. [Park, Joon Oh] Sungkyunkwan Univ, Sch Med, Div Hematol Oncol, Dept Med,Samsung Med Ctr, Seoul 135701, South Korea. [Park, Joon Oh; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. RP Mukohara, T (reprint author), Kobe Univ Hosp, Dept Med Oncol, Chuo Ku, 7-5-1 Kusunoki Cho, Kobe, Hyogo 6500017, Japan. EM mukohara@med.kobe-u.ac.jp RI Ishii, Genichiro/E-2913-2012 FU Foundation for Promotion of Cancer Research, Japan; Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science and Technology, Japan; Ministry of Health, Labour and Welfare, Japan FX This study is supported by a Grant from Foundation for Promotion of Cancer Research, Japan (T.M.), Start-up Research Grant for Young Investigators from Japan Society for the Promotion of Science (T.M.), Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (T.M.), and Grants-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan (H.M. and N.S.). NR 34 TC 38 Z9 39 U1 0 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 8 PY 2009 VL 282 IS 1 BP 14 EP 24 DI 10.1016/j.canlet.2009.02.056 PG 11 WC Oncology SC Oncology GA 475FE UT WOS:000268343000003 PM 19345478 ER PT J AU Mroz, P Bhaumik, J Dogutan, DK Aly, Z Kamal, Z Khalid, L Kee, HL Bocian, DF Holten, D Lindsey, JS Hamblin, MR AF Mroz, Pawel Bhaumik, Jayeeta Dogutan, Dilek K. Aly, Zarmeneh Kamal, Zahra Khalid, Laiqua Kee, Hooi Ling Bocian, David F. Holten, Dewey Lindsey, Jonathan S. Hamblin, Michael R. TI Imidazole metalloporphyrins as photosensitizers for photodynamic therapy: Role of molecular charge, central metal and hydroxyl radical production SO CANCER LETTERS LA English DT Article DE Structure function relationship; Photophysics; Phototoxicity; Metalloporphyrins; Apoptosis; Fluorescence microscopy; Reactive oxygen species; Hydroxyl radicals ID ELECTRON-SPIN-RESONANCE; SINGLET OXYGEN; HELA-CELLS; IN-VITRO; SUBCELLULAR-LOCALIZATION; METHYL PYROPHEOPHORBIDE; PD-BACTERIOPHEOPHORBIDE; ZINC PHTHALOCYANINES; CELLULAR UPTAKE; CANCER-CELLS AB The in vitro photodynamic therapy activity of four imidazole-substituted metalloporphyrins has been studied using human (HeLa) and mouse (CT26) cancer cell lines: an anionic Zn porphyrin and a homologous series of three cationic Zn, Pd or InCl porphyrins. A dramatic difference in phototoxicity was found: Pd cationic > InCl cationic > Zn cationic > Zn anionic. HeLa cells were more susceptible than CT26 cells. Induction of apoptosis was demonstrated using a fluorescent caspase assay. The anionic Zn porphyrin localized in lysosomes while the cationic Zn porphyrin localized in lysosomes and mitochondria, as assessed by fluorescence microscopy. Studies using fluorescent probes suggested that the cationic Pd porphyrin produced more hydroxyl radicals as the reactive oxygen species. Thus, the cationic Pd porphyrin has high potential as a photosensitizer and gives insights into characteristics for improved molecular designs. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Mroz, Pawel; Aly, Zarmeneh; Kamal, Zahra; Khalid, Laiqua; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Mroz, Pawel; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Bhaumik, Jayeeta; Dogutan, Dilek K.; Lindsey, Jonathan S.] N Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA. [Aly, Zarmeneh; Kamal, Zahra; Khalid, Laiqua] Aga Khan Med Coll, Karachi, Pakistan. [Kee, Hooi Ling; Holten, Dewey] Washington Univ, Dept Chem, St Louis, MO 63130 USA. [Bocian, David F.] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI Lindsey, Jonathan/J-7761-2012; OI Hamblin, Michael/0000-0001-6431-4605 FU NIH [NIH-CA/AI838801, NIH-GM36238, 5T90 DA022871] FX Work at Wellman Center for Photomedicine was funded by NIH-CA/AI838801 to MRH. Work at NCSU was supported by NIH-GM36238 to JSL. HLK was funded by the Imaging Sciences Pathway training grant from the NIH (5T90 DA022871) at Washington University. NR 61 TC 52 Z9 56 U1 5 U2 27 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 8 PY 2009 VL 282 IS 1 BP 63 EP 76 DI 10.1016/j.canlet.2009.02.054 PG 14 WC Oncology SC Oncology GA 475FE UT WOS:000268343000010 PM 19346065 ER PT J AU Mohammed, AA Agnihotri, AK van Kimmenade, RRJ Martinez-Rumayor, A Green, SM Quiroz, R Januzzi, JL AF Mohammed, Asim A. Agnihotri, Arvind K. van Kimmenade, Roland R. J. Martinez-Rumayor, Abelardo Green, Sandy M. Quiroz, Rene Januzzi, James L., Jr. TI Prospective, Comprehensive Assessment of Cardiac Troponin T Testing After Coronary Artery Bypass Graft Surgery SO CIRCULATION LA English DT Article DE coronary artery bypass; myocardial infarction; troponin ID PERIOPERATIVE MYOCARDIAL-INFARCTION; HEART-SURGERY; SHORT-TERM; I LEVELS; MORTALITY; DAMAGE; RISK; STRATIFICATION; DETERMINANTS; ELEVATION AB Background-The significance and clinical role of cardiac troponin testing after coronary artery bypass grafting remain unclear. Methods and Results-Cardiac troponin T (cTnT) was measured during the first 24 hours after coronary artery bypass graft surgery in 847 consecutive patients. Only 17 patients (2.0%) had new Q waves or left bundle-branch block after surgery; however, cTnT elevation was observed in nearly all subjects, with a median cTnT concentration of 1.08 ng/mL overall. Direct predictors of postoperative cTnT values included preoperative myocardial infarction (P < 0.001), preoperative intraaortic balloon pump (P < 0.001), intraoperative/postoperative intraaortic balloon pump (P < 0.001), number of distal anastomoses (P=0.005), bypass time (P < 0.001), and number of intraoperative defibrillations (P=0.009), whereas glomerular filtration rate (P < 0.001), off-pump coronary artery bypass grafting (P=0.003), and use of warm cardioplegia (P=0.02) were inversely associated with cTnT values. A linear association was seen between cTnT levels and length of stay and ventilator hours, and in an analysis adjusted for the Society for Thoracic Surgery Risk Model, cTnT remained independently prognostic for death (odds ratio, 3.20; P=0.003), death or heart failure (odds ratio, 2.04; P=0.008), death or need for vasopressors (odds ratio, 2.70; P < 0.001), and the composite of all 3 (odds ratio, 2.57; P < 0.001). In contrast to consensus-endorsed cTnT cut points for postoperative evaluation, a cTnT < 1.60 ng/mL had a negative predictive value of 93% to 99% for excluding various post-coronary artery bypass graft surgery complications. Conclusions-cTnT concentrations after coronary artery bypass graft surgery are nearly universally elevated, are determined by numerous factors, and are independently prognostic for impending postoperative complications when used at appropriate cut points. (Circulation. 2009; 120:843-850.) C1 [Mohammed, Asim A.; van Kimmenade, Roland R. J.; Martinez-Rumayor, Abelardo; Green, Sandy M.; Quiroz, Rene; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Mohammed, Asim A.; van Kimmenade, Roland R. J.; Martinez-Rumayor, Abelardo; Green, Sandy M.; Quiroz, Rene; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Agnihotri, Arvind K.] Massachusetts Gen Hosp, Dept Cardiac Surg, Boston, MA 02114 USA. [van Kimmenade, Roland R. J.] Univ Hosp Maastricht, Maastricht, Netherlands. RP Januzzi, JL (reprint author), 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM JJanuzzi@partners.org RI Kimmenade, R.R.J./L-4432-2015 FU Interuniversity Cardiology Institute of the Netherlands; Balson Scholar Fund; Dennis and Marilyn Barry Fund FX Dr Mohammed is supported by the Dennis and Marilyn Barry Fund for Cardiac Research. Dr van Kimmenade is sponsored by a research fellowship grant from the Interuniversity Cardiology Institute of the Netherlands. Dr Januzzi is supported in part by the Balson Scholar Fund. NR 27 TC 40 Z9 40 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 8 PY 2009 VL 120 IS 10 BP 843 EP U41 DI 10.1161/CIRCULATIONAHA.108.837278 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 492DC UT WOS:000269633700005 PM 19704098 ER PT J AU Minamishima, S Bougaki, M Sips, PY De Yu, J Minamishima, YA Elrod, JW Lefer, DJ Bloch, KD Ichinose, F AF Minamishima, Shizuka Bougaki, Masahiko Sips, Patrick Y. De Yu, Jia Minamishima, Yoji Andrew Elrod, John W. Lefer, David J. Bloch, Kenneth D. Ichinose, Fumito TI Hydrogen Sulfide Improves Survival After Cardiac Arrest and Cardiopulmonary Resuscitation via a Nitric Oxide Synthase 3-Dependent Mechanism in Mice SO CIRCULATION LA English DT Article DE apoptosis; cardiopulmonary resuscitation; heart arrest; myocardial contraction; nitric oxide synthase; physiology ID ISCHEMIA-REPERFUSION INJURY; PERMEABILITY TRANSITION; PROTEIN-KINASE; CELL-DEATH; CARDIOPROTECTION; PHOSPHORYLATION; INHIBITION; APOPTOSIS; MEDIATOR; PATHWAY AB Background-Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. We sought to evaluate the impact of hydrogen sulfide (H(2)S) on the outcome after CA and cardiopulmonary resuscitation (CPR) in mouse. Methods and Results-Mice were subjected to 8 minutes of normothermic CA and resuscitated with chest compression and mechanical ventilation. Seven minutes after the onset of CA (1 minute before CPR), mice received sodium sulfide (Na(2)S) (0.55 mg/kg IV) or vehicle 1 minute before CPR. There was no difference in the rate of return of spontaneous circulation, CPR time to return of spontaneous circulation, and left ventricular function at return of spontaneous circulation between groups. Administration of Na(2)S 1 minute before CPR markedly improved survival rate at 24 hours after CPR (15/15) compared with vehicle (10/26; P=0.0001 versus Na(2)S). Administration of Na(2)S prevented CA/CPR-induced oxidative stress and ameliorated left ventricular and neurological dysfunction 24 hours after CPR. Delayed administration of Na(2)S at 10 minutes after CPR did not improve outcomes after CA/CPR. Cardioprotective effects of Na(2)S were confirmed in isolated-perfused mouse hearts subjected to global ischemia and reperfusion. Cardiomyocyte-specific overexpression of cystathionine gamma-lyase (an enzyme that produces H(2)S) markedly improved outcomes of CA/CPR. Na(2)S increased phosphorylation of nitric oxide synthase 3 in left ventricle and brain cortex, increased serum nitrite/nitrate levels, and attenuated CA-induced mitochondrial injury and cell death. Nitric oxide synthase 3 deficiency abrogated the protective effects of Na2S on the outcome of CA/CPR. Conclusions-These results suggest that administration of Na(2)S at the time of CPR improves outcome after CA possibly via a nitric oxide synthase 3-dependent signaling pathway. (Circulation. 2009; 120:888-896.) C1 [Minamishima, Shizuka; Bougaki, Masahiko; Sips, Patrick Y.; De Yu, Jia; Bloch, Kenneth D.; Ichinose, Fumito] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Anesthesia Ctr Crit Care Res, Charlestown, MA 02129 USA. [Minamishima, Yoji Andrew] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. [Minamishima, Yoji Andrew] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. [Elrod, John W.] Cincinnati Childrens Hosp, Med Ctr, Dept Mol & Cardiovasc Biol, Cincinnati, OH USA. [Lefer, David J.] Emory Univ, Sch Med, Dept Surg, Atlanta, GA 30322 USA. RP Ichinose, F (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Anesthesia Ctr Crit Care Res, 149 13th St,3405, Charlestown, MA 02129 USA. EM fichinose@partners.org RI Lefer, David/A-6372-2012; Minamishima, Yoji/E-5380-2010; OI Minamishima, Yoji/0000-0001-7995-9318; Sips, Patrick/0000-0001-9241-5980; Elrod, John/0000-0003-3925-2224 FU National Institutes of Health [HL92141, HL92737, HL70896, HL71987, GM79360]; Gas-Enabled Medical Innovation Fund FX This work was supported by National Institutes of Health grants HL92141 (Drs Lefer and Elrod), HL92737 (Dr Elrod), HL70896 (Dr Bloch), HL71987 (Dr Ichinose), and GM79360 (Dr Ichinose) and the Gas-Enabled Medical Innovation Fund (Dr Ichinose). NR 30 TC 110 Z9 127 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 8 PY 2009 VL 120 IS 10 BP 888 EP U132 DI 10.1161/CIRCULATIONAHA.108.833491 PG 16 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 492DC UT WOS:000269633700010 PM 19704099 ER PT J AU Bonaca, MP Steg, PG Feldman, LJ Canales, JF Ferguson, JJ Wallentin, L Califf, RM Harrington, RA Giugliano, RP AF Bonaca, Marc P. Steg, Philippe Gabriel Feldman, Laurent J. Canales, John F. Ferguson, James J. Wallentin, Lars Califf, Robert M. Harrington, Robert A. Giugliano, Robert P. TI Antithrombotics in Acute Coronary Syndromes SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE antiplatelet; antithrombotic; anticoagulant; infarction; ischemia ID ST-SEGMENT ELEVATION; ACUTE MYOCARDIAL-INFARCTION; DIRECT THROMBIN INHIBITOR; MOLECULAR-WEIGHT HEPARIN; FACTOR XA INHIBITOR; HIGH-RISK PATIENTS; GLYCOPROTEIN IIB/IIIA INHIBITORS; RANDOMIZED CONTROLLED-TRIAL; SUBACUTE STENT THROMBOSIS; INDIVIDUAL PATIENTS DATA AB Antithrombotic agents are an integral component of the medical regimens and interventional strategies currently recommended to reduce thrombotic complications in patients with acute coronary syndromes (ACS). Despite great advances with these therapies, associated high risks for thrombosis and hemorrhage remain as the result of complex interactions involving patient comorbidities, drug combinations, multifaceted dosing adjustments, and the intricacies of the care environment. As such, the optimal combinations of antithrombotic therapies, their timing, and appropriate targeted subgroups remain the focus of intense research. During the last several years a number of new antithrombotic treatments have been introduced, and new data regarding established therapies have come to light. Although treatment guidelines include the most current available data, subsequent findings can be challenging to integrate. This challenge is compounded by the complexity associated with different efficacy and safety measures and the variability in study populations, presenting syndromes, physician, and patient preferences. In this work we review recent data regarding clinically available antiplatelet and anticoagulation agents used in the treatment of patients with ACS. We address issues including relative efficacy, safety, and timing of therapies with respect to conservative and invasive treatment strategies. In specific cases we will highlight remaining questions and controversies and ongoing trials, which will hopefully shed light in these areas. In addition to reviewing existing agents, we take a look forward at the most promising new antithrombotics currently in late-stage clinical development and their potential role in the context of ACS management. (J Am Coll Cardiol 2009; 54: 969-84) (C) 2009 by the American College of Cardiology Foundation C1 [Bonaca, Marc P.; Giugliano, Robert P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc Med, Boston, MA 02115 USA. [Steg, Philippe Gabriel; Feldman, Laurent J.] Univ Paris VII Denis Diderot, Ctr Hosp Bichat Claude Bernard, Paris, France. [Canales, John F.; Ferguson, James J.] St Lukes Episcopal Hosp, Texas Heart Inst, Baylor Coll Med, Houston, TX USA. [Ferguson, James J.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Wallentin, Lars] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Califf, Robert M.; Harrington, Robert A.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. RP Giugliano, RP (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc Med, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM rgiugliano@partners.org NR 99 TC 30 Z9 36 U1 1 U2 7 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 SEP 8 PY 2009 VL 54 IS 11 BP 969 EP 984 DI 10.1016/j.jacc.2009.03.083 PG 16 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 490DG UT WOS:000269477500001 PM 19729112 ER PT J AU Foo, SY Heller, ER Wykrzykowska, J Sullivan, CJ Manning-Tobin, JJ Moore, KJ Gerszten, RE Rosenzweig, A AF Foo, Shi Yin Heller, Eric R. Wykrzykowska, Joanna Sullivan, Christopher J. Manning-Tobin, Jennifer J. Moore, Kathryn J. Gerszten, Robert E. Rosenzweig, Anthony TI Vascular effects of a low-carbohydrate high-protein diet SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE atherosclerosis; dietary interventions; progenitor cells; neovascularization ID ENDOTHELIAL PROGENITOR CELLS; MONOCYTE CHEMOATTRACTANT PROTEIN-1; CORONARY-ARTERY-DISEASE; NITRIC-OXIDE SYNTHASE; E-DEFICIENT MICE; FREE FATTY-ACIDS; MOUSE MODELS; ATHEROSCLEROSIS; NEOVASCULARIZATION; MOBILIZATION AB The cardiovascular complications of obesity have prompted interest in dietary interventions to reduce weight, including low-carbohydrate diets that are generally high in protein and fat. However, little is known about the long-term effects of these diets on vascular health. We examined the cardiovascular effects of a low-carbohydrate, high-protein diet (LCHP) in the ApoE(-/-) mouse model of atherosclerosis and in a model of ischemia-induced neovascularization. Mice on a LCHP were compared with mice maintained on either the standard chow diet (SC) or the Western diet (WD) which contains comparable fat and cholesterol to the LCHP. LCHP-fed mice developed more aortic atherosclerosis and had an impaired ability to generate new vessels in response to tissue ischemia. These changes were not explained by alterations in serum cholesterol, inflammatory mediators or infiltrates, or oxidative stress. The LCHP diet substantially reduced the number of bone marrow and peripheral blood endothelial progenitor cells (EPCs), a marker of vascular regenerative capacity. EPCs from mice on a LCHP diet also manifest lower levels of activated (phosphorylated) Akt, a serine-threonine kinase important in EPC mobilization, proliferation, and survival. Taken together, these data demonstrate that in animal models LCHP diets have adverse vascular effects not reflected in serum markers and that nonlipid macronutrients can modulate vascular progenitor cells and pathophysiology. C1 [Foo, Shi Yin; Wykrzykowska, Joanna; Sullivan, Christopher J.; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Cardiovasc Inst, Boston, MA 02215 USA. [Foo, Shi Yin; Wykrzykowska, Joanna; Sullivan, Christopher J.; Rosenzweig, Anthony] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Foo, Shi Yin; Heller, Eric R.; Manning-Tobin, Jennifer J.; Moore, Kathryn J.; Gerszten, Robert E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Foo, Shi Yin; Heller, Eric R.; Manning-Tobin, Jennifer J.; Moore, Kathryn J.; Gerszten, Robert E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Rosenzweig, Anthony] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Rosenzweig, A (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, Cardiovasc Inst, RW 456,330 Brookline Ave, Boston, MA 02215 USA. EM arosenzw@bidmc.harvard.edu OI Moore, kathryn/0000-0003-2505-2547 FU Leducq Foundation Network of Research Excellence; American Heart Association; National Institutes of Health; Judith and David Ganz; Maxwell Hurston Charitable Foundation FX We thank Dr. Emerson Liu and Dr. Kenneth Cohen for technical advice and Dr. Serafima Zaltsman for expertly managing the mouse colony. S. Y. F. is a trainee of the Clinical Investigators Training Program: Beth Israel Deaconess Medical Center-Harvard/Massachusetts Institute of Technology Health Sciences and Technology, in collaboration with Pfizer Inc. and Merck and Co. This work was supported by a Leducq Foundation Network of Research Excellence (R. E. G., A. R.), an American Heart Association Grant-in-Aid (R. E. G.), and grants from the National Institutes of Health (A. R., R. E. G.) A. R. also gratefully acknowledges support from Judith and David Ganz and the Maxwell Hurston Charitable Foundation. A. R. is a principal faculty member of the Harvard Stem Cell Institute. NR 36 TC 32 Z9 33 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 SEP 8 PY 2009 VL 106 IS 36 BP 15418 EP 15423 DI 10.1073/pnas.0907995106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 492CR UT WOS:000269632400061 PM 19706393 ER PT J AU Quant, EC Jeste, SS Muni, RH Cape, AV Bhussar, MK Peleg, AY AF Quant, Eudocia C. Jeste, Shafali S. Muni, Rajeev H. Cape, Alison V. Bhussar, Manveen K. Peleg, Anton Y. TI The benefits of steroids versus steroids plus antivirals for treatment of Bell's palsy: a meta-analysis SO BRITISH MEDICAL JOURNAL LA English DT Article ID SIMPLEX-VIRUS TYPE-1; DOUBLE-BLIND; ACYCLOVIR; PREDNISOLONE; EFFICACY; QUALITY; VALACYCLOVIR; REACTIVATION; MULTICENTER; THERAPY AB Objective To determine whether steroids plus antivirals provide a better degree of facial muscle recovery in patients with Bell's palsy than steroids alone. Design Meta-analysis. Data sources PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies published in all languages from 1984 to January 2009. Additional studies were identified from cited references. Selection criteria Randomised controlled trials that compared steroids with the combination of steroids and antivirals for the treatment of Bell's palsy were included in this study. At least one month of follow-up and a primary end point of at least partial facial muscle recovery, as defined by a House-Brackmann grade of at least 2 (complete palsy is designated a grade of 6) or an equivalent score on an alternative recognised scoring system, were required. Review methods Two authors independently reviewed studies for methodological quality, treatment regimens, duration of symptoms before treatment, length of follow-up, and outcomes. Odds ratios with 95% confidence intervals were calculated and pooled using a random effects model. Results Six trials were included, a total of 1145 patients; 574 patients received steroids alone and 571 patients received steroids and antivirals. The pooled odds ratio for facial muscle recovery showed no benefit of steroids plus antivirals compared with steroids alone (odds ratio 1.50, 95% confidence interval 0.83 to 2.69; P=0.18). A one study removed analysis showed that the highest quality studies had the greatest effect on the lack of difference between study arms shown by the odds ratio. Subgroup analyses assessing causes of heterogeneity defined a priori (time from symptom onset to treatment, length of follow-up, and type of antiviral studied) showed no benefit of antivirals in addition to that provided by steroids. Conclusions Antivirals did not provide an added benefit in achieving at least partial facial muscle recovery compared with steroids alone in patients with Bell's palsy. This study does not, therefore, support the routine use of antivirals in Bell's palsy. Future studies should use improved herpes virus diagnostics and newer antivirals to assess whether combination therapy benefits patients with more severe facial paralysis at study entry. C1 [Jeste, Shafali S.; Peleg, Anton Y.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Jeste, Shafali S.] Childrens Hosp Boston, Div Neurol, Boston, MA 02115 USA. [Muni, Rajeev H.] Univ Toronto, St Michaels Hosp, Dept Ophthalmol & Vis Sci, Toronto, ON M5B 1W8, Canada. [Bhussar, Manveen K.; Peleg, Anton Y.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Peleg, Anton Y.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Peleg, AY (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM apeleg@bidmc.harvard.edu OI Peleg, Anton/0000-0002-2296-2126 FU American National Cancer Institute Paul Calabresi Award for Clinical Oncology [K12CA090354]; American Academy of Neurology Clinical Research Training fellowship; Canadian National Institute for the Blind; University of Queensland FX No specific funding was received for this study. However, ECQ was funded by an American National Cancer Institute Paul Calabresi Award for Clinical Oncology (K12CA090354), SSJ was funded by an American Academy of Neurology Clinical Research Training fellowship, RHM by an EA Baker Fellowship from the Canadian National Institute for the Blind, and AYP by a University of Queensland postgraduate fellowship. All researchers are independent of the funding body. NR 30 TC 36 Z9 37 U1 0 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD SEP 7 PY 2009 VL 339 AR b3354 DI 10.1136/bmj.b3354 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 493RB UT WOS:000269754500002 PM 19736282 ER PT J AU Bednarz, B Hancox, C Xu, XG AF Bednarz, Bryan Hancox, Cindy Xu, X. George TI Calculated organ doses from selected prostate treatment plans using Monte Carlo simulations and an anatomically realistic computational phantom SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID DYNAMIC MLC IMRT; RADIATION TREATMENT; 2ND CANCERS; MV BEAM; NEUTRON; RADIOTHERAPY; FIELD; ACCELERATOR; DOSIMETRY; THERAPY AB There is growing concern about radiation-induced second cancers associated with radiation treatments. Particular attention has been focused on the risk to patients treated with intensity-modulated radiation therapy (IMRT) due primarily to increased monitor units. To address this concern we have combined a detailed medical linear accelerator model of the Varian Clinac 2100 C with anatomically realistic computational phantoms to calculate organ doses from selected treatment plans. This paper describes the application to calculate organ-averaged equivalent doses using a computational phantom for three different treatments of prostate cancer: a 4-field box treatment, the same box treatment plus a 6-field 3D-CRT boost treatment and a 7-field IMRT treatment. The equivalent doses per MU to those organs that have shown a predilection for second cancers were compared between the different treatment techniques. In addition, the dependence of photon and neutron equivalent doses on gantry angle and energy was investigated. The results indicate that the box treatment plus 6-field boost delivered the highest intermediate-and low-level photon doses per treatment MU to the patient primarily due to the elevated patient scatter contribution as a result of an increase in integral dose delivered by this treatment. Inmost organs the contribution of neutron dose to the total equivalent dose for the 3D-CRT treatments was less than the contribution of photon dose, except for the lung, esophagus, thyroid and brain. The total equivalent dose per MU to each organ was calculated by summing the photon and neutron dose contributions. For all organs non-adjacent to the primary beam, the equivalent doses per MU from the IMRT treatment were less than the doses from the 3D-CRT treatments. This is due to the increase in the integral dose and the added neutron dose to these organs from the 18 MV treatments. However, depending on the application technique and optimization used, the required MU values for IMRT treatments can be two to three times greater than 3D CRT. Therefore, the total equivalent dose in most organs would be higher from the IMRT treatment compared to the box treatment and comparable to the organ doses from the box treatment plus the 6-field boost. This is the first time when organ dose data for an adult male patient of the ICRP reference anatomy have been calculated and documented. The tools presented in this paper can be used to estimate the second cancer risk to patients undergoing radiation treatment. C1 [Bednarz, Bryan; Hancox, Cindy] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 01208 USA. [Bednarz, Bryan; Hancox, Cindy] Harvard Univ, Sch Med, Boston, MA 01208 USA. [Xu, X. George] Rensselaer Polytech Inst, Troy, NY 12180 USA. RP Bednarz, B (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 01208 USA. EM bbednarz@partners.org FU National Cancer Institute [R01CA116743] FX This project was funded in part by a National Cancer Institute grant (R01CA116743). The authors would like to thank Mr Bin Han, doctoral student at RPI, for assistance with the Monte Carlo calculations. The authors would like to thank Dr Brian Wang, from University of Utah and Dr Stephen Kry from MD Anderson Cancer Center for information about various treatment plans. NR 37 TC 16 Z9 16 U1 3 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 7 PY 2009 VL 54 IS 17 BP 5271 EP 5286 DI 10.1088/0031-9155/54/17/013 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 484UY UT WOS:000269074500014 PM 19671968 ER PT J AU Gasic, GP Smoller, JW Perlis, RH Sun, M Lee, S Kim, BW Lee, MJ Holt, DJ Blood, AJ Makris, N Kennedy, DK Hoge, RD Calhoun, J Fava, M Gusella, JF Breiter, HC AF Gasic, G. P. Smoller, J. W. Perlis, R. H. Sun, M. Lee, S. Kim, B. W. Lee, M. J. Holt, D. J. Blood, A. J. Makris, N. Kennedy, D. K. Hoge, R. D. Calhoun, J. Fava, M. Gusella, J. F. Breiter, H. C. TI BDNF, Relative Preference, and Reward Circuitry Responses to Emotional Communication SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Review DE facial expression; relative preference; fMRI; orbitofrontal cortex; BDNF ID NEUROTROPHIC FACTOR VAL66MET; SEROTONIN TRANSPORTER GENE; ACTIVITY-DEPENDENT SECRETION; CEREBRAL WHITE-MATTER; LATE-LIFE DEPRESSION; HUMAN AMYGDALA; DECISION-MAKING; HUMAN BRAIN; ORBITOFRONTAL CORTEX; FACIAL EXPRESSIONS AB Brain derived neurotrophic factor (BDNF) regulates neural development and synaptic transmission. We have tested the hypothesis that functional variation in the BDNF gene (Val66Met polymorphism, rs6265) affects brain reward circuitry encoding human judgment and decision-making regarding relative preference. We quantified relative preference among faces with emotional expressions (angry, fearful, sad, neutral, and happy) by a keypress procedure performed offline to measure effort traded for viewing time. Keypress-based relative preferences across the ensemble of faces were mirrored significantly by fMRI signal in the orbitofrontal cortex, amygdala, and hippocampus when passively viewing these faces. For these three brain regions, there was also a statistically significant group difference by BDNF genotype in the fMRI responses to the emotional expressions. In comparison with Val/Met heterozygotes, Val/Val individuals preferentially sought exposure to positive emotions (e.g., happy faces) and had stronger regional fMRI activation to aversive stimuli (e.g., angry, fearful, and sad faces). BDNF genotype accounted for similar to 30% of the variance in fMRI signal that mirrors keypress responses to these stimuli. This study demonstrates that functional allelic variation in BDNF modulates human brain circuits processing reward/aversion information and relative preference transactions. (C) 2009 Wiley-Liss, Inc. C1 [Gasic, G. P.; Lee, S.; Kim, B. W.; Lee, M. J.; Blood, A. J.; Kennedy, D. K.; Hoge, R. D.; Calhoun, J.; Breiter, H. C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Boston, MA USA. [Smoller, J. W.; Perlis, R. H.; Holt, D. J.; Blood, A. J.; Makris, N.; Fava, M.; Breiter, H. C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Psychiat, Depress Clin & Res Program,Addict Res Program, Boston, MA USA. [Smoller, J. W.; Perlis, R. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA USA. [Sun, M.; Gusella, J. F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurogenet Unit,Ctr Human Genet Res, Boston, MA USA. [Makris, N.; Kennedy, D. K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Neurol, Ctr Morphometr Anal,Ctr Integrat Informat, Boston, MA USA. [Hoge, R. D.] Univ Montreal, Montreal, PQ H3C 3J7, Canada. RP Breiter, HC (reprint author), Athinoula A Martinos Ctr, 2nd Floor,149 13th St, Charlestown, MA 02129 USA. EM hbreiter@partners.org RI Kennedy, David/H-3627-2012 FU National Institute on Drug Abuse, Bethesda, MD [14118]; The Office of National Drug Control Policy-Counterdrug Technology Assessment Center (ONDCP-CTAC), Washington, D.C. [DABK39-03-0098, DABK39-03-C-0098]; Massachusetts General Hospital Department of Radiology; National Center for Research Resources [P41RR14075]; Mental Illness and Neuroscience Discovery (MIND) Institute; Amyotrophic Lateral Sclerosis Association; NARSAD Young Investigator Award; NINDS [34189]; Fairway Trust FX Grant sponsor: National Institute on Drug Abuse, Bethesda, MD; Grant number: 14118; Grant sponsor: The Office of National Drug Control Policy-Counterdrug Technology Assessment Center (ONDCP-CTAC), Washington, D.C. (The Phenotype Genotype Project in Addiction and Depression); Grant number: DABK39-03-0098, DABK39-03-C-0098; Grant sponsor: Massachusetts General Hospital Department of Radiology; Grant sponsor: National Center for Research Resources; Grant number: P41RR14075; Grant sponsor: Mental Illness and Neuroscience Discovery (MIND) Institute; Grant sponsor: Amyotrophic Lateral Sclerosis Association; Grant sponsor: NARSAD Young Investigator Award; Grant sponsor: NINDS; Grant number: 34189; Grant sponsor: Fairway Trust.; G.P. Gasic and H.C. Breiter contributed equally to this work. NR 104 TC 38 Z9 39 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2009 VL 150B IS 6 BP 762 EP 781 DI 10.1002/ajmg.b.30944 PG 20 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 491SO UT WOS:000269600000002 PM 19388013 ER PT J AU Shugart, YY Wang, Y Samuels, JF Grados, MA Greenberg, BD Knowles, JA McCracken, JT Rauch, SL Murphy, DL Rasmussen, SA Cullen, B Hoehn-Saric, R Pinto, A Fyer, AJ Piacentini, J Pauls, DL Bienvenu, OJ Riddle, MA Liang, KY Nestadt, G AF Shugart, Y. Y. Wang, Y. Samuels, J. F. Grados, M. A. Greenberg, B. D. Knowles, J. A. McCracken, J. T. Rauch, S. L. Murphy, D. L. Rasmussen, S. A. Cullen, B. Hoehn-Saric, R. Pinto, A. Fyer, A. J. Piacentini, J. Pauls, D. L. Bienvenu, O. J. Riddle, M. A. Liang, K. Y. Nestadt, G. TI A Family-Based Association Study of the Glutamate Transporter Gene SLC1A1 in Obsessive-Compulsive Disorder in 378 Families SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE genetics; candidate genes; association; OCD; heterogeneity ID COMPLEX SEGREGATION ANALYSIS; LINKAGE ANALYSIS; HISTORY; TESTS; ADOLESCENTS; RATIONALE; CHILDREN; LOCUS AB SLC1A encodes the neuronal and epithelial glutamate transporter and was previously tested as a candidate for obsessive-compulsive disorder (OCD) by several research groups. Recently, three independent research groups reported significant association findings between OCD and several genetic variants in SLC1A1. This study reports the results from a family-based association study, which examined the association between 13 single nucleotide polymorphisms (SNPs) within or in proximity to the SLC1A1 gene. Although we did not replicate association findings for those significant SNPs reported by previous studies, our study indicated a strong association signal with the SNP RS301443 (P-value = 0.000067; Bonferroni corrected P-value = 0.0167) under a dominant model, with an estimated odds ratio of 3.5 (confidence interval: 2.66-4.50). Further, we conducted single SNP analysis after stratifying the full data set by the gender status of affecteds in each family. The P-value for RS301443 in families with the male affecteds was 0.00027, and the P-value in families with female affecteds was 0.076. The fact that we identified a signal which was not previously reported by the other research groups may be due to differences in study designs and sample ascertainment. However, it is also possible that this significant SNP may be part of a regulator for SLC1A1, given that it is roughly 7.5 kb away from the boundary of the SLC1A1 gene. However, this potential finding needs to be validated biologically. Further functional studies in this region are planned by this research group. (C) 2009 Wiley-Liss, Inc. C1 [Shugart, Y. Y.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wang, Y.; Samuels, J. F.; Grados, M. A.; Cullen, B.; Hoehn-Saric, R.; Bienvenu, O. J.; Riddle, M. A.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Greenberg, B. D.; Rasmussen, S. A.; Pinto, A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Knowles, J. A.; McCracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Rauch, S. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rauch, S. L.] Harvard Univ, Sch Med, Boston, MA USA. [Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Fyer, A. J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. [Fyer, A. J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Pauls, D. L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Liang, K. Y.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Shugart, YY (reprint author), Dept Epidemiol & Biostat, 1629 Thames St,Suite 401, Baltimore, MD 21044 USA. EM yyao@jhsph.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 NR 38 TC 46 Z9 48 U1 2 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2009 VL 150B IS 6 BP 886 EP 892 DI 10.1002/ajmg.b.30914 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 491SO UT WOS:000269600000014 PM 19152386 ER PT J AU Sabatine, MS Antman, EM Widimsky, P Ebrahim, IO Kiss, RG Saaiman, A Polasek, R Contant, CF McCabe, CH Braunwald, E AF Sabatine, Marc S. Antman, Elliott M. Widimsky, Petr Ebrahim, Iftikhar O. Kiss, Robert G. Saaiman, Andre Polasek, Rostislav Contant, Charles F. McCabe, Carolyn H. Braunwald, Eugene TI Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial SO LANCET LA English DT Article ID FACTOR-XA INHIBITOR; MYOCARDIAL-INFARCTION; UNFRACTIONATED HEPARIN; RECEPTOR ANTAGONIST; ENOXAPARIN; EFFICACY; SAFETY; CLOPIDOGREL; FXV673; MODEL AB Background Otamixaban is an intravenous direct factor Xa inhibitor. We aimed to assess its efficacy and safety in non-ST-elevation acute coronary syndromes and to identify the optimum dose range for further assessment in a phase 3 study. Methods In this double-blind, phase 2 trial undertaken in 196 sites in 36 countries, 3241 patients with non-ST-elevation acute coronary syndromes were randomly assigned via a central, telephone-based interactive voice response system to one of five doses of otamixaban (0.08 mg/kg bolus followed by infusions of 0.035 [n=125], 0.070 [676], 0.105 [662], 0.140 [658], or 0.175 [671] mg/kg/h) or to a control of unfractionated heparin (60 IU/kg intravenous bolus followed by an infusion of 12 IU/kg/h) plus eptifibatide (180 mu g/kg intravenous bolus followed by an infusion of 1.0-2.0 mu g/kg/min [n=449]). Both investigators and patients were unaware of treatment allocation. Enrolment into the lowest dose group was stopped early at the recommendation of the Data Monitoring Committee. The primary efficacy endpoint was a composite of death, myocardial infarction, urgent revascularisation, or bailout glycoprotein IIb/IIIa inhibitor use up to 7 days. The primary safety endpoint was TIMI major or minor bleeding not related to coronary-artery bypass grafting. Efficacy analyses were by intention to treat; safety analyses were in treated patients. This study is registered with Clinical.Trials.gov, number NCT00317395. Findings Rates of the primary efficacy endpoint in the five otamixaban doses were 7.2% (nine of 125) with 0.035 mg/kg/h, 4.6% (31/676) with 0.070 mg/kg/h, 3.8% (25/662) with 0.105 mg/kg/h, 3.6% (24/658) with 0.140 mg/kg/h, and 4.3% (29/671) with 0.175 mg/kg/h (p=0.34 for trend). In the control group, the rate was 6.2% (28/449), yielding relative risks for the five otamixaban doses of 1.16 (95% CI 0.56-2.38), 0.74 (0.45-1.21), 0.61 (0.36-1.02), 0.58 (0.34-1.00), and 0.69 (0.42-1.15), respectively. Rates of the primary safety endpoint in the five otamixaban doses were 1.6% (two of 122), 1.6% (11/669), 3.1% (20/651), 3.4% (22/651), and 5.4% (36/664), respectively (p=0.0001 for trend); the rate in the control group was 2.7% (12/448). Interpretation In patients with non-ST-elevation acute coronary syndromes, otamixaban infusions of 0.100-0.140 mg/kg/h might reduce ischaemic events and have a safety profile similar to unfractionated heparin plus eptifibatide. Further testing in a phase 3 trial is warranted. C1 [Sabatine, Marc S.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, TIMI Study Grp, Boston, MA 02115 USA. [Sabatine, Marc S.; Antman, Elliott M.; Contant, Charles F.; McCabe, Carolyn H.; Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. [Widimsky, Petr] Charles Univ Prague, Cardioctr, Fac Med 3, Prague, Czech Republic. [Ebrahim, Iftikhar O.] Unitas Hosp, Pretoria, South Africa. [Kiss, Robert G.] Semmelweis Univ, Hungarian Acad Sci, Res Grp Inflammat Biol & Immunogenom, Dept Cardiol,State Hlth Ctr, H-1085 Budapest, Hungary. [Saaiman, Andre] Kuils River Heart Unit, Cape Town, South Africa. [Polasek, Rostislav] Dist Hosp Liberec, Dept Cardiol, Liberec, Czech Republic. RP Sabatine, MS (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, TIMI Study Grp, 7S Francis St, Boston, MA 02115 USA. EM msabatine@partners.org RI Widimsky, Petr/P-8088-2016 OI Widimsky, Petr/0000-0001-5686-7752 FU Sanofi-Aventis; Johnson Johnson; Bayer Healthcare AG; Daiichi Sankyo FX The TIMI Study Group receives research grant support from Sanofi-Aventis, Johnson & Johnson, Bayer Healthcare AG, and Daiichi Sankyo. Additionally, MSS reports receiving honoraria and consultant fees from Sanofi-Aventis and honoraria from Bristol-Myers Squibb. EMA reports receiving research grants from Sanofi-Aventis and Daaichi-Sankyo. RCK reports receiving honoraria from Sanofi-Aventis and Bayer AG. EB reports receiving grant support from Johnson & Johnson and honoraria and consultant fees from Sanofi-Aventis. All other authors declare that they have no conflicts of interest. NR 26 TC 82 Z9 89 U1 0 U2 5 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 SEP 5 PY 2009 VL 374 IS 9692 BP 787 EP 795 DI 10.1016/S0140-6736(09)61454-9 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 492QU UT WOS:000269675000027 PM 19717184 ER PT J AU Outeiro, TF Klucken, J Bercury, K Tetzlaff, J Putcha, P Oliveira, LMA Quintas, A McLean, PJ Hyman, BT AF Outeiro, Tiago F. Klucken, Jochen Bercury, Kathryn Tetzlaff, Julie Putcha, Preeti Oliveira, Luis M. A. Quintas, Alexandre McLean, Pamela J. Hyman, Bradley T. TI Dopamine-Induced Conformational Changes in Alpha-Synuclein SO PLOS ONE LA English DT Article AB Background: Oligomerization and aggregation of alpha-synuclein molecules play a major role in neuronal dysfunction and loss in Parkinson's disease [1]. However, alpha-synuclein oligomerization and aggregation have mostly been detected indirectly in cells using detergent extraction methods [2,3,4]. A number of in vitro studies showed that dopamine can modulate the aggregation of alpha-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils [5,6,7]. Methodology/Principal Findings: Here, we show that alpha-synuclein adopts a variety of conformations in primary neuronal cultures using fluorescence lifetime imaging microscopy (FLIM). Importantly, we found that dopamine, but not dopamine agonists, induced conformational changes in alpha-synuclein which could be prevented by blocking dopamine transport into the cell. Dopamine also induced conformational changes in alpha-synuclein expressed in neuronal cell lines, and these changes were also associated with alterations in oligomeric/aggregated species. Conclusion/Significance: Our results show, for the first time, a direct effect of dopamine on the conformation of alpha-synuclein in neurons, which may help explain the increased vulnerability of dopaminergic neurons in Parkinson's disease. RP Outeiro, TF (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Alzheimer Res Unit, Charlestown, MA USA. EM touteiro@fm.ul.pt; bhyman@partners.org RI Oliveira, Luis/I-7994-2014; Quintas, Alexandre/J-6436-2012 OI Oliveira, Luis/0000-0002-2958-181X; Quintas, Alexandre/0000-0002-5188-0453 FU NINDS NIH HHS [5P50-NS38372A-06, P50 NS038372, R01 NS063963] NR 36 TC 30 Z9 30 U1 1 U2 8 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 SEP 4 PY 2009 VL 4 IS 9 AR e6906 DI 10.1371/journal.pone.0006906 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 491ZF UT WOS:000269622100011 PM 19730729 ER PT J AU Ruderfer, DM Roberts, DC Schreiber, SL Perlstein, EO Kruglyak, L AF Ruderfer, Douglas M. Roberts, David C. Schreiber, Stuart L. Perlstein, Ethan O. Kruglyak, Leonid TI Using Expression and Genotype to Predict Drug Response in Yeast SO PLOS ONE LA English DT Article AB Personalized, or genomic, medicine entails tailoring pharmacological therapies according to individual genetic variation at genomic loci encoding proteins in drug-response pathways. It has been previously shown that steady-state mRNA expression can be used to predict the drug response (i.e., sensitivity or resistance) of non-genotyped mammalian cancer cell lines to chemotherapeutic agents. In a real-world setting, clinicians would have access to both steady-state expression levels of patient tissue(s) and a patient's genotypic profile, and yet the predictive power of transcripts versus markers is not well understood. We have previously shown that a collection of genotyped and expression-profiled yeast strains can provide a model for personalized medicine. Here we compare the predictive power of 6,229 steady-state mRNA transcript levels and 2,894 genotyped markers using a pattern recognition algorithm. We were able to predict with over 70% accuracy the drug sensitivity of 104 individual genotyped yeast strains derived from a cross between a laboratory strain and a wild isolate. We observe that, independently of drug mechanism of action, both transcripts and markers can accurately predict drug response. Marker-based prediction is usually more accurate than transcript-based prediction, likely reflecting the genetic determination of gene expression in this cross. RP Ruderfer, DM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM eperlste@princeton.edu; leonid@genomics.princeton.edu RI Ruderfer, Douglas/M-5795-2016; OI Ruderfer, Douglas/0000-0002-2365-386X; Perlstein, Ethan/0000-0002-4734-4391 FU Howard Hughes Medical Institute; NIGMS NIH HHS [50GM071508, P50 GM071508] NR 35 TC 9 Z9 10 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 SEP 4 PY 2009 VL 4 IS 9 AR e6907 DI 10.1371/journal.pone.0006907 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 491ZF UT WOS:000269622100012 PM 19730698 ER PT J AU Navarro, F Gutman, D Meire, E Caceres, M Rigoutsos, I Bentwich, Z Lieberman, J AF Navarro, Francisco Gutman, David Meire, Eti Caceres, Mario Rigoutsos, Isidore Bentwich, Zvi Lieberman, Judy TI miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53 SO BLOOD LA English DT Article ID TUMOR-SUPPRESSOR NETWORK; C-MYB; GENE-EXPRESSION; DOWN-REGULATION; TRANSCRIPTION FACTORS; MICRORNA; APOPTOSIS; LEUKEMIA; CANCER; RNA AB The role of miRNAs in regulating megakaryocyte differentiation was examined using bipotent K562 human leukemia cells. miR-34a is strongly up-regulated during phorbol ester-induced megakaryocyte differentiation, but not during hemin-induced erythrocyte differentiation. Enforced expression of miR-34a in K562 cells inhibits cell proliferation, induces cell-cycle arrest in G(1) phase, and promotes megakaryocyte differentiation as measured by CD41 induction. miR34a expression is also up-regulated during thrombopoietin-induced differentiation of CD34(+) hematopoietic precursors, and its enforced expression in these cells significantly increases the number of megakaryocyte colonies. miR-34a directly regulates expression of MYB, facilitating megakaryocyte differentiation, and of CDK4 and CDK6, to inhibit theG1/S transition. However, these miR-34a target genes are down-regulated rapidly after inducing megakaryocyte differentiation before miR-34a is induced. This suggests that miR-34a is not responsible for the initial down-regulation but may contribute to maintaining their suppression later on. Previous studies have implicated miR34a as a tumor suppressor gene whose transcription is activated by p53. However, in p53-null K562 cells, phorbol esters induce miR-34a expression independently of p53 by activating an alternative phorbol ester-responsive promoter to produce a longer pri-miR-34a transcript. (Blood. 2009; 114: 2181-2192) C1 [Navarro, Francisco; Gutman, David; Lieberman, Judy] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Navarro, Francisco; Gutman, David; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Meire, Eti; Bentwich, Zvi] Rosetta Genom, Rehovot, Israel. [Caceres, Mario] Ctr Genom Regulat, Genes & Dis Program, Barcelona, Spain. [Rigoutsos, Isidore] IBM Thomas J Watson Res Ctr, Bioinformat & Pattern Discovery Grp, Yorktown Hts, NY USA. RP Lieberman, J (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Warren Alpert Bldg Rm 255,200 Longwood Ave, Boston, MA 02115 USA. EM lieberman@idi.harvard.edu RI Lieberman, Judy/A-2717-2015; Caceres, Mario/A-6379-2009; OI Caceres, Mario/0000-0002-7736-3251; Rigoutsos, Isidore/0000-0003-1529-8631 NR 50 TC 79 Z9 83 U1 1 U2 10 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 SEP 3 PY 2009 VL 114 IS 10 BP 2181 EP 2192 DI 10.1182/blood-2009-02-205062 PG 12 WC Hematology SC Hematology GA 490RZ UT WOS:000269523300025 PM 19584398 ER PT J AU Hamer, DH Singh, MP Wylie, BJ Yeboah-Antwi, K Tuchman, J Desai, M Udhayakumar, V Gupta, P Brooks, MI Shukla, MM Awasthy, K Sabin, L MacLeod, WB Dash, AP Singh, N AF Hamer, Davidson H. Singh, Mrigendra P. Wylie, Blair J. Yeboah-Antwi, Kojo Tuchman, Jordan Desai, Meghna Udhayakumar, Venkatachalam Gupta, Priti Brooks, Mohamad I. Shukla, Manmohan M. Awasthy, Kiran Sabin, Lora MacLeod, William B. Dash, Aditya P. Singh, Neeru TI Burden of malaria in pregnancy in Jharkhand State, India SO MALARIA JOURNAL LA English DT Article ID RAPID DIAGNOSTIC-TEST; LOW-BIRTH-WEIGHT; EPIDEMIOLOGY; PREVENTION; STRATEGIES; WOMEN AB Background: Past studies in India included only symptomatic pregnant women and thus may have overestimated the proportion of women with malaria. Given the large population at risk, a cross sectional study was conducted in order to better define the burden of malaria in pregnancy in Jharkhand, a malaria-endemic state in central-east India. Methods: Cross-sectional surveys at antenatal clinics and delivery units were performed over a 12-month period at two district hospitals in urban and semi-urban areas, and a rural mission hospital. Malaria was diagnosed by Giemsa-stained blood smear and/or rapid diagnostic test using peripheral or placental blood. Results: 2,386 pregnant women were enrolled at the antenatal clinics and 718 at the delivery units. 1.8% (43/2382) of the antenatal clinic cohort had a positive diagnostic test for malaria (53.5% Plasmodium falciparum, 37.2% Plasmodium vivax, and 9.3% mixed infections). Peripheral parasitaemia was more common in pregnant women attending antenatal clinics in rural sites (adjusted relative risk [aRR] 4.31, 95% CI 1.84-10.11) and in those who were younger than 20 years (aRR 2.68, 95% CI 1.03-6.98). Among delivery unit participants, 1.7% (12/717) had peripheral parasitaemia and 2.4% (17/712) had placental parasitaemia. Women attending delivery units were more likely to be parasitaemic if they were in their first or second pregnancy (aRR 3.17, 95% CI 1.32-7.61), had fever in the last week (aRR 5.34, 95% CI 2.89-9.90), or had rural residence (aRR 3.10, 95% CI 1.66-5.79). Malaria control measures including indoor residual spraying (IRS) and untreated bed nets were common, whereas insecticide-treated bed nets (ITN) and malaria chemoprophylaxis were rarely used. Conclusion: The prevalence of malaria among pregnant women was relatively low. However, given the large at-risk population in this malaria-endemic region of India, there is a need to enhance ITN availability and use for prevention of malaria in pregnancy, and to improve case management of symptomatic pregnant women. C1 [Hamer, Davidson H.; Wylie, Blair J.; Yeboah-Antwi, Kojo; Brooks, Mohamad I.; Sabin, Lora; MacLeod, William B.] Boston Univ, Sch Publ Hlth, Ctr Global Hlth & Dev, Boston, MA 02118 USA. [Hamer, Davidson H.; Yeboah-Antwi, Kojo; Sabin, Lora; MacLeod, William B.] Boston Univ, Sch Publ Hlth, Dept Int Hlth, Boston, MA 02118 USA. [Hamer, Davidson H.] Boston Univ, Sch Publ Hlth, Dept Med, Infect Dis Sect, Boston, MA 02118 USA. [Singh, Mrigendra P.; Gupta, Priti; Shukla, Manmohan M.; Awasthy, Kiran; Singh, Neeru] Natl Inst Malaria Res Field Stn, Jabalpur, Madhya Pradesh, India. [Wylie, Blair J.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02114 USA. [Tuchman, Jordan] Ctr Leadership & Management, Cambridge, MA 02139 USA. [Desai, Meghna; Udhayakumar, Venkatachalam] Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. [Dash, Aditya P.; Singh, Neeru] Natl Inst Malaria Res, Delhi, India. [Singh, Neeru] Indian Council Med Res, Reg Med Res Ctr Tribals, Jabalpur, India. RP Hamer, DH (reprint author), Boston Univ, Sch Publ Hlth, Ctr Global Hlth & Dev, Boston, MA 02118 USA. EM dhamer@bu.edu; mrigendrapal@gmail.com; bwylie@partners.org; kyantwi@bu.edu; jtuchman@msh.org; mud8@cdc.gov; vxu0@cdc.gov; pritibiochem00@gmail.com; mib@bu.edu; mm_shukla57@yahoo.co.in; kiranawasthi4@gmail.com; lsabin@bu.edu; wmacleod@bu.edu; apdash2@rediffmail.com; oicmrc@yahoo.co.in OI MacLeod, William/0000-0001-8003-8874; Hamer, Davidson/0000-0002-4700-1495 FU United States Agency for International Development (USAID)/India [GHS-A-00-03-00020-00] FX We would like to thank Dr. MK Das, the study nurses, and Amrit Alok for their efforts on behalf of the study. We also would like to acknowledge the kind administrative and logistical support of the Chief Medical Officers at each of the district hospitals, the Jharkhand State health authorities, and the Indian Council of Medical Research. NR 31 TC 15 Z9 16 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD SEP 3 PY 2009 VL 8 AR 210 DI 10.1186/1475-2875-8-210 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 495FQ UT WOS:000269876400003 PM 19728882 ER PT J AU Schafer, ZT Grassian, AR Song, LL Jiang, ZY Gerhart-Hines, Z Irie, HY Gao, SZ Puigserver, P Brugge, JS AF Schafer, Zachary T. Grassian, Alexandra R. Song, Loling Jiang, Zhenyang Gerhart-Hines, Zachary Irie, Hanna Y. Gao, Sizhen Puigserver, Pere Brugge, Joan S. TI Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment SO NATURE LA English DT Article ID BREAST-CANCER; DUCTAL MORPHOGENESIS; EXTRACELLULAR-MATRIX; EPITHELIAL ACINI; CELL-GROWTH; APOPTOSIS; ANOIKIS; MECHANISMS; AUTOPHAGY; CULTURES AB Normal epithelial cells require matrix attachment for survival, and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence(1). Although apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment(2), recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells(3,4). Here we demonstrate that detachment of mammary epithelial cells from ECM causes an ATP deficiency owing to the loss of glucose transport. Overexpression of ERBB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and phosphatidylinositol-3-OH kinase (PI(3) K) activation, and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway. Notably, we found that the ATP deficiency could be rescued by antioxidant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation, which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an increase in ROS in matrix-deprived cells in the luminal space of mammary acini, and the discovery that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results show both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments by antioxidant restoration of ATP generation. C1 [Schafer, Zachary T.; Grassian, Alexandra R.; Song, Loling; Jiang, Zhenyang; Irie, Hanna Y.; Gao, Sizhen; Puigserver, Pere; Brugge, Joan S.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Gerhart-Hines, Zachary; Puigserver, Pere] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Gerhart-Hines, Zachary] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. RP Brugge, JS (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. EM joan_brugge@hms.harvard.edu FU National Cancer Institute; National Institutes of Health (NIH); NCI; National Science Graduate Research Fellowship FX We thank M. Overholtzer, G. Mouneimne, M. Mazzone and C. Leung for critical reading of the manuscript and/or experimental assistance. We thank A. Mailleux, A. Kaanta, V. Schafer, A. Zhou, K. Simpson, and the members of the Brugge laboratory for experimental assistance, comments, and/or discussion. This work was supported by a grant from the National Cancer Institute (J. S. B.) and a grant from the National Institutes of Health (NIH) (P. P.). Z. T. S. is the recipient of a Ruth L. Kirschstein National Research Service Award (NRSA) for Postdoctoral Fellows from the National Cancer Institute; L. S. an NCI Mentored Quantitative Research Development Award (K25); A. R. G. a National Science Graduate Research Fellowship; and H. Y. I. an NCI K08 Award. NR 34 TC 307 Z9 313 U1 2 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 3 PY 2009 VL 461 IS 7260 BP 109 EP U118 DI 10.1038/nature08268 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 490DT UT WOS:000269478800040 PM 19693011 ER PT J AU Bhatt, DL AF Bhatt, Deepak L. TI Prasugrel in Clinical Practice. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID STENTS C1 [Bhatt, Deepak L.] VA Boston Healthcare Syst, Dept Cardiol, Boston, MA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Integrated Intervent Cardiovasc Program, Boston, MA 02115 USA. RP Bhatt, DL (reprint author), VA Boston Healthcare Syst, Dept Cardiol, Boston, MA USA. NR 6 TC 52 Z9 52 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 SEP 3 PY 2009 VL 361 IS 10 BP 940 EP 942 DI 10.1056/NEJMp0806848 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 490EI UT WOS:000269480400002 PM 19605807 ER PT J AU Tsai, TT Nallamothu, BK Prasad, A Saint, S Bates, ER AF Tsai, Thomas T. Nallamothu, Brahmajee K. Prasad, Abhiram Saint, Sanjay Bates, Eric R. TI A Change of Heart. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID APICAL BALLOONING SYNDROME; ACUTE MYOCARDIAL-INFARCTION; TAKO-TSUBO; CARDIOMYOPATHY; STRESS; THROMBOLYSIS; WOMEN C1 [Tsai, Thomas T.] Univ Colorado, Cardiol Sect 111B, Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. [Tsai, Thomas T.] Univ Colorado, Dept Internal Med, Denver, CO 80220 USA. [Nallamothu, Brahmajee K.; Saint, Sanjay] Ann Arbor VA Med Ctr, Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Nallamothu, Brahmajee K.; Saint, Sanjay; Bates, Eric R.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Prasad, Abhiram] Mayo Clin & Mayo Fdn, Dept Internal Med, Rochester, MN 55905 USA. [Prasad, Abhiram] Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, Rochester, MN 55905 USA. RP Tsai, TT (reprint author), Univ Colorado, Cardiol Sect 111B, Denver Vet Affairs Med Ctr, 1055 Clermont St, Denver, CO 80220 USA. EM thomas.tsai@va.gov NR 15 TC 5 Z9 6 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 SEP 3 PY 2009 VL 361 IS 10 BP 1010 EP 1016 DI 10.1056/NEJMcps0903023 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 490EI UT WOS:000269480400012 PM 19726776 ER PT J AU Moritz, T Duckworth, W Abraira, C AF Moritz, Thomas Duckworth, William Abraira, Carlos TI Glucose control and vascular complications in veterans with type 2 diabetes (vol 360, pg 129, 2009) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Correction C1 [Moritz, Thomas] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Duckworth, William] Phoenix VA Hlth Care Syst, Phoenix, AZ USA. [Abraira, Carlos] Miami VA Med Ctr, Miami, FL USA. RP Moritz, T (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. EM thomas.moritz@va.gov NR 1 TC 28 Z9 28 U1 2 U2 14 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 SEP 3 PY 2009 VL 361 IS 10 BP 1024 EP 1025 DI 10.1056/NEJMc096250 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 490EI UT WOS:000269480400021 PM 19726779 ER PT J AU Wadlow, RC Wittner, BS Finley, SA Bergquist, H Upadhyay, R Finn, S Loda, M Mahmood, U Ramaswamy, S AF Wadlow, Raymond C. Wittner, Ben S. Finley, S. Aidan Bergquist, Henry Upadhyay, Rabi Finn, Stephen Loda, Massimo Mahmood, Umar Ramaswamy, Sridhar TI Systems-Level Modeling of Cancer-Fibroblast Interaction SO PLOS ONE LA English DT Article AB Cancer cells interact with surrounding stromal fibroblasts during tumorigenesis, but the complex molecular rules that govern these interactions remain poorly understood thus hindering the development of therapeutic strategies to target cancer stroma. We have taken a mathematical approach to begin defining these rules by performing the first large-scale quantitative analysis of fibroblast effects on cancer cell proliferation across more than four hundred heterotypic cell line pairings. Systems-level modeling of this complex dataset using singular value decomposition revealed that normal tissue fibroblasts variably express at least two functionally distinct activities, one which reflects transcriptional programs associated with activated mesenchymal cells, that act either coordinately or at cross-purposes to modulate cancer cell proliferation. These findings suggest that quantitative approaches may prove useful for identifying organizational principles that govern complex heterotypic cell-cell interactions in cancer and other contexts. RP Wadlow, RC (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM sridhar@mgh.harvard.edu OI Finn, Stephen/0000-0002-8628-5814 FU NCI NIH HHS [K08 CA100339, K08 CA100339-06] NR 37 TC 13 Z9 14 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 3 PY 2009 VL 4 IS 9 AR e6888 DI 10.1371/journal.pone.0006888 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 490RX UT WOS:000269522900017 PM 19727395 ER PT J AU Terauchi, M Li, JY Bedi, B Baek, KH Tawfeek, H Galley, S Gilbert, L Nanes, MS Zayzafoon, M Guldberg, R Lamar, DL Singer, MA Lane, TF Kronenberg, HM Weitzmann, MN Pacifici, R AF Terauchi, Masakazu Li, Jau-Yi Bedi, Brahmchetna Baek, Ki-Hyun Tawfeek, Hesham Galley, Sarah Gilbert, Linda Nanes, Mark S. Zayzafoon, Majd Guldberg, Robert Lamar, David L. Singer, Meredith A. Lane, Timothy F. Kronenberg, Henry M. Weitzmann, M. Neale Pacifici, Roberto TI T Lymphocytes Amplify the Anabolic Activity of Parathyroid Hormone through Wnt10b Signaling SO CELL METABOLISM LA English DT Article ID INCREASED BONE-FORMATION; LOSS IN-VIVO; BETA-CATENIN; DIFFERENTIATED OSTEOBLASTS; POSTMENOPAUSAL WOMEN; CELL PROLIFERATION; MICE DEFICIENT; STROMAL CELLS; EXPRESSION; INCREASES AB Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis because it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here, we show that PTH increases the production of Wnt10b by bone marrow CD8+ T cells and induces these lymphocytes to activate canonical Wnt signaling in preosteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in preosteoblasts and blunted osteoblastic commitment, proliferation, differentiation, and life span, which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wntl Ob, PTH has no anabolic activity in mice lacking T-cell-produced Wntl Ob. Therefore, T-cell-mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast crosstalk pathways may provide pharmacological targets for bone anabolism. C1 [Terauchi, Masakazu; Li, Jau-Yi; Bedi, Brahmchetna; Baek, Ki-Hyun; Tawfeek, Hesham; Galley, Sarah; Nanes, Mark S.; Weitzmann, M. Neale; Pacifici, Roberto] Emory Univ, Dept Med, Div Endocrinol Metab & Lipids, Atlanta, GA 30332 USA. [Lamar, David L.] Emory Univ, Dept Med, Kathleen B & Mason I Lowance Ctr Human Immunol, Atlanta, GA 30332 USA. [Weitzmann, M. Neale] Emory Univ, Emory Winship Canc Inst, Atlanta, GA 30332 USA. [Pacifici, Roberto] Emory Univ, Immunol & Mol Pathogenesis Program, Atlanta, GA 30332 USA. [Gilbert, Linda; Nanes, Mark S.; Weitzmann, M. Neale] Atlanta VA Med Ctr, Decatur, GA 30033 USA. [Zayzafoon, Majd] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Guldberg, Robert] Georgia Inst Technol, George W Woodruff Sch Mech Engn, Atlanta, GA 30332 USA. [Singer, Meredith A.; Lane, Timothy F.] Univ Calif Los Angeles, Dept Obstet & Gynecol, Dept Biol Chem, Los Angeles, CA 90095 USA. [Singer, Meredith A.; Lane, Timothy F.] Univ Calif Los Angeles, Orthoped Hosp, Res Ctr, Los Angeles, CA 90095 USA. [Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Pacifici, R (reprint author), Emory Univ, Dept Med, Div Endocrinol Metab & Lipids, Atlanta, GA 30332 USA. EM roberto.pacifici@emory.edu RI Terauchi, Masakazu/D-9831-2013 OI Terauchi, Masakazu/0000-0001-5577-0094 FU National Institutes of Health [AR54625, AG28278] FX This study was supported by grants from the National Institutes of Health (AR54625 and AG28278). We are grateful to Laurie McCauley (University of Michigan) for her review of the manuscript. NR 53 TC 60 Z9 62 U1 0 U2 2 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 SEP 2 PY 2009 VL 10 IS 3 BP 229 EP 240 DI 10.1016/j.cmet.2009.07.010 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 491SX UT WOS:000269600900010 PM 19723499 ER PT J AU Zinner, DE Campbell, EG AF Zinner, Darren E. Campbell, Eric G. TI Life-Science Research Within US Academic Medical Centers SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CLINICAL-RESEARCH; TRANSLATIONAL RESEARCH; BIOMEDICAL-RESEARCH; HEALTH CENTERS; CHALLENGES; INDUSTRY; NIH; FACULTY; MATTERS; CARE AB Context Besides the generic "basic" vs "applied" labels, little information is known about the types of life-science research conducted within academic medical centers (AMCs). Objective To determine the relative proportion, characteristics, funding, and productivity of AMC faculty by the type of research they conduct. Design Mailed survey conducted in 2007 of 3080 life-science faculty at the 50 universities with medical schools that received the most funding from the National Institutes of Health in 2004. Response rate was 74%. Setting and Participants Research faculty affiliated with a medical school or teaching hospital, representing 77% of respondents (n=1663). Main Outcome Measures Type of research ( basic, translational, clinical trials, health services research/clinical epidemiology, multimode, other), total funding, industry funding, publications, professional activities, patenting behavior, and industry relationships. Results Among AMC research faculty, 33.6% exclusively conducted basic science research as principal investigators compared with translational researchers (9.1%), clinical trial investigators (7.1%), and health services researchers/clinical epidemiologists (9.0%). While principal investigators garnered a mean of $410 755 in total annual research funding, 22.1% of all AMC research faculty were unsponsored, a proportion that ranged from 11.5% for basic science researchers to 46.8% for health services researchers (P < .001). The average AMC faculty member received $33 417 in industry-sponsored funding, with most of this money concentrated among clinical trial ($110 869) and multimode ($59 916) principal investigators. Translational (61.3%), clinical trial (67.3%), and multimode (70.9%) researchers were significantly more likely than basic science researchers (41.9%) to report a relationship with industry and that these relationships contributed to their most important scientific work (P < .05 for all comparisons). Conclusion The research function of AMCs is active and diverse, incorporating a substantial proportion of faculty who are conducting research and publishing without sponsorship. JAMA. 2009;302(9):969-976 www.jama.com C1 [Zinner, Darren E.] Brandeis Univ, Heller Sch Social Policy & Management, Schneider Inst Hlth Policy, Waltham, MA 02454 USA. [Campbell, Eric G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Hlth Policy, Boston, MA USA. RP Zinner, DE (reprint author), Brandeis Univ, Heller Sch Social Policy & Management, Schneider Inst Hlth Policy, 415 S St,MS 035, Waltham, MA 02454 USA. EM dzinner@brandeis.edu FU National Human Genome Research Institute of the National Institutes of Health [1R01GM074915-01] FX This research was supported by grant 1R01GM074915-01 from the National Human Genome Research Institute of the National Institutes of Health ( E. G. C.). NR 36 TC 28 Z9 28 U1 2 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 2 PY 2009 VL 302 IS 9 BP 969 EP 976 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 489TF UT WOS:000269444900022 PM 19724044 ER PT J AU Yabroff, KR Schrag, D AF Yabroff, K. Robin Schrag, Deborah TI Challenges and Opportunities for Use of Cost-Effectiveness Analysis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID COLORECTAL-CANCER; DRUGS; CHEMOTHERAPY; MUTATIONS; CETUXIMAB C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schrag, Deborah] Harvard Univ, Sch Med, Boston, MA USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Rm 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 21 TC 7 Z9 8 U1 0 U2 0 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 SEP 2 PY 2009 VL 101 IS 17 BP 1161 EP U11 DI 10.1093/jnci/djp258 PG 3 WC Oncology SC Oncology GA 491WS UT WOS:000269613500001 PM 19666852 ER PT J AU Cardoso, F Bedard, PL Winer, EP Pagani, O Senkus-Konefka, E Fallowfield, LJ Kyriakides, S Costa, A Cufer, T Albain, KS AF Cardoso, Fatima Bedard, Philippe L. Winer, Eric P. Pagani, Olivia Senkus-Konefka, Elzbieta Fallowfield, Lesley J. Kyriakides, Stella Costa, Alberto Cufer, Tanja Albain, Kathy S. CA ESO-MBC Task Force TI International Guidelines for Management of Metastatic Breast Cancer: Combination vs Sequential Single-Agent Chemotherapy SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PROSPECTIVE RANDOMIZED-TRIAL; PHASE-III TRIAL; ADVANCED COLORECTAL-CANCER; CAPECITABINE PLUS DOCETAXEL; 1ST-LINE THERAPY; LINE THERAPY; PACLITAXEL; SURVIVAL; ANTHRACYCLINE; DOXORUBICIN AB Compared with treatment options for early-stage breast cancer, few data exist regarding the optimal use of chemotherapy for metastatic breast cancer (MBC). The choice of using a combination of cytotoxic chemotherapies vs sequential single agents is controversial. At the 6th European Breast Cancer Conference, the European School of Oncology Metastatic Breast Cancer Task Force convened an open debate on the relative benefits of combination vs sequential therapy. Based on the available data, the Task Force recommends sequential monotherapy as the preferred choice in advanced disease, in the absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control. Patient- and disease-related factors should be used to choose between combination and sequential single-agent chemotherapy for MBC. Additional research is needed to determine the impact of therapy on patient-rated quality of life and to identify predictive factors that can be used to guide therapy. C1 [Cardoso, Fatima; Bedard, Philippe L.] Inst Jules Bordet, Med Oncol & Translat Res Unit, Dept Med Oncol, B-1000 Brussels, Belgium. [Winer, Eric P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Brigham & Womens Hosp, Boston, MA 02115 USA. [Pagani, Olivia] Osped Italiano, Dept Med Oncol, Oncol Inst So Switzerland, Lugano, Switzerland. [Pagani, Olivia] Switzerland & Swiss Grp Clin Canc Res, Bern, Switzerland. [Senkus-Konefka, Elzbieta] Med Univ Gdansk, Dept Radiotherapy & Oncol, Gdansk, Poland. [Fallowfield, Lesley J.] Univ Sussex, Dept Psychooncol, Brighton & Sussex Med Sch, Brighton BN1 9RH, E Sussex, England. [Kyriakides, Stella] European Breast Canc Coalit, Nicosia, Cyprus. [Costa, Alberto] European Sch Oncol, Milan, Italy. [Costa, Alberto] Maugeri Fdn Breast Unit, Pavia, Italy. [Cufer, Tanja] Univ Clin Golnik, Dept Med Oncol, Golnik, Slovenia. [Albain, Kathy S.] Loyola Univ, Dept Med Oncol, Chicago Stritch Sch Med, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. RP Cardoso, F (reprint author), Inst Jules Bordet, Med Oncol & Translat Res Unit, Dept Med Oncol, Blvd Waterloo 125, B-1000 Brussels, Belgium. EM fatima.cardoso@bordet.be RI Wardley, ANdrew/N-8135-2015; OI Wardley, ANdrew/0000-0002-9639-0888; Senkus, Elzbieta/0000-0001-6855-397X; Fallowfield, Lesley/0000-0002-3328-4447; Fallowfield, Lesley/0000-0003-0577-4518; Cardoso, Fatima/0000-0002-6692-2249 NR 57 TC 103 Z9 108 U1 3 U2 11 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 SEP 2 PY 2009 VL 101 IS 17 BP 1174 EP 1181 DI 10.1093/jnci/djp235 PG 8 WC Oncology SC Oncology GA 491WS UT WOS:000269613500006 PM 19657108 ER PT J AU Gervais, DA AF Gervais, D. A. TI Interventional oncology in the abdomen SO ABDOMINAL IMAGING LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Gervais, DA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 55 Fruit St, Boston, MA 02114 USA. EM Dgervais@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 J9 ABDOM IMAGING JI Abdom. Imaging PD SEP PY 2009 VL 34 IS 5 BP 545 EP 546 DI 10.1007/s00261-008-9473-8 PG 2 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA 487WC UT WOS:000269307300001 PM 18987908 ER PT J AU Saksena, M Gervais, D AF Saksena, Mansi Gervais, D. TI Percutaneous renal tumor ablation SO ABDOMINAL IMAGING LA English DT Article DE Renal cancer; Radiofrequency ablation; Cryoablation; Renal cell carcinoma; Percutaneous treatment ID GUIDED RADIOFREQUENCY ABLATION; RADIO-FREQUENCY ABLATION; CELL CARCINOMA; THERMAL ABLATION; INITIAL-EXPERIENCE; IMAGING GUIDANCE; MASSES; CRYOABLATION; COMPLICATIONS; CT AB Recent increase in utilization of cross-sectional imaging has resulted in increased detection of early renal cancer. Percutaneous ablation is a relatively new technique for the treatment of renal cancer. This article provides an overview of clinical indications, technique, and results of percutaneous ablation of renal cancer. C1 [Saksena, Mansi; Gervais, D.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02135 USA. RP Saksena, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Founder 2-216,White 270,55 Fruit St, Boston, MA 02135 USA. EM msaksena@partners.org NR 41 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 J9 ABDOM IMAGING JI Abdom. Imaging PD SEP PY 2009 VL 34 IS 5 BP 582 EP 587 DI 10.1007/s00261-008-9478-3 PG 6 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA 487WC UT WOS:000269307300005 PM 19089491 ER PT J AU Thabet, A Kalva, S Gervais, DA AF Thabet, Ashraf Kalva, Sanjeeva Gervais, Debra A. TI Percutaneous image-guided therapy of intra-abdominal malignancy: imaging evaluation of treatment response SO ABDOMINAL IMAGING LA English DT Article DE Percutaneous; Chemoembolization; Radioembolization; Ablation; Malignancy ID RENAL-CELL CARCINOMA; TRANSCATHETER ARTERIAL EMBOLIZATION; RADIOFREQUENCY THERMAL ABLATION; POSITRON-EMISSION-TOMOGRAPHY; SECONDARY LIVER MALIGNANCIES; HEPATOCELLULAR-CARCINOMA; HEPATIC-TUMORS; FOLLOW-UP; Y-90 MICROSPHERES; OILY CHEMOEMBOLIZATION AB The rising incidence of abdominal malignancies such as hepatocellular carcinoma (HCC) and renal cell carcinoma presents several challenges. Although surgery typically provides the best chance for cure, many patients are not surgical candidates. Innovative percutaneous therapies such as transarterial chemoembolization (TACE), radioembolization, and radiofrequency ablation (RFA) are increasingly being utilized as alternative treatment modalities, in some cases, with proven survival benefit. With the rise in interventional oncology, radiologists are being increasingly asked to interpret post-treatment imaging examinations that are critical to assessing treatment efficacy and complications. This article reviews the imaging manifestations of the most common percutaneous therapies, with special emphasis on TACE and RFA. Imaging findings of treatment-induced tumor necrosis, viable tumor, complications, and, in particular, benign ancillary findings that may be confused with viable tumor are reviewed, as manifested on computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). C1 [Kalva, Sanjeeva] Massachusetts Gen Hosp, Dept Radiol, Div Cardiovasc Imaging & Intervent, Boston, MA 02114 USA. [Thabet, Ashraf; Gervais, Debra A.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Kalva, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Cardiovasc Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dgervais@partners.org NR 67 TC 9 Z9 12 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD SEP PY 2009 VL 34 IS 5 BP 593 EP 609 DI 10.1007/s00261-008-9448-9 PG 17 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA 487WC UT WOS:000269307300007 ER PT J AU Roedl, JB Blake, MA Holalkere, NS Mueller, PR Colen, RR Harisinghani, MG AF Roedl, Johannes B. Blake, Michael A. Holalkere, Nagaraj S. Mueller, Peter R. Colen, Rivka R. Harisinghani, Mukesh G. TI Lymph node staging in esophageal adenocarcinoma with PET-CT based on a visual analysis and based on metabolic parameters SO ABDOMINAL IMAGING LA English DT Article DE Esophageal cancer; Lymph nodes; PET-CT; Diameter; SUV; Survival ID POSITRON-EMISSION-TOMOGRAPHY; SQUAMOUS-CELL CARCINOMA; GASTROESOPHAGEAL JUNCTION; ESOPHAGOGASTRIC JUNCTION; COMPUTED-TOMOGRAPHY; ENDOSCOPIC ULTRASONOGRAPHY; ADDITIONAL VALUE; FDG-PET; CANCER; ACCURACY AB In order to investigate the value of FDG positron emission tomography-computed tomography (PET-CT), FDG PET (reviewed side-by-side with CT), and metabolic parameters in the assessment of lymph node status and prognosis. Fifty-five subjects with lymph node positive (N1) and 26 subjects with lymph node negative (N0) disease were included. In the slice with the maximum FDG uptake of the tumor, the axial area of the primary tumor, the maximum diameter of the tumor, and the mean and maximum standardized uptake values were measured. Fused PET-CT correctly characterized 289 of 325 lymph node groups (accuracy 89%) compared to 273 of 325 with PET (accuracy 84%). In lymph node staging (N0 vs. N1), PET-CT (accuracy 83%) was more accurate than PET (accuracy 78%). Among the metabolic parameters, the tumor diameter measured on PET-CT was the best predictor of lymph node stage (N0 vs. N1: accuracy 86%; threshold 25.5 mm) and overall survival. However, the highest accuracy of lymph node staging (N0 vs. N1) was achieved with the synergistic combination of visual analysis and primary tumor diameter measurements (accuracy 95%). PET-CT increases accuracy of lymph node staging in esophageal adenocarcinoma compared to PET. The primary tumor diameter further improves accuracy in lymph node staging and was shown to be an independent predictor of overall survival. C1 [Roedl, Johannes B.; Blake, Michael A.; Holalkere, Nagaraj S.; Mueller, Peter R.; Colen, Rivka R.; Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Roedl, Johannes B.; Blake, Michael A.; Holalkere, Nagaraj S.; Mueller, Peter R.; Colen, Rivka R.; Harisinghani, Mukesh G.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Roedl, Johannes B.; Colen, Rivka R.] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Boston, MA 02114 USA. RP Roedl, JB (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM johannes.roedl@gmail.com OI Holalkere, Nagaraj/0000-0001-6324-7682 NR 23 TC 7 Z9 7 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 J9 ABDOM IMAGING JI Abdom. Imaging PD SEP PY 2009 VL 34 IS 5 BP 610 EP 617 DI 10.1007/s00261-008-9447-x PG 8 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA 487WC UT WOS:000269307300008 PM 18830663 ER PT J AU Oxnard, GR Zinkus, TM Bazari, H Wolf, M AF Oxnard, Geoffrey R. Zinkus, Tanya Milosh Bazari, Hasan Wolf, Myles TI Integrating Research Training Into Residency: Tools of Human Investigation SO ACADEMIC MEDICINE LA English DT Article ID CLINICAL-RESEARCH; PHYSICIAN-SCIENTISTS; MEDICINE; CURRICULUM AB Although the need for new physician-clinical scientists has never been greater, significant obstacles deter young physicians from careers in clinical research. Local and federal programs have sought to stimulate interest in clinical research among young physicians, medical students, and even undergraduates, but few formal programs have specifically focused on stimulating interest among residents in training. The recent implementation of strict duty hours regulations has provided residents with additional time to focus on career choices, and this has created an opportunity for training programs to offer new educational initiatives during residency. The authors present Tools of Human Investigation (THI), a two-week rotation offered during the second year of residency. The goals of THI are to provide seminar-based exposure to research methodologies, to impart the tools required to critically appraise the scientific literature, and to provide a small-group forum for career discussions. These three goals are achieved by drawing on a group of research faculty to lead sessions that combine didactics with career development guidance. A course like THI is one innovative way to stimulate interest in human research during residency that could help bridge the discontinuity between the research explorations promoted during medical school and the rigorous expectations of fellowship. C1 [Wolf, Myles] Univ Miami, Miller Sch Med, Div Nephrol & Hypertens, Clin Res Ctr, Miami, FL 33136 USA. [Zinkus, Tanya Milosh; Bazari, Hasan] Massachusetts Gen Hosp, Internal Med Residency Program, Boston, MA 02114 USA. [Bazari, Hasan] Harvard Univ, Sch Med, Boston, MA USA. RP Wolf, M (reprint author), Univ Miami, Miller Sch Med, Div Nephrol & Hypertens, Clin Res Ctr, 1120 NW 14th St, Miami, FL 33136 USA. EM mwolf2@med.miami.edu NR 15 TC 7 Z9 7 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD SEP PY 2009 VL 84 IS 9 BP 1295 EP 1300 DI 10.1097/ACM.0b013e3181b18861 PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 505RJ UT WOS:000270712100028 PM 19707076 ER PT J AU Oreskovic, NM Kuhlthau, KA Romm, D Perrin, JM AF Oreskovic, Nicolas M. Kuhlthau, Karen A. Romm, Diane Perrin, James M. TI Built Environment and Weight Disparities Among Children in High- and Low-Income Towns SO ACADEMIC PEDIATRICS LA English DT Article DE built environment; communities; disparities; fast food; GIS; income; obesity; pediatric ID FAST-FOOD RESTAURANTS; US STATE-LEVEL; PHYSICAL-ACTIVITY; OBESITY; MULTILEVEL; ACCESS; HEALTH; ASSOCIATION; OVERWEIGHT; SCHOOLS AB Objective. To assess differences in built environment and child weight, and associations between them in high- and low-income communities. Methods. By means of cross-sectional clinical and demographic data for children aged 2 to 18 years from an integrated health system in Massachusetts, we linked subject (n = 6680) and spatial data from Geographic Information Systems. We selected towns with at least 100 subjects per town (n = 46 towns), and we divided towns into quartiles by household income. We compared highest and lowest quartile towns on environmental characteristics (density of fast food restaurants. distance to nearest fast food restaurant, distance to nearest age-appropriate school) and overweight and obesity prevalence. We used clustered logistic regression to assess for associations between environmental characteristics and weight and carried out similar analyses stratified by age (2 to <5, 5 to <12, 12 to 18 years). Results. Low-income towns had more sidewalks, less open space, a greater density of fast food restaurants, and higher rates of overweight/obesity. Among low-income-town children, after adjusting for age, gender, race, and town, density of fast food restaurants was positively associated with overweight and obesity, whereas distance to nearest age-appropriate school and fast food restaurant were inversely associated with obesity. Children from low-income towns appeared to have more consistent associations between weight status and the built environment. Conclusions. Built environment varies by town income. Children living in low-income towns tend to have built environments that promote energy intake and decrease opportunities for energy expenditure. C1 [Oreskovic, Nicolas M.; Kuhlthau, Karen A.; Romm, Diane] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Oreskovic, Nicolas M.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Oreskovic, Nicolas M.; Perrin, James M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP Oreskovic, NM (reprint author), Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM noreskovic@partners.org OI Oreskovic, Nicolas/0000-0001-8702-8636 FU AHRQ [T32 HS000063-13] FX We thank Jeff Blossom at the Harvard Center for Geographic Analysis for assistance with GIS programming and analysis; and Jingyun Yang, PhD, Massachusetts General Hospital, for assistance with statistical analyses. Dr Oreskovic is funded by AHRQ grant T32 HS000063-13. NR 31 TC 38 Z9 38 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1876-2859 J9 ACAD PEDIATR JI Acad. Pediatr. PD SEP-OCT PY 2009 VL 9 IS 5 BP 315 EP 321 PG 7 WC Pediatrics SC Pediatrics GA 573KR UT WOS:000275912700008 PM 19477705 ER PT J AU Gorrindo, T Groves, JE AF Gorrindo, Tristan Groves, James E. TI Computer Simulation and Virtual Reality in the Diagnosis and Treatment of Psychiatric Disorders SO ACADEMIC PSYCHIATRY LA English DT Article ID EXPOSURE THERAPY; EDUCATION; ANXIETY; SKILLS; FEAR; SCHIZOPHRENIA; 21ST-CENTURY; METAANALYSIS C1 [Gorrindo, Tristan; Groves, James E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Gorrindo, T (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Yawkey 6A,55 Fruit St, Boston, MA 02114 USA. EM tristan.gorrindo@mgh.harvard.edu NR 30 TC 16 Z9 17 U1 2 U2 14 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1042-9670 J9 ACAD PSYCHIATR JI Acad. Psych. PD SEP-OCT PY 2009 VL 33 IS 5 BP 413 EP 417 PG 5 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 507FJ UT WOS:000270837000014 PM 19828861 ER PT J AU Wang, TW Spector, M AF Wang, Tzu-Wei Spector, Myron TI Development of hyaluronic acid-based scaffolds for brain tissue engineering SO ACTA BIOMATERIALIA LA English DT Article DE Scaffold; Collagen; Hyaluronic acid; Mechanical properties; Neural stem cell ID WATER-SOLUBLE CARBODIIMIDE; COLLAGEN-GAG SCAFFOLDS; CROSS-LINKING; IN-VITRO; EXTRACELLULAR-MATRIX; FABRICATION; PROTEINS; GELATIN; VIVO; RAT AB Three-dimensional biodegradable porous scaffolds play vital roles in tissue engineering. In this study, a hyaluronic acid-Collagen (HA-Coll) sponge with an open porous structure and mechanical behavior comparable to brain tissue was developed. HA-Coll scaffolds with different mixing ratios were prepared by a freeze-drying technique and crosslinked with water-soluble carbodiimide to improve mechanical stability. The pore structure of the samples was evaluated by light and scanning electron microscopy, and the mechanical behavior was analyzed by mechanical compression and tension testing. The degree of crosslinking was determined by the water absorption and trinitrobenzene sulfonic assay, and the HA content was determined by a carbazole assay. The results showed that HA-Coll scaffolds containing an open porous structure with a homogeneous pore size distribution could be fabricated. Certain features of the mechanical properties of HA-Coll scaffolds prepared with a Coll:HA mixing ratio of 1:2, and pure HA sponges, were comparable with brain tissue. Neural stem cells (NSCs) were expanded in number in monolayer culture and then seeded onto the three-dimensional scaffolds in order to investigate the effects of the different types of scaffolds on neurogenic induction of the cells. This study contributes to the understanding of the effects of HA content and crosslink treatment on pore characteristics, and mechanical behavior essential for the design of HA-Coll scaffolds suitable for NSC growth and differentiation for brain tissue engineering. (C) 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 [Spector, Myron] VA Boston Healthcare Syst, Tissue Engn Labs, Boston, MA 02130 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. RP Spector, M (reprint author), VA Boston Healthcare Syst, Tissue Engn Labs, Mail Stop 151 Res,150 S Huntington Ave, Boston, MA 02130 USA. EM mspector@rics.bwh.harvard.edu FU Department of Veterans Affairs; Department of Defense FX Funding for this work was provided by the Department of Veterans Affairs and the Department of Defense. M.S. is a Veterans Affairs Research Career Scientist. NR 40 TC 53 Z9 56 U1 2 U2 34 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 J9 ACTA BIOMATER JI Acta Biomater. PD SEP PY 2009 VL 5 IS 7 BP 2371 EP 2384 DI 10.1016/j.actbio.2009.03.033 PG 14 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 504SF UT WOS:000270636900002 PM 19403351 ER PT J AU Liang, HS Liang, P Xu, Y Wu, JN Liang, T Xu, XP Liu, EZ AF Liang, Hong Sheng Liang, Peng Xu, Ye Wu, Jia Ning Liang, Tao Xu, Xiao Ping Liu, En Zhong TI Denuded human amniotic membrane seeding bone marrow stromal cells as an effective composite matrix stimulates axonal outgrowth of rat neural cortical cells in vitro SO ACTA NEUROCHIRURGICA LA English DT Article DE Stem cell; Amniotic membrane; Axonal outgrowth; Matrix; Biomaterial ID NEURITE OUTGROWTH; EPITHELIAL-CELLS; STEM-CELLS; SURFACE RECONSTRUCTION; TRANSPLANTATION; EXPRESSION; SCAFFOLDS; HYDROGELS; DEFECTS; INTACT AB Previous studies have shown that axonal outgrowth in the damaged central nervous system is closely related to the local microenvironment. Transplantation of bone marrow stromal cells (BMSC) or BMSC with some biomaterials has been used to treat various central nervous system diseases with some success. In the current study, we investigated if BMSC on denuded human amniotic membrane (DhAM) as a composite matrix could stimulate axonal outgrowth or not. After completely removing the cells on the amniotic membrane with a tryptic and mechanical approach, we seeded BMSC on it. The MTS was applied to test the cytotoxicity of DhAM compared with PLGA and PLL. The morphology of the BMSC was observed by light, electronic and laser confocal microscopy. We also used four kinds of substance (PLL, DhAM, BMSC + PLL, BMSC + DhAM) to coculturing with the cortical neurons. Finally, the lengths of axons in each group were studied using the positive axon-specific marker NF-H. The DhAM was devoid of cellular components and only its intact basement membrane was left. BMSC grew on the substrate and proliferated with a flat to fusiform morphology. In the MTS test, the results indicated that BMSC cultured in DhAM extract had a high survival rate (> 80%). Moreover, the cortical neural axons in the experimental group (BMSC + DhAM) were longer (287.37 +/- 12.72 mu m) than in the other groups (P < 0.01). This study demonstrates that the DhAM was a good carrier to support growth of BMSC and BMSC on DhAM was an effective composite matrix to support the outgrowth of the axons of rat cortical neurons in vitro. Future studies of the use of the composite matrix in disorders are planned. C1 [Liang, Hong Sheng; Liang, Peng; Wu, Jia Ning; Xu, Xiao Ping; Liu, En Zhong] Harbin Med Coll, Affiliated Hosp 1, Dept Neurosurg, Harbin 150001, Peoples R China. [Xu, Ye] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Liang, Tao] Harbin Med Coll, Affiliated Hosp 1, Dept Digest, Harbin 150001, Peoples R China. [Liang, Peng] Minist Hlth China, Key Lab Cell Transplantat, Harbin 150001, Peoples R China. RP Liang, P (reprint author), Harbin Med Coll, Affiliated Hosp 1, Dept Neurosurg, Harbin 150001, Peoples R China. EM Liangpengd@Gmail.com FU National Natural Science Foundation of China [30500517]; Post-graduate Foundation of Harbin Medical University [2007003] FX This study was supported by grants from the National Natural Science Foundation of China ( No. 30500517) and Post-graduate Foundation of Harbin Medical University ( HCXB No. 2007003). We thank Dr. Lili Liu for generously providing PLGA and PLL, and Shangha Pan, Qi Huang, Aili Gao for their excellent technical assistance. NR 29 TC 11 Z9 13 U1 1 U2 3 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0001-6268 J9 ACTA NEUROCHIR JI Acta Neurochir. PD SEP PY 2009 VL 151 IS 9 BP 1113 EP 1120 DI 10.1007/s00701-009-0322-5 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 487WE UT WOS:000269307500013 PM 19404575 ER PT J AU Hilson, JB Merchant, SN Adams, JC Joseph, JT AF Hilson, Justin B. Merchant, Saumil N. Adams, Joe C. Joseph, Jeffrey T. TI Wolfram syndrome: a clinicopathologic correlation SO ACTA NEUROPATHOLOGICA LA English DT Article DE Wolfram syndrome; DIDMOAD; Neuropathology; Otopathology ID BETA-CELL LOSS; OPTIC ATROPHY; DIABETES-MELLITUS; DIDMOAD SYNDROME; TRANSMEMBRANE PROTEIN; HEARING IMPAIRMENT; VISUAL-CORTEX; WFS1 GENE; INSIPIDUS; ORGANIZATION AB Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a neurodegenerative disorder characterized by diabetes mellitus and optic atrophy as well as diabetes insipidus and deafness in many cases. We report the post-mortem neuropathologic findings of a patient with Wolfram syndrome and correlate them with his clinical presentation. In the hypothalamus, neurons in the paraventricular and supraoptic nuclei were markedly decreased and minimal neurohypophyseal tissue remained in the pituitary. The pontine base and inferior olivary nucleus showed gross shrinkage and neuron loss, while the cerebellum was relatively unaffected. The visual system had moderate to marked loss of retinal ganglion neurons, commensurate loss of myelinated axons in the optic nerve, chiasm and tract, and neuron loss in the lateral geniculate nucleus but preservation of the primary visual cortex. The patient's inner ear showed loss of the organ of Corti in the basal turn of the cochleae and mild focal atrophy of the stria vascularis. These findings correlated well with the patient's high-frequency hearing loss. The pathologic findings correlated closely with the patient's clinical symptoms and further support the concept of Wolfram syndrome as a neurodegenerative disorder. Our findings extend prior neuropathologic reports of Wolfram syndrome by providing contributions to our understanding of eye, inner ear and olivopontine pathology in this disease. C1 [Hilson, Justin B.] Harvard Univ, Dept Pathol, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Merchant, Saumil N.; Adams, Joe C.] Harvard Univ, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02215 USA. [Joseph, Jeffrey T.] Univ Calgary, Dept Pathol, Calgary, AB, Canada. RP Hilson, JB (reprint author), Harvard Univ, Dept Pathol, Beth Israel Deaconess Med Ctr, Sch Med, 330 Brookline Ave, Boston, MA 02215 USA. EM jhilson@bidmc.harvard.edu FU NIH [U24 DC 008559] FX The authors would like to express their sincere thanks to the patient's family for allowing us to conduct this study. We especially would like to thank the patient's mother who has been of invaluable assistance in providing pertinent medical records and overall inspiration. Supported by NIH (U24 DC 008559), Mr. Lakshmi Mittal and Mr. Axel Eliasen. NR 32 TC 22 Z9 24 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD SEP PY 2009 VL 118 IS 3 BP 415 EP 428 DI 10.1007/s00401-009-0546-8 PG 14 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 476ER UT WOS:000268421800010 PM 19449020 ER PT J AU Goebel, HH Jaynes, M Gutmann, L Schochet, S Sleat, DE Sims, KB AF Goebel, H. H. Jaynes, M. Gutmann, L. Schochet, S. Sleat, D. E. Sims, K. B. TI Adult neuronal ceroid-lipofuscinosis - the genetic spectrum is enlarging SO ACTA NEUROPATHOLOGICA LA English DT Meeting Abstract CT 54th Annual Meeting of the German-Society-of-Neuropathology-and-Neuroanatomy CY SEP 16-19, 2009 CL Dusseldorf, GERMANY SP German Soc Neuropathol & Neuroanat C1 [Goebel, H. H.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Neuropathol, D-55131 Mainz, Germany. [Jaynes, M.; Gutmann, L.] W Virginia Univ, Dept Neurol, Morgantown, WV 26506 USA. [Schochet, S.] W Virginia Univ, Dept Pathol, Morgantown, WV 26506 USA. [Sleat, D. E.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, Piscataway, NJ 08854 USA. [Sims, K. B.] Massachusetts Gen Hosp, Dept Mol Neurogenet, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD SEP PY 2009 VL 118 IS 3 BP 441 EP 441 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 476ER UT WOS:000268421800042 ER PT J AU Ryden, E Thase, ME Straht, D Aberg-Wistedt, A Bejerot, S Landen, M AF Ryden, E. Thase, M. E. Straht, D. Aberg-Wistedt, A. Bejerot, S. Landen, M. TI A history of childhood attention-deficit hyperactivity disorder (ADHD) impacts clinical outcome in adult bipolar patients regardless of current ADHD SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE bipolar disorder; attention-deficit disorder; comorbidity; classification; phenotype ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; DEFICIT/HYPERACTIVITY-DISORDER; STEP-BD; DSM-IV; COMORBIDITY; POPULATION; PREVALENCE; RATIONALE; CHILDREN; RECALL AB Objective: The occurrence of comorbid attention-deficit hyperactivity disorder (ADHD) might have an impact of the course of the bipolar disorder. Method: Patients with bipolar disorder (n = 159) underwent a comprehensive evaluation with respect to affective symptoms. Independent psychiatrists assessed childhood and current ADHD, and an interview with a parent was undertaken. Results: The prevalence of adult ADHD was 16%. An additional 12% met the criteria for childhood ADHD without meeting criteria for adult ADHD. Both these groups had significantly earlier onset of their first affective episode, more frequent affective episodes (except manic episodes), and more interpersonal violence than the bipolar patients without a history of ADHD. Conclusion: The fact that bipolar patients with a history of childhood ADHD have a different clinical outcome than the pure bipolar group, regardless of whether the ADHD symptoms remained in adulthood or not, suggests that it represent a distinct early-onset phenotype of bipolar disorder. C1 [Landen, M.] Karolinska Inst, Dept Clin Neurosci, Sect Psychiat, SE-11281 Stockholm, Sweden. [Thase, M. E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Thase, M. E.] Vet Affairs Med Ctr, Philadelphia, PA USA. RP Landen, M (reprint author), Karolinska Inst, Dept Clin Neurosci, Sect Psychiat, SE-11281 Stockholm, Sweden. EM mikael.landen@ki.se OI Bejerot, Susanne/0000-0002-3587-6075 FU Stockholm County Council; Karolinska Institutet; Swedish Medical Research Council [K2008-62x-14647-06-3]; S:t Goran foundation; Soderstrom-Konigska Foundation; Thuring Foundation; Swedish Psychiatry foundation; Swedish Society for Medical Research FX The authors would like to thank study coordinator Martina Wennberg for skilful assistance, and Dr Caroline Nilsson for the assessment of bipolar patients. Financial support was provided through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institutet; and through grants from the Swedish Medical Research Council (K2008-62x-14647-06-3), the S:t Goran foundation, the Soderstrom-Konigska Foundation, the Thuring Foundation, the Swedish Psychiatry foundation, the Swedish Society for Medical Research, and the Karolinska Institutet. NR 22 TC 57 Z9 57 U1 4 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD SEP PY 2009 VL 120 IS 3 BP 239 EP 246 DI 10.1111/j.1600-0447.2009.01399.x PG 8 WC Psychiatry SC Psychiatry GA 479TG UT WOS:000268683200010 PM 19426162 ER PT J AU Bongiovanni, M Sadow, PM Faquin, WC AF Bongiovanni, Massimo Sadow, Peter M. Faquin, William C. TI Poorly Differentiated Thyroid Carcinoma A Cytologic-histologic Review SO ADVANCES IN ANATOMIC PATHOLOGY LA English DT Review DE thyroid; poorly differentiated carcinoma; FNAB; diagnosis ID FINE-NEEDLE-ASPIRATION; AGGRESSIVE TUMOR PHENOTYPES; INSULAR CARCINOMA; PROGNOSTIC-SIGNIFICANCE; FOLLICULAR CARCINOMAS; INTACT INSULAE; BRAF MUTATIONS; PAPILLARY; FEATURES; EXPRESSION AB The term poorly differentiated thyroid carcinoma (PDTC) was first proposed in the 1980s, but it was not definitively recognized as a distinct pathologic entity until the most recent classification of endocrine tumors by the World Health Organization in 2004. More recently, as a result of discussions in Turin, Italy, in 2006, diagnostic criteria were made more specific by a consensus of expert thyroid pathologists. The histologic and cytologic aspects are detailed with particular attention to key features helpful in the diagnosis of PDTC, both in surgical pathology and in cytology-based studies. Histologically, insular, solid, and/or trabecular architecture, along with at least one of the following: convoluted nuclei, mitotic activity (>3/10 HPF), or tumor necrosis, are required for a diagnosis of PDTC. Cytologically, the combination of insular, solid, or trabecular cytoarchitectural pattern, single cells, high nuclear to cytoplasmic (N/C) ratio, and severe crowding are highly suggestive of PDTC. Most PDTCs are immunohistochemically positive for thyroglobulin and thyroid transcription factor 1 (TTF-1), and a subset is also positive for p53. On the molecular level, ras mutations are the most common finding. PDTCs are managed aggressively by total thyroidectomy, (131)I, and in some cases, external beam radiotherapy. C1 [Sadow, Peter M.; Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bongiovanni, Massimo] Hop Univ Geneva, Pathol Clin, Geneva, Switzerland. RP Faquin, WC (reprint author), Massachusetts Gen Hosp, Dept Pathol, WRN 219,55 Fruit St, Boston, MA 02114 USA. EM WFaquin@Partners.org RI Bongiovanni, Massimo/C-3144-2017 OI Bongiovanni, Massimo/0000-0001-9846-6682 NR 66 TC 17 Z9 21 U1 0 U2 3 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 SEP PY 2009 VL 16 IS 5 BP 283 EP 289 PG 7 WC Pathology SC Pathology GA 488TY UT WOS:000269374200002 PM 19700938 ER PT J AU Singh, H Weingart, SN AF Singh, Hardeep Weingart, Saul N. TI Diagnostic errors in ambulatory care: dimensions and preventive strategies SO ADVANCES IN HEALTH SCIENCES EDUCATION LA English DT Article DE Diagnostic error; Ambulatory care; Primary care; Diagnostic tests; Electronic communication; Patient behaviors; Patient follow-up ID MALPRACTICE CLAIMS; ADVERSE EVENTS; CANCER; COMMUNICATION; MEDICINE; SYSTEM AB Despite an increasing focus on patient safety in ambulatory care, progress in understanding and reducing diagnostic errors in this setting lag behind many other safety concerns such as medication errors. To explore the extent and nature of diagnostic errors in ambulatory care, we identified five dimensions of ambulatory care from which errors may arise: ( 1) the provider-patient encounter, ( 2) performance and interpretation of diagnostic tests, ( 3) follow-up of patients and diagnostic test results, ( 4) subspecialty consultation, and ( 5) patients seeking care and adhering to their instruction/appointments, i.e. patient behaviors. We presented these risk domains to conference participants to elicit their views about sources of and solutions to diagnostic errors in ambulatory care. In this paper, we present a summary of discussion in each of these risk domains. Many novel themes and hypotheses for future research and interventions emerged. C1 [Singh, Hardeep] Michael E DeBakey Vet Affairs Med Ctr 152, Houston VA HSR&D Ctr Excellence, Ctr Inquiry Improve Outpatient Safety Effect Elec, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Weingart, Saul N.] Dana Farber Canc Inst, Ctr Patient Safety, Boston, MA 02115 USA. [Weingart, Saul N.] Harvard Univ, Sch Med, Boston, MA USA. RP Singh, H (reprint author), Michael E DeBakey Vet Affairs Med Ctr 152, Houston VA HSR&D Ctr Excellence, Ctr Inquiry Improve Outpatient Safety Effect Elec, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.tmc.edu FU Houston VA HSR&D Center of Excellence [HFP90-020] FX Dr. Singh is supported in part by the Houston VA HSR&D Center of Excellence (HFP90-020). NR 17 TC 16 Z9 16 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1382-4996 J9 ADV HEALTH SCI EDUC JI Adv. Health Sci. Educ. PD SEP PY 2009 VL 14 BP 57 EP 61 DI 10.1007/s10459-009-9177-z PG 5 WC Education & Educational Research; Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 506ZQ UT WOS:000270819000007 PM 19669923 ER PT J AU Palacios, OM Carmona, JJ Michan, S Chen, KY Manabe, Y Ward, JL Goodyear, LJ Tong, Q AF Palacios, Orsolya M. Carmona, Juan J. Michan, Shaday Chen, Ke Yun Manabe, Yasuko Ward, Jack Lee, III Goodyear, Laurie J. Tong, Qiang TI Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1 alpha in skeletal muscle SO AGING-US LA English DT Article DE SIRT3; AMPK; PGC-1 alpha; caloric restriction; skeletal muscle; exercise; high-fat diet ID PROTEIN-KINASE; CALORIE RESTRICTION; MITOCHONDRIAL BIOGENESIS; DEPENDENT DEACETYLASE; LYSINE ACETYLATION; COACTIVATOR PGC-1; GENE-EXPRESSION; MOUSE SIRT3; C-ELEGANS; SIRTUINS AB SIRT3 is a member of the sirtuin family of NAD(+)-dependent deacetylases, which is localized to the mitochondria and is enriched in kidney, brown adipose tissue, heart, and other metabolically active tissues. We report here that SIRT3 responds dynamically to both exercise and nutritional signals in skeletal muscle to coordinate downstream molecular responses. We show that exercise training increases SIRT3 expression as well as associated CREB phosphorylation and PGC-1 alpha up-regulation. Furthermore, we show that SIRT3 is more highly expressed in slow oxidative type I soleus muscle-compared to fast type II extensor digitorum longus or gastrocnemius muscles. Additionally, we find that SIRT3 protein-levels in skeletal muscle are sensitive to diet, for SIRT3 expression increases by fasting and caloric restriction, yet it is decreased by high-fat diet. Interestingly, the caloric restriction regimen also leads to phospho-activation of AMPK in muscle. Conversely in SIRT3 knockout mice, we find that the phosphorylation of both AMPK and CREB and the expression of PGC-1 alpha are down regulated, suggesting that these key cellular factors may be important components of SIRT3-mediated biological signals in vivo. C1 [Palacios, Orsolya M.; Chen, Ke Yun; Ward, Jack Lee, III; Tong, Qiang] Baylor Coll Med, Childrens Nutr Res Ctr, USDA ARS, Dept Pediat, Houston, TX 77030 USA. [Carmona, Juan J.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Carmona, Juan J.; Michan, Shaday] Harvard Univ, Sch Med, Paul F Glenn Labs Biol Mech Aging, Dept Pathol, Boston, MA 02115 USA. [Carmona, Juan J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Carmona, Juan J.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Manabe, Yasuko; Goodyear, Laurie J.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Manabe, Yasuko; Goodyear, Laurie J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Tong, Q (reprint author), Baylor Coll Med, Childrens Nutr Res Ctr, USDA ARS, Dept Pediat, 1100 Bates St, Houston, TX 77030 USA. EM qtong@bcm.edu FU National Institutes of Health (NIH) [T32 HD007445]; Howard Hughes Medical Institute Predoctoral Fellowship; NIH [RO1DK068626, RO1DK075978]; U. S. Department of Agriculture [CRIS 6250-51000-049] FX We thank Dr. E. O'Brian Smith for assistance with statistical analysis, Dr. Martin Young for valuable discussions/suggestions, and Margaret Nguyen for technical assistance. O.M.P. was supported by a National Institutes of Health (NIH) training grant (T32 HD007445) and J.J.C. by a Howard Hughes Medical Institute Predoctoral Fellowship. L.J.G. received support from a NIH grant (RO1DK068626). This work was also supported by grants to Q. T. from the U. S. Department of Agriculture (CRIS 6250-51000-049) and the NIH (RO1DK075978). NR 64 TC 197 Z9 207 U1 2 U2 20 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD SEP PY 2009 VL 1 IS 9 BP 771 EP 783 PG 13 WC Cell Biology SC Cell Biology GA 579UU UT WOS:000276402400005 PM 20157566 ER PT J AU Stewart, SH Reuben, A Brzezinski, WA Koch, DG Basile, J Randall, PK Miller, PM AF Stewart, Scott H. Reuben, Adrian Brzezinski, Walter A. Koch, David G. Basile, Jan Randall, Patrick K. Miller, Peter M. TI Preliminary Evaluation of Phosphatidylethanol and Alcohol Consumption in Patients with Liver Disease and Hypertension SO ALCOHOL AND ALCOHOLISM LA English DT Article ID CARBOHYDRATE-DEFICIENT TRANSFERRIN; PHOSPHOLIPASE-D; HEAVY DRINKING; IN-VITRO; BLOOD; BIOMARKER; MARKER; MALES; MODEL AB Aims: The goal of this preliminary study was to evaluate the relationship between blood phosphatidylethanol (PEth) and recent drinking in patients with liver disease and hypertension. Methods: Twenty-one patients with liver disease and 21 patients with essential hypertension were recruited at an academic medical center. Alcohol consumption was estimated using validated self-report methods, and blood PEth was measured by HPLC-MS/MS at a contracted laboratory. Nonparametric comparisons were made between abstainers/light drinkers, moderate drinkers consuming between 1 and 3 drinks per day, and those drinking above this level. Regression methods were used to estimate the effects of liver disease, gender, and age on the relationship between PEth and alcohol use, and to estimate the strength of the linear relationship between PEth and drinking. Results: PEth differed significantly between the three drinking groups (P < 0.001). The relationship between PEth and alcohol did not differ between hypertension and liver disease patients (P = 0.696), nor by gender and age. While there was substantial variability between subjects in the PEth concentration given a similar level of reported drinking, the amount of ethanol consumed was strongly associated with the PEth concentration (P < 0.001). Conclusion: Results support PEth measurement by HPLC-MS/MS as a promising marker of past 1- to 2-week moderate to heavy alcohol consumption in patients with and without liver disease. PEth appears useful for differentiating abstinence or light drinking from moderate to heavy consumption, but may have limited utility for differentiating moderate from heavy alcohol use. C1 [Stewart, Scott H.; Randall, Patrick K.; Miller, Peter M.] Med Univ S Carolina, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. [Stewart, Scott H.; Brzezinski, Walter A.] Med Univ S Carolina, Div Gen Internal Med, Charleston, SC 29425 USA. [Reuben, Adrian; Koch, David G.] Med Univ S Carolina, Liver Dis & Liver Transplant Serv, Charleston, SC 29425 USA. [Basile, Jan] Ralph H Johnson VA Med Ctr, Dept Med, Charleston, SC 29425 USA. RP Stewart, SH (reprint author), Med Univ S Carolina, Ctr Drug & Alcohol Programs, POB 250861,67 President St, Charleston, SC 29425 USA. EM stewarsh@musc.edu FU National Institute on Alcohol Abuse and Alcoholism [K23AA014188] FX This work was supported by a Career Development Award from the National Institute on Alcohol Abuse and Alcoholism (K23AA014188). NR 23 TC 33 Z9 33 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP-OCT PY 2009 VL 44 IS 5 BP 464 EP 467 DI 10.1093/alcalc/agp039 PG 4 WC Substance Abuse SC Substance Abuse GA 491UZ UT WOS:000269607200005 PM 19535495 ER PT J AU Myrick, H Malcolm, R Randall, PK Boyle, E Anton, RF Becker, HC Randall, CL AF Myrick, Hugh Malcolm, Robert Randall, Patrick K. Boyle, Elizabeth Anton, Raymond F. Becker, Howard C. Randall, Carrie L. TI A Double-Blind Trial of Gabapentin Versus Lorazepam in the Treatment of Alcohol Withdrawal SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Gabapentin; Alcohol Dependence; Alcohol Withdrawal; Lorazepam ID DRINKERS; BRAIN; ABUSE; ANTICONVULSANT; METAANALYSIS; MECHANISMS; DEPENDENCE; DRINKING; PLACEBO; SCALE AB Introduction: Some anticonvulsants ameliorate signs and symptoms of alcohol withdrawal, but have an unacceptable side effect burden. Among the advantages of using anticonvulsant agents in this capacity is their purported lack of interaction with alcohol that could increase psychomotor deficits, increase cognitive impairment, or increase intoxication. The aim of this study was to evaluate alcohol use and symptom reduction of gabapentin when compared with lorazepam in the treatment of alcohol withdrawal in a double-blinded randomized clinical trial. Methods: One hundred individuals seeking outpatient treatment of alcohol withdrawal with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) ratings >= 10 were randomized to double-blind treatment with 2 doses of gabapentin (900 mg tapering to 600 mg or 1200 tapering to 800 mg) or lorazepam (6 mg tapering to 4 mg) for 4 days. Severity of alcohol withdrawal was measured by the CIWA-Ar on days 1 to 4 of treatment and on days 5, 7, and 12 post-treatment and alcohol use monitored by verbal report and breath alcohol levels. Results: CIWA-Ar scores decreased over time in all groups; high-dose gabapentin was statistically superior but clinically similar to lorazepam (p = 0.009). During treatment, lorazepam-treated participants had higher probabilities of drinking on the first day of dose decrease (day 2) and the second day off medication (day 6) compared to gabapentin-treated participants (p = 0.0002). Post-treatment, gabapentin-treated participants had less probability of drinking during the follow-up post-treatment period (p = 0.2 for 900 mg and p = 0.3 for 1200 mg) compared to the lorazepam-treated participants (p = 0.55). The gabapentin groups also had less craving, anxiety, and sedation compared to lorazepam. Conclusions: Gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal in our population especially at the higher target dose (1200 mg) used in this study. Gabapentin reduced the probability of drinking during alcohol withdrawal and in the immediate postwithdrawal week compared to lorazepam. C1 [Myrick, Hugh] Med Univ S Carolina, Inst Psychiat 4N, Dept Psychiat & Behav Sci, Alcohol Res Ctr, Charleston, SC 29425 USA. [Myrick, Hugh; Becker, Howard C.] Vet Affairs Med Ctr, Ralph H Johnson Dept, Charleston, SC 29403 USA. RP Myrick, H (reprint author), Med Univ S Carolina, Inst Psychiat 4N, Dept Psychiat & Behav Sci, Alcohol Res Ctr, 67 President St, Charleston, SC 29425 USA. EM myrickh@musc.edu FU NIAAA [AA10761, AA00314]; VA Medical Research FX This work was supported by NIAAA grants AA10761 and AA00314 and VA Medical Research. NR 40 TC 44 Z9 45 U1 2 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD SEP PY 2009 VL 33 IS 9 BP 1582 EP 1588 DI 10.1111/j.1530-0277.2009.00986.x PG 7 WC Substance Abuse SC Substance Abuse GA 486EW UT WOS:000269179700011 PM 19485969 ER PT J AU Mehta, KM Stewart, AL Langa, KM Yaffe, K Moody-Ayers, S Williams, BA Covinsky, KE AF Mehta, Kala M. Stewart, Anita L. Langa, Kenneth M. Yaffe, Kristine Moody-Ayers, Sandra Williams, Brie A. Covinsky, Kenneth E. TI "Below average" self-assessed school performance and Alzheimer's disease in the Aging, Demographics, and Memory Study SO ALZHEIMERS & DEMENTIA LA English DT Article DE Alzheimer's disease; Education; Cognition; Race; Ethnicity ID COGNITIVE IMPAIRMENT; AFRICAN-AMERICANS; COMMUNITY RESIDENTS; UNITED-STATES; RISK-FACTORS; EDUCATION; DEMENTIA; HEALTH; SCORES; PREVALENCE AB Background: A low level of formal education is becoming accepted as a risk factor for Alzheimer's disease (AD). Although increasing attention has been paid to differences in educational quality, no previous studies addressed participants' own characterizations of their overall performance in school. We examined whether self-assessed school performance is associated with AD beyond the effects of educational level alone. Methods: Participants were drawn from the population-representative Aging, Demographics, and Memory Study (ADAMS, 2000-2002). The ADAMS participants were asked about their performance in school. Possible response options included "above average," "average," or "below average." The ADAMS participants also underwent a full neuropsychological battery, and received a research diagnosis of possible or probable AD. Results: The 725 participants (mean age, 81.8 years, 59% female; 16% African-American) varied in self-assessed educational performance: 29% reported "above average," 64% reported "average," and 7% reported "below average" school performance. Participants with a lower self-assessed school performance had higher proportions of AD: 11% of participants with "above average" self-assessed performance had AD, as opposed to 12% of participants with "average" performance and 26% of participants with "below average" performance (P < 0.001). After controlling for subjects' years in school, a literacy test score (Wide-Range Achievement Test), age, sex, race/ethnicity, apolipoprotein E-epsilon 4 status, socioeconomic status, and self-reported comorbidities, respondents with "below average" self-assessed school performance were four times more likely to have AD compared with those of "average" performance (odds ratio, 4.0; 95% confidence interval, 1.2-14). "Above average" and "average" self-assessed school performance did not increase or decrease the odds of having AD (odds ratio, 0.9; 95% confidence interval, 0.5-1.7). Conclusions: We suggest an association between "below average" self-assessed school performance and AD beyond the known association with formal education. Efforts to increase cognitive reserve through better school performance, in addition to increasing the number of years of formal education in early life, may be important in reducing vulnerability throughout the life course. (C) 2009 The Alzheimer's Association. All rights reserved. C1 [Mehta, Kala M.; Moody-Ayers, Sandra; Williams, Brie A.; Covinsky, Kenneth E.] Univ Calif San Francisco, Div Geriatr Med, San Francisco, CA 94143 USA. [Mehta, Kala M.; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Mehta, Kala M.; Stewart, Anita L.] Univ Calif San Francisco, Med Effectiveness Res Ctr Diverse Populat, San Francisco, CA 94143 USA. [Stewart, Anita L.] Univ Calif San Francisco, Inst Hlth & Aging, San Francisco, CA 94143 USA. [Langa, Kenneth M.] Univ Michigan, Dept Med, Div Gen Med, Ann Arbor, MI 48109 USA. [Langa, Kenneth M.] Univ Michigan, Inst Social Res, Ann Arbor, MI 48109 USA. [Langa, Kenneth M.] Vet Affairs Ctr Practice Management & Outcomes Re, Ann Arbor, MI USA. [Yaffe, Kristine; Moody-Ayers, Sandra; Williams, Brie A.; Covinsky, Kenneth E.] Univ Calif San Francisco, Dept Neurol, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine; Moody-Ayers, Sandra; Williams, Brie A.; Covinsky, Kenneth E.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. RP Mehta, KM (reprint author), Univ Calif San Francisco, Div Geriatr Med, San Francisco, CA 94143 USA. EM Kala.Mehta@ucsf.edu FU National Institute on Aging [NIA-K-01AG025444-01A1, K08AG019180, R01-AG027010, NIA-U01AG009740]; National Institute of Nursing Research; National Center for Minority Health and Health Disparities [P30-AG-15272]; Paul Beeson Physician Faculty Scholars FX K.M.M. is supported by Research Career Scientist Award NIA-K-01AG025444-01A1 from the National Institute on Aging, and is affiliated with the Center for Aging in Diverse Communities at the University of California at San Francisco, part of the Resource Centers for Minority Aging Research Program (funded by the National Institute on Aging, the National Institute of Nursing Research, and the National Center for Minority Health and Health Disparities) (Grant # P30-AG-15272). K.M.L. was supported by grants K08AG019180 and R01-AG027010 from the National Institute on Aging and by a Paul Beeson Physician Faculty Scholars in Aging Research Award. The Health and Retirement Study is sponsored by grant NIA-U01AG009740 from the National Institute of Aging, and is conducted by the University of Michigan. The Aging, Demographics, and Memory Study was sponsored by grant U01-AG009740 from the National Institute of Aging. This work was presented as an oral presentation at the Annual Meeting of the Gerontology Society of America in 2007 (San Francisco, CA). NR 39 TC 7 Z9 7 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD SEP PY 2009 VL 5 IS 5 BP 380 EP 387 DI 10.1016/j.jalz.2009.07.039 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 503ZL UT WOS:000270581400003 PM 19751917 ER PT J AU Harrington, RA Van de Werf, F Armstrong, PW Aylward, P Veltri, E Mahaffey, KW Moliterno, DJ Strony, J Wallentin, L White, HD Diaz, R Huber, K Nicolau, JC Prieto, JC Isaza, D Widimsky, P Grande, P Nieminen, M Montalescot, G Bode, C Wong, L Ofner, P Lewis, BS Ambrosio, G Valgimigli, M Ogawa, H Yamaguchi, J Jukema, JW Cornel, JH Nordrehaug, JE Ruzyllo, W Providencia, L Tan, HC Dalby, A Seung-Jung, P Betriu, A Cequier, A Held, C Pfisterer, M Ming-Fong, C Timurkaynak, T Storey, RF Chen, E Hudson, MP Lincoff, AM Morrow, DA Tricoci, P Whellan, D AF Harrington, Robert A. Van de Werf, Frans Armstrong, Paul W. Aylward, Phil Veltri, Enrico Mahaffey, Kenneth W. Moliterno, David J. Strony, John Wallentin, Lars White, Harvey D. Diaz, Rafael Huber, Kurt Nicolau, Jose Carlos Carlos Prieto, Juan Isaza, Daniel Widimsky, Petr Grande, Peer Nieminen, Markku Montalescot, Gilles Bode, Christoph Wong, Lawrence Ofner, Peter Lewis, Basil S. Ambrosio, Giuseppe Valgimigli, Marco Ogawa, Hisao Yamaguchi, Jun-ichi Jukema, J. Wouter Cornel, Jan H. Nordrehaug, Jan Erik Ruzyllo, Witold Providencia, Luis Tan, Huay-Cheem Dalby, Anthony Seung-Jung, Park Betriu, Amadeo Cequier, Angel Held, Claes Pfisterer, Mathias Ming-Fong, Chen Timurkaynak, Timur Storey, Robert F. Chen, Edmond Hudson, Michael P. Lincoff, A. Michael Morrow, David A. Tricoci, Pierluigi Whellan, David CA TRA CER Executive Comm Steering Comm TI The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale SO AMERICAN HEART JOURNAL LA English DT Article ID ST-SEGMENT ELEVATION; HIGH-RISK PATIENTS; PROTEASE-ACTIVATED RECEPTOR-1; MYOCARDIAL-INFARCTION; UNFRACTIONATED HEPARIN; ANTIPLATELET THERAPY; RANDOMIZED-TRIAL; CLOPIDOGREL; OUTCOMES; ASPIRIN AB Background The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA.CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. Trial design TRA.CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least I year. The TRA.CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. Conclusion TRA.CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies. (Am Heart J 2009; 158:327-34.) C1 [Harrington, Robert A.; Mahaffey, Kenneth W.; Tricoci, Pierluigi] Duke Clin Res Inst, Durham, NC 27705 USA. [Van de Werf, Frans] Katholieke Univ Leuven, Dept Cardiol, Louvain, Belgium. [Armstrong, Paul W.] Univ Alberta, Div Cardiol, Edmonton, AB, Canada. [Aylward, Phil] Flinders Med Ctr, Dept Cardiovasc Med, Bedford Pk, SA, Australia. [Veltri, Enrico; Strony, John; Chen, Edmond] Schering Plough Corp, Res Inst, Kenilworth, NJ 07033 USA. [Moliterno, David J.] Univ Kentucky, Gill Heart Inst, Lexington, KY USA. [Moliterno, David J.] Univ Kentucky, Div Cardiovasc Med, Lexington, KY USA. [Wallentin, Lars; Held, Claes] Uppsala Clin Res Ctr, Uppsala, Sweden. [White, Harvey D.] Green Lane Cardiovasc Serv, Auckland, New Zealand. [Diaz, Rafael] Inst Cardiovasc Rosario, Rosario, Argentina. [Huber, Kurt] Wilhelminenspital Stadt Wien, Vienna, Austria. [Nicolau, Jose Carlos] Univ Sao Paulo, Sch Med, Heart Inst InCor, BR-05508 Sao Paulo, Brazil. [Carlos Prieto, Juan] Hosp Jose Joaquin Aguirre, Santiago, Chile. [Isaza, Daniel] Fdn Clin Shaio, Bogota, Colombia. [Widimsky, Petr] Univ Hosp Vinohrady, Cardioctr, Prague, Czech Republic. [Grande, Peer] Univ Copenhagen Hosp, Ctr Heart, DK-2100 Copenhagen, Denmark. [Nieminen, Markku] Helsinki Univ Cent Hosp, Div Cardiol, Helsinki, Finland. [Montalescot, Gilles] CHU Pitie Salpetriere, Dept Cardiol, Paris, France. [Bode, Christoph] Univ Freiburg Klinikum, Freiburg, Germany. [Wong, Lawrence] Chinese Univ Hong Kong, Div Neurol, Hong Kong, Hong Kong, Peoples R China. [Ofner, Peter] Natl Inst Cardiol, Budapest, Hungary. [Lewis, Basil S.] Heart Hosp, Lady Davis Carmel Med Ctr, Dept Cardiovasc Med, Haifa, Israel. Univ Perugia, Sch Med, Div Cardiol, I-06100 Perugia, Italy. [Valgimigli, Marco] Azienda Osped Univ Ferrara, Cattedra Cardiol, Ferrara, Italy. [Ogawa, Hisao] Kumamoto Univ, Grad Sch Med Sci, Dept Cardiovasc Med, Kumamoto, Japan. [Yamaguchi, Jun-ichi] Tokyo Womens Med Univ, Heart Inst Japan, Dept Cardiol, Tokyo, Japan. [Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Cornel, Jan H.] Med Ctr Alkmaar, Dept Cardiol, Alkmaar, Netherlands. [Nordrehaug, Jan Erik] Univ Bergen, Bergen, Norway. [Ruzyllo, Witold] Natl Inst Cardiol, Warsaw, Poland. [Providencia, Luis] Hosp Univ Coimbra, Div Cardiol, Coimbra, Portugal. [Tan, Huay-Cheem] Natl Univ Singapore Hosp, Dept Cardiol, Singapore 117548, Singapore. [Dalby, Anthony] Univ Witwatersrand, Johannesburg, South Africa. [Seung-Jung, Park] Asan Med Ctr, Seoul, South Korea. [Betriu, Amadeo] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Cequier, Angel] Univ Barcelona, Bellvitge Hosp, Div Cardiol, Barcelona, Spain. Univ Basel Hosp, Dept Cardiol, CH-4031 Basel, Switzerland. [Ming-Fong, Chen] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Timurkaynak, Timur] Gazi Univ Hosp, Dept Cardiol, Ankara, Turkey. [Storey, Robert F.] Univ Sheffield, Cardiovasc Res Unit, Sheffield S10 2TN, S Yorkshire, England. [Hudson, Michael P.] Henry Ford Hosp, Henry Ford Heart & Vasc Inst, Detroit, MI 48202 USA. [Lincoff, A. Michael] Cleveland Clin, Coordinating Ctr Clin Res, Cleveland, OH 44106 USA. [Morrow, David A.] TIMI Study Grp, Boston, MA USA. [Whellan, David] Thomas Jefferson Univ, Div Cardiol, Philadelphia, PA 19107 USA. RP Tricoci, P (reprint author), Duke Clin Res Inst, 2400 Pratt St,Room 0311 Terrace Level, Durham, NC 27705 USA. EM trico001@dcri.duke.edu RI Nicolau, Jose/E-1487-2012; Wong, Ka Sing Lawrence/N-3434-2015; Widimsky, Petr/P-8088-2016; OI Wong, Ka Sing Lawrence/0000-0002-2031-9866; Widimsky, Petr/0000-0001-5686-7752; Van de Werf, Frans/0000-0001-9479-7767; Held, Claes/0000-0001-9402-7404 NR 38 TC 55 Z9 56 U1 0 U2 16 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2009 VL 158 IS 3 BP 327 EP U5 DI 10.1016/j.ahj.2009.07.001 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 492FV UT WOS:000269641200002 ER PT J AU Morrow, DA Scirica, BM Fox, KAA Berman, G Strony, J Veltri, E Bonaca, MP Fish, P McCabe, CH Braunwald, E AF Morrow, David A. Scirica, Benjamin M. Fox, Keith A. A. Berman, Gail Strony, John Veltri, Enrico Bonaca, Marc P. Fish, Polly McCabe, Carolyn H. Braunwald, Eugene CA TRA 2 P-TIMI Invest TI Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: Design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE CORONARY SYNDROMES; ST-SEGMENT ELEVATION; MYOCARDIAL-INFARCTION; ANTITHROMBOTIC AGENTS; CLOPIDOGREL; ASPIRIN; THERAPY; STROKE; RISK AB Background Thrombin potently activates platelets via interaction with the protease-activated receptor 1. SCH 530348 is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin via antagonism of the protease-activated receptor 1. Because SCH 530348 does not interfere with other pathways for hemostasis, it is possible that SCH 530348 reduces thrombosis with less increase in bleeding than do other potent antiplatelet agents. Study design TRA 2 degrees P-TIMI 50 is a phase III, randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the efficacy and safety of SCH 530348 during long-term treatment of patients with established atherosclerotic disease receiving standard therapy (up to 27,000). Eligible patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease are randomized 1:1 to SCH 530348 2.5 mg daily or matched placebo until the end of study. Randomization is stratified by the qualifying disease and planned use of a thienopyridine. The primary end point is the composite of cardiovascular death, myocardial infarction, stroke, or urgent coronary revascularization. The major secondary end point is the composite of cardiovascular death, myocardial infarction, or stroke. The evaluation of long-term safety includes bleeding defined by the GUSTO and TIMI criteria. Recruitment began in September 2007. The trial will continue until 2,279 primary end points and 1,400 secondary end points are recorded with expected completion in 36 to 44 months from first enrollment. Conclusions TRA 2 degrees P-TIMI 50 is evaluating whether a new approach to platelet inhibition via interruption of thrombin-mediated platelet activation reduces major cardiovascular events with a favorable safety profile in patients with established atherosclerosis. (Am Heart J 2009;158:335-41.) C1 [Morrow, David A.; Scirica, Benjamin M.; Bonaca, Marc P.; Fish, Polly; McCabe, Carolyn H.; Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Berman, Gail; Strony, John; Veltri, Enrico] Schering Plough Corp, Res Inst, Kenilworth, NJ 07033 USA. RP Morrow, DA (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 NR 19 TC 113 Z9 118 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2009 VL 158 IS 3 BP 335 EP 341 DI 10.1016/j.ahj.2009.06.027 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 492FV UT WOS:000269641200003 PM 19699854 ER PT J AU Wilson, SR Sabatine, MS Braunwald, E Sloan, S Murphy, SA Morrow, DA AF Wilson, Sean R. Sabatine, Marc S. Braunwald, Eugene Sloan, Sarah Murphy, Sabina A. Morrow, David A. TI Detection of myocardial injury in patients with unstable angina using a novel nanoparticle cardiac troponin I assay: Observations from the PROTECT-TIMI 30 Trial SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE CORONARY SYNDROMES; INFARCTION; ELEVATION; ISCHEMIA; STANDARDIZATION; COMMITTEE; OUTCOMES; RISK AB Background At least 30% of patients with non-ST-elevation acute coronary syndrome present without evidence of myonecrosis using current generation troponin assays. A new generation of research assays for troponin that offer a >10-fold increase in analytical sensitivity has emerged. Methods To perform a pilot study to evaluate the clinical sensitivity of a new ultra-sensitive nanoparticle assay for cardiac troponin I (nano-cTnl), we identified 50 patients with unstable angina (serial negative cTnI) and 50 patients with non-ST-elevation myocardial infarction with an initially negative current generation cTnI result. We measured cTnI using an assay (Nanosphere, Northbrook, IL) that can detect pg/mL concentrations of cTnI (detection-limit 0.0002 mu g/L). Results Measured at 0, 2, and 8 hours with the nano-cTnI assay 44%, 62%, and 82% of patients with unstable angina defined by the current-generation assay had an elevated nano-cTnI result (>= 0.003 mu g/L, 99th percentile decision-limit, coefficient of variation <10%). In patients with definite myocardial injury (current-generation cTnI >= 0.1 mu g/L) but an initially negative cTnI, 72% and 98% had a nano-cTnl 0.003 pg/L at 0 and 2 hours. No patient had a positive current-generation cTnI without an elevated nano-cTnl level. Conclusions In this pilot study using a nanoparticle assay for cTnI, myocardial injury was detectable in a substantial proportion of patients presently classified as having unstable angina, suggesting that ischemia with rest pain without injury is rare. The emergence of a new generation of troponin assays has the potential to lead to new clinical applications based on enhanced analytical performance at very low concentrations of troponin. (Am Heart J 2009; 158:386-91.) C1 [Morrow, David A.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Wilson, Sean R.; Sabatine, Marc S.; Braunwald, Eugene; Sloan, Sarah; Murphy, Sabina A.; Morrow, David A.] Dept Med, Boston, MA USA. RP Morrow, DA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org NR 24 TC 56 Z9 58 U1 2 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2009 VL 158 IS 3 BP 386 EP 391 DI 10.1016/j.ahj.2009.06.011 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 492FV UT WOS:000269641200010 PM 19699861 ER PT J AU De Luca, G Gibson, CM Huber, K Zeymer, U Dudek, D Cutlip, D Bellandi, F Noc, M Emre, A Zorman, S Gabriel, HM Maioli, M Rakowski, T Gyongyosi, M van't Hof, AWJ AF De Luca, Giuseppe Gibson, C. Michael Huber, Kurt Zeymer, Uwe Dudek, Dariusz Cutlip, Donald Bellandi, Francesco Noc, Marko Emre, Ayse Zorman, Simona Gabriel, H. Mesquita Maioli, Mauro Rakowski, Tomasz Gyongyosi, Mariann van't Hof, Arnoud W. J. CA EGYPT Cooperation TI Association between advanced Killip class at presentation and impaired myocardial perfusion among patients with ST-segment elevation myocardial infarction treated with primary angioplasty and adjunctive glycoprotein IIb-IIIa inhibitors SO AMERICAN HEART JOURNAL LA English DT Article ID NO-REFLOW PHENOMENON; PERCUTANEOUS CORONARY INTERVENTION; CARDIOGENIC-SHOCK; NATIONAL REGISTRY; HEART-FAILURE; THERAPY; ABCIXIMAB; TRIAL; PEXELIZUMAB; ISCHEMIA AB Background Although primary angioplasty has been shown to improve survival as compared with thrombolysis, the outcome is still unsatisfactory in subsets of patients such as those with signs of heart failure at presentation. In fact, although primary angioplasty is able to restore TIMI 3 flow in most patients, suboptimal myocardial reperfusion is observed in a relatively large proportion of patients. The aim of this study was to investigate among patients with ST-segment elevation myocardial infarction undergoing primary angioplasty the association between heart failure at presentation and myocardial perfusion and its implications in terms of survival. Methods Our population is represented by patients undergoing primary angioplasty who are included in the EGYPT database. Congestive heart failure was defined as Killip class >1 at admission. Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Follow-up data were collected between 30 days and 1 year after primary angioplasty. Results Detailed data on Killip class at presentation were available in 1,427 of 1,662 patients (86% of the initial population) who represent the final population of this study. Killip class was associated with myocardial perfusion, distal embolization, enzymatic infarct size, predischarge ejection fraction, and 1-year mortality rate. Myocardial blush was an independent predictor of 1-year mortality (hazard ratio 7.44, 95% CI 1.82-30.4, P = .005) in patients with advanced Killip class at presentation. Conclusions Our study shows that patients with heart failure complicating ST-segment elevation myocardial infarction have impaired myocardial perfusion, which accounts for the poor outcome observed in these patients. Further efforts should be aimed at improving myocardial perfusion, beyond epicardial recanalization, to further improve the outcome of these high-risk patients. (Am Heart J 2009; 158:416-21.) C1 [De Luca, Giuseppe] Eastern Piedmont Univ, Maggiore della Carita Hosp, Div Cardiol, Novara, Italy. [Gibson, C. Michael] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Huber, Kurt] Wilhelminenspital Stadt Wien, Dept Med Cardiol & Emergency Med 3, Vienna, Austria. [Zeymer, Uwe] Herzzentrum Ludwigshafen, Div Cardiol, Ludwigshafen, Germany. [Dudek, Dariusz; Rakowski, Tomasz] Jagiellonian Univ, Inst Cardiol, Dept Cardiol 2, Krakow, Poland. [Cutlip, Donald] Beth Israel Deaconess Med Ctr, Intervent Cardiol Sect, Boston, MA 02215 USA. [Bellandi, Francesco; Maioli, Mauro] Prato Hosp, Div Cardiol, Prato, Italy. [Noc, Marko; Zorman, Simona] Univ Med Ctr, Ctr Intens Internal Med, Ljubljana, Slovenia. [Emre, Ayse] Siyami Ersek Thorac & Cardiovasc Surg Ctr, Instabul, Turkey. [Gabriel, H. Mesquita] Hosp Santa Maria, Div Cardiol, Lisbon, Portugal. [Gyongyosi, Mariann] Med Univ Vienna, Dept Cardiol, Vienna, Austria. [van't Hof, Arnoud W. J.] Hosp Weezenlanden, Div Cardiol, Zwolle, Netherlands. RP De Luca, G (reprint author), Eastern Piedmont Univ, Maggiore della Carita Hosp, Div Cardiol, Novara, Italy. EM giuseppe.deluca@maggioreosp.novara.it NR 26 TC 10 Z9 10 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2009 VL 158 IS 3 BP 416 EP 421 DI 10.1016/j.ahj.2009.06.029 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 492FV UT WOS:000269641200014 PM 19699865 ER PT J AU Pride, YB Wiviott, SD Buros, JL Zorkun, C Tariq, MU Antman, EM Braunwald, E Gibson, CM AF Pride, Yuri B. Wiviott, Stephen D. Buros, Jacqueline L. Zorkun, Cafer Tariq, M. Umer Antman, Elliott M. Braunwald, Eugene Gibson, C. Michael CA TIMI Study Grp TI Effect of prasugrel versus clopidogrel on outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention without stent implantation: A TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38 Substudy SO AMERICAN HEART JOURNAL LA English DT Article ID ST-SEGMENT ELEVATION; ASPIRIN; ANGIOPLASTY AB Background Prasugrel led to a significant reduction in ischemic cardiovascular events among patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PC]) with stent implantation compared to clopidogrel. Whether this benefit extends to patients undergoing PCI without stent implantation is unknown. Methods In TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38, patients (n = 13 608) undergoing PCI for ACS were randomized to aspirin plus clopidogrel or prasugrel. This postrandomization analysis of a prespecified subgroup was restricted to patients who underwent PCI without stent implantation (n = 569). Results Patients who underwent PCI without stent implantation were older and had a higher incidence of hypertension, diabetes, prior myocardial infarction (MI), prior coronary artery bypass (CABG) surgery, and renal dysfunction than patients who underwent stent implantation. In the group that did not undergo stent implantation, baseline characteristics were similar between patients receiving clopidogrel and prasugrel. The composite of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 14.2% of patients receiving prasugrel and 17.1% of patients receiving clopidogrel (HR 0.82, P = .27). There were significant reductions favoring prasugrel in the rates of urgent target vessel revascularization (TVR; HR 0.46, P = .040) and any TVR (HR 0.40, P = .009) and a trend toward a reduction in the incidence of nonfatal MI (HR 0.65, P = . 11). CABG-related TIMI major bleeding was more frequent among patients receiving prasugrel. There were no significant interactions between treatment and PCI type. Conclusion Among ACS patients who underwent PCI without stent implantation, prasugrel therapy tended to reduce clinical ischemic events and to increase bleeding events to a similar magnitude as among patients who received stents. (Am Heart J 2009; 158:e21-e26.) C1 [Pride, Yuri B.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Wiviott, Stephen D.; Antman, Elliott M.; Braunwald, Eugene] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Buros, Jacqueline L.; Zorkun, Cafer; Tariq, M. Umer; Gibson, C. Michael] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Gibson, CM (reprint author), 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM mgibson@perfuse.org FU Eli Lilly; Daiichi Sankyo FX Dr Wiviott has received consulting fees from Sanofi-Aventis, speaking honoraria from Daiichi Sankyo and Eli Lilly, and research funding from Eli Lilly and Daiichi Sankyo. Dr Antman has received consulting fees from and sat on the advisory board of Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Braunwald has received consulting fees from and sat on the advisory board of Sanofi-Aventis and Daiichi Sankyo; and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Gibson has received research funding from Eli Lilly and Daiichi Sankyo. None of the other authors has any relevant disclosures to report. NR 12 TC 16 Z9 16 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD SEP PY 2009 VL 158 IS 3 BP E21 EP E26 DI 10.1016/j.ahj.2009.06.021 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 492FV UT WOS:000269641200026 PM 19699846 ER PT J AU Michaud, DS Holick, CN Batchelor, TT Giovannucci, E Hunter, DJ AF Michaud, Dominique S. Holick, Crystal N. Batchelor, Tracy T. Giovannucci, Edward Hunter, David J. TI Prospective study of meat intake and dietary nitrates, nitrites, and nitrosamines and risk of adult glioma SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID N-NITROSO COMPOUNDS; FOOD FREQUENCY QUESTIONNAIRE; BRAIN-TUMORS; VOLATILE NITROSAMINES; BLADDER-CANCER; FRIED BACON; VITAMIN-E; FAT; NITROSODIMETHYLAMINE; REPRODUCIBILITY AB Background: The hypothesis that nitrosamine exposure may increase the risk of glioma has been circulating for several decades, but testing it has been difficult because of the ubiquitous nature of nitrosamine exposure. Diet has been the focus of many studies because it can substantially influence nitrosamine exposure, mostly from the endogenous formation of nitrosamines based on intake of nitrite and nitrate. Objective: The objective was to examine the relation between intakes of meats, nitrate, nitrite, and 2 nitrosamines [nitrosodimethylamine (NDMA) and nitrosopyrolidine (NPYR)] and glioma risk in a prospective analysis. Methods: Data from 3 US prospective cohort studies were combined for this analysis; 335 glioma cases were diagnosed during <= 24 y of follow-up. Dietary intake was assessed with food-frequency questionnaires. Nitrate, nitrite, and nitrosamine values were calculated based on published values of these nutrients in various foods over different periods in time. Cox proportional hazards models were used to estimate incidence rate ratios (RRs) and 95% CIs. Estimates from each cohort were pooled by using a random-effects model. Results: Risk of glioma was not elevated among individuals in the highest intake category of total processed meats (RR: 0.92; 95% CI: 0.48, 1.77), nitrate (RR: 1.02; 95% CI: 0.66, 1.58), nitrites (RR: 1.26; 95% CI: 0.89, 1.79), or NDMA (RR: 0.88; 95% CI: 0.57, 1.36) compared with the lowest category. No effect modification was observed by intake of vitamins C or E or other antioxidant measures. Conclusion: We found no suggestion that intake of meat, nitrate, nitrite, or nitrosamines is related to the risk of glioma. Am J Clin Nutr 2009;90:570-7. C1 [Michaud, Dominique S.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, Fac Med, London W2 1PG, England. [Michaud, Dominique S.; Giovannucci, Edward; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Holick, Crystal N.] i3 Drug Safety, Waltham, MA USA. [Batchelor, Tracy T.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Div Neurooncol,Med Sch, Boston, MA 02114 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward; Hunter, David J.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Channing Lab,Med Sch, Boston, MA 02115 USA. RP Michaud, DS (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, Fac Med, UG 43,St Marys Campus,Norfolk Pl, London W2 1PG, England. EM d.michaud@imperial.ac.uk RI Michaud, Dominique/I-5231-2014 FU National Cancer Institute [CA110948]; National Institutes of Health; Department of Health and Human Services. FX Supported by grant CA110948 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 67 TC 20 Z9 20 U1 0 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP 1 PY 2009 VL 90 IS 3 BP 570 EP 577 DI 10.3945/ajcn.2008.27199 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 487FW UT WOS:000269257300018 PM 19587083 ER PT J AU Worthley, DL Le Leu, RK Whitehall, VL Conlon, M Christophersen, C Belobrajdic, D Mallitt, KA Hu, Y Irahara, N Ogino, S Leggett, BA Young, GP AF Worthley, Daniel L. Le Leu, Richard K. Whitehall, Vicki L. Conlon, Michael Christophersen, Claus Belobrajdic, Damien Mallitt, Kylie-Ann Hu, Ying Irahara, Natsumi Ogino, Shuji Leggett, Barbara A. Young, Graeme P. TI A human, double-blind, placebo-controlled, crossover trial of prebiotic, probiotic, and synbiotic supplementation: effects on luminal, inflammatory, epigenetic, and epithelial biomarkers of colorectal cancer SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CHAIN FATTY-ACIDS; ISLAND METHYLATOR PHENOTYPE; GENOTOXIN-INDUCED APOPTOSIS; DIETARY RESISTANT STARCH; COLON-CANCER; MICROSATELLITE INSTABILITY; NONSTARCH POLYSACCHARIDES; BIFIDOBACTERIUM-LACTIS; HISTONE ACETYLATION; MAIZE STARCH AB Background: Diet is an important factor in colorectal carcinogenesis; thus, dietary supplements may have a role in colorectal cancer prevention. Objective: The objective was to establish the relative luminal, epithelial, and epigenetic consequences of prebiotic, probiotic, and synbiotic dietary supplementation in humans. Design: This was a randomized, double-blind, placebo-controlled, 4-wk crossover trial of resistant starch and Bifidobacterium lactis, either alone or as a combined synbiotic preparation, in 20 human volunteers. Rectal biopsy, feces, and serum samples were collected. The rectal mucosal endpoints were DNA methylation at 16 CpG island loci and LINE-1, epithelial proliferation (Ki67 immunohistochemistry), and crypt cellularity. The fecal endpoints were short-chain fatty acid concentrations, pH, ammonia, and microbiological profiles (by denaturing gradient gel electrophoresis and sequencing). Serum endpoints were a panel of cytokines and high-sensitivity C-reactive protein. Results: Seventeen subjects completed the entire study. The synbiotic intervention fostered a significantly different fecal stream bacterial community than did either the prebiotic (P = 0.032) or the probiotic (P = 0.001) intervention alone, in part because of a greater proportion of patients harboring fecal Lachnospiraceae spp. These changes developed in the absence of any significant differences in fecal chemistry. There were no differences in epithelial kinetics. Conclusions: This synbiotic supplementation with B. lactis and resistant starch, in the doses used, induced unique changes in fecal microflora but did not significantly alter any other fecal, serum, or epithelial variables. This trial was registered in the Australian New Zealand Clinical Trials Registry at www.anzctr.org.au as ACTRN012606000115538. Am J Clin Nutr 2009;90:578-86. C1 [Worthley, Daniel L.; Whitehall, Vicki L.; Leggett, Barbara A.] Royal Brisbane & Womens Hosp Res Fdn, Clin Res Ctr, Brisbane, Qld, Australia. [Worthley, Daniel L.; Whitehall, Vicki L.; Leggett, Barbara A.] Queensland Inst Med Res, Conjoint Gastroenterol Lab, Brisbane, Qld 4006, Australia. [Worthley, Daniel L.; Le Leu, Richard K.; Hu, Ying; Young, Graeme P.] Flinders Univ S Australia, Flinders Ctr Canc Prevent & Control, Adelaide, SA, Australia. [Le Leu, Richard K.; Conlon, Michael; Christophersen, Claus] CSIRO, Preventat Hlth Natl Res Flagship, Adelaide, SA, Australia. [Mallitt, Kylie-Ann] Queensland Inst Med Res, Stat Unit, Brisbane, Qld 4006, Australia. [Irahara, Natsumi; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Worthley, DL (reprint author), Bancroft Ctr, Queensland Inst Med Res, Room H07,PO RBH, Herston, Qld 4029, Australia. EM daniel.worthley@uqconnect.edu.au RI Christophersen, Claus T/C-5512-2008; Belobrajdic, Damien/B-5741-2011; Leggett, Barbara/D-3579-2011; Mallitt, Kylie-Ann/E-2240-2011; Conlon, Michael/H-6769-2013; Whitehall, Vicki/B-6262-2013; Le Leu, Richard/H-4555-2013 OI Christophersen, Claus T/0000-0003-1591-5871; Belobrajdic, Damien/0000-0002-5801-8663; Mallitt, Kylie-Ann/0000-0002-5722-7287; Whitehall, Vicki/0000-0002-8285-2391; Le Leu, Richard/0000-0003-4704-4943 FU National Starch Food Innovation; Gastroenterological Society of Australia postgraduate medical scholarship; Royal Australasian College of Physicians Cottrell Fellowship; Queensland State Government; Smart State PhD award FX Supported by the National Starch Food Innovation, the Gastroenterological Society of Australia postgraduate medical scholarship (to DLW), the Royal Australasian College of Physicians Cottrell Fellowship (to DLW), and the Queensland State Government, Smart State PhD award (to DLW). NR 59 TC 51 Z9 53 U1 2 U2 22 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP 1 PY 2009 VL 90 IS 3 BP 578 EP 586 DI 10.3945/ajcn.2009.28106 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 487FW UT WOS:000269257300019 PM 19640954 ER PT J AU Akiba, Y Kaunitz, JD AF Akiba, Yasutada Kaunitz, Jonathan D. TI Luminal chemosensing and upper gastrointestinal mucosal defenses SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 100th Anniversary Symposium of Umami Discovery - The Roles of Glutamate in Taste, Gastrointestinal Function, Metabolism and Physiology CY SEP 10-13, 2008 CL Tokyo, JAPAN SP Int Glutamate Tech Comm ID GASTRIC-ACID-SECRETION; MUCUS GEL THICKNESS; 100TH ANNIVERSARY SYMPOSIUM; RAT DUODENAL EPITHELIUM; BITTER TASTE RECEPTORS; UMAMI TASTE; INTRACELLULAR PH; ENTEROENDOCRINE CELLS; GLUTAMATE METABOLISM; CARBONIC-ANHYDRASES AB The upper gastrointestinal mucosa is exposed to endogenous and exogenous substances, including gastric acid, carbon dioxide, and foodstuffs. Physiologic processes such as secretion, digestion, absorption, and motility occur in the gastrointestinal tract in response to ingested substances, which implies the presence of mucosal sensors. We hypothesize that mucosal acid sensors and tastelike receptors are important components of the mucosal chemosensing system. We have shown that luminal acid/carbon dioxide is sensed via ecto- and cytosolic carbonic anhydrases and ion transporters in the epithelial cells and via acid sensors on the afferent nerves in the duodenum and esophagus. Furthermore, a luminal L-glutamate signal is mediated via mucosal L-glutamate receptors with activation of afferent nerves and cyclooxygenase in the duodenum, which suggests the presence of luminal L-glutamate sensing. These luminal chemosensors help to activate mucosal defense mechanisms to maintain the mucosal integrity and physiologic responses of the upper gastrointestinal tract. Because neural pathways are components of the luminal chemosensory system, investigation of these pathways may help to identify novel molecular targets in the treatment and prevention of mucosal injury and visceral sensation. Am J Clin Nutr 2009; 90(suppl): 826S-31S. C1 Univ Calif Los Angeles, Sch Med, Dept Med, Vet Affairs Greater Los Angles Healthcare Syst, Los Angeles, CA 90024 USA. Brentwood Biomed Res Inst, Los Angeles, CA USA. RP Akiba, Y (reprint author), VA Med Ctr, Bldg 114,Suite 217,W Los Angeles,11301 Wilshire B, Los Angeles, CA 90073 USA. EM yasuakiba@hotmail.com FU NIDDK NIH HHS [R01 DK54221] NR 82 TC 46 Z9 74 U1 0 U2 3 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD SEP 1 PY 2009 VL 90 IS 3 BP 826S EP 831S DI 10.3945/ajcn.2009.27462U PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 487FW UT WOS:000269257300064 PM 19571224 ER PT J AU Lee-Lewandrowski, E Nichols, J Van Cott, E Grisson, R Louissaint, A Benzer, T Lewandrowski, K AF Lee-Lewandrowski, Elizabeth Nichols, John Van Cott, Elizabeth Grisson, Ricky Louissaint, Abner Benzer, Theodore Lewandrowski, Kent TI Implementation of a Rapid Whole Blood D-Dimer Test in the Emergency Department of an Urban Academic Medical Center Impact on ED Length of Stay and Ancillary Test Utilization SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Rapid whole blood D-dimer test; Emergency department; Urban academic medical center; Length of stay; Ancillary test utilization; Turnaround time; Point-of-care testing; Venous thromboembolism ID PULMONARY-EMBOLISM; VENOUS THROMBOSIS; POINT; METAANALYSIS; TRIAL AB Overcrowding and prolonged patient length-of-stay (LOS) in emergency departments (EDs) are growing problems. We evaluated the impact of implementing a rapid whole blood quantitative D-dimer test (Biosite Triage, Biosite Diagnostics, San Diego, CA) in our ED satellite laboratory on 252 patients before vs 211 patients after implementation. All patients also underwent testing with the existing central laboratory method (VIDAS D-dimer, bioMerieux, Durham, NC). D-dimer turnaround time (from blood draw to result) decreased approximately 79% (similar to 2 hours vs 25 minutes). The mean ED LOS declined from 8.46 to 7.14 hours (P = .016). Hospital admissions decreased 13.8%, ED discharges increased 7.3%, and the number of patients admitted for observation increased 6.4% (P = .005). No difference in the utilization of radiologic studies was observed (P = .86). At 3 months' follow-up, none of the after-implementation patients with negative D-dimer results were admitted for subsequent venous thromboembolic disease. The rapid D-dimer test was associated with a shorter ED LOS and fewer hospital admissions. C1 [Lee-Lewandrowski, Elizabeth; Nichols, John; Van Cott, Elizabeth; Grisson, Ricky; Louissaint, Abner; Lewandrowski, Kent] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Benzer, Theodore] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lee-Lewandrowski, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, Gray 5, Boston, MA 02114 USA. FU Biosite Diagnostics FX Supported in part by a grant from Biosite Diagnostics. NR 17 TC 18 Z9 18 U1 0 U2 3 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2009 VL 132 IS 3 BP 326 EP 331 DI 10.1309/AJCP6US3ILGEAREE PG 6 WC Pathology SC Pathology GA 485XC UT WOS:000269157600001 PM 19687307 ER PT J AU Siegel, AJ d'Hemecourt, P Adner, MM Shirey, T Brown, JL Lewandrowski, KB AF Siegel, Arthur J. d'Hemecourt, Pierre Adner, Marvin M. Shirey, Terry Brown, Jeffrey L. Lewandrowski, Kent B. TI Exertional Dysnatremia in Collapsed Marathon Runners A Critical Role for Point-of-Care Testing to Guide Appropriate Therapy SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Dysnatremia; Encephalopathy; Exercise-associated hyponatremia; Inappropriate antidiuresis ID EXERCISE-ASSOCIATED HYPONATREMIA; BOSTON MARATHON; EXPERIENCE; SECRETION AB Dysnatremia may cause life-threatening encephalopathy in marathon runners. Hypernatremia and exercise-associated hyponatremia (EAH) may manifest with mental status changes and, if untreated, progress to coma and death. We reviewed the on-site blood sodium testing and treatment in collapsed runners at the finish-line medical tent at the Boston marathons from 2001 through 2008. Dysnatremia was diagnosed in 429 (32.5%) of 1,319 collapsed runners. Hypernatremia was present in 366 (27.7%) and hyponatremia in 63 (4.8%). Hypernatremic runners unable to drink fluids were treated with intravenous normal (0.9%) saline. Hyponatremic runners with seizures or coma received intravenous hypertonic (3%) saline. Sixteen runners with EAH able to drink a concentrated oral hypertonic solution recovered within 30 minutes. Based on on-site sodium testing, dysnatremic runners were treated with appropriate intravenous fluids according to validated standards of care. Hyponatremic runners able to drink an oral hypertonic solution recovered promptly. C1 [Lewandrowski, Kent B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Siegel, Arthur J.; Brown, Jeffrey L.] McLean Hosp, Belmont, MA 02178 USA. [d'Hemecourt, Pierre] Boston Childrens Hosp, Boston, MA USA. [Adner, Marvin M.] Metro W Med Ctr, Framingham, MA USA. [Shirey, Terry] Nova Biomed, Waltham, MA USA. [Siegel, Arthur J.; d'Hemecourt, Pierre; Brown, Jeffrey L.; Lewandrowski, Kent B.] Harvard Univ, Sch Med, Boston, MA USA. RP Lewandrowski, KB (reprint author), Massachusetts Gen Hosp, Gray 5,Fruit St, Boston, MA 02114 USA. NR 23 TC 23 Z9 24 U1 0 U2 2 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2009 VL 132 IS 3 BP 336 EP 340 DI 10.1309/AJCP30OGLSLWLEIY PG 5 WC Pathology SC Pathology GA 485XC UT WOS:000269157600003 PM 19687309 ER PT J AU Fassbender, P Geldner, G Blobner, M Hofmockel, R Rex, C Gautam, S Malhotra, A Eikermann, M AF Fassbender, Philipp Geldner, Goetz Blobner, Manfred Hofmockel, Rainer Rex, Christopher Gautam, Shiva Malhotra, Atul Eikermann, Matthias TI CLINICAL PREDICTORS OF DURATION OF ACTION OF CISATRACURIUM AND ROCURONIUM ADMINISTERED LONG-TERM SO AMERICAN JOURNAL OF CRITICAL CARE LA English DT Article ID CRITICALLY-ILL PATIENTS; ACUTE NORMOVOLEMIC HEMODILUTION; NEUROMUSCULAR BLOCKING-AGENTS; DOSE-RESPONSE RELATIONSHIP; TIME-COURSE; MECHANICAL VENTILATION; CARDIOPULMONARY BYPASS; INTENSIVE-CARE; REQUIREMENTS; PARALYSIS AB Background The duration of action of neuromuscular blocking drugs (NBDs) varies between individuals and even within individuals in different settings. Objectives To define predictors of variance in duration of action of rocuronium and cisatracurium administered long-term. Methods A prospective, double-blind, multicenter trial that included 113 patients scheduled for major abdominal surgery and postoperative admission to the intensive care unit. Patients received repetitive ( median, 7) equipotent doses of rocuronium or cisatracurium to maintain deep relaxation ( twitch height of the adductor pollicis muscle <25% of baseline). Effects of weight, age, sex, American Society of Anesthesiologists risk score, lowest core temperature, duration of NBD administration, and tobacco smoking history on duration of action of cisatracurium and rocuronium were determined via multiple regression analysis. Results Only duration of NBD administration was predictive of the duration of action of rocuronium. The predicted increase in time to recovery of the train-of-4 ratio to 0.9 ( duration TOF 0.9) per hour of continuous NBD treatment was 12.4 minutes. In contrast, only lowest core body temperature was predictive of cisatracurium's duration of action, and the predicted in crease in duration TOF 0.9 per degree Celsius decrease was 9.8 min. Conclusion Duration of NBD treatment is strongly predictive of the duration of action of rocuronium, and body temperature is predictive of the duration of action of cisatracurium. These data may help decrease the incidence of drug- induced muscle weakness in recovery rooms and surgical intensive care units, particularly if neuromuscular transmission monitoring is not available. ( American Journal of Critical Care. 2009;18:439-445) C1 [Fassbender, Philipp] Univ Klinikum Essen, Klin Anasthesiol & Intens Med, D-45122 Essen, Germany. [Fassbender, Philipp] Univ Duisburg Essen, Essen, Germany. [Geldner, Goetz] Univ Marburg, Marburg, Germany. [Geldner, Goetz] Klinikum Ludwigsburg, Marburg, Germany. [Blobner, Manfred] Tech Univ Munich, Klinikum Rechts Isar, D-8000 Munich, Germany. [Hofmockel, Rainer] Univ Klinikum Rostock, Rostock, Germany. [Rex, Christopher] Klinikum Steinenberg, Reutlingen, Germany. [Gautam, Shiva] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Malhotra, Atul; Eikermann, Matthias] Harvard Univ, Sch Med, Boston, MA USA. [Malhotra, Atul] Brigham & Womens Hosp, Boston, MA 02115 USA. [Eikermann, Matthias] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Fassbender, P (reprint author), Univ Klinikum Essen, Klin Anasthesiol & Intens Med, Hufelandstr 55, D-45122 Essen, Germany. EM philipp.fassbender@uk-essen.de NR 44 TC 2 Z9 6 U1 0 U2 3 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1062-3264 J9 AM J CRIT CARE JI Am. J. Crit. Care PD SEP 1 PY 2009 VL 18 IS 5 BP 439 EP 445 DI 10.4037/ajcc2009883 PG 7 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA 490ER UT WOS:000269481700013 PM 19723864 ER PT J AU Salanti, G Southam, L Altshuler, D Ardlie, K Barroso, I Boehnke, M Cornelis, MC Frayling, TM Grallert, H Grarup, N Groop, L Hansen, T Hattersley, AT Hu, FB Hveem, K Illig, T Kuusisto, J Laakso, M Langenberg, C Lyssenko, V McCarthy, MI Morris, A Morris, AD Palmer, CNA Payne, F Platou, CGP Scott, LJ Voight, BF Wareham, NJ Zeggini, E Ioannidis, JPA AF Salanti, Georgia Southam, Lorraine Altshuler, David Ardlie, Kristin Barroso, Ines Boehnke, Michael Cornelis, Marilyn C. Frayling, Timothy M. Grallert, Harald Grarup, Niels Groop, Leif Hansen, Torben Hattersley, Andrew T. Hu, Frank B. Hveem, Kristian Illig, Thomas Kuusisto, Johanna Laakso, Markku Langenberg, Claudia Lyssenko, Valeriya McCarthy, Mark I. Morris, Andrew Morris, Andrew D. Palmer, Colin N. A. Payne, Felicity Platou, Carl G. P. Scott, Laura J. Voight, Benjamin F. Wareham, Nicholas J. Zeggini, Eleftheria Ioannidis, John P. A. TI Underlying Genetic Models of Inheritance in Established Type 2 Diabetes Associations SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Review DE Bayes theorem; diabetes mellitus; type 2; meta-analysis; models; genetic; polymorphism; genetic; population characteristics ID GENOME-WIDE ASSOCIATION; MOLECULAR ASSOCIATION; METAANALYSIS; REPLICATION; LOCI; POLYMORPHISMS; EPIDEMIOLOGY; CHALLENGES; VARIANTS; DISEASE AB For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed- or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments. C1 [Salanti, Georgia; Ioannidis, John P. A.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. [Salanti, Georgia; Ioannidis, John P. A.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Clin Trials & Evidence Based Med Unit, GR-45110 Ioannina, Greece. [Southam, Lorraine; McCarthy, Mark I.; Morris, Andrew; Zeggini, Eleftheria] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Southam, Lorraine] Univ Oxford, Botnar Res Ctr, Nuffield Orthopaed Ctr, Inst Musculoskeletal Sci, Oxford, England. [Altshuler, David; Ardlie, Kristin; Voight, Benjamin F.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Altshuler, David; Ardlie, Kristin; Voight, Benjamin F.] MIT, Cambridge, MA 02139 USA. [Altshuler, David; Voight, Benjamin F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Altshuler, David; Voight, Benjamin F.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Barroso, Ines; Payne, Felicity; Zeggini, Eleftheria] Wellcome Trust Sanger Inst, Cambridge, England. [Boehnke, Michael; Scott, Laura J.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Boehnke, Michael; Scott, Laura J.] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Cornelis, Marilyn C.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hattersley, Andrew T.] Peninsula Med Sch, Mol Genet Res Grp, Exeter, Devon, England. [Grallert, Harald; Illig, Thomas] German Res Ctr Environm Hlth, Inst Epidemiol, Neuherberg, Germany. [Grarup, Niels; Hansen, Torben] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Groop, Leif; Lyssenko, Valeriya] Lund Univ, Diabet & Endocrinol Res Unit, Dept Clin Sci, Malmo, Sweden. [Hansen, Torben] Univ So Denmark, Fac Hlth Sci, Odense, Denmark. [Hveem, Kristian; Platou, Carl G. P.] Norwegian Univ Sci & Technol, Fac Med, HUNT Res Ctr, N-7034 Trondheim, Norway. [Hveem, Kristian; Platou, Carl G. P.] Levanger Hosp, Dept Med, Nord Trondelag Hlth Trust, Levanger, Norway. [Kuusisto, Johanna] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Kuusisto, Johanna] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Laakso, Markku; Langenberg, Claudia; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [McCarthy, Mark I.] Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Morris, Andrew] Univ Dundee, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland. [Palmer, Colin N. A.] Univ Dundee, Biomed Res Inst, Pharmacogenet Res Ctr, Dundee, Scotland. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Dept Med,Inst Clin Res & Hlth Policy Studies, Ctr Genet Epidemiol & Modeling, Boston, MA 02111 USA. RP Ioannidis, JPA (reprint author), Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. EM eleftheria@sanger.ac.uk; jioannid@cc.uoi.gr RI Palmer, Colin/C-7053-2008; Altshuler, David/A-4476-2009; Voight, Benjamin/F-1775-2011; Ioannidis, John/G-9836-2011; Grallert, Harald/B-3424-2013; Grarup, Niels/K-2807-2015; Study, GoDARTS/K-9448-2016; OI Palmer, Colin/0000-0002-6415-6560; Payne, Felicity/0000-0003-4228-581X; Altshuler, David/0000-0002-7250-4107; Grarup, Niels/0000-0001-5526-1070; Zeggini, Eleftheria/0000-0003-4238-659X FU National Institutes of Health/National Center for Research Resources [UL1 RR025752]; Wellcome Trust [WT088885/ Z/09/Z] FX Conflict of interest: none declared. NR 18 TC 40 Z9 40 U1 0 U2 2 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 SEP 1 PY 2009 VL 170 IS 5 BP 537 EP 545 DI 10.1093/aje/kwp145 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 486KN UT WOS:000269195000001 PM 19602701 ER PT J AU El-Serag, HB Fitzgerald, S Richardson, P AF El-Serag, Hashem B. Fitzgerald, Stephanie Richardson, Peter TI The Extent and Determinants of Prescribing and Adherence With Acid-Reducing Medications: A National Claims Database Study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID PROTON-PUMP INHIBITOR; BARRETTS-ESOPHAGUS; GASTROESOPHAGEAL-REFLUX; THERAPY; ADENOCARCINOMA; PERSISTENCE; DYSPLASIA; RISK AB OBJECTIVES: No community-based, large-scale studies have examined the extent of prescribing acid-reducing medications or adherence and persistence to these medication regimens. METHODS: We conducted a retrospective cohort study of patients with Barrett's esophagus (BE) and gastroesophageal reflux disease (GERD) without BE, diagnosed between 2000 and 2005, who had undergone an upper endoscopy within 1 year through a managed care plan in the United States. We identified filled prescriptions for oral proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) within 365 days after the index date of BE or GERD, and several measures of adherence (medication-ownership ratio (MOR)) and persistence (length of therapy, fill-refill ratio, discontinuation rate) for PPI treatment. RESULTS: We identified 10,159 patients with BE and 48,965 GERD patients with no BE. The mean duration of filled PPI prescriptions accounted for only 30.2% of the available year after the index date, whereas that of either PPI or H2RA prescriptions accounted for only 31.7%. PPI prescriptions were filled by 66.6 and 60.4% of patients with and without BE, respectively. These proportions declined significantly between 2000 and 2005. For those with at least one prescription, the median duration of therapy was 241 days for PPIs and 159 for H2RAs. Both groups had low MOR and length of treatment and high discontinuation rates; however, adherence and persistence were significantly higher in BE than in non-BE patients, and significantly lower in 2005 than in 2000. CONCLUSIONS: The use of prescription PPIs or H2RAs, as well as adherence and persistence with these medications, is lower than expected. The absence of BE and more recent diagnosis are associated with even lower prescription rates. C1 [El-Serag, Hashem B.; Fitzgerald, Stephanie; Richardson, Peter] Michael E DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Sect Gastroenterol & Hepatol, Houston, TX 77030 USA. [El-Serag, Hashem B.; Fitzgerald, Stephanie; Richardson, Peter] Baylor Coll Med, Houston, TX 77030 USA. RP El-Serag, HB (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Sect Gastroenterol & Hepatol, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hasheme@bcm.tmc.edu FU Astrazeneca FX This study was supported by a research grant from Astrazeneca. NR 12 TC 11 Z9 11 U1 1 U2 1 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 SEP PY 2009 VL 104 IS 9 BP 2161 EP 2167 DI 10.1038/ajg.2009.312 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 497AP UT WOS:000270024800008 PM 19568229 ER PT J AU Watnick, S AF Watnick, Suzanne TI Quality of Life and Depression in CKD: Improving Hope and Health SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; CHRONIC-RENAL-FAILURE; DIALYSIS PATIENTS; MAJOR DEPRESSION; HEMODIALYSIS; VALIDATION; INVENTORY; HEART C1 Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97201 USA. RP Watnick, S (reprint author), Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97201 USA. EM watnicks@ohsu.edu NR 33 TC 3 Z9 3 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD SEP PY 2009 VL 54 IS 3 BP 399 EP 402 DI 10.1053/j.ajkd.2009.06.009 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 492FP UT WOS:000269640600003 PM 19700059 ER PT J AU Brady, CB Gaziano, JM Cxypoliski, RA Guarino, PD Kaufman, JS Warren, SR Hartigan, P Goldfarb, DS Jamison, RL AF Brady, Christopher B. Gaziano, J. Michael Cxypoliski, Roberta A. Guarino, Peter D. Kaufman, James S. Warren, Stuart R. Hartigan, Pamela Goldfarb, David S. Jamison, Rex L. TI Homocysteine Lowering and Cognition in CKD: The Veterans Affairs Homocysteine Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Cognition; kidney disease; homocysteine; clinical trial ID CHRONIC KIDNEY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; FOLIC-ACID SUPPLEMENTATION; HEMODIALYSIS-PATIENTS; DIALYSIS PATIENTS; OLDER-ADULTS; CARDIOVASCULAR-DISEASE; PLASMA HOMOCYSTEINE; ALZHEIMERS-DISEASE; VASCULAR-DISEASE AB Background: Individuals with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) have high plasma total homocysteine (tHcy) levels, which may be a risk factor for cognitive impairment. Whether treatment with high-dose B vitamins to decrease high tHcy levels improves cognition in persons with kidney disease is unknown. Study Design: Randomized controlled trial. Setting & Participants: A substudy of 659 patients (mean age, 67.3 +/- 11.7 years) who participated in a randomized double-blind clinical trial 5 years in duration conducted in 36 US Department of Veterans Affairs medical centers of the effect on all-cause mortality of vitamin-induced lowering of plasma tHcy level. 236 (35.8%) were treated by using dialysis (ESRD) and 423 (64.2%) had a Cockcroft-Gault estimated creatinine clearance of 30 mL/min or less (advanced CKD). All had high tHcy levels (>= 15 mu mol/L) at baseline. Cognitive assessments began during the follow-up period of the main trial 3 years after treatment began; participants subsequently were retested 1 year later to assess cognitive change. Intervention: Daily high-dose B vitamin capsule (40 mg of folic acid, 100 mg of vitamin B-6, and 2 mg of vitamin B-12) or placebo. Outcomes: Cognitive function at initial assessment and 1 year later. Measurements: Telephone Interview of Cognitive Status-modified, supplemented with attention, working memory, and executive function tests. Results: Initial cognitive function was impaired in approximately 19% of patients regardless of treatment assignment (vitamin or placebo) or kidney disease status (advanced CKD or ESRD). Treatment decreased tHcy levels by 26.7%. Unadjusted and adjusted analyses showed that treatment did not improve initial cognitive outcomes or affect subsequent cognitive status 1 year later. Limitations: Cognitive assessments began after treatment was initiated; cognitive assessment was limited. Conclusion: Treatment with high daily doses of B vitamins, which decreased tHcy levels, did not affect cognitive outcomes in patients with advanced CKD and ESRD. Am J Kidney Dis 54:440-449. 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 [Brady, Christopher B.; Gaziano, J. Michael] Boston Univ, Sch Med, Ctr Geriatr Res Educ & Clin, Vet Affairs Boston Healthcare Syst, Boston, MA 02215 USA. [Brady, Christopher B.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Brady, Christopher B.; Gaziano, J. Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Aging, Cambridge, MA 02138 USA. [Gaziano, J. Michael; Cxypoliski, Roberta A.] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Guarino, Peter D.; Hartigan, Pamela] Vet Affairs Connecticut Healthcare Syst, Vet Affairs Cooperat Studies Program Coordinating, West Haven, CT USA. [Kaufman, James S.] Vet Affairs Boston Healthcare Syst, Renal Sect, Boston, MA USA. [Kaufman, James S.] Boston Univ, Sch Med, Renal Sect, Boston, MA 02118 USA. [Warren, Stuart R.] New Mexico Vet Affairs Hlth Care Syst, Clin Res Pharm Coordinating Ctr, Vet Affairs Cooperat Studies Program, Albuquerque, NM USA. [Warren, Stuart R.] Univ New Mexico, Coll Pharm, Albuquerque, NM 87131 USA. [Goldfarb, David S.] New York Harbor Healthcare Syst, Nephrol Sect, New York, NY USA. [Goldfarb, David S.] NYU, Sch Med, New York, NY USA. [Jamison, Rex L.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Jamison, Rex L.] Stanford Univ, Dept Med, Sch Med, Div Nephrol, Stanford, CA 94305 USA. RP Brady, CB (reprint author), VA Boston Healthcare Syst, GRECC 182, 150 S Huntington Ave, Boston, MA 02130 USA. EM cbbrady@bu.edu OI Brady, Christopher/0000-0002-6095-6480; Goldfarb, David/0000-0002-9215-1273 FU US Department of VA Office of Research and Development; National Institute of Diabetes and Digestive and Kidney Diseases [R21 DK071292] FX The present work was supported by funds from the Cooperative Studies and Merit Review Programs of the US Department of VA Office of Research and Development (Clinical Science Research and Development Program), the National Institute of Diabetes and Digestive and Kidney Diseases (Grant R21 DK071292), and ParnLab Pharmaceuticals LLC. Dr Gaziano received research support in the form of vitamin pills and packaging from BASF, DMS Pharmaceuticals, and Wyeth Pharmaceuticals. The CSP approved the manuscript for submission, but was not involved in the design of the study or the collection, management, analysis, or interpretation of data. None of the other funding sources were involved in the design or conduct of the study or the collection, management, analysis, and interpretation of the data or review or approval of the manuscript. NR 61 TC 37 Z9 39 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 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD SEP PY 2009 VL 54 IS 3 BP 440 EP 449 DI 10.1053/j.ajkd.2009.05.013 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 492FP UT WOS:000269640600010 PM 19628319 ER PT J AU Burkitt, KH Mor, MK Jain, R Kruszewski, MS McCray, EE Moreland, ME Muder, RR Obrosky, DS Sevick, MA Wilson, MA Fine, MJ AF Burkitt, Kelly H. Mor, Maria K. Jain, Rajiv Kruszewski, Matthew S. McCray, Ellesha E. Moreland, Michael E. Muder, Robert R. Obrosky, David Scott Sevick, Mary Ann Wilson, Mark A. Fine, Michael J. TI Toyota Production System Quality Improvement Initiative Improves Perioperative Antibiotic Therapy SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID PROCESS REDESIGN; INFECTION; PROPHYLAXIS AB Objective: To assess the role of a Toyota production system (TPS) quality improvement (QI) intervention on appropriateness of perioperative antibiotic therapy and in length of hospital stay (LOS) among surgical patients. Study Design: Pre-post quasi-experimental study using local and national retrospective cohorts. Methods: We used TPS methods to implement a multifaceted intervention to reduce nosocomial methicillin-resistant Staphylococcus aureus infections on a Veterans Affairs surgical unit, which led to a QI intervention targeting appropriate perioperative antibiotic prophylaxis. Appropriate perioperative antibiotic therapy was defined as selection of the recommended antibiotic agents for a duration not exceeding 24 hours from the time of the operation. The local computerized medical record system was used to identify patients undergoing the 25 most common surgical procedures and to examine changes in appropriate antibiotic therapy and LOS over time. Results: Overall, 2550 surgical admissions were identified from the local computerized medical records. The proportion of surgical admissions receiving appropriate perioperative antibiotics was significantly higher (P <.01) in 2004 after initiation of the TPS intervention (44.0%) compared with the previous 4 years (range, 23.4%-29.8%) primarily because of improvements in compliance with antibiotic therapy duration rather than appropriate antibiotic selection. There was no statistically significant decrease in LOS over time. Conclusion: The use of TPS methods resulted in a QI intervention that was associated with an increase in appropriate perioperative antibiotic therapy among surgical patients, without affecting LOS. (Am J Manag Care. 2009;15(9):633-642) C1 [Burkitt, Kelly H.; Mor, Maria K.; Obrosky, David Scott; Sevick, Mary Ann; Fine, Michael J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Mor, Maria K.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Obrosky, David Scott; Sevick, Mary Ann; Fine, Michael J.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. [Moreland, Michael E.] Vet Integrated Serv Network 4, Pittsburgh, PA USA. RP Burkitt, KH (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr 151C-H, Pittsburgh, PA 15206 USA. EM kelly.burkitt@va.gov FU VA Pittsburgh Healthcare System, Pittsburgh, PA; Office of Research and Development, Department of Veterans Affairs FX This study was supported by the VA Pittsburgh Healthcare System, Pittsburgh, PA. This material is based on work supported in part by the Office of Research and Development, Department of Veterans Affairs. The views expressed in this article are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. NR 23 TC 15 Z9 15 U1 0 U2 2 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD SEP PY 2009 VL 15 IS 9 BP 633 EP 642 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 497GP UT WOS:000270046600008 PM 19747028 ER PT J AU Roth, CP Lim, YW Pevnick, JM Asch, SM McGlynn, EA AF Roth, Carol P. Lim, Yee-Wei Pevnick, Joshua M. Asch, Steven M. McGlynn, Elizabeth A. TI The Challenge of Measuring Quality of Care From the Electronic Health Record SO AMERICAN JOURNAL OF MEDICAL QUALITY LA English DT Article DE electronic health record; quality of care; quality improvement ID MEDICAL-RECORD; UNINTENDED CONSEQUENCES; INFORMATION-TECHNOLOGY; ADVERSE EVENTS; UNITED-STATES; SYSTEM; TEXT; IMPLEMENTATION; PERFORMANCE; ATTITUDES AB The electronic health record (EHR) is seen by many as an ideal vehicle for measuring quality of health care and monitoring ongoing provider performance. It is anticipated that the availability of EHR-extracted data will allow quality assessment without the expensive and time-consuming process of medical record abstraction. A review of the data requirements for the indicators in the Quality Assessment Tools system suggests that only about a third of the indicators would be readily accessible from EHR data. Other factors involving complexity of required data elements, provider documentation habits, and EHR variability make the task of quality measurement more difficult than may be appreciated. Accurately identifying eligible cases for quality assessment and validly scoring those cases with EHR-extracted data will pose significant challenges but could potentially plummet the cost and therefore expand the use of quality assessment. ( Am J Med Qual 2009;24;385-394) C1 [Roth, Carol P.; Lim, Yee-Wei; Pevnick, Joshua M.; Asch, Steven M.; McGlynn, Elizabeth A.] RAND Hlth, Santa Monica, CA USA. [Pevnick, Joshua M.] Cedars Sinai Med Ctr, Dept Med, Div Gen Internal Med, Los Angeles, CA 90048 USA. [Asch, Steven M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Dept Med, Los Angeles, CA 90095 USA. RP Roth, CP (reprint author), RAND Corp Hlth, 1776 Main St,M4W, Santa Monica, CA 90407 USA. EM roth@rand.org NR 43 TC 36 Z9 37 U1 3 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1062-8606 J9 AM J MED QUAL JI Am. J. Med. Qual. PD SEP-OCT PY 2009 VL 24 IS 5 BP 385 EP 394 DI 10.1177/1062860609336627 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 493VH UT WOS:000269765900002 PM 19482968 ER PT J AU Waikar, SS Mount, DB Curhan, GC AF Waikar, Sushrut S. Mount, David B. Curhan, Gary C. TI Mortality after Hospitalization with Mild, Moderate, and Severe Hyponatremia SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Epidemiology; Hospitalization; Hyponatremia; Mortality; Outcomes ID ELEVATION MYOCARDIAL-INFARCTION; CLASSIFICATION-OF-DISEASES; HEART-FAILURE; SERUM SODIUM; ADMINISTRATIVE DATA; LIVER-TRANSPLANTATION; RISK ADJUSTMENT; CLINICAL-DATA; WAITING-LIST; CLAIMS DATA AB BACKGROUND: Hyponatremia is the most common electrolyte abnormality in hospitalized individuals. METHODS: To investigate the association between serum sodium concentration and mortality, we conducted a prospective cohort study of 98,411 adults hospitalized between 2000 and 2003 at 2 teaching hospitals in Boston, Massachusetts. The main outcome measures were in-hospital, 1-year, and 5-year mortality. Multivariable logistic regression and Cox proportional hazards models were used to compare outcomes in patients with varying degrees of hyponatremia against those with normal serum sodium concentration. RESULTS: Hyponatremia (serum sodium concentration < 135 mEq/L) was observed in 14.5% of patients on initial measurement. Compared with patients with normonatremia (135-144 mEq/L), those with hyponatremia were older (67.0 vs 63.1 years, P < .001) and had more comorbid conditions (mean Deyo-Charlson Index 1.9 vs 1.4, P < .001). In multivariable-adjusted models, patients with hyponatremia had an increased risk of death in hospital (odds ratio 1.47, 95% confidence interval [CI], 1.33-1.62), at 1 year (hazard ratio 1.38, 95% CI, 1.32-1.46), and at 5 years (hazard ratio 1.25, 95% CI, 1.21-1.30). The increased risk of death was evident even in those with mild hyponatremia (130-134 mEq/L; odds ratio 1.37, 95% CI, 1.23-1.52). The relationship between hyponatremia and mortality was pronounced in patients admitted with cardiovascular disease, metastatic cancer, and those admitted for procedures related to the musculoskeletal system. Resolution of hyponatremia during hospitalization attenuated the increased mortality risk conferred by hyponatremia. CONCLUSION: Hyponatremia, even when mild, is associated with increased mortality. (C) 2009 Elsevier Inc. All rights reserved. The American Journal of Medicine (2009) 122, 857-865 C1 [Waikar, Sushrut S.; Mount, David B.; Curhan, Gary C.] Harvard Univ, Brigham & Womens Hosp, Div Renal, Dept Med,Med Sch, Boston, MA 02115 USA. [Mount, David B.] VA Boston Healthcare Syst, Div Renal, Boston, MA USA. RP Waikar, SS (reprint author), Harvard Univ, Brigham & Womens Hosp, Div Renal, Dept Med,Med Sch, MRB 4,75 Francis St, Boston, MA 02115 USA. EM swaikar@partners.org FU Astellas Pharma US, Inc. FX Investigator-initiated grant from Astellas Pharma US, Inc. NR 49 TC 237 Z9 247 U1 1 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD SEP PY 2009 VL 122 IS 9 BP 857 EP 865 DI 10.1016/j.amjmed.2009.01.027 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 485UN UT WOS:000269150400015 PM 19699382 ER PT J AU Baker, AM Klein, RL Moss, KL Haeri, S Boggess, K AF Baker, Arthur M. Klein, Richard L. Moss, Kevin L. Haeri, Sina Boggess, Kim TI Maternal serum dyslipidemia occurs early in pregnancy in women with mild but not severe preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Mat Fetal Med DE preeclampsia; pregnancy; serum lipids ID HEART-DISEASE; RISK; ECLAMPSIA; TRIGLYCERIDES; HYPERTENSION; MANAGEMENT; COHORT AB OBJECTIVE: We sought to determine whether serum lipids at midgestation differ between normotensive women and women developing mild and severe preeclampsia STUDY DESIGN: A case-control study of 50 women with preeclampsia (mild = 26, severe = 24) and 100 women with uncomplicated term deliveries was conducted Maternal serum collected at 15-20 weeks was used to measure lipid profiles. RESULTS: The groups were similar with respect to demographic characteristics. Women with mild preeclampsia had higher triglyceride levels and a higher total cholesterol to high-density lipoprotein ratio than control subjects (200 +/- 79 5 mg/dL vs 164 +/- 56.2 mg/dL; P = 02, and 3.31 +/- 1.06 mg/dL vs 2 91 +/- 0 59, P = .02) Women with severe preeclampsia had lower levels of low-density lipoprotein than control subjects (85.5 +/- 213 mg/dL vs 102 +/- 30.0 mg/dL; P = 04) and a less atherogenic lipid profile than control subjects. CONCLUSION: Midgestation dyslipidemia is associated with mild but not severe preeclampsia These findings may aid in elucidating the different pathologic processes between mild and severe preeclampsia. C1 [Baker, Arthur M.; Haeri, Sina; Boggess, Kim] Univ N Carolina, Dept Obstet & Gynecol, Div Maternal Fetal Med, Sch Med, Chapel Hill, NC 27599 USA. [Klein, Richard L.] Med Univ S Carolina, Dept Med, Div Endocrinol Metab & Med Genet, Charleston, SC 29425 USA. [Klein, Richard L.] Ralph H Johnson Dept Vet Affairs Med Ctr, Res Serv, Charleston, SC 29403 USA. [Moss, Kevin L.] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. RP Baker, AM (reprint author), Univ N Carolina, Dept Obstet & Gynecol, Div Maternal Fetal Med, Sch Med, 3010 Old Clin Bldg,CB 7516, Chapel Hill, NC 27599 USA. EM abaker2@med.unc.edu NR 28 TC 5 Z9 7 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD SEP PY 2009 VL 201 IS 3 AR 293.e1 DI 10.1016/j.ajog.2009.05.037 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 495VA UT WOS:000269921900017 PM 19631926 ER PT J AU Bhat, PV Jakobiec, FA Papaliodis, G Sobrin, L AF Bhat, Pooja V. Jakobiec, Frederick A. Papaliodis, George Sobrin, Lucia TI Primary T-cell Lymphoma of the Retina and Cerebellum: Immunophenotypic and Gene Rearrangement Confirmation SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; PRIMARY INTRAOCULAR LYMPHOMA; PRIMARY-CNS-LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; POLYMERASE-CHAIN-REACTION; INTERLEUKIN-10; DIAGNOSIS; IMMUNOGLOBULIN; EXPRESSION; EXPERIENCE AB PURPOSE: To document fully the first credible primary T cell lymphoma of the retina and central nervous system in a 71 year,old man. DESIGN: Interventional, retrospective report. METHODS: Critical analysis of clinical history and findings, which included bilateral vitreitis with anterior chamber reaction, creamy intraretinal infiltrates, and retinal detachment; complete blood counts and other blood studies (anti-neutrophil cytoplasmic antibody [ANCA], angiotensin-converting enzyme levels, and Lyme and fluorescent treponemal antibody absorption titers); magnetic resonance imaging (MRI) scanning of the brain with total body computed tomographic and positron emission tomographic scanning; interleukin (IL) level determinations (IL-10 and IL-6); cytologic and electron microscopic evaluations; immunophenotyping of cells; and polymerase chain reaction studies for viral deoxyribonucleic acid and ribonucleic acid, and immunoglobulin heavy-chain, and T-cell receptor (TCR) gene rearrangements. RESULTS: The first vitreous specimen was diagnosed mistakenly as cytologically reactive and contained elevated levels of IL-10 and IL,6 in a ratio of 7 to 1. T cells predominated on immunophenotypic analysis. Computed tomographic and positron emission tomographic whole body scanning showed negative results for lymphoma. An MRI scan of the brain eventually revealed a cerebellar lesion. A retinal biopsy harbored cytologically atypical pleomorphic cells that were almost all immunophenotypically T cells; polymerase chain reaction studies demonstrated a clonal TCR gene rearrangement. T-cell lymphocytes in the biopsy specimen of the cerebellum had an identical clonal TCR gene rearrangement. CONCLUSIONS: This case unequivocally establishes that primary retinal T,cell lymphoma accompanied by central nervous system involvement can occur. Elevation in the IL-10 to IL-6 ratio in the face of inconclusive or confusing vitreous cytologic and immunophenotypic findings (a predominance of "reactive T cells with some atypicality") should lead to gene rearrangement studies on biopsies of involved tissues for the detection of T-cell clonality. (Am J Ophthalmol 2009;148:350-360. (C) 2009 by Elsevier Inc. All rights reserved.) C1 [Bhat, Pooja V.; Jakobiec, Frederick A.] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Dept Ophthalmol, Boston, MA 02114 USA. [Papaliodis, George; Sobrin, Lucia] Massachusetts Eye & Ear Infirm, Ocular Immunol & Uveitis Serv, Dept Ophthalmol, Boston, MA 02114 USA. [Sobrin, Lucia] Massachusetts Eye & Ear Infirm, Retina Serv, Dept Ophthalmol, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Dept Ophthalmol, R 321,3rd Floor,243 Charles St, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu FU National Eye Institute, Bethesda, Maryland [EY-16335-02]; Research to Prevent Blindness Career Development Award; Massachusetrs Lions Research Fund, New Bedford, Massachusetts FX THIS STUDY WAS SUPPORTED BY GRANT NO. EY-16335-02 (K12 HARVARD VISION CLINICIAN SCIENTIST DEVELOPMENT AWARD to Dr Sobrin) from the National Eye Institute, Bethesda, Maryland; Research to Prevent Blindness Career Development Award, New York, New York (Dr Sobrin); and Massachusetrs Lions Research Fund, New Bedford, Massachusetts (Dr Sobrin). The authors indicate no financial conflict of interest. Involved in design Of Study (F.A.J., P.B.); conduct of study (F.A.J., P.B., L.S., G.P.); collection of data (P.B., F.A.J.); management, analysis, and interpretation of data (F.A.J., L.S., G.P., P.B.); and preparation, review, and approval of the manuscript (P.B., F.A.J., L.S., G.P.). The Massachusetts Eye and Ear Institutional Review Board (IRB) considered this Study exempt under local IRB guidelines. Health Insurance Portability and Accountability Act (HIPAA) compliance was maintained. The study was in accordance with the Declaration of Helsinki and all federal and state laws. Dr Fred H. Hochberg, Department of Neuro-oncology , Massachusetts General Hospital, Boston, Massachusetts, was the neuro-oncology consultant on this case. NR 41 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD SEP PY 2009 VL 148 IS 3 BP 350 EP 360 DI 10.1016/j.ajo.2009.04.005 PG 11 WC Ophthalmology SC Ophthalmology GA 493RK UT WOS:000269755400005 PM 19477711 ER PT J AU Hanley, MA Ehde, DM Jensen, M Czerniecki, J Smith, DG Robinson, LR AF Hanley, Marisol A. Ehde, Dawn M. Jensen, Mark Czerniecki, Joseph Smith, Douglas G. Robinson, Lawrence R. TI Chronic Pain Associated with Upper-Limb Loss SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Upper Limb; Limb Loss; Amputation; Pain; Disability; Phantom Limb; Phantom-Limb Pain ID PHANTOM PAIN; BACK-PAIN; RESIDUAL LIMB; PREAMPUTATION PAIN; LONG-TERM; AMPUTEES; AMPUTATION; EXTREMITY; REHABILITATION; SENSATIONS AB Objective: To describe the prevalence, intensity, and functional impact of the following types of pain associated with upper-limb loss: phantom limb, residual limb, back, neck, and nonamputated-limb pain. Design: Cross-sectional survey; 104 respondents with upper-limb loss at least 6 months postamputation completed measures of pain intensity, interference, disability, and health-related quality-of-life. Results: Nearly all (90%) of the respondents reported pain, with 76% reporting more than one pain type. Phantom-limb pain and residual-limb pain were the most prevalent (79% and 71%, respectively), followed by back (52%), neck (43%), and nonamputated-limb pain (33%). Although nonamputated-limb pain was least prevalent, it was reported to cause the highest levels of interference and pain-related disability days. Self-reported quality-of-life was significantly lower for individuals with each type of pain compared with those without any pain. Age, time since amputation, and cause of amputation were not associated with pain. Conclusions: In addition to pain in the phantom and residual limb, back, neck, and nonamputated-limb pain are also common after upper-limb loss. All of these pain types are associated with significant disability and activity interference for some individuals, suggesting that assessment of multiple pain types in persons with upper-limb amputation may be important. C1 [Hanley, Marisol A.; Ehde, Dawn M.; Jensen, Mark; Czerniecki, Joseph; Smith, Douglas G.; Robinson, Lawrence R.] Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98195 USA. [Czerniecki, Joseph] VA Puget Sound HealthCare Syst, Seattle, WA USA. RP Hanley, MA (reprint author), 5837 221st Pl SE, Issaquah, WA 98027 USA. RI Robinson , Lawrence/D-8455-2013 FU National Institutes of Health [P01HD/NS33988]; National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke; National Center for Rehabilitation Research FX The work was supported by grant P01HD/NS33988 from the National Institutes of Health, the National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Center for Rehabilitation Research. NR 32 TC 33 Z9 34 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD SEP PY 2009 VL 88 IS 9 BP 742 EP 751 DI 10.1097/PHM.0b013e3181b306ec PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 488UH UT WOS:000269375100007 PM 19692791 ER PT J AU Balkovetz, DF Chumley, P Amlal, H AF Balkovetz, Daniel F. Chumley, Phillip Amlal, Hassane TI Downregulation of claudin-2 expression in renal epithelial cells by metabolic acidosis SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE paracellular transport ID COLLECTING DUCT AQUAPORIN-2; PROXIMAL TUBULE; RAT-KIDNEY; PARACELLULAR PERMEABILITY; WATER REABSORPTION; PROTEIN ABUNDANCE; MOUSE NEPHRON; MDCK CELLS; II CELLS; TIGHT AB Balkovetz DF, Chumley P, Amlal H. Downregulation of claudin-2 expression in renal epithelial cells by metabolic acidosis. Am J Physiol Renal Physiol 297: F604-F611, 2009. First published July 8, 2009; doi:10.1152/ajprenal.00043.2009. - Chronic metabolic acidosis (CMA) is associated with an inhibition of fluid reabsorption in the renal proximal tubule. The effects of CMA on paracellular transport across the renal epithelial tight junction (TJ) is unknown. Claudin-2 is a transmembrane TJ-associated protein which confers TJ paracellular permeability to Na(+). We examined the effects of CMA on the expression of TJ transport proteins using both in vivo and in vitro models of CMA. The results showed downregulation of claudin-2 mRNA and protein expression in the cortex of rats subjected to the NH4Cl loading model of CMA. Madin-Darby canine kidney (MDCK) and HK-2 cells are models of renal epithelial cells and express claudin-2 protein in their TJ. We examined the effects of acidic pH exposure on the expression of claudin-2 in MDCK and HK-2 renal epithelial cells. Exposure of MDCK cells to pH 6.96 medium caused a significant and reversible decrease in claudin-2 protein abundance. A dose-response analysis of acidic medium exposure of MDCK and HK-2 cells demonstrated a downregulation of claudin-2 protein. The downregulation effect of acidic pH is specific to claudin-2 expression as the expression of other TJ-associated proteins (i.e., claudin-1, -3, -4, and -7, occludin, and zonula occludens-1) remained unchanged compared with control pH (7.40). Collectively, these data demonstrate that CMA downregulates the expression of claudin-2 likely through a direct effect of acidic pH. Potential physiological significance of these changes is discussed. C1 [Balkovetz, Daniel F.; Chumley, Phillip] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Balkovetz, Daniel F.] Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA. [Balkovetz, Daniel F.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Amlal, Hassane] Univ Cincinnati, Coll Med, Dept Med, Cincinnati, OH USA. RP Balkovetz, DF (reprint author), Univ Alabama, Dept Med, 1530 3rd Ave S,LHRB 642, Birmingham, AL 35294 USA. EM balkovet@uab.edu NR 43 TC 15 Z9 15 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD SEP PY 2009 VL 297 IS 3 BP F604 EP F611 DI 10.1152/ajprenal.00043.2009 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 500AR UT WOS:000270269900007 PM 19587148 ER PT J AU Tucker-Seeley, RD Subramanian, SV Li, Y Sorensen, G AF Tucker-Seeley, Reginald D. Subramanian, S. V. Li, Yi Sorensen, Glorian TI Neighborhood Safety, Socioeconomic Status, and Physical Activity in Older Adults SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PUBLIC-HEALTH; ENVIRONMENT; POPULATION; WOMEN; LIFE; AMERICAN; LEISURE; WALKING; PEOPLE AB Background: Neighborhood environment can have a substantial influence on the level of physical activity among older adults. Yet, the moderating influence of various measures of SES on the association between perceived neighborhood safety and leisure-time physical activity (LTPA) among older adults remains unknown. Purpose: The study was designed to investigate the association between perceived neighborhood safety and LTPA in a nationally representative sample of older adults, and to evaluate SES characteristics as potential effect modifiers in the association between perceived neighborhood safety and LTPA. Methods: Cross-sectional data from the 2004 Health and Retirement Study of older adults aged >= 50 years were used to examine the association between perceived neighborhood safety and LTPA. Differences in LTPA were evaluated across three measures of SES: education, household income, and household wealth. SES was also evaluated as a potential effect modifier in the association between perceived neighborhood safety and LTPA. The analysis was conducted in 2008. Results: An SES gradient in LTPA was noted across measures of SES used in this Study. After controlling for SES and demographic characteristics and functional limitations, older adults who perceived their neighborhood as safe had an 8% higher mean rate of LTPA compared to older adults who perceived their neighborhood as unsafe. The association was no longer significant when self-rated health was added. Additionally, SES was not a significant effect modifier in the association between perceived neighborhood safety and LTPA. Conclusions: SES, demographic characteristics, and functional limitations substantially attenuated the positive association between perceived neighborhood safety and LTPA; however, with the inclusion of self-rated health, the association was no longer present. This finding suggets that self-rated health may mediate this association. The lack of significance in the interaction between perceived neighborhood safety and SES suggests that prevention efforts to increase physical activity among older adults should consider perceptions of neighborhood safety as a potential barrier regardless of SES. (Am J Prev Med 2009;37(3):207-213) (C) 2009 American Journal of Preventive Medicine C1 [Tucker-Seeley, Reginald D.; Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Li, Yi] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tucker-Seeley, Reginald D.; Subramanian, S. V.; Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Cambridge, MA 02138 USA. [Li, Yi] Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. RP Tucker-Seeley, RD (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St,LW 747, Boston, MA 02115 USA. EM retucker@hsph.harvard.edu FU National Institutes of Health Career Development Award [NHLBI K25 HL081275] FX The authors thank Miguel Marino for statistical computing support. RDT-S was funded as a predoctoral fellow by the National Cancer Institute's joint Harvard School of Public Health-Dana-Farber Cancer Institute Educational Program in Cancer Prevention. SVS is supported by a National Institutes of Health Career Development Award (NHLBI K25 HL081275). NR 36 TC 47 Z9 48 U1 1 U2 21 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 SEP PY 2009 VL 37 IS 3 BP 207 EP 213 DI 10.1016/j.amepre.2009.06.005 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 487RA UT WOS:000269291300006 PM 19595554 ER PT J AU Nelson, JC Papakostas, GI AF Nelson, J. Craig Papakostas, George I. TI Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID TREATMENT-RESISTANT DEPRESSION; SEROTONIN REUPTAKE INHIBITORS; DOUBLE-BLIND; OLANZAPINE/FLUOXETINE COMBINATION; RISPERIDONE AUGMENTATION; ADJUNCTIVE THERAPY; ANTIDEPRESSANTS; ARIPIPRAZOLE; FLUOXETINE; OLANZAPINE AB Objective: The authors sought to determine by meta-analysis the efficacy and tolerability of adjunctive atypical antipsychotic agents in major depressive disorder. Method: Searches were conducted of MEDLINE/PubMed ( 1966 to January 2009), the Cochrane database, abstracts of major psychiatric meetings since 2000, and online trial registries. Manufacturers of atypical antipsychotic agents without online registries were contacted. Trials selected were acute-phase, parallel-group, double-blind controlled trials with random assignment to adjunctive atypical antipsychotic or placebo. Patients had nonpsychotic unipolar major depressive disorder that was resistant to prior antidepressant treatment. Response, remission, and discontinuation rates were either reported or obtained. Data were extracted by one author and checked by the second. Data included study design, number of patients, patient characteristics, methods of establishing treatment resistance, drug doses, duration of the adjunctive trial, depression scale used, response and remission rates, and discontinuation rates for any reason or for adverse events. Results: Sixteen trials with 3,480 patients were pooled using a fixed-effects meta-analysis. Adjunctive atypical antipsychotics were significantly more effective than placebo ( response: odds ratio=1.69, 95% CI=1.46-1.95, z=7.00, N=16, p<0.00001; remission: odds ratio=2.00, 95% CI=1.69-2.37, z=8.03, N=16, p<0.00001). Mean odds ratios did not differ among the atypical agents and were not affected by trial duration or method of establishing treatment resistance. Discontinuation rates for adverse events were higher for atypical agents than for placebo ( odds ratio=3.91, 95% CI=2.68-5.72, z=7.05, N=15, p<0.00001). Conclusions: Atypical antipsychotics are effective augmentation agents in major depressive disorder but are associated with an increased risk of discontinuation due to adverse events. C1 [Nelson, J. Craig] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Nelson, JC (reprint author), Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave,Box 0984-F, San Francisco, CA 94143 USA. EM craign@lppi.ucsf.edu RI Papakostas, George/I-6905-2013 OI Papakostas, George/0000-0002-2465-5103 NR 34 TC 249 Z9 256 U1 4 U2 16 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2009 VL 166 IS 9 BP 980 EP 991 DI 10.1176/appi.ajp.2009.09030312 PG 12 WC Psychiatry SC Psychiatry GA 490FH UT WOS:000269483600009 PM 19687129 ER PT J AU Vinogradov, S Fisher, M Warm, H Holland, C Kirshner, MA Pollock, BG AF Vinogradov, Sophia Fisher, Melissa Warm, Heather Holland, Christine Kirshner, Margaret A. Pollock, Bruce G. TI The Cognitive Cost of Anticholinergic Burden: Decreased Response to Cognitive Training in Schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID REACTION-TIME-TASK; WORKING-MEMORY; SERUM ANTICHOLINERGICITY; DEPRESSED-PATIENTS; ATTENTION; PERFORMANCE; MODULATION; 192-IGG-SAPORIN; NEUROPLASTICITY; ACETYLCHOLINE AB Objective: Schizophrenia is treated with medications that raise serum anticholinergic activity and are known to adversely affect cognition. The authors examined the relationship between serum anticholinergic activity and baseline cognitive performance and response to computerized cognitive training in outpatients with schizophrenia. Method: Fifty-five patients were randomly assigned to either computerized cognitive training or a computer games control condition. A neurocognitive battery based on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was performed at baseline and after the intervention. Serum anticholinergic activity, measured at study entry by radioreceptor assay, was available for 49 patients. Results: Serum anticholinergic activity showed a significant negative correlation with baseline performance in verbal working memory and verbal learning and memory, accounting for 7% of the variance in these measures, independent of age, IQ, or symptom severity. Patients in the cognitive training condition (N=25) showed a significant gain in global cognition compared to those in the control condition, but this improvement was negatively correlated with anticholinergic burden. Serum anticholinergic activity uniquely accounted for 20% of the variance in global cognition change, independent of age, IQ, or symptom severity. Conclusions: Serum anticholinergic activity in schizophrenia patients shows a significant association with impaired performance in MATRICS-based measures of verbal working memory and verbal learning and memory and is significantly associated with a lowered response to an intensive course of computerized cognitive training. These findings underscore the cognitive cost of medications that carry a high anticholinergic burden. The findings also have implications for the design and evaluation of cognitive treatments for schizophrenia. C1 Univ Calif San Francisco, Langley Porter Psychiat Inst, Dept Psychiat, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, Mental Hlth Serv, San Francisco, CA USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Geriatr Psychopharmacol Lab, Pittsburgh, PA USA. Ctr Addict & Mental Hlth, Geriatr Mental Hlth Program, Toronto, ON, Canada. Rotman Res Inst, Toronto, ON, Canada. Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada. RP Vinogradov, S (reprint author), 116C-4150 Clement St, San Francisco, CA USA. EM sophia.vinogradov@ucsf.edu FU NIMH [RO1 MH068725-01A1]; San Francisco VA Medical Center; NIH/National Center for Research Resources; University of California San Francisco-Clinical and Translational Science Institute [UL1 RR024131] FX Supported by NIMH grant RO1 MH068725-01A1, the San Francisco VA Medical Center, and NIH/National Center for Research Resources, University of California San Francisco-Clinical and Translational Science Institute grant UL1 RR024131. The article's content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. NR 35 TC 74 Z9 77 U1 0 U2 10 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2009 VL 166 IS 9 BP 1055 EP 1062 DI 10.1176/appi.ajp.2009.09010017 PG 8 WC Psychiatry SC Psychiatry GA 490FH UT WOS:000269483600017 PM 19570929 ER PT J AU Seal, KH Metzler, TJ Gima, KS Bertenthal, D Maguen, S Marmar, CR AF Seal, Karen H. Metzler, Thomas J. Gima, Kristian S. Bertenthal, Daniel Maguen, Shira Marmar, Charles R. TI Trends and Risk Factors for Mental Health Diagnoses Among Iraq and Afghanistan Veterans Using Department of Veterans Affairs Health Care, 2002-2008 SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; WAR VETERANS; SYMPTOMS; ASSOCIATION; DEPLOYMENT; ATTRITION; PTSD AB Objectives. We sought to investigate longitudinal trends and risk factors for mental health diagnoses among Iraq and Afghanistan veterans. Methods. We determined the prevalence and predictors of mental health diagnoses among 289328 Iraq and Afghanistan veterans entering Veterans Affairs (VA) health care from 2002 to 2008 using national VA data. Results. Of 289328 Iraq and Afghanistan veterans, 106726 (36.9%) received mental health diagnoses; 62929 (21.8%) were diagnosed with posttraumatic stress disorder (PTSD) and 50432 (17.4%) with depression. Adjusted 2-year prevalence rates of PTSD increased 4 to 7 times after the invasion of Iraq. Active duty veterans younger than 25 years had higher rates of PTSD and alcohol and drug use disorder diagnoses compared with active duty veterans older than 40 years (adjusted relative risk=2.0 and 4.9, respectively). Women were at higher risk for depression than were men, but men had over twice the risk for drug use disorders. Greater combat exposure was associated with higher risk for PTSD. Conclusions. Mental health diagnoses increased substantially after the start of the Iraq War among specific subgroups of returned veterans entering VA health care. Early targeted interventions may prevent chronic mental illness. (Am J Public Health. 2009;99:1651-1658. doi:10.2105/AJPH.2008.150284) C1 [Seal, Karen H.; Metzler, Thomas J.; Gima, Kristian S.; Bertenthal, Daniel; Maguen, Shira; Marmar, Charles R.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Seal, Karen H.; Maguen, Shira; Marmar, Charles R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Seal, KH (reprint author), San Francisco VA Med Ctr, 1450 Clement St,Box 111A-1, San Francisco, CA 94121 USA. EM Karen.Seal@va.gov FU VA Health Services Research and Development Career Development Transition Award; VA Seattle Epidemiological Research and Information Center. FX This study was funded by a VA Health Services Research and Development Career Development Transition Award and the VA Seattle Epidemiological Research and Information Center.; We acknowledge and thank veterans of Iraq and Afghanistan for their service. NR 31 TC 317 Z9 317 U1 3 U2 25 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2009 VL 99 IS 9 BP 1651 EP 1658 DI 10.2105/AJPH.2008.150284 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 488FL UT WOS:000269334500024 PM 19608954 ER PT J AU Lin, HH Ezzati, M Chang, HY Murray, M AF Lin, Hsien-Ho Ezzati, Majid Chang, Hsing-Yi Murray, Megan TI Association between Tobacco Smoking and Active Tuberculosis in Taiwan Prospective Cohort Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE smoking; tuberculosis; cohort study; Taiwan ID PULMONARY TUBERCULOSIS; RISK-FACTORS; MYOCARDIAL-INFARCTION; CIGARETTE-SMOKING; SEX-DIFFERENCES; HONG-KONG; MORTALITY; CESSATION; GENDER; INDIA AB Rationale Previous case-control studies and a small number of cohort studies in high-risk populations have found an association between tobacco and active tuberculosis, but no cohort studies have been conducted in the general population on this association to date. Objectives: To investigate the association between tobacco smoking and active tuberculosis in a cohort of a general population. Methods: 17,699 participants (>= 12 y of age) in Taiwan National Health Interview Survey were followed up from 2001 to 2004. Smoking status and other covariates were measured by an in-person interview at baseline. Incident cases of active tuberculosis were identified from the National Health Insurance database. Multivariate logistic regression was used to estimate the association between smoking status and active tuberculosis, with adjustment for age, sex, alcohol consumption, socioeconomic status, and other covariates. Measurements and Main Results: Fifty-seven new cases of active tuberculosis occurred during the 3.3 years of follow-up. Current smoking was associated with an increased risk of active tuberculosis (adjusted odds ratio [OR], 1.94; 95% confidence interval, 1.01-3.73). The association was stronger among those less than 65 years of age (adjusted OR, 3.04) than those greater than 65 years of age (adjusted OR, 0.78; P-interaction = 0.036). We found significant dose-response relations for cigarettes per day (P-trend = 0.0036), years of smoking (P-trend = 0.023), and pack-years (P-trend = 0.0023). Conclusions: Tobacco smoking was associated with a twofold increased risk of active tuberculosis in a representative cohort of Taiwan's population. C1 [Lin, Hsien-Ho; Murray, Megan] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ezzati, Majid] Harvard Univ, Sch Publ Hlth, Dept Populat & Int Hlth, Boston, MA 02115 USA. [Ezzati, Majid] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Lin, Hsien-Ho] Mennonite Christian Hosp, Dept Community Hlth, Hualien, Taiwan. [Ezzati, Majid] Harvard Univ, Initiat Global Hlth, Cambridge, MA 02138 USA. [Chang, Hsing-Yi] Natl Hlth Res Inst, Ctr Hlth Policy Res & Dev, Miaoli, Taiwan. [Chang, Hsing-Yi] Natl Hlth Res Inst, Inst Populat Hlth Sci, Miaoli, Taiwan. [Murray, Megan] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Murray, Megan] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. RP Lin, HH (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 667 Huntington Ave,Kresge Bldg Room 801, Boston, MA 02115 USA. EM hhlin@hsph.harvard.edu RI Chang, Hsing-Yi /E-3973-2010; OI LIN, HSIEN-HO/0000-0002-7481-6016 FU World Bank through the International Union against Tuberculosis and Lung Disease; Taiwan American Foundation of Boston FX Supported by a grant from the World Bank through the International Union against Tuberculosis and Lung Disease and a fellowship from Taiwan American Foundation of Boston. NR 56 TC 77 Z9 78 U1 1 U2 6 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 SEP 1 PY 2009 VL 180 IS 5 BP 475 EP 480 DI 10.1164/rccm.200904-0549OC PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 489ZW UT WOS:000269467100014 PM 19542475 ER PT J AU Sheah, K Bredella, MA Warner, JJP Halpern, EF Palmer, WE AF Sheah, Kenneth Bredella, Miriam A. Warner, Jon J. P. Halpern, Elkan F. Palmer, William E. TI Transverse Thickening Along the Articular Surface of the Rotator Cuff Consistent With the Rotator Cable: Identification With MR Arthrography and Relevance in Rotator Cuff Evaluation SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE arthroscopy; MRI; rotator cable; rotator cuff; shoulder ID SUSPENSION BRIDGE; ANATOMY; LIGAMENTS; CAPSULE; CADAVER; JOINTS; TEARS; GROSS AB OBJECTIVE. The purposes of this study were to describe the imaging appearance of transverse thickening along the articular Surface of the supraspinatus and infraspinatus tendons presumed to represent the rotator cable on MR arthrographic images obtained with the shoulder in abduction and external rotation (ABER) and in the non-ABER position and to assess the role of the rotator cable in the diagnosis of rotator cuff tears. MATERIALS AND METHODS. The study group comprised 54 patients who underwent arthroscopy of the shoulder and preoperative MR arthrography in which ABER images were obtained. Two blinded reviewers independently examined the ABER and non-ABER images for the presence of the rotator cable and rotator cuff tears. RESULTS. In intact rotator cuffs, the presumed rotator cable was not well visualized on non-ABER images. In one case of prominent rotator cable, MR arthrography showed no tear on non-ABER images, but at arthroscopy, a partial-thickness undersurface tear was found. On non-ABER images, both readers readily visualized the rotator cable in eight and 10 of IS cases (44% and 56%) of partial-thickness undersurface tear and four of five cases (80%) of full-thickness tear. On ABER images, both readers readily Visualized the rotator cable in 15 and 17 of 31 cases (48% and 55%) of intact cuff, 14 and 15 of 18 cases (78% and 83%) of undersurface tear, and four and five cases (80% and 100%) of full-thickness tear. Interobserver agreement on cable visualization was almost perfect (kappa = 0.86). CONCLUSION. On non-ABER MR arthrographic images, thickening along the articular side of the supraspinatus and intraspinatus tendons presumed to represent the rotator cable suggests the presence of a partial-thickness rotator cuff tear. On ABER images, the cable is well defined in intact and torn rotator cuffs. C1 [Sheah, Kenneth; Bredella, Miriam A.; Halpern, Elkan F.; Palmer, William E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sheah, Kenneth; Bredella, Miriam A.; Warner, Jon J. P.; Halpern, Elkan F.; Palmer, William E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Warner, Jon J. P.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Palmer, WE (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,YAW 6030, Boston, MA 02114 USA. NR 13 TC 22 Z9 22 U1 1 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD SEP PY 2009 VL 193 IS 3 BP 679 EP 686 DI 10.2214/AJR.08.2285 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 487VN UT WOS:000269305600014 PM 19696281 ER PT J AU Sainani, NI Saokar, A Deshpande, V Fernandez-del Castillo, C Hahn, P Sahani, DV AF Sainani, Nisha I. Saokar, Anuradha Deshpande, Vikram Fernandez-del Castillo, Carlos Hahn, Peter Sahani, Dushyant V. TI Comparative Performance of MDCT and MRI With MR Cholangiopancreatography in Characterizing Small Pancreatic Cysts SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE MDCT; MR cholangiopancreatography; pancreatic cancer; pancreatic cysts ID PAPILLARY MUCINOUS NEOPLASMS; CLINICOPATHOLOGICAL CHARACTERISTICS; CLASSIFICATION-SYSTEM; SYMPTOMATIC PATIENTS; HELICAL CT; FOLLOW-UP; LESIONS; TUMORS; MANAGEMENT; MASSES AB OBJECTIVE. The objective Of Our study was to compare MDCT with MRI-MR cholangiopancreatography (MRCP) in characterizing small pancreatic cysts (<= 3 cm) and predicting aggressiveness. MATERIALS AND METHODS. In it retrospective analysis. contrast-enhanced MDCT and MRI examinations of 30 patients with 38 pathologically confirmed small pancreatic cysts were reviewed. MDCT and MRCP studies were independently evaluated by two readers for cyst morphology, cyst characterization, and prediction of lesion aggressiveness, which included lesions with moderate-grade dysplasia, high-grade dysplasia (carcinoma in situ), and invasive carcinomas. The sensitivity of MDCT and MRI for the detection of each morphologic feature, accuracy for cyst characterization, and predictive values for aggressiveness were calculated. RESULTS. Of 38 lesions, 14 were side-branch intraductal papillary mucinous neoplasms (IPMNs) 12 mixed IPMNs, six mucinous cystic neoplasms, and six nonneoplastic cysts. On histopathology, 26 lesions were nonaggressive (six nonneoplastic cysts, six benign mucinous cystic neoplasms, 14 low-grade dysplasias in IPMNs), whereas 12 lesions revealed aggressive biology (eight moderate-grade dysplasias, four high-grade dysplasias in IPMNs). The sensitivity of MRCP for the detection of morphologic features was better than that of MDCT, but the differences were not statistically significant (p = 0.25-1). Interreader agreement and MDCT-MRI agreement for morphologic features were good to perfect (kappa = 0.7-1). The accuracy of MDCT and MRI was higher in classifying cysts as mucinous or nonmucinous than in determining a specific diagnosis (71-84.2% vs 39.5-44.7%, respectively), whereas the accuracy of the two techniques in characterizing cysts into nonaggressive and aggressive categories was similar (MDCT vs MRI, 75-78% vs 78-86%, respectively; p > 0.05). CONCLUSION. MRI enables more confident assessment of the morphology of small cysts than MDCT, but the accuracy of the two imaging techniques for cyst characterization is comparable. MDCT and MRI have high accuracy in classifying cysts into mucinous and non-mucinous categories and perform similarly in estimating histologic aggressiveness. C1 [Sainani, Nisha I.; Saokar, Anuradha; Hahn, Peter; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent Radiol, Boston, MA 02114 USA. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Fernandez-del Castillo, Carlos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org NR 42 TC 51 Z9 51 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD SEP PY 2009 VL 193 IS 3 BP 722 EP 731 DI 10.2214/AJR.08.1253 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 487VN UT WOS:000269305600018 PM 19696285 ER PT J AU Abbara, S Mundo-Sagardia, JA Hoffmann, U Cury, RC AF Abbara, Suhny Mundo-Sagardia, Jorge A. Hoffmann, Udo Cury, Ricardo C. TI Cardiac CT Assessment of Left Atrial Accessory Appendages and Diverticula SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE atrial fibrillation; cardiac congenital disease; cardiac CT; left atrial accessory appendage; left atrial diverticulum; left atrial enlargement; thrombus; valvular heart disease ID JUXTAPOSITION; ANGIOGRAPHY AB OBJECTIVE. The purpose of this study is to describe the prevalence, morphology, size, and location of left atrial abnormalities including diverticula and accessory appendages in consecutive patients undergoing cardiac-gated CT for coronary artery evaluation. MATERIALS AND METHODS. Routine retrospectively gated contrast-enhanced 64-MDCT angiography (0.75-mm collimation, 330-milliseconds gantry rotation time) was performed in 529 consecutive patients. CT data sets were evaluated using axial, sagittal, coronal, and interactive multiplanar reconstructions; maximum intensity projections (MIPs) and interactive volume rendering. The presence, type, and location of left atrial appendages and diverticula were recorded. RESULTS. One hundred twenty-one patients had left atrial accessory appendages (n = 20) or left atrial diverticula (n = 81) or both (n = 20). One hundred four left atrial diverticula were found in 101 of the 529 patients (20%) and 44 accessory appendages in 41 patients (8%). of the atrial diverticula, 88% were superior and anterior, 9% were right lateral superior, and 3% were inferior. Of accessory appendages, 34% were inferior posterior, 32% were left inferior, 18% were superior anterior, 14% were inferior posterior, and 2% were right inferior posterior. The average sizes of diverticula were 6.4 +/- 2.5 x 6.2 +/- 2.4 mm, and accessory appendages were 4.9 +/- 2.1 x 3.9 +/- 2.4 mm. CONCLUSION. Left atrial diverticula and accessory appendages are commonly found on cardiac-gated CT. C1 [Abbara, Suhny; Mundo-Sagardia, Jorge A.; Hoffmann, Udo; Cury, Ricardo C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Sect Cardiovasc Imaging, Boston, MA 02114 USA. RP Abbara, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Sect Cardiovasc Imaging, 55 Fruit St,GRB-290, Boston, MA 02114 USA. EM sabbara@partners.org NR 12 TC 22 Z9 22 U1 1 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD SEP PY 2009 VL 193 IS 3 BP 807 EP 812 DI 10.2214/AJR.08.2229 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 487VN UT WOS:000269305600029 PM 19696296 ER PT J AU Song, EK Oh, LS Gill, TJ Li, G Gadikota, HR Seon, JK AF Song, Eun Kyoo Oh, Luke S. Gill, Thomas J. Li, Guoan Gadikota, Hemanth R. Seon, Jong Keun TI Prospective Comparative Study of Anterior Cruciate Ligament Reconstruction Using the Double-Bundle and Single-Bundle Techniques SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Orthopaedic-Society-for-Sports-Medicine CY JUL 09-12, 2009 CL Keystone, CO SP Amer Orthopaed Soc Sports Med DE anterior cruciate ligament; double-bundle; single-bundle; intraoperative stabilities; clinical outcomes ID HAMSTRING TENDON GRAFTS; IN-SITU FORCES; ACL RECONSTRUCTION; ANATOMIC RECONSTRUCTION; POSTEROLATERAL BUNDLES; NAVIGATION SYSTEM; KNEE-JOINT; KINEMATICS; LOADS; FIXATION AB Background: The intent of double-bundle anterior cruciate ligament reconstruction is to reproduce the normal anterior cruciate ligament anatomy and improve knee joint rotational stability. However, no consensus has been reached on the advantages of this technique over the single-bundle technique. Hypothesis: We hypothesized that double-bundle anterior cruciate ligament reconstruction could provide better intraoperative stability and clinical outcome than single-bundle reconstruction. Type of study: Cohort study; Level of evidence, 2. Methods: Forty patients with anterior cruciate ligament injury in one knee were recruited; 20 were allocated to a double-bundle anterior cruciate ligament reconstruction group and 20 to a single-bundle anterior cruciate ligament reconstruction group. Intraoperative stabilities at 30 degrees of knee flexion were compared between the 2 groups using a navigation system. Clinical outcomes including Lysholm knee scores, Tegner activity scores, Lachman and pivot-shift test results, and radiographic stabilities were also compared between the 2 groups after a minimum of 2 years of follow-up. Results: Intraoperative anterior and rotational stabilities after anterior cruciate ligament reconstruction in the double-bundle group were significantly better than those in single-bundle group (P = .020 and P < .001, respectively). Nineteen patients (95%) in each group were available at a minimum 2-year follow-up. Clinical outcomes including Lysholm knee and Tegner activity scores were similar in the 2 groups at 2-year follow-up (P > .05). Furthermore, stability results of the Lachman and pivot-shift tests, and radiologic findings at 2-year follow-up failed to reveal any significant intergroup differences (P > .05). Conclusion: Although double-bundle anterior cruciate ligament reconstruction produces better intraoperative stabilities than single-bundle anterior cruciate ligament reconstruction, the 2 modalities were found to be similar in terms of clinical outcomes and postoperative stabilities after a minimum of 2 years of follow-up. C1 [Song, Eun Kyoo; Seon, Jong Keun] Chonnam Natl Univ, Hwasun Hosp, Dept Orthopaed, Jeonnam 519809, South Korea. [Oh, Luke S.; Gill, Thomas J.; Li, Guoan; Gadikota, Hemanth R.; Seon, Jong Keun] Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. [Oh, Luke S.; Gill, Thomas J.; Li, Guoan; Gadikota, Hemanth R.; Seon, Jong Keun] Harvard Univ, Sch Med, Boston, MA USA. RP Seon, JK (reprint author), Chonnam Natl Univ, Hwasun Hosp, Dept Orthopaed, Jeonnam 519809, South Korea. EM seonbell@yahoo.co.kr OI Oh, Luke/0000-0002-6610-8204 FU NIAMS NIH HHS [R01 AR055612] NR 33 TC 32 Z9 36 U1 0 U2 1 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 SEP PY 2009 VL 37 IS 9 BP 1705 EP 1711 DI 10.1177/0363546509333478 PG 7 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 487FO UT WOS:000269256500005 PM 19509412 ER PT J AU Javid, SH Kirstein, LJ Rafferty, E Lipsitz, S Moore, R Rusby, JE Murphy, CD Hughes, KS Specht, MC Taghian, AG Smith, BL AF Javid, Sara H. Kirstein, Laurie J. Rafferty, Elizabeth Lipsitz, Stuart Moore, Richard Rusby, Jennifer E. Murphy, Colleen D. Hughes, Kevin S. Specht, Michelle C. Taghian, Alphonse G. Smith, Barbara L. TI Outcome of multiple-wire localization for larger breast cancers: do multiple wires translate into additional imaging, biopsies, and recurrences? SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Breast cancer; Multiple wire localization; Local recurrence ID COMPARING TOTAL MASTECTOMY; CARCINOMA IN-SITU; 20-YEAR FOLLOW-UP; CONSERVING SURGERY; MARGIN STATUS; CONSERVATION SURGERY; RADIATION-THERAPY; LOCAL RECURRENCE; RESIDUAL DISEASE; MAMMOGRAPHY AB BACKGROUND: Breast conservation is possible in breast cancer patients whose mammographic lesions are large enough to require multiple localizing wires for excision. METHODS: A retrospective review of 112 patients who underwent multiple-wire and 160 controls who underwent single-wire lumpectomy for breast cancer. Rates of in-breast recurrence, metastasis, and additional imaging and biopsy procedures were calculated. RESULTS: The median follow-up was 24 months. One multiple-wire and 2 single-wire patients developed in-breast recurrences (P = .84). No distant metastases developed among the multiple-wire patients. Additional follow-up imaging was obtained in 29% of multiple-wire and 22% of single-wire cases (P = .1). Seven (6%) of the multiple-wire and 11 (6%) of the single-wire cases underwent biopsy (P = .94). CONCLUSIONS: We found no increased risk of early local recurrence, metastasis, or additional imaging or biopsies in patients requiring multiple-wire localization for lumpectomy. Breast conservation should be considered a safe option even for patients with mammographically extensive lesions. (C) 2009 Elsevier Inc. All rights reserved. C1 [Javid, Sara H.; Kirstein, Laurie J.; Rusby, Jennifer E.; Murphy, Colleen D.; Hughes, Kevin S.; Specht, Michelle C.; Smith, Barbara L.] Dept Surg, Div Surg Oncol, Boston, MA 02114 USA. [Rafferty, Elizabeth; Moore, Richard] Massachusetts Gen Hosp, Dept Radiol, Div Breast Imaging, Boston, MA 02114 USA. [Lipsitz, Stuart] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Taghian, Alphonse G.] Massachusetts Gen Hosp, Div Radiat Oncol, Boston, MA 02114 USA. RP Smith, BL (reprint author), Dept Surg, Div Surg Oncol, 55 Fruit St,Yawkey 9A, Boston, MA 02114 USA. EM blsmith1@partners.org OI Hughes, Kevin/0000-0003-4084-6484 NR 18 TC 5 Z9 5 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 J9 AM J SURG JI Am. J. Surg. PD SEP PY 2009 VL 198 IS 3 BP 368 EP 372 DI 10.1016/j.amjsurg.2009.01.021 PG 5 WC Surgery SC Surgery GA 502FK UT WOS:000270440800011 PM 19716884 ER PT J AU Kumbhani, DJ Healey, NA Thatte, HS Birjiniuk, V Crittenden, MD Treanor, PR Khuri, SF AF Kumbhani, Dharam J. Healey, Nancy A. Thatte, Hemant S. Birjiniuk, Vladimir Crittenden, Michael D. Treanor, Patrick R. Khuri, Shukri F. TI Intraoperative myocardial acidosis as a risk for hospital readmission after cardiac surgery SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Cardiopulmonary bypass; Coronary artery bypass graft surgery; Ischemia; Reperfusion; Myocardial protection; Outcomes ID CORONARY-ARTERY-BYPASS; INTENSIVE-CARE; GRAFT-SURGERY; OUTCOMES; PREDICTORS; PH; REVASCULARIZATION AB BACKGROUND: This study elucidates the relationship between intraoperative myocardial acidosis/ischemia and the risk of unplanned hospital readmissions within 30 days and 6 months after cardiac surgery. METHODS: Myocardial tissue pH (corrected to 37 degrees C: pH(37C)) was monitored in 221 patients during cardiac surgery. Regional myocardial acidosis was defined in terms of specific pH thresholds. RESULTS: Fourteen percent and 27% of the patients were readmitted within 30 days and 6 month's postoperatively, respectively. The mean number of readmissions was 1.67 +/- 1.24; pH(37C) <6.85 at the end of cardiopulmonary bypass (CPB) was identified as the threshold most significantly associated with readmission. This threshold was associated with a 6-fold increased risk of readmission within 30 days and a 5-fold increased risk within 6 months. CONCLUSIONS: Persistent regional myocardial acidosis after weaning from CPB independently determines unplanned readmission rates up to 6 months postoperatively. This study underscores the importance of avoiding myocardial tissue acidosis during cardiac surgery. Published by Elsevier Inc. C1 [Crittenden, Michael D.; Khuri, Shukri F.] VA Boston Healthcare Syst, Cardiothorac Surg 112, W Roxbury, MA 02132 USA. [Kumbhani, Dharam J.; Healey, Nancy A.; Thatte, Hemant S.; Birjiniuk, Vladimir; Treanor, Patrick R.; Khuri, Shukri F.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kumbhani, Dharam J.; Healey, Nancy A.; Thatte, Hemant S.; Birjiniuk, Vladimir; Treanor, Patrick R.; Khuri, Shukri F.] Harvard Univ, Sch Med, Surg Serv, VA Boston Healthcare Syst, Boston, MA USA. RP Crittenden, MD (reprint author), VA Boston Healthcare Syst, Cardiothorac Surg 112, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM Michael.Crittenden@va.gov FU Richard Warren Surgical Research and Educational Fund, Westwood, MA FX Supported by the Richard Warren Surgical Research and Educational Fund, Westwood, MA. NR 26 TC 3 Z9 3 U1 1 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD SEP PY 2009 VL 198 IS 3 BP 373 EP 380 DI 10.1016/j.amjsurg.2009.01.013 PG 8 WC Surgery SC Surgery GA 502FK UT WOS:000270440800012 PM 19716885 ER PT J AU McGuire, BM Rosenthal, P Brown, CC Busch, AMH Calcatera, SM Claria, RS Hunt, NK Korenblat, KM Mazariegos, GV Moonka, D Orloff, SL Perry, DK Rosen, CB Scott, DL Sudan, DL AF McGuire, B. M. Rosenthal, P. Brown, C. C. Busch, A. M. H. Calcatera, S. M. Claria, R. S. Hunt, N. K. Korenblat, K. M. Mazariegos, G. V. Moonka, D. Orloff, S. L. Perry, D. K. Rosen, C. B. Scott, D. L. Sudan, D. L. TI Long-term Management of the Liver Transplant Patient: Recommendations for the Primary Care Doctor SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Review DE Immunosuppression; liver; long-term; management; transplantation ID BILIARY-TRACT COMPLICATIONS; CHRONIC HEPATITIS-C; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; BARR-VIRUS INFECTION; QUALITY-OF-LIFE; LATE GRAFT LOSS; CALCINEURIN INHIBITORS; MYCOPHENOLATE-MOFETIL; RENAL DYSFUNCTION; UNITED-STATES AB No official document has been published for primary care physicians regarding the management of liver transplant patients. With no official source of reference, primary care physicians often question their care of these patients. The following guidelines have been approved by the American Society of Transplantation and represent the position of the association. The data presented are based on formal review and analysis of published literature in the field and the clinical experience of the authors. These guidelines address drug interactions and side effects of immunosuppressive agents, allograft dysfunction, renal dysfunction, metabolic disorders, preventive medicine, malignancies, disability and productivity in the workforce, issues specific to pregnancy and sexual function, and pediatric patient concerns. These guidelines are intended to provide a bridge between transplant centers and primary care physicians in the long-term management of the liver transplant patient. C1 [McGuire, B. M.; Brown, C. C.; Calcatera, S. M.; Hunt, N. K.] Univ Alabama, Birmingham, AL USA. [Rosenthal, P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Busch, A. M. H.] Portland VA Med Ctr, Portland, OR USA. [Claria, R. S.] Univ Nebraska, Omaha, NE 68182 USA. [Korenblat, K. M.] Washington Univ, St Louis, MO USA. [Mazariegos, G. V.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Orloff, S. L.; Scott, D. L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Moonka, D.] Henry Ford Hosp, Detroit, MI 48202 USA. [Perry, D. K.; Rosen, C. B.] Mayo Clin, Rochester, MN USA. [Sudan, D. L.] Duke Univ, Durham, NC USA. RP McGuire, BM (reprint author), Univ Alabama, Birmingham, AL USA. EM bmcguire@uab.edu NR 124 TC 29 Z9 31 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD SEP PY 2009 VL 9 IS 9 BP 1988 EP 2003 DI 10.1111/j.1600-6143.2009.02733.x PG 16 WC Surgery; Transplantation SC Surgery; Transplantation GA 486FE UT WOS:000269180500005 PM 19563332 ER PT J AU Reich, DJ Mulligan, DC Abt, PL Pruett, TL Abecassis, MMI D'Alessandro, A Pomfret, EA Freeman, RB Markmann, JF Hanto, DW Matas, AJ Roberts, JP Merion, RM Klintmalm, GBG AF Reich, D. J. Mulligan, D. C. Abt, P. L. Pruett, T. L. Abecassis, M. M. I. D'Alessandro, A. Pomfret, E. A. Freeman, R. B. Markmann, J. F. Hanto, D. W. Matas, A. J. Roberts, J. P. Merion, R. M. Klintmalm, G. B. G. CA ASTS Stand Organ Transplantation C TI ASTS Recommended Practice Guidelines for Controlled Donation after Cardiac Death Organ Procurement and Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Expanded criteria donors; extended donor criteria; extended donor pool ID HEART-BEATING DONORS; NONANASTOMOTIC BILIARY STRICTURES; CONTROLLED NONHEARTBEATING DONORS; LIVER-TRANSPLANTATION; RISK-FACTORS; KIDNEY-TRANSPLANTATION; GRAFT-SURVIVAL; UNITED-STATES; EXPERIENCE; COMPLICATIONS AB The American Society of Transplant Surgeons (ASTS) champions efforts to increase organ donation. Controlled donation after cardiac death (DCD) offers the family and the patient with a hopeless prognosis the option to donate when brain death criteria will not be met. Although DCD is increasing, this endeavor is still in the midst of development. DCD protocols, recovery techniques and organ acceptance criteria vary among organ procurement organizations and transplant centers. Growing enthusiasm for DCD has been tempered by the decreased yield of transplantable organs and less favorable posttransplant outcomes compared with donation after brain death. Logistics and ethics relevant to DCD engender discussion and debate among lay and medical communities. Regulatory oversight of the mandate to increase DCD and a recent lawsuit involving professional behavior during an attempted DCD have fueled scrutiny of this activity. Within this setting, the ASTS Council sought best-practice guidelines for controlled DCD organ donation and transplantation. The proposed guidelines are evidence based when possible. They cover many aspects of DCD kidney, liver and pancreas transplantation, including donor characteristics, consent, withdrawal of ventilatory support, operative technique, ischemia times, machine perfusion, recipient considerations and biliary issues. DCD organ transplantation involves unique challenges that these recommendations seek to address. C1 [Reich, D. J.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Mulligan, D. C.] Mayo Clin, Scottsdale, AZ USA. [Pruett, T. L.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Abt, P. L.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Abecassis, M. M. I.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [D'Alessandro, A.] Univ Wisconsin, Sch Med, Madison, WI USA. [Pomfret, E. A.] Lahey Clin Fdn, Burlington, MA USA. [Freeman, R. B.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Markmann, J. F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hanto, D. W.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Matas, A. J.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Roberts, J. P.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Merion, R. M.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Klintmalm, G. B. G.] Baylor Univ, Med Ctr, Dallas, TX USA. RP Reich, DJ (reprint author), Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. EM david.reich@drexelmed.edu RI Abecassis, Michael/F-7977-2011 NR 46 TC 140 Z9 160 U1 0 U2 12 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD SEP PY 2009 VL 9 IS 9 BP 2004 EP 2011 DI 10.1111/j.1600-6143.2009.02739.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 486FE UT WOS:000269180500006 PM 19624569 ER PT J AU Cadena, J Levine, DJ Angel, LF Maxwell, PR Brady, R Sanchez, JF Michalek, JE Levine, SM Restrepo, MI AF Cadena, J. Levine, D. J. Angel, L. F. Maxwell, P. R. Brady, R. Sanchez, J. F. Michalek, J. E. Levine, S. M. Restrepo, M. I. TI Antifungal Prophylaxis with Voriconazole or Itraconazole in Lung Transplant Recipients: Hepatotoxicity and Effectiveness SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Aspergillus; itraconazole; lung transplantation; prophylaxis; voriconazole ID INVASIVE FUNGAL-INFECTIONS; STEM-CELL TRANSPLANTS; ASPERGILLUS INFECTIONS; CLINICAL-PRACTICE; AMPHOTERICIN-B; THERAPY; ZYGOMYCOSIS; GUIDELINES; MANAGEMENT; CONSENSUS AB This is a retrospective study in lung transplant recipients from July 2003 to July 2006 who received antifungal prophylaxis with itraconazole or voriconazole plus inhaled amphotericin B to compare the incidence of hepatotoxicity. Secondary outcomes include describing the incidence of IFI, clinical outcomes after IFI and mortality. Sixty-seven consecutive lung transplants received antifungal prophylaxis, 32 itraconazole and 35 voriconazole and inhaled amphotericin B. There were no significant differences between groups in the acute physiology and chronic health evaluation (APACHE) score at the time of transplantation, demographic characteristics, comorbidities and concomitant use of hepatotoxic medications. Hepatotoxicity occurred in 12 patients receiving voriconazole and inhaled amphotericin B and in no patients receiving itraconazole (p < 0.001). There was no significant difference between groups with regard to the percentage of transplants with IFI, but one case of zygomycosis occurred in a transplant treated with voriconazole. Voriconazole prophylaxis after lung transplantation was associated with a higher incidence of hepatotoxicity and similar clinical effectiveness when compared to itraconazole. C1 [Cadena, J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Infect Dis, San Antonio, TX 78229 USA. [Levine, D. J.; Angel, L. F.; Sanchez, J. F.; Levine, S. M.; Restrepo, M. I.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Pulm & Crit Care, San Antonio, TX 78229 USA. [Angel, L. F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Cardiothorac Surg, San Antonio, TX 78229 USA. [Maxwell, P. R.; Brady, R.] Univ Hlth Syst, Dept Pharm, San Antonio, TX USA. [Michalek, J. E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Restrepo, M. I.] S Texas Vet Hlth Care Syst, VERDICT, Audie L Murphy Div, San Antonio, TX USA. RP Cadena, J (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Infect Dis, San Antonio, TX 78229 USA. EM cadenazuluag@uthscsa.edu RI Restrepo, Marcos/H-4442-2014 FU Department of Veterans Affairs Veterans Integrated Service Network 17; National Health Institute [KL2] FX Dr. Restrepo is supported by a Department of Veterans Affairs Veterans Integrated Service Network 17 new faculty grant and National Health Institute KL2 Grant. NR 40 TC 47 Z9 48 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD SEP PY 2009 VL 9 IS 9 BP 2085 EP 2091 DI 10.1111/j.1600-6143.2009.02734.x PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 486FE UT WOS:000269180500014 PM 19645709 ER PT J AU Porcheray, F Wong, W Saidman, SL De Vito, J Girouard, TC Chittenden, M Shaffer, J Tolkoff-Rubin, N Dey, BR Spitzer, TR Colvin, RB Cosimi, AB Kawai, T Sachs, DH Sykes, M Zorn, E AF Porcheray, F. Wong, W. Saidman, S. L. De Vito, J. Girouard, T. C. Chittenden, M. Shaffer, J. Tolkoff-Rubin, N. Dey, B. R. Spitzer, T. R. Colvin, R. B. Cosimi, A. B. Kawai, T. Sachs, D. H. Sykes, M. Zorn, E. TI B-Cell Immunity in the Context of T-Cell Tolerance after Combined Kidney and Bone Marrow Transplantation in Humans SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Antibodies; B cell; tolerance induction ID VERSUS-HOST-DISEASE; CARDIAC TRANSPLANTATION; MULTIPLE-SCLEROSIS; AUTOANTIBODIES; REJECTION; PROTEASOME; ANTIBODIES; MAINTENANCE; LDL AB Five patients with end-stage kidney disease received combined kidney and bone marrow transplants from HLA haploidentical donors following nonmyeloablative conditioning to induce renal allograft tolerance. Immunosuppressive therapy was successfully discontinued in four patients with subsequent follow-up of 3 to more than 6 years. This allograft acceptance was accompanied by specific T-cell unresponsiveness to donor antigens. However, two of these four patients showed evidence of de novo antibodies reactive to donor antigens between 1 and 2 years posttransplant. These humoral responses were characterized by the presence of donor HLA-specific antibodies in the serum with or without the deposition of the complement molecule C4d in the graft. Immunofluorescence staining, ELISA assays and antibody profiling using protein microarrays demonstrated the co-development of auto- and alloantibodies in these two patients. These responses were preceded by elevated serum BAFF levels and coincided with B-cell reconstitution as revealed by a high frequency of transitional B cells in the periphery. To date, these B cell responses have not been associated with evidence of humoral rejection and their clinical significance is still unclear. Overall, our findings showed the development of B-cell allo- and autoimmunity in patients with T-cell tolerance to the donor graft. C1 [Porcheray, F.; De Vito, J.; Chittenden, M.; Shaffer, J.; Sachs, D. H.; Sykes, M.; Zorn, E.] Harvard Univ, Sch Med, Dept Surg, Transplantat Biol Res Ctr, Boston, MA 02115 USA. [Wong, W.; Tolkoff-Rubin, N.] Harvard Univ, Sch Med, Dept Med, Renal Unit, Boston, MA USA. [Saidman, S. L.; Girouard, T. C.; Colvin, R. B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Dey, B. R.; Spitzer, T. R.] Harvard Univ, Sch Med, Dept Med, Div Bone Marrow Transplantat, Boston, MA USA. [Cosimi, A. B.; Kawai, T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Transplant Unit, Boston, MA USA. RP Zorn, E (reprint author), Harvard Univ, Sch Med, Dept Surg, Transplantat Biol Res Ctr, Boston, MA 02115 USA. EM emmanuel.zorn@tbrc.mgh.harvard.edu RI porcheray, fabrice/B-9505-2012 FU National Institute of Allergy and Infectious Diseases [N01-AI-15416]; National Institute of Diabetes and Digestive and Kidney Diseases; Juvenile Diabetes Research Foundation FX The four patients under study were initially enrolled in a clinical trial supported by a contract from the Immune Tolerance Network (N01-AI-15416) sponsored by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Research Foundation. We are indebted to Drs Christian Leguern and Christene Huang for their thoughtful review of our manuscript. NR 22 TC 49 Z9 52 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD SEP PY 2009 VL 9 IS 9 BP 2126 EP 2135 DI 10.1111/j.1600-6143.2009.02738.x PG 10 WC Surgery; Transplantation SC Surgery; Transplantation GA 486FE UT WOS:000269180500019 PM 19624570 ER PT J AU Fitzsimons, MG Baker, KH AF Fitzsimons, Michael G. Baker, Keith H. TI Not All Strikes Are Easy to Call SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material ID DEPENDENCY TREATMENT OUTCOMES; ANESTHESIA TRAINING-PROGRAMS; IMPAIRED PHYSICIANS; SUBSTANCE-ABUSE; RESIDENTS C1 [Fitzsimons, Michael G.; Baker, Keith H.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Fitzsimons, MG (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM mfitzsimons@partners.org NR 12 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD SEP PY 2009 VL 109 IS 3 BP 693 EP 694 DI 10.1213/ane.0b013e3181adc826 PG 2 WC Anesthesiology SC Anesthesiology GA 488EB UT WOS:000269330800002 PM 19690233 ER PT J AU Sandberg, WS AF Sandberg, Warren S. TI Barbarians at the Gate SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material ID CLOSED-LOOP CONTROL; BISPECTRAL INDEX; ANESTHESIA GROUP; CONTROL-SYSTEM; PROPOFOL C1 [Sandberg, Warren S.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Sandberg, Warren S.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. RP Sandberg, WS (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St,Jackson 4, Boston, MA 02114 USA. EM wsandberg@partners.org OI Sandberg, Warren/0000-0002-9246-777X NR 14 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD SEP PY 2009 VL 109 IS 3 BP 695 EP 699 DI 10.1213/ane.0b013e3181af803e PG 5 WC Anesthesiology SC Anesthesiology GA 488EB UT WOS:000269330800003 PM 19690234 ER PT J AU Long, AA Fish, JE Rahmaoui, A Miller, MK Bradley, MS Taki, HN Demeo, AN Tilles, SA Szefler, SJ AF Long, Aidan A. Fish, James E. Rahmaoui, Abdelkader Miller, Mary K. Bradley, Mary S. Taki, Hassan N. Demeo, Anthony N. Tilles, Stephen A. Szefler, Stanley J. TI Baseline characteristics of patients enrolled in EXCELS: a cohort study SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID SEVERE ALLERGIC-ASTHMA; TO-TREAT ASTHMA; SEVERE PERSISTENT ASTHMA; ANTI-IGE ANTIBODY; QUALITY-OF-LIFE; ACTIVITY IMPAIRMENT; WORK PRODUCTIVITY; OMALIZUMAB; POPULATION; SEVERITY AB Background: The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) is a unique opportunity to evaluate the prospective, long-term clinical safety and effectiveness of the anti-IgE antibody omalizumab (Xolair) in real-world clinical practice. Objectives: To describe the study design and study cohorts of EXCELS at baseline and to compare the characteristics of this population with other large asthma cohorts. Methods: Patients with moderate-to-severe persistent asthma and a positive skin test result or in vitro reactivity to a perennial aeroallergen were eligible for EXCELS. Two cohorts of patients with asthma were enrolled: those treated with omalizumab and those not treated with omalizumab. We analyzed baseline demographic and clinical characteristics, including asthma history and control and allergy history. Results: Large proportions of patients enrolled in EXCELS had historically severe and poorly or not well-controlled asthma at the time of enrollment, objective evidence of airway obstruction, a history of long-term oral corticosteroid use, and/or other allergic disorders. Minor differences were observed between the omalizumab and nonomalizumab cohorts. Our total patient cohort was generally similar to other large cohorts. In a subgroup analysis, patients who had received omalizumab within 7 days before enrollment had more severe asthma and greater degrees of impairment at baseline than nonomalizumab patients. Conclusions: This study of baseline characteristics in EXCELS offers a unique opportunity to better understand the history of allergic patients with m oderate-to-severe asthma in a real-world treatment setting. This analysis of EXCELS baseline data sets the foundation for long-term assessment of the safety and effectiveness of omalizumab. Anti Allergy Asthma Immunol. 2009;103:212-219. C1 [Long, Aidan A.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Fish, James E.; Rahmaoui, Abdelkader; Miller, Mary K.; Bradley, Mary S.] Genentech Inc, San Francisco, CA 94080 USA. [Taki, Hassan N.] Ft Wayne Med Inst, Ft Wayne, IN USA. [Demeo, Anthony N.] John Muir Med Ctr, Walnut Creek, CA USA. [Tilles, Stephen A.] Univ Washington, Sch Med, NW Asthma & Allergy Ctr, Seattle, WA USA. [Szefler, Stanley J.] Natl Jewish Hlth, Denver, CO USA. RP Long, AA (reprint author), Cox 201,545 Fruit St, Boston, MA 02114 USA. EM aalong@partners.org FU Genentech Inc; Novartis Pharmaceuticals Corp FX EXCELS is sponsored by Genentech Inc and Novartis Pharmaceuticals Corp. NR 35 TC 28 Z9 28 U1 0 U2 2 PU AMER COLL ALLERGY ASTHMA IMMUNOLOGY PI ARLINGTON HTS PA 85 WEST ALGONQUIN RD SUITE 550, ARLINGTON HTS, IL 60005 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD SEP PY 2009 VL 103 IS 3 BP 212 EP 219 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 495QF UT WOS:000269908300007 PM 19788018 ER PT J AU Johnson, WE Liu, XS Liu, JS AF Johnson, W. Evan Liu, X. Shirley Liu, Jun S. TI DOUBLY STOCHASTIC CONTINUOUS-TIME HIDDEN MARKOV APPROACH FOR ANALYZING GENOME TILING ARRAYS SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Tiling microarray; continuous-space Markov chain; Hidden Markov Model; forward-backward algorithm; Bayesian hierarchical model; Expectation Conditional Maximization; Markov chain Monte Carlo ID CHIP-CHIP EXPERIMENTS; MODEL-BASED ANALYSIS; TRANSCRIPTION; CHROMOSOME-22 AB Microarrays have been developed that the the entire nonrepetitive genomes of many different organisms, allowing for the unbiased mapping of active transcription regions or protein binding sites across the entire genome. These tiling array experiments produce massive correlated data sets that have many experimental artifacts, presenting many challenges to researchers that require innovative analysis methods and efficient computational algorithms. This paper presents a doubly stochastic latent variable analysis method for transcript discovery and protein binding region localization using tiling array data. This model is unique in that it considers actual genomic distance between probes. Additionally, the model is designed to be robust to cross-hybridized and nonresponsive probes, which can often lead to false-positive results in microarray experiments. We apply our model to a transcript finding data set to illustrate the consistency of our method. Additionally, we apply our method to a spike-in experiment that can be used as a benchmark data set for researchers interested in developing and comparing future tiling array methods. The results indicate that our method is very powerful, accurate and can be used on a single sample and without control experiments, thus defraying some of the overhead cost of conducting experiments on tiling arrays. C1 [Johnson, W. Evan] Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. [Liu, Jun S.] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Dept Biostat & Computat Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Johnson, WE (reprint author), Brigham Young Univ, Dept Stat, 223 TMCB, Provo, UT 84602 USA. EM evan@stat.byu.edu; jliu@stat.harvard.edu; jliu@stat.harvard.edu FU NIH [T32-CA009337, R01-HG004069, R01-GM078990]; NSF [DMS-0706989] FX Supported in part by NIH Grants T32-CA009337 (WEJ), R01-HG004069 (XSL) and R01-GM078990 (JSL), and NSF Grant DMS-0706989 (JSL). NR 16 TC 4 Z9 4 U1 0 U2 1 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD SEP PY 2009 VL 3 IS 3 BP 1183 EP 1203 DI 10.1214/09-AOAS248 PG 21 WC Statistics & Probability SC Mathematics GA 522EF UT WOS:000271979900015 ER PT J AU Ginde, AA Sullivan, AF Camargo, CA AF Ginde, Adit A. Sullivan, Ashley F. Camargo, Carlos A., Jr. TI National Study of the Emergency Physician Workforce, 2008 SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID GENERAL-SURGERY WORKFORCE; UNITED-STATES; MEDICINE; DEPARTMENTS AB Study objective: We describe the characteristics of the US emergency physician workforce. Methods: We performed a cross-sectional analysis of the 2008 American Medical Association Physician Masterfile, which includes data on all physicians who have ever obtained a medical license in at least 1 US state. We included all physicians who designated emergency medicine as their primary or secondary specialty. Results: There were 39,061 clinically active emergency physicians, of which 57% were emergency medicine board certified and 69% were emergency medicine trained or emergency medicine board certified. Family medicine (31%) and internal medicine (23%) were the most common backgrounds for non-emergency medicine-trained/emergency medicine board certified emergency physicians, and most (75%) graduated from residency greater than or equal to 20 years ago. Nearly all (98%) emergency physicians who graduated within the past 5 years were emergency medicine trained or emergency medicine board certified. Rural emergency physicians were much less likely than urban emergency physicians to have emergency medicine training (31% versus 57%), emergency medicine board certified (43% versus 59%), and to have graduated in the past 5 years (8% versus 19%). The density of all emergency physicians per 100,000 population was highest in New England (16.0) and in urban areas (14.5). The lowest emergency physician densities were in West South Central (10.2) and rural areas (10.3). Density of emergency medicine-trained or emergency medicine board certified emergency physicians was 10.3 in urban, 5.3 in large rural, and 2.5 in small rural areas. Conclusion: Although newer emergency physicians are almost all emergency medicine trained or emergency medicine board certified, many non-emergency medicine-trained/emergency medicine board certified emergency physicians still provide clinical coverage of EDs. Demand for all emergency physicians will likely continue for several decades and the shortage may even increase in rural areas. [Ann Emerg Med. 2009;54:349-359.] C1 [Ginde, Adit A.] Univ Colorado, Denver Sch Med, Dept Emergency Med, Aurora, CO 80045 USA. [Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Ginde, AA (reprint author), Univ Colorado, Denver Sch Med, Dept Emergency Med, 12401 E 17th Ave,B-215, Aurora, CO 80045 USA. EM adit.ginde@ucdenver.edu RI Siry, Bonnie/D-7189-2017 NR 35 TC 42 Z9 45 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 BP 349 EP 359 DI 10.1016/j.annemergmed.2009.03.016 PG 11 WC Emergency Medicine SC Emergency Medicine GA 488JM UT WOS:000269345900011 PM 19398242 ER PT J AU Liu, SW Thomas, SH Gordon, JA Hamedani, AG Weissman, JS AF Liu, Shan W. Thomas, Stephen H. Gordon, James A. Hamedani, Azita G. Weissman, Joel S. TI A Pilot Study Examining Undesirable Events Among Emergency Department-Boarded Patients Awaiting Inpatient Beds SO ANNALS OF EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Academic-Emergency-Medicine (SAEM) CY MAY 22-25, 2005 CL New York, NY SP Soc Acad Emergency Med ID ADVERSE EVENTS; MANAGEMENT; CARE; PAIN AB Study objective: We describe the frequency of undesirable events among patients boarding at a single, urban, tertiary, teaching emergency department (ED) through retrospective chart abstraction. Methods: This was a chart review of all patients admitted during 3 randomly selected days in 2003 (n=162) to track the frequency of undesirable events such as missed relevant home medications, missed laboratory test results, arrhythmias, or other adverse events. Results: One hundred fifty-one charts were abstracted (93.2%); 27.8% had an undesirable event, 17.9% missed a relevant home medication, and 3.3% had a preventable adverse event. There was a higher frequency of undesirable events among older patients (35.9%, aged >50 years; 7.3%, aged 20 to 49 years; 28.6%, aged 0 to 19 years) and those with more comorbidities (44.4% among Charlson score >= 3; 30.8% score 2; 36.1% score 1; 14.5% score 0). Conclusion: A substantial frequency of undesirable events occurs while patients board in the ED. These events are more frequent in older patients or those with more comorbidities. Future studies need to compare the rates of undesirable events among patients boarding in the ED versus inpatient units. [Ann Emerg Med. 2009;54:381-385.] C1 [Liu, Shan W.; Thomas, Stephen H.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Gordon, James A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Liu, Shan W.; Thomas, Stephen H.; Gordon, James A.] Massachusetts Gen Hosp, Dept Emergency Serv, Boston, MA 02114 USA. [Hamedani, Azita G.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Div Emergency Med, Madison, WI USA. [Weissman, Joel S.] Univ Massachusetts, Dept Family & Community Med, Boston, MA 02125 USA. RP Liu, SW (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St,Zero Emerson,Room 358, Boston, MA 02114 USA. EM sliu1@partners.org NR 10 TC 34 Z9 35 U1 1 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 BP 381 EP 385 DI 10.1016/j.annemergmed.2009.02.001 PG 5 WC Emergency Medicine SC Emergency Medicine GA 488JM UT WOS:000269345900015 PM 19303168 ER PT J AU Camargo, CA Ginde, AA Handel, DA Keadey, MT Raja, AS Rogers, J Sullivan, AF Espinola, JA AF Camargo, Jr C. A. Ginde, A. A. Handel, D. A. Keadey, M. T. Raja, A. S. Rogers, J. Sullivan, A. F. Espinola, J. A. TI A Classification System for Emergency Departments: Massachusetts, 2008 SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Colorado, Denver Sch Med, Aurora, CO USA. Oregon Hlth & Sci Univ Hosp, Portland, OR 97201 USA. Emory Univ Hosp, Atlanta, GA 30322 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Monroe Cty Hosp, Forsyth, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S86 EP S87 PG 2 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100275 ER PT J AU Capp, R Brown, D AF Capp, R. Brown, D. TI Antibiotic Prescription by Emergency and ICU Physicians in Patients Admitted to the Intensive Care Unit With the Diagnosis of Septic Shock SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 [Capp, R.; Brown, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S103 EP S104 PG 2 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100330 ER PT J AU Chan, Y Richardson, L Moskowitz, A Katz, M Chason, K Singhal, A Poojary, I Kramer, S Levine, SR AF Chan, Y. Richardson, L. Moskowitz, A. Katz, M. Chason, K. Singhal, A. Poojary, I Kramer, S. Levine, S. R. TI Out-of-Hospital Normobaric Oxygen Therapy in Presumptive Acute Stroke Patients: A Preliminary Study SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Mt Sinai Sch Med, New York, NY USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Coll Osteopath Med, Old Westbury, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S72 EP S72 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100230 ER PT J AU Delgado, MK Wang, N Acosta, C Khandwala, Y West, AM Strehlow, MC Ginde, AA Camargo, CA AF Delgado, M. K. Wang, N. Acosta, C. Khandwala, Y. West, A. M. Strehlow, M. C. Ginde, A. A. Camargo, Jr C. A. TI National Survey of Preventive Health Services in United States Emergency Departments SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Stanford Kaiser Emergency Med Residency, Palo Alto, CA USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Univ Colorado, Sch Med, Denver, CO USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S20 EP S20 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100061 ER PT J AU Gabayan, GZ Asch, SM Starks, SL Sun, BC AF Gabayan, G. Z. Asch, S. M. Starks, S. L. Sun, B. C. TI Does Having and Using a Usual Source of Care Decrease Emergency Department Use? SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 [Gabayan, G. Z.; Asch, S. M.; Starks, S. L.; Sun, B. C.] VA Greater Los Angeles Hlth Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S64 EP S64 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100208 ER PT J AU Ginde, AA Talley, BE Trent, SA Raja, AS Sullivan, AF Camargo, CA AF Ginde, A. A. Talley, B. E. Trent, S. A. Raja, A. S. Sullivan, A. F. Camargo, Jr C. A. TI Primary and Specialty Care Follow-Up for Uninsured Emergency Department Patients SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Univ Colorado, Denver Sch Med, Aurora, CO USA. Denver Hlth Med Ctr, Denver, CO USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S75 EP S75 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100240 ER PT J AU Handel, DA Boehland, A Ginde, AA Raja, AS Rogers, J Sullivan, AF Camargo, CA AF Handel, D. A. Boehland, A. Ginde, A. A. Raja, A. S. Rogers, J. Sullivan, A. F. Camargo, C. A. TI Implementation of Crowding Solutions From the American College of Emergency Physicians Task Force Report on Boarding SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Univ Colorado, Denver, CO 80202 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Monroe Cty Hosp, Forsyth, GA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S51 EP S51 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100167 ER PT J AU Hariharan, P Kabrhel, C AF Hariharan, P. Kabrhel, C. TI Does the Pulmonary Embolism Severity Index Identify Patients at Risk for Short Term Clinical Deterioration? SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 [Hariharan, P.; Kabrhel, C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S23 EP S23 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100071 ER PT J AU Kimberly, H Murray, A Mennicke, M Ngoma, B Chisanga, C Ngoma, E Tyer-Viola, L Ahn, R Liteplo, A Burke, T Noble, VE AF Kimberly, H. Murray, A. Mennicke, M. Ngoma, B. Chisanga, C. Ngoma, E. Tyer-Viola, L. Ahn, R. Liteplo, A. Burke, T. Noble, V. E. TI Teaching Focused Obstetric Ultrasound to Midwives in Rural Zambia SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. Brigham & Womens Hosp, Boston, MA 02115 USA. Kapiri Mposhi Dist Hosp, Kapiri, Zambia. Nkole Rural Hlth Ctr, Nkole, Zambia. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S87 EP S87 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100277 ER PT J AU Levine, AC Shah, S Noble, VE Epino, H AF Levine, A. C. Shah, S. Noble, V. E. Epino, H. TI Ultrasound Assessment of Dehydration in Children With Gastroenteritis SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Alameda Cty Med Ctr, Oakland, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S91 EP S91 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100289 ER PT J AU Liteplo, AS Patel, P Huang, C Dipre, M Kimberly, H Noble, VE AF Liteplo, A. S. Patel, P. Huang, C. Dipre, M. Kimberly, H. Noble, V. E. TI INSPIRED: Instruction of Sonographic Placement of IVs by RNs in the Emergency Department SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 [Liteplo, A. S.; Patel, P.; Huang, C.; Dipre, M.; Kimberly, H.; Noble, V. E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S67 EP S67 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100217 ER PT J AU Liu, SW Chang, Y Weissman, J Griffey, R Hamedani, A Thomas, J Nergui, S Singer, S AF Liu, S. W. Chang, Y. Weissman, J. Griffey, R. Hamedani, A. Thomas, J. Nergui, S. Singer, S. TI Emergency Department Boarding Is Associated With Higher Medication-Related Errors but Fewer Laboratory Errors During the Early Admission Period SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Massachusetts, Boston, MA 02125 USA. Washington Univ, Sch Med, St Louis, MO USA. Good Samaritan Hosp, Brockton, MA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S66 EP S66 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100214 ER PT J AU Patel, P Melissa, S Brunko, M Domeier, R Funk, D Greenberg, R Judge, T Lowell, M MacDonald, R Madden, J Thomas, S Howard, Z AF Patel, P. Melissa, S. Brunko, M. Domeier, R. Funk, D. Greenberg, R. Judge, T. Lowell, M. MacDonald, R. Madden, J. Thomas, S. Howard, Z. TI Intubation Success Rates in Helicopter Emergency Medical Services: A Prospective Multicenter Analysis SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Harvard Affiliated Emergency Med Residency, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Flight Life Colorado, Denver, CO USA. St Josephs Mercy Hosp, Ypsilanti, MI USA. Albany Med Coll, Albany, NY 12208 USA. Texas A&M Univ, PHI Air Med StatAir, Temple, TX USA. LifeFlight Maine, Bangor, ME USA. Univ Michigan, Hlth Sci Ctr, Ann Arbor, MI 48109 USA. Univ Toronto, ORNGE Transport Med, Toronto, ON, Canada. Christiana Care, Wilmington, DE USA. Univ Oklahoma, Sch Community Med, Tulsa, OK USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S60 EP S61 PG 2 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100196 ER PT J AU Peacock, W Diercks, D Hollander, J Singer, A Birkhahn, R Shapiro, N Lewandrowski, E Nagumey, J AF Peacock, W. Diercks, D. Hollander, J. Singer, A. Birkhahn, R. Shapiro, N. Lewandrowski, E. Nagumey, J. TI Can Point-of-Care Assays Deliver Lab Quality Accuracy? SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Cleveland Clin, Cleveland, OH 44106 USA. Univ Calif Davis, Sacramento, CA 95817 USA. Univ Penn, Philadelphia, PA 19104 USA. Stony Brook Univ & Med Ctr, Stony Brook, NY USA. New York Methodist Hosp, Brooklyn, NY USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Shapiro, Nathan/F-1718-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S7 EP S8 PG 2 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100021 ER PT J AU Raja, AS Sullivan, AF Pallin, DJ Bohan, J Camargo, CA AF Raja, A. S. Sullivan, A. F. Pallin, D. J. Bohan, J. Camargo, Jr C. A. TI The Use of Video Laryngoscopy In Massachusetts Emergency Departments SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Pallin, Daniel/H-6382-2013 OI Pallin, Daniel/0000-0002-8517-9702 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S9 EP S10 PG 2 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100028 ER PT J AU Schechter-Perkins, E Murray, K St George, J Mitchell, P AF Schechter-Perkins, E. Murray, K. St George, J. Mitchell, P. TI A Survey of Provider Opinions Regarding Implementing Rapid HIV Testing in the Emergency Department of a Safety Net Hospital SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Boston Univ, Sch Med, Boston, MA 02118 USA. Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S104 EP S104 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100332 ER PT J AU Schuur, J Moreau, J Bohan, J Fauchet, G Lobon, L Lyn, E Nathanson, L Stack, A Temin, E Tibbles, C AF Schuur, J. Moreau, J. Bohan, J. Fauchet, G. Lobon, L. Lyn, E. Nathanson, L. Stack, A. Temin, E. Tibbles, C. TI Emergency Department Consultation Practices and Documentation Vary Widely Across Hospitals SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Cambridge Hlth Alliance, Cambridge, MA USA. N Shore Med Ctr, Salem, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Childrens Hosp Boston, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S6 EP S6 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100017 ER PT J AU Shear, ML Adler, JN Shewakramani, S Iligen, J Soremekun, O Nelson, SW Thomas, SH AF Shear, M. L. Adler, J. N. Shewakramani, S. Iligen, J. Soremekun, O. Nelson, S. W. Thomas, S. H. TI Transbuccal Fentanyl for Rapid Relief of Orthopedic Pain in the Emergency Department SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Oklahoma, Sch Community Med, Tulsa, OK USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S128 EP S128 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100409 ER PT J AU Smulowitz, PB Adelman, L Lipton, R Burke, L Weiner, S Sayah, A Baugh, CW Burke, MC Landon, BE AF Smulowitz, P. B. Adelman, L. Lipton, R. Burke, L. Weiner, S. Sayah, A. Baugh, C. W. Burke, M. C. Landon, B. E. TI The Impact of Health Care Reform in Massachusetts on Emergency Department Use by Uninsured and Publicly Subsidized Individuals SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT Annual Research Forum of the American-College-of-Emergency-Physicians CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Tufts Med Ctr, Boston, MA USA. Cambridge Hlth Alliance, Cambridge, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Milford Reg Med Ctr, Milford, MA USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S84 EP S85 PG 2 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100270 ER PT J AU Smulowitz, PB Baugh, CW Schuur, JD Liu, SW Lipton, RB Wharam, JF Landon, BE AF Smulowitz, P. B. Baugh, C. W. Schuur, J. D. Liu, S. W. Lipton, R. B. Wharam, J. F. Landon, B. E. TI Change in Acuity of Emergency Department Visits After Massachusetts Health Care Reform SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT Annual Research Forum of the American-College-of-Emergency-Physicians CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Pilgrim Hlth Care, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S84 EP S84 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100268 ER PT J AU Sullivan, AF Ginde, AA Weiner, SG Pallin, DJ Betz, ME Oldfield, JH Camargo, CA AF Sullivan, A. F. Ginde, A. A. Weiner, S. G. Pallin, D. J. Betz, M. E. Oldfield, J. H. Camargo, Jr C. A. TI Multicenter Study of Internet Use by Emergency Department Patients in Boston SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Colorado Denver, Sch Med, Aurora, CO USA. Tufts Med Ctr, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RI Pallin, Daniel/H-6382-2013 OI Pallin, Daniel/0000-0002-8517-9702 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S19 EP S20 PG 2 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100059 ER PT J AU Talley, B Ginde, A Raja, A Sullivan, A Camargo, C AF Talley, B. Ginde, A. Raja, A. Sullivan, A. Camargo, C., Jr. TI Access to Immediate Bedside Ultrasound in the Emergency Department SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Denver Hlth Med Ctr, Denver, CO USA. Univ Colorado, Denver Sch Med, Aurora, CO USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S102 EP S102 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100325 ER PT J AU Thomas, LE Goldstein, JN Hakimelahi, R Gonzalez, RG AF Thomas, L. E. Goldstein, J. N. Hakimelahi, R. Gonzalez, R. G. TI Should This Stroke Patient Be Transferred? Computed Tomographic Angiography Predicts Use of Tertiary Interventional Services SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 [Thomas, L. E.; Goldstein, J. N.; Hakimelahi, R.; Gonzalez, R. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Goldstein, Joshua/H-8953-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S70 EP S70 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100225 ER PT J AU Tollefsen, WW Chapman, J Frakes, M Gallagher, M Shear, M Thomas, SH AF Tollefsen, W. W. Chapman, J. Frakes, M. Gallagher, M. Shear, M. Thomas, S. H. TI Endotracheal Tube Cuff Pressures In Pediatric Patients Intubated Prior to Aeromedical Transport SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Harvard Univ, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Boston MedFlight, Boston, MA USA. Univ Oklahoma, Sch Community Med, Tulsa, OK USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S17 EP S18 PG 2 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100052 ER PT J AU Tsai, C Magid, DJ Sullivan, AF Gordon, JA Kaushal, R Blumenthal, D Camargo, CA AF Tsai, C. Magid, D. J. Sullivan, A. F. Gordon, J. A. Kaushal, R. Blumenthal, D. Camargo, C. A., Jr. TI Quality of Care for Acute Myocardial Infarction in 58 US Emergency Departments SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. Kaiser Permanente Colorado, Inst Hlth Res, Aurora, CO USA. Univ Colorado, Hlth Sci Ctr, Dept Emergency Med, Aurora, CO USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Aurora, CO USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. New York Presbyterian Hosp, New York, NY USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S2 EP S2 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100004 ER PT J AU White, BA Brown, DF Sinclair, J Chang, Y Carignan, S McIntyre, JA Biddinger, PD AF White, B. A. Brown, D. F. Sinclair, J. Chang, Y. Carignan, S. McIntyre, J. A. Biddinger, P. D. TI Supplemented Triage and Rapid Treatment in the Emergency Department SO ANNALS OF EMERGENCY MEDICINE LA English DT Meeting Abstract CT American-College-of-Emergency-Physicians Forum 2009 CY OCT 05-06, 2009 CL Boston, MA SP Amer Coll Emergency Phys, Boston Exhibit & Convent Ctr C1 [White, B. A.; Brown, D. F.; Sinclair, J.; Chang, Y.; Carignan, S.; McIntyre, J. A.; Biddinger, P. D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD SEP PY 2009 VL 54 IS 3 SU S BP S74 EP S74 PG 1 WC Emergency Medicine SC Emergency Medicine GA 488JO UT WOS:000269346100237 ER PT J AU Jacobson, IG White, MR Smith, TC Smith, B Wells, TS Gackstetter, GD Boyko, EJ AF Jacobson, Isabel G. White, Martin R. Smith, Tyler C. Smith, Besa Wells, Timothy S. Gackstetter, Gary D. Boyko, Edward J. CA Millennium Cohort Study Team TI Self-Reported Health Symptoms and Conditions Among Complementary and Alternative Medicine Users in a Large Military Cohort SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Cohort Studies; Complementary Therapies; Signs and Symptoms ID UNITED-STATES; MILLENNIUM COHORT; PRIMARY-CARE; PRIME-MD; PREVALENCE; UTILITY; SERVICES AB PURPOSE: To describe medical symptom and condition reporting in relation to complementary and alternative medicine (CAM) use among members of the US military. METHODS: CAM was defined as health treatments not widely taught at US medical schools or typically available at US hospitals. By using data from the Millennium Cohort Study, we included participants who completed a survey from 2004 to 2006 (n = 86,131) as part of this cross-sectional analysis in which we sought to identify demographic characteristics and types of health-related symptoms and conditions associated with CAM use. Chi-square tests were used to compare health assessed by self-reported symptoms and conditions among those not reporting CAM use with those reporting practitioner-assisted or self-administered CAM. RESULTS: Of 86,131 participants, 30% reported using at least one practitioner-assisted CAM therapy, 27% reported using at least one self-administered CAM therapy, whereas 59% did not report using any CAM therapy. Both women and men who used CAM reported a greater proportion of specific health conditions and health-related symptoms compared with those not reporting CAM use (p < 0.05). CONCLUSIONS: These findings illustrate that a relatively young adult occupational cohort of military personnel using CAM therapies also report multiple comorbidities which may indicate chronic illness management and poorer overall health. Ann Epidemiol 2009;19:613-622. (C) Published by Elsevier Inc. C1 [Jacobson, Isabel G.; White, Martin R.; Smith, Tyler C.; Smith, Besa] USN, Hlth Res Ctr, US Dept Def, Ctr Deployment Hlth Res, San Diego, CA 92106 USA. [Wells, Timothy S.] USAF, Res Lab, Wright Patterson AFB, OH 45433 USA. [Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Epidetniol Res & Informat Ctr, Seattle, WA USA. [Gackstetter, Gary D.] Analyt Serv Inc, ANSER, Arlington, VA USA. RP Jacobson, IG (reprint author), USN, Hlth Res Ctr, US Dept Def, Ctr Deployment Hlth Res, Dept 164,140 Sylvester Rd, San Diego, CA 92106 USA. EM isabel.jacobson@med.navy.mil NR 30 TC 18 Z9 18 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD SEP PY 2009 VL 19 IS 9 BP 613 EP 622 DI 10.1016/j.annepidem.2009.05.001 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 488ES UT WOS:000269332600002 PM 19596206 ER PT J AU Lin, EHB Heckbert, SR Rutter, CM Katon, WJ Ciechanowski, P Ludman, EJ Oliver, M Young, BA McCulloch, DK Von Korff, M AF Lin, Elizabetb H. B. Heckbert, Susan R. Rutter, Carolyn M. Katon, Wayne J. Ciechanowski, Paul Ludman, Evette J. Oliver, Malia Young, Bessie A. McCulloch, David K. Von Korff, Michael TI Depression and Increased Mortality in Diabetes: Unexpected Causes of Death SO ANNALS OF FAMILY MEDICINE LA English DT Article DE Diabetes; depression; mortality ID CORONARY-HEART-DISEASE; COMORBID DEPRESSION; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIAL; PRIMARY-CARE; ALL-CAUSE; RISK; HEALTH; ADULTS; METAANALYSIS AB PURPOSE Recent evidence suggests that depression is linked to increased mortality among patients with diabetes. This study examines the association of depression with all-cause and cause-specific mortality in diabetes. METHODS We conducted a prospective cohort study of primary care patients with type 2 diabetes at Group Health Cooperative in Washington state. We used the Patient Health Questionnaire (PHQ-9) to assess depression at baseline and reviewed medical records supplemented by the Washington state mortality registry to ascertain the causes of death. RESULTS Among a cohort of 4,184 patients, 581 patients died during the follow-up period. Deaths occurred among 428 (12.9%) patients with no depression, among 88 (17.8%) patients with major depression, and among 65 (18.2%) patients with minor depression. Causes of death were grouped as cardiovascular disease, 42.7%; cancer, 26.9%; and deaths that were not due to cardiovascular disease or cancer, 30.5%. Infections, dementia, renal failure, and chronic obstructive pulmonary disease were the most frequent causes in the latter group. Adjusting for demographic characteristics, baseline major depression (relative to no depression) was significantly associated with all-cause mortality (hazard ratio [HR] = 2.26, 95% confidence interval [CI], 1.79-2.85), with cardiovascular mortality (HR = 2.00; 95% CI, 1.37-2.94), and with noncardiovascular, noncancer mortality (HR = 3.35; 95% CI, 2.30-4.89). After additional adjustment for baseline clinical characteristics and health habits, major depression was significantly associated only with all-cause mortality (HR = 1.52; 95% CI, 1.19-1.95) and with death not caused by cancer or atherosclerotic cardiovascular disease (HR = 2.15; 95% CI, 1.43-3.24). Minor depression showed similar but nonsignificant associations. CONCLUSIONS Patients with diabetes and coexisting depression face substantially elevated mortality risks beyond cardiovascular deaths. C1 [Lin, Elizabetb H. B.; Heckbert, Susan R.; Rutter, Carolyn M.; Ludman, Evette J.; Oliver, Malia; McCulloch, David K.; Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Heckbert, Susan R.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Katon, Wayne J.; Ciechanowski, Paul] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Young, Bessie A.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA 98195 USA. RP Lin, EHB (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM lin.e@ghc.org FU National Institutes of Health [MH 073686] FX This research was supported by grants from the National Institutes of Health MH 073686. NR 35 TC 112 Z9 112 U1 3 U2 13 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 J9 ANN FAM MED JI Ann. Fam. Med. PD SEP-OCT PY 2009 VL 7 IS 5 BP 414 EP 421 DI 10.1370/afm.998 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 505MS UT WOS:000270698400005 PM 19752469 ER PT J AU Singer, DE Chang, YC Fang, MC Borowsky, LH Pomernacki, NK Udaltsova, N Go, AS AF Singer, Daniel E. Chang, Yuchiao Fang, Margaret C. Borowsky, Leila H. Pomernacki, Niela K. Udaltsova, Natalla Go, Alan S. TI The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; CLOPIDOGREL PLUS ASPIRIN; EVENTS ACTIVE-W; ORAL ANTICOAGULATION; STROKE PREVENTION; VASCULAR EVENTS; RISK-FACTORS; ANTITHROMBOTIC THERAPY; THROMBOEMBOLISM; STRATIFICATION AB Background: Guidelines recommend warfarin use in patients with atrial fibrillation solely on the basis of risk for ischemic stroke without antithrombotic therapy. These guidelines rely on ischemic stroke rates observed in older trials and do not explicitly account for increased risk for hemorrhage. Objective: To quantify the net clinical benefit of warfarin therapy in a cohort of patients with atrial fibrillation. Design: Mixed retrospective and prospective cohort study of patients with atrial fibrillation between 1996 and 2003. Setting: An integrated health care delivery system. Patients: 13 559 adults with nonvalvular atrial fibrillation. Measurements: Warfarin exposure, patient characteristics, CHADS(2) score ( 1 point for each of congestive heart failure, hypertension, age, and diabetes and 2 points for stroke), and outcome events were ascertained from health plan records and databases. Net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by warfarin minus intracranial hemorrhages attributable to warfarin, multiplied by an impact weight. The base-case impact weight was 1.5, reflecting the greater clinical impact of intracranial hemorrhage versus thromboembolism. Results: Patients accumulated more than 66 000 person-years of follow-up. The adjusted net clinical benefit of warfarin for the cohort overall was 0.68% per year (95% CI, 0.34% to 0.87%). Adjusted net clinical benefit was greatest for patients with a history of ischemic stroke (2.48% per year [ CI, 0.75% to 4.22%]) and for those 85 years or older (2.34% per year [ CI, 1.29% to 3.30%]). The net clinical benefit of warfarin increased from essentially zero in CHADS(2) stroke risk categories 0 and 1 to 2.22% per year ( CI, 0.58% to 3.75%) in CHADS(2) categories 4 to 6. The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used. Limitations: Residual confounding is a possibility. Some outcome events were probably missed by the screening algorithm or when medical records were unavailable. Conclusion: Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category. Risk assessment that incorporates both risk for thromboembolism and risk for intracranial hemorrhage provides a more quantitatively informed basis for the decision on antithrombotic therapy in patients with atrial fibrillation. C1 [Singer, Daniel E.] Massachusetts Gen Hosp, Clin Epidemiol Unit, Boston, MA 02114 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Kaiser Permanente No Calif, Oakland, CA 94612 USA. RP Singer, DE (reprint author), Massachusetts Gen Hosp, Clin Epidemiol Unit, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM dsinger@partners.org FU National Institute on Aging [R01 AG15478, K23 AG28978]; National Heart, Lung, and Blood Institute [U19 HL091179]; Massachusetts General Hospital; National Heart, Lung, and Blood Institute FX By the National Institute on Aging (R01 AG15478); the National Heart, Lung, and Blood Institute (U19 HL091179); and the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital. Dr. Fang's efforts were also partially supported by the National Institute on Aging (K23 AG28978). NR 28 TC 314 Z9 321 U1 1 U2 6 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 1 PY 2009 VL 151 IS 5 BP 297 EP U16 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 492KB UT WOS:000269653100001 PM 19721017 ER PT J AU Rudavsky, R Pollack, CE Mehrotra, A AF Rudavsky, Rena Pollack, Craig Evan Mehrotra, Ateev TI The Geographic Distribution, Ownership, Prices, and Scope of Practice at Retail Clinics SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HEALTH-CARE; VISITS AB Background: Retail clinics are clinics within a retail store that provide simple acute and preventive care services for a fixed price without an appointment. Objective: To describe characteristics of retail clinics, including their location, scope of practice, prices, acceptance of insurance, and ownership, and to estimate the proportion of the U. S. population that lives within a short driving distance of such a clinic. Design: Cross-sectional descriptive study. Setting: United States. Participants: All 982 retail clinics operating as of August 2008. Measurements: Population living within a 5- and 10-minute driving distance of a retail clinic. Results: In August 2008, 42 operators ran 982 clinics in 33 states; 88.4% were located in urban areas. Nearly half (44%) of all clinics were located in 5 states ( Florida, California, Texas, Minnesota, and Illinois). All offered sore throat treatment ( average price, $78) and more than 95% offered treatment of skin conditions, immunizations, pregnancy testing, and lipid or diabetes screening. Almost all (97%) accepted private insurance and Medicare fee-for-service (93%). Among 42 clinic operators, 25 are existing health care companies that operate 11% of the clinics, and 3 are for-profit retail chains that operate 73% of the clinics. An estimated 10.6% of the total U. S. and 13.4% of the urban U. S. population lives within a 5- minute driving distance of a retail clinic, whereas 28.7% ( total) and 35.8% ( urban) live within a 10-minute driving distance. Limitation: Our inventory of clinics stopped in August 2008 and estimates of proximity are based on 2000 census data. Conclusion: Retail clinics are positioned to provide immunizations and care for simple acute conditions for a substantial segment of the urban U. S. population. C1 [Mehrotra, Ateev] RAND Hlth, Pittsburgh, PA 15213 USA. RAND Hlth, Washington, DC USA. Univ Penn, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Mehrotra, A (reprint author), RAND Hlth, 4570 5th Ave,Suite 600, Pittsburgh, PA 15213 USA. EM mehrotra@rand.org FU California Healthcare Foundation; National Center for Research Resources [KL2 RR024154-03]; National Institutes of Health; Department of Veterans Affairs; Robert Wood Johnson Foundation Clinical Scholars Program FX By the California Healthcare Foundation; a career development award (KL2 RR024154-03) from the National Center for Research Resources, a component of the National Institutes of Health (Dr. Mehrotra); and the Department of Veterans Affairs and the Robert Wood Johnson Foundation Clinical Scholars Program ( Dr. Pollack). NR 31 TC 44 Z9 44 U1 0 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 1 PY 2009 VL 151 IS 5 BP 315 EP U41 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 492KB UT WOS:000269653100003 PM 19721019 ER PT J AU Rabaglio, M Sun, Z Price, KN Castiglione-Gertsch, M Hawle, H Thurlimann, B Mouridsen, H Campone, M Forbes, JF Paridaens, RJ Colleoni, M Pienkowski, T Nogaret, JM Lang, I Smith, I Gelber, RD Goldhirsch, A Coates, AS AF Rabaglio, M. Sun, Z. Price, K. N. Castiglione-Gertsch, M. Hawle, H. Thurlimann, B. Mouridsen, H. Campone, M. Forbes, J. F. Paridaens, R. J. Colleoni, M. Pienkowski, T. Nogaret, J. -M. Lang, I. Smith, I. Gelber, R. D. Goldhirsch, A. Coates, A. S. CA Big 1-98 Collaborative Int Breast TI Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial SO ANNALS OF ONCOLOGY LA English DT Article DE aromatase inhibitor; bone fracture; hormonal therapy; letrozole; tamoxifen ID RANDOMIZED-TRIAL; ADJUVANT THERAPY; MINERAL DENSITY; AROMATASE INHIBITORS; ESTRONE SULFATE; WOMEN; ANASTROZOLE; EXEMESTANE; ESTRADIOL; SUBSETS AB Methods: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. Results: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. Conclusions: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients. C1 [Rabaglio, M.; Castiglione-Gertsch, M.; Hawle, H.] IBCSG Coordinating Ctr, CH-3008 Bern, Switzerland. [Rabaglio, M.] Univ Bern, Inselspital, CH-3010 Bern, Switzerland. [Gelber, R. D.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. [Price, K. N.] Frontier Sci & Technol Res, Boston, MA USA. [Thurlimann, B.] Kantonsspital, Senol Ctr Eastern Switzerland, St Gallen, Switzerland. [Thurlimann, B.] Kantonsspital, Swiss Grp Clin Canc Res SAKK, St Gallen, Switzerland. [Mouridsen, H.] Rigshosp, Danish Breast Canc Cooperat Grp, DK-2100 Copenhagen, Denmark. [Forbes, J. F.] Univ Newcastle, Australian New Zealand Breast Canc Trials Grp, Newcastle, NSW 2308, Australia. [Paridaens, R. J.] Catholic Univ Louvain, Univ Hosp Gasthuisberg, Dept Med Oncol, B-3000 Leuven, Belgium. [Colleoni, M.] European Inst Oncol, Dept Med, Res Unit Med Senol, Milan, Italy. [Pienkowski, T.] Canc Ctr Maria Sklodowska Curie Mem Inst Oncol, Warsaw, Poland. [Nogaret, J. -M.] Inst Jules Bordet, Dept Mammary & Pelv Surg, B-1000 Brussels, Belgium. [Lang, I.] Natl Inst Oncol, Dept Med Oncol, Budapest, Hungary. [Smith, I.] Royal Marsden Hosp, Breast Unit, London SW3 6JJ, England. [Gelber, R. D.] Harvard Univ, Sch Med, Boston, MA USA. [Goldhirsch, A.] European Inst Oncol, Dept Med, Milan, Italy. [Goldhirsch, A.] Oncol Inst So Switzerland, Bellinzona, Switzerland. [Coates, A. S.] Univ Sydney, Sydney, NSW 2006, Australia. [Coates, A. S.] Int Breast Canc Study Grp, Sydney, NSW, Australia. RP Rabaglio, M (reprint author), IBCSG Coordinating Ctr, Effingerstr 40, CH-3008 Bern, Switzerland. EM manuela.rabaglio@ibcsg.org RI friedlander, michael/G-3490-2013; Cheuk, Robyn/H-1944-2013; GLADIEFF, Laurence/O-5129-2014; Wardley, ANdrew/N-8135-2015; Aebi, Stefan/F-2004-2010; Gonzalez Larriba, Jose Luis/G-6177-2016; Petruzelka, Lubos/A-2750-2017; Rimassa, Lorenza/N-4884-2016; Sedlackova, Eva/B-9959-2017; Wyld, David/B-8893-2015; Munzone, Elisabetta/G-8848-2011; OI friedlander, michael/0000-0002-6488-0604; Cheuk, Robyn/0000-0001-9516-5526; GLADIEFF, Laurence/0000-0002-6980-9719; Wardley, ANdrew/0000-0002-9639-0888; Aebi, Stefan/0000-0002-3383-9449; Gonzalez Larriba, Jose Luis/0000-0003-2631-0309; Petruzelka, Lubos/0000-0002-4397-0635; Rimassa, Lorenza/0000-0001-9957-3615; Sedlackova, Eva/0000-0002-0089-1611; Wyld, David/0000-0001-9523-4333; Segelov, Eva/0000-0002-4410-6144 FU NCI NIH HHS [U24 CA075362] NR 24 TC 71 Z9 73 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2009 VL 20 IS 9 BP 1489 EP 1498 DI 10.1093/annonc/mdp033 PG 10 WC Oncology SC Oncology GA 496FS UT WOS:000269955700005 PM 19474112 ER PT J AU Grant, C AF Grant, Calvin TI Treating Central Retinal Vein Occlusion SO ANNALS OF OPHTHALMOLOGY LA English DT Editorial Material C1 [Grant, Calvin] Chicago Metro Area, Chicago, IL USA. [Grant, Calvin] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Cambridge, MA 02138 USA. RP Grant, C (reprint author), Chicago Metro Area, Chicago, IL USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CONTEMPORARY MEDICINE SURGERY & OPHTHALMOLOGY PI LINCOLNWOOD PA 7250 N CICERO AVE, STE LL 6, LINCOLNWOOD, IL 60172 USA SN 1530-4086 J9 ANN OPHTHALMOL JI Ann. Ophthalmol. PD FAL-WIN PY 2009 VL 41 IS 3-4 BP 137 EP 139 PG 3 WC Ophthalmology SC Ophthalmology GA 562EU UT WOS:000275033300002 PM 20214044 ER PT J AU Zeitels, SM Lopez-Guerra, G Burns, JA Lutch, M Friedman, AM Hillman, RE AF Zeitels, Steven M. Lopez-Guerra, Gerardo Burns, James A. Lutch, Matthew Friedman, Aaron M. Hillman, Robert E. TI Microlaryngoscopic and Office-Based Injection of Bevacizumab (Avastin) to Enhance 532-nm Pulsed KTP Laser Treatment of Glottal Papillomatosis SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article; Proceedings Paper CT 130th Annual Meeting of the American-Laryngological-Association Combined Otolaryngology Spring Meeting CY MAY 28, 2009 CL Phoenix, AZ SP Amer Laryngol Assoc DE Avastin; bevacizumab; glottis; KTP laser; larynx; laser; papilloma; papillomatosis; recurrent respiratory papillomatosis; vocal cord; vocal fold; voice ID RECURRENT RESPIRATORY PAPILLOMATOSIS; JUVENILE LARYNGEAL PAPILLOMATOSIS; ENDOTHELIAL GROWTH-FACTOR; VOCAL FOLD; DYE-LASER; CANCER; ANGIOGENESIS; MANAGEMENT; ANESTHESIA; DYSPLASIA AB Objectives: Photoangiolytic lasers effectively treat glottal papillomatosis, but do not reliably prevent recurrence. Therefore, sublesional injections of the antiangiogenic agent bevacizumab (Avastin) were given to assess the effect on disease recurrence and phonatory function. Methods: A retrospective investigation was done in a pilot group of 10 adult patients with bilateral glottal papillomatosis who had prior angiolytic laser treatment with established patterns of recurrence. The patients underwent 5 bevacizumab injections (5 to 10 mg) into the diseased vocal folds along with 5327-nm pulsed KTP laser photoangiolysis treatments 4 to 6 weeks apart. Their disease resolution was compared to findings from prior laser treatment alone, and objective measures of vocal function (acoustic, aerodynamic, Voice-Related Quality of Life survey) were obtained. Results: All 10 patients had a greater than 90% reduction in recurrence. Four of the 10 had resolution. Four of the 10 have limited recurrent or persistent disease, receive injections of bevacizumab at 8- to 12-week intervals, and have not required laser treatment. Two of the 10 have ongoing periodic office-based KTP laser treatment along with bevacizumab injections. No patient has required microlaryngeal surgery with general anesthesia, and all 10 have had substantial improvement in vocal function. Conclusions: This pilot investigation provides preliminary evidence that bevacizumab injections enhance photoangiolytic laser treatment of glottal papillomatosis while enhancing phonatory function. Coupling an anti angiogenesis agent with pulsed KTP laser photoangiolysis is conceptually promising, since the mechanisms of action are complementary. C1 [Zeitels, Steven M.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Zeitels, SM (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. NR 68 TC 1 Z9 1 U1 1 U2 5 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD SEP PY 2009 VL 118 IS 9 BP 2 EP 24 PG 23 WC Otorhinolaryngology SC Otorhinolaryngology GA 499BB UT WOS:000270190400001 ER PT J AU Bahmad, F DePalma, SR Merchant, SN Bezerra, RL Oliveira, CA Seidman, CE Seidman, JG AF Bahmad, Fayez, Jr. DePalma, Steven R. Merchant, Saumil N. Bezerra, Roberta L. Oliveira, Carlos A. Seidman, Christine E. Seidman, Jonathan G. TI Locus for Familial Migrainous Vertigo Disease Maps to Chromosome 5q35 SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE familial disease; gene; linkage study; migraine; vertigo ID SUSCEPTIBILITY LOCUS; MENIERES-SYNDROME; LINKAGE; AURA; GENOME; GENES AB Objectives: Migrainous vertigo (episodic vertigo associated with migraine) is sometimes inherited as an autosomal dominant trait. However, neither disease genes nor loci that might be responsible have been reported. We sought to map the genetic locus for familial migrainous vertigo in a 4-generation family and to define the progression of disease in this family. Methods: We studied 23 members in a family in whom migrainous vertigo was inherited as an autosomal dominant trait. Clinical information obtained included case histories and results of otolaryngological, neurologic, audiometric, and imaging evaluations. Genome-wide linkage analysis was performed with Affymetrix Genechip Human Mapping 10K microarrays. Genotyping of family members' DNA with microsatellite markers was used to further assess candidate loci identified from the whole-genome scan. Results: Of 23 family members, 10 suffered from migrainous vertigo beginning after 35 years of age. Migraine head aches usually preceded the onset of vertigo by 15 to 20 years. Longitudinal audiometric Studies over 12 years showed stable, high-frequency sensorineural hearing loss consistent with presbycusis. Low-frequency or fluctuating hearing loss was not observed. The results of vestibular testing and imaging Studies were unremarkable. Genetic analysis defined a 12.0 MB interval on chromosome 5q35 between loci rs244895 and D5S2073 that contained the disease gene (logarithm of odds score, 4.21). Conclusions: We report the first locus for familial migrainous vertigo, which mapped to 5q35. C1 [Bahmad, Fayez, Jr.; Merchant, Saumil N.] Harvard Univ, Dept Otol & Laryngol, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Bahmad, Fayez, Jr.; DePalma, Steven R.; Seidman, Christine E.; Seidman, Jonathan G.] Harvard Univ, Dept Genet, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Seidman, Christine E.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Bahmad, Fayez, Jr.; Bezerra, Roberta L.; Oliveira, Carlos A.] Univ Brasilia, Dept Otolaryngol Head & Neck Surg, Sch Med, Brasilia Univ Hosp, Brasilia, DF, Brazil. RP Merchant, SN (reprint author), Harvard Univ, Dept Otol & Laryngol, Sch Med, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. FU National Institutes of Health [U24DC008559]; National Council for Scientific and Technological Development-CNPq, Brazil (Bahmad); Lakshmi Mittal and Axel Eliasen FX Supported by grants from the National Institutes of Health (J. G. Seidman and C. E. Seidman, and U24DC008559 to Merchant), by the National Council for Scientific and Technological Development-CNPq, Brazil (Bahmad), and by Lakshmi Mittal and Axel Eliasen. NR 31 TC 17 Z9 18 U1 0 U2 0 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD SEP PY 2009 VL 118 IS 9 BP 670 EP 676 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 499AX UT WOS:000270190000011 PM 19810609 ER PT J AU Conrad, MF Adams, AB Guest, JM Paruchuri, V Brewster, DC LaMuraglia, GM Cambria, RP AF Conrad, Mark F. Adams, Andrew B. Guest, Julie M. Paruchuri, Vikram Brewster, David C. LaMuraglia, Glenn M. Cambria, Richard P. TI Secondary Intervention After Endovascular Abdominal Aortic Aneurysm Repair SO ANNALS OF SURGERY LA English DT Article; Proceedings Paper CT 129th Annual Meeting of the American-Surgical-Association CY APR 23, 2009 CL Indian Wells, CA SP Amer Surg Assoc ID PROSPECTIVE CLINICAL-TRIAL; STENT GRAFT MIGRATION; OPEN SURGICAL REPAIR; FOLLOW-UP; II ENDOLEAKS; SAC PRESSURE; PREDICTIVE FACTORS; MULTICENTER TRIAL; OUTCOMES; EVAR AB Objective: Endovascular Abdominal Aortic Aneurysm Repair (EVAR) has been criticized because of the need for frequent secondary interventions (2ndINT) to maintain effective abdominal aortic aneurysm (AAA) exclusion. The study goal is to detail such interventions and determine their effect on clinical outcomes. Methods: From January 1997 to December 2007, 832 patients underwent EVAR. Those requiring 2ndINT were stratified according to the indications and specific nature of 2ndINT and treatment. Study endpoints included freedom from 2ndINT, aneurysm-related and overall survival. Results: There were 91 (11%) patients who underwent 131 2ndINT (mean follow-up 35 months). No demographic features (age, gender, etc) predicted the need for 2ndINT. Actuarial 5-year freedom from 2ndINT was 80%. Indications for 2ndINT included: sac rupture 5 (4%), graft migration/ type I endoleak 37 (28%), persistent type II endoleak 40 (38%), endotension with sac growth 5 (4%), and limb occlusion/kinking 24 (18%). The majority of 2ndFNT were accomplished with an endovascular approach (76%) with a >80% initial success rate for all indications except type II endoleak in which the initial intervention was successful only 34% of the time. Initial 2ndINT were successful in 62% and 35 (38%) patients underwent more than one 2ndINT. Multivariate predictors of 2ndINT were AAA sac size >5.5cm (OR = 2.1, P = 0.004), and preprocedure coil embolization (hypogastric or inferior mesenteric artery) (OR = 2.1, P = 0.008). The actuarial survival was 70% at 5 years and the aneurysm-related survival was 97.5% with no difference in either parameter in patients who underwent 2ndlNT compared with those who did not. Conclusions: Although 2ndINT are common after EVAR, most were addressed through an endovascular approach; technical success thereof varies widely with the specific indication for 2ndINT. Secondary intervention did not adversely affect aneurysm-related or overall actuarial 5-year survival. C1 [Conrad, Mark F.; Adams, Andrew B.; Guest, Julie M.; Paruchuri, Vikram; Brewster, David C.; LaMuraglia, Glenn M.; Cambria, Richard P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg,Dept Surg, Boston, MA 02114 USA. RP Conrad, MF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg,Dept Surg, WACC 4,15 Parkman St, Boston, MA 02114 USA. EM mconrad@partners.org RI Adams, Andrew/G-3133-2011 OI Adams, Andrew/0000-0001-8925-9956 NR 50 TC 54 Z9 57 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD SEP PY 2009 VL 250 IS 3 BP 383 EP 389 DI 10.1097/SLA.0b013e3181b365bd PG 7 WC Surgery SC Surgery GA 488PG UT WOS:000269361400004 PM 19652592 ER PT J AU Regenbogen, SE Gawande, AA Lipsitz, SR Greenberg, CC Jha, AK AF Regenbogen, Scott E. Gawande, Atul A. Lipsitz, Stuart R. Greenberg, Caprice C. Jha, Ashish K. TI Do Differences in Hospital and Surgeon Quality Explain Racial Disparities in Lower-Extremity Vascular Amputations? SO ANNALS OF SURGERY LA English DT Article; Proceedings Paper CT 129th Annual Meeting of the American-Surgical-Association CY APR 23-24, 2009 CL Indian Wells, CA SP Amer Surg Assoc ID ACUTE MYOCARDIAL-INFARCTION; CRITICAL LIMB ISCHEMIA; HEALTH-CARE; PATIENT CHARACTERISTICS; ADMINISTRATIVE DATA; SURGICAL-PROCEDURES; OCCLUSIVE DISEASE; SALVAGE ALWAYS; CANCER-SURGERY; BLACK PATIENTS AB Objective: To understand whether racial disparities in surgery for lower-extremity arterial disease are minimized by high-quality providers, or instead, differential treatment of otherwise similar patients pervades all settings. Summary Background Data: Black patients are substantially more likely than whites to undergo amputation rather than revascularization for lower-extremity arterial disease. Because their care is disproportionately concentrated among a small share of providers, some have attributed such disparities to the quality and capacity of these sites. Methods: We evaluated all 86,865 white or black fee-for-service Medicare beneficiaries 65 and older who underwent major lower-extremity vascular procedures. Using generalized linear mixed models with random effects, we computed risk-adjusted odds of amputation by race overall, and after serial substratification by salient patient and provider characteristics. Results: Blacks were far more likely to undergo amputation (45% vs. 20%). Their procedures were performed more often by nonspecialists (41% vs. 27%; P < 0.001), in low-volume hospitals (40% vs. 32%; P < 0.001), with high amputation rates (5.3% vs. 29%; P < 0.001). Controlling for differences in comorbidity, disease severity, and surgeon and hospital performance, blacks' odds of amputation remained 1.7 times greater (95% confidence interval: 1.6-1.9). Even among highest-performing providers-vascular specialists in high-volume, urban teaching hospitals with angioplasty facilities-racial gaps persisted (risk-adjusted amputation rates: 7% for blacks vs. 4% for whites, P < 0.001; odds ratio: 1.8, 95% confidence interval: 1.5-2.1). Conclusions: Black patients with critical limb ischemia face significantly higher risk of major amputation, even when treated by providers with highest likelihoods of revascularization. Increased referral to high-performing providers might increase limb-preservation, but cannot eliminate disparities until equitable treatment can be ensured in all settings. C1 [Regenbogen, Scott E.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Regenbogen, Scott E.; Gawande, Atul A.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Gawande, Atul A.; Lipsitz, Stuart R.; Greenberg, Caprice C.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Lipsitz, Stuart R.; Jha, Ashish K.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. RP Regenbogen, SE (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,GRB-425, Boston, MA 02114 USA. EM sregenbogen@partners.org OI Gawande, Atul/0000-0002-1824-9176 NR 52 TC 41 Z9 41 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD SEP PY 2009 VL 250 IS 3 BP 424 EP 431 DI 10.1097/SLA.0b013e3181b41d53 PG 8 WC Surgery SC Surgery GA 488PG UT WOS:000269361400010 PM 19652590 ER PT J AU Robinson, TN Eiseman, B Wallace, JI Church, SD McFann, KK Pfister, SM Sharp, TJ Moss, M AF Robinson, Thomas N. Eiseman, Ben Wallace, Jeffrey I. Church, Skotti D. McFann, Kim K. Pfister, Shirley M. Sharp, Terra J. Moss, Marc TI Redefining Geriatric Preoperative Assessment Using Frailty, Disability and Co-Morbidity SO ANNALS OF SURGERY LA English DT Article; Proceedings Paper CT 129th Annual Meeting of the American-Surgical-Association CY APR 23, 2009 CL Indian Wells, CA SP Amer Surg Assoc ID NONCARDIAC SURGERY; ELDERLY-PATIENTS; RISK-ASSESSMENT; MORTALITY-RATE; SURGICAL CARE; OLDER-ADULTS; INDEX; COMPLICATIONS; VALIDATION; OUTCOMES AB Objectives: (1) Determine the relationship of geriatric assessment markers to 6-month postoperative mortality in elderly patients. (2) Create a clinical prediction rule using geriatric markers from preoperative assessment. Background: Geriatric surgery patients have unique physiologic vulnerability requiring preoperative assessment beyond the traditional evaluation of older adults. The constellation of frailty, disability and comorbidity predict poor outcomes in elderly hospitalized patients. Methods: Prospectively, subjects >= 65 years undergoing a major operation requiring postoperative intensive care unit admission were enrolled. Preoperative geriatric assessments included: Mini-Cog Test (cognition), albumin, having fallen in the past 6-months, hematocrit, Katz Score (function), and Charlson Index (comorbidities). Outcome measures included 6-month mortality (primary) and postdischarge institutionalization (secondary). Results: One hundred ten subjects (age 74 +/- 6 years) were studied. Six-month mortality was 15% (16/110). Preoperative markers related to 6-month mortality included: impaired cognition (P < 0.01), recent falls (P < 0.01), lower albumin (P < 0.01), greater anemia (P < 0.01), functional dependence (P < 0.01), and increased comorbiditics (P < 0.01). Similar statistical relationships were found for all 6 markers and postdischarge institutionalization. Logistic regression identified any functional dependence (odds ratio 13.9) as the strongest predictor of 6-month mortality. Four or more markers in any one patient predicted 6-month mortality with a sensitivity of 81% (13/16) and specificity of 86% (81/94). Conclusions: Geriatric assessment markers for frailty, disability and comorbidity predict 6-month postoperative mortality and postdischarge institutionalization. The preoperative presence of 4 geriatric-specific markets has high sensitivity and specificity for 6-month mortality. Preoperative assessment using geriatric-specific markers is a substantial paradigm shift from the traditional preoperative evaluation of older adults. C1 [Robinson, Thomas N.; Eiseman, Ben; Church, Skotti D.] Univ Colorado, Denver Sch Med, Dept Surg, Aurora, CO USA. [Robinson, Thomas N.; Eiseman, Ben] Denver Vet Affairs Med Ctr, Dept Surg, Denver, CO USA. [Wallace, Jeffrey I.; Moss, Marc] Univ Colorado, Denver Sch Med, Dept Med, Aurora, CO USA. [McFann, Kim K.] Univ Colorado, Denver Sch Med, Dept Biostat, Aurora, CO USA. [Pfister, Shirley M.; Sharp, Terra J.] Denver Vet Affairs Med Ctr, Dept Anesthesia, Denver, CO USA. RP Robinson, TN (reprint author), 12631 E 17th Ave,UCDHSC MS C313, Aurora, CO 80045 USA. EM thomas.robinson@ucdenver.edu FU NHLBI NIH HHS [K24-HL-089223] NR 42 TC 178 Z9 181 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD SEP PY 2009 VL 250 IS 3 BP 449 EP 455 DI 10.1097/SLA.0b013e3181b45598 PG 7 WC Surgery SC Surgery GA 488PG UT WOS:000269361400013 PM 19730176 ER PT J AU Morse, CR AF Morse, Christopher R. TI Repair of Bronchial Esophageal Fistula Using Alloderm SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material ID CLOSURE AB We describe the use of Alloderm (LifeCell Corp, Branchburg, NJ), a biologic scaffold, to repair a large fistula between the proximal left mainstem bronchus and the esophagus. (Ann Thorac Surg 2009;88:1018-9) (C) 2009 by The Society of Thoracic Surgeons C1 Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Morse, CR (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. EM crmorse@partners.org NR 4 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD SEP PY 2009 VL 88 IS 3 BP 1018 EP 1019 DI 10.1016/j.athoracsur.2008.12.091 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 485UO UT WOS:000269150500058 PM 19699951 ER PT J AU Dai, TH Tegos, GP Lu, ZS Huang, LY Zhiyentayev, T Franklin, MJ Baer, DG Hamblin, MR AF Dai, Tianhong Tegos, George P. Lu, Zongshun Huang, Liyi Zhiyentayev, Timur Franklin, Michael J. Baer, David G. Hamblin, Michael R. TI Photodynamic Therapy for Acinetobacter baumannii Burn Infections in Mice SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID GRAM-NEGATIVE BACTERIA; PSEUDOMONAS-AERUGINOSA; TRANSLOCATION; OPERATIONS; WOUNDS AB Multidrug-resistant Acinetobacter baumannii infections represent a growing problem, especially in traumatic wounds and burns suffered by military personnel injured in Middle Eastern conflicts. Effective treatment with traditional antibiotics can be extremely difficult, and new antimicrobial approaches are being investigated. One of these alternatives to antimicrobials could be the combination of nontoxic photosensitizers (PSs) and visible light, known as photodynamic therapy (PDT). We report on the establishment of a new mouse model of full-thickness thermal burns infected with a bioluminescent derivative of a clinical Iraqi isolate of A. baumannii and its PDT treatment by topical application of a PS produced by the covalent conjugation of chlorin(e6) to polyethylenimine, followed by illumination of the burn surface with red light. Application of 10(8) A. baumannii cells to the surface of 10-s burns made on the dorsal surface of shaved female BALB/c mice led to chronic infections that lasted, on average, 22 days and that were characterized by a remarkably stable bacterial bioluminescence. PDT carried out on day 0 soon after application of the bacteria gave over 3 log units of loss of bacterial luminescence in a light exposure-dependent manner, while PDT carried out on day 1 and day 2 gave an approximately 1.7-log reduction. The application of PS dissolved in 10% or 20% dimethyl sulfoxide without light gave only a modest reduction in the bacterial luminescence from mouse burns. Some bacterial regrowth in the treated burn was observed but was generally modest. It was also found that PDT did not lead to the inhibition of wound healing. The data suggest that PDT may be an effective new treatment for multidrug-resistant localized A. baumannii infections. C1 [Dai, Tianhong; Tegos, George P.; Lu, Zongshun; Huang, Liyi; Zhiyentayev, Timur; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Dai, Tianhong; Tegos, George P.; Huang, Liyi; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Lu, Zongshun] Tianjin Med Univ, Gen Hosp, Dept Gastroenterol, Tianjin, Peoples R China. [Huang, Liyi] Guangxi Med Univ, Affiliated Coll & Hosp 1, Dept Infect Dis, Nanning, Peoples R China. [Zhiyentayev, Timur] Moscow MV Lomonosov State Univ, Dept Chem, Moscow, Russia. [Franklin, Michael J.] Montana State Univ, Dept Microbiol, Bozeman, MT 59717 USA. [Baer, David G.] USA, Inst Surg Res, San Antonio, TX USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, BAR414,40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI Tegos, George/C-8830-2011; OI Hamblin, Michael/0000-0001-6431-4605 FU U.S. Air Force MFEL program [FA9550-04-1-0079]; NIH [AI050875]; Bullock-Wellman Postdoctoral Fellowship Award FX This work was supported by the U.S. Air Force MFEL program ( contract FA9550-04-1-0079) and the NIH ( grant AI050875). T. Dai was supported by a Bullock-Wellman Postdoctoral Fellowship Award. NR 28 TC 65 Z9 69 U1 0 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2009 VL 53 IS 9 BP 3929 EP 3934 DI 10.1128/AAC.00027-09 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 496XR UT WOS:000270014200042 PM 19564369 ER PT J AU Finegold, SM Bolanos, M Sumannen, PH Molitoris, DR AF Finegold, Sydney M. Bolanos, Mauricio Sumannen, Paula H. Molitoris, Denise R. TI In Vitro Activities of Telavancin and Six Comparator Agents against Anaerobic Bacterial Isolates SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; COMPLICATED SKIN; HEALTHY-SUBJECTS; INFECTIONS; VANCOMYCIN; PHARMACOKINETICS; LIPOGLYCOPEPTIDE; VOLUNTEERS; DAPTOMYCIN; TD-6424 AB The antimicrobial activities of telavancin and six comparators were evaluated against 460 isolates of anaerobic bacteria. Telavancin demonstrated excellent activity against gram-positive anaerobes (MIC(90), 2 mu g/ml) and was the most potent agent tested against Clostridium difficile (MIC(90), 0.25 mu g/ml). As expected, gram-negative isolates were not inhibited by telavancin. C1 [Finegold, Sydney M.] Vet Adm Greater Los Angeles Healthcare Syst, Med Serv, Los Angeles, CA USA. [Bolanos, Mauricio; Sumannen, Paula H.; Molitoris, Denise R.] Vet Adm Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. [Finegold, Sydney M.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Finegold, Sydney M.] Univ Calif Los Angeles, Dept Microbiol, Sch Med, Los Angeles, CA 90024 USA. [Finegold, Sydney M.] Univ Calif Los Angeles, Sch Med, Dept Immunol & Mol Genet, Los Angeles, CA 90024 USA. RP Finegold, SM (reprint author), VA Med Ctr, Infect Dis Sect 111F, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM sidfinegol@aol.com FU Theravance, Inc., South San Francisco, CA FX Editorial support was provided by I. Stoilov, Envision Scientific Solutions. NR 22 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2009 VL 53 IS 9 BP 3996 EP 4001 DI 10.1128/AAC.00908-08 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 496XR UT WOS:000270014200052 PM 19581457 ER PT J AU Ganis, G Patnaik, P AF Ganis, Giorgio Patnaik, Pooja TI Detecting Concealed Knowledge Using a Novel Attentional Blink Paradigm SO APPLIED PSYCHOPHYSIOLOGY AND BIOFEEDBACK LA English DT Article DE Concealed information test; Concealed knowledge test; Lie detection; Detection of deception; Attentional blink; Applied psychology; Forensics ID PROCESSING RESOURCES; GUILTY KNOWLEDGE; AROUSING DISTRACTORS; ORIENTING RESPONSE; VISUAL-ATTENTION; INFORMATION; ALLOCATION; TIME; PERCEPTION; EMOTION AB Traditional concealed information paradigms rely on the idea that stimuli that are meaningful to a person (critical items) will draw attentional resources disproportionately, relative to stimuli that are not (irrelevant items), generating detectable differences on a suitable dependent variable (behavioral, psychophysiological, or neural). Here, we introduce a behavioral paradigm that could be used to reveal concealed information by exploiting the link between concealed information and attentional processes more directly. This novel paradigm is based on the attentional blink phenomenon in which detection of a stimulus reduces detection accuracy rates of subsequent target stimuli within a 200-500 ms time window. We hypothesized that a well-known face used as a critical item could capture attentional resources automatically, making it harder to detect the occurrence of a subsequently presented target face. The results confirmed this hypothesis, and showed that concealed knowledge of a famous face could be detected in 9 out of 12 individuals by looking for a relative dip in target detection accuracy after the presentation of a critical item. C1 [Ganis, Giorgio] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ganis, Giorgio] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Ganis, Giorgio; Patnaik, Pooja] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Ganis, G (reprint author), Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Bldg 149,13th St, Charlestown, MA 02129 USA. EM ganis@nmr.mgh.harvard.edu OI Ganis, Giorgio/0000-0001-6175-2618 NR 34 TC 6 Z9 6 U1 1 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-0586 J9 APPL PSYCHOPHYS BIOF JI Appl. Psychophysiol. Biofeedback PD SEP PY 2009 VL 34 IS 3 BP 189 EP 196 DI 10.1007/s10484-009-9094-1 PG 8 WC Psychology, Clinical SC Psychology GA 483UW UT WOS:000268994900006 PM 19557325 ER PT J AU Contardo, C Black, AC Beauvais, J Dieckhaus, K Rosen, MI AF Contardo, Christopher Black, Anne C. Beauvais, John Dieckhaus, Kevin Rosen, Marc I. TI Relationship of Prospective Memory to Neuropsychological Function and Antiretroviral Adherence SO ARCHIVES OF CLINICAL NEUROPSYCHOLOGY LA English DT Article DE HIV; Neuropsychological function; Adherence; Medication compliance; Substance use ID COGNITIVE DYSFUNCTION; MEDICATION ADHERENCE; PARKINSONS-DISEASE; REGIMEN COMPLEXITY; HIV-1 INFECTION; IMPAIRMENT; NONADHERENCE; MANAGEMENT; DEFICITS; THERAPY AB Prospective memory is defined as the ability to "remember to remember" something at a future time despite intervening distractions and may be particularly important in remembering to take prescribed medication among people infected with HIV. Ninety-seven HIV-positive participants in a clinical trial had their adherence measured by electronic pillcaps and were administered neuropsychological screening tests and the memory for intentions screening test (MIST). Factor analysis of the MIST and other neuropsychological measures identified four factors. Two were derived from MIST subscales and accounted for approximately 50% of the variance in cognitive functioning. Only one factor was significantly correlated with adherence, and this was a MIST factor. In this preliminary study, the MIST assessed a memory function that (a) could be distinguished from traditional retrospective recall and executive functioning and (b) was correlated with antiretroviral adherence. C1 [Contardo, Christopher] VA Boston Healthcare Syst, Neuropsychol Serv, Boston, MA 02132 USA. [Black, Anne C.; Beauvais, John; Rosen, Marc I.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Black, Anne C.; Beauvais, John; Rosen, Marc I.] Yale Univ, Sch Med, New Haven, CT USA. [Dieckhaus, Kevin] Univ Connecticut, Ctr Hlth, Farmington, CT USA. RP Contardo, C (reprint author), VA Boston Healthcare Syst, Neuropsychol Serv, 150 S Huntington Ave, Boston, MA 02132 USA. EM chriscontardo@gmail.com FU MIR [R01 DA15215]; VISN 1 MIRECC [P50 DA09241] FX The project was supported by R01 DA15215 (MIR), P50 DA09241, VISN 1 MIRECC, and M01RR06192. NR 37 TC 24 Z9 24 U1 1 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 SEP PY 2009 VL 24 IS 6 BP 547 EP 554 DI 10.1093/arclin/acp046 PG 8 WC Psychology, Clinical; Psychology SC Psychology GA 502GX UT WOS:000270445900002 PM 19648150 ER PT J AU Choca, JP Krueger, KR de la Torre, GG Corral, S Garside, D AF Choca, James P. Krueger, Kristin R. de la Torre, Gabriel G. Corral, S. Garside, Dan TI Demographic Adjustments for the Spanish Version of the WAIS-III SO ARCHIVES OF CLINICAL NEUROPSYCHOLOGY LA English DT Article DE Neuropsychology; Hispanics; Intelligence testing; Demographic adjustments; Education and IQ ID NEUROPSYCHOLOGICAL TEST-PERFORMANCE; SEMANTIC VERBAL FLUENCY; SOUTH-AFRICA; EDUCATION; LITERACY; NORMS; AGE; POPULATION; AMERICANS; LANGUAGE AB The Spanish version of the third edition of the Wechsler Adult Intelligence Scale (WAIS-III) by TEA Ediciones is an excellent addition to available instruments for Spanish speakers. The Spanish norms function similarly to US norms for individuals aged 16-35. The norms become increasingly different for individuals 35 and older, seemingly because of the lower levels of formal education of the older Spanish cohorts. Using data from a random half of the Spanish sample, the authors developed regression equations to adjust the scaled scores for individuals with a low level of education. The adjustment is made to the level that would have been expected if the individual had 12 years of education, the median level of education of the US norms. The article includes the methodology and values necessary to make the adjustments. The scaled scores were then adjusted for individuals on the second random half of the Spanish sample and compared to the United States norms. The results showed the adjustments succeed in bringing the Spanish norms closer to the US norms. C1 [Choca, James P.] Roosevelt Univ, Dept Psychol, Chicago, IL 60614 USA. [Krueger, Kristin R.] Audie L Murphy Mem Hosp, S Texas Vet Hlth Care Syst, San Antonio, TX USA. [de la Torre, Gabriel G.] Univ Cadiz, Dept Psicol, Cadiz, Spain. [Corral, S.] TEA Ediciones, Madrid, Spain. [Garside, Dan] Northwestern Univ, Sch Med, Evanston, IL 60208 USA. RP Choca, JP (reprint author), Roosevelt Univ, Dept Psychol, 430 S Michigan Ave, Chicago, IL 60614 USA. EM jchoca@roosevelt.edu RI DE LA TORRE, GABRIEL/A-5598-2015 OI DE LA TORRE, GABRIEL/0000-0001-8636-5956 NR 39 TC 4 Z9 5 U1 0 U2 1 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 SEP PY 2009 VL 24 IS 6 BP 619 EP 629 DI 10.1093/arclin/acp049 PG 11 WC Psychology, Clinical; Psychology SC Psychology GA 502GX UT WOS:000270445900009 PM 19679592 ER PT J AU Aalborg, J Morelli, JG Mokrohisky, ST Asdigian, NL Byers, TE Dellavalle, RP Box, NF Crane, LA AF Aalborg, Jenny Morelli, Joseph G. Mokrohisky, Stefan T. Asdigian, Nancy L. Byers, Tim E. Dellavalle, Robert P. Box, Neil F. Crane, Lori A. TI Tanning and Increased Nevus Development in Very-Light-Skinned Children Without Red Hair SO ARCHIVES OF DERMATOLOGY LA English DT Article ID ACQUIRED MELANOCYTIC NEVI; SUN EXPOSURE; CUTANEOUS MELANOMA; MALIGNANT-MELANOMA; RISK-FACTORS; COLORADO CHILDREN; PREVALENCE; FREQUENCY; NUMBER; COMMON AB Objective: To examine the relationship between tanning and nevus development in very-light-skinned children. Design: Prospective cohort nested within a randomized controlled trial. Skin examinations in 3 consecutive years (2004, 2005, and 2006) included full-body counts of nevi, skin color and tanning measurement using colorimetry, and hair and eye color evaluation by comparison with charts. Telephone interviews of parents provided sun exposure, sun protection, and sunburn history. Setting: Large managed-care organization and private pediatric offices in the Denver, Colorado, metropolitan area. Participants: A total of 131 very-light-skinned white children without red hair and 444 darker-skinned white children without red hair born in Colorado in 1998. Main Outcome Measures: Full-body nevus counts at ages 6 to 8 years. Results: Among very-light-skinned white children, geometric mean numbers of nevi for minimally tanned children were 14.8 at age 6 years; 18.8 at age 7 years; and 22.3 at age 8 years. Mean numbers of nevi for tanned children were 21.2 at age 6 years; 27.9 at age 7 years; and 31.9 at age 8 years. Differences in nevus counts between untanned and tanned children were statistically significant at all ages (P < .05 for all comparisons). The relationship between tanning and number of nevi was independent of the child's hair and eye color, parent-reported sun exposure, and skin phototype. Among darker-skinned white children, there was no relationship between tanning and nevi. Conclusions: Very-light-skinned children who tan (based on objective measurement) develop more nevi than children who do not tan. These results suggest that light-skinned children who develop tans may be increasing their risk for developing melanoma later in life. C1 [Aalborg, Jenny; Asdigian, Nancy L.; Crane, Lori A.] Univ Colorado, Colorado Sch Publ Hlth, Dept Community & Behav Hlth, Denver, CO 80202 USA. [Byers, Tim E.] Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Denver, CO 80202 USA. [Morelli, Joseph G.; Dellavalle, Robert P.; Box, Neil F.] Univ Colorado, Dept Dermatol, Sch Med, Denver, CO 80202 USA. [Morelli, Joseph G.; Mokrohisky, Stefan T.] Univ Colorado, Dept Pediat, Sch Med, Denver, CO 80202 USA. [Mokrohisky, Stefan T.] Kaiser Fdn Hlth Plan Colorado, Denver, CO USA. [Dellavalle, Robert P.] Denver Vet Affairs Hosp, Dept Dermatol, Denver, CO USA. RP Crane, LA (reprint author), Univ Colorado Denver, 13001 E 17th Pl, Aurora, CO 80045 USA. EM lori.crane@ucdenver.edu RI Box, Neil/F-3591-2010; Dellavalle, Robert/L-2020-2013 OI Box, Neil/0000-0002-3486-0346; Dellavalle, Robert/0000-0001-8132-088X FU National Cancer Institute [RO1-CA74592] FX This study was supported in part by grant RO1-CA74592 from the National Cancer Institute (Dr Crane). NR 55 TC 14 Z9 14 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD SEP PY 2009 VL 145 IS 9 BP 989 EP 996 PG 8 WC Dermatology SC Dermatology GA 497FC UT WOS:000270041300003 PM 19770437 ER PT J AU Marx, BP Brailey, K Proctor, SP MacDonald, HZ Graefe, AC Amoroso, P Heeren, T Vasterling, JJ AF Marx, Brian P. Brailey, Kevin Proctor, Susan P. MacDonald, Helen Z. Graefe, Anna C. Amoroso, Paul Heeren, Timothy Vasterling, Jennifer J. TI Association of Time Since Deployment, Combat Intensity, and Posttraumatic Stress Symptoms With Neuropsychological Outcomes Following Iraq War Deployment SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID MENTAL-HEALTH PROBLEMS; GULF-WAR; PTSD SYMPTOMS; NEUTRAL INFORMATION; VIETNAM VETERANS; TRAUMA SURVIVORS; MILITARY SERVICE; PHYSICAL HEALTH; US SOLDIERS; DISORDER AB Context: Previous research has demonstrated neuropsychological changes following Iraq deployment. It is unknown whether these changes endure without subsequent war-zone exposure or chronic stress symptoms. Objective: To determine the associations of time since deployment, combat intensity, and posttraumatic stress disorder (PTSD) and depression symptoms with longer-term neuropsychological outcomes in war-deployed soldiers. Design: Prospective cohort study involving (1) soldiers assessed at baseline (median, 42 days prior to deployment) and following return from Iraq (median, 404 days after return and 885 days since baseline), and (2) soldiers more recently returned from deployment assessed at baseline (median, 378 days prior to deployment) and following return from Iraq (median, 122 days after return and 854 days since baseline assessment). Setting: Active-duty military installations. Participants: Two hundred sixty-eight male and female regular active-duty soldiers (164 with 1-year follow-up; 104 recently returned). Main Outcome Measures: Neuropsychological performances (verbal learning, visual memory, attention, and reaction time). Results: There was a significant interaction between time and PTSD symptom severity (B=-0.01 [unstandardized], P=.04). Greater PTSD symptoms were associated with poorer attention in soldiers tested at 1-year follow-up (B=0.01, P=.03) but not in recently returned soldiers. At 1-year follow-up, mean adjusted attention error scores increased by 0.10 points for every 10 points on the PTSD scale. Greater combat intensity was associated with more efficient postdeployment reactiontime performances, regardless of time since deployment (B=0.48, P=.004), with mean adjusted reaction efficiency scores increasing by 4.8 points for every 10 points on the combat experiences scale. Neither depression nor contextual variables (alcohol use and deployment head injury) were significantly related to neuropsychological outcomes. Conclusions: In this study of army soldiers deployed to the Iraq war, only PTSD symptoms (among soldiers back from deployment for 1 year) were associated with a neuropsychological deficit (reduced attention). Greater combat intensity was associated with enhanced reaction time, irrespective of time since return. C1 [Marx, Brian P.; Brailey, Kevin; MacDonald, Helen Z.; Graefe, Anna C.; Vasterling, Jennifer J.] Vet Affairs Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Marx, Brian P.; Brailey, Kevin; MacDonald, Helen Z.; Vasterling, Jennifer J.] Vet Affairs Boston Healthcare Syst, Psychol Serv, Boston, MA USA. [Proctor, Susan P.] Vet Affairs Boston Healthcare Syst, Res Serv, Boston, MA USA. [Marx, Brian P.; Brailey, Kevin; MacDonald, Helen Z.; Vasterling, Jennifer J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Proctor, Susan P.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02118 USA. [Heeren, Timothy] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Proctor, Susan P.] USA, Environm Med Res Inst, Natick, MA 01760 USA. [Amoroso, Paul] Madigan Army Med Ctr, Ft Lewis, WA USA. RP Vasterling, JJ (reprint author), VA Boston Healthcare Syst, Psychol Serv 116B, 150 S Huntington Ave, Boston, MA 02130 USA. EM jvaster@bu.edu FU US Army Medical Research and Materiel Command [17-03-0020, A-11815]; Veterans Affairs Clinical Sciences Research and Development awards; South Central Mental Illness Research Education, and Clinical Cente; US Army Research Institute for Environmental Medicine FX This work was supported by US Army Medical Research and Materiel Command (DAMD 17-03-0020; HSRRB Log No. A-11815) and Veterans Affairs Clinical Sciences Research and Development awards. This work was also supported in part by resources provided by the South Central Mental Illness Research, Education, and Clinical Center and US Army Research Institute for Environmental Medicine. Some of the work was completed at the Southeast Louisiana Veterans Healthcare System and Tulane University. The US Army Medical Research Acquisition Activity, Fort Detrick, Maryland, is the awarding and administering acquisition office for DAMD 17-03-0020. NR 61 TC 55 Z9 55 U1 4 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD SEP PY 2009 VL 66 IS 9 BP 996 EP 1004 PG 9 WC Psychiatry SC Psychiatry GA 491PI UT WOS:000269590900009 PM 19736356 ER PT J AU Tyler, KL AF Tyler, Kenneth L. TI Emerging Viral Infections of the Central Nervous System Part 2 SO ARCHIVES OF NEUROLOGY LA English DT Article; Proceedings Paper CT 132nd Annual Meeting of the American-Neurological-Association CY OCT 07-10, 2007 CL Washington, DC SP Amer Neurol Assoc ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; NIPAH VIRUS ENCEPHALITIS; INDIAN-OCEAN ISLANDS; LYSSAVIRUS TYPE 2A; HUMAN MONKEYPOX; MULTIPLE-SCLEROSIS; FATAL ENCEPHALITIS; CHIKUNGUNYA-VIRUS; UNITED-STATES; RISK-FACTORS AB The first part of this review ended with a discussion of new niches for known viruses as illustrated by viral central nervous system (CNS) disease associated with organ transplant and the syndrome of human herpesvirus 6-associated posttransplant acute limbic encephalitis. In this part, we begin with a continuation of this theme, reviewing the association of JC virus-associated progressive multifocal leukoencephalopathy (PML) with novel immunomodulatory agents. This part then continues with emerging viral infections associated with importation of infected animals (monkeypox virus), then spread of vectors and enhanced vector competence (chikungunya virus [CHIK]), and novel viruses causing CNS infections including Nipah and Hendra viruses and bat lyssaviruses (BLV). Arch Neurol. 2009; 66(9): 1065-1074 C1 [Tyler, Kenneth L.] Univ Colorado Denver, Hlth Sci Ctr, Dept Neurol, Aurora, CO 80045 USA. [Tyler, Kenneth L.] Univ Colorado Denver, Hlth Sci Ctr, Dept Med Infect Dis, Aurora, CO 80045 USA. [Tyler, Kenneth L.] Univ Colorado Denver, Hlth Sci Ctr, Dept Microbiol, Aurora, CO 80045 USA. [Tyler, Kenneth L.] Denver Vet Affairs Med Ctr, Neurol Serv, Denver, CO USA. RP Tyler, KL (reprint author), Univ Colorado Denver, Hlth Sci Ctr, Dept Neurol, Neurol B-182,Res Complex 2,12700 E 19th Ave, Aurora, CO 80045 USA. EM ken.tyler@ucdenver.edu OI Tyler, Kenneth/0000-0003-3294-5888 FU NINDS NIH HHS [R01 NS051403-05, R01 NS050138-05S1, R01 NS050138-05, R01 NS051403, R01 NS050138] NR 75 TC 35 Z9 38 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9942 EI 1538-3687 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD SEP PY 2009 VL 66 IS 9 BP 1065 EP 1074 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 493UY UT WOS:000269765000003 PM 19752295 ER PT J AU Yeh, S Cebulla, CM Witherspoon, R Emerson, GG Emerson, MV Suhler, EB Albini, TA Flaxel, CJ AF Yeh, Steven Cebulla, Colleen M. Witherspoon, Robert Emerson, Geoffrey G. Emerson, M. Vaughn Suhler, Eric B. Albini, Thomas A. Flaxel, Christina J. TI Management of Fluocinolone Implant Dissociation During Implant Exchange SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID POSTERIOR UVEITIS; ACETONIDE IMPLANT; CLINICAL-TRIAL; REIMPLANTATION AB Three patients with chronic, noninfectious uveitis requiring immunosuppressive therapy underwent fluocinolone acetonide (FA) implant exchange complicated by dissociation of the medication reservoir from its anchoring strut. In 2 patients, the medication reservoir descended into the vitreous cavity and required pars plana vitrectomy with intraocular foreign body removal techniques for its retrieval. The use of viscoelastic or perfluorocarbon to elevate the device was helpful in the safe removal of the FA implant device. Surgeons performing FA implant exchange should be aware of this potential complication and anticipate the possible need for vitreoretinal instrumentation and personnel. Patients undergoing FA explantation or exchange should be counseled regarding this potential complication prior to surgery. Arch Ophthalmol. 2009; 127(9): 1218-1221 C1 [Flaxel, Christina J.] Oregon Hlth & Sci Univ, Casey Eye Inst, Dept Ophthalmol, Portland, OR 97239 USA. [Suhler, Eric B.] Portland VA Med Ctr, Ophthalmol Serv, Portland, OR USA. [Cebulla, Colleen M.; Albini, Thomas A.] Bascom Palmer Eye Inst, Dept Ophthalmol, Miami, FL 33136 USA. RP Flaxel, CJ (reprint author), Oregon Hlth & Sci Univ, Casey Eye Inst, Dept Ophthalmol, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM flaxelc@ohsu.edu RI Cebulla, Colleen/E-2861-2011; OI Albini, Thomas/0000-0003-2199-9047 FU Research to Prevent Blindness FX This work was supported by an unrestricted grant to the Casey Eye Institute from Research to Prevent Blindness. NR 7 TC 14 Z9 14 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD SEP PY 2009 VL 127 IS 9 BP 1218 EP 1221 PG 4 WC Ophthalmology SC Ophthalmology GA 493VD UT WOS:000269765500018 PM 19752436 ER PT J AU Koch, WM Ridge, JA Forastiere, A Manola, J AF Koch, Wayne M. Ridge, John A. Forastiere, Arlene Manola, Judith TI Comparison of Clinical and Pathological Staging in Head and Neck Squamous Cell Carcinoma Results From Intergroup Study ECOG 4393/RTOG 9614 SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article AB Objectives: To compare the results of clinical and pathological staging for a large cohort of patients with head and neck squamous cell carcinoma (HNSCC) and to examine patterns and ramifications of the disparity between staging methods. Design: Prospective inception cohort (median follow-up, 7 years). Setting: Multi-institutional cooperative group study (Eastern Cooperative Oncology Group 4393/Radiation Therapy Oncology Group 9614) involving 17 academic medical centers. Patients: A total of 560 patients with new-onset or recurrent HNSCC enrolled during a 7-year period. Interventions: Surgical resection with curative intent with or without adjuvant or previous radiotherapy or chemotherapy. Main Outcome Measures: Clinical staging and pathological staging and the component TN tumor categorieswere compared with overall and disease-specific Survival. Association of survival With staging was derived by means Of the proportional hazards model. Results: Of the 501 cases in which both clinical and pathological staging was available, a disparity was found between at least 1 component tumor category assigned by the 2 methods in almost 50% of cases. Both methods showed a strong association of stage with overall survival for the cohort at large. However, pathological nodal category was a superior predictor (P<.001 vs P=.005), whereas there was an advantage to pathological tumor category in predicting disease-specific survival (P=.01). Conclusions: Both staging methods are useful in predicting survival, whereas information gained at neck dissection regarding nodal metastases provides some refinement in prognostic results. These findings demonstrate the need for enhanced methods of tumor assessment and apparent benefit of data gathered at neck dissection for accurate disease assessment and stratification. C1 [Koch, Wayne M.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [Ridge, John A.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Manola, Judith] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Koch, WM (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 601 N Caroline St, Baltimore, MD 21287 USA. EM wkoch@jhmi.edu FU NCI NIH HHS [U10 CA023318, CA16116, CA21115, CA23318, CA27525, CA66636, U10 CA016116, U10 CA021115, U10 CA027525, U10 CA066636]; NIDCR NIH HHS [R01 DE013152, R01 DE013152-09] NR 11 TC 15 Z9 15 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0886-4470 EI 1538-361X J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD SEP PY 2009 VL 135 IS 9 BP 851 EP 858 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 494GB UT WOS:000269798700001 PM 19770416 ER PT J AU Ganske, I Faquin, W Cunningham, M AF Ganske, Ingrid Faquin, William Cunningham, Michael TI Pathology Quiz Case 2: Diagnosis: Nasal chondromesenchymal hamartoma (NCMH) SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Editorial Material ID ADOLESCENT; CHILDREN; INFANCY C1 [Ganske, Ingrid; Cunningham, Michael] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02115 USA. [Faquin, William] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Ganske, I (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02115 USA. NR 10 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD SEP PY 2009 VL 135 IS 9 BP 945 EP + PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 494GB UT WOS:000269798700020 PM 19770433 ER PT J AU Moriarty, AT Darragh, TM Souers, R Fatheree, LA Wilbur, DC AF Moriarty, Ann T. Darragh, Teresa M. Souers, Rhona Fatheree, Lisa A. Wilbur, David C. TI Performance of Herpes Simplex Challenges in Proficiency Testing Observations From the College of American Pathologists Proficiency Testing Program SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT 56th Annual Scientific Meeting of the American-Society-of-Cytopathology CY NOV 07-11, 2008 CL Orlando, FL SP Amer Soc Cytopathol ID INTERLABORATORY COMPARISON PROGRAM; CERVICOVAGINAL CYTOLOGY; VALIDATION AB Context.-Herpes simplex virus (HSV) is a common sexually transmitted disease that is decreasing in prevalence. Herpes simplex virus challenge cases have performed well in the educational College of American Pathologists Inter-laboratory Comparison Program in Cervicovaginal Cytology. However, since gynecologic cytology proficiency testing (PT) was instituted, performance of HSV challenge cases has worsened. Objective.-To determine if the decrease in performance for HSV challenges is due to inexperience in identifying herpes virus or "gaming'' of PT. Design.-We compare graded (field-validated) and ungraded (educational) slides with HSV prior to PT (1991 2005) and after PT (2006 and 2007) in an attempt to characterize changes in performance of slides demonstrating purely HSV cellular features. All HSV slides were negative for intraepithelial lesion with the specific reference interpretation of HSV. Slides were excluded from analysis if they demonstrated more than one diagnostic category or had squamous intraepithelial lesion in addition to HSV changes. Results.-A total of 40 634 HSV responses were evaluated. A significant difference existed in the diagnosis of HSV in PT compared with graded challenges prior to PT (96.6 versus 98.6; P<.001). No difference was seen in educational challenges pre-PT and post-PT (P=.14). No difference was present between slide preparation type; however, a difference was seen between cytotechnologist and pathologist response. Conclusions.-There is a change in the performance of slide challenges demonstrating the cellular features of HSV in PT, most likely due to testing strategies of participants, rather than lack of recognition of HSV secondary to decreased prevalence. (Arch Pathol Lab Med. 2009; 133: 1379-1382) C1 [Moriarty, Ann T.] AmeriPath Indiana, Dept Pathol, Indianapolis, IN 46219 USA. [Darragh, Teresa M.] Univ Calif San Francisco, Mt Zion Med Ctr Clin, Dept Pathol & Cytol, San Francisco, CA 94143 USA. [Fatheree, Lisa A.] Coll Amer Pathologists, Cytol Surveys, Northfield, IL USA. [Wilbur, David C.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Moriarty, AT (reprint author), AmeriPath Indiana, Dept Pathol, 2560 N Shadeland Ave,Suite A, Indianapolis, IN 46219 USA. EM amoriarty@ameripath.com NR 8 TC 2 Z9 2 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD SEP PY 2009 VL 133 IS 9 BP 1379 EP 1382 PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 490GC UT WOS:000269486600014 PM 19722743 ER PT J AU Lagwinski, N Hunt, JL AF Lagwinski, Nikolaj Hunt, Jennifer L. TI Fellowship Trends of Pathology Residents SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT Conference of the College-of-American-Pathologists-Futurescape-of-Pathology CY JUN 07-08, 2008 CL Rosemont, IL SP Coll Amer Pathol Futurescape Pathol ID LABORATORY MEDICINE; ANATOMIC PATHOLOGY; COMPETENCE; CURRICULUM; EDUCATION; FUTURE AB Context.-Recent changes in pathology residency education have included a decrease in the program length (from 5 years to 4 years for combined anatomic and clinical pathology training) and a national mandate for programs to assess 6 general competencies of trainees. These have undoubtedly led to changes in program curricula and in residents' desires to seek fellowship training. Objective.-This study was designed to gather information about what residents are seeking from fellowship training programs. Design.-This study used an online survey to assess attitudes of residents in training programs toward fellowship training. The survey instrument had 26 questions pertaining to fellowship choices, motivations for pursuing fellowships, expectations of the fellowships, and postresidency concerns. Results.-There were 213 respondents from a mix of program types and representing each postgraduate year. Most residents will seek at least 1 or 2 fellowships after residency training. The most popular first-choice fellowship was surgical pathology (26%), followed by cytopathology (16%), hematopathology (15%), gastrointestinal pathology (10%), dermatopathology (8%), and forensic pathology (5%). The most common reasons for pursuing fellowship training were to "increase marketability (43%) or to "become an expert in a particular area" (33%). Most trainees got their information about fellowship training programs from Internet sources. Conclusions.-Fellowship programs will benefit from an optimally designed Web site because residents seek information predominantly from the Internet. Residents seeking fellowships are particularly concerned with selecting programs that provide job connections, an increase in their marketability, and the opportunity to develop diagnostic expertise.(Arch Pathol Lab Med. 2009; 133: 1431-1436) C1 [Lagwinski, Nikolaj; Hunt, Jennifer L.] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 USA. RP Hunt, JL (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM jhunt5@partners.org NR 13 TC 16 Z9 16 U1 0 U2 2 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD SEP PY 2009 VL 133 IS 9 BP 1431 EP 1436 PG 6 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 490GC UT WOS:000269486600021 PM 19722750 ER PT J AU Impink, BG Boninger, ML Walker, H Collinger, JL Niyonkuru, C AF Impink, Bradley G. Boninger, Michael L. Walker, Heather Collinger, Jennifer L. Niyonkuru, Christian TI Ultrasonographic Median Nerve Changes After a Wheelchair Sporting Event SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article; Proceedings Paper CT State of the Science Symposium on Ultrasound CY SEP 25-26, 2008 CL Walter Reed Army Med Ctr, Washington, DC HO Walter Reed Army Med Ctr DE Carpal tunnel syndrome; Median nerve; Ultrasonography; Wheelchairs ID CARPAL-TUNNEL-SYNDROME; HIGH-RESOLUTION SONOGRAPHY; CROSS-SECTIONAL AREA; BODY-MASS INDEX; GENERAL-POPULATION; UPPER EXTREMITY; PARAPLEGIC PATIENTS; RISK-FACTORS; ULNAR NERVE; ULTRASOUND AB Objectives: To investigate the acute median nerve response to intense wheelchair propulsion by using ultrasonography and to examine the relationship between carpal tunnel syndrome (CTS) signs and symptoms and the acute median nerve response. Design: Case series. Setting: Research room at the National Veterans Wheelchair Games. Participants: Manual wheelchair users (N=28) competing in wheelchair basketball. Intervention: Ultrasound images collected before and after a wheelchair basketball game. Main Outcome Measures: Median nerve cross-sectional area, flattening ratio, and swelling ratio and changes in these after activity. Comparison of median nerve characteristics and patient characteristics between participants with and without positive physical examination findings and with and without symptoms of CTS. Results: Significant changes in median nerve ultrasound characteristics were noted after activity. The group as a whole showed a significant decrease in cross-sectional area at the radius of 4.05% (P=.023). Participants with positive physical examinations showed significantly different (P=.029) and opposite changes in swelling ratio compared with the normal group. Subjects with CTS symptoms had a significantly (P=.022) greater duration of wheelchair use (17.1y) compared with the asymptomatic participants (9y). Conclusions: Manual wheelchair propulsion induces acute changes in median nerve characteristics that can be visualized by using ultrasound. Studying the acute median nerve response may be useful for optimizing various interventions, such as wheelchair set up or propulsion training, to decrease both acute and chronic median nerve damage and the likelihood of developing CTS. C1 [Impink, Bradley G.; Boninger, Michael L.; Collinger, Jennifer L.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. [Impink, Bradley G.; Boninger, Michael L.; Collinger, Jennifer L.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Boninger, Michael L.; Walker, Heather; Collinger, Jennifer L.; Niyonkuru, Christian] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. RP Boninger, ML (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs, 7180 Highland Dr,151R1-H,Bldg 4,2nd Fl,East Wing, Pittsburgh, PA 15206 USA. EM boninger@pitt.edu OI Boninger, Michael/0000-0001-6966-919X NR 40 TC 7 Z9 7 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD SEP PY 2009 VL 90 IS 9 BP 1489 EP 1494 DI 10.1016/j.apmr.2009.02.019 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 496AA UT WOS:000269938100005 PM 19735775 ER PT J AU Mega, JL Morrow, DA Brown, A Cannon, CP Sabatine, MS AF Mega, Jessica L. Morrow, David A. Brown, Alison Cannon, Christopher P. Sabatine, Marc S. TI Identification of Genetic Variants Associated With Response to Statin Therapy SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE cholesterol-lowering drugs; lipids; pharmacogenetics ID DENSITY-LIPOPROTEIN CHOLESTEROL; APOLIPOPROTEIN-E GENOTYPES; ACUTE CORONARY SYNDROMES; COA REDUCTASE INHIBITORS; P-GLYCOPROTEIN; HEART-DISEASE; LIPID-LEVELS; ATORVASTATIN; POLYMORPHISM; GEMFIBROZIL AB Objective-The purpose of this study was to test the association between polymorphisms in genes involved in either LDL cholesterol (LDL-C) metabolism or statin pharmacokinetics and LDL-C reduction with statins. Methods and Results-49 tagging and candidate polymorphisms in 9 genes were genotyped in 1507 post-ACS subjects randomized to atorvastatin or pravastatin. Two polymorphisms (rs7412, rs429358) that define the epsilon 2, epsilon 3, and epsilon 4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (epsilon 2 carriers 53.8%, epsilon 3/epsilon 3 48.1%, and epsilon 4 carriers 46.4%, respectively, P=0.00039) and replicated in the pravastatin arm (epsilon 2 carriers 22.1%, epsilon 3/epsilon 3 21.8%, and epsilon 4 carriers 16.6%, respectively, P=0.00038). The proportion of subjects achieving an LDL-C <= 70 mg/dL at day 30 was higher for epsilon 2 than epsilon 4 carriers (P=1.3x10(-5)). In the pravastatin group, the triallelic rs2032582 variant (G2677T/A) in ABCB1 was associated with the percent reduction in LDL-C (GG 23.3%, non-G heterozygote 20.3%, and non-G homozygote 17.4%, P=0.042). Conclusion-Carriers of APOE epsilon 2 versus epsilon 4 had significantly greater LDL-C reduction with atorvastatin and with pravastatin, and more frequently achieved a guideline-recommended LDL-C <= 70 mg/dL. Polymorphisms in triallelic G2677T/A variant in ABCB1 were associated with the degree of LDL-C lowering with pravastatin. (Arterioscler Thromb Vasc Biol. 2009;29:1310-1315.) C1 [Mega, Jessica L.; Morrow, David A.; Cannon, Christopher P.; Sabatine, Marc S.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Brown, Alison] Harvard Med Sch Partners Ctr Personalized Genet M, Boston, MA USA. RP Mega, JL (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Dept Med, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM jmega@partners.org FU Leadership Council for Improving Cardiovascular Care (Schering-Plough) FX The PROVE IT-TIMI 22 trial was funded by Bristol-Myers Squibb. Dr Mega was supported in part by a grant from the Leadership Council for Improving Cardiovascular Care (Schering-Plough). The TIMI Study Group reports receiving significant research grant support from AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol- Myers Squibb, CV Therapeutics, Eli Lilly, Genentech, GlaxoSmithKline,Integrated Therapeutics Group, Johnson & Johnson, Merck, Nanosphere, Novartis, Pfizer, Roche Diagnostics, Sanofi-Aventis, Siemens Medical Solutions, Singulex, and Schering-Plough. NR 28 TC 45 Z9 48 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP PY 2009 VL 29 IS 9 BP 1310 EP 1315 DI 10.1161/ATVBAHA.109.188474 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 485CL UT WOS:000269098200012 PM 19667110 ER PT J AU Bartels, C Bell, C Rosenthal, A Shinki, K Bridges, A AF Bartels, Christie Bell, Carolyn Rosenthal, Ann Shinki, Kazuhiko Bridges, Alan TI Decline in Rheumatoid Vasculitis Prevalence Among US Veterans A Retrospective Cross-Sectional Study SO ARTHRITIS AND RHEUMATISM LA English DT Article ID TURESSON ET-AL; EXTRAARTICULAR MANIFESTATIONS; ARTHRITIS; DISEASE; MILDER; DECREASE; ARTICLE; TIME AB Objective. To examine trends in the prevalence of rheumatoid vasculitis in a national US population comprising both hospitalized and ambulatory patients with rheumatoid arthritis (RA). Methods. In this serial cross-sectional study, we analyzed data on hospitalized and ambulatory patients spanning 22 years (1985-2006) and 10 years (19972006), respectively, to determine the prevalence of rheumatoid vasculitis, as defined by the International Classification of Diseases, Ninth Revision. Our search encompassed data collected on a predominantly male study population during 10 million hospitalizations and outpatient visits, and included annual data on >37,000 RA patients. To test for a decrease in rheumatoid vasculitis prevalence, breakpoint analysis was performed using stepwise Chow and Durbin-Watson tests. Results. There was a clear decline in the prevalence of rheumatoid vasculitis, and this decline remained evident even after accounting for a decreased number of hospitalizations among RA patients. Peak prevalence occurred among hospitalized patients in the 1980s, and prevalence gradually declined throughout the 1990s. Furthermore, simultaneous breakpoints representing a significant drop in rheumatoid vasculitis prevalence between the years 2000 and 2001 were demonstrated for both inpatients (P < 0.000) and outpatients (P < 0.003). The prevalence of vasculitis dropped 53% among inpatients and 31% among outpatients between 2000 and 2001. Conclusion. Our results demonstrate a significant decline in rheumatoid vasculitis prevalence after 2000 in this nationwide sample of hospitalized and ambulatory patients. The clear, consistent drop in prevalence provides an opportunity for the formulation of causal hypotheses, including consideration of the impact of biologic agents used to treat RA, on rheumatoid vasculitis. C1 [Bartels, Christie; Bell, Carolyn; Bridges, Alan] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Bartels, Christie; Bridges, Alan] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Rosenthal, Ann] Zablocki Vet Adm Med Ctr, Milwaukee, WI 53295 USA. [Rosenthal, Ann] Med Coll Wisconsin, Milwaukee, WI 53226 USA. RP Bartels, C (reprint author), 600 Highland Ave,MC 3244, Madison, WI 53792 USA. EM cb4@medicine.wisc.edu FU NIH [1KL2-RR-025012-01] FX Dr. Bartels' work was supported by NIH grant 1KL2-RR-025012-01. NR 15 TC 16 Z9 16 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2009 VL 60 IS 9 BP 2553 EP 2557 DI 10.1002/art.24775 PG 5 WC Rheumatology SC Rheumatology GA 497JI UT WOS:000270054900003 PM 19714622 ER PT J AU Chen, B Wang, YB Zhang, ZL Xia, WL Wang, HX Xiang, ZQ Hu, K Han, YF Wang, YX Huang, YR Wang, Z AF Chen, Bin Wang, Yu-Bin Zhang, Zhi-Ling Xia, Wei-Liang Wang, Hong-Xiang Xiang, Zu-Qiong Hu, Kai Han, Yin-Fa Wang, Yi-Xin Huang, Yi-Ran Wang, Zheng TI Xeno-free culture of human spermatogonial stem cells supported by human embryonic stem cell-derived fibroblast-like cells SO ASIAN JOURNAL OF ANDROLOGY LA English DT Article DE human embryonic stem cell-derived fibroblast-like cells (hdFs); spermatogonial stem cells (SSCs); xeno-free culture ID LONG-TERM CULTURE; IN-VITRO; GERM-CELLS; HUMAN BLASTOCYSTS; MOUSE TESTIS; C-KIT; EXPRESSION; LINES; DIFFERENTIATION; TRANSPLANTATION AB Spermatogonial stem cells (SSCs) divide continuously to support spermatogenesis throughout postnatal life and transmit genetic information to the next generation. Here, we report the successful establishment of the method for the isolation and identification of human SSCs from testicular tissue, and to determine the culture conditions required to expand SSCs on human embryonic stem cell-derived fibroblast-like cells (hdFs). Large-scale cultures of SSCs were maintained on hdF feeder layers and expanded in the presence of a combination of cytokines and glial cell line-derived neurotrophic factor for at least 2 months. Cell surface marker analysis showed that SSCs retained high levels of alkaline phosphatase activity and stained strongly for anti-stage- specific embryonic antigen (SSEA)-1, OCT4 and CD49f. They also expressed the genes OCT4, SOX3 and STRA8 as detected by reverse transcription polymerase chain reaction (RT-PCR) analysis. These data clearly illustrate a novel approach for the growth of human SSCs using hdFs as feeder cells, potentially eliminating xenogeneic contaminants. This system provides a new opportunity for the study of the regulatory mechanism of the 'niche' that governs SSC self-renewal, and will be a valuable source of SSCs for potential clinical applications. C1 [Chen, Bin; Wang, Yu-Bin; Wang, Hong-Xiang; Xiang, Zu-Qiong; Hu, Kai; Han, Yin-Fa; Wang, Yi-Xin; Huang, Yi-Ran] Shanghai Jiao Tong Univ, Dept Urol, Sch Med, Shanghai Inst Androl,Renji Hosp, Shanghai 200001, Peoples R China. [Zhang, Zhi-Ling] Shanghai Jiao Tong Univ, Dept Obstet Gynecol, Sch Med, Renji Hosp, Shanghai 200001, Peoples R China. [Xia, Wei-Liang] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Xia, Wei-Liang] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Wang, Zheng] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Digest Dis, Stem Cell Lab, Shanghai 200001, Peoples R China. RP Chen, B (reprint author), Shanghai Jiao Tong Univ, Dept Urol, Sch Med, Shanghai Inst Androl,Renji Hosp, Shanghai 200001, Peoples R China. EM dr_binchen@126.com; zheng.w.dr@gmail.com RI Xia, Weiliang/C-2650-2008 OI Xia, Weiliang/0000-0002-0256-4219 FU Shanghai Municipal Population and Family Planning Commission, China [2007JG06]; Shanghai Leading Academic Discipline Project, China [Y0205] FX This study was supported by grants from the Shanghai Municipal Population and Family Planning Commission, China (No. 2007JG06) and the Shanghai Leading Academic Discipline Project, China (No. Y0205). NR 29 TC 13 Z9 14 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1008-682X J9 ASIAN J ANDROL JI Asian J. Androl. PD SEP PY 2009 VL 11 IS 5 BP 557 EP 565 DI 10.1038/aja.2009.21 PG 9 WC Andrology; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 491GX UT WOS:000269567800004 PM 19734913 ER PT J AU Rizvi, SL Vogt, DS Resick, PA AF Rizvi, Shireen L. Vogt, Dawne S. Resick, Patricia A. TI Cognitive and affective predictors of treatment outcome in cognitive processing therapy and prolonged exposure for posttraumatic stress disorder SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Trauma; PTSD; Cognitive-behavioral therapy; Treatment outcome ID ADMINISTERED PTSD SCALE; INTRUSIVE MEMORIES; RANDOMIZED-TRIAL; RAPE VICTIMS; DEPRESSION; INVENTORY; BEHAVIOR; GUILT; FEAR AB This study examined cognitive and affective predictors of treatment dropout and treatment efficacy in Cognitive Processing Therapy (CPT) and Prolonged Exposure (PE) for PTSD. Study participants were women with PTSD from a sexual assault who received at least one session of either treatment (n = 145) as part of a randomized clinical trial. Results revealed that younger age, lower intelligence, and less education were associated with higher treatment dropout, whereas higher depression and guilt at pretreatment were associated with greater improvement in PTSD symptomatology. Results by treatment condition indicated that women with higher anger at pretreatment were more likely to dropout of PE and that older women in PE and younger women in CPT had the best overall outcomes. These findings have implications for efforts to enhance treatment efficacy and retention in CBT treatment protocols. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Rizvi, Shireen L.] New Sch Social Res, New York, NY 10011 USA. [Vogt, Dawne S.; Resick, Patricia A.] VA Boston Hlth Care Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Vogt, Dawne S.; Resick, Patricia A.] Boston Univ, Dept Med, Div Psychiat, Boston, MA 02215 USA. RP Rizvi, SL (reprint author), New Sch Social Res, 80 5th Ave,7th Floor, New York, NY 10011 USA. EM slrizvi@rci.rutgers.edu FU NIMH NIH HHS [R01 MH051509, 1 R01-MH51509, R01 MH051509-10] NR 45 TC 54 Z9 54 U1 8 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD SEP PY 2009 VL 47 IS 9 BP 737 EP 743 DI 10.1016/j.brat.2009.06.003 PG 7 WC Psychology, Clinical SC Psychology GA 489JU UT WOS:000269417200002 PM 19595295 ER PT J AU Kharfan-Dabaja, MA Mhaskar, AR Djulbegovic, B Cutler, C Mohty, M Kumar, A AF Kharfan-Dabaja, Mohamed A. Mhaskar, Asmita R. Djulbegovic, Benjamin Cutler, Corey Mohty, Mohamad Kumar, Ambuj TI Efficacy of Rituximab in the Setting of Steroid-Refractory Chronic Graft-versus-Host Disease: A Systematic Review and Meta-Analysis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Review DE Rituximab; Chronic graft-versus-host disease; Systematic review; Meta-analysis ID CONSENSUS DEVELOPMENT PROJECT; BONE-MARROW-TRANSPLANTATION; WORKING GROUP-REPORT; CLINICAL-TRIALS; CHRONIC GVHD; EXTRACORPOREAL PHOTOPHERESIS; MYCOPHENOLATE-MOFETIL; CELL TRANSPLANTATION; MONOCLONAL-ANTIBODY; DONOR-PROGRAM AB Increased insight into the role of B lymphocytes in the pathophysiology of graft-versus-host disease has led to a number of studies assessing the efficacy of the anti-CD20 monoclonal antibody (mAb) rituximab in treating steroid-refractory chronic graft-versus-host disease (cGVHD). Findings vary greatly among these studies, however. We conducted a systematic review to summarize the totality of evidence on the efficacy of rituximab in steroid-refractory cGVHD. We performed a PubMed search and contacted experts in the field to identify relevant studies. Endpoints included overall response rate (including organ-specific) and ability of rituximab to allow dosage reduction of immunosuppressive therapies. Data were pooled under a random-effects model. Seven studies (3 prospective and 4 retrospective, with a total of I I I patients) met the inclusion criteria. The pooled proportion of overall response was 0.66 (95% confidence interval = 0.57 to 0.74). There was no heterogeneity among the pooled studies. Response rates were 13% to 100% for cGVHD of the skin, 0 to 83% for cGVHD of the oral mucosa, 0 to 66% for cGVHD of the liver, and 0 to 38% for cGVHD of the lung. Common adverse events were related to infusion reactions or infectious complications. The relatively small number of patients and the varying criteria for reporting organ response and dosage reduction of steroids, among other limitations, hinders our ability to reach definitive conclusions on the overall efficacy of rituximab for cGVHD involving other organs. Biol Blood Marrow Transplant 15: 1005-1013 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Kharfan-Dabaja, Mohamed A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Djulbegovic, Benjamin; Kumar, Ambuj] Univ S Florida, Coll Med, Ctr Evidence Based Med, Tampa, FL 33612 USA. [Cutler, Corey] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mohty, Mohamad] Univ Nantes, Ctr Hosp, Hematol Clin, Nantes, France. RP Kumar, A (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr,MRC 232A, Tampa, FL 33612 USA. EM Ambuj.kumar@moffitt.org RI Djulbegovic, Benjamin/I-3661-2012; Kumar, Ambuj/I-4940-2012 OI Djulbegovic, Benjamin/0000-0003-0671-1447; NR 27 TC 69 Z9 74 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2009 VL 15 IS 9 BP 1005 EP 1013 DI 10.1016/j.bbmt.2009.04.003 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 486EK UT WOS:000269178400001 PM 19660713 ER PT J AU Hammond, SP Borchelt, AM Ukomadu, C Ho, VT Baden, LR Marty, FM AF Hammond, Sarah P. Borchelt, Anne Marie Ukomadu, Chinweike Ho, Vincent T. Baden, Lindsey R. Marty, Francisco M. TI Hepatitis B Virus Reactivation following Allogeneic Hematopoietic Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Hepatitis B; Stem cell transplant; Chronic graft-versus-host disease ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; OF-THE-LITERATURE; REVERSE SEROCONVERSION; VIRAL REACTIVATION; POSITIVE PATIENTS; UNITED-STATES; CHRONIC GRAFT; CHRONIC GVHD; HIGH-RISK AB Reactivation of resolved hepatitis B virus (HBV) infection has been reported in allogeneic hematopoetic stem cell transplantation (HSCT) recipients, but its epidemiology is not well characterized. We performed a retrospective assessment of the timing and risk factors of HBV reactivation among patients with resolved HBV infection undergoing allogeneic HSCT between January 2000 and March 2008. HBV reactivation was defined as development of positive hepatitis B surface antigen after transplant. Among the 61 patients with resolved HBV infection before transplant (hepatitis B core anti body-positive, hepatitis B surface antigen-negative), 12 (19.7%) developed HBV reactivation. The cumulative probability of HBV reactivation 1, 2, and 4 years after transplant was 9.0%, 21.7%, and 42.9%, respectively. In a time-dependent Cox model, the adjusted hazard ratio (HR) of HBV reactivation for patients with pretransplant hepatitis B surface antibody levels < 10 milli-international units per milliliter (mIU/mL) was 4.56 (95% confidence interval [CI] 1.23-16.9) compared to those with levels >= 10 mIU/mL; the adjusted HR among patients who developed extensive chronic graft-versus-host disease (cGVHD) was 7.21 (95% CI 1.25-41.5) compared to those who did not. HBV reactivation is a common late complication among allogeneic HSCT recipients with pretransplant resolved infection. Screening for HBV reactivation should be considered for at-risk HSCT recipients. In this cohort, HBV reactivation often developed in patients with cGVHD. Liver biopsy was useful in those patients with both to delineate the contribution of each to liver dysfunction. Biol Blood Marrow Transplant 15: 1049-1059 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Hammond, Sarah P.; Borchelt, Anne Marie; Baden, Lindsey R.; Marty, Francisco M.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Hammond, Sarah P.; Ukomadu, Chinweike; Ho, Vincent T.; Baden, Lindsey R.; Marty, Francisco M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hammond, Sarah P.; Ukomadu, Chinweike; Ho, Vincent T.; Baden, Lindsey R.; Marty, Francisco M.] Harvard Univ, Sch Med, Boston, MA USA. [Ukomadu, Chinweike] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Ho, Vincent T.] Brigham & Womens Hosp, Div Med Oncol, Boston, MA 02115 USA. RP Hammond, SP (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St,PBB A4, Boston, MA 02115 USA. EM shammond2@partners.org NR 30 TC 51 Z9 52 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2009 VL 15 IS 9 BP 1049 EP 1059 DI 10.1016/j.bbmt.2009.05.001 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 486EK UT WOS:000269178400005 PM 19660717 ER PT J AU Toro, JJ Haile, DJ Chao, JH Schneider, D Jewell, PS Lee, S Freytes, CO AF Toro, Juan J. Haile, David J. Chao, Ju-Hsien Schneider, Deanna Jewell, Pamela S. Lee, Shuko Freytes, Cesar O. TI The Department of Veterans Affairs Nutritional Status Classification Scheme Allows for Rapid Assessment of Nutritional Status Prior to Autologous Peripheral Blood Stem Cell Transplantation and Identifies Patients at High Risk of Transplant-Related Complications SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Nutritional assessment; Lymphoid malignancies; Hematopoietic stem cell transplantation; Transplant-related complications ID BONE-MARROW-TRANSPLANTATION; BIOCHEMICAL INDEXES AB The nutritional assessment of patients prior to autologous peripheral blood stem cell transplantation (APBSCT) is labor intensive. A simple method of nutritional assessment prior to APSCT would be extremely helpful, especially if this method could identify patients at high risk of transplant-related complications. The Department of Veterans Affairs (VA) developed a Nutritional Status Classification Scheme (NSCS) to identify nutritionally compromised inpatients rapidly and reliably. The objective of this study was to determine if the use of the VA-NSCS could be utilized as a tool for the evaluation of patients prior to APBSCT and to determine if this tool could be used to identify patients at high risk of transplant-related complications. The nutritional status of 128 patients who underwent APBSCT was assessed by a registered dietician, utilizing the VA-NSCS, upon admission to the hospital and prior to conditioning regimen. Patients with moderately compromised nutritional status pretransplantation experienced a higher incidence of infections, longer duration of diarrhea, and longer length of hospital stay when compared to patients with normal or mildly compromised nutritional status. Our study demonstrates that the VA-NSCS, a simple and inexpensive tool to assess nutritional status, was useful in determining the pretransplant nutritional status of patients with lymphogenous malignancies who underwent APBSCT In addition, this method was able to identify patients at a higher risk of posttransplant complications. Future studies should be undertaken to determine the optimal method for the nutritional assessment of autologous stem cell transplant candidates. Biol Blood Marrow Transplant 15: 1060-1065 (2009) Published by Elsevier Inc. C1 [Toro, Juan J.; Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Toro, Juan J.; Haile, David J.; Chao, Ju-Hsien; Schneider, Deanna; Jewell, Pamela S.; Lee, Shuko; Freytes, Cesar O.] Audie L Murphy Mem Vet Adm Med Ctr, S Texas Vet Hlth Care Syst, San Antonio, TX 78284 USA. RP Toro, JJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Mail Code 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM toro@uthscsa.edu NR 11 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2009 VL 15 IS 9 BP 1060 EP 1065 DI 10.1016/j.bbmt.2009.05.004 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 486EK UT WOS:000269178400006 PM 19660718 ER PT J AU Chen, YB Kim, HT McDonough, S Odze, RD Yao, XP Lazo-Kallanian, S Spitzer, TR Soiffer, R Antin, JH Ritz, J AF Chen, Yi-Bin Kim, Haesook T. McDonough, Sean Odze, Robert D. Yao, Xiaopan Lazo-Kallanian, Suzan Spitzer, Thomas R. Soiffer, Robert Antin, Joseph H. Ritz, Jerome TI Up-Regulation of alpha 4 beta 7 Integrin on Peripheral T Cell Subsets Correlates with the Development of Acute Intestinal Graft-versus-Host Disease following Allogeneic Stem Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE GVHD; alpha 4 beta 7 integrin; Lymphocyte trafficking ID MUCOSAL VASCULAR ADDRESSIN; SECONDARY LYMPHOID ORGANS; GALT DENDRITIC CELLS; CHEMOKINE RECEPTOR 9; PEYERS PATCH; L-SELECTIN; CIRCULATING LYMPHOCYTES; ADHESION MOLECULE-1; TISSUE; EXPRESSION AB Acute graft-versus-host disease (aGVHD) is a major complication after hematopoietic stem cell transplantation (HSCT). The pathophysiology of aGVHD involves priming of naive donor T cells in host secondary lymphoid tissue, followed by migration of effector T cells to target organs. Mediators of lymphocyte trafficking are believed to play a significant role in this migration. In this retrospective case-controlled study, we analyzed the expression of alpha 4 beta 7 integrin and CCR9, 2 surface T cell molecules specific for intestinal trafficking, from blood samples collected previously from 59 patients after HSCT (20 without aGVHD, 20 with skin aGVHD, and 19 with intestinal aGVHD). All samples had been obtained before the onset of aGVHD symptoms (with I sample collected on the day of symptom onset). Analysis by flow cytometry demonstrated that alpha 4 beta 7 integrin was significantly increased on both naive and memory T cells in patients who subsequently developed intestinal aGVHD, with the most significant differences observed in memory subsets. Immunohistochemical staining on rectal biopsy specimens from patients with intestinal aGVHD showed that expression of alpha 4 beta 7 integrin was concentrated on mononuclear cells in blood vessels within the intestinal mucosa. These results suggest that alpha 4 beta 7 integrin likely is involved in lymphocyte trafficking in intestinal aGVHD and may have potential clinical use as a correlative biomarker or as a target for the treatment and prophylaxis of intestinal aGVHD after HSCT Biol Blood Marrow Transplant 15: 1066-1076 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Chen, Yi-Bin; Spitzer, Thomas R.] Massachusetts Gen Hosp, Dept Hematol Oncol, Div Bone Marrow Transplantat, Boston, MA 02114 USA. [Kim, Haesook T.; Yao, Xiaopan] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [McDonough, Sean; Lazo-Kallanian, Suzan; Soiffer, Robert; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, Boston, MA 02115 USA. [Odze, Robert D.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ritz, Jerome] Harvard Stem Cell Inst, Boston, MA USA. RP Chen, YB (reprint author), Massachusetts Gen Hosp, Dept Hematol Oncol, Div Bone Marrow Transplantat, 55 Fruit St, Boston, MA 02114 USA. EM ychen6@partners.org OI Ritz, Jerome/0000-0001-5526-4669 FU National Institutes of Health [AI29530, HL070149]; Ted and Ellen Pasquarello Research Fund; Wernick Family Fund for Cancer Care; Leukemia & Lymphoma Society FX This research was supported in part by National Institutes of Health Grants AI29530 and HL070149, the Ted and Ellen Pasquarello Research Fund, the Wernick Family Fund for Cancer Care, and the Leukemia & Lymphoma Society. Y.-B.C. is a Special Fellow in Clinical Research of the Leukemia & Lymphoma Society. Y.-B.C. designed the research, performed research, collected data, analyzed data, and wrote the manuscript; H.T.K. analyzed data, wrote part of the manuscript, and reviewed the manuscript, S.M. processed specimens, performed research, and collected data, R.D.O. performed research, analyzed data, and reviewed the manuscript, X.Y. analyzed data; S.L.-K. processed specimens, T.R.S. designed the research and reviewed the manuscript; R.S. designed the research and reviewed the manuscript; J.H.A. designed the research and reviewed the manuscript; and J.R. designed the research and reviewed the manuscript. The authors declare no conflicts of interest. NR 45 TC 17 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2009 VL 15 IS 9 BP 1066 EP 1076 DI 10.1016/j.bbmt.2009.05.003 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 486EK UT WOS:000269178400007 PM 19660719 ER PT J AU Tanwar, PS Lee, HJ Zhang, LH Zukerberg, LR Taketo, MM Rueda, BR Teixeira, JM AF Tanwar, Pradeep S. Lee, Ho-Joon Zhang, LiHua Zukerberg, Lawrence R. Taketo, Makoto M. Rueda, Bo R. Teixeira, Jose M. TI Constitutive Activation of Beta-Catenin in Uterine Stroma and Smooth Muscle Leads to the Development of Mesenchymal Tumors in Mice SO BIOLOGY OF REPRODUCTION LA English DT Article DE adenomyosis; beta-catenin; developmental biology; endometrial stromal sarcoma; hypertrophic scarring; leiomyoma; signal transduction; uterine fibroids; uterus; WNT signaling ID GROWTH-FACTOR-BETA; REPRODUCTIVE-TRACT; WNT/BETA-CATENIN; TGF-BETA; INCREASED EXPRESSION; PROTEIN EXPRESSION; SEXUAL DEVELOPMENT; MOUSE UTERUS; KIT PROTEIN; EXON 3 AB Leiomyomas and other mesenchymally derived tumors are the most common neoplasms of the female reproductive tract. Presently, very little is known about the etiology and progression of these tumors, which are the primary indication for hysterectomies. Dysregulated WNT signaling through beta-catenin is a well-established mechanism for tumorigenesis. We have developed a mouse model that expresses constitutively activated beta-catenin in uterine mesenchyme driven by the expression of Cre recombinase knocked into the Mullerian-inhibiting substance type 11 receptor promoter locus to investigate its effects on uterine endometrial stroma and myometrium. These mice show myometrial hyperplasia and develop mesenchymal tumors with 100% penetrance that exhibit histological and molecular characteristics of human leiomyomas and endometrial stromal sarcomas. By immunohistochemistry, we also show that both transforming growth factor beta and the mammalian target of rapamycin are induced by constitutive activation of betacatenin. The prevalence of the tumors was greater in multiparous mice, suggesting that their development may be a hormonally driven process or that changes in uterine morphology during pregnancy and after parturition induce injury and repair mechanisms that stimulate tumorigenesis from stem/progenitor cells, which normally do not express constitutively activated beta-catenin. Additionally, adenomyosis and endometrial gland hyperplasia were occasionally observed in some mice. These results show evidence suggesting that dysregulated, stromal, and myometrial WNT/beta-catenin signaling has pleiotropic effects on uterine function and tumorigenesis. C1 [Tanwar, Pradeep S.; Lee, Ho-Joon; Zhang, LiHua; Rueda, Bo R.; Teixeira, Jose M.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Obstet Serv, Boston, MA 02114 USA. [Tanwar, Pradeep S.; Lee, Ho-Joon; Zhang, LiHua; Rueda, Bo R.; Teixeira, Jose M.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Gynecol Serv, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Taketo, Makoto M.] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto 6068501, Japan. RP Teixeira, JM (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol Thier 913, 55 Fruit St, Boston, MA 02114 USA. EM teixeira@helix.mgh.harvard.edu OI Teixeira, Jose/0000-0002-6438-5064 FU National Institute of Child Health and Human Development [HD052701] FX Supported by a grant from the National Institute of Child Health and Human Development, HD052701, to J.M.T. NR 52 TC 56 Z9 57 U1 3 U2 7 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD SEP PY 2009 VL 81 IS 3 BP 545 EP 552 DI 10.1095/biolreprod.108.075648 PG 8 WC Reproductive Biology SC Reproductive Biology GA 487FN UT WOS:000269256400013 PM 19403928 ER PT J AU Chen, H Geng, Z Zhou, XH AF Chen, Hua Geng, Zhi Zhou, Xiao-Hua TI Identifiability and Estimation of Causal Effects in Randomized Trials with Noncompliance and Completely Nonignorable Missing Data SO BIOMETRICS LA English DT Article DE Causal inference; Identifiability; Maximum likelihood estimates; Missing data; Noncompliance; Nonignorable ID INFERENCE AB P>In this article, we first study parameter identifiability in randomized clinical trials with noncompliance and missing outcomes. We show that under certain conditions the parameters of interest are identifiable even under different types of completely nonignorable missing data: that is, the missing mechanism depends on the outcome. We then derive their maximum likelihood and moment estimators and evaluate their finite-sample properties in simulation studies in terms of bias, efficiency, and robustness. Our sensitivity analysis shows that the assumed nonignorable missing-data model has an important impact on the estimated complier average causal effect (CACE) parameter. Our new method provides some new and useful alternative nonignorable missing-data models over the existing latent ignorable model, which guarantees parameter identifiability, for estimating the CACE in a randomized clinical trial with noncompliance and missing data. C1 [Chen, Hua; Geng, Zhi] Peking Univ, Sch Math Sci, Beijing 100871, Peoples R China. [Chen, Hua; Zhou, Xiao-Hua] VA Puget Sound Hlth Care Syst, Biostat Unit, HSR&D Ctr Excellence, Seattle, WA 98101 USA. [Chen, Hua; Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Chen, H (reprint author), Peking Univ, Sch Math Sci, Beijing 100871, Peoples R China. EM azhou@u.washington.edu FU NIH/NHLBI [R01HL62567]; NSFC; NBRP [2003CB715900]; Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development [IAD-06-088] FX We would like to thank the referees for their valuable comments and suggestions that greatly improved the presentation and structure of this article. X-HZ, Ph.D., is presently a Core Investigator and Biostatistics Unit Director at the Northwest HSR&D Center of Excellence, Department of Veterans Affairs Medical Center, Seattle, Washington. This work was supported in part by NIH/NHLBI grant R01HL62567, NSFC, NBRP 2003CB715900, and Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development grant IAD-06-088. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 12 TC 13 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2009 VL 65 IS 3 BP 675 EP 682 DI 10.1111/j.1541-0420.2008.01120.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 494HC UT WOS:000269801400001 PM 18759847 ER PT J AU Ng, F Mammen, OK Wilting, I Sachs, GS Ferrier, IN Cassidy, F Beaulieu, S Yatham, LN Berk, M AF Ng, Felicity Mammen, Oommen K. Wilting, Ingeborg Sachs, Gary S. Ferrier, I. Nicol Cassidy, Frederick Beaulieu, Serge Yatham, Lakshmi N. Berk, Michael TI The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments SO BIPOLAR DISORDERS LA English DT Review DE atypical antipsychotics; bipolar disorder; guidelines; iatrogenesis; lithium; metabolic; monitoring; mood stabilizers; safety ID TOXIC EPIDERMAL NECROLYSIS; STEVENS-JOHNSON-SYNDROME; LONG-TERM LITHIUM; NEPHROGENIC DIABETES-INSIPIDUS; TORSADE-DE-POINTES; NEURAL-TUBE DEFECTS; TREATMENTS CANMAT GUIDELINES; ATYPICAL ANTIPSYCHOTIC USE; POLYCYSTIC-OVARY-SYNDROME; NEWLY-DIAGNOSED EPILEPSY AB Objectives: Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. Methods: These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. Results: General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. Conclusions: These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice. C1 [Berk, Michael] Univ Melbourne, Swanston Ctr, Dept Clin & Biomed Sci, Barwon Hlth, Geelong, Vic 3220, Australia. [Ng, Felicity] Univ Adelaide, Sch Med, Discipline Psychiat, Adelaide, SA, Australia. [Ng, Felicity] Cent No Adelaide Hlth Serv, Adelaide, SA, Australia. [Ng, Felicity; Berk, Michael] Geelong Clin, Geelong, Vic, Australia. [Mammen, Oommen K.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Wilting, Ingeborg] Univ Med Ctr Utrecht, Dept Clin Pharm, Utrecht, Netherlands. [Wilting, Ingeborg] Univ Utrecht, Div Pharmacoepidemiol & Pharmacotherapy, Utrecht Inst Pharmaceut Sci, Fac Sci, Utrecht, Netherlands. [Sachs, Gary S.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA USA. [Sachs, Gary S.] Harvard Univ, Dept Psychiat, Boston, MA USA. [Ferrier, I. Nicol] Univ Newcastle Tyne, Sch Neurol Neurobiol & Psychiat Psychiat, Newcastle Upon Tyne, Tyne & Wear, England. [Cassidy, Frederick] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Beaulieu, Serge] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Beaulieu, Serge] Douglas Mental Hlth Univ Inst, Verdun, PQ, Canada. [Yatham, Lakshmi N.] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Berk, Michael] Orygen Res Ctr, Melbourne, Vic, Australia. [Berk, Michael] Mental Hlth Res Inst Victoria, Melbourne, Vic, Australia. RP Berk, M (reprint author), Univ Melbourne, Swanston Ctr, Dept Clin & Biomed Sci, Barwon Hlth, POB 281, Geelong, Vic 3220, Australia. EM mikebe@barwonhealth.org.au OI Berk, Michael/0000-0002-5554-6946 NR 298 TC 69 Z9 72 U1 5 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD SEP PY 2009 VL 11 IS 6 BP 559 EP 595 PG 37 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 481ZE UT WOS:000268851800001 PM 19689501 ER PT J AU Misra, M McGrane, J Miller, KK Goldstein, MA Ebrahimi, S Weigel, T Klibanski, A AF Misra, Madhusmita McGrane, Jacob Miller, Karen K. Goldstein, Mark A. Ebrahimi, Seda Weigel, Thomas Klibanski, Anne TI Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa SO BONE LA English DT Article DE IGF-1; Bone turnover markers; Adolescents; Anorexia nervosa; Bone metabolism ID GROWTH-HORMONE; MINERAL DENSITY; GIRLS; OSTEOPOROSIS; METABOLISM; WOMEN; CHILDREN; SKELETON; ADULT AB Background: Adolescents with anorexia nervosa (AN) have low bone density and low levels Of Surrogate markets of bone formation. Low bone density is a consequence of hormonal alterations that include hypogonadism and decreases in IGF-1, a bone trophic factor. Although IGF-1 is key to pubertal bone accretion, and effects have been demonstrated in adults, there are no data regarding the effect of recombinant human (rh) IGF-1 administration in adolescents with AN. Objectives: We hypothesized that rhIGF-1 would cause an increase in PINP, a bone formation marker, in girls with AN, without any effect on CTX, a bone resorption marker. Subjects and methods: RhIGF-1 was administered at a dose of 30-10 mcg/k twice daily to 10 consecutive girls with AN 12-18 years old for 7-9 days. Ten age-matched girls with AN were followed without rhIGF-1 for a similar period. IGF-1, PINP and CTX levels were measured. Results: RhIGF-1 administration caused an increase in IGF-1 from day-1 to day-4/5 (p<0.0001) and day-1 to day-8/9 (p<0.0001). Simultaneously, PINP increased from day-1 to day-4/5 (p=0.004) and day-1 to day-8/9 (p=0.004),with a smaller increase from day-4/5 to day-8/9 (p=0.048). CTX levels did not change with rhIGF-1 administration. No changes occurred in IGF-1 or PINP levels in girls not receiving rhIGF-1; however, CTX levels increased significantly (p=0.01). Percent change in PINP was significantly higher (p=0.02) and percent change in CTX was significantly lower (p=0.006) in girls who received rhIGF-1 compared to those who did not receive any intervention. RhIGF-1 was well tolerated without hypoglycemia. Conclusion: Short-term administration of rhIGF-1 causes an increase in a surrogate bone formation markers in girls with AN without significant side effects. (C) 2009 Elsevier Inc. All rights reserved. C1 [Misra, Madhusmita; McGrane, Jacob; Miller, Karen K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Misra, Madhusmita; McGrane, Jacob; Miller, Karen K.; Goldstein, Mark A.; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Misra, Madhusmita] MassGen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. [Goldstein, Mark A.] MassGen Hosp Children, Adolescent Med Unit, Boston, MA 02114 USA. [Ebrahimi, Seda] Cambridge Eating Disorders Ctr, Cambridge, MA 02138 USA. [Weigel, Thomas] McLean Hosp, Belmont, MA 02478 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, Boston, MA 02114 USA. EM mmisra@partners.org FU NIH [R01 DK 062249, K23 RR018851, M01-RR-01066] FX Statement of Financial Support: The study was supported by an investigator initiated grant received from Tercica, and in part by NIH grants R01 DK 062249, K23 RR018851 and M01-RR-01066. NR 34 TC 37 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD SEP PY 2009 VL 45 IS 3 BP 493 EP 498 DI 10.1016/j.bone.2009.06.002 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 488VK UT WOS:000269378200014 PM 19523548 ER PT J AU Martella, G Tassone, A Sciamanna, G Platania, P Cuomo, D Viscomi, MT Bonsi, P Cacci, E Biagioni, S Usiello, A Bernardi, G Sharma, N Standaert, DG Pisani, A AF Martella, Giuseppina Tassone, Annalisa Sciamanna, Giuseppe Platania, Paola Cuomo, Dario Viscomi, Maria Teresa Bonsi, Paola Cacci, Emanuele Biagioni, Stefano Usiello, Alessandro Bernardi, Giorgio Sharma, Nutan Standaert, David G. Pisani, Antonio TI Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine SO BRAIN LA English DT Article DE dystonia; synaptic plasticity; striatum; acetylcholine; electrophysiology ID LONG-TERM POTENTIATION; MEDIUM SPINY NEURONS; FOCAL HAND DYSTONIA; BASAL GANGLIA; CHOLINERGIC INTERNEURONS; MOVEMENT-DISORDERS; FREQUENCY STIMULATION; DOPAMINERGIC CONTROL; TORSION DYSTONIA; TRANSGENIC MICE AB DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M(1) receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M(2)/M(4) receptor knockout mice, in which an increased striatal acetylcholine level has been documented. The loss of LTD and SD on one hand, and the increase in LTP on the other, demonstrate that a loss of inhibition characterizes the impairment of synaptic plasticity in this model of DYT1 dystonia. More importantly, our results indicate that an unbalanced cholinergic transmission plays a pivotal role in these alterations, providing a clue to understand the ability of anticholinergic agents to restore motor deficits in dystonia. C1 [Martella, Giuseppina; Platania, Paola; Bernardi, Giorgio; Pisani, Antonio] Univ Roma Tor Vergata, Dept Neurosci, I-00133 Rome, Italy. [Tassone, Annalisa; Sciamanna, Giuseppe; Cuomo, Dario; Viscomi, Maria Teresa; Bonsi, Paola; Bernardi, Giorgio; Pisani, Antonio] Fdn Santa Lucia IRCCS, Rome, Italy. [Cacci, Emanuele; Biagioni, Stefano] Univ Roma La Sapienza, Neurobiol Res Unit, Dept Cell & Dev Biol, Rome, Italy. [Cacci, Emanuele; Biagioni, Stefano] Univ Roma La Sapienza, Daniel Bovet Neurobiol Res Ctr, Rome, Italy. [Usiello, Alessandro] CEINGE Biotecnol Avanzate, Naples, Italy. [Usiello, Alessandro] Univ Molise, Dept Hlth Sci, Molise, Italy. [Sharma, Nutan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Standaert, David G.] Univ Alabama, Birmingham, AL USA. RP Pisani, A (reprint author), Univ Roma Tor Vergata, Dept Neurosci, I-00133 Rome, Italy. EM dstandaert@uab.edu; pisani@uniroma2.it RI usiello, alessandro/B-2368-2012; Sciamanna, Giuseppe/B-6553-2013; Viscomi, Maria Teresa/G-4173-2011; Tassone, Annalisa/J-9950-2016; Bonsi, Paola/K-4688-2012; OI Standaert, David/0000-0003-2921-8348; Sciamanna, Giuseppe/0000-0002-0070-1638; Viscomi, Maria Teresa/0000-0002-9096-4967; Tassone, Annalisa/0000-0001-9643-2446; Bonsi, Paola/0000-0001-5940-9028; Usiello, Alessandro/0000-0001-9203-853X FU Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia & Parkinson's Foundation; USPHS [P50NS37409] FX Dystonia Medical Research Foundation and Bachmann-Strauss Dystonia & Parkinson's Foundation ( to A. P.); Ministero Salute (Prog. Finalizzato and Art. 56 to G. B. and A. P.); Istituto Superiore Sanita (Malattie Rare to A. P.); Agenzia Spaziale Italiana ( DCMC grant to G. B.); USPHS grant (P50NS37409 to N.S. and D.G. S.). These authors contributed equally to this work. NR 72 TC 82 Z9 82 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD SEP PY 2009 VL 132 BP 2336 EP 2349 DI 10.1093/brain/awp194 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 496IJ UT WOS:000269963600006 PM 19641103 ER PT J AU Stoodley, CJ Schmahmann, JD AF Stoodley, Catherine J. Schmahmann, Jeremy D. TI The cerebellum and language: Evidence from patients with cerebellar degeneration SO BRAIN AND LANGUAGE LA English DT Article DE Cerebellum; Degeneration; Language; Fluency; Word stem completion; Naming speed ID COGNITIVE-AFFECTIVE SYNDROME; ATAXIA RATING-SCALE; RHESUS-MONKEY; FLUENCY PERFORMANCE; TUMOR RESECTION; VERBAL FLUENCY; BASIS PONTIS; LESIONS; PROJECTIONS; ATROPHY AB Clinical and imaging studies suggest that the cerebellum is involved in language tasks, but the extent to which slowed language production in cerebellar patients contributes to their poor performance on these tasks is not clear. We explored this relationship in 18 patients with cerebellar degeneration and 16 healthy controls who completed measures of verbal fluency (phonemic and semantic), word stem completion, and oral naming speed. Cerebellar patients showed significantly slower response times when naming common nouns, which correlated with their degree of motor impairment. Patients were significantly impaired on both phonemic and semantic fluency measures compared to controls (p < 0.001), even when naming speed was entered as a covariate (p = 0.03). On the word stem completion task, patients were significantly less accurate (p < 0.001), had more errors due to non-responses (p = 0.008), and were slower to respond (p = 0.036) than controls; group effects were significant for overall accuracy, but not response time, when the effects of naming speed were covaried (p = 0.014). These findings suggest that cerebellar patients' poorer performance on language tasks cannot be explained solely by slower language production, and that the integrity of cerebellar-prefrontal loops might underlie poorer performance on measures of executive function in cerebellar patients. (C) 2009 Elsevier Inc. All rights reserved. C1 [Stoodley, Catherine J.] Massachusetts Gen Hosp, Dept Neurol, Cognit Behav Neurol Unit, Ataxia Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Stoodley, CJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Cognit Behav Neurol Unit, Ataxia Unit, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM cstoodley@partners.org RI Stoodley, Catherine/P-2081-2016 OI Stoodley, Catherine/0000-0003-2629-0213 FU Birmingham Foundation; Massachusetts General Hospital FX We would like to thank the participants of the study. Dr. Ryeowon Ko contributed to the task design and data collection. Funding was provided by the Birmingham Foundation and a Fund for Medical Discovery Award from the Executive Committee on Research of Massachusetts General Hospital. NR 43 TC 50 Z9 51 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD SEP PY 2009 VL 110 IS 3 BP 149 EP 153 DI 10.1016/j.bandl.2009.07.006 PG 5 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 534GD UT WOS:000272883400004 PM 19664816 ER PT J AU Ries, ML Wichmann, A Bendlin, BB Johnson, SC AF Ries, Michele L. Wichmann, Allison Bendlin, Barbara B. Johnson, Sterling C. TI Posterior Cingulate and Lateral Parietal Gray Matter Volume in Older Adults with Depressive Symptoms SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Aging; Alzheimer disease; Depression; Magnetic resonance imaging; Affect ID MILD COGNITIVE IMPAIRMENT; GERIATRIC DEPRESSION; ALZHEIMERS-DISEASE; ANTERIOR CINGULATE; PROSPECTIVE COHORT; PREFRONTAL CORTEX; MAJOR DEPRESSION; ONSET DEPRESSION; DEFAULT MODE; ABNORMALITIES AB Depressive symptoms occurring late in life are an important risk factor for Alzheimer's disease (AD). The latest research finds that onset of depressive symptoms in late life may herald the development of AD, not only for amnestic Mild Cognitive Impairment (aMCI) patients, but also for cognitively-normal older adults. Neuroimaging of brain structure, blood flow, and glucose metabolism indicates that depressive symptoms in late life are accompanied by structural and functional changes in limbic brain regions vulnerable to AD. The present cross-sectional study was guided by the hypothesis that compared to their non-depressed counterparts, older adults with mild to moderate depressive symptoms have less volume in limbic structures vulnerable to changes in AD-specifically, cortical midline structures such as anterior cingulate and posterior cingulate cortex as well as mesial temporal regions such as bilateral hippocampi and amygdalae. Consistent with our hypothesis, results of a voxel-based morphometry analysis revealed smaller retrosplenial, posterior cingulate, and precuneus gray matter volumes in depressed individuals relative to healthy controls. Right lateral parietal cortex-another region vulnerable to change in AD-was also smaller in the group with depressive symptoms. Contrary to our hypothesis, no volumetric differences were found in the anterior cingulate cortex or mesial temporal lobe. Results of this study show a relationship between geriatric depressive symptoms and brain volume in regions vulnerable to AD. Follow-up of participants over time will tell if brain changes detected here predict development of AD. C1 [Ries, Michele L.; Wichmann, Allison; Bendlin, Barbara B.; Johnson, Sterling C.] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI 53705 USA. [Ries, Michele L.; Wichmann, Allison; Bendlin, Barbara B.; Johnson, Sterling C.] Univ Wisconsin, Madison, WI 53705 USA. RP Ries, ML (reprint author), William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI 53705 USA. EM mlr@medicine.wisc.edu OI Bendlin, Barbara/0000-0002-0580-9875; Johnson, Sterling/0000-0002-8501-545X FU [AG021155] FX This study was supported by AG021155 (SCJ). The research was greatly facilitated by Dr. Ries' involvement in the University ofWisconsin Institute for Clinical and Translational Research (ICTR) KL2 program and the facilities and resources at the William S. Middleton Memorial Veterans Hospital. We thank the participants who took part in this study. GRECC manuscript # 2008-33. NR 41 TC 10 Z9 10 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD SEP PY 2009 VL 3 IS 3 BP 233 EP 239 DI 10.1007/s11682-009-9065-4 PG 7 WC Neuroimaging SC Neurosciences & Neurology GA 510LT UT WOS:000271090700001 PM 19701486 ER PT J AU Chian, RJ Li, JH Ay, I Celia, SA Kashi, BB Tamrazian, E Matthews, JC Bronson, RT Rossomando, A Pepinsky, RB Fishman, PS Brown, RH Francis, JW AF Chian, Ru-Ju Li, Jianhong Ay, Ilknur Celia, Samuel A. Kashi, Brenda B. Tamrazian, Eric Matthews, Jonathan C. Bronson, Roderick T. Rossomando, Anthony Pepinsky, R. Blake Fishman, Paul S. Brown, Robert H., Jr. Francis, Jonathan W. TI IGF-1:Tetanus toxin fragment C fusion protein improves delivery of IGF-1 to spinal cord but fails to prolong survival of ALS mice SO BRAIN RESEARCH LA English DT Article DE Drug delivery; IGF-1; Tetanus toxin fragment C; Fusion protein; Motor neuron; Amyotrophic lateral sclerosis; SOD1(G93A) transgenic mice ID GROWTH-FACTOR-I; RETROGRADE AXONAL-TRANSPORT; AMYOTROPHIC-LATERAL-SCLEROSIS; RECEPTOR-BINDING DOMAIN; CENTRAL-NERVOUS-SYSTEM; MOTOR-NEURON DEATH; TETANUS TOXIN; MOUSE MODEL; ESCHERICHIA-COLI; GANGLIOSIDE BINDING AB To improve delivery of human insulin-like growth factor-1 (hIGF-1) to brain and spinal cord, we generated a soluble IGF-1:tetanus toxin fragment C fusion protein (IGF-1:TTC) as a secreted product from insect cells. IGF-1:TTC exhibited IGF-1 and TTC activity in vitro; it increased levels of immunoreactive phosphoAkt in treated MCF-7 cells and bound to immobilized ganglioside GT1b. In mice, the fusion protein underwent retrograde transport by spinal cord motor neurons following intramuscular injection, and exhibited both TTC- and IGF-1 activity in the CNS following intrathecal infusion. Analogous to the case with TTC, intrathecal infusion of the fusion protein resulted in substantial levels of IGF-1:TTC in spinal cord tissue extracts. Tissue concentrations of hIGF-1 in lumbar spinal cords of mice infused with IGF-1:TTC were estimated to be approximate to 500-fold higher than those in mice treated with unmodified recombinant hIGF-1 (rhIF-1). Like rhIGF-1, infusion of IGF-1:TTC reduced levels of IGF-1 receptor immunoreactivity in the same extracts. Despite raising levels of exogenous hIGF-1 in spinal cord, intramuscular- or intrathecal administration of IGF-1:TTC had no significant effect on disease progression or survival of high-expressing SOD1(G93A) transgenic mice. IGF-1:TTC may prove to be neuroprotective in other animal models of CNS disease or injury known to be responsive to unmodified IGF-1. (C) 2009 Elsevier B.V. All rights reserved. C1 [Chian, Ru-Ju; Li, Jianhong; Ay, Ilknur; Celia, Samuel A.; Kashi, Brenda B.; Tamrazian, Eric; Matthews, Jonathan C.; Brown, Robert H., Jr.; Francis, Jonathan W.] Massachusetts Gen Hosp, Dept Neurol, Cecil B Day Lab Neuromuscular Res, Charlestown, MA 02129 USA. [Bronson, Roderick T.] Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Rossomando, Anthony; Pepinsky, R. Blake] Biogen Idec Inc, Cambridge Ctr 14, Cambridge, MA 02142 USA. [Fishman, Paul S.] Baltimore Vet Affairs Med Ctr, Res Serv, Baltimore, MD 21201 USA. [Fishman, Paul S.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. RP Francis, JW (reprint author), Massachusetts Gen Hosp, Dept Neurol, Cecil B Day Lab Neuromuscular Res, Bldg 114,16th St,Room 3003, Charlestown, MA 02129 USA. EM jwfrancisby@gmail.com RI li, jianhong/D-3483-2009 FU National Institute of Neurological Disorders and Stroke [R01 NS038679]; Muscular Dystrophy Association FX The authors would like to express their appreciation to Dr. Neil Fairweather for providing the cDNA for tetanus toxin fragment C, and Dr. Joe D'Ercole for providing the cDNA for human IGF-1. We are also grateful to Dr. Konrad Miatkowski from BiogenIdec for his technical advice on the production of recombinant proteins from insect cells. This work was supported by the National Institute of Neurological Disorders and Stroke WF, RJC, SAC, RHB; R01 NS038679), the Muscular Dystrophy Association WF, JL), the ALS Therapy Alliance WF, BBK, JL, RJC), Project ALS OWF, RHB) and AviTx, Inc (JWF, RHB). NR 65 TC 12 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 1 PY 2009 VL 1287 BP 1 EP 19 DI 10.1016/j.brainres.2009.06.066 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 489XR UT WOS:000269460100001 PM 19563785 ER PT J AU Hui, KKS Marina, O Claunch, JD Nixon, EE Fang, JL Liu, J Li, M Napadow, V Vangel, M Makris, N Chan, ST Kwong, KK Rosen, BR AF Hui, Kathleen K. S. Marina, Ovidiu Claunch, Joshua D. Nixon, Erika E. Fang, Jiliang Liu, Jing Li, Ming Napadow, Vitaly Vangel, Mark Makris, Nikos Chan, Suk-tak Kwong, Kenneth K. Rosen, Bruce R. TI Acupuncture mobilizes the brain's default mode and its anti-correlated network in healthy subjects SO BRAIN RESEARCH LA English DT Article DE Acupuncture; fMRI; Limbic-paralimbic-neocortical network; Default mode network; Deqi; Amygdala ID INDEPENDENT COMPONENT ANALYSIS; STATE FUNCTIONAL CONNECTIVITY; RESTING HUMAN BRAIN; ALZHEIMERS-DISEASE; STRUCTURAL CONNECTIVITY; SINGLE-BLIND; PILOT TRIAL; BOLD SIGNAL; BASE-LINE; FMRI AB Previous work has shown that acupuncture stimulation evokes deactivation of a limbic-paralimbic-neocortical network (LPNN) as well as activation of somatosensory brain regions. This study explores the activity and functional connectivity of these regions during acupuncture vs. tactile stimulation and vs. acupuncture associated with inadvertent sharp pain. Acupuncture during 201 scans and tactile stimulation during 74 scans for comparison at acupoints LI4, ST36 and LV3 was monitored with fMRI and psychophysical response in 48 healthy subjects. Clusters of deactivated regions in the medial prefrontal, medial parietal and medial temporal lobes as well as activated regions in the sensorimotor and a few paralimbic structures can be identified during acupuncture by general linear model analysis and seed-based cross correlation analysis. Importantly, these clusters showed virtual identity with the default mode network and the anti-correlated task-positive network in response to stimulation. In addition, the amygdala and hypothalamus, structures not routinely reported in the default mode literature, were frequently involved in acupuncture. When acupuncture induced sharp pain, the deactivation was attenuated or became activated instead. Tactile stimulation induced greater activation of the somatosensory regions but less extensive deactivation of the LPNN. These results indicate that the deactivation of the LPNN during acupuncture cannot be completely explained by the demand of attention that is commonly proposed in the default mode literature. Our results suggest that acupuncture mobilizes the anti-correlated functional networks of the brain to mediate its actions, and that the effect is dependent on the psychophysical response. Published by Elsevier B.V. C1 [Hui, Kathleen K. S.; Marina, Ovidiu; Claunch, Joshua D.; Nixon, Erika E.; Fang, Jiliang; Liu, Jing; Li, Ming; Napadow, Vitaly; Vangel, Mark; Chan, Suk-tak; Kwong, Kenneth K.; Rosen, Bruce R.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hui, Kathleen K. S.; Marina, Ovidiu; Claunch, Joshua D.; Nixon, Erika E.; Fang, Jiliang; Liu, Jing; Li, Ming; Napadow, Vitaly; Vangel, Mark; Makris, Nikos; Chan, Suk-tak; Kwong, Kenneth K.; Rosen, Bruce R.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Marina, Ovidiu] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Fang, Jiliang] Guang An Men Hosp, China Acad Tradit Chinese Med, Dept Radiol, Beijing, Peoples R China. [Makris, Nikos] Massachusetts Gen Hosp, Dept Neurol, Ctr Morphometr Anal, Charlestown, MA 02129 USA. [Chan, Suk-tak] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. RP Hui, KKS (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM hui@nmr.mgh.harvard.edu RI anand, amit/A-7222-2009; Chan, Suk-tak/G-5846-2015 FU NIH/National Center for Complementary and Alternative Medicine [R21AT00978, 1-P01-002048-01, K01-AT-002166-01]; National Center for Research Resources [P41RR14075]; Mental illness and Neuroscience Discovery institute and the Brain Project [34189] FX The work was supported in part by the NIH/National Center for Complementary and Alternative Medicine (R21AT00978) (1-P01-002048-01) (K01-AT-002166-01), the National Center for Research Resources (P41RR14075), the Mental illness and Neuroscience Discovery institute and the Brain Project Grant NS 34189. We thank Randy L. Buckner and Moshe Bar for their insightful comments and advice and Justin L. Vincent for the valuable suggestions on data analysis. NR 87 TC 70 Z9 82 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD SEP 1 PY 2009 VL 1287 BP 84 EP 103 DI 10.1016/j.brainres.2009.06.061 PG 20 WC Neurosciences SC Neurosciences & Neurology GA 489XR UT WOS:000269460100009 PM 19559684 ER PT J AU Pagani, O Price, KN Gelber, RD Castiglione-Gertsch, M Holmberg, SB Lindtner, J Thurlimann, B Collins, J Fey, MF Coates, AS Goldhirsch, A AF Pagani, Olivia Price, Karen N. Gelber, Richard D. Castiglione-Gertsch, Monica Holmberg, Stig B. Lindtner, Jurij Thuerlimann, Beat Collins, John Fey, Martin F. Coates, Alan S. Goldhirsch, Aron CA IBCSG TI Patterns of recurrence of early breast cancer according to estrogen receptor status: a therapeutic target for a quarter of a century SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Chemotherapy; Estrogen receptor; Hormonal therapy ID ENDOCRINE THERAPY; SYSTEMIC THERAPY; CHEMOTHERAPY; SURVIVAL; PROGRESS; TRIALS; ASSAYS; IV AB The current therapeutic strategy in breast cancer is to identify a target, such as estrogen receptor (ER) status, for tailoring treatments. We investigated the patterns of recurrence with respect to ER status for patients treated in two randomized trials with 25 years' median follow-up. In the ER-negative subpopulations most breast cancer events occurred within the first 5-7 years after randomization, while in the ER-positive subpopulations breast cancer events were spread through 10 years. In the ER-positive subpopulation, 1 year endocrine treatment alone significantly prolonged disease-free survival (DFS) with no additional benefit observed by adding 1 year of chemotherapy. In the small ER-negative subpopulation chemo-endocrine therapy had a significantly better DFS than endocrine alone or no treatment. Despite small numbers of patients, "old-fashioned" treatments, and competing causes of treatment failure, the value of ER status as a target for response to adjuvant treatment is evident through prolonged follow-up. C1 [Pagani, Olivia] Osped Italiano, Oncol Inst So Switzerland, Lugano, Switzerland. [Pagani, Olivia; Thuerlimann, Beat; Fey, Martin F.] Swiss Grp Clin Canc Res SAKK, Bern, Switzerland. [Gelber, Richard D.] Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. [Price, Karen N.; Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Castiglione-Gertsch, Monica] IBCSG Coordinating Ctr, Bern, Switzerland. [Holmberg, Stig B.] Sahlgrens Univ Hosp, Dept Surg, S-41345 Gothenburg, Sweden. [Lindtner, Jurij] Inst Oncol, Ljubljana, Slovenia. [Thuerlimann, Beat] Kantonsspital, Senol Ctr Eastern Switzerland, St Gallen, Switzerland. [Collins, John] Royal Melbourne Hosp, Dept Surg, Melbourne, Vic, Australia. [Fey, Martin F.] Univ Bern, Inselspital, Dept Med Oncol, CH-3010 Bern, Switzerland. [Coates, Alan S.] Univ Sydney, Sydney, NSW 2006, Australia. [Goldhirsch, Aron] European Inst Oncol, Dept Med, Milan, Italy. [Goldhirsch, Aron] Oncol Inst So Switzerland, Bellinzona, Switzerland. [Coates, Alan S.] IBCSG, Bern, Switzerland. RP Pagani, O (reprint author), Osped Italiano, Oncol Inst So Switzerland, Lugano, Switzerland. EM olivia.pagani@ibcsg.org; price@jimmy.harvard.edu; gelber@jimmy.harvard.edu; monica.castiglione@bluewin.ch; stig.holmberg@vgregion.se; JLindtner@onko-i.si; beat.thurlimann@kssg.ch; johncol@bigpond.net.au; martin.fey@insel.ch; alan.coates@ibcsg.org; aron.goldhirsch@ibcsg.org FU West Swedish Breast Cancer Group; Institute of Oncology, Ljubljana, Slovenia; Swiss Group for Clinical Cancer Research (SAKK); Australian New Zealand Breast Cancer Trials Group (ANZ BCTG); Groote Shuur Hospital, Cape Town, South Africa; Ludwig Institute for Cancer Research; Swedish Cancer Society; The Cancer Council Australia; National Health Medical Research Council of Australia; Frontier Science and Technology Research Foundation; US-National Cancer Institute [CA-75362]; Cancer Association of South Africa (CANSA); Foundation of Clinical Cancer Research of Eastern Switzerland (OSKK) FX We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials. We thank Rita Hinkle for data management and IBCSG patients and participants who have submitted yearly trial patient data for 30 years: West Swedish Breast Cancer Group; Institute of Oncology, Ljubljana, Slovenia; Swiss Group for Clinical Cancer Research (SAKK); Australian New Zealand Breast Cancer Trials Group (ANZ BCTG); Groote Shuur Hospital, Cape Town, South Africa. Funding (in addition to above) provided by: Ludwig Institute for Cancer Research, Swedish Cancer Society, The Cancer Council Australia, National Health Medical Research Council of Australia, Frontier Science and Technology Research Foundation, US-National Cancer Institute (CA-75362), Cancer Association of South Africa (CANSA), and Foundation of Clinical Cancer Research of Eastern Switzerland (OSKK). NR 23 TC 19 Z9 20 U1 0 U2 0 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 SEP PY 2009 VL 117 IS 2 BP 319 EP 324 DI 10.1007/s10549-008-0282-0 PG 6 WC Oncology SC Oncology GA 483XD UT WOS:000269005500011 PM 19137426 ER PT J AU Chang, HL Lerwill, MF Goldstein, AM AF Chang, Henry L. Lerwill, Melinda F. Goldstein, Allan M. TI Breast Hamartomas in Adolescent Females SO BREAST JOURNAL LA English DT Article DE hamartoma; mammary hamartoma; pediatric breast masses ID MAMMARY HAMARTOMA; DUCTAL CARCINOMA; MASSES; RISK; FIBROADENOMA; CANCER AB Breast hamartomas are uncommon lesions that have not been extensively characterized in the adolescent population. A search of patient records at our institution over a 17-year period identified seven cases of breast hamartomas in patients less than 18 years of age. We examine and report the clinical, radiographic, and pathologic characteristics of these cases. Breast hamartomas present as painless, palpable masses in the adolescent population. Ultrasonography reveals a well-defined, solid, oval mass, similar to the more common fibroadenoma. Two of the patients underwent core needle biopsy for diagnosis as the only intervention with the remainder undergoing surgical excision. None of the patients had any complications from surgery. There was one recurrence 9 months after initial excision. Histologically, the hamartomas consisted of densely packed, enlarged lobules set within a fibrous stroma. Breast hamartomas are rare in the adolescent population. The clinical and radiographic features are similar to the more common fibroadenoma, but the pathologic findings are diagnostic. Recurrence can occur if excision is incomplete. Increased recognition and accurate diagnosis will improve our understanding of the natural history of these lesions. C1 [Chang, Henry L.; Goldstein, Allan M.] Harvard Univ, Dept Pediat Surg, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Lerwill, Melinda F.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Lerwill, Melinda F.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. RP Goldstein, AM (reprint author), Harvard Univ, Dept Pediat Surg, Massachusetts Gen Hosp, Sch Med, Warren 1153, Boston, MA 02114 USA. EM agoldstein@partners.org NR 21 TC 4 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1075-122X J9 BREAST J JI Breast J. PD SEP-OCT PY 2009 VL 15 IS 5 BP 515 EP 520 DI 10.1111/j.1524-4741.2009.00769.x PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 487IP UT WOS:000269265800012 PM 19624414 ER PT J AU Drohan, B Ozanne, EM Hughes, KS AF Drohan, Brian Ozanne, Elissa M. Hughes, Kevin S. TI Electronic Health Records and the Management of Women at High Risk of Hereditary Breast and Ovarian Cancer SO BREAST JOURNAL LA English DT Article DE clinical decision support; electronic health records; hereditary breast cancer; hereditary ovarian cancer; risk management ID FAMILY-HISTORY; GENETIC SUSCEPTIBILITY; BREAST/OVARIAN CANCER; PRIMARY-CARE; MUTATION; IDENTIFICATION; PROBABILITY; STATEMENT; UPDATE AB Currently, management strategies exist that can decrease the morbidity and mortality associated with having a BRCA1 or BRCA2 mutation. Unfortunately, the task of identifying these patients at high risk is a daunting challenge. This problem is intensified because Electronic Health Records (EHRs) today lack the functionality needed to identify these women and to manage those women once they have been identified. Numerous niche software programs have been developed to fill this gap. Unfortunately, these extremely valuable niche programs are prevented from being interoperable with the EHRs, on the premise that each EHR vendor will build their own programs. Effectively, in our efforts to adopt EHRs, we have lost sight of the fact that they can only have a major impact on quality of care if they contain structured data and if they interact with robust Clinical Decision Support (CDS) tools. We are at a cross roads in the development of the health care Information Technology infrastructure. We can choose a path where each EHR vendor develops each CDS module independently. Alternatively, we can choose a path where experts in each field develop external niche software modules that are interoperable with any EHR vendor. We believe that the modular approach to development of niche software programs that are interoperable with current EHRs will markedly increase the speed at which useful and functional EHRs that improve quality of care become a reality. Thus, in order to realize the benefits of CDS, we suggest vendors develop means to become interoperable with external modular niche programs. C1 [Hughes, Kevin S.] Harvard Univ, Avon Breast Evaluat Ctr, Massachusetts Gen Hosp, Sch Med,Newton Wellesley Hosp, Cambridge, MA 02138 USA. [Drohan, Brian] Univ Massachusetts Lowell, Dept Comp Sci, Lowell, MA USA. [Ozanne, Elissa M.] Harvard Univ, Inst Technol Assessment, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. RP Hughes, KS (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, 55 Fruit St,YAW 7, Boston, MA 02114 USA. EM kshughes@partners.org FU MGH; NWH FX This work was supported by Philanthropic Funds from the MGH and the NWH. NR 27 TC 8 Z9 8 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1075-122X J9 BREAST J JI Breast J. PD SEP-OCT PY 2009 VL 15 BP S46 EP S55 DI 10.1111/j.1524-4741.2009.00796.x PG 10 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 498IB UT WOS:000270130000008 PM 19775330 ER PT J AU Vogiatzi, MG Macklin, EA Trachtenberg, FL Fung, EB Cheung, AM Vichinsky, E Olivieri, N Kirby, M Kwiatkowski, JL Cunningham, M Holm, IA Fleisher, M Grady, RW Peterson, CM Giardina, PJ AF Vogiatzi, Maria G. Macklin, Eric A. Trachtenberg, Felicia L. Fung, Ellen B. Cheung, Angela M. Vichinsky, Elliott Olivieri, Nancy Kirby, Melody Kwiatkowski, Janet L. Cunningham, Melody Holm, Ingrid A. Fleisher, Martin Grady, Robert W. Peterson, Charles M. Giardina, Patricia J. CA Thalassemia Clinical Res Network TI Differences in the prevalence of growth, endocrine and vitamin D abnormalities among the various thalassaemia syndromes in North America SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE thalassemia; short stature; hypogonadism; endocrinopathies; vitamin D; hypercalciuria ID BETA-THALASSEMIA; IRON OVERLOAD; FINAL HEIGHT; D DEFICIENCY; COMPLICATIONS; INTERMEDIA; ADULTS; HYPOPARATHYROIDISM; POPULATION; SURVIVAL AB P>This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23 center dot 2 years (range 6 center dot 1-75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = -0 center dot 73 +/- 1 center dot 24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12 center dot 8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents. C1 [Vogiatzi, Maria G.; Grady, Robert W.; Giardina, Patricia J.] Weill Cornell Med Coll, Dept Pediat, New York, NY USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Macklin, Eric A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Trachtenberg, Felicia L.] New England Res Inst, Watertown, MA 02172 USA. [Fung, Ellen B.; Vichinsky, Elliott] Childrens Hosp Oakland, Oakland, CA USA. [Cheung, Angela M.; Olivieri, Nancy] Toronto Gen Hosp, Dept Med, Univ Hlth Network, Toronto, ON M5G 1L7, Canada. [Kirby, Melody] Toronto Hosp Sick Children, Toronto, ON, Canada. [Kwiatkowski, Janet L.] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. [Kwiatkowski, Janet L.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Cunningham, Melody; Holm, Ingrid A.] Childrens Hosp Boston, Div Hematol & Oncol, Boston, MA USA. [Fleisher, Martin] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Peterson, Charles M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Vogiatzi, MG (reprint author), Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, 525 E 68th St,Box 103, New York, NY 10065 USA. EM mvogiatz@med.cornell.edu RI Vichinsky, Elliott/F-8541-2011; Macklin, Eric/E-2955-2013; OI Vichinsky, Elliott/0000-0002-0500-9579; Macklin, Eric/0000-0003-1618-3502; Quinn, Charles/0000-0002-2372-2175 FU National Heart, Lung, and Blood Institute; National Institutes of Health [U01-HL-65232, U01-HL-65233, U01-HL-65239, U01-HL-65244, U01-HL-65260, U01-HL-65238, 5K24HL004184-08]; Weill Medical College of Cornell University [K08 HL088231]; NIH-NCRR [UL1-RR024134, M01-RR02172] FX Supported by a cooperative agreement with the National Heart, Lung, and Blood Institute, National Institutes of Health (U01-HL-65232 to Children's Hospital of Philadelphia, U01-HL-65233 to University Health Network Toronto General Hospital, U01-HL-65239 to Children's Hospital and Research Center at Oakland, U01-HL-65244 to Weill Medical College of Cornell University, U01-HL-65260 to Children's Hospital Boston, and U01-HL-65238 to New England Research Institutes). The study was also supported, in part, at Weill Medical College of Cornell University grant K08 HL088231 awarded to Maria G. Vogiatzi, at Children's Hospital of Philadelphia by NIH-NCRR grant UL1-RR024134, and at Children's Hospital Boston by NIH-NCRR grant M01-RR02172 and NIH grant 5K24HL004184-08 to Ellis Neufeld. NR 25 TC 50 Z9 51 U1 0 U2 3 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 SEP PY 2009 VL 146 IS 5 BP 546 EP 556 DI 10.1111/j.1365-2141.2009.07793.x PG 11 WC Hematology SC Hematology GA 482XK UT WOS:000268923700009 PM 19604241 ER PT J AU Song, MK Rosenthal, MJ Song, AM Uyemura, K Yang, H Ament, ME Yamaguchi, DT Cornford, EM AF Song, M. K. Rosenthal, M. J. Song, A. M. Uyemura, K. Yang, H. Ament, M. E. Yamaguchi, D. T. Cornford, E. M. TI Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro) SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE Cyclo-(His-Pro); insulin degrading enzyme; zinc; leptin; adiponectin; obese S-D rats; diabetic G-K rats ID CYCLO HIS-PRO; PROLINE-DIKETOPIPERAZINE CYCLO(HIS-PRO); THYROTROPIN-RELEASING-HORMONE; INSULIN-DEGRADING ENZYME; SUCROSE-INDUCED OBESITY; METABOLIC SYNDROME; FOOD-INTAKE; LEPTIN CONCENTRATIONS; RICH GLYCOPROTEIN; SERUM AB Background and purpose: We have previously shown that treatment with zinc plus cyclo-(His-Pro) (CHP) significantly stimulated synthesis of the insulin degrading enzyme and lowered plasma insulin and blood glucose levels, alongside improving oral glucose tolerance in genetically type 2 diabetic Goto-Kakizaki (G-K) rats and in aged obese Sprague-Dawley (S-D) rats. Thus, we postulated that zinc plus CHP (ZC) treatment might also improve body weight control in these rats. We therefore determined the effects of ZC treatment on body weights in both genetically diabetic, mature G-K rats and non-diabetic, obese S-D rats. Experimental approach: G-K rats aged 1.5-10 months and non-diabetic overweight or obese S-D rats aged 6-18 months were treated with 0-6 mg CHP plus 0-10 mg zinc center dot L(-1) drinking water for 2-4 weeks, and changes in weight, serum leptin and adiponectin levels, food and water intakes were measured. Key results: The optimal dose of CHP (in combination with zinc) to reduce weight and plasma leptin levels and to increase plasma adiponectin levels was close to 0.1 mg center dot kg(-1)center dot day(-1), in either mature G-K rats and aged overweight or obese S-D rats. Food and water intake significantly decreased in ZC treated rats in both aged S-D rats and mature G-K rats, but not in young S-D and G-K rats. Conclusions and implications: ZC treatment improved weight control and may be a possible treatment for overweight and obesity. C1 [Song, M. K.; Yang, H.; Yamaguchi, D. T.; Cornford, E. M.] VA Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Song, M. K.; Ament, M. E.] Univ Calif Los Angeles, Dept Pediat, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Rosenthal, M. J.; Uyemura, K.; Yang, H.; Yamaguchi, D. T.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Rosenthal, M. J.; Uyemura, K.] VA Greater Los Angeles Healthcare Syst, Ctr Geriatr Res Educ & Clin, Los Angeles, CA 90073 USA. [Song, A. M.] Kaiser Permanente Med Ctr, Dept Surg, Panorama City, CA USA. [Cornford, E. M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. RP Song, MK (reprint author), VA Greater Los Angeles Healthcare Syst, Res Serv, Bldg 113,Room 205, Los Angeles, CA 90073 USA. EM mksong@earthlink.net FU NIH [NS 052456] FX This research was supported financially by the NIH grant number NS 052456 and DVA merit review funding. We thank Dr Yan Ao and Karl Austin for their expert technical assistance. NR 50 TC 18 Z9 21 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD SEP PY 2009 VL 158 IS 2 BP 442 EP 450 DI 10.1111/j.1476-5381.2009.00201.x PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 492RI UT WOS:000269676500005 PM 19422374 ER PT J AU Latini, DM Allen, JG Seo, M Mahoney, JS Ellis, TE Frueh, BC AF Latini, David M. Allen, Jon G. Seo, Munseok Mahoney, Jane S. Ellis, Thomas E. Frueh, B. Christopher TI Psychosocial characteristics of psychiatric inpatients at admissions and discharge: The Menninger Clinic Adult Outcomes Project SO BULLETIN OF THE MENNINGER CLINIC LA English DT Article ID CHRONIC DISEASE; RELIABILITY; VALIDITY AB The authors present a first look at the data from The Menninger Clinic Adult Outcomes Project. They provide descriptive data from 443 patients admitted to the Clinic between April 2008 and May 2009. Patients show significant improvement on a range of standardized measures from admission to discharge (effect sizes range from moderate to large, 0.31 to 1.44), and there are some differences among clinical programs within the hospital in the extent of change on some scales. A comparison of patients who did and did not complete discharge assessments showed minimal differences between groups on admissions variables. These results attest to the substantial impact of relatively long-term intensive inpatient treatment on improving clinical symptoms and functioning, but further studies are needed to determine the trajectory of change in the hospital and, most importantly, at follow-tip. (Bulletin of the Menninger Clinic, 73[4], 296-310) C1 [Latini, David M.] Michael E DeBakey Vet Affairs Med Ctr 152, Hlth Serv Res & Dev Ctr Excellence, Houston, TX 77030 USA. RP Latini, DM (reprint author), Michael E DeBakey Vet Affairs Med Ctr 152, Hlth Serv Res & Dev Ctr Excellence, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM latini@bcm.tmc.edu OI Latini, David/0000-0002-6161-4861; Ellis, Thomas/0000-0002-4496-5280 NR 11 TC 6 Z9 6 U1 0 U2 0 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0025-9284 J9 B MENNINGER CLIN JI Bull. Menninger Clin. PD FAL PY 2009 VL 73 IS 4 BP 296 EP 310 PG 15 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA 532VH UT WOS:000272777700004 PM 20025426 ER PT J AU Seow, H Snyder, CF Shugarman, LR Mularski, RA Kutner, JS Lorenz, KA Wu, AW Dy, SM AF Seow, Hsien Snyder, Claire F. Shugarman, Lisa R. Mularski, Richard A. Kutner, Jean S. Lorenz, Karl A. Wu, Albert W. Dy, Sydney M. TI Developing Quality Indicators for Cancer End-of-Life Care Proceedings From a National Symposium SO CANCER LA English DT Editorial Material DE care planning; communication; depression; dyspnea; end-of-life care; pain; psychosocial care; quality indicators; spirituality; symptom assessment ID PALLIATIVE CARE; PERFORMANCE; HOSPICE AB Quality indicators applicable to cancer end-of-life care exist, but have not been widely implemented. To advance this field, the authors worked with the Agency for Health Care Research and Quality and the National Cancer Institute to organize a national symposium to discuss key issues and future goals, based on a conceptual framework. Discussions focused on 8 key domains in end-of-life cancer care: pain; dyspnea; communication, care planning, and decision making; psychosocial care; communication about chemotherapy; depression; continuity, coordination, and care transitions; and spirituality and closure. Key themes included the need for clarity on definitions and key aspects of care within domains, the need to start implementing indicators in more developed domains, and the importance of high-quality symptom assessment and documentation of key processes. Key areas for future work include development of more outcome indicators, methods to better incorporate indicators and patient-reported outcomes into clinical processes of care, and coordination across domains and settings. Measuring the quality of end-of-life cancer care is essential to understanding how best to improve patient outcomes and care. Cancer 2009;115:3820-9. (C) 2009 American Cancer Society. C1 [Seow, Hsien; Snyder, Claire F.; Wu, Albert W.; Dy, Sydney M.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Shugarman, Lisa R.] RAND Corp, Santa Monica, CA USA. [Mularski, Richard A.] Kaiser Permanente NW, Ctr Hlth Res, Portland, OR USA. [Kutner, Jean S.] Univ Colorado, Sch Med, Denver, CO USA. [Lorenz, Karl A.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Dy, SM (reprint author), 624 N Broadway,Rm 609, Baltimore, MD 21205 USA. EM sdy@jhsph.edu FU AHRQ HHS [T32 HS000029] NR 21 TC 29 Z9 29 U1 1 U2 8 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 SEP 1 PY 2009 VL 115 IS 17 BP 3820 EP 3829 DI 10.1002/cncr.24439 PG 10 WC Oncology SC Oncology GA 486WF UT WOS:000269230700007 PM 19514090 ER PT J AU Ogino, S Nosho, K Shima, K Baba, Y Irahara, N Kirkner, GJ Hazra, A De Vivo, I Giovannucci, EL Meyerhardt, JA Fuchs, CS AF Ogino, Shuji Nosho, Katsuhiko Shima, Kaori Baba, Yoshifumi Irahara, Natsumi Kirkner, Gregory J. Hazra, Aditi De Vivo, Immaculata Giovannucci, Edward L. Meyerhardt, Jeffrey A. Fuchs, Charles S. TI p21 Expression in Colon Cancer and Modifying Effects of Patient Age and Body Mass Index on Prognosis SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; CYCLE REGULATORY PROTEINS; BRAF V600E MUTATION; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; CELL-CYCLE; DNA METHYLATION; P21(WAF1/CIP1) EXPRESSION; LINE-1 HYPOMETHYLATION; ADJUVANT CHEMOTHERAPY AB p21 (Cyclin-dependent kinase inhibitor-1A, CDKN1A or CIP1) plays a role in regulating cell cycle, and its expression is lost in most colorectal cancers. p21 Is related with energy balance status, cellular senescence, and stem cell aging. Thus, the influence of p21 loss on tumor behavior and clinical outcome may be modified by patient age and body mass index (BMI). Using 647 colon cancers in two independent prospective cohorts, p21 loss was observed in 509 (79%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratio (HR) for death, adjusted for potential confounders, including p53, cyclin D1, KRAS, BRAF, PIK3CA, LINE-1 hypomethylation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI). p21 Loss was independently associated with low colon cancer-specific mortality [HR, 0.58; 95% confidence interval (95% CI), 0.38-0.89; adjusted for the covariates including MSI, CIMP, and LINE-1 methylation]. The prognostic effect of p21 loss differed significantly by age at diagnosis (P(interaction) < 0.0001) and BMI P(interaction) = 0.002). The adjusted HR for cancer-specific mortality (p21 loss versus p21 expression) was 4.09 (95% CI, 1.13-14.9) among patients <60 year old and 0.37 (95% CI, 0.24-0.59) among patients >= 60 year old. The adverse prognostic effect of obesity was limited to p21-expressing cases (adjusted HR, 5.85; 95% CI, 2.28-15.0; BMI, >= 30 versus <30 kg/m(2)), but no such effect was observed among p21-lost cases. In conclusion, p21 loss in colon cancer is associated with longer survival among patients >= 60 year old, whereas it is associated with shorter survival among patients <60 year old. Patient BMI also differentially influences prognosis according to p21 CDKN1A status. Our data suggest host-tumor interactions influencing tumor aggressiveness. (Cancer Epidemiol Biomarkers Prev 2009;18(9):251,3-21) C1 [Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp,Dept Med Oncol, Dana Farber Canc Inst,Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kirkner, Gregory J.; Hazra, Aditi; De Vivo, Immaculata; Giovannucci, Edward L.; Fuchs, Charles S.] Harvard Univ, Sch Med, Channing Lab, Dept Med, Boston, MA 02115 USA. [De Vivo, Immaculata; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp,Dept Med Oncol, Dana Farber Canc Inst,Ctr Mol Oncol Pathol, Room JF-215C,44 Binney St, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU U.S. NIH [P50 CA127003, K07 CA122826, K07 CA97992]; Bennett Family Fund; the Entertainment Industry Foundation National Colorectal Cancer Research Alliance; Japan Society for Promotion of Science FX U.S. NIH (P50 CA127003, C.S. Fuchs; K07 CA122826, S. Ogino; K07 CA97992, J.A. Meyerhardt); the Bennett Family Fund; the Entertainment Industry Foundation National Colorectal Cancer Research Alliance; and a fellowship grant from the Japan Society for Promotion of Science (K. Nosho). NR 55 TC 28 Z9 30 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2009 VL 18 IS 9 BP 2513 EP 2521 DI 10.1158/1055-9965.EPI-09-0451 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 493KA UT WOS:000269734100025 PM 19723919 ER PT J AU Settle, K Posner, MR Schumaker, LM Tan, M Suntharalingam, M Goloubeva, O Strome, SE Haddad, RI Patel, SS Cambell, EV Sarlis, N Lorch, J Cullen, KJ AF Settle, Kathleen Posner, Marshall R. Schumaker, Lisa M. Tan, Ming Suntharalingam, Mohan Goloubeva, Olga Strome, Scott E. Haddad, Robert I. Patel, Shital S. Cambell, Earl V., III Sarlis, Nicholas Lorch, Jochen Cullen, Kevin J. TI Racial Survival Disparity in Head and Neck Cancer Results from Low Prevalence of Human Papillomavirus Infection in Black Oropharyngeal Cancer Patients SO CANCER PREVENTION RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; CERVICAL-CANCER; UNITED-STATES; BREAST-CANCER; RISK-FACTOR; DIAGNOSIS; STAGE; WOMEN; RACE AB The burden of squamous cell carcinoma of the head and neck (SCCHN) is greater for blacks than for whites, especially in oropharyngeal cases. We previously showed retrospectively that disease-free survival was significantly greater in white than in black SCCHN patients treated with chemoradiation, the greatest difference occurring in the oropharyngeal subgroup. Oropharyngeal cancer is increasing in incidence and in its association with human papillomavirus (HPV) infection; HPV-positive oropharyngeal cancer patients have significantly better outcomes (versus HPV-negative). These collective data led to the present analyses of overall survival (OS) in our retrospective cohort and of OS and HPV status (tested prospectively in pretreatment biopsy specimens) in the phase 3, multicenter TAX 324 trial of induction chemotherapy followed by concurrent chemoradiation in SCCHN patients. Median OS in the retrospective cohort of 106 white and 95 black SCCHN patients was 52.1 months (white) versus only 23.7 months (black; P = 0.009), due entirely to OS in the subgroup of patients with oropharyngeal cancer-69.4 months (whites) versus 25.2 months (blacks; P = 0.0006); no significant difference by race occurred in survival of non-oropharyngeal SCCHN (P = 0.58). In TAX 324, 196 white patients and 28 black patients could be assessed for HPV status. Median OS was significantly worse for black patients (20.9 months) than for white patients (70.6 months; P = 0.03) and dramatically improved in HPV-positive (not reached) versus HPV-negative (26.6 months, 5.1 hazard ratio) oropharyngeal patients (P < 0.0001), 49% of whom were HPV-16 positive. Overall, HPV positivity was 34% in white versus 4% in black patients (P = 0.0004). Survival was similar for black and white HPV-negative patients (P = 0.56). This is the first prospective assessment of confirmed HPV status in black versus white SCCHN patients. Worse OS for black SCCHN patients was driven by oropharyngeal cancer outcomes, and that for black oropharyngeal cancer patients by a lower prevalence of HPV infection. These findings have important implications for the etiology, prevention, prognosis, and treatment of SCCHN. C1 [Settle, Kathleen; Schumaker, Lisa M.; Tan, Ming; Suntharalingam, Mohan; Goloubeva, Olga; Strome, Scott E.; Patel, Shital S.; Cambell, Earl V., III; Cullen, Kevin J.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Posner, Marshall R.; Haddad, Robert I.; Lorch, Jochen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Sarlis, Nicholas] Sanofi Aventis, Bridgewater, NJ USA. RP Cullen, KJ (reprint author), Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Room N9E17,22 S Greene St, Baltimore, MD 21201 USA. EM kcullen@umm.edu FU sanofi-aventis US; State of Maryland Cigarette Restitution; Orokawa Foundation FX Grant support: Supported by a grant from sanofi-aventis US, by the State of Maryland Cigarette Restitution Fund, and by the Orokawa Foundation. NR 31 TC 149 Z9 153 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD SEP PY 2009 VL 2 IS 9 BP 776 EP 781 DI 10.1158/1940-6207.CAPR-09-0149 PG 6 WC Oncology SC Oncology GA 492YY UT WOS:000269700400003 PM 19641042 ER PT J AU Campbell, I Polyak, K Haviv, I AF Campbell, Ian Polyak, Kornelia Haviv, Izhak TI Clonal Mutations in the Cancer-Associated Fibroblasts: The Case against Genetic Coevolution SO CANCER RESEARCH LA English DT Review ID CARCINOMA-ASSOCIATED FIBROBLASTS; STROMAL CELLS; BREAST-CANCER; TUMOR STROMA; OVARIAN CARCINOMAS; TP53 MUTATIONS; INSTABILITY; EPITHELIUM; MICROENVIRONMENT; HETEROZYGOSITY C1 [Campbell, Ian] Peter MacCallum Canc Ctr, Ctr Canc Genet & Predict Med, VBCRC Canc Genet Lab, Melbourne, Vic 3002, Australia. [Campbell, Ian] Univ Melbourne, Sch Med, Dept Pathol, Melbourne, Vic, Australia. [Haviv, Izhak] Univ Melbourne, Sch Med, Dept Biochem, Melbourne, Vic, Australia. [Polyak, Kornelia] Dana Farber Canc Inst, Boston, MA 02115 USA. [Polyak, Kornelia] Harvard Univ, Sch Med, Boston, MA USA. [Haviv, Izhak] Baker IDI Inst, Prahran, Vic, Australia. RP Campbell, I (reprint author), Peter MacCallum Canc Ctr, Ctr Canc Genet & Predict Med, VBCRC Canc Genet Lab, St Andrews Pl, Melbourne, Vic 3002, Australia. EM ian.campbell@petermac.org RI campbell, Ian/F-6006-2011 NR 35 TC 47 Z9 47 U1 2 U2 5 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 SEP 1 PY 2009 VL 69 IS 17 BP 6765 EP 6768 DI 10.1158/0008-5472.CAN-08-4253 PG 4 WC Oncology SC Oncology GA 491GH UT WOS:000269566000003 PM 19706773 ER PT J AU Lu, KV Zhu, SJ Cvrljevic, A Huang, TT Sarkaria, S Ahkavan, D Dang, J Dinca, EB Plaisier, SB Oderberg, I Lee, Y Chen, ZG Caldwell, JS Xie, YM Loo, JA Seligson, D Chakravari, A Lee, FY Weinmann, R Cloughesy, TF Nelson, SF Bergers, G Graeber, T Furnari, FB James, CD Cavenee, WK Johns, TG Mischel, PS AF Lu, Kan V. Zhu, Shaojun Cvrljevic, Anna Huang, Tiffany T. Sarkaria, Shawn Ahkavan, David Dang, Julie Dinca, Eduard B. Plaisier, Seema B. Oderberg, Isaac Lee, Yohan Chen, Zugen Caldwell, Jeremy S. Xie, Yongmin Loo, Joseph A. Seligson, David Chakravari, Arnab Lee, Francis Y. Weinmann, Roberto Cloughesy, Timothy F. Nelson, Stanley F. Bergers, Gabriele Graeber, Thomas Furnari, Frank B. James, C. David Cavenee, Webster K. Johns, Terrance G. Mischel, Paul S. TI Fyn and Src Are Effectors of Oncogenic Epidermal Growth Factor Receptor Signaling in Glioblastoma Patients SO CANCER RESEARCH LA English DT Article ID CANCER CELLS; LUNG-CANCER; DASATINIB BMS-354825; C-SRC; KINASE INHIBITORS; IN-VITRO; INVASION; EGFR; THERAPY; MUTATIONS AB Activating epidermal growth factor receptor (EGFR) mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors are infrequent and short-lived. We show that the Src family kinases (SFK) Fyn and Src are effectors of oncogenic EGFR signaling, enhancing invasion and tumor cell survival in vivo. Expression of a constitutively active EGFR mutant, EGFRvIII, resulted in activating phosphorylation and physical association with Src and Fyn, promoting tumor growth and motility. Gene silencing of Fyn and Src limited EGFR- and EGFRvIII-dependent tumor cell motility. The SFK inhibitor dasatinib inhibited invasion, promoted tumor regression, and induced apoptosis in vivo, significantly prolonging survival of an orthotopic glioblastoma model expressing endogenous EGFR-vIII. Dasatinib enhanced the efficacy of an anti-EGFR monoclonal antibody (mAb 806) in vivo, further limiting tumor growth and extending survival. Examination of a large cohort of clinical samples showed frequent coactivation of EGFR and SFKs in glioblastoma patients. These results establish a mechanism linking EGFR signaling with Fyn and Src activation to promote tumor progression and invasion in vivo and provide rationale for combined anti-EGFR and anti-SFK targeted therapies. [Cancer Res 2009;69(17):6889-98] C1 [Lu, Kan V.; Zhu, Shaojun; Huang, Tiffany T.; Sarkaria, Shawn; Ahkavan, David; Dang, Julie; Oderberg, Isaac; Seligson, David; Mischel, Paul S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Lee, Yohan; Chen, Zugen; Nelson, Stanley F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Cloughesy, Timothy F.; Nelson, Stanley F.; Mischel, Paul S.] Univ Calif Los Angeles, David Geffen Sch Med, Henry E Singleton Brain Tumor Program, Los Angeles, CA 90095 USA. [Plaisier, Seema B.; Graeber, Thomas] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Xie, Yongmin; Loo, Joseph A.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Lu, Kan V.; Bergers, Gabriele; James, C. David] Univ Calif San Francisco, Dept Neurol Surg, Brain Tumor Res Ctr, San Francisco, CA 94143 USA. [Cvrljevic, Anna] Austin Hosp, Ludwig Inst Canc Res, Melbourne Branch, Melbourne, Vic 3084, Australia. [Dinca, Eduard B.] Mayo Clin, Grad Program Neurosci, Rochester, MN USA. [Caldwell, Jeremy S.] Novartis Res Fdn, Genom Inst, San Diego, CA USA. [Chakravari, Arnab] Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Lee, Francis Y.; Weinmann, Roberto] Bristol Myers Squibb Co, Pharmaceut Res & Dev, Princeton, NJ USA. [Furnari, Frank B.; Cavenee, Webster K.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Johns, Terrance G.] Monash Inst Med Res, Clayton, Vic, Australia. RP Mischel, PS (reprint author), 10833 Le Conte Ave,Box 951732, Los Angeles, CA 90095 USA. EM pmischel@mednet.ucla.edu RI Johns, Terrance/C-2441-2008; Nelson, Stanley/D-4771-2009; James, Charles/E-2721-2012; OI Johns, Terrance/0000-0002-8874-4543; James, Charles/0000-0002-1027-203X; Cvrljevic, Anna/0000-0003-2851-8701; Graeber, Thomas/0000-0001-8574-9181 FU Brain Tumor Funders' Collaborative, National Institute for Neurological Disorders and Stroke [NS050151]; National Cancer Institute [CA119347, CA108633, 5T32CA09056]; Accelerate Brain Cancer Cure Award; NIH [NSG49720, CA097257]; Harry Allgauer Foundation; Ziering Family Foundation; Leonard Heyman/American Brain Tumor Association Fellowship; National Health and Medical Research Council of Australia [433615]; University of California-Los Angeles DNA Microarray Facility FX Brain Tumor Funders' Collaborative, National Institute for Neurological Disorders and Stroke grant. NS050151. National Cancer Institute grants CA119347 and CA108633, and Accelerate Brain Cancer Cure Award (P.S. Mischel); NIH grants NSG49720 and CA097257 (C.D. James); Harry Allgauer Foundation through The The Doris R. Ullman Fund for Brain Tumor Research Technologies, Henry E. Single(on Brain Tumor Fellowship (P.S. Mischel), and Ziering Family Foundation (in memory of Sigi Ziering); Leonard Heyman/American Brain Tumor Association Fellowship and University of California-Los Angeles Turner Cell Biology Training Grant funded by the National Cancer Institute grant. 5T32CA09056 (K.V. Lu); and National Health and Medical Research Council of Australia project. grant 433615 (T.G. Johns). Microarray studies were supported by the University of California-Los Angeles DNA Microarray Facility. NR 44 TC 76 Z9 77 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2009 VL 69 IS 17 BP 6889 EP 6898 DI 10.1158/0008-5472.CAN-09-0347 PG 10 WC Oncology SC Oncology GA 491GH UT WOS:000269566000019 PM 19690143 ER PT J AU Muhlenberg, T Zhang, YX Wagner, AJ Grabellus, F Bradner, J Taeger, G Lang, H Taguchi, T Schuler, M Fletcher, JA Bauer, S AF Muehlenberg, Thomas Zhang, Yixiang Wagner, Andrew J. Grabellus, Florian Bradner, James Taeger, Georg Lang, Hauke Taguchi, Takahiro Schuler, Martin Fletcher, Jonathan A. Bauer, Sebastian TI Inhibitors of Deacetylases Suppress Oncogenic KIT Signaling, Acetylate HSP90, and Induce Apoptosis in Gastrointestinal Stromal Tumors SO CANCER RESEARCH LA English DT Article ID IMATINIB MESYLATE; LEUKEMIA-CELLS; BCR-ABL; C-KIT; GLUCOCORTICOID-RECEPTOR; HISTONE DEACETYLASES; CHAPERONE FUNCTION; MUTATIONS; EXPRESSION; CANCER AB Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor A (PDGFRA), and treatment with the tyrosine kinase inhibitor imatinib yields responses in the majority of patients. However, most patients develop secondary resistance, which is associated with a dismal prognosis. Histone deacetylase inhibitors (HDACI) have been shown to enhance imatinib activity in imatinib-resistant chronic myelogenous leukemia. Against this background, we explored whether HDACI might provide an alternative therapeutic strategy to KIT/PDGFRA kinase inhibitors in GIST. Inhibition of cell proliferation by HDACI was seen in KIT-positive but not in KIT-negative GIST cell lines, suggesting that HDACI activity is mainly conferred by targeting oncogenic KIT. KIT activity, expression, and activation of downstream pathways were strongly inhibited by several HDACI (SAHA, LBH589, VPA, trichostatin A, and NaButyrate). SAHA and LBH589 induced apoptosis in KIT-positive GIST, and strong synergism with imatinib was observed at low concentrations of SAHA and LBH589. Mechanistically, treatment with HDACI reduced KIT mRNA transcript levels and led to strong acetylation of HSP90, interfering with its activity as KIT chaperone. These results provide preclinical evidence for a disease-specific effect of HDACI in KIT-positive GIST, which could translate into therapeutic activity. [Cancer Res 2009;69(17):6941-50] C1 [Bauer, Sebastian] Univ Essen Gesamthsch, Sch Med, W German Canc Ctr, Sarcoma Ctr,Dept Internal Med Canc Res, D-45122 Essen, Germany. [Zhang, Yixiang; Wagner, Andrew J.; Bradner, James] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Fletcher, Jonathan A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Lang, Hauke] Univ Hosp Mainz, Dept Surg, Mainz, Germany. [Taguchi, Takahiro] Kochi Univ, Grad Sch Kuroshio Sci, Div Human Hlth & Med Sci, Nanko Ku, Kochi 780, Japan. RP Bauer, S (reprint author), Univ Essen Gesamthsch, Sch Med, W German Canc Ctr, Sarcoma Ctr,Dept Internal Med Canc Res, Hufelandstr 55, D-45122 Essen, Germany. EM sebastian.bauer@uni-due.de RI Bauer, Sebastian/D-8120-2012 OI Bauer, Sebastian/0000-0001-5949-8120 FU Dr. Mildred Scheel Stiftung fur Krebsforschung; Life-raft Group Research Initiative FX Anonymous donor, Max-Eder Fellowship from the Dr. Mildred Scheel Stiftung fur Krebsforschung (S. Bauer), and Life-raft Group Research Initiative (S. Bauer). NR 46 TC 38 Z9 39 U1 0 U2 3 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 SEP 1 PY 2009 VL 69 IS 17 BP 6941 EP 6950 DI 10.1158/0008-5472.CAN-08-4004 PG 10 WC Oncology SC Oncology GA 491GH UT WOS:000269566000025 PM 19706776 ER PT J AU Ahmad, R Raina, D Joshi, MD Kawano, T Ren, J Kharbanda, S Kufe, D AF Ahmad, Rehan Raina, Deepak Joshi, Maya Datt Kawano, Takeshi Ren, Jian Kharbanda, Surender Kufe, Donald TI MUC1-C Oncoprotein Functions as a Direct Activator of the Nuclear Factor-kappa B p65 Transcription Factor SO CANCER RESEARCH LA English DT Article ID CARCINOMA-ASSOCIATED ANTIGEN; BETA-CATENIN; APOPTOTIC RESPONSE; MEDIATED APOPTOSIS; SURVIVAL RESPONSE; OXIDATIVE STRESS; C-SRC; COMPLEX; DEATH; PHOSPHORYLATION AB Nuclear factor-kappa B (NF-kappa B) is constitutively activated in diverse human malignancies. The mucin 1 (MUC1) oncoprotein is overexpressed in human carcinomas and, like NF-kappa B, blocks cell death and induces transformation. The present studies show that MUC1 constitutively associates with NF-kappa B p65 in carcinoma cells. The MUC1 COOH-terminal subunit (MUC1-C) cytoplasmic domain binds directly to NF-kappa B p65 and, importantly, blocks the interaction between NF-kappa B p65 and its inhibitor I kappa B alpha.. We show that NF-kappa B p65 and MUC1-C constitutively occupy the promoter of the Bcl-xL gene in carcinoma cells and that MUC1-C contributes to NF-kappa B-mediated transcriptional activation. Studies in nonmalignant epithelial cells show that MUC1-C interacts with NF-kappa B in the response to tumor necrosis factor-alpha stimulation. Moreover, tumor necrosis factor-alpha induces the recruitment of NF-kappa B p65-MUC1-C complexes to NF-kappa B target genes, including the promoter of the MUC1 gene itself. We also show that an inhibitor of MUC1-C oligomerization blocks the interaction with NF-kappa B p65 in vitro and in cells. The MUC1-C inhibitor decreases MUC1-C and NF-kappa B p65 promoter occupancy and expression of NF-kappa B target genes. These findings indicate that MUC1-C is a direct activator of NF-kappa B p65 and that an inhibitor of MUC1 function is effective in blocking activation of the NF-kappa B pathway. [Cancer Res 2009;69(17):7013-21] C1 [Ahmad, Rehan; Joshi, Maya Datt; Kawano, Takeshi; Ren, Jian; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Raina, Deepak; Kharbanda, Surender] Genus Oncol, Boston, MA USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Dana 830, Boston, MA 02115 USA. EM Donald_Kufe@dfci.harvard.edu FU National Cancer Institute [CA42802, CA97098, CA 100707] FX The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 38 TC 78 Z9 81 U1 0 U2 3 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 SEP 1 PY 2009 VL 69 IS 17 BP 7013 EP 7021 DI 10.1158/0008-5472.CAN-09-0523 PG 9 WC Oncology SC Oncology GA 491GH UT WOS:000269566000033 PM 19706766 ER PT J AU De Nicolo, A Parisini, E Zhong, Q Palma, MD Stoeckert, KA Domchek, SM Nathanson, KL Caligo, MA Vidal, M Cusick, ME Garber, JE AF De Nicolo, Arcangela Parisini, Emilio Zhong, Quan Palma, Maurizia Dalla Stoeckert, Kathryn A. Domchek, Susan M. Nathanson, Katherine L. Caligo, Maria A. Vidal, Marc Cusick, Michael E. Garber, Judy E. TI Multimodal Assessment of Protein Functional Deficiency Supports Pathogenicity of BRCA1 p.V1688del SO CANCER RESEARCH LA English DT Article ID CELL-CYCLE CHECKPOINT; UNCLASSIFIED GENETIC-VARIANTS; UNKNOWN CLINICAL-SIGNIFICANCE; OVARIAN-CANCER FAMILIES; DNA-SEQUENCE VARIANTS; BREAST-CANCER; STRUCTURAL BASIS; TRANSCRIPTIONAL ACTIVATION; PHOSPHOPEPTIDE RECOGNITION; BACH1 PHOSPHOPEPTIDE AB Unequivocal discrimination between neutral variants and deleterious mutations is crucial for appropriate counseling of individuals with a BRCA1 or BRCA2 sequence change. An increasing number of variants of uncertain significance (VUS) are being identified, the unclassified biological effect of which poses clinical concerns. A multifactorial likelihood-based approach recently suggested disease causality for BRCA1 p.V1688del, a VUS recurrent in Italian breast/ovarian cancer families. Whether and how this single amino acid deletion in the BRCA1 COOH terminus (BRCT) domain affects the function of the mutant protein (Delta ValBRCA1) has not been elucidated. We undertook comprehensive functional characterization of AValBRCA1, comprising comparative structural modeling, analysis of protein stability and associations, and analysis of DNA repair function. Our model predicted BRCT domain destabilization and folding disruption caused by BRCA1 p.V1688del. Consistently, the recombinant Delta ValBRCA1 was less stable than wild-type BRCA1 and, unlike the latter, failed to associate with BRIP1, CtIP, and Rap80 and to relocalize to sites of DNA damage. Yeast two-hybrid analysis revealed a compromised interaction with FHL2 and KPNA2, which is likely responsible for improper subcellular localization of Delta ValBRCA1. In addition, we found four new breast/ovarian cancer families of Italian ancestry who carried this sequence alteration. These results provide the first evidence of the effect of BRCA1 p.V1688del on protein stability and function, supporting the view that it is a deleterious mutation. Multimodal analyses like ours could advance understanding of tumor suppression by BRCA1 and ultimately contribute to developing efficient strategies for screening and characterization of VUS. [Cancer Res 2009;69(17):7030-7] C1 [De Nicolo, Arcangela; Zhong, Quan; Vidal, Marc; Cusick, Michael E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Parisini, Emilio; Stoeckert, Kathryn A.; Garber, Judy E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [De Nicolo, Arcangela; Zhong, Quan; Vidal, Marc; Cusick, Michael E.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [De Nicolo, Arcangela; Zhong, Quan; Vidal, Marc; Cusick, Michael E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Palma, Maurizia Dalla; Nathanson, Katherine L.] Univ Penn, Sch Med, Dept Med, Abramson Canc Ctr,Div Med Genet, Philadelphia, PA 19104 USA. [Domchek, Susan M.] Univ Penn, Sch Med, Dept Med, Abramson Canc Ctr,Div Hematol Oncol, Philadelphia, PA 19104 USA. [Caligo, Maria A.] Univ Pisa, Sect Oncogenet, Div Surg Mol & Ultrastruct Pathol, Dept Oncol Transplants & New Technol Med, Pisa, Italy. [Caligo, Maria A.] Univ Hosp Pisa, Pisa, Italy. RP De Nicolo, A (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Smith Bldg,Room 806,44 Binney St, Boston, MA 02115 USA. EM Arcangela_Denicolo@dfci.harvard.edu OI Nathanson, Katherine/0000-0002-6740-0901 FU Cure research grant [PDF 0601163]; Ellison Foundation; National Cancer Institute [R33-CA132073]; Dana-Farber Cancer Institute FX Susan G. Komen for the Cure research grant PDF#0601163 (A. De Nicole), Ellison Foundation and National Cancer Institute grant R33-CA132073 (NI. Vidal), and institute-sponsored research funds from the Dana-Farber Cancer Institute Strategic Initiative awarded to Center for Cancer Systems Biology. NR 50 TC 11 Z9 11 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2009 VL 69 IS 17 BP 7030 EP 7037 DI 10.1158/0008-5472.CAN-09-1440 PG 8 WC Oncology SC Oncology GA 491GH UT WOS:000269566000035 PM 19706752 ER PT J AU Mueller, J Gazzoli, I Bandipalliam, P Garber, JE Syngal, S Kolodner, RD AF Mueller, James Gazzoli, Isabella Bandipalliam, Prathap Garber, Judy E. Syngal, Sapna Kolodner, Richard D. TI Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Cases SO CANCER RESEARCH LA English DT Article ID REVISED BETHESDA GUIDELINES; MSH6 GERMLINE MUTATIONS; MICROSATELLITE INSTABILITY; ENDOMETRIAL CANCER; GENOMIC DELETIONS; CLINICAL-CRITERIA; COLON-CANCER; CELL-LINES; MLH1 GENE; HNPCC AB An accurate algorithm is essential for effective molecular diagnosis of hereditary colorectal cancer (CRC). Here, we have extended the analysis of 71 CRC cases suspected to be Lynch syndrome cases for MSH2, MLH1, MSH6, and PMS2 gene defects. All cases were screened for mutations in MSH2,MLH1, and MSH6, and all cases where tumors were available were screened for microsatellite instability (MSI) and expression of MSH2 and MLH1. Subsequently, mutation-negative cases were screened for MLH1 methylation and mutations in PMS2. Of the MSI-high (MSI-H) cases, 96% had a mismatch repair (MMR) gene defect, mostly involving MSH2 or MLH1; one PMS2 mutation, one MLH1 epimutation, and no MSH6 mutations were found. Four of the 28 MSI-H cases, including one Amsterdam criteria case, had biallelic tumor MLH1 methylation, indicating that sporadic cases can be admixed in with Lynch syndrome cases, even those meeting the strongest criteria for Lynch syndrome. MMR gene defects were found in similar frequency in cases where tumors were and were not available. One MLH1 and one MSH2 deletion mutation were found in MSI-stable/low cases, indicating that MSI testing can exclude cases with pathogenic mutations. Our analysis supports a diagnostic algorithm where cases are selected for analysis based on clinical criteria or prediction models; isolated sporadic young-onset cases can be prescreened by tumor testing, whereas familial cases may be directly subjected to molecular analysis for mutations in MMR genes followed by MSI, protein expression, and DNA methylation analysis to aid in the resolution of mutation-negative cases. [Cancer Res 2009;69(17):7053-61] C1 [Mueller, James; Gazzoli, Isabella; Kolodner, Richard D.] Univ Calif San Diego, Sch Med, Dept Med, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Mueller, James; Gazzoli, Isabella; Kolodner, Richard D.] Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Mueller, James; Gazzoli, Isabella; Kolodner, Richard D.] Univ Calif San Diego, Sch Med, Biomed Sci Grad Program, La Jolla, CA 92093 USA. [Bandipalliam, Prathap; Garber, Judy E.; Syngal, Sapna] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Bandipalliam, Prathap; Garber, Judy E.; Syngal, Sapna] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. RP Kolodner, RD (reprint author), Univ Calif San Diego, Sch Med, Dept Med, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. EM rkolodner@ucsd.edu FU NIH [CA85759, GM50006] FX We thank Rick Fishel (Ohio State University Medical School) for helpful discussions and comments on the manuscript and Christopher Putnam and Jason Chan (Ludwig Institute) for help with statistical calculations about MSI measurements. NR 56 TC 27 Z9 28 U1 0 U2 3 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 SEP 1 PY 2009 VL 69 IS 17 BP 7053 EP 7061 DI 10.1158/0008-5472.CAN-09-0358 PG 9 WC Oncology SC Oncology GA 491GH UT WOS:000269566000038 PM 19690142 ER PT J AU Alper, O Stetler-Stevenson, WG Harris, LN Leitner, WW Ozdemirli, M Hartmann, D Raffeld, M Abu-Asab, M Byers, S Zhuang, Z Oldfield, EH Tong, Y Bergmann-Leitner, E Criss, WE Nagasaki, K Mol, SC Cramer, DW Karaveli, FS Goldbach-Mansky, R Leo, P Stromberg, K Weil, RJ AF Alper, Oezge Stetler-Stevenson, William G. Harris, Lyndsay N. Leitner, Wolfgang W. Ozdemirli, Metin Hartmann, Dan Raffeld, Mark Abu-Asab, Mones Byers, Stephen Zhuang, Zhengping Oldfield, Edward H. Tong, Yanhe Bergmann-Leitner, Elke Criss, Wayne E. Nagasaki, Koichi Mol, Samuel C. Cramer, Daniel W. Karaveli, F. Seyda Goldbach-Mansky, Raphaela Leo, Paul Stromberg, Kurt Weil, Robert J. TI Novel anti-filamin-A antibody detects a secreted variant of filamin-A in plasma from patients with breast carcinoma and high-grade astrocytoma SO CANCER SCIENCE LA English DT Article ID CATHEPSIN-B; SERUM HER-2/NEU; CANCER CELLS; EXPRESSION; BINDING; TRAFFICKING; ABP-280 AB Identification of tumor-derived proteins in the circulation may allow for early detection of cancer and evaluation of therapeutic responses. To identify circulating tumor-derived proteins, mice were immunized with concentrated culture medium conditioned by human breast cancer cells. Antibodies generated by hybridomas were screened against conditioned media from both normal epithelial cells and tumor cells. Antibody selectively reacting with tumor cell-conditioned media was further characterized. This led to the development of a monoclonal antibody (Alper-p280) that reacts with a newly identified 280-kDa secreted variant of human filamin-A. Circulating filamin-A was detected in patient plasma samples using Alper-p280 in an ELISA assay. Human plasma samples from 134 patients with brain, breast, or ovarian cancer, 15 patients with active arthritis, and 76 healthy controls were analyzed. Filamin-A protein levels in human cell lines and tissues were analyzed by western blotting, immunohistochemistry, and electron and confocal microscopy. Circulating filamin-A was detected in the plasma of 109 of 143 patients with breast cancer and primary brain tumors. Plasma levels of filamin-A showed 89.5% sensitivity (95% confidence interval [CI] = 0.67% to 0.99%) and 97.8% specificity (95% CI = 0.88% to 0.99%) for glioblastoma at a cut-off of 21.0 ng/mL. Plasma levels of filamin-A (> 36.0 ng/mL) had 96.7% sensitivity (95% CI = 0.80% to 0.99%) and 67.8% specificity (95% CI = 0.54% to 0.79%) for metastatic breast cancer. Filamin-A levels were increased in malignant breast or brain tissues, but not in normal control tissues. Filamin-A localized to lysosomes in MDA.MB.231 breast cancer cells, but not in normal human mammary epithelial cells, suggesting that filamin-A may undergo cancer-specific processing. Plasma filamin-A appears to be a specific and sensitive marker for patients with high-grade astrocytoma or metastatic breast cancer. Additional novel cancer biomarkers have been identified and are being developed alongside Alper-p280 for use in diagnosis of breast carcinoma and high-grade astrocytoma, and for use in the evaluation of therapeutic responses. (Cancer Sci 2009; 100: 1748-1756). C1 [Alper, Oezge] Alper Biotech LLC, Rockville, MD USA. [Stetler-Stevenson, William G.] NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Harris, Lyndsay N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Leitner, Wolfgang W.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Ozdemirli, Metin; Hartmann, Dan] Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Dept Pathol, Washington, DC 20007 USA. [Raffeld, Mark; Abu-Asab, Mones] NCI, Pathol Branch, Bethesda, MD 20892 USA. [Byers, Stephen] Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Dept Oncol, Washington, DC 20007 USA. [Zhuang, Zhengping; Oldfield, Edward H.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Tong, Yanhe] VaxGen Inc, San Francisco, CA USA. [Bergmann-Leitner, Elke] Walter Reed Army Inst Res, Dept Immunol, Silver Spring, MD USA. [Criss, Wayne E.] Hacettepe Univ, Dept Biochem, Ankara, Turkey. [Nagasaki, Koichi] Natl Genome Res Ctr, Tokyo, Japan. [Mol, Samuel C.; Cramer, Daniel W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Karaveli, F. Seyda] Akdeniz Univ, Sch Med, Dept Pathol, TR-07058 Antalya, Turkey. [Goldbach-Mansky, Raphaela] NIAMSD, NIH, Bethesda, MD 20892 USA. [Leo, Paul] NIH, Human Genome Res Ctr, Bethesda, MD 20892 USA. [Stromberg, Kurt] US FDA, Div Therapeut Prot, Bethesda, MD 20014 USA. [Weil, Robert J.] Cleveland Clin Fdn, Neurol Inst, Dept Neurosurg, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44195 USA. RP Alper, O (reprint author), Alper Biotech LLC, Rockville, MD USA. EM oalper@alperbiotech.com RI Bergmann-Leitner, Elke/B-3548-2011; Leitner, Wolfgang/F-5741-2011; Stetler-Stevenson, William/H-6956-2012; Leo, Paul/B-3470-2011; KARAVELI, FATMA SEYDA/C-6335-2016; OI Bergmann-Leitner, Elke/0000-0002-8571-8956; Leitner, Wolfgang/0000-0003-3125-5922; Stetler-Stevenson, William/0000-0002-5500-5808; Leo, Paul/0000-0001-8325-4134; Abu-Asab, Mones/0000-0002-4047-1232 FU National Institute Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA FX This research was supported in part by the Intramural Research Program of the National Institute Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. The authors thank Dianne Hirsch, PhD, for critical reading and editing of the manuscript. The authors thank Ken Yamaguchi, MD, for scientific discussions and support during the early stages of project development. NR 27 TC 25 Z9 27 U1 1 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD SEP PY 2009 VL 100 IS 9 BP 1748 EP 1756 DI 10.1111/j.1349-7006.2009.01244.x PG 9 WC Oncology SC Oncology GA 482XL UT WOS:000268923800028 PM 19594548 ER PT J AU Chen, CY Chai, H Wang, XW Lin, PH Yao, QZ AF Chen, Changyi Chai, Hong Wang, Xinwen Lin, Peter H. Yao, Qizhi TI Chlamydia heat shock protein 60 decreases expression of endothelial nitric oxide synthase in human and porcine coronary artery endothelial cells SO CARDIOVASCULAR RESEARCH LA English DT Article DE Chlamydia pneumonia; Heat shock protein 60; Endothelial nitric oxide synthase; Superoxide anion; MAPK; Oxidative stress; Antioxidant; SeMet; MnTBAP; Atherosclerosis ID SMOOTH-MUSCLE-CELLS; CHLAMYDOPHILA-PNEUMONIAE; OXIDATIVE STRESS; ATHEROSCLEROSIS; OXYGEN; PROLIFERATION; MECHANISMS; MICE; ENOS AB Clinically, Chlamydia pneumoniae infection and its heat shock protein 60 (cHSP60) may contribute to atherogenesis; however, its underlying mechanisms are largely unknown. The objective of this study was to determine whether cHSP60 could cause endothelial dysfunction in human coronary artery endothelial cells (HCAECs) and porcine coronary arteries. When HCAECs were treated with recombinant cHSP60, endothelial nitric oxide synthase (eNOS) mRNA and protein levels, enzyme activities, cellular NO levels, mRNA stability, and promoter activities were significantly decreased. Superoxide anion production was significantly increased due to the inhibition of mitochondrial membrane potential and catalase and superoxide dismutase (SOD) activities as well as activation of NADPH oxidase. Antioxidant seleno-l-methionine (SeMet) or SOD mimetic MnTBAP effectively blocked cHSP60-induced eNOS downregulation. In addition, cHSP60 activated mitogen-activated protein kinases (MAPKs) including p38, c-Jun-N-terminal kinase/stress-activated protein kinase, and extracellular signal-regulated kinases. Specific chemical inhibitors or their dominant-negative mutant forms of these MAPKs effectively blocked cHSP60-induced eNOS downregulation. cHSP60-induced eNOS downregulation and oxidative stress were also demonstrated in porcine coronary artery rings in vitro. Functionally, endothelium-dependent vasorelaxation was significantly reduced in cHSP60-treated vessels. cHSP60 directly induces eNOS downregulation through oxidative stress and MAPK activation in both HCAECs and porcine coronary arteries, thereby causing endothelial dysfunction. C1 [Chen, Changyi; Chai, Hong; Wang, Xinwen; Lin, Peter H.; Yao, Qizhi] Baylor Coll Med, Mol Surg Res Ctr, Michael E DeBakey Dept Surg R413, Div Vasc Surg & Endovasc Therapy, Houston, TX 77030 USA. [Chen, Changyi; Lin, Peter H.; Yao, Qizhi] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Chen, CY (reprint author), Baylor Coll Med, Mol Surg Res Ctr, Michael E DeBakey Dept Surg R413, Div Vasc Surg & Endovasc Therapy, 1 Baylor Plaza,Mail Stop BCM390, Houston, TX 77030 USA. EM jchen@bcm.tmc.edu RI Chai, Hong/H-5438-2011 FU National Institutes of Health [HL65916, HL72716]; Baylor College of Medicine, Houston, TX, USA FX This work was partially supported by research grants from the National Institutes of Health (HL65916 and HL72716 to C. C.) and by the Baylor College of Medicine, Houston, TX, USA. NR 37 TC 17 Z9 17 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD SEP 1 PY 2009 VL 83 IS 4 BP 768 EP 777 DI 10.1093/cvr/cvp150 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 484AD UT WOS:000269014100021 PM 19443423 ER PT J AU Andersson, KB Finsen, AV Sjaland, C Winer, LH Sjaastad, I Odegaard, A Louch, WE Wang, YB Chen, J Chien, KR Sejersted, OM Christensen, G AF Andersson, Kristin B. Finsen, Alexandra V. Sjaland, Cecilie Winer, Lisbeth H. Sjaastad, Ivar Odegaard, Annlaug Louch, William E. Wang, Yibin Chen, Ju Chien, Kenneth R. Sejersted, Ole M. Christensen, Geir TI Mice carrying a conditional Serca2(flox) allele for the generation of Ca2+ handling-deficient mouse models SO CELL CALCIUM LA English DT Article DE Serca2; Calcium ATPase; Endoplasmic reticulum; Sarcoplasmic reticulum; Flax; Transgenic mouse ID SARCOPLASMIC-RETICULUM CA2+-ATPASE; CONGESTIVE-HEART-FAILURE; CARDIAC-PERFORMANCE; DARIERS-DISEASE; CALCIUM; MUSCLE; EXPRESSION; TRANSPORT; SERCA2A; GENE AB Sarco(endo)plasmic reticulum calcium ATPases (SERCA) are cellular pumps that transport Ca2+ into the sarcoplasmic reticulum (SR). Serca2 is the most widely expressed gene family member. The very early embryonic lethality of Serca2(null) mouse embryos has precluded further evaluation of loss of Serca2 function in the context of organ physiology. We have generated mice carrying a conditional Serca2(flox) allele which allows disruption of the Serca2 gene in an organ-specific and/or inducible manner. The model was tested by mating Serca2(flox) mice with MLC-2v(wt/cre) mice and with alpha MHC-Cre transgenic mice. In heterozygous Serca2(wt/flox)MLC-2v(wt/Cre) mice. the expression of SERCA2a and SERCA2b proteins were reduced in the heart and slow skeletal muscle. in accordance with the expression pattern of the MLC-2v gene. In Serca2(flox/flox) Tg(alpha MHC-Cre) embryos with early homozygous cardiac Serca2 disruption, normal embryonic development and yolk sac circulation was maintained up to at least embryonic stage E10.5. The Serca2(flox) mouse is the first murine conditional gene disruption model for the SERCA family of Ca2+ ATPases, and should be a powerful tool for investigating specific physiological roles of SERCA2 function in a range of tissues and organs in vivo both in adult and embryonic stages. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Andersson, Kristin B.; Finsen, Alexandra V.; Sjaland, Cecilie; Winer, Lisbeth H.; Sjaastad, Ivar; Odegaard, Annlaug; Louch, William E.; Sejersted, Ole M.; Christensen, Geir] Univ Oslo, Ullevaal Hosp, Expt Med Res Inst, N-0407 Oslo, Norway. [Andersson, Kristin B.; Finsen, Alexandra V.; Sjaland, Cecilie; Winer, Lisbeth H.; Sjaastad, Ivar; Odegaard, Annlaug; Louch, William E.; Sejersted, Ole M.; Christensen, Geir] Univ Oslo, Ctr Heart Failure Res, N-0407 Oslo, Norway. [Wang, Yibin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Los Angeles, CA 90095 USA. [Wang, Yibin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. [Wang, Yibin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Chen, Ju] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Chien, Kenneth R.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. RP Andersson, KB (reprint author), Univ Oslo, Ullevaal Hosp, Expt Med Res Inst, Kirkeveien 166, N-0407 Oslo, Norway. EM k.b.andersson@medisin.uio.no RI Sejersted, Ole/D-5601-2009; Chen, Ju/E-5579-2011; OI Sejersted, Ole/0000-0001-8817-3296; Wang, Yibin/0000-0003-0852-0767 FU Norwegian Research Council; Anders Jahre's Fund; Ulleval University Hospital Fund; Eastern Norway Regional Health Authority; Norwegian Research Council Research FX This work has been supported by the Norwegian Research Council, Anders Jahre's Fund for the Promotion of Science, the Ulleval University Hospital Fund (K.B.A.), a University of Oslo EMBIO senior research fellowship (K.B.A.), an Eastern Norway Regional Health Authority senior fellow grant (K.B.A.) and a Norwegian Research Council Research fellowship (A.V.F). NR 40 TC 20 Z9 20 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD SEP PY 2009 VL 46 IS 3 BP 219 EP 225 DI 10.1016/j.ceca.2009.07.004 PG 7 WC Cell Biology SC Cell Biology GA 499WA UT WOS:000270256000008 PM 19692123 ER PT J AU Singh, A Settleman, J AF Singh, Anurag Settleman, Jeff TI Oncogenic K-ras "addiction" and synthetic lethality SO CELL CYCLE LA English DT Editorial Material DE Ras; oncogene addiction; cancer; therapeutic targets; signature ID HUMAN CANCER; MOUSE; GENE C1 [Singh, Anurag] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Singh, A (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St,Room 7320, Charlestown, MA 02129 USA. EM asingh3@partners.org NR 13 TC 16 Z9 17 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 1 PY 2009 VL 8 IS 17 BP 2676 EP 2677 PG 2 WC Cell Biology SC Cell Biology GA 494FK UT WOS:000269795800003 PM 19690457 ER PT J AU Chen, LY Yabuuchi, A Eminli, S Takeuchi, A Lu, CW Hochedlinger, K Daley, GQ AF Chen, Lingyi Yabuuchi, Akiko Eminli, Sarah Takeuchi, Ayumu Lu, Chi-Wei Hochedlinger, Konrad Daley, George Q. TI Cross-regulation of the Nanog and Cdx2 promoters SO CELL RESEARCH LA English DT Article DE Cdx2; Nanog; embryonic stem cells; trophectoderm stem cells ID EMBRYONIC STEM-CELLS; MOUSE EMBRYOS; SELF-RENEWAL; RNA INTERFERENCE; ES CELLS; DIFFERENTIATION; PLURIPOTENCY; TROPHECTODERM; EXPRESSION; OCT4 AB The first cell fate choice in the mammalian embryo, the segregation of the inner cell mass (ICM) and trophectoderm (TE), is regulated by the mutually antagonistic effects of the transcription factors, Oct4 and Cdx2, while the pluripotency factor, Nanog, is essential to specify the epiblast. We have analyzed the promoters of Nanog and Cdx2, and have found that these two transcription factors are likewise regulated reciprocally. Using an embryonic stem cell line with conditional TE differentiation, we show that Nanog overexpression suppresses the upregulation of TE markers, while Nanog knockdown upregulates th