FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Beirne, OR Busaidy, KF Eisig, SB Larsen, PE White, RP Dodson, TB Rafetto, LK AF Beirne, O. Ross Busaidy, Kamal F. Eisig, Sidney B. Larsen, Peter E. White, Raymond P., Jr. Dodson, Thomas B. Rafetto, Louis K. TI Summary of the Third Molar Clinical Trials: Report of the AAOMS Task Force for Third Molar Summary SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID QUALITY-OF-LIFE; PERIODONTAL INFLAMMATORY DISEASE; CORONARY-HEART-DISEASE; YOUNG-ADULTS; 3RD-MOLAR SURGERY; CARIES EXPERIENCE; ASYMPTOMATIC 3RD-MOLARS; ATHEROSCLEROSIS RISK; TOPICAL MINOCYCLINE; OLDER AMERICANS C1 [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Dodson, TB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren Bldg,Suite 1201, Boston, MA 02114 USA. EM tbdodson@partners.org FU American Association of Oral and Maxillofacial Surgeons; Center for Applied Clinical Investigation, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital FX This report was funded in part by the American Association of Oral and Maxillofacial Surgeons and the Center for Applied Clinical Investigation, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital. NR 50 TC 0 Z9 0 U1 1 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD SEP PY 2012 VL 70 IS 9 BP 2238 EP 2248 DI 10.1016/j.joms.2012.06.180 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 999NG UT WOS:000308319900039 ER PT J AU Gros, DF Price, M Gros, KS Paul, LA McCauley, JL Ruggiero, KJ AF Gros, Daniel F. Price, Matthew Gros, Kirstin Stauffacher Paul, Lisa A. McCauley, Jenna L. Ruggiero, Kenneth J. TI Relations between Loss of Services and Psychiatric Symptoms in Urban and Non-Urban Settings following a Natural Disaster SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE PTSD; Depression; Worry; Preparedness; Disaster; Urban; Non-urban ID MENTAL-HEALTH PROBLEMS; PSYCHOMETRIC PROPERTIES; PTSD CHECKLIST; VICTIMS SPEAK; PREPAREDNESS; CONTEXT; IMPACT; MODEL AB Disasters have been associated with both acute and prolonged distress and significant post-disaster psychiatric symptoms. These outcomes may be further complicated by extended periods without vital services and supplies, such as electricity and drinking water. The present study investigated the relations between post-disaster loss of services and psychiatric symptoms in urban/non-urban disaster victims. Random-digit-dial methodology was used to interview 1,249 victims of Hurricane Ike, a strong storm that hit Galveston, TX in 2008. Findings demonstrated significant relations between loss of services and post-disaster symptoms of posttraumatic stress disorder (PTSD), depression, and worry. These relations varied by urban/non-urban settings; there were significant positive relations between loss of services and symptoms of depression in non-urban settings, but not in urban settings. Similarly, a stronger relation between loss of services and symptoms of PTSD also was demonstrated in non-urban compared to urban settings. Findings highlight the potential importance of pre-disaster preparation, post-disaster restoration of services, and post-disaster community support in post-disaster psychiatric outcomes, with a particular emphasis in non-urban settings. C1 [Gros, Daniel F.] Ralph H Johnson VAMC, Mental Hlth Serv 116, Charleston, SC 29401 USA. [Gros, Daniel F.; Price, Matthew; Gros, Kirstin Stauffacher; Paul, Lisa A.; McCauley, Jenna L.; Ruggiero, Kenneth J.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Gros, DF (reprint author), Ralph H Johnson VAMC, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. EM grosd@musc.edu FU NIMH NIH HHS [R01 MH081056, T32 MH018869, R34 MH077149] NR 29 TC 2 Z9 2 U1 3 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD SEP PY 2012 VL 34 IS 3 BP 343 EP 350 DI 10.1007/s10862-012-9290-9 PG 8 WC Psychology, Clinical SC Psychology GA 995GW UT WOS:000307997200005 PM 23105170 ER PT J AU Sinclair, SJ Bello, I Nyer, M Slavin-Mulford, J Stein, MB Renna, M Antonius, D Blais, MA AF Sinclair, Samuel Justin Bello, Iruma Nyer, Maren Slavin-Mulford, Jenelle Stein, Michelle B. Renna, Megan Antonius, Daniel Blais, Mark A. TI The Suicide (SPI) and Violence Potential Indices (VPI) from the Personality Assessment Inventory: A Preliminary Exploration of Validity in an Outpatient Psychiatric Sample SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Personality assessment inventory; Risk assessment; Suicide potential; Violence potential ID NATIONAL INTELLIGENCE; FORENSIC EVALUATION; PCL-R; ATTEMPTERS; PAI; IDEATION; SCALES; OFFENDERS; VETERANS; DISORDER AB Assessing risk of harm to self and others is an important component of psychological assessment, although methods for risk assessment vary considerably. The Personality Assessment Inventory (PAI) is frequently administered to evaluate general psychological functioning, as well as to provide information about suicide and violence risk. The purpose of this study was to evaluate the construct validity of the PAI Suicide (SPI) and Violence Potential (VPI) indices in a sample of 158 psychiatric outpatients referred for psychological and neuropsychological assessment within a large northeastern academic medical center between 2007 and 2011. Results generally supported the convergent and divergent validity of both SPI and VPI when evaluating groups with and without a history of suicide and violence risk, and effect sizes were moderate to large even after controlling for other covariates. SPI and VPI scores were also found to vary significantly across different psychiatric groups in ways that would be expected. Finally, we explored the relationship between SPI and VPI, and executive functioning impairment-a neuropsychological variable found to be associated with impulsive self and other-harming behaviors. Consistent with prior research, SPI and VPI were found to be significantly elevated in groups demonstrating executive dysfunction. The implications of these findings and specifically the utility of using SPI and VPI in the assessment of risk are discussed. C1 [Sinclair, Samuel Justin; Bello, Iruma; Nyer, Maren; Slavin-Mulford, Jenelle; Stein, Michelle B.; Renna, Megan; Blais, Mark A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sinclair, Samuel Justin; Bello, Iruma; Nyer, Maren; Slavin-Mulford, Jenelle; Stein, Michelle B.; Renna, Megan; Blais, Mark A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Antonius, Daniel] SUNY Buffalo, Buffalo, NY 14260 USA. [Antonius, Daniel] NYU, Sch Med, New York, NY USA. RP Sinclair, SJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM SJSinclair@Partners.org NR 47 TC 5 Z9 5 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD SEP PY 2012 VL 34 IS 3 BP 423 EP 431 DI 10.1007/s10862-012-9277-6 PG 9 WC Psychology, Clinical SC Psychology GA 995GW UT WOS:000307997200013 ER PT J AU Gutierrez, OM Katz, R Peralta, CA de Boer, IH Siscovick, D Wolf, M Roux, AD Kestenbaum, B Nettleton, JA Ix, JH AF Gutierrez, Orlando M. Katz, Ronit Peralta, Carmen A. de Boer, Ian H. Siscovick, David Wolf, Myles Roux, Ana Diez Kestenbaum, Bryan Nettleton, Jennifer A. Ix, Joachim H. TI Associations of Socioeconomic Status and Processed Food Intake With Serum Phosphorus Concentration in Community-Living Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) SO JOURNAL OF RENAL NUTRITION LA English DT Article ID NUTRITION EXAMINATION SURVEY; CHRONIC KIDNEY-DISEASE; 3RD NATIONAL-HEALTH; GROWTH-FACTOR 23; DIETARY PHOSPHATE; MORTALITY; MEN; HEMODIALYSIS; CALCIUM; QUESTIONNAIRE AB Objective: Higher serum phosphorus concentrations are associated with cardiovascular disease events and mortality. Low socioeconomic status is linked with higher serum phosphorus concentration, but the reasons are unclear. Poor individuals disproportionately consume inexpensive processed foods commonly enriched with phosphorus-based food preservatives. Accordingly, we hypothesized that excess intake of these foods accounts for a relationship between lower socioeconomic status and higher serum phosphorus concentration. Design: Cross-sectional analysis. Setting and Participants: We examined a random cohort of 2,664 participants with available phosphorus measurements in the Multi-Ethnic Study of Atherosclerosis, a community-based sample of individuals free of clinically apparent cardiovascular disease from across the United States. Predictor Variables: Socioeconomic status, the intake of foods commonly enriched with phosphorus-based food additives (processed meats, sodas), and frequency of fast-food consumption. Outcomes: Fasting morning serum phosphorus concentrations. C1 [Gutierrez, Orlando M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Gutierrez, Orlando M.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Katz, Ronit] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [de Boer, Ian H.; Siscovick, David; Kestenbaum, Bryan] Univ Washington, Dept Med, Seattle, WA USA. [de Boer, Ian H.; Siscovick, David; Kestenbaum, Bryan] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Wolf, Myles] Univ Miami, Dept Med, Miami, FL USA. [Roux, Ana Diez] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. RP Gutierrez, OM (reprint author), Univ Alabama Birmingham, Dept Med, ZRB 614,1530 3rd Ave S, Birmingham, AL 35294 USA. EM ogutierr@uab.edu FU associated ARRA supplement [R21HL091217-01A2S1]; National Institutes of Health [N01-HC-95169]; [K23DK081673]; [R21HL091217]; [N01-HC95159]; [N01-HC95160]; [N01-HC95161]; [N01-HC95162]; [N01-HC95163]; [N01-HC95164]; [N01-HC-95165] FX This study was supported by grants K23DK081673 (O.M.G.), R21HL091217 and an associated ARRA supplement R21HL091217-01A2S1 (JHI), and contracts N01-HC95159 through N01-HC-95165 and N01-HC-95169 from the National Institutes of Health. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 43 TC 9 Z9 9 U1 0 U2 30 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1051-2276 J9 J RENAL NUTR JI J. Renal Nutr. PD SEP PY 2012 VL 22 IS 5 BP 480 EP 489 DI 10.1053/j.jrn.2011.08.008 PG 10 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA 997YB UT WOS:000308202800006 PM 22217539 ER PT J AU McCoy, AB Wright, A Laxmisan, A Ottosen, MJ McCoy, JA Butten, D Sittig, DF AF McCoy, Allison B. Wright, Adam Laxmisan, Archana Ottosen, Madelene J. McCoy, Jacob A. Butten, David Sittig, Dean F. TI Development and evaluation of a crowdsourcing methodology for knowledge base construction: identifying relationships between clinical problems and medications SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ELECTRONIC HEALTH RECORDS; PROVIDER ORDER ENTRY; UNINTENDED CONSEQUENCES; DRUG KNOWLEDGE; SYSTEM; INFORMATION; INTERNET; QUALITY; ERRORS AB Objective We describe a novel, crowdsourcing method for generating a knowledge base of problem-medication pairs that takes advantage of manually asserted links between medications and problems. Methods Through iterative review, we developed metrics to estimate the appropriateness of manually entered problem-medication links for inclusion in a knowledge base that can be used to infer previously unasserted links between problems and medications. Results Clinicians manually linked 231 223 medications (55.30% of prescribed medications) to problems within the electronic health record, generating 41 203 distinct problem-medication pairs, although not all were accurate. We developed methods to evaluate the accuracy of the pairs, and after limiting the pairs to those meeting an estimated 95% appropriateness threshold, 11 166 pairs remained. The pairs in the knowledge base accounted for 183 127 total links asserted (76.47% of all links). Retrospective application of the knowledge base linked 68 316 medications not previously linked by a clinician to an indicated problem (36.53% of unlinked medications). Expert review of the combined knowledge base, including inferred and manually linked problem-medication pairs, found a sensitivity of 65.8% and a specificity of 97.9%. Conclusion Crowdsourcing is an effective, inexpensive method for generating a knowledge base of problememedication pairs that is automatically mapped to local terminologies, up-to-date, and reflective of local prescribing practices and trends. C1 [McCoy, Allison B.; Sittig, Dean F.] Univ Texas Hlth Sci Ctr Houston UTHealth, Sch Biomed Informat, Houston, TX 77030 USA. [McCoy, Allison B.; Ottosen, Madelene J.; Sittig, Dean F.] Univ Texas Houston, Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX USA. [Wright, Adam] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Laxmisan, Archana; Butten, David] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston VA Hlth Serv Res & Dev Ctr Excellence, Houston, TX 77030 USA. [Laxmisan, Archana; Butten, David] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [McCoy, Jacob A.] Univ Texas Med Sch Houston, Houston, TX USA. RP McCoy, AB (reprint author), Univ Texas Hlth Sci Ctr Houston UTHealth, Sch Biomed Informat, 6410 Fannin St,UTPB 1100, Houston, TX 77030 USA. EM allison.b.mccoy@uth.tmc.edu RI McCoy, Allison/I-1951-2013 OI McCoy, Allison/0000-0003-2292-9147 FU Office of the National Coordinator for Health Information Technology [10510592]; NCRR [3UL1RR024148] FX This project was supported in part by Grant No. 10510592 for Patient-Centered Cognitive Support under the Strategic Health IT Advanced Research Projects Program (SHARP) from the Office of the National Coordinator for Health Information Technology. The UTHealth Clinical Data Warehouse is supported by NCRR Grant 3UL1RR024148. NR 32 TC 18 Z9 18 U1 2 U2 30 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2012 VL 19 IS 5 BP 713 EP 718 DI 10.1136/amiajnl-2012-000852 PG 6 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 994MJ UT WOS:000307934600005 PM 22582202 ER PT J AU Schnipper, JL Gandhi, TK Wald, JS Grant, RW Poon, EG Volk, LA Businger, A Williams, DH Siteman, E Buckel, L Middleton, B AF Schnipper, Jeffrey L. Gandhi, Tejal K. Wald, Jonathan S. Grant, Richard W. Poon, Eric G. Volk, Lynn A. Businger, Alexandra Williams, Deborah H. Siteman, Elizabeth Buckel, Lauren Middleton, Blackford TI Effects of an online personal health record on medication accuracy and safety: a cluster-randomized trial SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ADVERSE DRUG EVENTS; PATIENT; IMPACT; CARE AB Objective To determine the effects of a personal health record (PHR)-linked medications module on medication accuracy and safety. Design From September 2005 to March 2007, we conducted an on-treatment sub-study within a cluster-randomized trial involving 11 primary care practices that used the same PHR. Intervention practices received access to a medications module prompting patients to review their documented medications and identify discrepancies, generating 'eJournals' that enabled rapid updating of medication lists during subsequent clinical visits. Measurements A sample of 267 patients who submitted medications eJournals was contacted by phone 3 weeks after an eligible visit and compared with a matched sample of 274 patients in control practices that received a different PHR-linked intervention. Two blinded physician adjudicators determined unexplained discrepancies between documented and patient-reported medication regimens. The primary outcome was proportion of medications per patient with unexplained discrepancies. Results Among 121 046 patients in eligible practices, 3979 participated in the main trial and 541 participated in the sub-study. The proportion of medications per patient with unexplained discrepancies was 42% in the intervention arm and 51% in the control arm (adjusted OR 0.71, 95% CI 0.54 to 0.94, p = 0.01). The number of unexplained discrepancies per patient with potential for severe harm was 0.03 in the intervention arm and 0.08 in the control arm (adjusted RR 0.31, 95% CI 0.10 to 0.92, p = 0.04). Conclusions When used, concordance between documented and patient-reported medication regimens and reduction in potentially harmful medication discrepancies can be improved with a PHR medication review tool linked to the provider's medical record. Trial registration number This study was registered at ClinicalTrials.gov (NCT00251875). C1 [Schnipper, Jeffrey L.; Gandhi, Tejal K.; Wald, Jonathan S.; Poon, Eric G.; Businger, Alexandra; Middleton, Blackford] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02120 USA. [Schnipper, Jeffrey L.; Gandhi, Tejal K.; Wald, Jonathan S.; Grant, Richard W.; Poon, Eric G.; Middleton, Blackford] Harvard Univ, Sch Med, Boston, MA USA. [Gandhi, Tejal K.] Partners HealthCare Syst, Patient Safety, Boston, MA USA. [Wald, Jonathan S.] RTI Int, Waltham, MA USA. [Grant, Richard W.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Grant, Richard W.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Volk, Lynn A.; Williams, Deborah H.; Siteman, Elizabeth; Buckel, Lauren] Partners HealthCare Syst, Clin & Qual Anal, Boston, MA USA. [Middleton, Blackford] Partners HealthCare Syst, Clin Informat Res & Dev, Boston, MA USA. RP Schnipper, JL (reprint author), Brigham & Womens Hosp, Div Gen Med, 1620 Tremont St, Boston, MA 02120 USA. EM jschnipper@partners.org OI Middleton, Blackford/0000-0002-1819-1234; Grant, Richard/0000-0002-6164-8025 FU AHRQ [R01-HS013660-02]; National Heart, Lung, and Blood Institute [1 K08 HL072806-01]; Sanofi Aventis FX This work was supported by AHRQ Grant R01-HS013660-02: Shared Online Health Records for Patient Safety and Quality. Dr Schnipper was also supported by a mentored career development award from the National Heart, Lung, and Blood Institute (1 K08 HL072806-01). AHRQ and NHLBI were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.; Drs Schnipper, Gandhi, and Poon are consultants to QuantiaMD, for whom they have created on-line educational materials for both providers and patients regarding patient safety, including medication safety. The findings of this study are not a part of those materials and the work with QuantiaMD in no way influenced the content of this manuscript. Dr Schnipper has received grant funding from Sanofi Aventis for an investigator-initiated study to design and evaluate an intensive discharge and follow-up intervention in patients with diabetes. The funder has no role in the design of the study, and the content is not relevant to the current manuscript. Dr Poon is a consultant to Becton, Dickinson, and Company, for whom he has presented at an internal educational forum. The findings of this study are not a part of those materials and the work with Becton, Dickinson, and Company in no way influenced the content of this manuscript. No other authors have any financial interests in the subject matter or materials discussed in the manuscript. NR 22 TC 29 Z9 29 U1 3 U2 12 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2012 VL 19 IS 5 BP 728 EP 734 DI 10.1136/amiajnl-2011-000723 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 994MJ UT WOS:000307934600007 PM 22556186 ER PT J AU Akins, CW AF Akins, Cary W. TI An issue of accountability SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Cardiac Surg, Boston, MA 02114 USA. RP Akins, CW (reprint author), Massachusetts Gen Hosp, Dept Cardiac Surg, White 503-55 Fruit St, Boston, MA 02114 USA. EM cakins@partners.org NR 2 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 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP 530 EP 531 DI 10.1016/j.jtcvs.2012.05.052 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200031 PM 22704286 ER PT J AU Agnihotri, A AF Agnihotri, Arvind TI 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: Executive summary SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 [Agnihotri, Arvind] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Agnihotri, Arvind] Harvard Univ, Sch Med, Boston, MA USA. RP Agnihotri, A (reprint author), Massachusetts Gen Hosp, Dept Surg, COX 642,55 Fruit St, Boston, MA 02114 USA. EM aagnihotri@partners.org NR 0 TC 7 Z9 8 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP 534 EP 537 DI 10.1016/j.jtcvs.2012.07.021 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200033 PM 22898502 ER PT J AU Heon, S Johnson, BE AF Heon, Stephanie Johnson, Bruce E. TI Adjuvant chemotherapy for surgically resected non-small cell lung cancer SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 3rd International Biennial Minimally Invasive Thoracic Surgery Summit CY OCT 07-08, 2011 CL Harvard Med Sch, Boston, MA HO Harvard Med Sch ID SYNCHRONOUS BRAIN METASTASES; VINORELBINE PLUS CISPLATIN; POOLED ANALYSIS; TRIAL; METAANALYSIS AB Despite surgical resection, patients with early-stage (I to IIIA) non-small cell lung cancer (NSCLC) are at considerable risk of recurrence and death from their lung cancer. In recent years, multiple, large, randomized trials assessing the efficacy of adjuvant chemotherapy for resected NSCLC have been reported. Three of 6 trials with 300 or more patients with early-stage NSCLC have demonstrated that adjuvant cisplatin-based chemotherapy can significantly improve 5-year survival in carefully selected patients with resected NSCLC. These benefits have been confirmed in a meta-analysis of modern cisplatin-based adjuvant trials. The most consistent benefit has been reported in patients with resected stage II and IIIA NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. Herein, we review the results of the major adjuvant chemotherapy trials and their implications for the treatment of patients with completely resected NSCLC. A future challenge will be to identify the subsets of patients who will derive the greatest benefit from adjuvant chemotherapy. Current trials are also under-way to define the role of novel targeted therapies, such as inhibitors of the epidermal growth factor receptor and monoclonal antibodies, in adjuvant treatment strategies. (J Thorac Cardiovasc Surg 2012; 144:S39-42) C1 [Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, 450 Brookline Ave,Dana Bldg 1234, Boston, MA 02215 USA. EM bejohnson@partners.org NR 19 TC 16 Z9 16 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP S39 EP S42 DI 10.1016/j.jtcvs.2012.03.039 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200019 PM 22502967 ER PT J AU Lagisetty, KH Gangadharan, SP AF Lagisetty, Kiran H. Gangadharan, Sidhu P. TI Tracheobronchoplasty for the treatment of tracheobronchomalacia SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 3rd International Biennial Minimally Invasive Thoracic Surgery Summit CY OCT 07-08, 2011 CL Harvard Med Sch, Boston, MA HO Harvard Med Sch ID AIRWAY STABILIZATION; COLLAPSE C1 [Lagisetty, Kiran H.; Gangadharan, Sidhu P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Thorac Surg & Intervent Pulmonol, Sch Med, Boston, MA 02215 USA. RP Gangadharan, SP (reprint author), Thorac Surg Beth Israel Deaconess Med Ctr, Chest Dis Ctr, 185 Pilgrim Rd W,DC 201, Boston, MA 02215 USA. EM sgangadh@bidmc.harvard.edu NR 7 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP S58 EP S59 DI 10.1016/j.jtcvs.2012.05.025 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200023 PM 22676978 ER PT J AU Wee, JO Morse, CR AF Wee, Jon O. Morse, Christopher R. TI Minimally invasive Ivor Lewis esophagectomy SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 3rd International Biennial Minimally Invasive Thoracic Surgery Summit CY OCT 07-08, 2011 CL Harvard Med Sch, Boston, MA HO Harvard Med Sch C1 [Wee, Jon O.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Morse, Christopher R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wee, JO (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jwee@partners.org NR 9 TC 6 Z9 6 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP S60 EP S62 DI 10.1016/j.jtcvs.2011.12.051 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200024 PM 22305551 ER PT J AU Gorrostieta, C Ombao, H Prado, R Patel, S Eskandar, E AF Gorrostieta, Cristina Ombao, Hernando Prado, Raquel Patel, Shaun Eskandar, Emad TI Exploring dependence between brain signals in a monkey during learning SO JOURNAL OF TIME SERIES ANALYSIS LA English DT Article DE Bivariate time series; cross-coherence; dual frequency coherence; coherence between amplitudes; Fourier transform; harmonizable processes; lagged coherence; Loeve spectrum; spectral analysis ID FUNCTIONAL CONNECTIVITY; OSCILLATIONS; COHERENCE AB Our goal is to investigate dependence between brain wave oscillations in the nucleus accumbens (NAc) and the hippocampus (Hc) regions of a macaque monkey during a learning association task. The classical approach to studying dependence in the spectral domain is via cross-coherence. It is computed for each frequency (or band) and identifies the frequency bands that drive the linear association between the components in a multi-variate time series. However, cross-coherence may not fully capture the complex dependence structure in brain signals such as local field potentials. In this article, we develop new tools for discovering associations between the theta (48 Hz) and gamma (3250 Hz) activities at both contemporaneous blocks and lagged time blocks. We propose a class of piecewise harmonizable processes under which we give a precise definition of these dependence measures and develop simple estimators in the case where the time-series data are recorded over several replicated trials. Our analysis clearly demonstrates strong dependence between the theta and gamma oscillations in the NAc and the Hc regions of a macaque monkey during learning. Moreover, we determined the lagged dependence that differentiate the correct responses (i.e., the monkey was able to identify the correct association) from the incorrect responses. C1 [Ombao, Hernando] Univ Calif Irvine, Dept Stat, Donald Bren Sch Informat & Comp Sci, Irvine, CA 92697 USA. [Gorrostieta, Cristina; Ombao, Hernando] Brown Univ, Providence, RI 02912 USA. [Prado, Raquel] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Patel, Shaun; Eskandar, Emad] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ombao, H (reprint author), Univ Calif Irvine, Dept Stat, Donald Bren Sch Informat & Comp Sci, Bren Hall 2019, Irvine, CA 92697 USA. EM hombao@uci.edu FU CONACyT Mexico; NSF DMS; NSF SSE; Conte Center FX This research was supported in part by CONACyT Mexico (Gorrostieta), NSF DMS (Ombao), NSF SSE (Ombao and Prado) and the Conte Center Grant (Eskandar and Ombao). NR 17 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0143-9782 J9 J TIME SER ANAL JI J. Time Ser. Anal. PD SEP PY 2012 VL 33 IS 5 SI SI BP 771 EP 778 DI 10.1111/j.1467-9892.2011.00767.x PG 8 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 996KB UT WOS:000308083800007 ER PT J AU Abularrage, CJ Patel, VI Conrad, MF Schneider, EB Cambria, RP Kwolek, CJ AF Abularrage, Christopher J. Patel, Virendra I. Conrad, Mark F. Schneider, Eric B. Cambria, Richard P. Kwolek, Christopher J. TI Improved results using Onyx glue for the treatment of persistent type 2 endoleak after endovascular aneurysm repair SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 25th Annual Meeting of the Eastern-Vascular-Society CY SEP 22-24, 2011 CL Washington, DC SP Eastern Vasc Soc ID ABDOMINAL AORTIC-ANEURYSM; II ENDOLEAKS; RANDOMIZED-TRIAL; COST-EFFECTIVENESS; OUTCOMES; EMBOLIZATION; EVAR AB Objective: Persistent type 2 (PT2) endoleaks (present >= 6 months) after endovascular aneurysm repair are associated with adverse outcomes, and selective secondary intervention is indicated in those patients with an expanding aneurysm sac. This study evaluated the outcomes of secondary intervention for PT2. Methods: From 1999 to 2007, 136 patients who underwent endovascular aneurysm repair developed PT2 and comprised the study cohort. Primary end points included PT2 resolution (secondary interventional success) and survival, and were evaluated using multiple logistic regression and Kaplan-Meier analyses, respectively. Results: Fifty-one patients underwent a total of 68 secondary interventions for PT2 with expanding aneurysm sacs with a median postsecondary interventional follow-up of 13.7 months. Secondary interventions included 20 inferior mesenteric artery coil embolizations, 17 Onyx glue embolizations, 11 aneurysm sac coil embolizations, 10 non-Onyx glue embolizations, 7 lumbar artery coil embolizations, 2 open lumbar ligations, and 1 graft explant. The overall secondary interventional success rate was 43% (29 of 68). Onyx glue embolization was associated with a greater success rate when used as the initial secondary intervention (odds ratio, 59.61; 95% confidence interval, 4.78-742.73; P < .001). There was no difference in success between the different techniques when multiple secondary interventions were required. Five-year survival was 72% +/- 0.08% and was unrelated to any of the secondary interventional techniques. Conclusions: Secondary intervention for PT2 is associated with success in less than half of all cases. Onyx glue embolization was associated with greater long-term success when used as the initial secondary intervention. (J Vasc Surg 2012;56:630-6.) C1 [Abularrage, Christopher J.; Patel, Virendra I.; Conrad, Mark F.; Cambria, Richard P.; Kwolek, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Abularrage, Christopher J.] Johns Hopkins Univ Hosp, Div Vasc Surg & Endovasc Therapy, Baltimore, MD 21287 USA. [Schneider, Eric B.] Johns Hopkins Univ Hosp, Ctr Surg Trials & Outcomes Res, Baltimore, MD 21287 USA. RP Kwolek, CJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, WAC440,15 Parkman St, Boston, MA 02114 USA. EM ckwolek@partners.org NR 24 TC 31 Z9 31 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2012 VL 56 IS 3 BP 630 EP 636 DI 10.1016/j.jvs.2012.02.038 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 996KM UT WOS:000308085500007 PM 22572009 ER PT J AU Jones, DW Stone, DH Conrad, MF Baribeau, YR Westbrook, BM Likosky, DS Cronenwett, JL Goodney, PP AF Jones, Douglas W. Stone, David H. Conrad, Mark F. Baribeau, Yvon R. Westbrook, Benjamin M. Likosky, Donald S. Cronenwett, Jack L. Goodney, Philip P. TI Regional use of combined carotid endarterectomy/coronary artery bypass graft and the effect of patient risk SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID NORTHERN NEW-ENGLAND; HOSPITAL VOLUME; CORONARY-BYPASS; STATEWIDE ANALYSIS; OUTCOMES; SURGERY; REVASCULARIZATION; DISEASE; STROKE; ASSOCIATION AB Introduction: Although carotid artery stenosis and coronary artery disease often coexist, many debate which patients are best served by combined concurrent revascularization (carotid endarterectomy [CEA]/coronary artery bypass graft [CABG]). We studied the use of CEA/CABG in New England and compared indications and outcomes, including stratification by risk, symptoms, and performing center. Methods: Using data from the Vascular Study Group of New England from 2003 to 2009, we studied all patients who underwent combined CEA/CABG across six centers in New England. Our main outcome measure was in-hospital stroke or death. We compared outcomes between all patients undergoing combined CEA/CABG to a baseline CEA risk group comprised of patients undergoing isolated CEA at non-CEA/CABG centers. Further, we compared in-hospital stroke and death rates between high and low neurologic risk patients, defining high neurologic risk patients as those who had at least one of the following clinical or anatomic features: (1) symptomatic carotid disease, (2) bilateral carotid stenosis >70%, (3) ipsilateral stenosis >70% and contralateral occlusion, or (4) ipsilateral or bilateral occlusion. Results: Overall, compared to patients undergoing isolated CEA at non-CEA/CABG centers (n = 1563), patients undergoing CEA/CABG (n = 109) were more likely to have diabetes (44% vs 29%; P = .001), creatinine >1.8 mg/dL (11% vs 5%; P = .007), and congestive heart failure (23% vs 10%; P < .001). Patients undergoing CEA/CABG were also more likely to take preoperative beta-blockers (94% vs 75%; P < .001) and less likely to take preoperative clopidogrel (7% vs 25%; P < .001). Patients undergoing CEA/CABG had higher rates of contralateral carotid occlusion (13% vs 5%; P = .001) and were more likely to undergo an urgent/emergent procedure (30% vs 15%; P < .001). The risk of complications was higher in CEA/CABG compared to isolated CEA, including increased risk of stroke (5.5% vs 1.2%; P < . 001), death (5.5% vs 0.3%; P < . 001), and return to the operating room for any reason (7.6% vs 1.2%; P < . 001). Of 109 patients undergoing CEA/CABG, 61 (56%) were low neurologic risk and 48 (44%) were high neurologic risk but showed no demonstrable difference in stroke (4.9% vs 6.3%; P = .76), death, (4.9 vs 6.3%; P = .76), or return to the operating room (10.2% vs 4.3%; P = .25). Conclusions: Although practice patterns in the use of CEA/CABG vary across our region, the risk of complications with CEA/CABG remains significantly higher than in isolated CEA. Future work to improve patient selection in CEA/CABG is needed to improve perioperative results with combined coronary and carotid revascularization. (J Vasc Surg 2012;56:668-76.) C1 [Jones, Douglas W.] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Surg, New York, NY USA. [Stone, David H.; Cronenwett, Jack L.; Goodney, Philip P.] Dartmouth Hitchcock Med Ctr, Dept Vasc Surg, Lebanon, NH 03766 USA. [Conrad, Mark F.] Massachusetts Gen Hosp, Dept Vasc Surg, Boston, MA 02114 USA. [Baribeau, Yvon R.; Westbrook, Benjamin M.] Cathol Med Ctr, Dept Cardiothorac Surg, Manchester, Lancs, England. [Likosky, Donald S.] Dartmouth Med Sch, Dartmouth Inst Hlth Policy & Clin Practice, Hannover, Germany. [Goodney, Philip P.] VA Med Ctr, White River Junct Outcomes Grp, White River Jct, VT USA. RP Jones, DW (reprint author), Weill Cornell Med Ctr, Dept Surg, 525 E 68th St, New York, NY 10065 USA. EM doj9016@gmail.com FU NHLBI NIH HHS [1K08HL05676-01, K08 HL105676]; NIMHD NIH HHS [L32 MD006323] NR 31 TC 2 Z9 2 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2012 VL 56 IS 3 BP 668 EP 676 DI 10.1016/j.jvs.2012.02.028 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 996KM UT WOS:000308085500013 PM 22560308 ER PT J AU Finzi, A Pacheco, B Xiang, SH Pancera, M Herschhorn, A Wang, LP Zeng, X Desormeaux, A Kwong, PD Sodroski, J AF Finzi, Andres Pacheco, Beatriz Xiang, Shi-Hua Pancera, Marie Herschhorn, Alon Wang, Liping Zeng, Xing Desormeaux, Anik Kwong, Peter D. Sodroski, Joseph TI Lineage-Specific Differences between Human and Simian Immunodeficiency Virus Regulation of gp120 Trimer Association and CD4 Binding SO JOURNAL OF VIROLOGY LA English DT Article ID ENVELOPE GLYCOPROTEIN TRIMERS; INFECTIOUS MOLECULAR CLONES; T-LYMPHOTROPIC RETROVIRUS; HIV-1 GP120; AIDS PATIENTS; INNER DOMAIN; HTLV-III; TRANSMEMBRANE GLYCOPROTEIN; CD4-BOUND CONFORMATION; MACROPHAGE TROPISM AB Metastable conformations of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SW) must be maintained in the unliganded state of the envelope glycoprotein trimer. Binding of gp120 to the primary receptor, CD4, triggers the transition to an open conformation of the trimer, promoting interaction with the CCR5 chemokine receptor and ultimately leading to gp41-mediated virus-cell membrane fusion and entry. Topological layers in the gp120 inner domain contribute to gp120-trimer association in the unliganded state and to CD4 binding. Here we describe similarities and differences between HIV-1 and SIVmac gp120. In both viruses, the gp120 N/C termini and the inner domain beta-sandwich and layer 2 support the noncovalent association of gp120 with the envelope glycoprotein trimer. Layer 1 of the SIVmac gp120 inner domain contributes more to trimer association than the corresponding region of HIV-1 gp120. On the other hand, layer 1 plays an important role in stabilizing the CD4-bound conformation of HIV-1 but not SIVmac gp120 and thus contributes to HIV-1 binding to CD4. In SIVmac, CD4 binding is instead enhanced by tryptophan 375, which fills the Phe 43 cavity of gp120. Activation of SIVmac by soluble CD4 is dependent on tryptophan 375 and on layer 1 residues that determine a tight association of gp120 with the trimer. Distinct biological requirements for CD4 usage have resulted in lineage-specific differences in the HIV-1 and SIV gp120 structures that modulate trimer association and CD4 binding. C1 [Finzi, Andres; Pacheco, Beatriz; Xiang, Shi-Hua; Herschhorn, Alon; Wang, Liping; Zeng, Xing; Sodroski, Joseph] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Med, Div Aids, Dept Microbiol & Immunobiol, Boston, MA USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Pancera, Marie; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Sodroski, Joseph] MIT & Harvard, Massachusetts Gen Hosp, Ragon Inst, Charlestown, MA USA. [Desormeaux, Anik] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada. RP Sodroski, J (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU VRC; NIAID; National Institutes of Health [AI24755, GM56550, AI67854]; International AIDS Vaccine Initiative; William F. McCarty-Cooper; amfAR Mathilde Krim Fellowship in Basic Biomedical Research [107963-49-RKVA, 108092-50-RKVA]; Canada Foundation for Innovation Program [29866]; CIHR [257792] FX This work was supported by intramural funding by the VRC, NIAID, and by grants from the National Institutes of Health (AI24755, GM56550, and AI67854), by the International AIDS Vaccine Initiative, by the late William F. McCarty-Cooper (to J.S.), and by an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (phase I, 107963-49-RKVA; phase II, 108092-50-RKVA), by a Canada Foundation for Innovation Program Leader grant (no. 29866), and by a CIHR operating grant, 257792, to A.F. NR 80 TC 15 Z9 15 U1 0 U2 7 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 PY 2012 VL 86 IS 17 BP 8974 EP 8986 DI 10.1128/JVI.01076-12 PG 13 WC Virology SC Virology GA 990JW UT WOS:000307627800005 PM 22696649 ER PT J AU Finer, G Schnaper, HW Kanwar, YS Liang, XY Lin, HY Hayashida, T AF Finer, Gal Schnaper, H. William Kanwar, Yashpal S. Liang, Xiaoyan Lin, Herbert Y. Hayashida, Tomoko TI Divergent roles of Smad3 and PI3-kinase in murine adriamycin nephropathy indicate distinct mechanisms of proteinuria and fibrogenesis SO KIDNEY INTERNATIONAL LA English DT Article DE cell signaling; fibrosis; glomerulosclerosis; podocyte; TGF-beta ID COLLAGEN-I EXPRESSION; HUMAN MESANGIAL CELLS; KIDNEY-DISEASE; DIABETIC-NEPHROPATHY; SIGNAL-TRANSDUCTION; BETA; KINASE; MICE; PI3K-GAMMA; PODOCYTES AB Multiple transforming growth factor (TGF)-beta-induced fibrogenic signals have been described in vitro. To evaluate mechanisms in vivo, we used an adriamycin nephropathy model in 129x1/Svj mice that display massive proteinuria by days 5 to 7 and pathological findings similar to human focal segmental glomerulosclerosis by day 14. TGF-beta mRNA expression increased after day 7 along with nuclear translocation of the TGF-beta receptor-specific transcription factor Smad3. Inhibiting TGF-beta prevented both pathological changes and type-I collagen and fibronectin mRNA expression, but proteinuria persisted. Renal Akt was phosphorylated in adriamycin-treated mice, suggesting PI3-kinase activation. Expression of mRNA for the p110 gamma isozyme of PI3-kinase was specifically increased and p110 gamma colocalized with nephrin by immunohistochemistry early in disease. Nephrin levels subsequently decreased. Inhibition of p110 gamma by AS605240 preserved nephrin expression and prevented proteinuria. In cultured podocytes, adriannycin stimulated p110 gamma expression. AS605240, but not a TGF-beta receptor kinase inhibitor, prevented adriamycin-induced cytoskeletal disorganization and apoptosis, supporting a role for p110 gamma in podocyte injury. AS605240, at a dose that decreased proteinuria, prevented renal collagen mRNA expression in vivo but did not affect TGF-beta-stimulated collagen induction in vitro. Thus, PI3-kinase p110 gamma mediates initial podocyte injury and proteinuria, both of which precede TGF-beta-mediated glomerular scarring. C1 [Finer, Gal; Schnaper, H. William; Liang, Xiaoyan; Hayashida, Tomoko] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. [Finer, Gal; Schnaper, H. William; Liang, Xiaoyan; Hayashida, Tomoko] Childrens Mem Hosp, Div Kidney Dis, Chicago, IL 60614 USA. [Finer, Gal; Schnaper, H. William; Liang, Xiaoyan; Hayashida, Tomoko] Childrens Mem Hosp, Childrens Mem Res Ctr, Chicago, IL 60614 USA. [Kanwar, Yashpal S.] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. [Lin, Herbert Y.] Massachusetts Gen Hosp, Program Membrane Biol, Ctr Syst Biol, Div Nephrol,Dept Med, Boston, MA 02114 USA. [Lin, Herbert Y.] Harvard Univ, Sch Med, Boston, MA USA. RP Hayashida, T (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Pediat, 310 Super St,Morton 4-685, Chicago, IL 60611 USA. EM hayashida@northwestern.edu RI Finer, Gal/C-7858-2015; OI Hayashida, Tomoko/0000-0002-4160-7859 FU Amgen Fellowship; NCI [CCSG P30 CA060553]; [R01-DK049362]; [R01-DK075663]; [R01-DK060635]; [R01-DK069533]; [R01-DK071837] FX This study was supported in part by grants R01-DK049362, R01-DK075663 (HWS), R01-DK060635 (YSK), and R01-DK069533 and R01-DK071837 (HYL). GF was the recipient of an Amgen Fellowship. The Cell Imaging Facility and Mouse Histology and Phenotyping Laboratory of the Northwestern University are supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. We thank members of the Schnaper lab for helpful discussions. NR 40 TC 14 Z9 14 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2012 VL 82 IS 5 BP 525 EP 536 DI 10.1038/ki.2012.139 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 992TS UT WOS:000307803200006 PM 22534961 ER PT J AU Skupien, J Warram, JH Smiles, AM Niewczas, MA Gohda, T Pezzolesi, MG Cantarovich, D Stanton, R Krolewski, AS AF Skupien, Jan Warram, James H. Smiles, Adam M. Niewczas, Monika A. Gohda, Tomohito Pezzolesi, Marcus G. Cantarovich, Diego Stanton, Robert Krolewski, Andrzej S. TI The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease SO KIDNEY INTERNATIONAL LA English DT Article DE creatinine; diabetes mellitus ID GLOMERULAR-FILTRATION-RATE; KIDNEY-FUNCTION DECLINE; OLDER-ADULTS; SERUM CREATININE; NEPHROPATHY; PROGRESSION; AGE; FAILURE; DYSFUNCTION; ERRORS AB The risk of end-stage renal disease (ESRD) remains high in patients with type 1 diabetes and proteinuria; however, little is known about the rate of decline in their renal function. To help determine this, we enrolled patients with type 1 diabetes and proteinuria whose estimated glomerular filtration rate (eGFR) was normal (equal to or above 60 ml/min per 1.73 m(2)). Using a minimum of five serial measurements of serum creatinine for 161 patients, we determined individual trajectories of eGFR change and the occurrence of ESRD during 5-18 years of follow-up. The rates were linear for 110 patients, for 24 the nonlinear rate was mild enough to satisfy a linear model, and the rates were clearly nonlinear for only 27 patients. Overall, in more than one-third of patients, the eGFR decline was less than 3.5 ml/min per 1.73m(2) per year and the lifetime risk of ESRD could be considered negligible. In the remainder of patients, eGFR declined with widely different slopes and ESRD developed within 2 to 18 years. Based on up to 5 years observation, when renal function was within the normal range, the estimates of early eGFR slope predicted the risk of ESRD during subsequent follow-up better than the baseline clinical characteristics of glycated hemoglobin, blood pressure, or the albumin to creatinine ratio. Thus, the early slope of eGFR decline in patients with type 1 diabetes and proteinuria can be used to predict the risk of ESRD. C1 [Skupien, Jan; Warram, James H.; Smiles, Adam M.; Niewczas, Monika A.; Gohda, Tomohito; Pezzolesi, Marcus G.; Stanton, Robert; Krolewski, Andrzej S.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Skupien, Jan; Warram, James H.; Smiles, Adam M.; Niewczas, Monika A.; Gohda, Tomohito; Pezzolesi, Marcus G.; Stanton, Robert; Krolewski, Andrzej S.] Joslin Diabet Ctr, Clin Div, Boston, MA 02215 USA. [Skupien, Jan; Niewczas, Monika A.; Gohda, Tomohito; Pezzolesi, Marcus G.; Krolewski, Andrzej S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gohda, Tomohito] Juntendo Univ, Sch Med, Dept Internal Med, Div Nephrol, Tokyo 113, Japan. [Cantarovich, Diego] Nantes Univ Hosp, Inst Transplantat Urol & Nephrol, Nantes, France. [Stanton, Robert] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA USA. RP Krolewski, AS (reprint author), Brigham & Womens Hosp, Joslin Diabet Ctr, Dept Med, Sect Genet & Epidemiol, 1 Joslin Pl, Boston, MA 02215 USA. EM andrzej.krolewski@joslin.harvard.edu FU JDRF research grant [1-2008-1018]; NIH grant [DK41526]; JDRF fellowship grant [3-2009-397] FX This project was supported through JDRF research grant 1-2008-1018 (ASK), NIH grant DK41526 (ASK), and a JDRF fellowship grant 3-2009-397 (JS). We thank TH Hostetter and WE Mitch for their valuable comments. NR 31 TC 38 Z9 39 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2012 VL 82 IS 5 BP 589 EP 597 DI 10.1038/ki.2012.189 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 992TS UT WOS:000307803200012 PM 22622493 ER PT J AU Ponikau, JU Hamilos, DL Barreto, A Cecil, J Jones, SW Manthei, SE Collins, J AF Ponikau, Jens U. Hamilos, Daniel L. Barreto, Angelique Cecil, John Jones, Stephen W. Manthei, Scott E. Collins, Jason TI An exploratory trial of Cyclamen europaeum extract for acute rhinosinusitis SO LARYNGOSCOPE LA English DT Article DE Cyclamen europaeum; acute rhinosinusitis; sinus opacification; computed tomography scans; total symptom scores; Level of Evidence: 1b ID ACUTE SINUSITIS; ACUTE BRONCHITIS; DOUBLE-BLIND; MANAGEMENT; SINUFORTE; GUIDELINES; EFFICACY; CHILDREN; ADULTS AB Objectives/Hypothesis: An exploratory US trial in patients with acute rhinosinusitis was conducted to evaluate the efficacy and safety of Cyclamen europeaum extract, a product marketed in Europe that causes reflex nasal discharge and subsequent decongestion. Study Design: Prospective, randomized, placebo-controlled, double-blind, and parallel group. Methods: Outpatients (n = 29) with cardinal symptoms of acute rhinosinusitis and both endoscopic and radiographic (computed tomography [CT] scan) evidence at 25 US centers were randomized to receive intranasal, lyophilized, reconstituted Cyclamen europeaum extract (Cyclamen) or placebo spray for 7 days. Primary outcomes were reduction in percent sinus opacification on CT scans and reduction in PM predose instantaneous total symptom scores measured on a six-point scale. Secondary outcomes included other measures of symptom score change and endoscopic signs of mucopurulence and inflammation. Results: Cyclamen treatment significantly reduced sinus opacification compared with placebo treatment (P < .045). Although Cyclamen treatment reduced total symptom scores from baseline more than placebo treatment (-2.4 vs. -1.4), there were no significant treatment group differences (P = .312). Cyclamen treatment was well tolerated. Conclusions: Cyclamen treatment significantly reduced sinus opacification in patients with acute rhinosinusitis. Further exploration of Cyclamen treatment in larger patient populations is warranted. C1 [Ponikau, Jens U.] SUNY Buffalo, Dept Otolaryngol, Buffalo, NY 14260 USA. [Hamilos, Daniel L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barreto, Angelique] Mem Clin Res, Oklahoma City, OK USA. [Cecil, John] Four Rivers Clin Res, Paducah, KY USA. [Jones, Stephen W.] Carolina Res Ctr Inc, Shelby, NC USA. [Manthei, Scott E.] Nevada Eye & Ear, Henderson, NV USA. [Collins, Jason] Dey Pharma LP, Napa, CA USA. RP Ponikau, JU (reprint author), SUNY Buffalo, Dept Clin Otorhinolaryngol, Buffalo, NY 14260 USA. EM jponikau@buffalo.edu FU Dey Pharma, LP; Napa, California; Hartington Pharmaceutical, Barcelona, Spain FX The study sponsors were Dey Pharma, LP, Napa, California, and Hartington Pharmaceutical, Barcelona, Spain. Employees of Dey were involved in the study design and in the collection and analysis of data. Jens U. Ponikau, MD, is a consultant for Dey Pharma and Hartington Pharmaceutical. Angelique Barreto, MD, John Cecil, MD, Stephen W. Jones, MD, and Scott E. Manthei, DO, were clinical trial investigators for the clinical trial described in this article. Dr. Collins was an employee of Dey Pharma at the time of the trial. Authors were assisted by a professional medical writer, Elizabeth Field, PhD, of Field Advantage Medical Communication, LLC, in the preparation of the manuscript, funded by Hartington Pharmaceutical. NR 30 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2012 VL 122 IS 9 BP 1887 EP 1892 DI 10.1002/lary.23366 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 994VT UT WOS:000307962900002 PM 22674586 ER PT J AU Heaton, JT Kobler, JB Ottensmeyer, MP Lopez-Guerra, G Karajanagi, SS Burns, JA Zeitels, SM AF Heaton, James T. Kobler, James B. Ottensmeyer, Mark P. Lopez-Guerra, Gerardo Karajanagi, Sandeep S. Burns, James A. Zeitels, Steven M. TI Modification and testing of a pneumatic dispensing device for controlled delivery of injectable materials SO LARYNGOSCOPE LA English DT Article DE Dysphonia; larynx; phonosurgery; vocal fold injection ID VOCAL FOLD; AUTOGENOUS FAT; INJECTION AB Objectives/Hypothesis: Vocal fold (VF) injections of viscous materials are typically performed using hand-operated syringes or injection guns; however, these methods can be imprecise due to accumulation of pressure, effort-related tremor, and poor feedback regarding injection volume and rate. Study Design: Apparatus development with laboratory bench-top and animal model testing. Methods: A foot pedal-triggered device for dispensing viscous materials was modified by adding a linear transducer and display for monitoring dispensed volume. In bench tests, bovine VFs were injected with fluids/materials of different viscosities (saline, glycerol, hydrogel, and liposuctioned fat) through narrow-bore needles using a range of driving pressures and air pulse durations. The device was further evaluated in >50 in vivo VF injection experiments. Results: Device function was repeatable, with high correlations (typically R2 > 0.98) between the readout and direct measures of volume, even for small volumes (<5 mu L/pulse). Foot pedal control enabled surgeons to make steady, accurate injections into ferret and dog VFs during phonosurgery, and, because the dispenser released all driving pressure between pulses, there were no instances of clog-related overinjection when the obstruction cleared. Conclusions: This VF injection system shows promise for development to enhance human phonosurgery by increasing injection control and precision. Laryngoscope, 2012 C1 [Heaton, James T.; Kobler, James B.; Lopez-Guerra, Gerardo; Karajanagi, Sandeep S.; Burns, James A.; Zeitels, Steven M.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Heaton, James T.; Kobler, James B.; Lopez-Guerra, Gerardo; Karajanagi, Sandeep S.; Burns, James A.; Zeitels, Steven M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Ottensmeyer, Mark P.] Massachusetts Gen Hosp, Dept Imaging, Simulat Grp, Cambridge, MA USA. [Karajanagi, Sandeep S.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Heaton, JT (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM james.heaton@mgh.harvard.edu OI Lopez-Guerra, Gerardo/0000-0003-0305-4680 FU Eugene B. Casey Foundation; Voice Health Institute FX This work was supported by the Eugene B. Casey Foundation and Voice Health Institute. NR 17 TC 2 Z9 2 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2012 VL 122 IS 9 BP 2023 EP 2028 DI 10.1002/lary.23468 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 994VT UT WOS:000307962900022 PM 22865123 ER PT J AU Stone, RM Fischer, T Paquette, R Schiller, G Schiffer, CA Ehninger, G Cortes, J Kantarjian, HM DeAngelo, DJ Huntsman-Labed, A Dutreix, C del Corral, A Giles, F AF Stone, R. M. Fischer, T. Paquette, R. Schiller, G. Schiffer, C. A. Ehninger, G. Cortes, J. Kantarjian, H. M. DeAngelo, D. J. Huntsman-Labed, A. Dutreix, C. del Corral, A. Giles, F. TI Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia SO LEUKEMIA LA English DT Article DE FMS-like tyrosine kinase 3 receptor; acute myeloid leukemia; midostaurin; PKC412; newly diagnosed ID ACUTE MYELOGENOUS LEUKEMIA; RISK MYELODYSPLASTIC SYNDROME; INTERNAL TANDEM DUPLICATIONS; POOR-PROGNOSIS; MUTANT FLT3; WILD-TYPE; GROUP-B; MUTATIONS; PKC412; CYTOGENETICS AB This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261). C1 [Stone, R. M.; DeAngelo, D. J.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Fischer, T.] Otto von Guericke Univ, Med Ctr, Dept Hematol Oncol, Magdeburg, Germany. [Paquette, R.; Schiller, G.] UCLA Med Ctr, Los Angeles, CA USA. [Schiffer, C. A.] Karmanos Canc Inst, Detroit, MI USA. [Ehninger, G.] Tech Univ Dresden, D-01062 Dresden, Germany. [Cortes, J.; Kantarjian, H. M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Huntsman-Labed, A.; Dutreix, C.] Novartis Pharma AG, Basel, Switzerland. [del Corral, A.] Novartis Oncol, E Hanover, NJ USA. [Giles, F.] Natl Univ Ireland, HRB Clin Res Facil, Galway, Ireland. [Giles, F.] Trinity Coll Dublin, Dublin, Ireland. RP Stone, RM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM rstone@partners.org FU Novartis Pharmaceuticals Corporation FX The authors acknowledge the study coordinators, nurses and physicians who contributed to this study and the patients and their families for their participation. Susie Crowley provided secretarial assistance. Sandra Harris and Erinn Goldman of Articulate Science, LLC, provided medical writing assistance. This study was sponsored by Novartis Pharmaceuticals Corporation. NR 21 TC 85 Z9 92 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2012 VL 26 IS 9 BP 2061 EP 2068 DI 10.1038/leu.2012.115 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 999VK UT WOS:000308342900011 PM 22627678 ER PT J AU Blackburn, JS Liu, S Raiser, DM Martinez, SA Feng, H Meeker, ND Gentry, J Neuberg, D Look, AT Ramaswamy, S Bernards, A Trede, NS Langenau, DM AF Blackburn, J. S. Liu, S. Raiser, D. M. Martinez, S. A. Feng, H. Meeker, N. D. Gentry, J. Neuberg, D. Look, A. T. Ramaswamy, S. Bernards, A. Trede, N. S. Langenau, D. M. TI Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency SO LEUKEMIA LA English DT Article DE thymocyte; relapse; Myc; zebrafish; self-renewal ID TRANSGENIC ZEBRAFISH; INITIATING CELLS; C-MYC; PATHWAY SIGNATURES; STEM-CELL; GENE; TRANSFORMATION; EXPRESSION; MUTATIONS; ONCOGENE AB NOTCH1 pathway activation contributes to the pathogenesis of over 60% of T-cell acute lymphoblastic leukemia (T-ALL). While Notch is thought to exert the majority of its effects through transcriptional activation of Myc, it also likely has independent roles in T-ALL malignancy. Here, we utilized a zebrafish transgenic model of T-ALL, where Notch does not induce Myc transcription, to identify a novel Notch gene expression signature that is also found in human T-ALL and is regulated independently of Myc. Cross-species microarray comparisons between zebrafish and mammalian disease identified a common T-ALL gene signature, suggesting that conserved genetic pathways underlie T-ALL development. Functionally, Notch expression induced a significant expansion of pre-leukemic clones; however, a majority of these clones were not fully transformed and could not induce leukemia when transplanted into recipient animals. Limiting-dilution cell transplantation revealed that Notch signaling does not increase the overall frequency of leukemia-propagating cells (LPCs), either alone or in collaboration with Myc. Taken together, these data indicate that a primary role of Notch signaling in T-ALL is to expand a population of pre-malignant thymocytes, of which a subset acquire the necessary mutations to become fully transformed LPCs. C1 [Blackburn, J. S.; Liu, S.; Martinez, S. A.; Langenau, D. M.] Massachusetts Gen Hosp, Dept Pathol, Mol Pathol Unit, Boston, MA 02114 USA. [Blackburn, J. S.; Liu, S.; Martinez, S. A.; Gentry, J.; Ramaswamy, S.; Bernards, A.; Langenau, D. M.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Blackburn, J. S.; Liu, S.; Raiser, D. M.; Martinez, S. A.; Ramaswamy, S.; Langenau, D. M.] Harvard Stem Cell Inst, Boston, MA USA. [Neuberg, D.] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Meeker, N. D.; Trede, N. S.] Univ Utah, Dept Pediat, Huntsman Canc Inst, Salt Lake City, UT USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Dept Pathol, 149 13th St,6102, Charlestown, MA 02129 USA. EM dlangenau@partners.org OI Feng, Hui/0000-0003-1318-821X FU NIH [5T32CA09126-26, K01AR05562190]; American Cancer Society Research Scholar Grant; Leukemia Research Foundation; Alex Lemonade Stand Foundation; Harvard Stem Cell Institute FX We thank Dr Ravi Mylvaganam for expert advice and assistance with cell sorting, Eric Stone and Marcellino Pena for excellent animal husbandry, and Dr Finola Moore and Tommy Jones help with data interpretation and critical review of the manuscript. JSB is supported by NIH 5T32CA09126-26. DML is supported by an American Cancer Society Research Scholar Grant, the Leukemia Research Foundation, the Alex Lemonade Stand Foundation, the Harvard Stem Cell Institute, and NIH K01AR05562190. NR 48 TC 23 Z9 25 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD SEP PY 2012 VL 26 IS 9 BP 2069 EP 2078 DI 10.1038/leu.2012.116 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 999VK UT WOS:000308342900012 PM 22538478 ER PT J AU Wolf, JL Siegel, D Goldschmidt, H Hazell, K Bourquelot, PM Bengoudifa, BR Matous, J Vij, R de Magalhaes-Silverman, M Abonour, R Anderson, KC Lonial, S AF Wolf, Jeffrey L. Siegel, David Goldschmidt, Hartmut Hazell, Katharine Bourquelot, Priscille M. Bengoudifa, Bourras R. Matous, Jeffrey Vij, Ravi de Magalhaes-Silverman, Margarida Abonour, Rafat Anderson, Kenneth C. Lonial, Sagar TI Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma SO LEUKEMIA & LYMPHOMA LA English DT Letter ID WORKING GROUP; BORTEZOMIB; LBH589; LENALIDOMIDE; PROTEASOME; SURVIVAL; CRITERIA C1 [Lonial, Sagar] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Wolf, Jeffrey L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Siegel, David] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Goldschmidt, Hartmut] Heidelberg Univ, Heidelberg, Germany. [Hazell, Katharine; Bourquelot, Priscille M.; Bengoudifa, Bourras R.] Novartis Pharma AG, Basel, Switzerland. [Matous, Jeffrey] Colorado Blood Canc Inst, Denver, CO USA. [Vij, Ravi] Washington Univ, St Louis, MO USA. [de Magalhaes-Silverman, Margarida] Univ Iowa, Iowa City, IA USA. [Abonour, Rafat] Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. [Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lonial, S (reprint author), Emory Univ, Winship Canc Inst, 1365 Clifton Rd,Bldg C,Room 4004, Atlanta, GA 30322 USA. EM sloni01@emory.edu NR 15 TC 55 Z9 55 U1 2 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD SEP PY 2012 VL 53 IS 9 BP 1820 EP 1823 DI 10.3109/10428194.2012.661175 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 985WP UT WOS:000307301500032 PM 22288662 ER PT J AU Stone, M AF Stone, Martha TI Ballerina: Sex, Scandal, and Suffering Behind the Symbol of Perfection SO LIBRARY JOURNAL LA English DT Book Review C1 [Stone, Martha] Massachusetts Gen Hosp Lib, Boston, MA USA. RP Stone, M (reprint author), Massachusetts Gen Hosp Lib, Boston, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU REED BUSINESS INFORMATION PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD SEP 1 PY 2012 VL 137 IS 14 BP 102 EP 102 PG 1 WC Information Science & Library Science SC Information Science & Library Science GA 001IY UT WOS:000308455300103 ER PT J AU Emile, JF Brahimi, S Coindre, JM Bringuier, PP Monges, G Samb, P Doucet, L Hostein, I Landi, B Buisine, MP Neuville, A Bouche, O Cervera, P Pretet, JL Tisserand, J Gauthier, A Le Cesne, A Sabourin, JC Scoazec, JY Bonvalot, S Corless, CL Heinrich, MC Blay, JY Aegerter, P AF Emile, J. F. Brahimi, S. Coindre, J. M. Bringuier, P. P. Monges, G. Samb, P. Doucet, L. Hostein, I. Landi, B. Buisine, M. P. Neuville, A. Bouche, O. Cervera, P. Pretet, J. L. Tisserand, J. Gauthier, A. Le Cesne, A. Sabourin, J. C. Scoazec, J. Y. Bonvalot, S. Corless, C. L. Heinrich, M. C. Blay, J. Y. Aegerter, P. TI Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs SO MEDICAL ONCOLOGY LA English DT Article DE Epidemiology; Sarcoma; Gastrointestinal tumor; Tyrosine kinase receptor ID GASTROINTESTINAL STROMAL TUMORS; C-KIT; PROGNOSIS; IMATINIB; SURVIVAL; TRIAL AB Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma. Most of the data available on GISTs derive from retrospective studies of patients referred to oncology centers. The MolecGIST study sought to determine and correlate clinicopathological and molecular characteristics of GISTs. Tumor samples and clinical records were prospectively obtained and reviewed for patients diagnosed in France during a 24-month period. Five hundred and ninety-six patients were included, of whom 10% had synchronous metastases. GISTs originated from the stomach, small bowel or other site in 56.4, 30.2 and 13.4% of cases, respectively. The main prognostic markers, tumor localization, size and mitotic index were not independent variables (P<0.0001). Mutational status was determined in 492 (83%) patients, and 138 different mutations were identified. KIT and PDGFRA mutations were detected in 348 (71%) and 74 (15%) patients, respectively, contrasting with 82.8 and 2.1% in patients with advanced GIST (MetaGIST) (P<0.0001). Further comparison of localized GISTs in the MolecGIST cohort with advanced GISTs from previous clinical trials showed that the mutations of PDGFRA exon18 (D842V and others) as well as KIT exon11 substitutions (W557R and V559D) were more likely to be seen in patients with localized GISTs (odds ratio 7.9, 3.1, 2.7 and 2.5, respectively), while KIT exon 9 502_503dup and KIT exon 11 557_559del were more frequent in metastatic GISTs (odds ratio of 0.3 and 0.5, respectively). These data suggest that KIT and PDGFRA mutations and standardized mitotic count deserve to be investigated to evaluate the relapse risk of GISTs. C1 [Emile, J. F.] Ambroise Pare Hosp, APHP, Dept Pathol, Boulogne, France. [Emile, J. F.; Brahimi, S.; Tisserand, J.; Gauthier, A.] Versailles SQY Univ, Hop Ambroise Pare, Serv Pathol, EA4340, F-92104 Boulogne, France. [Coindre, J. M.; Hostein, I.] Bergonie Inst, Dept Pathol, Bordeaux, France. [Bringuier, P. P.; Scoazec, J. Y.] E Herriot Hosp, HCL, Lyon, France. [Monges, G.] Inst J Paoli I Calmettes, Dept Pathol, F-13009 Marseille, France. [Samb, P.; Aegerter, P.] Versailles SQY Univ, Ambroise Pare Hosp, APHP, EA2506,Publ Hlth Dept, Boulogne, France. [Doucet, L.] CHU Brest, Dept Pathol, F-29285 Brest, France. [Landi, B.] Gorges Pompidou European Hosp, APHP, Paris, France. [Buisine, M. P.] CHU Lille, Biochem & Mol Biol Dept, F-59037 Lille, France. [Neuville, A.] CHU Strasbourg, Dept Pathol, F-67000 Strasbourg, France. [Bouche, O.] CHU Reims, Reims, France. [Cervera, P.] St Antoine Hosp, APHP, Dept Pathol, Paris, France. [Pretet, J. L.] Univ Franche Comte, CHU Besancon, F-25030 Besancon, France. [Le Cesne, A.; Bonvalot, S.] Inst Gustave Roussy, Villejuif, France. [Sabourin, J. C.] CHU Rouen, Dept Pathol, Rouen, France. [Corless, C. L.; Heinrich, M. C.] Portland VA Med Ctr, OHSU Knight Canc Inst, Portland, OR USA. [Blay, J. Y.] Ctr Leon Berard, F-69373 Lyon, France. RP Emile, JF (reprint author), Ambroise Pare Hosp, APHP, Dept Pathol, Boulogne, France. EM Jean-francois.emile@apr.aphp.fr RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X FU Ligue contre le Cancer, Institut National du Cancer (INCa); Novartis Pharma FX MolecGIST study was supported by grants from Ligue contre le Cancer, Institut National du Cancer (INCa) and unrestricted grants from Novartis Pharma. The authors would like to thank patients who participated to MolecGIST study and their families, as well as all the pathologists, oncologists, surgeons, gastroenterologists, physicians and clinical research assistants who participated to the collection of the data. The list is available on http://www.gist-france.org/remerciements.html. NR 30 TC 32 Z9 33 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 J9 MED ONCOL JI Med. Oncol. PD SEP PY 2012 VL 29 IS 3 BP 1765 EP 1772 DI 10.1007/s12032-011-0074-y PG 8 WC Oncology SC Oncology GA 994WE UT WOS:000307964100053 PM 21953054 ER PT J AU Wiernik, PH Sun, ZX Gundacker, H Dewald, G Slovak, ML Paietta, E Kim, HT Appelbaum, FR Cassileth, PA Tallman, MS AF Wiernik, Peter H. Sun, Zhuoxin Gundacker, Holly Dewald, Gordon Slovak, Marilyn L. Paietta, Elisabeth Kim, Haesook T. Appelbaum, Frederick R. Cassileth, Peter A. Tallman, Martin S. TI Prognostic implications of additional chromosome abnormalities among patients with de novo acute promyelocytic leukemia with t(15;17) SO MEDICAL ONCOLOGY LA English DT Article DE Acute promyelocytic leukemia; Karyotype; All-trans retinoic acid; t(15;17) ID ACUTE MYELOID-LEUKEMIA; TRANS-RETINOIC ACID; SECONDARY CYTOGENETIC CHANGES; IMATINIB MESYLATE; POOR-PROGNOSIS; ABERRATIONS; IMPACT; CHEMOTHERAPY; WORKSHOP; PROTOCOL AB This retrospective study performed by the Eastern Cooperative Oncology Group and the Southwest Oncology Group enrolled 140 acute promyelocytic leukemia (APL) patients with t(15;17) to determine the influence of additional karyotypic abnormalities on treatment outcome. Karyotypes were centrally reviewed by both study groups. The complete response rate after induction for patients with t(15;17) treated with chemotherapy, or all-trans retinoic acid (ATRA) as induction therapy was not affected by additional cytogenetic aberrations. Disease-free (DFS) and overall survival (OS) were unaffected by additional cytogenetic abnormalities if treatment was chemotherapy without ATRA. Patients with t(15; 17) only, treated with ATRA with or without chemotherapy, had an improved DFS (P = 0.06) and a better OS (P = 0.01) compared with ATRA-treated patients with additional cytogenetic abnormalities. Patients with APL and t(15;17) alone are significantly more sensitive to treatment with ATRA than are patients with t(15;17) and additional cytogenetic abnormalities. C1 [Wiernik, Peter H.] Roosevelt Hosp Ctr, Roosevelt Ctr, Continuum Canc Ctr New York St Lukes, New York, NY 10019 USA. [Wiernik, Peter H.; Sun, Zhuoxin; Dewald, Gordon; Paietta, Elisabeth; Kim, Haesook T.; Cassileth, Peter A.; Tallman, Martin S.] Eastern Cooperat Oncol Grp, Brookline, MA USA. [Sun, Zhuoxin; Kim, Haesook T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gundacker, Holly; Slovak, Marilyn L.; Appelbaum, Frederick R.] SW Oncol Grp, San Antonio, TX USA. [Gundacker, Holly; Appelbaum, Frederick R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Dewald, Gordon] Mayo Clin, Rochester, MN USA. [Slovak, Marilyn L.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Cassileth, Peter A.] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Wiernik, PH (reprint author), Roosevelt Hosp Ctr, Roosevelt Ctr, Continuum Canc Ctr New York St Lukes, Ste 11C-02,1000 10th Ave, New York, NY 10019 USA. EM pwiernik@chpnet.org FU National Cancer Institute, National Institutes of Health [CA21115, ECOG, CA91151, CA32102]; SWOG Leukemia; Cytogenetics Program FX Supported in part by DHHS grants from the National Cancer Institute, National Institutes of Health grants CA21115, ECOG; CA91151 (PHW), and CA32102, SWOG Leukemia, and Cytogenetics Program. Presented in part at the national meeting of the American Society of Hematology, 2001. NR 26 TC 9 Z9 9 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 J9 MED ONCOL JI Med. Oncol. PD SEP PY 2012 VL 29 IS 3 BP 2095 EP 2101 DI 10.1007/s12032-012-0251-7 PG 7 WC Oncology SC Oncology GA 994WE UT WOS:000307964100102 PM 22729365 ER PT J AU Lipinski, B Pretorius, E Oberholzer, HM Van der Spuy, WJ AF Lipinski, Boguslaw Pretorius, Etheresia Oberholzer, Hester Magdalena Van der Spuy, Wendy Jeanette TI Iron enhances generation of fibrin fibers in human blood: Implications for pathogenesis of stroke SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE iron; fibrin fibers; plasma; stroke; hydroxyl radicals ID OXIDATIVE STRESS; ARTERIAL THROMBOSIS; INTRAVASCULAR HEMOLYSIS; HYDROXYL RADICALS; ISCHEMIC-STROKE; HEMOGLOBIN; DISEASES; OXYGEN; ATHEROSCLEROSIS; THROMBOLYSIS AB Stroke is associated with the intracerebral formation of fibrin clots which may lead to irreversible brain damage. Thrombolytic therapies employ a variety of natural and/or recombinant plasminogen activators to initiate fibrinolytic degradation of cerebral thrombi. However, such therapies when installed beyond 4- to 6-h window, may fail to achieve the expected outcome. This is due to the hydroxyl radical-induced modification of fibrin(ogen) molecules rendering them refractory to fibrinolytic degradation, but no cause of the increased free radical generation in stroke was offered. Here, we show by means of electron microscopy that iron ions added to human blood dramatically enhances fibrin fibers formation with thrombin, and significantly delays fibrinolysis during spontaneous clotting of native blood. Iron ions caused the appearance dense matted fibrin deposits, similar, if not identical, to those observed in plasma of patients with stroke. These results may explain a known relationship between thrombotic diseases and the increased body concentrations of free iron and/or hemoglobin derivatives. We conclude that any action resulting in the inhibition of hemostatic abnormalities, as well as in the reduction of body free iron and scavenging of hydroxyl radicals (e.g., by polyphenols) can potentially prevent pathological reactions associated with consequences of stroke. Microsc. Res. Tech. 75:11851190, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Pretorius, Etheresia] Univ Pretoria, Dept Physiol, Fac Hlth Sci, ZA-0007 Arcadia, South Africa. [Lipinski, Boguslaw] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Oberholzer, Hester Magdalena; Van der Spuy, Wendy Jeanette] Univ Pretoria, Dept Anat, Fac Hlth Sci, ZA-0007 Arcadia, South Africa. RP Pretorius, E (reprint author), Univ Pretoria, Dept Physiol, Fac Hlth Sci, Private Bag X323, ZA-0007 Arcadia, South Africa. EM resia.pretorius@up.ac.za RI van der Spuy, Wendy/M-7480-2013; OI van der Spuy, Wendy/0000-0003-1892-073X; Pretorius, Etheresia/0000-0002-9108-2384 NR 51 TC 21 Z9 21 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD SEP PY 2012 VL 75 IS 9 BP 1185 EP 1190 DI 10.1002/jemt.22047 PG 6 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 994VL UT WOS:000307961900006 PM 22488824 ER PT J AU Nelson, P Lucisano, MP Da Silva, RAB Da Silva, RS Serra, MC Gerlach, RF Neto, FCR Carneiro, ZA Zamarioli, A Morse, L Battaglino, R AF Nelson-Filho, Paulo Lucisano, Marilia Pacifico Bezerra Da Silva, Raquel Assed Da Silva, Roberto Santana Serra, Monica Campos Gerlach, Raquel Fernanda Rehder Neto, Francisco Carlos Carneiro, Zumira Aparecida Zamarioli, Ariane Morse, Leslie Battaglino, Ricardo TI Systemically alendronate was incorporated into dental tissues but did not cause morphological or mechanical changes in rats teeth SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE sodium alendronate; bone mineral density; mineralized dental tissues ID 1-HYDROXYETHYLIDENE-1,1-BISPHOSPHONATE HEBP; 1-BISPHOSPHONATE HEBP; ENAMEL FORMATION; SECRETORY AMELOBLASTS; SUCCESSIVE INJECTIONS; CLINICAL-EFFICACY; INCISORS; BISPHOSPHONATES; OSTEOPOROSIS; CHILDHOOD AB This study evaluated the effect of the systemic use of sodium alendronate in rats in vivo. Forty-five Wistar rats aged 36 to 42 days and weighing 200 to 230 g were randomly assigned to a control group (n = 20), which received distilled water, and an experimental group (n = 25), which received 2 weekly doses of 1 mg/kg of chemically pure sodium alendronate. The animals were killed after 60 days of treatment. The tibias were removed for analysis of bone mineral density by dual-energy X-ray absorptiometry (DXA). Then, the maxillary incisors were extracted for analysis of the mineralized dental tissues using fluorescence spectroscopy (FS), scanning electron microscopy (SEM), bright field microscopy (BFM), and cross-sectional microhardness (CSMH) testing. DXA and CSMH data were subjected to statistical analysis by Kruskal-Wallis test (5% significance level). The experimental group presented higher bone mineral density than the control group by DXA. FS analysis revealed presence of alendronate in the mineralized dental tissues of the specimens of the experimental group. Significant morphological differences were not found by SEM and BFM. Enamel and dentin (100 and 300 mu m from the dentinoenamel junction) CSMH data did not show significant difference between the control and experimental groups. Based on the obtained results, we conclude that while alendronate increased the bone mineral density and was incorporated into the mineralized dental tissues it did not cause significant alterations in the morphology and microhardness of rat incisor enamel and dentin. Microsc. Res. Tech. 75:12651271, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Nelson-Filho, Paulo; Lucisano, Marilia Pacifico; Bezerra Da Silva, Raquel Assed; Rehder Neto, Francisco Carlos] Univ Sao Paulo, Sch Dent Ribeirao Preto, Dept Pediat Clin Prevent & Community Dent, BR-14040904 Ribeirao Preto, SP, Brazil. [Da Silva, Roberto Santana; Carneiro, Zumira Aparecida] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Chem & Phys, BR-14040904 Ribeirao Preto, SP, Brazil. [Serra, Monica Campos] Univ Sao Paulo, Sch Dent Ribeirao Preto, Dept Restorat Dent, BR-14040904 Ribeirao Preto, SP, Brazil. [Gerlach, Raquel Fernanda] Univ Sao Paulo, Sch Dent Ribeirao Preto, Dept Morphol Stomatol & Physiol, BR-14040904 Ribeirao Preto, SP, Brazil. [Zamarioli, Ariane] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biomech Med & Rehabil Locomotor Syst, BR-14040904 Ribeirao Preto, SP, Brazil. [Morse, Leslie] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Battaglino, Ricardo] Forsyth Inst, Dept Skeletal Biol, Cambridge, MA USA. RP Nelson, P (reprint author), Univ Sao Paulo, Fac Odontol Ribeirao Preto, Dept Clin Infantil Odontol Prevent & Social, Ave Cafe S-N, BR-14040904 Ribeirao Preto, SP, Brazil. EM nelson@forp.usp.br RI Zamarioli, Ariane/K-7001-2012; Serra, Monica/E-5549-2014; battaglino, ricardo/D-2892-2015; Morse, Leslie/C-9442-2015; Bezerra da Silva, Raquel /M-8655-2016; Nelson-Filho, Paulo/L-1272-2016 OI Zamarioli, Ariane/0000-0002-7939-0528; Morse, Leslie/0000-0002-7426-6341; Bezerra da Silva, Raquel /0000-0002-0230-1347; Nelson-Filho, Paulo/0000-0001-8802-6480 FU Brazilian Ministry of Health's Federal Agency for Support and Evaluation of Graduate Education (CAPES) FX Contract grant sponsor: Brazilian Ministry of Health's Federal Agency for Support and Evaluation of Graduate Education (CAPES) NR 43 TC 4 Z9 4 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-910X EI 1097-0029 J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD SEP PY 2012 VL 75 IS 9 BP 1265 EP 1271 DI 10.1002/jemt.22059 PG 7 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 994VL UT WOS:000307961900017 PM 22508272 ER PT J AU Bergen, SE O'Dushlaine, CT Ripke, S Lee, PH Ruderfer, DM Akterin, S Moran, JL Chambert, KD Handsaker, RE Backlund, L Osby, U McCarroll, S Landen, M Scolnick, EM Magnusson, PKE Lichtenstein, P Hultman, CM Purcell, SM Sklar, P Sullivan, PF AF Bergen, S. E. O'Dushlaine, C. T. Ripke, S. Lee, P. H. Ruderfer, D. M. Akterin, S. Moran, J. L. Chambert, K. D. Handsaker, R. E. Backlund, L. Osby, U. McCarroll, S. Landen, M. Scolnick, E. M. Magnusson, P. K. E. Lichtenstein, P. Hultman, C. M. Purcell, S. M. Sklar, P. Sullivan, P. F. TI Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE schizophrenia; bipolar disorder; genetic; genome-wide association; major histocompatibility complex; copy number variation ID COMMON VARIANTS; COPY NUMBER; CONFERRING RISK; INCREASE RISK; 16P11.2; DELETIONS; AUTISM; GENES; REARRANGEMENTS; MICRODELETION AB Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P = 4.54 x 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P = 0.003, BD: P = 0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P = 0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P = 0.0035) and 22q11 deletions (P = 0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD. C1 [Bergen, S. E.; O'Dushlaine, C. T.; Lee, P. H.; Ruderfer, D. M.; Purcell, S. M.; Sklar, P.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Bergen, S. E.; O'Dushlaine, C. T.; Ripke, S.; Lee, P. H.; Ruderfer, D. M.; Moran, J. L.; Chambert, K. D.; Handsaker, R. E.; McCarroll, S.; Scolnick, E. M.; Purcell, S. M.; Sklar, P.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [O'Dushlaine, C. T.; Ripke, S.; Lee, P. H.; Ruderfer, D. M.; Purcell, S. M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Akterin, S.; Landen, M.; Magnusson, P. K. E.; Lichtenstein, P.; Hultman, C. M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Handsaker, R. E.; McCarroll, S.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Backlund, L.; Osby, U.] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Landen, M.] Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden. [Purcell, S. M.; Sklar, P.] Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY USA. [Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Bergen, SE (reprint author), Broad Inst, 7 Cambridge Ctr,6055H, Cambridge, MA 02142 USA. EM sbergen@gmail.com RI Bergen, Sarah/I-8313-2012; Ruderfer, Douglas/M-5795-2016; Magnusson, Patrik/C-4458-2017; OI Ruderfer, Douglas/0000-0002-2365-386X; Bergen, Sarah/0000-0002-5888-0034; Backlund, Lena/0000-0001-9399-5024; lichtenstein, paul/0000-0003-3037-5287; Moran, Jennifer/0000-0002-5664-4716 FU Stanley Center for Psychiatric Research; Stanley Medical Research Institute; NIMH [MH077139]; Karolinska Institutet, Karolinska University Hospital; Swedish Research Council; Swedish County Council; Soderstrom Konigska Foundation FX We are deeply grateful for the participation of all subjects contributing to this research, and to the collection team that worked to recruit them: Emma Flordal-Thelander, Ann-Britt Holmgren, Marie Hallin, Marie Lundin, Ann-Kristin Sundberg, Christina Pettersson, Radja Satgunanthan-Dawoud, Sonja Hassellund, Malin Radstrom, Birgitta Ohlander, Leila Nyren, Isabelle Kizling, Louise Frisen, Inger Rohmer, Catharina Lavebratt, Malin Karn, Martina Wennberg and Agneta Carsward-Kjellin. We would also like to thank Professor Martin Schalling for facilitating collection of many subjects with BD. Funding support was provided by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute, NIMH MH077139 (PFS), the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, ALF grant from Swedish County Council and Soderstrom Konigska Foundation. NR 52 TC 93 Z9 93 U1 2 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2012 VL 17 IS 9 BP 880 EP 886 DI 10.1038/mp.2012.73 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 996DI UT WOS:000308063900005 PM 22688191 ER PT J AU Klawiter, EC Xu, JQ Naismith, RT Benzinger, TLS Shimony, JS Lancia, S Snyder, AZ Trinkaus, K Song, SK Cross, AH AF Klawiter, Eric C. Xu, Junqian Naismith, Robert T. Benzinger, Tammie L. S. Shimony, Joshua S. Lancia, Samantha Snyder, Abraham Z. Trinkaus, Kathryn Song, Sheng-Kwei Cross, Anne H. TI Increased radial diffusivity in spinal cord lesions in neuromyelitis optica compared with multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Diffusion tensor imaging; neuromyelitis optica (NMO); multiple sclerosis (MS); spinal cord; MRI ID APPEARING WHITE-MATTER; TENSOR MRI; DIAGNOSTIC-CRITERIA; PRIMATE BRAIN; DAMAGE; MOUSE; DEMYELINATION; PATHOGENESIS; ANISOTROPY; PATHOLOGY AB Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology. Objective: Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions. Methods: Subjects greater than or equal to 12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS and 10 healthy controls were included. Results: Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared with healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared with controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and fractional anisotropy within white matter regions upstream and downstream of T2 lesions were different from controls in each disease. Conclusions: Higher radial diffusivity within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared with MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions and may be a surrogate of anterograde and retrograde degeneration. C1 [Klawiter, Eric C.; Xu, Junqian; Naismith, Robert T.; Lancia, Samantha; Snyder, Abraham Z.; Cross, Anne H.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Klawiter, Eric C.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Benzinger, Tammie L. S.; Shimony, Joshua S.; Snyder, Abraham Z.; Song, Sheng-Kwei] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Trinkaus, Kathryn] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. RP Klawiter, EC (reprint author), 15 Parkman St,WACC 835, Boston, MA 02114 USA. EM eklawiter@partners.org RI Xu, Junqian/D-2247-2009; Benzinger, Tammie/L-6104-2013 OI Xu, Junqian/0000-0001-8438-2066; FU National Institutes of Health [P01 NS059560, R01 NS047592, UL1RR024992, K23NS052430-01A1, CO6 RR020092, RR024992]; National Multiple Sclerosis Society [RG 4009]; American Academy of Neurology Foundation; National MS Society [FG 1782]; Bracco/American Roentgen Ray Society; Manny and Rosalyn Rosenthal-Dr John L Trotter Chair in Neuroimmunology of Barnes-Jewish Hospital Foundation; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1RR024992]; NIH Roadmap for Medical Research NIH; Bayer Healthcare; Teva Neuroscience; Acorda Therapeutics; Biogen-Idec; EMD Serono; Genzyme Corp; Renovo; Avid; Biomedical Systems; ICON Medical Imaging; Hoffman-La Roche; Coronado Biosciences; Sanofi-Aventis FX This work was supported by the National Institutes of Health (P01 NS059560 to AHC, R01 NS047592 to S-KS) and the National Multiple Sclerosis Society (RG 4009 to AHC). ECK was supported by an American Academy of Neurology Foundation Clinical Research Training Fellowship and the National Institutes of Health (UL1RR024992). JX was supported by a National MS Society Postdoctoral Fellowship (FG 1782). RTN was supported by the National Institutes of Health (K23NS052430-01A1). TB was supported by a Bracco/American Roentgen Ray Society Scholar Award. AHC was supported in part by the Manny and Rosalyn Rosenthal-Dr John L Trotter Chair in Neuroimmunology of Barnes-Jewish Hospital Foundation. An institutional Clinical and Translational Science Award (UL1RR024992) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research NIH, provided funding for the Neuroclinical Research Unit where research subjects were examined. This research was also supported in part by NIH grants CO6 RR020092 and RR024992 (Washington University Institute of Clinical and Translational Sciences - Brain, Behavioral and Performance Unit).; ECK has received consulting fees and/or speaking honoraria from Bayer Healthcare and Teva Neuroscience. RTN has received consulting fees and/or speaking honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen-Idec, EMD Serono, Genzyme Corp and Teva Neuroscience. TLSB has received research grants or consulting fees from Renovo, Avid, Biomedical Systems and ICON Medical Imaging. JSS, JX, SL, AZS, KT and S-KS have nothing to disclose. AHC has received consulting fees from Teva Neuroscience, Biogen-Idec, Bayer Healthcare, Hoffman-La Roche, Coronado Biosciences and Sanofi-Aventis. NR 38 TC 19 Z9 20 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2012 VL 18 IS 9 BP 1259 EP 1268 DI 10.1177/1352458512436593 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 997BD UT WOS:000308138200050 PM 22354742 ER PT J AU Miller, JC Brown, BD Shay, T Gautier, EL Jojic, V Cohain, A Pandey, G Leboeuf, M Elpek, KG Helft, J Hashimoto, D Chow, A Price, J Greter, M Bogunovic, M Bellemare-Pelletier, A Frenette, PS Randolph, GJ Turley, SJ Merad, M AF Miller, Jennifer C. Brown, Brian D. Shay, Tal Gautier, Emmanuel L. Jojic, Vladimir Cohain, Ariella Pandey, Gaurav Leboeuf, Marylene Elpek, Kutlu G. Helft, Julie Hashimoto, Daigo Chow, Andrew Price, Jeremy Greter, Melanie Bogunovic, Milena Bellemare-Pelletier, Angelique Frenette, Paul S. Randolph, Gwendalyn J. Turley, Shannon J. Merad, Miriam CA Immunological Genome Consortium TI Deciphering the transcriptional network of the dendritic cell lineage SO NATURE IMMUNOLOGY LA English DT Article ID IN-VIVO; LYMPH-NODES; IMMUNE REGULATION; BONE-MARROW; FLT3 LIGAND; RECEPTOR; EXPRESSION; MICE; HETEROGENEITY; HEMATOPOIESIS AB Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens. C1 [Miller, Jennifer C.; Brown, Brian D.; Gautier, Emmanuel L.; Leboeuf, Marylene; Helft, Julie; Hashimoto, Daigo; Chow, Andrew; Price, Jeremy; Greter, Melanie; Bogunovic, Milena; Randolph, Gwendalyn J.; Merad, Miriam] Mt Sinai Sch Med, Inst Immunol, New York, NY 10029 USA. [Miller, Jennifer C.; Leboeuf, Marylene; Helft, Julie; Hashimoto, Daigo; Chow, Andrew; Price, Jeremy; Greter, Melanie; Bogunovic, Milena; Merad, Miriam] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY USA. [Brown, Brian D.; Cohain, Ariella; Pandey, Gaurav] Mt Sinai Sch Med, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY USA. [Shay, Tal] Broad Inst, Cambridge, MA USA. [Gautier, Emmanuel L.; Randolph, Gwendalyn J.] Mt Sinai Sch Med, Dept Regenerat Biol, New York, NY USA. [Gautier, Emmanuel L.; Randolph, Gwendalyn J.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Jojic, Vladimir; Greter, Melanie] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Elpek, Kutlu G.; Bellemare-Pelletier, Angelique; Turley, Shannon J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chow, Andrew; Frenette, Paul S.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Merad, M (reprint author), Mt Sinai Sch Med, Inst Immunol, New York, NY 10029 USA. EM miriam.merad@mssm.edu RI Frenette, Paul/J-8272-2012; Price, Jeremy /G-1612-2013; Hashimoto, Daigo/O-1013-2013; Shay, Tal/J-4028-2016; Gautier, Emmanuel L./E-2259-2017; OI Price, Jeremy /0000-0003-0491-3176; Hashimoto, Daigo/0000-0001-9489-9704; Shay, Tal/0000-0003-0755-1350; Gautier, Emmanuel L./0000-0003-2976-7566; Malhotra, Deepali/0000-0002-8215-7639; Gazit, Roi/0000-0002-0548-2147; Kim, Charles/0000-0001-6474-8227 FU National Institute of Allergy and Infectious Diseases of the US National Institutes of Health [R24 AI072073, AI080884, HL086899, JDRF172010770, DP2DK083052-01, DK074500, AI045757, HL69438, DK056638, HL097819, HL097700, U54CA149145] FX We thank colleagues of the ImmGen Project, especially the technical team, including M. Painter, J. Ericson and S. Davis, for contributions; C. Benoist for contributions to the design and writing of the manuscript; and eBioscience and Affymetrix for support of the ImmGen Project. Supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R24 AI072073 to the ImmGen Project (led by C. Benoist); AI080884 and HL086899 to M.M.; JDRF172010770 and DP2DK083052-01 to B.D.B.; DK074500 and AI045757 to S.J.T.; HL69438, DK056638, HL097819 and HL097700 to P.S.F.; and U54CA149145 to V.J.). NR 58 TC 288 Z9 290 U1 5 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD SEP PY 2012 VL 13 IS 9 BP 888 EP 899 DI 10.1038/ni.2370 PG 12 WC Immunology SC Immunology GA 993MK UT WOS:000307863600018 PM 22797772 ER PT J AU Haining, WN AF Haining, W. Nicholas TI Thinking inside the box: how T cell inhibitory receptors signal SO NATURE MEDICINE LA English DT Editorial Material ID TIM-3; PD-1; INFECTION; AUTOIMMUNE; ACTIVATION; EXHAUSTION; EXPRESSION; TOLERANCE; REGULATOR; RESPONSES C1 [Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Haining, W. Nicholas] Broad Inst Harvard & MIT, Boston, MA USA. RP Haining, WN (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM nicholas_haining@dfci.harvard.edu FU NIAID NIH HHS [R01 AI091493] NR 16 TC 3 Z9 4 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2012 VL 18 IS 9 BP 1338 EP 1339 DI 10.1038/nm.2921 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 001PJ UT WOS:000308472300024 PM 22961161 ER PT J AU Rangachari, M Zhu, C Sakuishi, K Xiao, S Karman, J Chen, A Angin, M Wakeham, A Greenfield, EA Sobel, RA Okada, H McKinnon, PJ Mak, TW Addo, MM Anderson, AC Kuchroo, VK AF Rangachari, Manu Zhu, Chen Sakuishi, Kaori Xiao, Sheng Karman, Jozsef Chen, Andrew Angin, Mathieu Wakeham, Andrew Greenfield, Edward A. Sobel, Raymond A. Okada, Hitoshi McKinnon, Peter J. Mak, Tak W. Addo, Marylyn M. Anderson, Ana C. Kuchroo, Vijay K. TI Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion SO NATURE MEDICINE LA English DT Article ID CHRONIC VIRAL-INFECTION; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MULTIPLE INHIBITORY RECEPTORS; TH1/TH2 CELLS; UP-REGULATION; TIM-3; ACTIVATION; EXPRESSION; PROTEIN; VIRUS AB T cell immunoglobulin and mucin domain-containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (T(H)1) cells from galectin-9-mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigen-specific CD4(+) T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3(hi), interferon-gamma (IFN-gamma)(lo)CD4(+) cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3(+) T cells from mouse tumors and HIV-1-infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3-dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers. C1 [Rangachari, Manu; Zhu, Chen; Sakuishi, Kaori; Xiao, Sheng; Karman, Jozsef; Chen, Andrew; Anderson, Ana C.; Kuchroo, Vijay K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Angin, Mathieu; Addo, Marylyn M.] Ragon Inst MGH MIT & Harvard, Charlestown, MA USA. [Wakeham, Andrew; Okada, Hitoshi; Mak, Tak W.] Princess Margaret Hosp, Campbell Family Breast Canc Res Inst, Toronto, ON M4X 1K9, Canada. [Greenfield, Edward A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sobel, Raymond A.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Okada, Hitoshi] Ontario Canc Inst, Div Signaling Biol, Toronto, ON M4X 1K9, Canada. [Okada, Hitoshi] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [McKinnon, Peter J.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. RP Kuchroo, VK (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. EM vkuchroo@rics.bwh.harvard.edu OI Angin, Mathieu/0000-0002-6867-4680 FU Multiple Sclerosis Society of Canada (MSSOC); Canadian Institutes of Health Research (CIHR); EMD Serono, Canada; Multiple Sclerosis Scientific Research Foundation; Sankyo Foundation of Life Science; US National Institutes of Health [NS045937, AI073748, NS038037, K01DK090105]; Ragon Institute of MGH; MIT; Harvard; American Cancer Society; Harvard University Center for AIDS Research [P30 AI060354]; MSSOC FX We thank D. Kozoriz, D. Lee, J. Sullivan and M. King for technical assistance; J. Zhang (Brigham and Women's Hospital, Boston) for reagents; B.H. Waksman for valuable guidance and discussion; and B. Walker for critical reading of the manuscript. M. R. was previously supported by Fellowships from the Multiple Sclerosis Society of Canada (MSSOC) and the Canadian Institutes of Health Research (CIHR) and is currently supported by the EMD Serono, Canada and an MS Research and Training Network Transitional Career Development Award from the MSSOC and the Multiple Sclerosis Scientific Research Foundation. K.S. holds a Fellowship from the Sankyo Foundation of Life Science. These studies were funded by grants from the US National Institutes of Health to V.K.K. (NS045937, AI073748 and NS038037) and S.X. (K01DK090105), the Ragon Institute of MGH, MIT and Harvard (V.K.K., C.Z. and M.M.A.), the American Cancer Society (A.C.A.) and the Harvard University Center for AIDS Research (M.M.A.; P30 AI060354). NR 46 TC 61 Z9 65 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2012 VL 18 IS 9 BP 1394 EP + DI 10.1038/nm.2871 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 001PJ UT WOS:000308472300035 PM 22863785 ER PT J AU Bergwitz, C AF Bergwitz, Clemens TI Dietary phosphate modifies lifespan in Drosophila SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE CKD; drosophila; hyperphosphatemia; lifespan; phosphate metabolism ID CHRONIC KIDNEY-DISEASE; SACCHAROMYCES-CEREVISIAE; INORGANIC POLYPHOSPHATE; VASCULAR CALCIFICATION; HYPERTROPHIC CHONDROCYTES; ARTERY CALCIFICATION; PARATHYROID-HORMONE; MINERAL METABOLISM; INDUCED APOPTOSIS; PTH SECRETION AB Phosphate is required for many important cellular processes and having too little phosphate (hypophosphatemia) or too much (hyperphosphatemia) can cause disease and reduce lifespan in humans. Drosophila melanogaster has been a powerful tool to discover evolutionarily well-conserved nutrient-sensing pathways that are important for the lifespan extension. We have established Drosophila as a model system for studying the effects of dietary phosphate during development and adult life. When absorption of phosphate is blocked by sevelamer or cellular uptake is inhibited by phosphonoformic acid (PFA), larval development is delayed in a phosphate-dependent fashion. Conversely, restriction of phosphate absorption with sevelamer or reduced cellular uptake after treatment with PFA is able to extend the adult lifespan of otherwise normal flies. Gaining an understanding of the specific pathways and mediators that regulate cellular and organismic phosphate levels might ultimately lead to the development of improved dietary and therapeutic approaches to the treatment of human disorders of hypo- and hyperphosphatemia. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM cbergwitz@partners.org FU NIH [K08 DK08361] FX Funding was provided by NIH K08 DK08361. This work would not have been possible without the contributions of Mark Wee, Charles DeRobertis, Sumi Sinha, Joanne Huang, Helen H. Chen and Lawrence B. Mensah. NR 67 TC 5 Z9 5 U1 0 U2 32 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD SEP PY 2012 VL 27 IS 9 BP 3399 EP 3406 DI 10.1093/ndt/gfs362 PG 8 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 998MS UT WOS:000308244400008 PM 22942172 ER PT J AU Weaver, KJ Neal, D Hoh, DJ Mocco, J Barker, FG Hoh, BL AF Weaver, Kristin J. Neal, Dan Hoh, Daniel J. Mocco, J. Barker, Fred G., II Hoh, Brian L. TI The "July Phenomenon" for Neurosurgical Mortality and Complications in Teaching Hospitals: An Analysis of More Than 850 000 Neurosurgical Patients in the Nationwide Inpatient Sample Database, 1998 to 2008 SO NEUROSURGERY LA English DT Article DE Hemorrhage; Hydrocephalus; Retrospective; Trauma; Tumor ID LENGTH-OF-STAY; ACADEMIC YEAR; WORK HOURS; CARE; INTERNS; QUALITY; FICTION; FACT AB BACKGROUND: The evidence of or against the presence of a "July phenomenon" in resident teaching hospitals has been inconsistent. Moreover, there are limited data on the "July phenomenon" in the field of neurosurgery. OBJECTIVE: To determine whether a "July phenomenon" exists for neurosurgical mortality or complications. METHODS: A search of the National Inpatient Sample database from 1998 to 2008 was performed for all admissions for International Classification of Diseases, 9th Revision codes corresponding to nontraumatic hemorrhage, central nervous system (CNS) trauma, CNS tumor, and hydrocephalus. Generalized linear mixed-model analysis was performed, adjusted for patient demographics and hospital characteristics, for the outcomes of mortality and complications for the month of July compared with all other months in teaching hospitals. RESULTS: Generalized linear mixed-model analysis demonstrated that the risk of dying in the month of July vs any other month in a teaching hospital was not statistically different for any of the 4 diagnoses: nontraumatic hemorrhage (P=.071), CNS trauma category (P=.485), CNS tumor category (P=.578), hydrocephalus category (P=.1505). Moreover, the risk of any complication in the month of July vs any other month in a teaching hospital was not statistically different for any of the 4 diagnoses: nontraumatic hemorrhage (P=.529), CNS trauma category (P=.378), CNS tumor category (P=.461), and hydrocephalus category (P=.441). The same findings were true in an analysis of nonteaching hospitals performed as a control. CONCLUSION: No "July phenomenon" was found for neurosurgical mortality or complications in patients with nontraumatic hemorrhage, CNS trauma, CNS tumor, or hydrocephalus. C1 [Weaver, Kristin J.; Neal, Dan; Hoh, Daniel J.; Mocco, J.; Hoh, Brian L.] Univ Florida, Dept Neurosurg, Gainesville, FL 32610 USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Hoh, BL (reprint author), Univ Florida, Dept Neurosurg, POB 100265, Gainesville, FL 32610 USA. EM brian.hoh@neurosurgery.ufl.edu NR 22 TC 11 Z9 11 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2012 VL 71 IS 3 BP 562 EP 571 DI 10.1227/NEU.0b013e31825ea51b PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 996HB UT WOS:000308074400010 PM 22592329 ER PT J AU Barnard, Z Wakimoto, H Zaupa, C Patel, AP Klehm, J Martuza, RL Rabkin, SD Curry, WT AF Barnard, Zachary Wakimoto, Hiroaki Zaupa, Cecile Patel, Anoop P. Klehm, Jacquelyn Martuza, Robert L. Rabkin, Samuel D. Curry, William T., Jr. TI Expression of FMS-like Tyrosine Kinase 3 Ligand by Oncolytic Herpes Simplex Virus Type I Prolongs Survival in Mice Bearing Established Syngeneic Intracranial Malignant Glioma SO NEUROSURGERY LA English DT Article DE Brain tumor; Flt3-ligand; Glioma; Herpes; Immunotherapy; Oncolytic virus; Vaccine ID SYSTEMIC ANTITUMOR IMMUNITY; CELL-MEDIATED-IMMUNITY; DENDRITIC CELLS; FLT3 LIGAND; TUMOR-REGRESSION; BRAIN-TUMORS; PHASE-I; CANCER; THERAPY; G207 AB BACKGROUND: Glioblastoma is a fatal brain tumor in needing urgent effective therapy. Treatments with both oncolytic viruses and immunotherapy have shown preclinical efficacy and clinical promise. We sought to exploit possible synergies between oncolytic herpes simplex virus type 1 (oHSV-1) infection of intracranial gliomas and delivery of immune-stimulating fms-like tyrosine kinase 3 ligand (Flt3L) by engineering a herpes vector to express the cytokine. OBJECTIVE: To construct an oHSV-1 vector that expresses high levels of Flt3L and examine its antiglioma efficacy in an immunocompetent murine model. METHODS: G47 Delta and a bacterial artificial chromosome system were used to generate a novel oHSV-1, termed G47 Delta-Flt3L, expressing Flt3L. Cytokine expression was confirmed, and G47 Delta-Flt3L was injected intratumorally into established intracranial CT-2A gliomas in syngeneic C57/Bl6 mice. Animals were followed for survival and assessed by the Kaplan-Meier method. RESULTS: G47 Delta-Flt3L expressed high levels of Flt3L in culture. Expression of Flt3L affected neither viral replication nor had a cytotoxic effect on CT2A glioma cells. Direct inoculation into intracerebral CT2A glioma cells resulted in high levels of detectable Flt3L in mouse blood and was superior to parental G47 Delta in prolonging survival in glioma-bearing animals. CONCLUSION: Treatment with G47 Delta-Flt3L improves survival of glioma-bearing mice. C1 [Curry, William T., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Pappas Ctr Neurooncol, Simches Brain Tumor Res Labs,Dept Neurosurg, Boston, MA 02114 USA. RP Curry, WT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Pappas Ctr Neurooncol, Simches Brain Tumor Res Labs,Dept Neurosurg, 55 Fruit St,Y9E, Boston, MA 02114 USA. EM wcurry@partners.org OI rabkin, samuel/0000-0003-2344-2795 FU Amos Medical Faculty Development Plan of the Robert Wood Johnson Foundation; Mass General Hospital Physician Scientist Development Award; NIH [NS-032677] FX Funding provided by the Amos Medical Faculty Development Plan of the Robert Wood Johnson Foundation and Mass General Hospital Physician Scientist Development Award. This work was supported in part by NIH grant NS-032677. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 46 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2012 VL 71 IS 3 BP 741 EP 748 DI 10.1227/NEU.0b013e318260fd73 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 996HB UT WOS:000308074400049 PM 22653387 ER PT J AU Simonen, M Dali-Youcef, N Kaminska, D Venesmaa, S Kakela, P Paakkonen, M Hallikainen, M Kolehmainen, M Uusitupa, M Moilanen, L Laakso, M Gylling, H Patti, ME Auwerx, J Pihlajamaki, J AF Simonen, M. Dali-Youcef, N. Kaminska, D. Venesmaa, S. Kakela, P. Paakkonen, M. Hallikainen, M. Kolehmainen, M. Uusitupa, M. Moilanen, L. Laakso, M. Gylling, H. Patti, M. E. Auwerx, J. Pihlajamaki, Jussi TI Conjugated Bile Acids Associate with Altered Rates of Glucose and Lipid Oxidation after Roux-en-Y Gastric Bypass SO OBESITY SURGERY LA English DT Article DE Obesity surgery; Bile acids; Glucose and lipid oxidation; DIO2; CYP27A1 ID FARNESOID-X-RECEPTOR; GLUCAGON-LIKE PEPTIDE-1; BARIATRIC SURGERY; WEIGHT-LOSS; INDIRECT CALORIMETRY; ENERGY-EXPENDITURE; MORBID-OBESITY; HOMEOSTASIS; METABOLISM; ACTIVATION AB Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profile than expected by weight loss alone. In this study, we investigated the effect of RYGB on serum bile acid levels and their relation to clinical outcomes. We included 30 obese patients who underwent RYGB (BMI = 46.1 +/- 5.9 kg/m(2)). Clinical measurements and laboratory determinations were performed before surgery and 1 year after surgery. Fasting serum bile acids were measured by an enzymatic method and individual bile acids were quantified by HLPC-tandem mass spectrometry. Indirect calorimetry was performed to measure the rates of energy expenditure and substrate oxidation. Fasting total serum bile acid levels increased twofold after RYGB (pre, 3.68 +/- 2.03 vs. post, 7.06 +/- 9.65 mu mol/l, +92 %, p = 0.002). This increase in total bile acids was accompanied by a decrease in conjugated bile acids, which correlated with decreased glucose oxidation (r = 0.571, p = 0.002) and with increased lipid oxidation (r = -0.626, p = 0.0004). The change in taurine-conjugated bile acids correlated with altered DIO2 mRNA expression in adipose tissue (r = -0.498, p = 0.013) potentially linking bile acid conjugation to substrate oxidation through DIO2. Fasting serum bile acid levels increase after RYGB. More specifically, changes in bile acid conjugation after RYGB associate with altered energy metabolism. C1 [Kaminska, D.; Hallikainen, M.; Kolehmainen, M.; Uusitupa, M.; Gylling, H.; Pihlajamaki, Jussi] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Pihlajamaki, Jussi] Kuopio Univ Hosp, Dept Clin Nutr, SF-70210 Kuopio, Finland. [Simonen, M.; Moilanen, L.; Laakso, M.] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Dali-Youcef, N.] Univ Strasbourg, Hop Univ Strasbourg, Strasbourg, France. [Dali-Youcef, N.] Univ Strasbourg, Inst Genet Biol Mol & Cellulaire, Strasbourg, France. [Venesmaa, S.; Kakela, P.; Paakkonen, M.] Univ Eastern Finland, Dept Surg, Kuopio, Finland. [Patti, M. E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Auwerx, J.] Ecole Polytech Fed Lausanne, Lab Integrat Syst Physiol, Lausanne, Switzerland. [Pihlajamaki, Jussi] Kuopio Univ Hosp, Obes Ctr, SF-70210 Kuopio, Finland. RP Pihlajamaki, J (reprint author), Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. EM jussi.pihlajamaki@uef.fi RI DALI-YOUCEF, Nassim/O-2549-2016; OI DALI-YOUCEF, Nassim/0000-0001-6958-1331; Kaminska, Dorota/0000-0003-1829-576X FU Finnish Diabetes Research Foundation; Academy of Finland [120979, 138006]; EU Ideas program [ERC-2008-AdG-23118]; Swiss National Science Foundation (FNS); Ecole Polytechnique Federale de Lausanne FX This study was supported by the Finnish Diabetes Research Foundation (to JPI). JPI has an Academy of Finland Clinical Researcher fellowship (grant 120979 2008-2010 and 138006 2011-2013). JA acknowledges grant support of the EU Ideas program (ERC-2008-AdG-23118), the Swiss National Science Foundation (FNS), and the Ecole Polytechnique Federale de Lausanne. NR 33 TC 51 Z9 52 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 J9 OBES SURG JI Obes. Surg. PD SEP PY 2012 VL 22 IS 9 BP 1473 EP 1480 DI 10.1007/s11695-012-0673-5 PG 8 WC Surgery SC Surgery GA 996ER UT WOS:000308067800460 PM 22638681 ER PT J AU Scholl, J Durfee, SM Russell, MA Heard, AJ Iyer, C Alammari, R Coletta, J Craigo, SD Fuchs, KM D'Alton, M House, M Jennings, RW Ecker, J Panda, B Tanner, C Wolfberg, A Benson, CB AF Scholl, Jessica Durfee, Sara M. Russell, Michelle A. Heard, Asha J. Iyer, Chitra Alammari, Roa Coletta, Jaclyn Craigo, Sabrina D. Fuchs, Karin M. D'Alton, Mary House, Michael Jennings, Russell W. Ecker, Jeffrey Panda, Britta Tanner, Cassandre Wolfberg, Adam Benson, Carol B. TI First-Trimester Cystic Hygroma: Relationship of Nuchal Translucency Thickness and Outcomes SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID 1ST TRIMESTER; FETUSES; DIAGNOSIS; ANOMALIES; DEFECTS; EDEMA AB OBJECTIVE: To estimate the relationship between nuchal translucency thickness and abnormal karyotype, major congenital anomaly, perinatal loss, and composite abnormal outcome in fetuses with first-trimester nuchal cystic hygroma. METHODS: We performed a retrospective cohort study of first-trimester fetuses with ultrasound-diagnosed nuchal cystic hygroma collected over a 10-year period. RESULTS: There were 944 first-trimester fetuses with nuchal cystic hygroma. A karyotype abnormality occurred in 54.9% (400 of 729) of fetuses. A major congenital anomaly occurred in 28.8% (61 of 212) of fetuses with a normal karyotype. Perinatal loss occurred in 39% (115 of 295) of fetuses not electively terminated. Overall, an abnormal outcome occurred in 86.6% (543 of 627) of fetuses. After adjusting for potential confounders, every 1-mm increase in nuchal translucency thickness increased the odds of an abnormal karyotype by 44% (adjusted odds ratio [OR] 1.44, 95% confidence interval [CI] 1.29 -1.60, P<.001), the odds of major congenital anomaly by 26% (adjusted OR 1.26, 95% CI, 1.08 -1.47, P=.003), the odds of perinatal loss by 47% (adjusted OR 1.47, 95% CI 1.07-2.02, P=.019), and the odds of a composite abnormal outcome by 77% (adjusted OR 1.77, 95% CI 1.15-2.74, P=.01). CONCLUSION: First-trimester nuchal cystic hygroma is associated with high rates of karyotype abnormality, major congenital anomaly, perinatal loss, and abnormal outcome. As the thickness of the nuchal translucency increases, the odds of abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcome increase. (Obstet Gynecol 2012; 120: 551-9) DOI: http://10.1097/AOG.0b013e318264f829 LEVEL OF EVIDENCE: II C1 [Scholl, Jessica] Dartmouth Hitchcock Med Ctr, Dept Obstet & Gynecol, Lebanon, NH 03756 USA. Childrens Hosp, Brigham & Womens Hosp, Tufts Med Ctr, Boston, MA 02115 USA. Columbia Univ, Med Ctr, New York, NY USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Scholl, J (reprint author), Dartmouth Hitchcock Med Ctr, Dept Obstet & Gynecol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM Jessica.E.Scholl@Hitchcock.org NR 19 TC 11 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2012 VL 120 IS 3 BP 551 EP 559 DI 10.1097/AOG.0b013e318264f829 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 999EX UT WOS:000308293300009 PM 22872145 ER PT J AU Tracy, EE Haas, S Lauria, MR AF Tracy, Erin E. Haas, Susan Lauria, Michele R. TI Newborn Care and Safety The Black Box of Obstetric Practices and Residency Training SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID INFANT SLEEPING ENVIRONMENT; DEATHS EXPANSION; SIDS; RECOMMENDATIONS AB Certain causes of newborn mortality such as sudden unexpected infant death, which includes sleep-related infant death and sudden unexplained infant death syndrome, are potentially preventable. Obstetricians are uniquely positioned to counsel new parents about safe practices regarding newborn sleep, feeding, and transportation. Patients often do not develop a relationship with their pediatricians until the neonate has been discharged, and the newborn period is a time of particular vulnerability. Newborn safety should be routinely taught in obstetric curricula, and the American College/Congress of Obstetricians and Gynecologists and the American Academy of Pediatrics (AAP) should partner to disseminate updated literature and guidelines to health care providers regarding newborn safety. Current guidelines from the Academy of Pediatrics Task Force on Sudden Infant Syndrome are summarized in this article. (Obstet Gynecol 2012; 120: 643-6) DOI: http://10.1097/AOG.0b013e318265af0a C1 [Tracy, Erin E.] Massachusetts Gen Hosp, Harvard Vanguard Med Associates Atrius Hlth, Vincent Obstet & Gynecol, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. RP Tracy, EE (reprint author), Massachusetts Gen Hosp, Harvard Vanguard Med Associates Atrius Hlth, Vincent Obstet & Gynecol, 55 Fruit St,406 Founders House, Boston, MA 02114 USA. EM EETracy@partners.org NR 24 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2012 VL 120 IS 3 BP 643 EP 646 DI 10.1097/AOG.0b013e318265af0a PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 999EX UT WOS:000308293300021 PM 22914475 ER PT J AU Minkoff, H Ecker, J AF Minkoff, Howard Ecker, Jeffrey TI When Legislators Play Doctor The Ethics of Mandatory Preabortion Ultrasound Examinations SO OBSTETRICS AND GYNECOLOGY LA English DT Article AB Many states have proposed or enacted laws that mandate that women undergo ultrasonography before electing pregnancy termination. In some cases, the legislation prescribes the form of ultrasound examination, requires that a woman review the images produced, or both. Although ultrasonography may be a part of good and standard care before many abortion procedures, we argue that legislating imaging procedures inappropriately limits women's autonomy and undermines the physician-patient relationship as well as the physician's professional obligations to the patient. The timing, context, and way in which ultrasonography, or any medical test, is used and viewed should be decisions made between patient and provider, not decisions scripted by law. (Obstet Gynecol 2012; 120: 647-9) DOI: http://10.1097/AOG.0b013e318265e101 C1 [Minkoff, Howard] SUNY Downstate, Maimonides Med Ctr, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. Harvard Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Minkoff, H (reprint author), SUNY Downstate, Maimonides Med Ctr, Dept Obstet & Gynecol, 967 48th St, Brooklyn, NY 11219 USA. EM hminkoff@maimonidesmed.org NR 5 TC 1 Z9 1 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2012 VL 120 IS 3 BP 647 EP 649 DI 10.1097/AOG.0b013e318265e101 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 999EX UT WOS:000308293300022 PM 22914476 ER PT J AU Schiotz, M Frolich, A Krasnik, A Taylor, W Hsu, J AF Schiotz, Michaela Frolich, Anne Krasnik, Allan Taylor, Warren Hsu, John TI Social organization of self-management support of persons with diabetes: A health systems comparison SO SCANDINAVIAN JOURNAL OF PRIMARY HEALTH CARE LA English DT Article DE Denmark; diabetes mellitus; general practice; health system; international comparison; patient education; self-management support ID KAISER-PERMANENTE; GENERAL-PRACTICE; CARE; DENMARK; PROGRAM; NHS AB Objective. Identify important organizational elements for providing self-management support (SMS). Design. Semi-structured qualitative interviews conducted in two healthcare systems. Setting. Kaiser Permanente Northern California and the Danish Health Care System. Subjects. 36 managers and healthcare professionals in the two healthcare systems. Main outcome measures. Elements important to providing self-management support to persons with diabetes. Results. Healthcare professionals 'provision of SMS was influenced by healthcare system organization and their perceptions of SMS, the capability and responsibility of healthcare systems, and their roles in the healthcare organization. Enabling factors for providing SMS included: strong leadership; aligned incentives; use of an integrated health information technology (HIT) system; multidisciplinary healthcare provider teams; ongoing training for healthcare professionals; outreach; and quality goals. Barriers to providing SMS included lack of collaboration between providers and skeptical attitudes towards prevention and outreach. Conclusions and implications. Implementation of SMS can be improved by an understanding of the elements that enhance its provision: (1) initiatives seeking to improve collaboration and integration between providers; (2) implementation of an integrated HIT system; and (3) ongoing training of healthcare professionals. C1 [Schiotz, Michaela] Steno Diabet Ctr, Steno Hlth Promot Ctr, DK-2820 Gentofte, Denmark. [Frolich, Anne] Copenhagen Hosp Cooperat, Copenhagen, Denmark. [Krasnik, Allan] Univ Copenhagen, Fac Hlth Sci, Dept Publ Hlth, Sect Hlth Serv Res, Copenhagen, Denmark. [Taylor, Warren] Massachusetts Gen Hosp, Permanente Med Grp, Boston, MA 02114 USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Schiotz, M (reprint author), Steno Diabet Ctr, Steno Hlth Promot Ctr, Niels Steensens Vej 8, DK-2820 Gentofte, Denmark. EM mlsz@steno.dk FU Rockwool Foundation FX The authors would like to thank the Rockwool Foundation who funded this study. Jennifer Green provided English text revision and correction.; We received Institutional Review Board approval to conduct the study in KP. It was not necessary to obtain ethical approval in the DHS. The study was funded by the Rockwool Foundation. WT and JH were employed by KP during the study period. AF was employed by the DHS during the study period. NR 26 TC 3 Z9 3 U1 2 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0281-3432 J9 SCAND J PRIM HEALTH JI Scand. J. Prim. Health Care PD SEP PY 2012 VL 30 IS 3 BP 189 EP 194 DI 10.3109/02813432.2012.704810 PG 6 WC Health Care Sciences & Services; Primary Health Care; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 997UV UT WOS:000308193300013 PM 22839353 ER PT J AU Kuna, ST Maislin, G Pack, FM Staley, B Hachadoorian, R Coccaro, EF Pack, AI AF Kuna, Samuel T. Maislin, Greg Pack, Frances M. Staley, Bethany Hachadoorian, Robert Coccaro, Emil F. Pack, Allan I. TI Heritability of Performance Deficit Accumulation During Acute Sleep Deprivation in Twins SO SLEEP LA English DT Article DE Sleep homeostasis; sleep deprivation; twins ID NUMBER TANDEM REPEAT; CLOCK GENE PERIOD3; HUMAN PER3 GENE; LENGTH POLYMORPHISM; DIURNAL PREFERENCE; COLLABORATIVE CROSS; CAGE QUESTIONNAIRE; VIGILANT ATTENTION; CIRCADIAN PHASE; EEG SLEEP AB Study Objectives: To determine if the large and highly reproducible interindividual differences in rates of performance deficit accumulation during sleep deprivation, as determined by the number of lapses on a sustained reaction time test, the Psychomotor Vigilance Task (PVT), arise from a heritable trait. Design: Prospective, observational cohort study. Setting: Academic medical center. Participants: There were 59 monozygotic (mean age 29.2 +/- 6.8 [SD] yr; 15 male and 44 female pairs) and 41 dizygotic (mean age 26.6 +/- 7.6 yr; 15 male and 26 female pairs) same-sex twin pairs with a normal polysomnogram. Interventions: Thirty-eight hr of monitored, continuous sleep deprivation. Measurements and Results: Patients performed the 10-min PVT every 2 hr during the sleep deprivation protocol. The primary outcome was change from baseline in square root transformed total lapses (response time >= 500 ms) per trial. Patient-specific linear rates of performance deficit accumulation were separated from circadian effects using multiple linear regression. Using the classic approach to assess heritability, the intraclass correlation coefficients for accumulating deficits resulted in a broad sense heritability (h(2)) estimate of 0.834. The mean within-pair and among-pair heritability estimates determined by analysis of variance-based methods was 0.715. When variance components of mixed-effect multilevel models were estimated by maximum likelihood estimation and used to determine the proportions of phenotypic variance explained by genetic and non-genetic factors, 51.1% (standard error = 8.4%, P < 0.0001) of twin variance was attributed to combined additive and dominance genetic effects. Conclusion: Genetic factors explain a large fraction of interindividual variance among rates of performance deficit accumulations on PVT during sleep deprivation. C1 [Kuna, Samuel T.] Philadelphia VA Med Ctr, Dept Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.; Maislin, Greg; Pack, Frances M.; Staley, Bethany; Hachadoorian, Robert; Pack, Allan I.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.; Maislin, Greg; Pack, Frances M.; Staley, Bethany; Hachadoorian, Robert; Pack, Allan I.] Univ Penn, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA. [Coccaro, Emil F.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. RP Kuna, ST (reprint author), Philadelphia VA Med Ctr, Dept Med, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM skuna@mail.med.upenn.edu FU NIH from National Center for Research Resources [P50 HL060287, P01 HL094307, UL1RR024134]; Philips-Respironics; Philips-Respironics Foundation; Azevan Pharmaceuticals, Inc. FX This study was supported by NIH P50 HL060287, P01 HL094307 and UL1RR024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The Penn Twins Cohort and the MidAtlantic Twins Registry assisted in recruitment of the twin pairs. The contributions of Melissa Fernando, Michele Pliner, Marian Whitlock, and Colleen Crowley to the study are gratefully acknowledged and to Daniel Barrett for assistance in manuscript preparation.; Dr. Kuna receives grant support from Philips-Respironics. Mr. Maislin is the owner of Biomedical Statistical Consulting Services. Dr. Coccaro is a member of the Scientific Advisory Board of Azevan Pharmaceuticals, Inc. and receives grant support from that company. Dr. Pack is The John L. Miclot Professor of Medicine at the University of Pennsylvania. Funds for this endowment were provided by the Philips-Respironics Foundation. The other authors have indicated no financial conflicts of interest. NR 64 TC 31 Z9 32 U1 0 U2 10 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD SEP 1 PY 2012 VL 35 IS 9 BP 1223 EP 1233 DI 10.5665/sleep.2074 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 000AY UT WOS:000308360100009 PM 22942500 ER PT J AU Szabo, S Tache, Y Somogyi, A AF Szabo, Sandor Tache, Yvette Somogyi, Arpad TI The legacy of Hans Selye and the origins of stress research: A retrospective 75 years after his landmark brief "Letter" to the Editor of Nature SO STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS LA English DT Article DE Anti-inflammatory drugs; corticosteroids; distress; eustress; Hans Selye; stress ID STEROIDS; SPIRONOLACTONE; CLASSIFICATION; CYSTEAMINE; HORMONES; ULCERS; MODEL; RAT AB Hans Selye's single author short letter to Nature (1936, 138(3479): 32) inspired a huge and still growing wave of medical research. His experiments with rats led to recognition of the "general adaptation syndrome", later renamed by Selye "stress response": the triad of enlarged adrenal glands, lymph node and thymic atrophy, and gastric erosions/ulcers. Because of the major role of glucocorticoids (named by Selye), he performed extensive structure-activity studies in the 1930s-1940s, resulting in the first rational classification of steroid hormones, e. g. corticoids, testoids/androgens, and folliculoids/estrogens. During those years, he recognized the respective anti-and pro-inflammatory actions of gluco- and mineralocorticoids in animal models, several years before demonstration of anti-rheumatic actions of cortisone and adrenocorticotrophic hormones in patients. Nevertheless, Selye did not receive a Nobel Prize, which was awarded in 1950 to the clinician Hench and the two chemists who isolated and synthesized some of the glucocorticoids. Nonetheless, Selye was internationally recognized as a world authority in endocrinology, steroid chemistry, experimental surgery, and pathology. He wrote over 1500 original and review articles, singly authored 32 books, and trained 40 PhD students, one of whom (Roger Guillemin) won a Nobel Prize for isolating the hypothalamic releasing factors/hormones. Here, we consider the main implications of his first article launching the biological stress concept and the key ideas and problems that occupied him. Selye considered "Stress in heath and disease is medically, sociologically, and philosophically the most meaningful subject for humanity that I can think of". C1 [Szabo, Sandor] Univ Calif Irvine, VA Med Ctr, VA Long Beach Healthcare Syst, Long Beach, CA 90822 USA. [Szabo, Sandor] Univ Calif Irvine, Dept Pathol, Long Beach, CA 90822 USA. [Szabo, Sandor] Univ Calif Irvine, Dept Pharmacol, Long Beach, CA 90822 USA. [Tache, Yvette] Univ Calif Los Angeles, Dept Med, Oppenheimer Family Ctr Ctr Neurobiol Stress, Digest Dis Div,CURE Digest Dis Res Ctr, Los Angeles, CA 90024 USA. [Tache, Yvette] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Somogyi, Arpad] EU Select Inc, Brussels, Belgium. RP Szabo, S (reprint author), Univ Calif Irvine, VA Med Ctr, VA Long Beach Healthcare Syst, 5901 E 7th St, Long Beach, CA 90822 USA. EM sandor.szabo@va.gov NR 49 TC 43 Z9 46 U1 5 U2 46 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1025-3890 J9 STRESS JI Stress PD SEP PY 2012 VL 15 IS 5 BP 472 EP 478 DI 10.3109/10253890.2012.710919 PG 7 WC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences SC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences & Neurology GA 994AW UT WOS:000307904200002 PM 22845714 ER PT J AU Kopeikina, KJ Hyman, BT Spires-Jones, TL AF Kopeikina, Katherine J. Hyman, Bradley T. Spires-Jones, Tara L. TI Soluble forms of tau are toxic in Alzheimer's disease SO TRANSLATIONAL NEUROSCIENCE LA English DT Review DE Alzheimer; Tauopathy; Neurofibrillary tangle; Hyperphosphorylated tau ID TANGLE-BEARING NEURONS; INDUCIBLE MOUSE MODELS; WILD-TYPE TAU; AXONAL-TRANSPORT; TRANSGENIC MICE; AMYLOID-BETA; NEURODEGENERATIVE DISEASES; MITOCHONDRIAL DYSFUNCTION; DENDRITIC SPINES; IN-VIVO AB Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer's disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer's disease and other tauopathies. C1 [Kopeikina, Katherine J.; Hyman, Bradley T.; Spires-Jones, Tara L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Kopeikina, Katherine J.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. RP Kopeikina, KJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. EM tspires@partners.org OI Spires-Jones, Tara/0000-0003-2530-0598 FU National Institute of Health [AG08487, T32AG000277, AG026249, K99AG33670, P50AG05134]; Alzheimer's Association Zenith Award FX This work was supported by National Institute of Health Grants AG08487, T32AG000277, AG026249, K99AG33670, P50AG05134 and the Alzheimer's Association Zenith Award. We thank Rose Pitstick and George Carlson at the McLaughlin Research Institute for animal breeding and genotyping. NR 133 TC 43 Z9 45 U1 1 U2 24 PU VERSITA PI WARSAW PA SOLIPSKA 14A-1, 02-482 WARSAW, POLAND SN 2081-3856 J9 TRANSL NEUROSCI JI Transl. Neurosci. PD SEP PY 2012 VL 3 IS 3 BP 223 EP 233 DI 10.2478/s13380-012-0032-y PG 11 WC Neurosciences SC Neurosciences & Neurology GA 996FN UT WOS:000308070300001 PM 23029602 ER PT J AU Eisner, BH AF Eisner, Brian H. TI A New Scoring System for Predicting Stone-free Rate After Retrograde Intrarenal Surgery: The "Resorlu-Unsal Stone Score" EDITORIAL COMMENT SO UROLOGY LA English DT Editorial Material ID SHOCK-WAVE LITHOTRIPSY; NOMOGRAM C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. RP Eisner, BH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. NR 5 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 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 BP 517 EP 517 DI 10.1016/j.urology.2012.02.073 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 000FX UT WOS:000308373000009 PM 22840864 ER PT J AU Evans, CS Harris, NS AF Evans, C. Scott Harris, N. Stuart TI Ultrasound and Ski Resort Clinics: Mapping Out the Potential Benefits SO WILDERNESS & ENVIRONMENTAL MEDICINE LA English DT Article; Proceedings Paper CT Wilderness and Mountain Medicine Conference of the Wilderness-Medical-Society CY FEB 05-09, 2011 CL Pk City, UT SP Wilderness Med Soc DE bedside ultrasound; skier injury; snowboarder injury; prehospital ultrasound; mountainside clinic ID ACUTE MOUNTAIN-SICKNESS; ANTERIOR SHOULDER DISLOCATION; OPTIC-NERVE ULTRASONOGRAPHY; ALTITUDE PULMONARY-EDEMA; INTRACRANIAL-PRESSURE; EMERGENCY-DEPARTMENT; SNOWBOARDING INJURIES; FOCUSED ASSESSMENT; CHEST RADIOGRAPHY; NASAL FRACTURES AB Background.-Skiing and snowboarding are popular activities that involve high kinetic energies, often at altitude, and injuries are common. As a portable imaging modality, ultrasound may be a useful adjunct for mountainside clinics. This review briefly discusses skier and snowboarder injury profiles and focuses on the role of ultrasound for each injury type. Methods.-Twenty-two sources including 17 reviews and observational studies were obtained describing skier and snowboarder injuries. Forty-nine studies were identified defining ultrasound applications for these injuries, including 38 reviews and observational studies, 6 case reports or case series, 3 cross-sectional studies, and 2 randomized, blinded studies. Results.-Approximately 200 000 rider injuries are evaluated in the Unites States seasonally. Musculoskeletal injuries are the most common, and head, face, neck, and abdominal injuries are also prevalent, as are exacerbations of preexisting disease. Ultrasound has been shown to be useful and accurate for evaluating the aforementioned injury types, including joint, ligament, tendon, and fracture evaluation. Ultrasound has not been extensively studied in the prehospital setting, and only limited data address the utility of how it might influence management in a mountainside clinic setting. Conclusions.-Ultrasound has the potential to be a useful diagnostic modality in ski resort clinics. The most promising areas for future, applied studies include evaluation of musculoskeletal injuries (especially injuries to joints and tendons and ruling out fractures), assessing for elevated intracranial pressure in minor head injuries and symptoms of altitude illness, and focused assessment with sonography for trauma and extended focused assessment with sonography for trauma examinations for cases of chest and abdominal trauma of unknown significance. C1 [Evans, C. Scott] Duke Univ, Med Ctr, Div Emergency Med, Dept Surg, Durham, NC 27710 USA. [Harris, N. Stuart] Massachusetts Gen Hosp, Dept Emergency Med, Div Wilderness Med, Boston, MA 02114 USA. RP Evans, CS (reprint author), Duke Univ, Med Ctr, Div Emergency Med, Dept Surg, DUMC Box 3935,2301 Erwin Rd,Suite 2600, Durham, NC 27710 USA. EM scott.evans@duke.edu NR 71 TC 3 Z9 3 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1080-6032 J9 WILD ENVIRON MED JI Wildern. Environ. Med. PD FAL PY 2012 VL 23 IS 3 BP 239 EP 247 PG 9 WC Public, Environmental & Occupational Health; Sport Sciences SC Public, Environmental & Occupational Health; Sport Sciences GA 999BR UT WOS:000308284600009 PM 22704080 ER PT J AU Aspinall, SL Cunningham, FE Zhao, XH Boresi, JS Tonnu-Mihara, IQ Smith, KJ Stone, RA Good, CB AF Aspinall, Sherrie L. Cunningham, Francesca E. Zhao, Xinhua Boresi, Joy S. Tonnu-Mihara, Ivy Q. Smith, Kenneth J. Stone, Roslyn A. Good, Chester B. CA ESA Clinic Study Grp TI Impact of Pharmacist-Managed Erythropoiesis-Stimulating Agents Clinics for Patients With Non-Dialysis-Dependent CKD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; anemia; erythropoietin ID CHRONIC KIDNEY-DISEASE; IMPLEMENTED ANEMIA MANAGEMENT; STAGE RENAL-DISEASE; ECONOMIC-BENEFITS; HEMOGLOBIN LEVEL; VARIABILITY; MORTALITY; PROTOCOL; PROGRAM; TARGET AB Background: Erythropoiesis-stimulating agents (ESAs) are associated with serious adverse events, and maintaining hemoglobin levels within a narrow range can be difficult. We examined the quality of ESA prescribing and monitoring in pharmacist-managed ESA clinics versus usual care in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). Study Design: Historical cohort. Setting & Participants: Outpatients receiving ESAs for NDD-CKD at 10 Veterans Affairs Medical Centers with both pharmacist-managed ESA clinics (n = 314) and physician-based care (ie, usual care; n = 91) and 6 sites with usual care only (n = 167) on January 1, 2009, were followed up for 6 months. Predictor: Type/site of care (ie, pharmacist-managed ESA clinic, usual care at ESA clinic site, usual-care site). Outcomes: Primary outcomes were proportion of hemoglobin values in the target range of 10-12 g/dL, ESA dose, and frequency of hemoglobin monitoring. Factors associated with hemoglobin values out of target range were identified using multinomial logistic regression. Results: More hemoglobin values were in the target range in pharmacist-managed ESA clinics (71.1% vs 56.9% for usual-care sites; P < 0.001). The average 30-day dose of darbepoetin was 163 mu g in pharmacist-managed ESA clinic patients versus 240 mu g in usual-care site patients and 258 mu g in usual-care patients at ESA clinic sites. For epoetin, corresponding average 30-day doses were 44,890 versus 47,141 and 57,436 IU. Veterans in pharmacist-managed ESA clinics had more hemoglobin measurements on average (5.8 vs 3.6 in usual-care sites and 3.8 in usual care at ESAclinic sites; P = 0.007). In the multinomial model, usual care was associated with hemoglobin levels out of target range, whereas heart failure and diabetes were associated with values in range. Limitations: We could not assess whether different hemoglobin targets were used by usual-care providers. Conclusions: Relative to usual care, pharmacist-managed clinics provided improved quality of ESA dosing and monitoring for patients with NDD-CKD. Am J Kidney Dis. 60(3): 371-379. 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 [Aspinall, Sherrie L.; Cunningham, Francesca E.; Good, Chester B.] Vet Affairs Ctr Medicat Safety, Hines, IL USA. [Aspinall, Sherrie L.; Zhao, Xinhua; Stone, Roslyn A.; Good, Chester B.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Aspinall, Sherrie L.; Good, Chester B.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. [Good, Chester B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Stone, Roslyn A.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Smith, Kenneth J.] Univ Pittsburgh, Div Clin Modeling & Decis Sci, Pittsburgh, PA USA. [Boresi, Joy S.] St Louis Vet Affairs Med Ctr, St Louis, MO USA. [Tonnu-Mihara, Ivy Q.] Vet Affairs Long Beach Healthcare Syst, Long Beach, CA USA. RP Aspinall, SL (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr,151C-H, Pittsburgh, PA 15206 USA. EM sherrie.aspinall@va.gov OI Smith, Kenneth J/0000-0001-8088-566X FU VA Center for Medication Safety/VA Pharmacy Benefits Management Services, Hines, IL; VA Pittsburgh Healthcare System, Pittsburgh, PA; VA medical centers FX There was no specific funding support for the work. However, these findings are the result of work supported in kind by the VA Center for Medication Safety/VA Pharmacy Benefits Management Services, Hines, IL; VA Pittsburgh Healthcare System, Pittsburgh, PA; and the other VA medical centers that participated in the study. The views expressed in this report are those of the authors, and no official endorsement by the Department of Veteran Affairs or the United States Government is intended or should be inferred. NR 25 TC 8 Z9 8 U1 1 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD SEP PY 2012 VL 60 IS 3 BP 371 EP 379 DI 10.1053/j.ajkd.2012.04.013 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 994OT UT WOS:000307941200011 PM 22633556 ER PT J AU Jutras-Aswad, D Widlitz, M Scimeca, MM AF Jutras-Aswad, Didier Widlitz, Michelle Scimeca, Michael M. TI Treatment of Buprenorphine Precipitated Withdrawal: A Case Report SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID METHADONE C1 [Jutras-Aswad, Didier; Widlitz, Michelle; Scimeca, Michael M.] James J Peters Vet Affairs Med Ctr, Dept Psychiat, Bronx, NY 10468 USA. [Jutras-Aswad, Didier; Widlitz, Michelle; Scimeca, Michael M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Jutras-Aswad, Didier] Univ Montreal, Dept Psychiat, Quebec City, PQ, Canada. [Jutras-Aswad, Didier] Ctr Hosp Univ Montreal, CRCHUM, Quebec City, PQ, Canada. RP Scimeca, MM (reprint author), James J Peters Vet Affairs Med Ctr, Dept Psychiat, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM scimecas@aol.com NR 5 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SEP-OCT PY 2012 VL 21 IS 5 BP 492 EP 493 DI 10.1111/j.1521-0391.2012.00262.x PG 2 WC Substance Abuse SC Substance Abuse GA 986WT UT WOS:000307377400016 PM 22882402 ER PT J AU Shefner, J Cedarbaum, JM Cudkowicz, ME Maragakis, N Lee, J Jones, D Watson, ML Mahoney, K Chen, M Saikali, K Mao, J Russell, AJ Hansen, RL Malik, F Wolff, AA AF Shefner, Jeremy Cedarbaum, Jesse M. Cudkowicz, Merit E. Maragakis, Nicholas Lee, Jacqueline Jones, Drew Watson, Mary Lou Mahoney, Katy Chen, Michael Saikali, Khalil Mao, John Russell, Alan J. Hansen, Richard L. Malik, Fady Wolff, Andrew A. CA NEALS Cytokinetics Study Team TI Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article DE Amyotrophic lateral sclerosis; clinical trials; muscle; riluzole; pharmacokinetics ID PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; PSEUDOBULBAR AFFECT; PULMONARY-FUNCTION; ALS; TRIAL AB This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted. C1 [Shefner, Jeremy] Upstate Med Univ, HSC Syracuse, Dept Neurol, Syracuse, NY 13210 USA. [Cedarbaum, Jesse M.; Lee, Jacqueline; Jones, Drew; Chen, Michael; Saikali, Khalil; Mao, John; Russell, Alan J.; Hansen, Richard L.; Malik, Fady; Wolff, Andrew A.] Cytokinet Inc, San Francisco, CA USA. [Cudkowicz, Merit E.; Mahoney, Katy] Massachusetts Gen Hosp, Neurol Clin Trial Unit, Charlestown, MA USA. [Maragakis, Nicholas] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Shefner, J (reprint author), Upstate Med Univ, HSC Syracuse, Dept Neurol, 750 E Adams St, Syracuse, NY 13210 USA. EM shefnerj@upstate.edu FU Cytokinetics, Inc. South San Francisco, CA; Teva Pharmaceuticals; Neurostem; Isis Pharmaceuticals; Cytokinetics; Glaxo SmithKline; Biogen-Idec; Knopp Pharmaceuticals; Sanofi-Aventis; NIH; ALS Association; INDS; NINDS; US Department of Defense; Cytokinetics, Inc.; UpToDate-AmyotrophicLateralSclerosis FX The authors wish to thank ACI for copyediting assistance. This study was sponsored by Cytokinetics, Inc. South San Francisco, CA.; Jeremy Shefner serves as a consultant for Cytokinetics, Glaxo-SmithKline, Trophos and Biogenidec; he receives or has received research support from Teva Pharmaceuticals, Neurostem, Isis Pharmaceuticals, Cytokinetics, Glaxo SmithKline, Biogen-Idec, Knopp Pharmaceuticals, Sanofi-Aventis, NIH and the ALS Association. He is the neuromuscular section editor for UpToDate, and receives royalties for his services.; Merit E. Cudkowicz has served as a consultant to Cytokinetics and to Trophos; she has received research support from Biogen-Idec, Cytokinetics, Trophos, INDS and the ALS Association. Nicholas Maragakis has been a scientific advisor to Q Therapeutics (2009-2011), serves as a consultant to Johnson & Johnson, Inc. and has received research support from NINDS, the US Department of Defense, and Cytokinetics, Inc. He receives royalties from UpToDate-AmyotrophicLateralSclerosis. NR 21 TC 23 Z9 23 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1748-2968 J9 AMYOTROPH LATERAL SC JI Amyotroph. Lateral. Scler. PD SEP PY 2012 VL 13 IS 5 BP 430 EP 438 DI 10.3109/17482968.2012.684214 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 989UD UT WOS:000307585200004 PM 22591195 ER PT J AU Rutkove, SB Caress, JB Cartwright, MS Burns, TM Warder, J David, WS Goyal, N Maragakis, NJ Clawson, L Benatar, M Usher, S Sharma, KR Gautam, S Narayanaswami, P Raynor, EM Watson, ML Shefner, JM AF Rutkove, Seward B. Caress, James B. Cartwright, Michael S. Burns, Ted M. Warder, Judy David, William S. Goyal, Namita Maragakis, Nicholas J. Clawson, Lora Benatar, Michael Usher, Sharon Sharma, Khema R. Gautam, Shiva Narayanaswami, Pushpa Raynor, Elizabeth M. Watson, Mary Lou Shefner, Jeremy M. TI Electrical impedance myography as a biomarker to assess ALS progression SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article DE Clinical trials; amyotrophic lateral sclerosis; electrical impedance myography ID AMYOTROPHIC-LATERAL-SCLEROSIS; CLINICAL-TRIALS; DEGENERATION; ATROPHY AB Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM's potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique's correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials. C1 [Rutkove, Seward B.; Narayanaswami, Pushpa; Raynor, Elizabeth M.] Beth Israel Deaconess Med Ctr, Div Neuromuscular Dis, Boston, MA 02215 USA. [Caress, James B.; Cartwright, Michael S.] Wake Forest Sch Med, Dept Neurol, Winston Salem, NC USA. [Burns, Ted M.; Warder, Judy] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [David, William S.; Goyal, Namita] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Maragakis, Nicholas J.; Clawson, Lora] Johns Hopkins Med Ctr, Dept Neurol, Baltimore, MD 21218 USA. [Benatar, Michael; Sharma, Khema R.] Univ Miami, Dept Neurol, Miami, FL USA. [Usher, Sharon] Univ S Florida, Tampa, FL USA. [Gautam, Shiva] Beth Israel Deaconess Med Ctr, Gen Clin Res Ctr, Boston, MA 02215 USA. [Watson, Mary Lou; Shefner, Jeremy M.] Upstate Med Ctr, Dept Neurol, Syracuse, NY USA. RP Rutkove, SB (reprint author), Beth Israel Deaconess Med Ctr, Div Neuromuscular Dis, 330 Brookline Ave,TCC-810, Boston, MA 02215 USA. EM srutkove@bidmc.harvard.edu OI Caress, James/0000-0002-5814-6083 FU ALS Association; Neuralstem, Inc.; GlaxoSmithKline, Inc.; UpToDate; NIH; NASA; Spinal Muscular Atrophy Foundation; Knopp Neurosciences Inc.; Myasthenia Gravis Foundation of America; Michael S. Ansari Gift Fund for basic science research; Sangamo BioSciences, Inc.; TEDCO-Maryland Stem Cell Research Fund; NIH/NINDS; U.S. Department of Defense; ALS Association Packard Center for ALS Research at Johns Hopkins; Neuromuscular Disease; BluePrints in Neurology; Field of Vision: A Manual and Atlas of Perimetry; CytRx Corporation; Muscular Dystrophy Association; Food and Drug Administration; Centers for Disease Control and Prevention; Woodruff Health Sciences Center (Emory University); Teva Pharmaceutical Industries Ltd.; Gilead Sciences, Inc.; GlaxoSmithKline; Trophos; BrainGate; Isis Pharmaceuticals, Inc.; Sanofi-Aventis FX This study was funded by the ALS Association. We thank Lindsay Garmirian, Connie Lin, Philip Mongiovi, Lucy Wang, Tuhin Srivastava, and Andrew Spieker for their assistance with this project.; S. B. Rutkove serves as a consultant and holds equity in Convergence Medical Devices, Inc. He has also receives consulting fees from Neuralstem, Inc., GlaxoSmithKline, Inc. and royalties from UpToDate. He also has two patent applications submitted in the field of electrical impedance. He receives grant funding from NIH, NASA, and the Spinal Muscular Atrophy Foundation. J. B. Caress receives grant funding from NIH.; M. S. Cartwright receives grant funding from NIH. T. Burns serves as Podcast Section Editor for Neurology (R); has served as a consultant for Bayhill Therapeutics; and has received research support from Knopp Neurosciences Inc. and the Myasthenia Gravis Foundation of America.; N. Maragakis serves on a scientific advisory board for Q Therapeutics, Inc.; received support from the Michael S. Ansari Gift Fund for basic science research; serves as a contributor to UpToDate; has served as a consultant for California Institute for Regenerative Medicine (CIRM); and receives/has received research support from Cytokinetics Inc., Sangamo BioSciences, Inc., TEDCO-Maryland Stem Cell Research Fund, NIH/NINDS, U.S. Department of Defense, and the ALS Association Packard Center for ALS Research at Johns Hopkins. M. Benatar has served as a consultant for Bayhill Therapeutics and Cytokinetics Inc.; receives publishing royalties for Neuromuscular Disease: Evidence and Analysis in Clinical Neurology (Humana Press, 2006), BluePrints in Neurology (Lippincott Williams & Wilkins, 2002), and Field of Vision: A Manual and Atlas of Perimetry (Humana Press, 2010); receives/has received research support from CytRx Corporation, the Muscular Dystrophy Association, the ALS Association, the Food and Drug Administration, and the Centers for Disease Control and Prevention, theWoodruff Health Sciences Center (Emory University), and the NIH; and has participated in medico-legal cases. J. M. Shefner serves on a DSMB for the NIH; serves as Neuromuscular Section Editor for and receives publishing royalties from UpToDate; has served as a consultant for Teva Pharmaceutical Industries Ltd., Gilead Sciences, Inc., GlaxoSmithKline, Trophos, and BrainGate; and receives research support from Isis Pharmaceuticals, Inc., Neuralstem, Inc., GlaxoSmithKline, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd., Knopp Neurosciences Inc., Cytokinetics Inc., the NIH, and the ALS Association. NR 26 TC 42 Z9 42 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1748-2968 J9 AMYOTROPH LATERAL SC JI Amyotroph. Lateral. Scler. PD SEP PY 2012 VL 13 IS 5 BP 439 EP 445 DI 10.3109/17482968.2012.688837 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 989UD UT WOS:000307585200005 PM 22670883 ER PT J AU Horibe, M Nair, BG Yurina, G Neradilek, MB Rozet, I AF Horibe, Mayumi Nair, Bala G. Yurina, Gary Neradilek, Moni B. Rozet, Irene TI A Novel Computerized Fading Memory Algorithm for Glycemic Control in Postoperative Surgical Patients SO ANESTHESIA AND ANALGESIA LA English DT Article ID CRITICALLY-ILL PATIENTS; INTENSIVE INSULIN THERAPY; GLUCOSE CONTROL; DELIVERY; VARIABILITY; MORTALITY; INFUSION; RELEASE; TRIAL AB BACKGROUND: Hyperglycemia is commonly encountered in critically ill patients and is associated with increased mortality and morbidity. To better control blood glucose levels, we previously developed a new computerized fading memory (FM) algorithm.(1) In this study we evaluated the safety and efficacy of this algorithm in surgical intensive care unit (SICU) patients and compared its performance against the existing insulin-infusion algorithm (named VA algorithm) used in our institution. METHODS: A computer program was developed to run the FM and VA algorithms. Forty eight patients, who were scheduled to have elective surgery, were randomly assigned to receive insulin infusion on the basis of either the FM or VA algorithm. On SICU admission, an insulin infusion was either continued from the operating room or initiated when the glucose level exceeded the target level of 140 mg/dL. Hourly blood glucose measurements were performed and entered into the computer program, which then prescribed the next insulin dose. The randomly assigned algorithm was applied for the first 8 hours of SICU stay, after which the VA algorithm was used. The number of episodes of hypoglycemia (glucose <60 mg/dL) and excessive hyperglycemia (>300 mg/dL) were noted. Additionally, the time required to bring the glucose level within target range (140 +/- 20 mg/dL), the number of glucose measurements within the target range, glycemic variability, and insulin usage were analyzed and compared between the 2 algorithms. RESULTS: Patient demographics and starting glucose levels were similar between the groups. With the existing VA algorithm, 1 episode of severe hypoglycemia was observed. Three patients did not reach the target range within 8 hours. With the FM algorithm no hypoglycemia occurred, and all patients achieved the target range within 8 hours. Glycemic variability measured by the SD of mean glucose levels was 28% (95% confidence interval, 14% to 39%) lower for the FM algorithm (P < 0.001). The FM algorithm used 1.1 U/h less insulin than did the VA algorithm (P = 0.043). CONCLUSION: The novel computerized FM algorithm for glycemic control, which emulates physiologic biphasic insulin secretion, managed glucose better than the existing algorithm without any episodes of hypoglycemia. The FM algorithm had less glycemic variability and used less insulin when compared to the conventional clinical algorithm. (Anesth Analg 2012;115:580-7) C1 [Horibe, Mayumi; Yurina, Gary; Rozet, Irene] VA Puget Sound Hlth Care Syst, Dept Anesthesiol, Seattle, WA 98108 USA. [Horibe, Mayumi; Nair, Bala G.; Rozet, Irene] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Neradilek, Moni B.] Mt Whisper Light Stat, Seattle, WA USA. RP Horibe, M (reprint author), VA Puget Sound Hlth Care Syst, Dept Anesthesiol, Mail Stop S-112-ANES,1660 S Columbian Way, Seattle, WA 98108 USA. EM Mayumi.Horibe@va.gov FU Anesthesiology and Pain Medicine Department of the University of Washington; Washington State Society of Anesthesiologists FX This study was funded by a new investigator seed fund provided by the Anesthesiology and Pain Medicine Department of the University of Washington as well as a Seafair Education and Research Grant by the Washington State Society of Anesthesiologists. NR 32 TC 5 Z9 5 U1 0 U2 1 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 2012 VL 115 IS 3 BP 580 EP 587 DI 10.1213/ANE.0b013e318259ee31 PG 8 WC Anesthesiology SC Anesthesiology GA 994PI UT WOS:000307942900015 PM 22669346 ER PT J AU Frick, CG Blobner, M Martyn, JAJ AF Frick, Christiane G. Blobner, Manfred Martyn, J. A. Jeevendra TI Animal Studies with Botulinum Toxins May Produce Misleading Results Response SO ANESTHESIA AND ANALGESIA LA English DT Letter ID MUSCULOSKELETAL-TISSUE ALLOGRAFTS; NEUROMUSCULAR BLOCKADE; DRUG-USERS; INFECTIONS C1 [Frick, Christiane G.; Blobner, Manfred] Tech Univ Munich, Klin Anaesthesiol, Munich, Germany. [Martyn, J. A. Jeevendra] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Martyn, J. A. Jeevendra] Harvard Univ, Shriners Hosp Children, Sch Med, Boston, MA USA. RP Frick, CG (reprint author), Tech Univ Munich, Klin Anaesthesiol, Munich, Germany. EM c.frick@lrz.tu-muenchen.de NR 10 TC 0 Z9 0 U1 0 U2 1 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 2012 VL 115 IS 3 BP 736 EP 737 DI 10.1213/ANE.0b013e318263c911 PG 2 WC Anesthesiology SC Anesthesiology GA 994PI UT WOS:000307942900039 ER PT J AU Gao, S Seker, E Casali, M Wang, FJ Bale, SS Price, GM Yarmush, ML AF Gao, Shan Seker, Erkin Casali, Monica Wang, Fangjing Bale, Shyam Sundhar Price, Gavrielle M. Yarmush, Martin L. TI Ex Vivo Gene Delivery to Hepatocytes: Techniques, Challenges, and Underlying Mechanisms SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Non-viral transfection; Lentiviruses; Primary rat hepatocytes; Huh7.5.1; Transfection efficiency; Hepatic function ID LIVING CELL ARRAY; C VIRUS-INFECTION; LENTIVIRAL VECTORS; RETROVIRAL VECTORS; STEM-CELLS; IN-VIVO; SANDWICH CONFIGURATION; ADENOASSOCIATED VIRUS; EXTRACELLULAR-MATRIX; REPORTER CELLS AB Gene delivery to primary hepatocytes is an important tool for a number of applications including the study of liver cell biology and pathology, drug screening, and gene therapy. Robust transfection of primary hepatocytes, however, is significantly more difficult to achieve than in cell lines or readily dividing primary cells. In this report, we investigated in vitro gene delivery to both primary rat hepatocytes and Huh7.5.1 cells (a hepatoma cell line) using a number of viral and non-viral methods, including Lipofectamine 2000, FuGene HD, Nucleofection, Magnetofection, and lentiviruses. Our results showed that Lipofectamine 2000 is the most efficient reagent for green fluorescent protein (GFP) gene delivery to primary rat hepatocytes (33.3 +/- A 1.8% transfection efficiency) with minimal adverse effect on several hepatic functions, such as urea and albumin secretion. The lentiviral vectors used in this study exhibited undetectable gene delivery to primary rat hepatocytes but significant delivery to Huh7.5.1 cells (> 80% transfection efficiency). In addition, we demonstrated lentiviral-based and spatially defined delivery of the GFP gene to Huh7.5.1 cells for use in biological microelectromechanical systems. C1 [Gao, Shan; Casali, Monica; Wang, Fangjing; Bale, Shyam Sundhar; Price, Gavrielle M.; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Gao, Shan; Casali, Monica; Wang, Fangjing; Bale, Shyam Sundhar; Price, Gavrielle M.; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA 02114 USA. [Seker, Erkin] Univ Calif Davis, Dept Elect & Comp Engn, Davis, CA 95616 USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Yarmush, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org OI Seker, Erkin/0000-0003-2401-3562 FU NIH/NBIB [(P41) EB002503]; Shriners Hospitals for Children in Boston; Massachusetts General Hospital Fund for Medical Discovery award [217035] FX We thank Drs. Stelios Andreadis and Feng Zhang for providing us dual fluorescent lentivirses (GAS-RE), pVSV-G and p Delta vectors, respectively. Authors gratefully acknowledge support by NIH/NBIB (P41) EB002503 and Shriners Hospitals for Children in Boston. ES acknowledges support by Massachusetts General Hospital Fund for Medical Discovery award 217035. NR 43 TC 5 Z9 5 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD SEP PY 2012 VL 40 IS 9 BP 1851 EP 1861 DI 10.1007/s10439-012-0555-y PG 11 WC Engineering, Biomedical SC Engineering GA 987FB UT WOS:000307400900001 PM 22484829 ER PT J AU Skwara, AJ Karwoski, TE Czambel, RK Rubin, RT Rhodes, ME AF Skwara, Amanda J. Karwoski, Tracy E. Czambel, R. Kenneth Rubin, Robert T. Rhodes, Michael E. TI Influence of environmental enrichment on hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine, continuous nicotine by osmotic mini-pumps, and nicotine withdrawal by mecamylamine in male and female rats SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Environmental enrichment; HPA axis; Mecamylamine; Nicotine; Sexual diergism; Withdrawal ID CENTRAL-NERVOUS-SYSTEM; SEXUAL DIERGISM; AXIS RESPONSES; CHOLINERGIC STIMULATION; PSYCHOLOGICAL STRESS; MESOLIMBIC DOPAMINE; ADRENOCORTICAL AXIS; ABSTINENCE SYNDROME; COCAINE ADDICTION; LABORATORY RATS AB In the present study, we determined the effects of environmental enrichment (EE; Kong Toys (R) and Nestlets (R)) on sexually diergic HPA axis responses to single-dose nicotine (NIC), single-dose NIC following continuous NIC administration for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) in male and female rats. Blood sampling occurred before and after MEC and NIC administrations for the determination of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Supporting and extending our previous findings, EE appeared to produce anxiolytic effects by reducing hormone responses: Male and female rats housed with EE had lower baseline ACTH and significantly lower HPA axis responses to the mild stress of saline (SAL) injection than did those housed without EE. The sexually diergic responses to single dose NIC, continuous NIC, and MEC-induced NIC withdrawal were reduced by EE in many male and female groups. ACTH responses to continuous NIC and MEC-induced NIC withdrawal were blunted to a greater extent in female EE groups than in male EE groups, suggesting that females are more sensitive to the anxiolytic effects of EE. Because EE lowered stress-responsive hormones of the HPA axis in most groups, EE may be a useful intervention for stress reduction in animal models of NIC addiction. As well, the effectiveness of EE in animal studies of NIC withdrawal may enlighten human studies addressing coping styles and tobacco cessation in men and women. (C) 2012 Elsevier B.V. All rights reserved. C1 [Skwara, Amanda J.; Rhodes, Michael E.] St Vincent Coll, Dept Biol, Latrobe, PA 15650 USA. [Karwoski, Tracy E.; Czambel, R. Kenneth] Allegheny Gen Hosp, Neurosci Res Ctr, Pittsburgh, PA 15212 USA. [Rubin, Robert T.] VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. [Rubin, Robert T.] Univ Calif Los Angeles, Dept Psychiat, Pittsburgh, PA USA. RP Rhodes, ME (reprint author), St Vincent Coll, Dept Biol, 300 Fraser Purchase Rd, Latrobe, PA 15650 USA. EM michael.rhodes@email.stvincent.edu FU Department of Health Tobacco Settlement Funds; NIH [MH28380] FX The technical assistance of Natalie E. Gentile and Julie D. Andrekanic is gratefully acknowledged. Supported by 2004 Department of Health Tobacco Settlement Funds to MER and by NIH grant MH28380 to RTR. NR 82 TC 19 Z9 19 U1 3 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD SEP 1 PY 2012 VL 234 IS 1 BP 1 EP 10 DI 10.1016/j.bbr.2012.06.003 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 991HV UT WOS:000307693000001 PM 22705101 ER PT J AU Dhonnchadha, BAN Lovascio, BF Shrestha, N Lin, A Leite-Morris, KA Man, HY Kaplan, GB Kantak, KM AF Dhonnchadha, B. A. Nic Lovascio, B. F. Shrestha, N. Lin, A. Leite-Morris, K. A. Man, H. Y. Kaplan, G. B. Kantak, K. M. TI Changes in expression of c-Fos protein following cocaine-cue extinction learning SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Basolateral amygdala; c-Fos protein; Cocaine; Extinction learning; GluR2 protein; Self-administration ID DRUG-SEEKING BEHAVIOR; BASOLATERAL AMYGDALA; FEAR EXTINCTION; AMPA RECEPTORS; INDUCED REINSTATEMENT; NUCLEUS-ACCUMBENS; CONDITIONED CUES; RATS; CONSOLIDATION; INACTIVATION AB Extinguishing abnormally strengthened learned responses to cues associated with drugs of abuse remains a key tactic for alleviating addiction. To assist in developing pharmacotherapies to augment exposure therapy for relapse prevention, investigation into neurobiological underpinnings of drug-cue extinction learning is needed. We used regional analyses of c-Fos and GluR2 protein expression to delineate neural activity and plasticity that may be associated with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a light cue, and later underwent a single 2 h extinction session for which cocaine was withheld but response-contingent cues were presented (cocaine-cue extinction). Control groups consisted of rats yoked to animals self-administering cocaine and receiving saline non-contingently followed by an extinction session, or rats trained to self-administer cocaine followed by a no-extinction session for which levers were retracted, and cocaine and cues were withheld. Among 11 brain sites examined, extinction training increased c-Fos expression in basolateral amygdala and prelimbic prefrontal cortex of cocaine-cue extinguished rats relative to both control conditions. In dorsal subiculum and infralimbic prefrontal cortex, extinction training increased c-Fos expression in both cocaine-cue and saline-cue extinguished rats relative to the no-extinction control condition. GluR2 protein expression was not altered in any site examined after extinction or control training. Findings suggest that basolateral amygdala and prelimbic prefrontal cortex neurons are activated during acquisition of cocaine-cue extinction learning, a process that is independent of changes in GluR2 abundance. Other sites are implicated in processing the significance of cues that are present early in extinction training. (C) 2012 Elsevier B.V. All rights reserved. C1 [Dhonnchadha, B. A. Nic; Lovascio, B. F.; Shrestha, N.; Kantak, K. M.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Lin, A.; Man, H. Y.] Boston Univ, Dept Biol, Boston, MA 02215 USA. [Leite-Morris, K. A.; Kaplan, G. B.] VA Boston Healthcare, Res & Mental Hlth Serv, Boston, MA USA. [Leite-Morris, K. A.; Kaplan, G. B.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Leite-Morris, K. A.; Kaplan, G. B.] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02215 USA. RP Kantak, KM (reprint author), Boston Univ, Dept Psychol, 64 Cummington St, Boston, MA 02215 USA. EM kkantak@bu.edu OI Leite-Morris, Kimberly/0000-0003-3407-7375 FU Boston University Center for Neuroscience; [DA024315]; [DA024315-S1] FX This study was supported by DA024315, DA024315-S1 and seed funding from the Boston University Center for Neuroscience. We thank Carolyn Kirkman, Angela J. Young and Marsha D. Guy for expert technical assistance. NR 54 TC 8 Z9 8 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD SEP 1 PY 2012 VL 234 IS 1 BP 100 EP 106 DI 10.1016/j.bbr.2012.06.010 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 991HV UT WOS:000307693000014 ER PT J AU Faje, AT Fazeli, PK Katzman, DK Miller, KK Breggia, A Rosen, CJ Mendes, N Klibanski, A Misra, M AF Faje, Alexander T. Fazeli, Pouneh K. Katzman, Debra K. Miller, Karen K. Breggia, Anne Rosen, Clifford J. Mendes, Nara Klibanski, Anne Misra, Madhusmita TI Sclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls SO BONE LA English DT Article DE Anorexia nervosa; Sclerostin; Osteoporosis ID SERUM SCLEROSTIN; POSTMENOPAUSAL WOMEN; PRIMARY HYPERPARATHYROIDISM; CIRCULATING SCLEROSTIN; PARATHYROID-HORMONE; SOST; ESTROGEN; DENSITY; OSTEOPOROSIS; METABOLISM AB Sclerostin, product of the SOST gene, is an important determinant of bone formation and resorption. Adolescents with anorexia nervosa (AN) have low bone density and decreased levels of bone turnover markers. However, sclerostin has not been examined in AN as a potential mediator of impaired bone metabolism. Our study objectives were to (i) assess associations of sclerostin with surrogate bone turnover markers in girls with AN and controls and (ii) examine effects of transdermal estradiol on sclerostin in AN. 69 girls (44 with AN and 25 normal-weight controls) 13-18 years old were studied at baseline. 22 AN girls were randomized to transdermal estradiol (plus cyclic medroxyprogesterone) or placebo in a double-blind study for 12 months. Sclerostin correlated positively with P1NP and CTX in controls (r=0.67 and 0.53, p=0.0002 and 0.005, respectively) but not in AN despite comparable levels at baseline. Changes in sclerostin over twelve months did not differ in girls randomized to estradiol or placebo. The relationship between sclerostin and bone turnover markers is disrupted in adolescent girls with AN. Despite an increase in BMD with estradiol administration in AN, estrogen does not impact sclerostin levels in this group. (C) 2012 Elsevier Inc. All rights reserved. C1 [Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, Boston, MA 02114 USA. [Faje, Alexander T.; Fazeli, Pouneh K.; Miller, Karen K.; Mendes, Nara; Klibanski, Anne; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. [Katzman, Debra K.] Hosp Sick Children, Div Adolescent Med, Toronto, ON M5G 1X8, Canada. [Breggia, Anne; Rosen, Clifford J.] Maine Med Ctr, Res Inst, Portland, ME 04074 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, 55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org RI Mendes Estella, Nara/E-4682-2013; Mendes Estella, Nara/A-1469-2015 FU NIH [UL1 RR025758-01, R01 DK062249] FX This study was supported by NIH grants UL1 RR025758-01 and R01 DK062249. NR 36 TC 16 Z9 16 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD SEP PY 2012 VL 51 IS 3 BP 474 EP 479 DI 10.1016/j.bone.2012.06.006 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990FW UT WOS:000307617400020 PM 22728230 ER PT J AU Battaglino, RA Sudhakar, S Lazzari, AA Garshick, E Zafonte, R Morse, LR AF Battaglino, Ricardo A. Sudhakar, Supreetha Lazzari, Antonio A. Garshick, Eric Zafonte, Ross Morse, Leslie R. TI Circulating sclerostin is elevated in short-term and reduced in long-term SCI SO BONE LA English DT Article DE Osteoporosis; Sclerostin; Spinal cord injury; Rehabilitation medicine ID SPINAL-CORD-INJURY; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; SERUM SCLEROSTIN; OSTEOPOROSIS; CORRELATE AB Spinal cord injury (SCI) causes profound bone loss due to muscle paralysis resulting in the inability to walk. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short-term studies in rodent models have demonstrated increased sclerostin in response to mechanical unloading that is reversed with reloading. Although sclerostin inhibition has been proposed as a potential therapy for bone loss, it is not known if sclerostin levels vary with duration of SCI in humans. We analyzed circulating sclerostin in 155 men with varying degrees of SCI who were 1 year or more post-injury. We report that sclerostin levels are greatest in subjects with short-term SCI (<= 5 years post-injury) and decrease significantly over the first 5 years post-injury. There was no association between sclerostin and injury duration in subjects with long-term SCI (>5 years post-injury). In subjects with long-term SCI, sclerostin levels were positively associated with lower extremity bone density and bone mineral content. These data suggest that sclerostin levels are initially increased after SCI in response to mechanical unloading. This response is time-limited and as bone loss progresses, circulating sclerostin is lowest in subjects with severe osteoporosis. These findings support a dual role for sclerostin after SCI: a therapeutic target in acute SCI, and a biomarker of osteoporosis severity in chronic SCI. (C) 2012 Elsevier Inc. All rights reserved. C1 [Zafonte, Ross; Morse, Leslie R.] Harvard Univ, Sch Med, Dept PMR, Boston, MA 02114 USA. [Battaglino, Ricardo A.; Morse, Leslie R.] Forsyth Inst, Cambridge, MA USA. [Battaglino, Ricardo A.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02114 USA. [Sudhakar, Supreetha; Zafonte, Ross; Morse, Leslie R.] Spaulding Rehabil Hosp, Spaulding Harvard SCI Model Syst, Boston, MA USA. [Lazzari, Antonio A.] VA Boston Healthcare Syst, Primary Care Sect, Boston, MA USA. [Lazzari, Antonio A.] VA Boston Healthcare Syst, Rheumatol Sect, Boston, MA USA. [Lazzari, Antonio A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Garshick, Eric] VA Boston Healthcare Syst, Med Serv, Pulm & Crit Care Med Sect, Boston, MA USA. [Garshick, Eric] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Lab, Boston, MA 02114 USA. RP Morse, LR (reprint author), Harvard Univ, Sch Med, Dept PMR, 125 Nashua St, Boston, MA 02114 USA. EM lmorse4@partners.org RI battaglino, ricardo/D-2892-2015; Morse, Leslie/C-9442-2015 OI Morse, Leslie/0000-0002-7426-6341 FU National Institute of Child Health and Human Development [R21HD057030, R21HD057030-02S1]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [1R01AR059270-02]; Office of Research and Development, Rehabilitation Research and Development [B6618R]; Massachusetts Veterans Epidemiology Research and Information Center, Cooperative Studies Program, Department of Veterans Affairs FX 0This study received support from: the National Institute of Child Health and Human Development [R21HD057030 and R21HD057030-02S1], the National Institute of Arthritis and Musculoskeletal and Skin Diseases [1R01AR059270-02], the Office of Research and Development, Rehabilitation Research and Development [Merit Review Grant B6618R], and the Massachusetts Veterans Epidemiology Research and Information Center, Cooperative Studies Program, Department of Veterans Affairs. NR 18 TC 16 Z9 17 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD SEP PY 2012 VL 51 IS 3 BP 600 EP 605 DI 10.1016/j.bone.2012.04.019 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990FW UT WOS:000307617400036 PM 22575440 ER PT J AU Azagury, DE Ryou, M Shaikh, SN Estepar, RS Lengyel, BI Jagadeesan, J Vosburgh, KG Thompson, CC AF Azagury, D. E. Ryou, M. Shaikh, S. N. Estepar, R. San Jose Lengyel, B. I. Jagadeesan, J. Vosburgh, K. G. Thompson, C. C. TI Real-time computed tomography-based augmented reality for natural orifice transluminal endoscopic surgery navigation SO BRITISH JOURNAL OF SURGERY LA English DT Article ID LAPAROSCOPIC PERITONEOSCOPY; TRANSGASTRIC NOTES; METASTASES; TRIAL AB Background: Natural orifice transluminal endoscopic surgery (NOTES) is technically challenging owing to endoscopic short-sighted visualization, excessive scope flexibility and lack of adequate instrumentation. Augmented reality may overcome these difficulties. This study tested whether an image registration system for NOTES procedures (IR-NOTES) can facilitate navigation. Methods: In three human cadavers 15 intra-abdominal organs were targeted endoscopically with and without IR-NOTES via both transgastric and transcolonic routes, by three endoscopists with different levels of expertise. Ease of navigation was evaluated objectively by kinematic analysis, and navigation complexity was determined by creating an organ access complexity score based on the same data. Results: Without IR-NOTES, 21 (11.7 per cent) of 180 targets were not reached (expert endoscopist 3, advanced 7, intermediate 11), compared with one (1 per cent) of 90 with IR-NOTES (intermediate endoscopist) (P = 0.002). Endoscope movements were significantly less complex in eight of the 15 listed organs when using IR-NOTES. The most complex areas to access were the pelvis and left upper quadrant, independently of the access route. The most difficult organs to access were the spleen (5 failed attempts; 3 of 7 kinematic variables significantly improved) and rectum (4 failed attempts; 5 of 7 kinematic variables significantly improved). The time needed to access the rectum through a transgastric approach was 206.3 s without and 54.9 s with IR-NOTES (P = 0.027). Conclusion: The IR-NOTES system enhanced both navigation efficacy and ease of intra-abdominal NOTES exploration for operators of all levels. The system rendered some organs accessible to non-expert operators, thereby reducing one impediment to NOTES procedures. Copyright (c) 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. C1 [Ryou, M.; Shaikh, S. N.; Thompson, C. C.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Estepar, R. San Jose; Lengyel, B. I.; Vosburgh, K. G.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Azagury, D. E.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Jagadeesan, J.] Massachusetts Gen Hosp, Ctr Integrat Med, Boston, MA 02114 USA. [Jagadeesan, J.] Massachusetts Gen Hosp, Innovat Technol Image Guidance Lab, Boston, MA 02114 USA. RP Thompson, CC (reprint author), Brigham & Womens Hosp, Div Gastroenterol, 75 Francis St,ASB 2, Boston, MA 02115 USA. EM cthompson@hms.harvard.edu OI Azagury, Dan/0000-0002-3992-8792 FU Center for Integration of Medicine and Innovative Technology under US Army Medical Research Acquisition Activity Cooperative Agreement [W81XWH-09-2-0001]; National Heart Lung and Blood Institute [K25HL104085]; National Institutes of Health [R25 CA089017] FX The authors thank Vaibhav Patil, Inbar Spofford, Keith Obstein and Michele B. Ryan for their invaluable time and contribution throughout this project. This work was supported by the Center for Integration of Medicine and Innovative Technology under US Army Medical Research Acquisition Activity Cooperative Agreement W81XWH-09-2-0001. R.S.J.E. was supported by award no. K25HL104085 from the National Heart Lung and Blood Institute, and B.I.L. by National Institutes of Health grant R25 CA089017. The information contained herein is solely the responsibility of the authors and does not necessarily reflect the position or policy of the Government, the National Heart Lung and Blood Institute or the National Institutes of Health, and no official endorsement should be inferred. NR 19 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1323 J9 BRIT J SURG JI Br. J. Surg. PD SEP PY 2012 VL 99 IS 9 BP 1246 EP 1253 DI 10.1002/bjs.8838 PG 8 WC Surgery SC Surgery GA 982UO UT WOS:000307071100014 PM 22864885 ER PT J AU Maan, A Padmanabhan, R Shaikh, AY Mansour, M Ruskin, JN Heist, EK AF Maan, Abhishek Padmanabhan, Ram Shaikh, Amir Y. Mansour, Moussa Ruskin, Jeremy N. Heist, E. Kevin TI Newer Anticoagulants in Cardiovascular Disease A Systematic Review of the Literature SO CARDIOLOGY IN REVIEW LA English DT Review DE oral anticoagulants; vitamin K antagonist; factor Xa inhibitor; direct thrombin inhibitor ID FACTOR-XA INHIBITOR; DIRECT THROMBIN INHIBITOR; ORAL DIRECT THROMBIN; NONVALVULAR ATRIAL-FIBRILLATION; ACUTE CORONARY SYNDROME; TOTAL KNEE REPLACEMENT; TOTAL HIP-REPLACEMENT; HEALTHY MALE-SUBJECTS; RANDOMIZED CONTROLLED-TRIAL; VITAMIN-K ANTAGONISTS AB Vitamin K antagonists (VKAs) such as warfarin have traditionally been the major therapeutic option for anticoagulation in clinical practice. VKAs are effective and extensively recommended for the prevention of venous and arterial thromboembolism in cardiovascular disease. Despite its effectiveness, warfarin is limited by factors such as a narrow therapeutic index, drug-drug interactions, food interactions, slow onset and offset of action, hemorrhage, and routine anticoagulation monitoring to maintain therapeutic international normalized ratio. During the last 2 decades, the approval of anticoagulants, such as low-molecular-weight heparins, indirect factor Xa inhibitors (eg, fondaparinux), and direct thrombin inhibitors (eg, argatroban, lepirudin, and desirudin), have expanded the number of available antithrombotic compounds with additional targets within the anticoagulation pathway. Although these medications offer several potential therapeutic advantages, they all require parenteral or subcutaneous administration and are substantially more expensive than VKAs. Thus, VKAs, despite several limitations, have remained the major option for most patients requiring chronic anticoagulation. These limitations have prompted interest in the development of newer oral anticoagulants. Novel anticoagulants targeting inhibition of factor Xa and thrombin (factor Ha) have now been incorporated into clinical practice based on the results of large randomized clinical trials, with the recent U.S. Food and Drug Administration approval of dabigatran for stroke prevention in atrial fibrillation and rivaroxaban for deep vein thrombosis and stroke prevention in atrial fibrillation, with multiple other agents in various stages of development for these and other indications. This review discusses the pharmacological properties, clinical results, and therapeutic applications of novel and new anticoagulants, thereby providing an outline for the future of anticoagulation in cardiovascular disease. C1 [Mansour, Moussa; Ruskin, Jeremy N.; Heist, E. Kevin] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Maan, Abhishek; Padmanabhan, Ram; Shaikh, Amir Y.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Mansour, Moussa; Ruskin, Jeremy N.; Heist, E. Kevin] Harvard Univ, Sch Med, Boston, MA USA. RP Heist, EK (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. EM kheist@partners.org FU Endosense; MC10; St. Jude Medical; Voyage Medical; Boston Scientific FX M.M.: Biosense-Webster (consultant), Boston Scientific (consultant), Cardiofocus (research grant), Endosense (research grant), MC10 (research grant), Medtronic (consultant), St. Jude Medical (consultant, research grant), Voyage Medical (research grant). J.N.R.: Astellas/Cardiome-Consultant (significant); Biosense Webster-Consultant (modest) and Fellowship Support (significant); Boston Scientific-Fellowship Support (significant); CardioFocus-Clinical Oversight Committee (no compensation); Cardiolnsight-Scientific Advisory Board (modest); CryoCath-Scientific Steering Committee (no compensation); Medtronic-Consultant (modest) and Fellowship Support (significant); Med-IQ-Honoraria (modest); Pfizer-Consultant and Scientific Steering Committee (modest); Portola-Consultant and equity (modest); Sanofi-Consultant (modest), St. Jude Medical -Fellowship Support (significant); Third Rock Ventures- consultant (significant). E.K.H.: (all modest in amount): Biotronik (research grant, honoraria), Boston Scientific (research grant, consultant, honoraria), Medtronic (honoraria), Sanofi (consultant), Sorin (consultant, honoraria), St. Jude Medical (research grant, consultant, honoraria). The remaining authors have not disclosed any potential conflicts of interest. NR 128 TC 14 Z9 14 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1061-5377 J9 CARDIOL REV JI Cardiol. Rev. PD SEP-OCT PY 2012 VL 20 IS 5 BP 209 EP 221 DI 10.1097/CRD.0b013e3182503e2d PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 991BV UT WOS:000307676700001 PM 22370770 ER PT J AU Zappaterra, MW Lehtinen, MK AF Zappaterra, Mauro W. Lehtinen, Maria K. TI The cerebrospinal fluid: regulator of neurogenesis, behavior, and beyond SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Cerebrospinal fluid; Choroid plexus; Neurogenesis; Traumatic brain injury ID TRAUMATIC BRAIN-INJURY; CENTRAL-NERVOUS-SYSTEM; FIBROBLAST-GROWTH-FACTOR; FOCAL CEREBRAL-ISCHEMIA; REDUCES INFARCT VOLUME; TUMOR-NECROSIS-FACTOR; HINDBRAIN CHOROID-PLEXUS; BINDING-PROTEINS IGFBPS; CORTICAL IMPACT INJURY; FACTOR-II GENE AB The cerebrospinal fluid (CSF) has attracted renewed interest as an active signaling milieu that regulates brain development, homeostasis, and disease. Advances in proteomics research have enabled an improved characterization of the CSF from development through adulthood, and key neurogenic signaling pathways that are transmitted via the CSF are now being elucidated. Due to its immediate contact with neural stem cells in the developing and adult brain, the CSF's ability to swiftly distribute signals across vast distances in the central nervous system is opening avenues to novel and exciting therapeutic approaches. In this review, we will discuss the development of the choroid plexus-CSF system, and review the current literature on how the CSF actively regulates mammalian brain development, behavior, and responses to traumatic brain injury. C1 [Lehtinen, Maria K.] Harvard Univ, Childrens Hosp Boston, Dept Pathol, Sch Med, Boston, MA 02115 USA. [Zappaterra, Mauro W.] VA Greater Los Angeles Healthcare Syst, Dept Phys Med & Rehabil, Los Angeles, CA 90073 USA. RP Lehtinen, MK (reprint author), Harvard Univ, Childrens Hosp Boston, Dept Pathol, Sch Med, 300 Longwood Ave, Boston, MA 02115 USA. EM mauro.zappaterra@ucla.edu; maria.lehtinen@childrens.harvard.edu FU Eleanor and Miles Shore Fellowship Program for Scholars in Medicine/Children's Hospital Boston Career Development Award; NIH [R00 NS072192] FX We thank V. Ho and A. Malesz for critical reading of this manuscript. We are grateful for support from the Eleanor and Miles Shore Fellowship Program for Scholars in Medicine/Children's Hospital Boston Career Development Award, and the NIH (Award number R00 NS072192). M.K.L. is an Alfred P. Sloan Research Fellow. NR 183 TC 44 Z9 46 U1 1 U2 15 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD SEP PY 2012 VL 69 IS 17 BP 2863 EP 2878 DI 10.1007/s00018-012-0957-x PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 988UQ UT WOS:000307516600005 PM 22415326 ER PT J AU Fatemi, SH Aldinger, KA Ashwood, P Bauman, ML Blaha, CD Blatt, GJ Chauhan, A Chauhan, V Dager, SR Dickson, PE Estes, AM Goldowitz, D Heck, DH Kemper, TL King, BH Martin, LA Millen, KJ Mittleman, G Mosconi, MW Persico, AM Sweeney, JA Webb, SJ Welsh, JP AF Fatemi, S. Hossein Aldinger, Kimberly A. Ashwood, Paul Bauman, Margaret L. Blaha, Charles D. Blatt, Gene J. Chauhan, Abha Chauhan, Ved Dager, Stephen R. Dickson, Price E. Estes, Annette M. Goldowitz, Dan Heck, Detlef H. Kemper, Thomas L. King, Bryan H. Martin, Loren A. Millen, Kathleen J. Mittleman, Guy Mosconi, Matthew W. Persico, Antonio M. Sweeney, John A. Webb, Sara J. Welsh, John P. TI Consensus Paper: Pathological Role of the Cerebellum in Autism SO CEREBELLUM LA English DT Review DE Cerebellum; Autism ID FRAGILE-X-SYNDROME; FUNCTIONAL MAGNETIC-RESONANCE; PERVASIVE DEVELOPMENTAL DISORDERS; LYMPHOCYTE CYTOKINE PROFILES; PURKINJE-CELL DEGENERATION; TUBEROUS SCLEROSIS COMPLEX; RECEPTOR TYROSINE KINASE; LHERMITTE-DUCLOS-DISEASE; GAMMA-AMINOBUTYRIC-ACID; MESSENGER-RNA LEVELS AB There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation. C1 [Fatemi, S. Hossein] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Aldinger, Kimberly A.] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Ashwood, Paul] Univ Calif Davis, Dept Med Microbiol & Immunol, Med Invest Neurodev Disorders MIND Inst, Davis, CA 95616 USA. [Bauman, Margaret L.] Harvard Univ, Sch Med, Boston, MA USA. [Bauman, Margaret L.] Massachusetts Gen Hosp, Dept Pediat & Neurol, Boston, MA 02114 USA. [Blaha, Charles D.; Dickson, Price E.; Mittleman, Guy] Univ Memphis, Dept Psychol, Memphis, TN 38152 USA. [Blatt, Gene J.; Kemper, Thomas L.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Chauhan, Abha; Chauhan, Ved] NYS Inst Basic Res Dev Disabil, Staten Isl, NY USA. [Dager, Stephen R.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Dager, Stephen R.] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Dager, Stephen R.; Estes, Annette M.] Univ Washington, Autism Ctr, Seattle, WA 98195 USA. [Goldowitz, Dan] Univ British Columbia, Dept Med Genet, Ctr Mol Med & Therapeut, Vancouver, BC, Canada. [Heck, Detlef H.] Univ Tennessee, Dept Anat & Neurobiol, Hlth Sci Ctr, Memphis, TN USA. [King, Bryan H.; Webb, Sara J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle Childrens Autism Ctr, Seattle, WA 98195 USA. [Martin, Loren A.] Azusa Pacific Univ, Dept Psychol, Azusa, CA USA. [Mosconi, Matthew W.; Sweeney, John A.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Mosconi, Matthew W.; Sweeney, John A.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Persico, Antonio M.] Univ Campus Biomed, Child Neuropsychiat Unit, Lab Mol Psychiat & Neurogenet, Rome, Italy. [Persico, Antonio M.] IRCCS Fdn Santa Lucia, Dept Expt Neurosci, Rome, Italy. [Welsh, John P.] Univ Washington, Dept Pediat, Ctr Integrat Brain Res, Seattle Childrens Res Inst, Seattle, WA 98195 USA. RP Fatemi, SH (reprint author), Univ Minnesota, Sch Med, 420 Delaware St SE,MMC 392, Minneapolis, MN 55455 USA. EM fatem002@umn.edu OI Persico, Antonio/0000-0001-8910-4479; Blaha, Charles/0000-0001-5155-1505 FU Alfred and Ingrid Lenz Harrison Autism Initiative; Autism Speaks Foundation; Jane Botsford Johnson Foundation; National Alliance for Research on Schizophrenia and Depression; National Institute of Neurological Disorders and Stroke [R21HD065269]; Peter Emch Foundation; Nancy Lurie Marks Family Foundation; NINDS [NS38975-05]; NAAR/Autism Speaks; Autism Speaks [4853]; NIH/NINDS [R01 NS063009]; Hussman Foundation; Department of Defense [AS073224P2]; Autism Research Institute; Autism Collaboration (autism.org); NYS Office for People with Developmental Disabilities; Autism Centers of Excellence [NICHD P50-HD055782]; NICHD [HD35465 NICHD, RO1-HD055741]; ACE Network (NICHD) [HD05571]; American Recovery and Reinvestment Act [NICHD R01-HD065283]; National Institute for Neurological Disorders and Stroke [NINDS R01-NS31224-18, R01 NS31224-18]; Simons Foundation; NIH [RO1NS060887, R01NS063009]; Eunice Kennedy Shriver National Institute of Child Health & Human Development [P50 HD055782]; Autism Center of Excellence from the Eunice Kennedy Shriver NICHD [P50HD055751]; NIMH [1K23MH092696]; Janssen Foundation; Italian Ministry of University, Research and Technology [2006058195, 2008BACT54]; Italian Ministry of Health [RFPS-2007-5-640174]; Autism Research Institute (San Diego, CA); Autism Speaks (Princeton, NJ); Fondazione Gaetano e Mafalda Luce (Milan, Italy); Cure Autism now; Eunice Kennedy Shriver National Institute of Child Health and Human Development [5R01HD052074-05, 3R01HD05207403-S1] FX (1) Dr. S. Hossein Fatemi appreciates the excellent technical assistance by Rachel Elizabeth Kneeland in editing of this consensus paper, and the critical review of the manuscript by Mr. Timothy D. Folsom. Research support for Dr. Fatemi's work is from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD052074-05 and 3R01HD05207403-S1 supplemental grant), as well as the Alfred and Ingrid Lenz Harrison Autism Initiative; (2) Research support for work by Drs. Kimberly A. Aldinger and Kathleen J. Millen is from the Autism Speaks Foundation; (3) Research support for work by Dr. Paul Ashwood is from Autism Speaks Foundation, the Jane Botsford Johnson Foundation, National Alliance for Research on Schizophrenia and Depression, and National Institute of Neurological Disorders and Stroke R21HD065269, and the Peter Emch Foundation is gratefully acknowledged; (4) Research support for work by Drs. Margaret L. Bauman and Thomas L. Kemper is from the Nancy Lurie Marks Family Foundation, by NINDS (NS38975-05) and by NAAR/Autism Speaks. We would also like to acknowledge and thank the many families whose generous donation of postmortem brain tissue has made this research possible; (5) Research support for work by Drs. Charles D. Blaha, Price E. Dickson, Dan Goldowitz, Loren A. Martin, and Guy Mittleman is from Cure Autism Now, Autism Speaks, and R01 NS063009 from NIH/NINDS; (6) Research support for work by Dr. Gene Blatt is from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD039459-06) and The Hussman Foundation; (7) Research support for work by Drs. Abha Chauhan and Ved Chauhan is from the Department of Defense Autism Spectrum Disorders Research Program AS073224P2, the Autism Research Institute, the Autism Collaboration (autism.org), and the NYS Office for People with Developmental Disabilities; (8) Drs. Stephen R. Dager, Annette M. Estes, and John P. Welsh would like to thank Elizabeth Kelly for assistance in preparing their manuscript. Research support for their work is from Autism Centers of Excellence (NICHD P50-HD055782), Collaborative Programs of Excellence in Autism (NICHD #HD35465 NICHD, RO1-HD055741), ACE Network (NICHD RO1 supplement HD05571), American Recovery and Reinvestment Act (NICHD R01-HD065283), and National Institute for Neurological Disorders and Stroke (NINDS R01-NS31224-18). Support from Autism Speaks and the Simons Foundation is also gratefully acknowledged; (9) Research support for Dr. Detlef H. Heck is from NIH grants RO1NS060887 and R01NS063009. The content of this publication is solely the responsibility of the author and does not necessarily represent the official views of the NIH; (10) Research support for Drs. Bryan H. King, Sara J. Webb, and John P. Welsh is from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (P50 HD055782; King/Webb) and the National Institute for Neurological Disorders and Stroke (R01 NS31224-18; Welsh). We want to thank the families of and individuals with autism who have participated in research; (11) Research support for work by Drs. Matthew W. Mosconi and John A. Sweeney is from the Autism Center of Excellence Award Number P50HD055751 from the Eunice Kennedy Shriver NICHD, NIMH Grant 1K23MH092696, and Autism Speaks Grant 4853. Dr. John Sweeney consults with Pfizer and Takeda and has received a grant from the Janssen Foundation.; The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding institutes; (12) Research support for work by Dr. Antonio M. Persico is from the Italian Ministry of University, Research and Technology (PRIN 2006058195 and 2008BACT54), the Italian Ministry of Health (RFPS-2007-5-640174), Autism Speaks (Princeton, NJ), the Autism Research Institute (San Diego, CA), and the Fondazione Gaetano e Mafalda Luce (Milan, Italy). NR 310 TC 172 Z9 173 U1 20 U2 83 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD SEP PY 2012 VL 11 IS 3 BP 777 EP 807 DI 10.1007/s12311-012-0355-9 PG 31 WC Neurosciences SC Neurosciences & Neurology GA 985SX UT WOS:000307291500017 PM 22370873 ER PT J AU Zanni, MV Burdo, TH Makimura, H Williams, KC Grinspoon, SK AF Zanni, Markella V. Burdo, Tricia H. Makimura, Hideo Williams, Kenneth C. Grinspoon, Steven K. TI Relationship between monocyte/macrophage activation marker soluble CD163 and insulin resistance in obese and normal-weight subjects SO CLINICAL ENDOCRINOLOGY LA English DT Article ID SCAVENGER RECEPTOR CD163; NECROSIS-FACTOR-ALPHA; UP-REGULATION; RISK; ATHEROSCLEROSIS; IDENTIFICATION; INFLAMMATION; THERAPY; PLASMA; GAIN AB Context The relationship of monocyte/macrophage activation to insulin resistance in obesity is unknown. Objective To investigate a marker of macrophage activation, soluble CD163 (sCD163), in relationship to insulin resistance and metabolic parameters in obese and normal-weight subjects. Design and Participants Ninety-five healthy subjects (65 obese and 30 normal-weight) were studied. Plasma concentrations of sCD163 were assessed, as well as markers of glucose homeostasis, anthropometrics, cytokines and adipokines. The relationships between sCD163 and these parameters were investigated, and multiple regression modelling assessing the contribution of sCD163 to insulin resistance (HOMA-IR) was performed. Results Soluble CD163 was significantly increased in obese subjects compared with normal-weight controls [974 (657, 1272) ng/ml vs 599 (423, 892) ng/ml, median (IQR); P < 0.0001]. sCD163 was strongly associated with HOMA-IR (Spearmans ? = 0.37, P = 0.0003) and other metabolic parameters. In multiple regression modelling for log HOMA-IR, sCD163 remained significantly associated (P = 0.005) controlling for known mediators of insulin resistance including age, gender, visceral adiposity and inflammatory markers (model R2 = 0.54, P < 0.0001). Additional nested multiple regression models for log HOMA-IR showed that sCD163 added more than other adipokines and inflammatory markers to the prediction of HOMA-IR. Conclusions Monocyte/macrophage activation, as reflected by sCD163 levels, is strongly associated with HOMA-IR in normal-weight and obese subjects after controlling for known mediators of insulin resistance. Moreover, sCD163 adds to standard risk markers for predicting insulin resistance. These data suggest that monocyte/macrophage activation may be an important determinant of insulin resistance in obesity. C1 [Zanni, Markella V.; Makimura, Hideo; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Zanni, Markella V.; Makimura, Hideo; Grinspoon, Steven K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Burdo, Tricia H.; Williams, Kenneth C.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, LON5-207,55 Fruit St, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NIH [F32 DK085969, K23 DK087857, NS37654, NS40237, K24 DK064545, R01 HL085268] FX NIH funding was provided through F32 DK085969 to M.Z., K23 DK087857 to H. M, and NS37654 and NS40237 to K. W, and through K24 DK064545 and R01 HL085268 to S. G. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. M.Z., T.B., H.M., K.W. and S.G. have nothing to declare. NR 29 TC 34 Z9 35 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2012 VL 77 IS 3 BP 385 EP 390 DI 10.1111/j.1365-2265.2011.04284.x PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 989TL UT WOS:000307583300008 PM 22098563 ER PT J AU Lin, E Wexler, TL Nachtigall, L Tritos, N Swearingen, B Hemphill, L Loeffler, J Biller, BMK Klibanski, A Miller, KK AF Lin, E. Wexler, T. L. Nachtigall, L. Tritos, N. Swearingen, B. Hemphill, L. Loeffler, J. Biller, B. M. K. Klibanski, A. Miller, K. K. TI Effects of growth hormone deficiency on body composition and biomarkers of cardiovascular risk after definitive therapy for acromegaly SO CLINICAL ENDOCRINOLOGY LA English DT Article ID GH DEFICIENCY; IGF-I; ADULTS; REPLACEMENT; MORTALITY; MARKERS; TRIAL; HYPOPITUITARISM; METAANALYSIS; METABOLISM AB Background Both growth hormone (GH) excess and GH deficiency are associated with abnormalities in body composition and biomarkers of cardiovascular risk in patients with pituitary disorders. However, the effects of developing GH deficiency after definitive treatment of acromegaly are largely unknown. Objective To determine whether development of GH deficiency after definitive therapy for acromegaly is associated with increased visceral adiposity and biomarkers of cardiovascular risk compared with GH sufficiency after definitive therapy for acromegaly. Design Cross-sectional. Patients We studied three groups of subjects, all with a history of acromegaly (n=76): subjects with subsequent GH deficiency (GHD; n=31), subjects with subsequent GH sufficiency (GHS; n=25) and subjects with active acromegaly (AA; n=20). No study subjects were receiving somatostatin analogues, dopamine agonists or hGH. Measurements Body composition (by DXA), abdominal adipose tissue depots (by cross-sectional CT), total body water (by bioimpedance analysis) and carotid intima-media thickness (IMT) were measured. Fasting morning serum was collected for high-sensitivity C-reactive protein (hsCRP), lipids and lipoprotein levels. An oral glucose tolerance test was performed, and homoeostasis model of assessment-insulin resistance (HOMA-IR) was calculated. Results Abdominal visceral adipose tissue, total adipose tissue and total body fat were higher in subjects with GHD than GHS or AA (P<0.05). Subcutaneous abdominal fat was higher, and fibrinogen and IMT were lower in GHD (but not GHS) than AA (P<0.05). Patients with GHD had the highest hsCRP, followed by GHS, and hsCRP was lowest in AA (P<0.05). Fasting glucose, 120-min glucose, fasting insulin, HOMA-IR and per cent total body water were lower in GHD and GHS than AA (P<0.05). Triglycerides were higher in GHS than AA (P<0.05). Lean body mass, mean arterial pressure, total cholesterol, HDL and LDL were comparable among groups. Conclusions Development of GHD after definitive treatment of acromegaly may adversely affect body composition and inflammatory biomarkers of cardiovascular risk but does not appear to adversely affect glucose homoeostasis, lipids and lipoproteins, or other cardiovascular risk markers. C1 [Miller, K. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Dept Neuroendocrine Unit, Boston, MA 02114 USA. [Swearingen, B.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Hemphill, L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Loeffler, J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Loeffler, J.] Harvard Univ, Sch Med, Boston, MA USA. RP Miller, KK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Dept Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM KKMiller@partners.org FU Pfizer; Guthart Family Foundation; NIH [MO1-RR-01066, ULI-RR-025758, T32-DK-007028-36] FX This work was supported in part by an investigator-initiated research grant from Pfizer, a grant from the Guthart Family Foundation, and NIH grants MO1-RR-01066, ULI-RR-025758, and T32-DK-007028-36. NR 38 TC 15 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2012 VL 77 IS 3 BP 430 EP 438 DI 10.1111/j.1365-2265.2012.04361.x PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 989TL UT WOS:000307583300014 PM 22315983 ER PT J AU Tsao, CK Small, AC Moshier, EL Gartrell, BA Wisnivesky, JP Sonpavde, G Godbold, JH Palese, MA Hall, SJ Oh, WK Galsky, MD AF Tsao, Che-Kai Small, Alexander C. Moshier, Erin L. Gartrell, Benjamin A. Wisnivesky, Juan P. Sonpavde, Guru Godbold, James H. Palese, Michael A. Hall, Simon J. Oh, William K. Galsky, Matthew D. TI Trends in the Use of Cytoreductive Nephrectomy in the United States SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Kidney cancer; Renal cell carcinoma; Socioeconomic differences; Tyrosine kinase inhibitor ID RENAL-CELL CARCINOMA; TARGETED THERAPY; SURVIVAL; CANCER; IMPACT; DISEASE AB Cytoreductive nephrectomy had been considered a standard in the treatment of metastatic renal cell carcinoma in the cytokine era, but with the introduction of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) an 'evidence void' for this approach has been created. In this study, we found that the use of cytoreductive nephrectomy (CyNx) has declined in the VEGFR TKI era, and in addition, potential racial and socioeconomic disparities exist. Background: Two randomized trials published in 2001 established CyNx for patients with metastatic renal carcinoma (mRCC) as a treatment standard in the cytokine era. However, first-line systemic therapy for mRCC changed in 2005 with FDA approval of VEGFR TKIs. We evaluated the patterns of use of CyNx from 2000 to 2008. Materials and Methods: The National Cancer Database was queried for patients diagnosed with mRCC. Patients who underwent CyNx were identified and were further categorized by pre-VEGFR versus VEGFR TKI era, race, insurance status, and hospital. For these subcategories, prevalence ratios (PRs) were generated using the proportion of patients with mRCC undergoing CyNx versus those not undergoing CyNx. Results: Of the 47,417 patients (pts) identified with mRCC, the prevalence of cytoreductive nephrectomy increased 3% each year from 2000 to 2005 (P < .0001), then decreased 3% each year from 2005 to 2008 (P = .0048), with a significant difference between the eras (0.97 vs. 1.025; P < .0001). Black and Hispanic pts were less likely than Caucasian pts to undergo CyNx. Pts with Medicaid, Medicare, and no insurance were less likely than pts with private insurance to undergo CyNx. Pts diagnosed at community hospitals were significantly less likely than pts at teaching hospitals to undergo CyNx. Conclusion: The use of CyNx has declined in the VEGFR-TKI era. In addition, racial and socioeconomic disparities exist in the use of CyNx. The results of pending randomized trials evaluating the role of CyNx in the VEGFR-TKI era are awaited to optimize use of this modality and address potential disparities. C1 [Tsao, Che-Kai; Small, Alexander C.; Moshier, Erin L.; Gartrell, Benjamin A.; Godbold, James H.; Oh, William K.; Galsky, Matthew D.] Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY 10029 USA. [Sonpavde, Guru] Texas Oncol, Houston, TX USA. [Sonpavde, Guru] Baylor Coll Med, Dept Med, Michael E DeBakey Vet Affairs Med Ctr, Sect Med Oncol, Houston, TX 77030 USA. [Palese, Michael A.; Hall, Simon J.] Mt Sinai Sch Med, Dept Urol, New York, NY USA. RP Galsky, MD (reprint author), Tisch Canc Inst, Div Hematol & Med Oncol, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM matthew.galsky@mssm.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 FU NCI NIH HHS [R21 CA176551] NR 24 TC 13 Z9 13 U1 0 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD SEP PY 2012 VL 10 IS 3 BP 159 EP 163 DI 10.1016/j.clgc.2012.03.008 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 992ZJ UT WOS:000307820600004 PM 22651971 ER PT J AU Butt, AA Umbleja, T Andersen, JW Sherman, KE Chung, RT AF Butt, Adeel A. Umbleja, Triin Andersen, Janet W. Sherman, Kenneth E. Chung, Raymond T. CA ACTG A5178 Study Team TI Impact of Peginterferon Alpha and Ribavirin Treatment on Lipid Profiles and Insulin Resistance in Hepatitis C Virus/HIV-Coinfected Persons: The AIDS Clinical Trials Group A5178 Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SUSTAINED VIROLOGICAL RESPONSE; INTERFERON PLUS RIBAVIRIN; TYPE-2 DIABETES-MELLITUS; PEGYLATED INTERFERON; COMBINATION THERAPY; INFECTED PATIENTS; SERUM-LIPIDS; HCV; CLEARANCE; RISK AB Background. The effect of peginterferon alpha/ribavirin (PEG-IFN/RBV) and hepatitis C virus (HCV) clearance on lipid and insulin resistance (IR) profiles in HCV/human immunodeficiency virus (HIV) coinfection is unknown. Methods. We measured fasting total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoproteins (HDL-C), triglycerides (TG), glucose, and insulin at defined intervals in the A5178 study (N = 329), a prospective treatment trial in HCV/HIV coinfection. Changes from baseline and the relation between baseline values of these variables to sustained virologic response (SVR) were determined. Results. Of 182 subjects with metabolic data, 98 achieved early virologic response (EVR) and continued PEG-IFN/RBV. Among those, median pretreatment HCV RNA was 6.6 log10 IU/mL; 73% had HCV genotype 1. Median pretreatment TC was 176 mg/dL (interquartile range [IQR], 150-205]; median LDL-C was 99 mg/dL (IQR, 79-123); median HDL-C was 40 mg/dL (IQR, 31-47); and median TG was 147 mg/dL (IQR, 101-221). Median homeostasis model assessment of IR (HOMA-IR) was 3.3 (IQR, 1.7-5.3). The EVRs demonstrated a decline in TC, LDL-C, and HDL-C, whereas TG increased on treatment but returned to near baseline 24 weeks after end of treatment (EOT). The HOMA-IR decline from entry to 24 weeks after EOT was significant among non-sustained virologic responders and nonsignificant among sustained virologic responders; this difference was offset after adjusting for higher HOMA-IR at baseline among the former. Among all 182 subjects, entry LDL-C was associated with SVR in a joint logistic model adjusted for HCV genotype, race, and prior IFN (odds ratio, 1.17 per 10 mg/dL increase; 95% confidence interval, 1.03-1.32), but TC, HDL, TG, and IR were not. Conclusions. Peginterferon alpha and RBV can significantly affect lipid profile and IR in HCV/HIV-coinfected persons. Although the lipid profile returns to near pretreatment levels after completion of treatment, our data suggest persistent modest improvement in IR with treatment. C1 [Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Butt, Adeel A.] Sheikh Khalifa Med City, Abu Dhabi, U Arab Emirates. [Umbleja, Triin; Andersen, Janet W.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Sherman, Kenneth E.] Univ Cincinnati, Cincinnati, OH 45221 USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Butt, AA (reprint author), Univ Pittsburgh, Sch Med, 3520 5th Ave,Ste 510, Pittsburgh, PA 15213 USA. EM aabutt@pitt.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636, U01AI068634]; National Institute of Mental Health; National Institute of Dental and Craniofacial Research; Gilead Sciences FX This study was supported by the National Institute of Allergy and Infectious Diseases (U01AI068636 and U01AI068634) and by the National Institute of Mental Health and the National Institute of Dental and Craniofacial Research.; A. A. B. has received consulting fees from Gilead Sciences. All other authors report no potential conflicts. NR 31 TC 6 Z9 6 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2012 VL 55 IS 5 BP 631 EP 638 DI 10.1093/cid/cis463 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988NR UT WOS:000307498300004 PM 22563020 ER PT J AU Fishman, JA Greenwald, MA Grossi, PA AF Fishman, Jay A. Greenwald, Melissa A. Grossi, Paolo A. TI Transmission of Infection With Human Allografts: Essential Considerations in Donor Screening SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ORGAN TRANSPLANT RECIPIENTS; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; WEST-NILE-VIRUS; MUSCULOSKELETAL TISSUE DONORS; TRANSMITTED VIRAL-INFECTIONS; UNITED-STATES; LIVER-TRANSPLANTATION; DISEASE TRANSMISSION; BLOOD-DONORS AB Transmission of infection via transplantation of allografts including solid organs, eyes, and tissues are uncommon but potentially life-threatening events. Donor-derived infections have been documented following organ, tissue, and ocular transplants. Each year, more than 70 000 organs, 100 000 corneas, and 2 million human tissue allografts are implanted worldwide. Single donors may provide allografts for >100 organ and tissue recipients; each allograft carries some, largely unquantifiable, risk of disease transmission. Protocols for screening of organ or tissue donors for infectious risk are nonuniform, varying with the type of allograft, national standards, and availability of screening assays. In the absence of routine, active surveillance, coupled with the common failure to recognize or report transmission events, few data are available on the incidence of allograft-associated disease transmission. Research is needed to define the optimal screening assays and the transmissibility of infection with allografts. Approaches are reviewed that may contribute to safety in allograft transplantation. C1 [Fishman, Jay A.] Harvard Univ, Massachusetts Gen Hosp, MGH Transplantat Ctr,Med Sch, Transplant Infect Dis Program,Infect Dis Div, Boston, MA USA. [Greenwald, Melissa A.] US FDA, US PHS, Div Human Tissues,Ctr Biol Evaluat & Res, Reprod Branch Off Cellular Tissue & Gene Therapie, Rockville, MD 20857 USA. [Grossi, Paolo A.] Univ Insubria, Dept Infect Dis, Varese, Italy. [Grossi, Paolo A.] Natl Ctr Transplantat, Rome, Italy. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, Transplant Infect Dis & Compromised Host Program, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM jfishman@partners.org RI GROSSI, PAOLO/A-6158-2013; Snydman, David/O-3889-2014 OI Snydman, David/0000-0003-0119-3978 NR 62 TC 24 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2012 VL 55 IS 5 BP 720 EP 727 DI 10.1093/cid/cis519 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988NR UT WOS:000307498300017 PM 22670038 ER PT J AU Justice, AC Tate, JP Freiberg, MS Rodriguez-Barradas, MC Tracy, R AF Justice, Amy C. Tate, Janet P. Freiberg, Matthew S. Rodriguez-Barradas, Maria C. Tracy, Russ TI Role of the Veterans Aging Cohort Study Index in Assessing Total Atherosclerotic Burden Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID CARDIOVASCULAR-DISEASE; CALCIFICATION; ASSOCIATION; HIV C1 [Justice, Amy C.; Tate, Janet P.] Vet Affairs Connecticut Healthcare Syst, West Haven, CT 06516 USA. [Justice, Amy C.; Tate, Janet P.] Yale Univ, Dept Med, Gen Internal Med Sect, New Haven, CT 06520 USA. [Freiberg, Matthew S.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA 15260 USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Infect Dis Sect, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Tracy, Russ] Univ Vermont, Coll Med, Burlington, VT 05405 USA. RP Justice, AC (reprint author), Vet Affairs Connecticut Healthcare Syst, 950 Campbell Ave,11 ACSLG, West Haven, CT 06516 USA. EM amy.justice2@va.gov NR 11 TC 8 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2012 VL 55 IS 5 BP 751 EP 752 DI 10.1093/cid/cis539 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988NR UT WOS:000307498300024 ER PT J AU Dransfield, MT Harnden, S Burton, RL Albert, RK Bailey, WC Casaburi, R Connett, J Cooper, JAD Criner, GJ Curtis, JL Han, MK Make, B Marchetti, N Martinez, FJ McEvoy, C Nahm, MH Niewoehner, DE Porszasz, J Reilly, J Scanlon, PD Scharf, SM Sciurba, FC Washko, GR Woodruff, PG Lazarus, SC AF Dransfield, Mark T. Harnden, Sarah Burton, Robert L. Albert, Richard K. Bailey, William C. Casaburi, Richard Connett, John Cooper, J. Allen D., Jr. Criner, Gerard J. Curtis, Jeffrey L. Han, MeiLan K. Make, Barry Marchetti, Nathaniel Martinez, Fernando J. McEvoy, Charlene Nahm, Moon H. Niewoehner, Dennis E. Porszasz, Janos Reilly, John Scanlon, Paul D. Scharf, Steven M. Sciurba, Frank C. Washko, George R. Woodruff, Prescott G. Lazarus, Stephen C. CA NIH COPD Clinical Res Network TI Long-term Comparative Immunogenicity of Protein Conjugate and Free Polysaccharide Pneumococcal Vaccines in Chronic Obstructive Pulmonary Disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID OLDER-ADULTS; STREPTOCOCCUS-PNEUMONIAE; ELDERLY ADULTS; VACCINATION; EFFICACY; ANTIBODY; RESPONSES; PROTECTION; INFLUENZA; SAFETY AB Background. Although the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years. Methods. One hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years. Results. Relative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed. Conclusions. PCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points. C1 [Dransfield, Mark T.; Bailey, William C.; Cooper, J. Allen D., Jr.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Dransfield, Mark T.; Cooper, J. Allen D., Jr.] Birmingham VA Med Ctr, Pulm Sect, Birmingham, AL USA. [Harnden, Sarah; Connett, John] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Burton, Robert L.; Nahm, Moon H.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Burton, Robert L.; Nahm, Moon H.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Albert, Richard K.] Denver Hlth Med Ctr, Dept Med, Denver, CO USA. [Casaburi, Richard; Porszasz, Janos] Harbor UCLA Med Ctr, Div Resp & Crit Care Physiol & Med, Torrance, CA 90509 USA. [Criner, Gerard J.; Marchetti, Nathaniel] Temple Univ, Div Pulm & Crit Care Med, Philadelphia, PA 19122 USA. [Curtis, Jeffrey L.; Han, MeiLan K.; Martinez, Fernando J.] Univ Michigan, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Make, Barry] Univ Colorado, Natl Jewish Hlth, Denver, CO 80202 USA. [McEvoy, Charlene; Niewoehner, Dennis E.] Univ Minnesota, VA Med Ctr, Pulm Sect, Minneapolis, MN USA. [Reilly, John; Sciurba, Frank C.] Univ Pittsburgh, Div Pulm & Crit Care Med, Pittsburgh, PA 15260 USA. [Scanlon, Paul D.] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA. [Scharf, Steven M.] Univ Maryland, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. [Washko, George R.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Woodruff, Prescott G.; Lazarus, Stephen C.] Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Woodruff, Prescott G.; Lazarus, Stephen C.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. RP Dransfield, MT (reprint author), Univ Alabama Birmingham, Div Pulm & Crit Care, 422 THT 1900 Univ Blvd, Birmingham, AL 35294 USA. EM mdransfield99@msn.com RI Reilly, John/H-8755-2012; OI Curtis, Jeffrey/0000-0001-5191-4847; Nahm, Moon/0000-0002-6922-1042; Porszasz, Janos/0000-0002-5823-0031 FU Division of Lung Diseases of the National Heart, Lung, and Blood Institute; GCRC [RR02635, RR00051, RR16500, RR00056]; UpToDate; ePocrates; Pfizer; Actelion; GSK; Forest; MPex; Nycomed; American Lung Association; Almirall; Altana/Nycomed; Astra Zeneca; Boehringer Ingelheim; CME Incite; France Foundation; MedEd; NACE; Potomac; Prescott; Sanofi Aventis; Vox Medic; WebMD; Associates in Medical Marketing; Castle Connolly; Merck; Genentech; [HL074428]; [HL074409]; [1U10-HL074416]; [HL074408]; [HL074418]; [1U10-HL074431]; [HL074441]; [HL074422]; [HL074439]; [1U10-HL074424] FX The COPD Clinical Research Network is supported by a Cooperative Agreement from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute.; Brigham and Women's Hospital: J. J. Reilly, Jr, G. Washko (PIs), S. Peterson (Coordinator). Grant HL074428, GCRC Grant RR02635.; Denver Health Medical Center: R. K. Albert (PI), B. Make (Co-PI), M. Schwarz, C. Welsh (Investigators), C. Verano, J. Binford, J. Herrell (Coordinators). Grant HL074409, GCRC Grant RR00051.; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center: R. Casaburi, (PI), G. Mason, J. Porszasz, (Investigators), K. Norulak, R. Kiledjian, L. Diaz, R. Love, P. Walker (Coordinators). Grant HL074407, GCRC Grant RR00425.; Minnesota Veterans Research Institute, Minneapolis (Affiliated Sites: HealthPartners Research Foundation, Mayo Clinic): D. E. Niewoehner (PI), C. McEvoy, K. R. Rice, P. D. Scanlon (Co-PIs). C. Andrist, J. Hart, K. Timm (Coordinators). Grant 1U10-HL074416.; Temple University: G. J. Criner (PI), W. Chatila, N. Marchetti, V. Kim, G. D'Alonzo, S. Krachman, F. Cordova, K. Brennan, N. Patel, J. Mamary (Investigators), C. Grabianowski, G. Jones, N. Krayger, A. M. Kuzma, H. Smith (Coordinators). Grant HL074408.; University of Alabama at Birmingham: M. T. Dransfield (PI), J. A. D. Cooper (Co-PI), W. C. Bailey, L. B. Gerald, P. O'Reilly (Investigators), S. Tidwell (Coordinator). Grant HL074418.; University of California, San Francisco: S. C. Lazarus (PI), H. A. Boushey, J. V. Fahy, P. G. Woodruff (Investigators), K. Schardein, C. Nguyen, R. Sakurai, M. Dyjak (Coordinators). 1U10-HL074431.; University of Maryland, Baltimore: S. M. Scharf (PI), M. Alattar, P. Amelung, M. Cowan, J. Hanson, J. Hasday, A. Iacono, C. Shanholtz, N. Todd, A. Verceles (Investigators), W. Bell-Farrell, T. Fitzgerald, P. Wood(Coordinators). Grant HL074441, GCRC Grant RR16500.; University of Michigan, Ann Arbor: F. J. Martinez (PI), J. L. Curtis, M. K. Han, S. E. Gay, T. H. Sisson, P. J. Christensen, M. Mendez (Investigators), D. Thompson (Project Manager), C. Flaherty, T. Felt, S. Smith, L. Husselman, D. White (Coordinators at UM), C. Getty, C. Jett, L. McCloskey, M. Christensen (Coordinators at VA). Grant HL074422.; University of Pittsburgh: F. Sciurba (PI), L. Kniolek, L. Lane, M. Pitaro (Coordinators). Grant HL074439, GCRC Grant RR00056.; University of Minnesota (Data Coordinating Center): J. E. Connett (PI), N. R. Anthonisen (Steering Committee Chair), C. Wendt (Co-PI), S. Harnden, W. Patrek, H. Voelker (Coordinators). Grant 1U10-HL074424.; M. T. D. has served as an advisory board member for GlaxoSmithKline and Boehringer Ingelheim and has received industry contracts for clinical trials from GlaxoSmithKline, Boehringer Ingelheim, Otsuka, Boston Scientific and Centocor. R. C. has served in the speakers' bureau for Pfizer Pharmaceuticals. M. K. H. has participated in advisory boards for Boehringer Ingelheim GmbH, Pfizer, GlaxoSmithKline, Genentech, Novartis, and Medimmune; has participated on speaker's bureaus for Boehringer Ingelheim GmbH, Pfizer, GlaxoSmithKline, the National Association for Continuing Education, and WebMD; has consulted for Novartis and Nycomed; and has received royalties from UpToDate and ePocrates. B. M. has served on an advisory boards for Merck and Pfizer and has been the local principal investigator for multicenter trials sponsored by Pfizer. F. J. M. has participated in Advisory Boards in COPD development for Actelion, Astra Zeneca, Bayer, Boom-Comm, fbCommunications, Forest/Almirall, GSK, Ikaria, MedImmune, Merck, Novartis, Nycomed, Pearl, Pfizer, Roche, Schering, and Talecris; has been a member of Steering Committee for COPD studies sponsored by Actelion, GSK, Forest, MPex, and Nycomed; has participated in FDA Mock panels for Boehringer Ingelheim and Forest; has served on speaker's bureaus or in CME activities sponsored by American Lung Association, Almirall, Altana/Nycomed, Astra Zeneca, Boehringer Ingelheim, CME Incite, ePocrates, Forest, France Foundation, GSK, MedEd, NACE, Pfizer, Potomac, Prescott, Sanofi Aventis, Vox Medic, WebMD, and UpToDate; and has received royalties from Associates in Medical Marketing, Castle Connolly. D. E. N has received advisory fees from Merck and Pfizer. P. D, S. has participated in clinical trials funded by Pfizer and Boehringer Ingelheim, and his wife works for Merck Research Laboratories. P. G. W. has had a recent research grant with Genentech, recent consulting for Medimmune, and is co-inventor on a patent pending for asthma diagnostics. The University of Alabama at Birmingham owns the intellectual property rights to some of the reagents described in this work. M. H. N., R. L. B., W. C. B., J. A. D. C. and M. T. D. are employees of the University of Alabama at Birmingham, and M. H. N. has been a consultant to Merck regarding the diagnosis of pneumonia. All other authors report no potential conflicts. NR 32 TC 21 Z9 22 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2012 VL 55 IS 5 BP E35 EP E44 DI 10.1093/cid/cis513 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988NR UT WOS:000307498300001 PM 22652582 ER PT J AU Suri, P Saunders, KW Von Korff, M AF Suri, Pradeep Saunders, Kathleen W. Von Korff, Michael TI Prevalence and Characteristics of Flare-ups of Chronic Nonspecific Back Pain in Primary Care A Telephone Survey SO CLINICAL JOURNAL OF PAIN LA English DT Article DE back pain; flare; flare-up; exacerbation; disability; coping ID ELECTRONIC DIARY ASSESSMENT; ANKYLOSING-SPONDYLITIS; NATURAL-HISTORY; DISABILITY; QUESTIONNAIRE; INTENSITY AB Objectives: To describe the prevalence and characteristics of flare-ups of chronic nonspecific back pain (CNSBP) among primary care patients, and to examine associations with measures of pain severity and psychosocial factors. Methods: Six hundred thirty-four participants with nonspecific back pain were interviewed by telephone 2 years after an initial primary care visit for back pain. Participants experiencing flare-ups in the last 6 months reported on frequency, duration, and other characteristics of flare-ups. Using bivariate and multivariate analyses, we compared individuals with and without CNSBP flare-ups with respect to demographic characteristics, measures of pain severity, and psychosocial factors. Results: Approximately 51% of the participants reported flare-ups. Physical activities, including lifting and bending, were the most common perceived triggers of flare-ups. Participants with flare-ups experienced greater levels of pain intensity, disability, opioid medication use, and psychosocial comorbidities. After adjustment for demographic factors, pain intensity, and pain frequency, participants with flare-ups were more disabled than those without [mean (95% confidence interval) disability score 4.2 (3.9-4.4) vs. 3.3 (2.9-3.6); P < 0.0001] and demonstrated higher levels of passive coping [mean passive coping score 4.1(3.8-4.3) vs. 3.4 (3.1-3.7); P = 0.0008]. Discussion: Flare-ups of CNSBP are common among primary care patients, and are independently associated with higher levels of pain intensity, disability, and passive coping. The presence of flare-ups and the perception of activity as a trigger may predispose patients with flare-ups to experience disability not explained by pain intensity alone. Further longitudinal studies are required to better characterize CNSBP flare-ups and determine their clinical implications. C1 [Suri, Pradeep] VA Boston Healthcare Syst, Div Phys Med & Rehabil, Boston, MA 02130 USA. [Suri, Pradeep] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Suri, Pradeep] Spaulding Rehabil Hosp, Boston, MA USA. [Suri, Pradeep] New England Baptist Hosp, Div Res, Boston, MA USA. [Saunders, Kathleen W.; Von Korff, Michael] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. RP Suri, P (reprint author), VA Boston Healthcare Syst, Div Phys Med & Rehabil, 150 S Huntington Ave, Boston, MA 02130 USA. EM pradeep.suri@va.gov FU Rehabilitation Medicine Scientist Training Program (RMSTP), Pittsburgh, PA; National Institutes of Health, Bethesda, MD [K12 HD001097-12]; NIA, Bethesda, MD [R01 AG034181]; NIDCR, Bethesda, MD [P01 DE08773] FX P.S. is funded by the Rehabilitation Medicine Scientist Training Program (RMSTP), Pittsburgh, PA, and the National Institutes of Health (K12 HD001097-12), Bethesda, MD. K. W. S. and M. V. K. are funded by the NIA (R01 AG034181), Bethesda, MD. This research was supported by the NIDCR (P01 DE08773), Bethesda, MD. The authors declare no conflict of interest. NR 25 TC 3 Z9 3 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-8047 J9 CLIN J PAIN JI Clin. J. Pain PD SEP PY 2012 VL 28 IS 7 BP 573 EP 580 DI 10.1097/AJP.0b013e31823ae173 PG 8 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 990ON UT WOS:000307640500003 PM 22699128 ER PT J AU Krishna, V Lazaridis, C Ellegala, D Glazier, S Kindy, M Spampinato, M Chalela, JA AF Krishna, Vibhor Lazaridis, Christos Ellegala, Dilantha Glazier, Steven Kindy, Mark Spampinato, Maria Chalela, Julio A. TI Spinal cord infarction associated with subarachnoid hemorrhage SO CLINICAL NEUROLOGY AND NEUROSURGERY LA English DT Article DE Delayed ischemia; Subarachnoid hemorrhage; Spinal cord stroke C1 [Krishna, Vibhor; Lazaridis, Christos; Ellegala, Dilantha; Glazier, Steven; Chalela, Julio A.] Med Univ S Carolina, Div Neurosurg, Dept Neurosci, Charleston, SC 29407 USA. [Kindy, Mark] Med Univ S Carolina, Div Res, Dept Neurosci, Charleston, SC 29407 USA. [Kindy, Mark] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Spampinato, Maria] Med Univ S Carolina, Dept Radiol, Charleston, SC 29407 USA. [Lazaridis, Christos; Chalela, Julio A.] Med Univ S Carolina, Div Neurol, Dept Neurosci, Charleston, SC 29407 USA. RP Krishna, V (reprint author), Med Univ S Carolina, Div Neurosurg, Dept Neurosci, 96 Jonathan Lucas St, Charleston, SC 29407 USA. EM Krishna@musc.edu FU NCRR NIH HHS [P20 RR021949]; NIEHS NIH HHS [R01 ES016774]; NIGMS NIH HHS [P20 GM103444] NR 6 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0303-8467 J9 CLIN NEUROL NEUROSUR JI Clin. Neurol. Neurosurg. PD SEP PY 2012 VL 114 IS 7 BP 1030 EP 1032 DI 10.1016/j.clineuro.2012.01.037 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 993JU UT WOS:000307855800042 PM 22386902 ER PT J AU Cheng, G Alavi, A Lim, E Akers, SR AF Cheng, Gang Alavi, Abass Lim, Esther Akers, Scott R. TI Superscan-like Hypermetabolic Lesions on Delayed FDG PET/CT Imaging in a Patient With Lung Cancer SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE FDG PET/CT; superscan; bone marrow metastasis; lung cancer ID BONE-SCINTIGRAPHY; PULMONARY NODULES; F-18-FDG PET; POINT AB A 69-year-oldman with a lung mass underwent multiple-time-point FDG PET/CT imaging for diagnostic evaluation. The initial PET imaging (performed at 1 hour after tracer injection) revealed equivocal bone marrow uptake in the right iliac bone and proximal femurs in addition to lung and mediastinal lesions. The 3-hour delayed PET imaging, however, demonstrated widespread bone marrow metastases. Biopsies of the right lung mass and right iliac bone marrow were later performed and revealed a poorly differentiated squamous cell carcinoma in both sites. This case indicates the value of delayed FDG PET in detecting superscan-like hypermetabolic bone marrow lesions in patients with lung cancer. C1 [Cheng, Gang; Lim, Esther; Akers, Scott R.] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA 19104 USA. [Alavi, Abass] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Akers, SR (reprint author), Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM Scott.Akers@va.gov NR 9 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD SEP PY 2012 VL 37 IS 9 BP 912 EP 913 DI 10.1097/RLU.0b013e31825b23d5 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 992VL UT WOS:000307808000034 PM 22889790 ER PT J AU Tamez, H Thadhani, RI AF Tamez, Hector Thadhani, Ravi I. TI Vitamin D and hypertension: an update and review SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE activated vitamin D analogs; blood pressure; hypertension; vitamin D ID 25-HYDROXYVITAMIN D LEVELS; RANDOMIZED CONTROLLED-TRIAL; PARATHYROID-HORMONE LEVELS; RENIN-ANGIOTENSIN SYSTEM; CARDIOVASCULAR RISK-FACTORS; ARTERIAL-BLOOD PRESSURE; INCIDENT HYPERTENSION; D DEFICIENCY; APPARENTLY HEALTHY; D SUPPLEMENTATION AB Purpose of review Vitamin D deficiency and hypertension are highly prevalent. This review will discuss the association between vitamin D deficiency and blood pressure. Recent findings During the past several years multiple prospective cohorts and randomized studies have been published. Recent studies have focused mostly on 25-hydroxy vitamin D, but a small number of trials used active vitamin D analog compounds. Summary Data from cross-sectional studies report that low 25-hydroxy vitamin D is associated with higher systolic blood pressure and higher incidence of hypertension. Large observational studies show a weaker, yet similar association, but they have not largely accounted for the change in vitamin D levels over time. Randomized control trials conflict with observational data probably due to differences in populations studied, doses of vitamin D used, and unmeasured confounders. Further research is needed before clinical practice recommends vitamin D prescription as treatment for hypertension in the general population. C1 [Tamez, Hector; Thadhani, Ravi I.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Tamez, H (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, 55 Fruit St,Bulfinch 127, Boston, MA 02114 USA. EM htamez@partners.org FU Abbott Laboratories FX Dr. Thadhani has a research grant from Abbott Laboratories. NR 60 TC 22 Z9 23 U1 0 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD SEP PY 2012 VL 21 IS 5 BP 492 EP 499 DI 10.1097/MNH.0b013e3283557bf0 PG 8 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 990RQ UT WOS:000307649300006 PM 22820371 ER PT J AU Krapf, D Ruan, YC Wertheimer, EV Battistone, MA Pawlak, JB Sanjay, A Pilder, SH Cuasnicu, P Breton, S Visconti, PE AF Krapf, Dario Ruan, Ye Chun Wertheimer, Eva V. Battistone, Maria A. Pawlak, John B. Sanjay, Archana Pilder, Stephen H. Cuasnicu, Patricia Breton, Sylvie Visconti, Pablo E. TI cSrc is necessary for epididymal development and is incorporated into sperm during epididymal transit SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Epididymal maturation; Extracellular trafficking; Src kinase; Sperm capacitation; Sperm motility ID TYROSINE PHOSPHORYLATION; MOUSE SPERMATOZOA; RAT EPIDIDYMIS; V-ATPASE; SRC; CAPACITATION; EXPRESSION; PROTEINS; TESTIS; CELLS AB Changes that occur to mammalian sperm upon epididymal transit and maturation render these cells capable of moving progressively and capacitating. Signaling events leading to mammalian sperm capacitation depend on the modulation of proteins by phosphorylation and dephosphorylation cascades. Recent experiments have demonstrated that the Src family of kinases plays an important role in the regulation of these events. However, sperm from cSrc null mice display normal tyrosine phosphorylation associated with capacitation. We report here that, despite normal phosphorylation, sperm from cSrc null mice display a severe reduction in forward motility, and are unable to fertilize in vitro. Histological analysis of seminiferous tubules in the testes, caput and corpus epididymis do not reveal obvious defects. However, the cauda epididymis is significantly smaller, and expression of key transport proteins in the epithelial cells lining this region is reduced in cSrc null mice compared to wild type littermates. Although previously, we and others have shown the presence of cSrc in mature sperm from cauda epididymis, a closer evaluation indicates that this tyrosine kinase is not present in sperm from the caput epididymis, suggesting that this protein is acquired by sperm later during epididymal maturation. Consistent with this observation, cSrc is enriched in vesicles released by the epididymal epithelium known as epididymosomes. Altogether, these observations indicate that cSrc is essential for cauda epididymal development and suggest an essential role of this kinase in epididymal sperm maturation involving cSrc extracellular trafficking. (c) 2012 Elsevier Inc. All rights reserved. C1 [Krapf, Dario; Wertheimer, Eva V.; Pawlak, John B.; Visconti, Pablo E.] Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA. [Krapf, Dario] CONICET UNR, Inst Mol & Cell Biol Rosario, Rosario, Argentina. [Ruan, Ye Chun; Breton, Sylvie] Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. [Ruan, Ye Chun; Breton, Sylvie] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Ruan, Ye Chun; Breton, Sylvie] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Battistone, Maria A.; Cuasnicu, Patricia] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Buenos Aires, DF, Argentina. [Sanjay, Archana] Univ Connecticut, Ctr Hlth, New England Musculoskeletal Inst, Dept Orthopaed Surg, Farmington, CT 06030 USA. [Pilder, Stephen H.] Temple Univ, Sch Med, Dept Anat & Cell Biol, Philadelphia, PA 19140 USA. RP Visconti, PE (reprint author), Univ Massachusetts, Dept Vet & Anim Sci, 661 N Pleasant ST, Amherst, MA 01003 USA. EM pvisconti@vasci.umass.edu FU NIH [HD44044, HD038082, HD40793, HD45821, DK38452]; National Agency for Scientific and Technological Promotion of Argentina [PICT 633]; WHO [H9-TSA-037]; Lalor Foundation postdoctoral fellowship FX This work was supported by NIH: R01 HD44044 and HD038082 (to PEV), HD40793, HD45821 and DK38452 (to SB), National Agency for Scientific and Technological Promotion of Argentina PICT 633 and WHO H9-TSA-037 (to PSC) and by a Lalor Foundation postdoctoral fellowship (to YCR). We would also like to thank Dr. Paula Stein for her assistance in in vitro fertilization experiments. Authors declare no conflict of interests. NR 44 TC 25 Z9 25 U1 1 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 1 PY 2012 VL 369 IS 1 BP 43 EP 53 DI 10.1016/j.ydbio.2012.06.017 PG 11 WC Developmental Biology SC Developmental Biology GA 986TN UT WOS:000307368600004 PM 22750823 ER PT J AU Singer, JR Palmas, W Teresi, J Weinstock, R Shea, S Luchsinger, JA AF Singer, Jessica R. Palmas, Walter Teresi, Jeanne Weinstock, Ruth Shea, Steven Luchsinger, Jose A. TI Adiponectin and All-Cause Mortality in Elderly People With Type 2 Diabetes SO DIABETES CARE LA English DT Article ID MOLECULAR-WEIGHT ADIPONECTIN; CORONARY-HEART-DISEASE; COLUMBIA-UNIVERSITY INFORMATICS; TELEMEDICINE IDEATEL PROJECT; PLASMA ADIPONECTIN; INSULIN-RESISTANCE; METABOLIC SYNDROME; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; RISK AB OBJECTIVE To assess the association between serum adiponectin level and all-cause mortality in people with type 2 diabetes. Because of the insulin-sensitizing, anti-inflammatory, and antiatherogenic effects of adiponectin, we hypothesized that higher adiponectin level would be associated with lower all-cause mortality. RESEARCH DESIGN AND METHODS A total of 609 men and women aged 72 +/- 6.3 years with type 2 diabetes and information on total and high molecular weight adiponectin were followed for a median of 5 years. The longitudinal association between adiponectin and all-cause mortality was analyzed with Cox proportional hazards models with time from adiponectin measurement to death as the time-to-event variable. Analyses were adjusted for demographic variables and significant diabetes parameters, significant cardiovascular parameters, and significant diabetes medications. RESULTS Total and high molecular weight adiponectin were highly correlated. The highest adiponectin quartile was strongly associated with higher all-cause mortality compared with the lowest quartile (hazard ratio = 4.0 [95% CI: 1.7-9.2]) in the fully adjusted model. These results did not change in analyses stratified by sex and thiazolidinedione use, after exclusion of people who died within one year of adiponectin measurement, or when change in weight before adiponectin measurement was considered. CONCLUSIONS Contrary to our hypothesis, higher adiponectin level was related to higher all-cause mortality. This association was not explained by confounding by other characteristics, including medications or preceding weight loss. C1 [Singer, Jessica R.; Palmas, Walter; Shea, Steven; Luchsinger, Jose A.] Columbia Univ, Dept Med, Div Gen Med, New York, NY 10027 USA. [Teresi, Jeanne] Hebrew Home Riverdale, Res Div, Bronx, NY USA. [Teresi, Jeanne] Columbia Univ, Stroud Ctr, New York, NY USA. [Teresi, Jeanne] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Weinstock, Ruth] SUNY Upstate Med Univ, Joslin Diabet Ctr, Syracuse, NY USA. [Weinstock, Ruth] SUNY Upstate Med Univ, Div Endocrinol Diabet & Metab, Syracuse, NY USA. [Weinstock, Ruth] VA Med Ctr, Dept Vet Affairs, Syracuse, NY USA. [Shea, Steven; Luchsinger, Jose A.] Columbia Univ, Joseph Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Luchsinger, JA (reprint author), Columbia Univ, Dept Med, Div Gen Med, New York, NY 10027 USA. EM jal94@columbia.edu FU National Institute on Minority Health and Health Disparities [P60 MD 000206]; Alzheimer's Association [IIRG-05-15053]; Fidelity Foundation; Centers for Medicare and Medicaid Services [95-C-90998] FX This work is supported by National Institute on Minority Health and Health Disparities grant P60 MD 000206 (J.A.L., W.P., S.S., J.T.), Alzheimer's Association grant IIRG-05-15053 (J.A.L.), the Fidelity Foundation (J.A.L.), and Cooperative Agreement 95-C-90998 from the Centers for Medicare and Medicaid Services (R.W., S.S., J.T., W.P., J.A.L.). NR 34 TC 20 Z9 21 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2012 VL 35 IS 9 BP 1858 EP 1863 DI 10.2337/dc11-2215 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 998XG UT WOS:000308273100010 PM 22773703 ER PT J AU Florez, JC Jablonski, KA Taylor, A Mather, K Horton, E White, NH Barrett-Connor, E Knowler, WC Shuldiner, AR Pollin, TI AF Florez, Jose C. Jablonski, Kathleen A. Taylor, Andrew Mather, Kieren Horton, Edward White, Neil H. Barrett-Connor, Elizabeth Knowler, William C. Shuldiner, Alan R. Pollin, Toni I. CA Diabet Prevention Program Res Grp TI The C Allele of ATM rs11212617 Does Not Associate With Metformin Response in the Diabetes Prevention Program SO DIABETES CARE LA English DT Article ID LIFE-STYLE INTERVENTION; EUROPEAN ASSOCIATION; CONSENSUS ALGORITHM; MEDICAL-MANAGEMENT; STATEMENT; GLUCOSE; HYPERGLYCEMIA; ADJUSTMENT; INITIATION; MELLITUS AB OBJECTIVE-The C allele at the rs11212617 polymorphism in the ataxia-telangiectasia-mutated (ATM) gene has been associated with greater clinical response to metformin in people with type 2 diabetes. We tested whether this variant modified the effect of metformin in the Diabetes Prevention Program (DPP), in which metformin reduced diabetes incidence by 31% in volunteers with impaired glucose tolerance. RESEARCH DESIGN AND METHODS-We genotyped rs11212617 in 2,994 DPP participants and analyzed its effects on diabetes incidence and related traits. RESULTS-Contrary to expectations, C carriers enjoyed no preventive advantage on metformin ; their hazard ratio, compared with A carriers, was 1.17 ([95% CI 0.96-1.42], P = 0.13) under metformin. There were no significant differences by genotype in metformin's effects on insulin sensitivity, fasting glucose, glycated hemoglobin, or disposition index. CONCLUSIONS-The reported association of rs11212617 with metformin response was not confirmed for diabetes prevention or for effects on relevant physiologic parameters in the DPP. C1 [Florez, Jose C.; Taylor, Andrew] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.; Taylor, Andrew] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Florez, Jose C.; Taylor, Andrew] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.; Horton, Edward] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Jablonski, Kathleen A.] George Washington Univ, Biostat Ctr, Dept Epidemiol & Biostat, Rockville, MD USA. [Mather, Kieren] Indiana Univ Sch Med, Div Endocrinol & Metab, Dept Med, Indianapolis, IN USA. [Horton, Edward] Joslin Diabet Ctr, Sect Clin Behav & Outcomes Res, Boston, MA 02215 USA. [White, Neil H.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [White, Neil H.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family Med, San Diego, CA 92103 USA. [Knowler, William C.] NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Shuldiner, Alan R.; Pollin, Toni I.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.; Pollin, Toni I.] Univ Maryland, Sch Med, Program Genet & Genom Med, Baltimore, MD 21201 USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM jcflorez@partners.org RI Altshuler, David/A-4476-2009; de Bakker, Paul/B-8730-2009; Uwaifo, Gabriel/M-2361-2016; OI Altshuler, David/0000-0002-7250-4107; de Bakker, Paul/0000-0001-7735-7858; Uwaifo, Gabriel/0000-0002-6962-9304; Franks, Paul/0000-0002-0520-7604 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Research on Women's Health; Centers for Disease Control and Prevention; American Diabetes Association; T.I.P. McKesson BioServices Corp.; Matthews Media Group, Inc.; Henry M. Jackson Foundation; National Institute on Aging; [R01-DK-072041] FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the coordinating center for the design and conduct of the study, including collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Aging, the Office of Research on Women's Health, the Centers for Disease Control and Prevention, and the American Diabetes Association. This research was also supported, in part, by the intramural research program of the NIDDK and Grant R01-DK-072041 to J.C.F., K.A.J., A.R.S., and T.I.P. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the coordinating center. NR 13 TC 22 Z9 22 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2012 VL 35 IS 9 BP 1864 EP 1867 DI 10.2337/dc11-2301 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 998XG UT WOS:000308273100011 PM 22751958 ER PT J AU Rutter, MK Massaro, JM Hoffmann, U O'Donnell, CJ Fox, CS AF Rutter, Martin K. Massaro, Joseph M. Hoffmann, Udo O'Donnell, Christopher J. Fox, Caroline S. TI Fasting Glucose, Obesity, and Coronary Artery Calcification in Community-Based People Without Diabetes SO DIABETES CARE LA English DT Article ID INTIMA-MEDIA THICKNESS; SERVICES TASK-FORCE; RISK-FACTORS; METABOLIC SYNDROME; HEART-DISEASE; CARDIOVASCULAR-DISEASE; SCIENTIFIC STATEMENT; ASYMPTOMATIC ADULTS; VISCERAL ADIPOSITY; INSULIN-RESISTANCE AB OBJECTIVE-Our objective was to assess whether impaired fasting glucose (IFG) and obesity are independently related to coronary artery calcification (CAC) in a community-based population. RESEARCH DESIGN AND METHODS-We assessed CAC using multidetector computed tomography in 3,054 Framingham Heart Study participants (mean [SD] age was 50 [10] years, 49% were women, 29% had IFG, and 25% were obese) free from known vascular disease or diabetes. We tested the hypothesis that IFG (5.6-6.9 mmol/L) and obesity (BMI >= 30 kg/m(2)) were independently associated with high CAC (>90th percentile for age and sex) after adjusting for hypertension, lipids, smoking, and medication. RESULTS-High-CAC was significantly related to IFG in an age- and sex-adjusted model (odds ratio 1.4 [95% Cl 1.1-1.7], P = 0.002; referent: normal fasting glucose) and after further adjustment for obesity (1.3 [1.0-1.6], P = 0.045). However, IFG was not associated with high CAC in multivariable-adjusted models before (1.2 [0.9-1.4], P = 0.20) or after adjustment for obesity. Obesity was associated with high CAC in age- and sex-adjusted models (1.6 [1.3-2.0], P < 0.001) and in multivariable models that included IFG (1.4 [1.1-1.7], P = 0.005). Multivariableadjusted spline regression models suggested nonlinear relationships linking high CAC with BMI (J-shaped), waist circumference 0-shaped), and fasting glucose. CONCLUSIONS-In this community-based cohort, CAC was associated with obesity, but not IFG, after adjusting for important confounders. With the increasing worldwide prevalence of obesity and nondiabetic hyperglycemia, these data underscore the importance of obesity in the pathogenesis of CAC. C1 [Rutter, Martin K.] Univ Manchester, Sch Biomed, Cardiovasc Res Grp, Manchester, Lancs, England. [Rutter, Martin K.] Natl Hlth Serv Fdn Trust, Manchester Acad Hlth Sci Ctr, Natl Inst Hlth Res,Cent Manchester Biomed Res Ctr, Manchester Diabet Ctr,Cent Manchester Univ Hosp, Manchester, Lancs, England. [Massaro, Joseph M.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Div Biostat, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Cardiol, Boston, MA USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [O'Donnell, Christopher J.; Fox, Caroline S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. RP Rutter, MK (reprint author), Univ Manchester, Sch Biomed, Cardiovasc Res Grp, Manchester, Lancs, England. EM martin.rutter@manchester.ac.uk OI Massaro, Joseph/0000-0002-2682-4812; Rutter, Martin/0000-0001-6380-539X FU National Heart, Lung, and Blood Institute's Framingham Heart Study (Bethesda, Maryland) [N01-HC-25195]; Higher Education Funding Council for England (Clinical Senior Lecturer Award); Manchester National Institute for Health Research Biomedical Research Centre; Manchester Academic Health Science Centre FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Bethesda, Maryland; N01-HC-25195). M.K.R. was supported by the Higher Education Funding Council for England (Clinical Senior Lecturer Award). We also acknowledge support from the Manchester National Institute for Health Research Biomedical Research Centre and Manchester Academic Health Science Centre. NR 34 TC 18 Z9 18 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2012 VL 35 IS 9 BP 1944 EP 1950 DI 10.2337/dc11-1950 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 998XG UT WOS:000308273100025 PM 22773705 ER PT J AU Munshi, MN Hayes, M Iwata, I Lee, Y Weinger, K AF Munshi, M. N. Hayes, M. Iwata, I. Lee, Y. Weinger, K. TI Which aspects of executive dysfunction influence ability to manage diabetes in older adults? SO DIABETIC MEDICINE LA English DT Article DE cognition; diabetes; elderly ID COGNITIVE IMPAIRMENT; DYSEXECUTIVE SYMPTOMS; MELLITUS; TRAIL; QUESTIONNAIRE; DECLINE; SAMPLE; WOMEN AB Diabet. Med. 29, 1171-1177 (2012) Abstract Aims To examine whether different aspects of executive function as measured by different assessment tools are associated with glycaemic control and other clinical characteristics in older adults with Type 2 diabetes. Methods We performed a cross-sectional study of older adults aged >= 70 years with Type 2 diabetes at a tertiary care diabetes centre. The Dysexecutive Questionnaire was used to measure self-reported executive dysfunction. Objective tests of executive functions included a modified clock drawing test (Clock-in-a-Box), Trail Making Tests (parts A and B) and verbal fluency. Demographic and clinical information was collected using questionnaires and surveys. Glycaemic control was measured by HbA1c. Results We evaluated 145 patients [average age 77 +/- 5 years, diabetes duration 15 +/- 11 years, mean HbA1c 56 +/- 11 mmol/mol (7.3 +/- 1.1%)]. Poor performances on objective tests (low scores on Clock-in-a-Box and verbal fluency; and high scores on Trail Making Tests A and B) but not on the subjective test (the Dysexecutive Questionnaire), were associated with poor glycaemic control (r = -0.23, P < 0.005; r = -0.17, P < 0.04; r = 0.20, P < 0.01, r = 0.22, P < 0.008, r = -0.07, P < 0.42, respectively). In a multiple regression model (r2 = 0.39), high Dysexecutive Questionnaire scores were associated with higher diabetes-related distress (P < 0.0004), depressive symptoms (P < 0.004), number of falls (P < 0.009), fear of falling (P < 0.01), less years of education (P < 0.0007) and fewer medications (P < 0.001). Conclusions On the one hand, in older adults, executive dysfunction detected by objective tests is associated with poor glycaemic control and may be considered before prescribing complex treatment regimens. On the other hand, self-reported executive dysfunction is associated with risk and fear of falls, and more affective symptoms, which may indicate higher awareness of subtle deficits. C1 [Munshi, M. N.; Lee, Y.; Weinger, K.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Munshi, M. N.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Munshi, M. N.; Weinger, K.] Harvard Univ, Sch Med, Boston, MA USA. [Hayes, M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Iwata, I.] Duke Univ, Med Ctr, Durham, NC USA. RP Munshi, MN (reprint author), 1 Joslin Pl, Boston, MA 02215 USA. EM medha.munshi@joslin.harvard.edu FU American Diabetes Association [1-07-CR-40]; Department of Defense PRMRP of the Office of the Congressionally Directed Medical Research Programs [W81XWH-07-1-0282]; Joslin Diabetes Center Clinical Research Center FX The study was partly supported by a grant from a clinical research award from American Diabetes Association, 1-07-CR-40 (MM), Department of Defense PRMRP of the Office of the Congressionally Directed Medical Research Programs, W81XWH-07-1-0282 (MM), and the Joslin Diabetes Center Clinical Research Center. NR 29 TC 8 Z9 9 U1 6 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD SEP PY 2012 VL 29 IS 9 BP 1171 EP 1177 DI 10.1111/j.1464-5491.2012.03606.x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 988EC UT WOS:000307470200029 PM 22340082 ER PT J AU Brodsky, MB Abbott, KV McNeil, MR Palmer, CV Grayhack, JP Martin-Harris, B AF Brodsky, Martin B. Abbott, Katherine Verdolini McNeil, Malcolm R. Palmer, Catherine V. Grayhack, Judith P. Martin-Harris, Bonnie TI Effects of Divided Attention on Swallowing in Persons with Idiopathic Parkinson's Disease SO DYSPHAGIA LA English DT Article DE Deglutition; Deglutition disorders; Attention; Reaction time; Cognition; Parkinson's disease ID COGNITIVE STATUS EXAMINATION; DUAL-TASK; CORTICAL REPRESENTATION; MOTOR; ACTIVATION; GAIT; DYSPHAGIA; VALIDITY; HUMANS; BOTTLENECK AB The purpose of this study was to determine whether attentional resources are involved in swallowing in persons with idiopathic Parkinson's disease, and if so, in which phase(s) of swallowing. The approach involved a dual-task, reaction time (RT) paradigm using ten participants with Parkinson's disease. Single-task baseline measures were obtained for durations of the anticipatory phase and oropharyngeal phase of swallowing and RTs were obtained for nonword auditory stimuli. A dual-task then required participants to swallow 5 ml of water from an 8-oz. cup while listening for a target nonword presented auditorily during the anticipatory or oropharyngeal phase. Target stimuli were randomized across baseline and dual-task trials. Durations of the anticipatory and oropharyngeal phases of swallowing and RTs during baseline and dual-task trials were determined. Results showed a nonsignificant change in speed of completion for both the anticipatory phase and the oropharyngeal phase of swallowing during dual-task trials. However, there was a statistically significant increase in RT during the anticipatory phase during the dual-task condition. RT during the oropharyngeal phase remained unaffected. Given a need for additional research using more complex competing tasks, these data on attention are consistent with earlier claims of an automatic, nonresource-demanding, oropharyngeal swallowing mechanism that is preserved for persons with early-to-mid-stage Parkinson's disease. Clinical implications of these data suggest that disruptive environmental stimuli to individuals with early-to-mid-stage Parkinson's disease may alter feeding but have little effect on the oropharyngeal swallow. C1 [Brodsky, Martin B.] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD 21231 USA. [Abbott, Katherine Verdolini; McNeil, Malcolm R.; Palmer, Catherine V.; Grayhack, Judith P.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA USA. [McNeil, Malcolm R.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Washington, DC USA. [Martin-Harris, Bonnie] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. RP Brodsky, MB (reprint author), Johns Hopkins Univ, Dept Phys Med & Rehabil, 98 N Broadway,Suite 403, Baltimore, MD 21231 USA. EM brodsky@jhmi.edu FU Mark and Evelyn Trammell Trust, Atlanta, Georgia; Evelyn Trammell Institute for Voice and Swallowing in the Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina; Trident Parkinson's Support Group FX The authors thank the Mark and Evelyn Trammell Trust, Atlanta, Georgia; the Evelyn Trammell Institute for Voice and Swallowing in the Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina; and the Trident Parkinson's Support Group for their support. The authors also thank Neil Szuminsky and Pete Arvenitis for their dedication, ingenuity, and technical expertise that lead to the design and creation of the hardware and programming necessary for this research. NR 50 TC 5 Z9 8 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-051X J9 DYSPHAGIA JI Dysphagia PD SEP PY 2012 VL 27 IS 3 BP 390 EP 400 DI 10.1007/s00455-011-9381-x PG 11 WC Otorhinolaryngology SC Otorhinolaryngology GA 988VF UT WOS:000307518100011 PM 22197910 ER PT J AU Oudega, M Chao, OY Avison, DL Bronson, RT Buchser, WJ Hurtado, A Grimpe, B AF Oudega, Martin Chao, Owen Y. Avison, Donna L. Bronson, Roderick T. Buchser, William J. Hurtado, Andres Grimpe, Barbara TI Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Spinal cord injury; Glial scar; Chondroitin sulfate proteoglycans; DNA enzyme; Neurotherapeutics; Regeneration; Functional recovery ID CHONDROITIN SULFATE PROTEOGLYCANS; ADULT-RAT; GLIAL SCAR; CORTICOSPINAL TRACT; FUNCTIONAL RECOVERY; ARTICULAR-CARTILAGE; NERVOUS-SYSTEM; AXON GROWTH; REGENERATION; PLASTICITY AB After spinal cord injury, proteoglycans with growth-inhibitory glycosaminoglycan (GAG-) side chains in scar tissue limit spontaneous axonal sprouting/regeneration. Interventions that reduce scar-related inhibition facilitate an axonal growth response and possibly plasticity-based spinal cord repair. Xylosyltransferase-1 (XT-1) is the enzyme that initiates GAG-chain formation. We investigated whether intravenous administration of a deoxyribozyme (DNA enzyme) to XT-1 mRNA (DNAXT-1as) would elicit plasticity after a clinically relevant contusion of the spinal cord in adult rats. Our data showed that systemic DNAXT-1as administration resulted in a significant increase in sensorimotor function and serotonergic axon presence caudal to the injury. DNAXT1as treatment did not cause pathological or toxicological side effects. Importantly, intravenous delivery of DNAXT-1as did not exacerbate contusion-induced neuropathic pain. Collectively, our data demonstrate that DNAXT-1as is a safe neurotherapeutic, which holds promise to become an integral component of therapies that aim to improve the quality of life of persons with spinal cord injury. (C) 2012 Elsevier Inc. All rights reserved. C1 [Grimpe, Barbara] Univ Dusseldorf, Dept Neurol, D-40225 Dusseldorf, Germany. [Oudega, Martin] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Pittsburgh, PA 15213 USA. [Oudega, Martin] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Oudega, Martin] Univ Pittsburgh, Sch Med, Dept Bioengn, Pittsburgh, PA 15213 USA. [Chao, Owen Y.] Univ Dusseldorf, Dept Expt Psychol, D-40225 Dusseldorf, Germany. [Avison, Donna L.] Univ Miami, Leonard M Miller Sch Med, Dept Surg, Miami, FL 33136 USA. [Bronson, Roderick T.] Dana Faber Harvard Canc Ctr, Boston, MA 02115 USA. [Buchser, William J.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. [Hurtado, Andres] Johns Hopkins Univ, Hugo W Moser Res Inst Kennedy Krieger, Int Ctr Spinal Cord Injury, Dept Neurol,Sch Med, Baltimore, MD 21205 USA. RP Grimpe, B (reprint author), Univ Dusseldorf, Dept Neurol, Moorenstr 5, D-40225 Dusseldorf, Germany. EM moudega@pitt.edu; owenchao@gmail.com; d.avison@miami.edu; Roderick_Bronson@hms.harvard.edu; buchserw@upmc.edu; hurtado@kennedykrieger.edu; Barbara.Grimpe@med.uni-duesseldorf.de OI Buchser, William/0000-0002-6675-6359 FU Department of Physical Medicine and Rehabilitation at the University of Pittsburgh; German Research Foundation (DFG); Forschungskommission of the HHU; Ralph Wilson Medical Research Foundation; Buoniconti Fund; Florida State Fund FX We thank the Animal/Behavioral and Histology Core Facilities, Dr. Alex Marcillo, and Dr. Beata Frydel of the Miami Project to Cure Paralysis, and Heidrun Podini and Julia Domke. This work was supported by the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh (MO); the German Research Foundation (DFG, BG); Forschungskommission of the HHU (BG); Ralph Wilson Medical Research Foundation (BG); Buoniconti Fund (BG); and the Florida State Fund (BG). The authors declare no conflict of interest. NR 56 TC 5 Z9 5 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD SEP PY 2012 VL 237 IS 1 BP 170 EP 179 DI 10.1016/j.expneurol.2012.06.006 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 991JI UT WOS:000307696900021 PM 22721770 ER PT J AU van der Laan, AM Nahrendorf, M Piek, JJ AF van der Laan, Anja M. Nahrendorf, Matthias Piek, Jan J. TI Healing and adverse remodelling after acute myocardial infarction: role of the cellular immune response SO HEART LA English DT Article ID PERIPHERAL-BLOOD; MONOCYTE SUBSETS; STEM-CELLS; INFLAMMATION; ANGIOPLASTY; INTRACORONARY; RECEPTOR; INJURY C1 [van der Laan, Anja M.; Piek, Jan J.] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1100 DD Amsterdam, Netherlands. [Nahrendorf, Matthias] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. RP Piek, JJ (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Cardiol, POB 22660, NL-1100 DD Amsterdam, Netherlands. EM j.j.piek@amc.uva.nl FU Graduate School for Medical Sciences of the Academic Medical Centre, Amsterdam, The Netherlands; National Institutes of Health [R01HL096576] FX This work was supported by a grant by the Graduate School for Medical Sciences of the Academic Medical Centre, Amsterdam, The Netherlands to AML, and a grant from the National Institutes of Health (R01HL096576) to MN. NR 20 TC 23 Z9 23 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD SEP PY 2012 VL 98 IS 18 BP 1384 EP 1390 DI 10.1136/heartjnl-2012-301623 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 990QV UT WOS:000307646800011 PM 22904145 ER PT J AU Cerliani, L Thomas, RM Jbabdi, S Siero, JCW Nanetti, L Crippa, A Gazzola, V D'Arceuil, H Keysers, C AF Cerliani, Leonardo Thomas, Rajat M. Jbabdi, Saad Siero, Jeroen C. W. Nanetti, Luca Crippa, Alessandro Gazzola, Valeria D'Arceuil, Helen Keysers, Christian TI Probabilistic tractography recovers a rostrocaudal trajectory of connectivity variability in the human insular cortex SO HUMAN BRAIN MAPPING LA English DT Review DE DTI; insula; laplacian eigenmaps; diffusion-weighted imaging; connectivity-based parcellation ID HUMAN CEREBRAL-CORTEX; OLD-WORLD MONKEY; COMPARATIVE CYTOARCHITECTONIC ANALYSIS; VENTROLATERAL PREFRONTAL CORTEX; SUPERIOR PARIETAL CORTEX; MACAQUE MONKEY; HUMAN BRAIN; RHESUS-MONKEY; CORTICOCORTICAL CONNECTIONS; CORTICAL CONNECTIONS AB The insular cortex of macaques has a wide spectrum of anatomical connections whose distribution is related to its heterogeneous cytoarchitecture. Although there is evidence of a similar cytoarchitectural arrangement in humans, the anatomical connectivity of the insula in the human brain has not yet been investigated in vivo. In the present work, we used in vivo probabilistic white-matter tractography and Laplacian eigenmaps (LE) to study the variation of connectivity patterns across insular territories in humans. In each subject and hemisphere, we recovered a rostrocaudal trajectory of connectivity variation ranging from the anterior dorsal and ventral insula to the dorsal caudal part of the long insular gyri. LE suggested that regional transitions among tractography patterns in the insula occur more gradually than in other brain regions. In particular, the change in tractography patterns was more gradual in the insula than in the medial premotor region, where a sharp transition between different tractography patterns was found. The recovered trajectory of connectivity variation in the insula suggests a relation between connectivity and cytoarchitecture in humans resembling that previously found in macaques: tractography seeds from the anterior insula were mainly found in limbic and paralimbic regions and in anterior parts of the inferior frontal gyrus, while seeds from caudal insular territories mostly reached parietal and posterior temporal cortices. Regions in the putative dysgranular insula displayed more heterogeneous connectivity patterns, with regional differences related to the proximity with either putative granular or agranular regions. Hum Brain Mapp 33:20052034, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Cerliani, Leonardo] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, BCN NeuroImaging Ctr, NL-9713 AW Groningen, Netherlands. [Cerliani, Leonardo; Gazzola, Valeria; Keysers, Christian] Royal Netherlands Acad Arts & Sci, Social Brain Lab, Netherlands Inst Neurosci, Amsterdam, Netherlands. [Thomas, Rajat M.] Univ Groningen, Kapteyn Astron Inst, Fac Math & Nat Sci, NL-9700 AV Groningen, Netherlands. [Jbabdi, Saad] Univ Oxford, Oxford Ctr Funct Magnet Resonance Imaging Brain F, Dept Clin Neurol, Oxford OX1 2JD, England. [Siero, Jeroen C. W.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [Crippa, Alessandro] Univ Groningen, Inst Math & Comp Sci, Sci Visualizat & Comp Graph Grp, NL-9700 AV Groningen, Netherlands. [D'Arceuil, Helen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. RP Cerliani, L (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, BCN NeuroImaging Ctr, Antonius Deusinglaan 2, NL-9713 AW Groningen, Netherlands. EM leonardo.cerliani@gmail.com RI Thomas, Rajat/B-7105-2014; OI Thomas, Rajat/0000-0002-5362-4816; Gazzola, Valeria/0000-0003-0324-0619; Jbabdi, Saad/0000-0003-3234-5639; Keysers, Christian/0000-0002-2845-5467; cerliani, leonardo/0000-0002-2655-6133 FU Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Cognitive Pilot Project [051.07.003]; NWO VIDI [452-04-305]; NWO MaGW [400-08-089]; Marie Curie Excellence Grant [MEXT-CT-2005-023253] FX Contract grant sponsor: Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Cognitive Pilot Project; Contract grant number: 051.07.003; Contract grant sponsor: NWO VIDI; Contract grant number: 452-04-305; Contract grant sponsor: NWO MaGW; Contract grant number: 400-08-089; Contract grant sponsor: Marie Curie Excellence Grant; Contract grant number: MEXT-CT-2005-023253. NR 177 TC 70 Z9 71 U1 3 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2012 VL 33 IS 9 BP 2005 EP 2034 DI 10.1002/hbm.21338 PG 30 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 989XB UT WOS:000307593400001 PM 21761507 ER PT J AU Ciesielski, KT Rauch, SL Ahlfors, SP Vangel, ME Wilhelm, S Rosen, BR Hamalainen, MS AF Ciesielski, Kristina T. Rauch, Scott L. Ahlfors, Seppo P. Vangel, Mark E. Wilhelm, Sabine Rosen, Bruce R. Haemaelaeinen, Matti S. TI Role of medial cortical networks for anticipatory processing in obsessive-compulsive disorder SO HUMAN BRAIN MAPPING LA English DT Article DE OCD; MEG; anticipatory top-down control; posterior medial self-regulatory networks; compensatory mechanism ID VISUAL-ATTENTION; DEFAULT-MODE; RETROSPLENIAL CORTEX; COGNITIVE CONTROL; NEURONAL-ACTIVITY; MACAQUE MONKEY; BRAIN-FUNCTION; MEMORY TASK; ACTIVATION; MEG AB Recurrent anticipation of ominous events is central to obsessions, the core symptom of obsessive-compulsive disorder (OCD), yet the neural basis of intrinsic anticipatory processing in OCD is unknown. We studied nonmedicated adults with OCD and case matched healthy controls in a visual-spatial working memory task with distractor. Magnetoencephalography was used to examine the medial cortex activity during anticipation of to-be-inhibited distractors and to-be-facilitated retrieval stimuli. In OCD anticipatory activation to distractors was abnormally reduced within the posterior cingulate and fusiform gyrus compared to prominent activation in controls. Conversely, OCD subjects displayed significantly increased activation to retrieval stimuli within the anterior cingulate and supplementary motor cortex. This previously unreported discordant pattern of medial anticipatory activation in OCD was accompanied by normal performance accuracy. While increased anterior cortex activation in OCD is commonly viewed as failure of inhibition, the current pattern of data implicates the operation of an anterior compensatory mechanism amending the posterior medial self-regulatory networks disrupted in OCD. Hum Brain Mapp 33:2125-2134, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Ciesielski, Kristina T.; Ahlfors, Seppo P.; Vangel, Mark E.; Rosen, Bruce R.; Haemaelaeinen, Matti S.] Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ciesielski, Kristina T.; Ahlfors, Seppo P.; Vangel, Mark E.; Rosen, Bruce R.; Haemaelaeinen, Matti S.] Harvard Univ, McLean Hosp, Sch Med, Charlestown, MA USA. [Ciesielski, Kristina T.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Rauch, Scott L.; Wilhelm, Sabine] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ahlfors, Seppo P.; Vangel, Mark E.; Rosen, Bruce R.; Haemaelaeinen, Matti S.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Ciesielski, KT (reprint author), Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS AA Martinos Ctr Biomed Imaging, Bldg 149,13th St, Charlestown, MA USA. EM ktc@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; Ahlfors, Seppo/P-3644-2016 FU National Center for Research Resources/National Institutes of Health [P41RR14075] FX Contract grant sponsor: National Center for Research Resources/National Institutes of Health; Contract grant number: P41RR14075. NR 52 TC 6 Z9 6 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2012 VL 33 IS 9 BP 2125 EP 2134 DI 10.1002/hbm.21341 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 989XB UT WOS:000307593400009 PM 21882299 ER PT J AU Al-Sukhni, W Joe, S Lionel, AC Zwingerman, N Zogopoulos, G Marshall, CR Borgida, A Holter, S Gropper, A Moore, S Bondy, M Klein, AP Petersen, GM Rabe, KG Schwartz, AG Syngal, S Scherer, SW Gallinger, S AF Al-Sukhni, Wigdan Joe, Sarah Lionel, Anath C. Zwingerman, Nora Zogopoulos, George Marshall, Christian R. Borgida, Ayelet Holter, Spring Gropper, Aaron Moore, Sara Bondy, Melissa Klein, Alison P. Petersen, Gloria M. Rabe, Kari G. Schwartz, Ann G. Syngal, Sapna Scherer, Stephen W. Gallinger, Steven TI Identification of germline genomic copy number variation in familial pancreatic cancer SO HUMAN GENETICS LA English DT Article ID COLORECTAL-CANCER; PROSTATE-CANCER; RISK; POPULATION; VARIANTS; GENE; ASSOCIATION; DELETIONS; ONSET; DISEASES AB Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer. C1 [Gallinger, Steven] Toronto Gen Hosp, Toronto, ON M5G 2C4, Canada. [Al-Sukhni, Wigdan; Zogopoulos, George; Gallinger, Steven] Univ Torontom, Div Gen Surg, Dept Surg, Toronto, ON, Canada. [Lionel, Anath C.; Marshall, Christian R.; Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Lionel, Anath C.; Scherer, Stephen W.] Univ Toronto, Dept Mol Genet, McLaughlin Ctr, Toronto, ON, Canada. [Bondy, Melissa] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Klein, Alison P.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sol Goldman Pancreat Res Ctr, Baltimore, MD USA. [Petersen, Gloria M.; Rabe, Kari G.] Mayo Clin, Coll Med, Rochester, MN USA. [Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Syngal, Sapna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Al-Sukhni, Wigdan; Joe, Sarah; Zwingerman, Nora; Zogopoulos, George; Borgida, Ayelet; Holter, Spring; Gropper, Aaron; Moore, Sara; Gallinger, Steven] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. RP Gallinger, S (reprint author), Toronto Gen Hosp, 10th Floor,Rm 10EN206,200 Elizabeth St, Toronto, ON M5G 2C4, Canada. EM wigdan.al.sukhni@utoronto.ca; steven.gallinger@uhn.on.ca RI Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013; Gallinger, Steven/E-4575-2013 OI Scherer, Stephen /0000-0002-8326-1999; FU National Institute of Health, Pancreatic Cancer Genetic Epidemiology Consortium (PACGENE) [5R01CA097975-08]; Lustgarten Foundation; Princess Margaret Hospital Invest-in-Research Fund; Canadian Institute for Health Research; Canadian Society for Surgical Oncology; American Hepato-Pancreato-Biliary Association; Johnson & Johnson Medical Products/University of Toronto Surgeon Scientist Program Fellowship FX Sources of funding were from National Institute of Health, Pancreatic Cancer Genetic Epidemiology Consortium (PACGENE) Grant#5R01CA097975-08; Lustgarten Foundation; Princess Margaret Hospital Invest-in-Research Fund; Canadian Institute for Health Research (Graduate Research Award; Vanier Doctoral Award); Canadian Society for Surgical Oncology; American Hepato-Pancreato-Biliary Association; Johnson & Johnson Medical Products/University of Toronto Surgeon Scientist Program Fellowship. We thank the following individuals for their contributions: A. Fiebig, A. Franke and S. Schreiber at POPGEN (University of Kiel, Kiel, Germany) and A. Stewart, R. McPherson and R. Roberts of the University of Ottawa Heart Institute (University of Ottawa, Ottawa, Canada) for generously providing population control microarray data; D. Merico and D. Pinto (The Centre for Applied Genomics, Toronto, Canada) for assistance with data review; G. Bader (University of Toronto, Toronto, Canada) and S. Narod (Women's College Hospital, Toronto, Canada) for review of the manuscript; H. Rothenmund (Samuel Lunenefeld Research Institute, Toronto, Canada) for her help with patient selection for the study; T. Selander of the Biospecimen Repository (Samuel Lunenfeld Research Institute, Toronto, Canada) for DNA extraction and storage. PACGENE coordinators (Mayo Clinic: J. Cogswell, T. Hammer, C. Wong; JHU: D. Echavarria; Karmanos: K. Sargent; MDA: P. Adatto, G. Armstrong; Dana Farber: M. Lenn, M. Perez, C. Ukaegbu). NR 52 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD SEP PY 2012 VL 131 IS 9 BP 1481 EP 1494 DI 10.1007/s00439-012-1183-1 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 988UG UT WOS:000307515600007 PM 22665139 ER PT J AU Usenovic, M Knight, AL Ray, A Wong, V Brown, KR Caldwell, GA Caldwell, KA Stagljar, I Krainc, D AF Usenovic, Marija Knight, Adam L. Ray, Arpita Wong, Victoria Brown, Kevin R. Caldwell, Guy A. Caldwell, Kim A. Stagljar, Igor Krainc, Dimitri TI Identification of novel ATP13A2 interactors and their role in alpha-synuclein misfolding and toxicity SO HUMAN MOLECULAR GENETICS LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; KUFOR-RAKEB SYNDROME; P-TYPE ATPASE; CAENORHABDITIS-ELEGANS; IN-VIVO; NEURODEGENERATIVE DISEASES; DOPAMINERGIC-NEURONS; PARKINSONS-DISEASE; SPLIT-UBIQUITIN; PROTEIN AB Lysosomes are responsible for degradation and recycling of bulky cell material, including accumulated misfolded proteins and dysfunctional organelles. Increasing evidence implicates lysosomal dysfunction in several neurodegenerative disorders, including Parkinson's disease and related synucleinopathies, which are characterized by the accumulation of alpha-synuclein (alpha-syn) in Lewy bodies. Studies of lysosomal proteins linked to neurodegenerative disorders present an opportunity to uncover specific molecular mechanisms and pathways that contribute to neurodegeneration. Loss-of-function mutations in a lysosomal protein, ATP13A2 (PARK9), cause Kufor-Rakeb syndrome that is characterized by early-onset parkinsonism, pyramidal degeneration and dementia. While loss of ATP13A2 function plays a role in alpha-syn misfolding and toxicity, the normal function of ATP13A2 in the brain remains largely unknown. Here, we performed a screen to identify ATP13A2 interacting partners, as a first step toward elucidating its function. Utilizing a split-ubiquitin membrane yeast two-hybrid system that was developed to identify interacting partners of full-length integral membrane proteins, we identified 43 novel interactors that primarily implicate ATP13A2 in cellular processes such as endoplasmic reticulum (ER) translocation, ER-to-Golgi trafficking and vesicular transport and fusion. We showed that a subset of these interactors modified alpha-syn aggregation and alpha-syn-mediated degeneration of dopaminergic neurons in Caenorhabditis elegans, further suggesting that ATP13A2 and alpha-syn are functionally linked in neurodegeneration. These results implicate ATP13A2 in vesicular trafficking and provide a platform for further studies of ATP13A2 in neurodegeneration. C1 [Usenovic, Marija; Krainc, Dimitri] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. [Usenovic, Marija] Mediterranean Inst Life Sci, Split 21000, Croatia. [Knight, Adam L.; Ray, Arpita; Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. [Wong, Victoria; Stagljar, Igor] Univ Toronto, Dept Biochem, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Wong, Victoria; Stagljar, Igor] Univ Toronto, Dept Mol Genet, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Brown, Kevin R.] Univ Toronto, Donnelly Ctr, Banting & Best Dept Med Res, Toronto, ON M5S 3E1, Canada. [Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Dept Neurol, Birmingham, AL 35294 USA. [Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Dept Neurobiol, Birmingham, AL 35294 USA. RP Krainc, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, 114 16th St,Room 2008, Charlestown, MA 02129 USA. EM krainc@helix.mgh.harvard.edu FU National Institutes of Health [R01NS051303, R15NS075684]; Canadian Foundation for Innovation (CFI); Canadian Institutes of Health Research (CIHR); Canadian Cancer Society Research Institute (CCSRI); Heart and Stroke Foundation; Cystic Fibrosis Foundation; Ontario Genomics Institute; Natural Sciences and Engineering Research Council of Canada (NSERC); Novartis FX This work was supported by National Institutes of Health (R01NS051303 to D. K. and R15NS075684 to G. A. C.). The research in the Stagljar lab is supported by grants from the Canadian Foundation for Innovation (CFI), the Canadian Institutes of Health Research (CIHR), the Canadian Cancer Society Research Institute (CCSRI), the Heart and Stroke Foundation, the Cystic Fibrosis Foundation, the Ontario Genomics Institute, Natural Sciences and Engineering Research Council of Canada (NSERC), and Novartis. NR 53 TC 32 Z9 33 U1 3 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 1 PY 2012 VL 21 IS 17 BP 3785 EP 3794 DI 10.1093/hmg/dds206 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 988PX UT WOS:000307504100005 PM 22645275 ER PT J AU Fasching, PA Pharoah, PDP Cox, A Nevanlinna, H Bojesen, SE Karn, T Broeks, A van Leeuwen, FE van 't Veer, LJ Udo, R Dunning, AM Greco, D Aittomaki, K Blomqvist, C Shah, M Nordestgaard, BG Flyger, H Hopper, JL Southey, MC Apicella, C Garcia-Closas, M Sherman, M Lissowska, J Seynaeve, C Huijts, PEA Tollenaar, RAEM Ziogas, A Ekici, AB Rauh, C Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Andrulis, IL Ozcelik, H Mulligan, AM Glendon, G Hall, P Czene, K Liu, JJ Chang-Claude, J Wang-Gohrke, S Eilber, U Nickels, S Doerk, T Schiekel, M Bremer, M Park-Simon, TW Giles, GG Severi, G Baglietto, L Hooning, MJ Martens, JWM Jager, A Kriege, M Lindblom, A Margolin, S Couch, FJ Stevens, KN Olson, JE Kosei, M Cross, SS Balasubramanian, SP Reed, MWR Miron, A John, EM Winqvist, R Pylkas, K Jukkola-Vuorinen, A Kauppila, S Burwinkel, B Marme, F Schneeweiss, A Sohn, C Chenevix-Trench, G Lambrechts, D Dieudonne, AS Hatse, S van Limbergen, E Benitez, J Milne, RL Zamora, MP Perez, JIA Bonanni, B Peissel, B Loris, B Peterlongo, P Rajaraman, P Schonfeld, SJ Anton-Culver, H Devilee, P Beckmann, MW Slamon, DJ Phillips, KA Figueroa, JD Humphreys, MK Easton, DF Schmidt, MK AF Fasching, Peter A. Pharoah, Paul D. P. Cox, Angela Nevanlinna, Heli Bojesen, Stig E. Karn, Thomas Broeks, Annegien van Leeuwen, Flora E. van 't Veer, Laura J. Udo, Renate Dunning, Alison M. Greco, Dario Aittomaki, Kristiina Blomqvist, Carl Shah, Mitul Nordestgaard, Borge G. Flyger, Henrik Hopper, John L. Southey, Melissa C. Apicella, Carmel Garcia-Closas, Montserrat Sherman, Mark Lissowska, Jolanta Seynaeve, Caroline Huijts, Petra E. A. Tollenaar, Rob A. E. M. Ziogas, Argyrios Ekici, Arif B. Rauh, Claudia Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Andrulis, Irene L. Ozcelik, Hilmi Mulligan, Anna-Marie Glendon, Gord Hall, Per Czene, Kamila Liu, Jianjun Chang-Claude, Jenny Wang-Gohrke, Shan Eilber, Ursula Nickels, Stefan Doerk, Thilo Schiekel, Maria Bremer, Michael Park-Simon, Tjoung-Won Giles, Graham G. Severi, Gianluca Baglietto, Laura Hooning, Maartje J. Martens, John W. M. Jager, Agnes Kriege, Mieke Lindblom, Annika Margolin, Sara Couch, Fergus J. Stevens, Kristen N. Olson, Janet E. Kosei, Matthew Cross, Simon S. Balasubramanian, Sabapathy P. Reed, Malcolm W. R. Miron, Alexander John, Esther M. Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Burwinkel, Barbara Marme, Frederik Schneeweiss, Andreas Sohn, Christof Chenevix-Trench, Georgia Lambrechts, Diether Dieudonne, Anne-Sophie Hatse, Sigrid van Limbergen, Erik Benitez, Javier Milne, Roger L. Pilar Zamora, M. Arias Perez, Jose Ignacio Bonanni, Bernardo Peissel, Bernard Loris, Bernard Peterlongo, Paolo Rajaraman, Preetha Schonfeld, Sara J. Anton-Culver, Hoda Devilee, Peter Beckmann, Matthias W. Slamon, Dennis J. Phillips, Kelly-Anne Figueroa, Jonine D. Humphreys, Manjeet K. Easton, Douglas F. Schmidt, Marjanka K. CA KConFab Investigators TI The role of genetic breast cancer susceptibility variants as prognostic factors SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CONFER SUSCEPTIBILITY; COMMON VARIANTS; ATM GENE; RISK; SURVIVAL; POLYMORPHISMS; LOCUS; WOMEN; CONSORTIUM AB Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers1.21; 95 CI: 1.091.35, P0.0002 and HR1.29; 95 CI: 1.121.47, P0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. C1 [Fasching, Peter A.; Rauh, Claudia; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Univ Breast Ctr,Comprehens Canc Ctr Erlangen Nure, D-91054 Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. [Fasching, Peter A.; Slamon, Dennis J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D. P.; Humphreys, Manjeet K.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Cox, Angela] Univ Sheffield, Inst Canc Studies, CRUK YCR Sheffield Canc Res Ctr, Dept Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England. [Balasubramanian, Sabapathy P.; Reed, Malcolm W. R.] Univ Sheffield, Acad Unit Surg Oncol, CRUK YCR Sheffield Canc Res Ctr, Dept Oncol, Sheffield, S Yorkshire, England. [Nevanlinna, Heli; Greco, Dario] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Karn, Thomas] Goethe Univ Frankfurt, Univ Hosp, Dept Gynecol & Obstet, Frankfurt, Germany. [Broeks, Annegien; van 't Veer, Laura J.; Schmidt, Marjanka K.] Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [van Leeuwen, Flora E.; Udo, Renate; Giles, Graham G.; Schmidt, Marjanka K.] Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Hopper, John L.; Apicella, Carmel; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Enviromental Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Sherman, Mark; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Seynaeve, Caroline; Jager, Agnes; Kriege, Mieke] Dr Daniel Den Hoed Canc Ctr, Erasmus Med Ctr, Rotterdam Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands. [Huijts, Petra E. A.; Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Tollenaar, Rob A. E. M.; Hooning, Maartje J.] Leiden Univ, Dept Surg Oncol, Med Ctr, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Ziogas, Argyrios; Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, UCI Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Canc Ctr Eastern Finland, Bioctr Kuopio, Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Inst Clin Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Kataja, Vesa; Glendon, Gord] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Andrulis, Irene L.] Canc Care Ontario, Ontario Canc Genet Network, Toronto, ON, Canada. [Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna-Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Andrulis, Irene L.; Ozcelik, Hilmi] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet,Dept Lab Med & Patho, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.; Mulligan, Anna-Marie] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet,Dept Mol Genet, Toronto, ON M5G 1X5, Canada. St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [Hall, Per; Czene, Kamila] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden. [Liu, Jianjun] Genome Inst Singapore, Human Genet Lab, Singapore, Singapore. [Chang-Claude, Jenny; Eilber, Ursula; Nickels, Stefan] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Unit, Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Univ Hosp Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Doerk, Thilo; Schiekel, Maria; Park-Simon, Tjoung-Won] Hannover Med Sch, Clin Obstet, D-3000 Hannover, Germany. [Doerk, Thilo; Schiekel, Maria; Park-Simon, Tjoung-Won] Hannover Med Sch, Clin Gynaecol, D-3000 Hannover, Germany. [Bremer, Michael] Hannover Med Sch, Clin Radiat Oncol, D-3000 Hannover, Germany. [Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Martens, John W. M.] Erasmus Univ, Josephine Nefkens Inst, Dept Med Oncol, Med Ctr, Rotterdam, Netherlands. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Stevens, Kristen N.; Olson, Janet E.; Kosei, Matthew] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Miron, Alexander] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [John, Esther M.] Stanford Canc Inst, Stanford, CA USA. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Dept Clin Genet, Lab Canc Genet, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Dept Oncol, Oulu Univ Hosp, Oulu, Finland. [Kauppila, Saila] Univ Oulu, Dept Pathol, Oulu Univ Hosp, Oulu, Finland. [Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof] Heidelberg Univ, Univ Heidelberg Hosp, Dept Obstet & Gynecol, Heidelberg, Germany. [Marme, Frederik; Schneeweiss, Andreas] Univ Heidelberg Hosp, Natl Ctr Tumor Dis, Sect Gynecol Oncol, Heidelberg, Germany. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Lambrechts, Diether] Katholieke Univ Leuven VIB, Vesalius Res Ctr, Louvain, Belgium. [Dieudonne, Anne-Sophie; Hatse, Sigrid; van Limbergen, Erik] Katholieke Univ Leuven, Univ Hosp, Leuven Multidisciplinary Breast Ctr, Louvain, Belgium. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain. [Milne, Roger L.] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Genet & Mol Epidemiol Grp, Madrid, Spain. [Pilar Zamora, M.] Hosp Univ La Paz, Serv Oncol Med, Madrid, Spain. [Arias Perez, Jose Ignacio] Hosp Mt Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Loris, Bernard] Ist Europeo Oncol, Dept Expt Oncol, Milan, Italy. [Peissel, Bernard] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Peterlongo, Paolo] IFOM, Fdn Ist FIRC Oncol Mol, Milan, Italy. [Rajaraman, Preetha; Schonfeld, Sara J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Div Canc Med, Melbourne, Vic, Australia. [Phillips, Kelly-Anne] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic 3010, Australia. RP Fasching, PA (reprint author), Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Univ Breast Ctr,Comprehens Canc Ctr Erlangen Nure, D-91054 Erlangen, Germany. EM peter.fasching@uk-erlangen.de RI Verdrengh, Evelien/H-4571-2012; Peissel, Bernard/E-8187-2017; Ekici, Arif/C-3971-2013; Andrulis, Irene/E-7267-2013; Dork, Thilo/J-8620-2012; karn, t/C-7452-2013; Garcia-Closas, Montserrat /F-3871-2015; Hartikainen, Jaana/E-6256-2015; OI Peissel, Bernard/0000-0001-9233-3571; Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Phillips, Kelly-Anne/0000-0002-0475-1771; karn, t/0000-0002-3264-6573; Garcia-Closas, Montserrat /0000-0003-1033-2650; Greco, Dario/0000-0001-9195-9003; Dunning, Alison Margaret/0000-0001-6651-7166; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099 FU European Community [223175 (HEALTH-F2-2009-223175) (COGS)]; CR-UK [C1287/A10118, C1287/A12014]; European Union COST programme [BM0606]; Cancer Research UK [C1287/A12014, C490/A10124, C490/A10119]; Cambridge Biomedical Research Centre; Dutch Cancer Society [NKI 2001-2423, NKI 2007-3839, DDHK 2004-3124, DDHK 2009-4318]; Dutch National Genomics Initiative; Dutch Biobanking and Biomolecular Resources Research Infrastructure; National Institutes of Health (NIH) National Cancer Institute (NCI) [CA122340]; NCI Recovery Act grant [CA122340Z]; NCI Specialized Program of Research Excellence (SPORE) in breast cancer [CA116201]; ELAN research program; University Hospital Erlangen; Deutsche Krebshilfe e. V. [70492]; state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm [P.685]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Associazione Italiana per la Ricerca sul Cancro [4017]; Fondazione IRCCS Istituto Nazionale Tumori; 'Stichting tegen Kanker' [232-2008, 196-2010]; Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; Academy of Finland; University of Eastern Finland; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Copenhagen University Hospital; Herlev Hospital; Rudolf Bartling Foundation; National Breast Cancer Foundation of Australia; Cancer Australia; National Health and Medical Research Council of Australia; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; Victorian Health Promotion Foundation (Australia); Breast Cancer Campaign [2004Nov49]; Yorkshire Cancer Research [S295, S299]; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Finnish Cancer Foundation; University of Oulu; Oulu University Hospital; Biocenter Oulu; Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Swedish Cancer Society; Stockholm Cancer Society; Gustav V Jubilee foundation; Bert von Kantzow foundation; Agency for Science; Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Marit and Hans Rausings Initiative Against Breast Cancer; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI081583, PI081120]; United States National Cancer Institute, National Institutes of Health (NIH) [RFA-CA-06-503] FX This work was supported by funding from the European Community's Seventh Framework Programme under grant agreement - 223175 (HEALTH-F2-2009-223175) (COGS). Co-ordination and genotyping in BCAC was funded by CR-UK (C1287/A10118 and C1287/A12014). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). D. F. E. is a Principal Research Fellow of CR-UK. The genotyping was supported by Cancer Research UK (C490/A10124) and (C1287/A12014). Funding of the constituent studies and data analysis was supported by the Cambridge Biomedical Research Centre, Cancer Research UK (C490/A10119). Other studies have been funded by the Dutch Cancer Society (grants NKI 2001-2423; NKI 2007-3839), the Dutch National Genomics Initiative, the Dutch Biobanking and Biomolecular Resources Research Infrastructure, the National Institutes of Health (NIH) National Cancer Institute (NCI) grant CA122340, NCI Recovery Act grant CA122340Z, NCI Specialized Program of Research Excellence (SPORE) in breast cancer CA116201, the ELAN research program, University Hospital Erlangen, the Deutsche Krebshilfe e. V. (70492), the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm (P.685), the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, the Associazione Italiana per la Ricerca sul Cancro (4017) and funds from Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000"), the 'Stichting tegen Kanker' (232-2008 and 196-2010), the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland, the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Copenhagen University Hospital, Herlev Hospital, Rudolf Bartling Foundation, the National Breast Cancer Foundation of Australia, Cancer Australia, the National Health and Medical Research Council of Australia, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, the Cancer Foundation of Western Australia, the Victorian Health Promotion Foundation (Australia), the Breast Cancer Campaign (2004Nov49), Yorkshire Cancer Research (S295, S299 and core funding), the Dietmar-Hopp Foundation, the Helmholtz Society, the German Cancer Research Center (DKFZ), the Finnish Cancer Foundation, the Academy of Finland, the University of Oulu, the Oulu University Hospital, Biocenter Oulu; the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union and the Sigrid Juselius Foundation; the Dutch Cancer Society, grants DDHK 2004-3124 and DDHK 2009-4318, the Swedish Cancer Society, the Stockholm Cancer Society, the Gustav V Jubilee foundation, the Bert von Kantzow foundation, the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH), the Susan G. Komen Breast Cancer Foundation and Marit and Hans Rausings Initiative Against Breast Cancer, the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI081583 and PI081120).; The ABCFS, NC-BCFR and OFBCR work was supported by the United States National Cancer Institute, National Institutes of Health (NIH) under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417) and University of Melbourne (U01 CA69638). Samples from the NC-BCFR were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. NR 61 TC 41 Z9 41 U1 0 U2 19 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 1 PY 2012 VL 21 IS 17 BP 3926 EP 3939 DI 10.1093/hmg/dds159 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 988PX UT WOS:000307504100018 PM 22532573 ER PT J AU de Jesus-Gonzalez, N Robinson, E Moslehi, J Humphreys, BD AF de Jesus-Gonzalez, Nilka Robinson, Emily Moslehi, Javid Humphreys, Benjamin D. TI Management of Antiangiogenic Therapy-Induced Hypertension SO HYPERTENSION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; NITRIC-OXIDE SYNTHASE; ANGIOGENESIS INHIBITOR BEVACIZUMAB; ARTERIAL THROMBOEMBOLIC EVENTS; PREECLAMPSIA-LIKE SYNDROME; HIGH BLOOD-PRESSURE; CANCER-PATIENTS; KINASE INHIBITORS; PLUS BEVACIZUMAB C1 [de Jesus-Gonzalez, Nilka] Boston Childrens Hosp, Div Nephrol, Boston, MA USA. [Robinson, Emily; Humphreys, Benjamin D.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Moslehi, Javid] Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA USA. [Moslehi, Javid; Humphreys, Benjamin D.] Dana Farber Canc Inst, Lance Armstrong Fdn, Boston, MA 02115 USA. RP Humphreys, BD (reprint author), Harvard Inst Med, Room 554,4 Blackfan Cir, Boston, MA 02115 USA. EM bhumphreys@partners.org FU National Institutes of Health Training Grant [T32-DK007726-27S1, DK088923] FX This work was supported by the National Institutes of Health Training Grant T32-DK007726-27S1 (to N.D.G.) and DK088923 (to B.D.H.). NR 67 TC 21 Z9 21 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2012 VL 60 IS 3 BP 607 EP 615 DI 10.1161/HYPERTENSIONAHA.112.196774 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 994SM UT WOS:000307951900015 PM 22851729 ER PT J AU Chiu, CY Gomolka, B Dierkes, C Huang, NR Schroeder, M Purschke, M Manstein, D Dangi, B Weylandt, KH AF Chiu, Cheng-Ying Gomolka, Beate Dierkes, Cordula Huang, Nora R. Schroeder, Maik Purschke, Martin Manstein, Dieter Dangi, Bindi Weylandt, Karsten H. TI Omega-6 docosapentaenoic acid-derived resolvins and 17-hydroxydocosahexaenoic acid modulate macrophage function and alleviate experimental colitis SO INFLAMMATION RESEARCH LA English DT Article DE PUFA; 17-HDHA; 17-HDPA; 10,17-HDPA; Colitis; Lipid mediators ID INFLAMMATORY-BOWEL-DISEASE; ASPIRIN-TRIGGERED LIPOXIN; ALTERNATIVE ACTIVATION; DOCOSAHEXAENOIC ACID; APOPTOTIC NEUTROPHILS; CROHNS-DISEASE; RESOLUTION; PHAGOCYTOSIS; MICE; E1 AB Enzymatically oxygenated lipid products derived from omega-3 and omega-6 fatty acids play an important role in inflammation dampening. This study examined the anti-inflammatory effects of n-6 docosapentaenoic acid-derived (17S)-hydroxy-docosapentaenoic acid (17-HDPAn-6) and (10,17S)-dihydroxy-docosapentaenoic acid (10,17-HDPAn-6) as well as n-3 docosahexaenoic acid-derived 17(R/S)-hydroxy-docosahexaenoic acid (17-HDHA). The effects of 17-HDPAn-6, 10,17-HDPAn-6 or 17-HDHA on activity and M1/M2 polarization of murine macrophage cell line RAW 264.7 were examined by phagocytosis assay and real-time PCR. To assess anti-inflammatory effects in vivo, dextran sodium sulfate (DSS) colitis was induced in mice treated with 17-HDPAn-6, 10,17-HDPAn-6, 17-HDHA or NaCl. Our results show that 17-HDPAn-6, 10,17-HDPAn-6 and 17-HDHA increase phagocytosis in macrophages in vitro and promote polarization towards the anti-inflammatory M2 phenotype with decreased gene expression of TNF-alpha and inducible Nitric oxide synthase and increased expression of the chemokine IL-1 receptor antagonist and the Scavenger receptor Type A. Intraperitoneal treatment with 17-HDPAn-6, 10,17-HDPAn-6, or 17-HDHA alleviated DSS-colitis and significantly improved body weight loss, colon epithelial damage, and macrophage infiltration. These results suggest that DPAn-6-derived 17-HDPAn-6 and 10,17-HDPAn-6 as well as the DHA-derived 17-HDHA have inflammation-dampening and resolution-promoting effects that could be used to treat inflammatory conditions such as inflammatory bowel disease. C1 [Weylandt, Karsten H.] Charite Campus Virchow Hosp, Med Klin MS Gastroenterol & Hepatol, D-13353 Berlin, Germany. [Chiu, Cheng-Ying; Gomolka, Beate; Dierkes, Cordula; Huang, Nora R.; Schroeder, Maik; Weylandt, Karsten H.] Charite, Campus Virchow Klinikum, Dept Hepatol Gastroenterol & Endocrinol, D-13353 Berlin, Germany. [Chiu, Cheng-Ying; Huang, Nora R.; Weylandt, Karsten H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lab Lipid Med & Technol, Boston, MA USA. [Purschke, Martin; Manstein, Dieter] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Dangi, Bindi] DSM Nutr Prod, Columbia, MD USA. RP Weylandt, KH (reprint author), Charite Campus Virchow Hosp, Med Klin MS Gastroenterol & Hepatol, Augustenburger Pl 1, D-13353 Berlin, Germany. EM karsten.weylandt@charite.de FU German Research Fund (DFG); Charite intramural research funds; Martek Biosciences; German Academic Exchange Service FX 17-HDPA and 10,17-HDPA were provided by Martek Biosciences (a division of DSM Nutritional Products). K.H.W. is supported by the German Research Fund (DFG) and Charite intramural research funds. Part of the research work presented here was funded by Martek Biosciences. C.Y.C. was supported by a grant from the German Academic Exchange Service (Biomedical Sciences Exchange Program). NR 53 TC 27 Z9 28 U1 0 U2 7 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD SEP PY 2012 VL 61 IS 9 BP 967 EP 976 DI 10.1007/s00011-012-0489-8 PG 10 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 988UX UT WOS:000307517300007 PM 22618200 ER PT J AU Bandelow, B Sher, L Bunevicius, R Hollander, E Kasper, S Zohar, J Moller, HJ AF Bandelow, Borwin Sher, Leo Bunevicius, Robertas Hollander, Eric Kasper, Siegfried Zohar, Joseph Moeller, Hans-Juergen TI Guidelines for the pharmacological treatment of anxiety disorders, obsessive compulsive disorder and post-traumatic stress disorder in primary care (vol 16, pg 77, 2012) SO INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE LA English DT Correction C1 [Sher, Leo] Mt Sinai Sch Med, New York, NY USA. [Sher, Leo] James J Peters Vet Adm Med Ctr, New York, NY USA. RI Bandelow, Borwin/E-7295-2011 OI Bandelow, Borwin/0000-0003-2511-3768 NR 1 TC 0 Z9 0 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1365-1501 J9 INT J PSYCHIAT CLIN JI Int. J. Psychiat. Clin. PD SEP PY 2012 VL 16 IS 3 BP 242 EP 242 DI 10.3109/13651501.2012.700008 PG 1 WC Psychiatry SC Psychiatry GA 985WF UT WOS:000307300500013 ER PT J AU Zickmund, SL Campbell, SA Tirado, CF Zook, CL Weinrieb, RM AF Zickmund, Susan L. Campbell, Scott A. Tirado, Carlos F. Zook, Carolyn L. Weinrieb, Robert M. TI Perceived Barriers to Hepatitis C Therapy for Patients Receiving Opioid Agonist Treatment SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE barriers to antiviral therapy; hepatitis C; opioid agonist treatment; provider communication; stigmatization ID METHADONE-MAINTENANCE PATIENTS; VIRUS-INFECTION; DRUG-USERS; ANTIVIRAL TREATMENT; TREATMENT SERVICES; UNITED-STATES; KNOWLEDGE; EXPERIENCES; CLIENTS; MANAGEMENT AB Objectives: To explore attitudes toward hepatitis C antiviral therapy in a real-world setting, we asked patients in opioid agonist treatment who were offered antiviral therapy about perceived barriers to initiating therapy. Methods: We recruited patients in opioid agonist treatment who had previously been offered cost-free hepatitis C antiviral therapy in a clinical trial. We collected demographic and open-ended interview data. The semistructured interview guide included questions about attitudes toward hepatitis C therapy and barriers to initiating treatment. Each interview was audio recorded and transcribed verbatim. We used the qualitative editing method to analyze the interview transcripts. Results: We enrolled 19 patients who had been approached to initiate hepatitis C therapy in a clinical trial. All participants were low-income men, with one third self-identifying as racial minorities. When asked about possible barriers to treatment, multiple problems emerged, including the fear of treatment side effects, difficulties with health care providers, limited access to medical care and health information, and misperceptions about antiviral therapy. Conclusions: Despite intense educational efforts, concerns over antiviral therapy, relations with providers, and access to the health care system remain critical barriers. These factors should be addressed to improve antiviral therapy rates for patients receiving opioid agonist treatment. C1 [Zickmund, Susan L.; Zook, Carolyn L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Zickmund, Susan L.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Campbell, Scott A.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Tirado, Carlos F.] Univ Texas SW Med Ctr, Dept Psychiat, Austin, TX USA. [Zook, Carolyn L.] Univ Pittsburgh, Dept Sociol, Pittsburgh, PA USA. [Weinrieb, Robert M.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. RP Zickmund, SL (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr 151C-H, Pittsburgh, PA 15206 USA. EM Susan.Zickmund@va.gov FU Veterans Administration (VA) Health Services Research & Development (HSR&D) Merit Review Entry Program Career Development Award and Merit Review; VA VISN 4 Mental Illness Research, Education, and Clinical Center; VA HSRD; National Institutes of Health (NIH) FX Supported in part by the Veterans Administration (VA) Health Services Research & Development (HSR&D) Merit Review Entry Program Career Development Award and Merit Review and was also supported by pilot funds from the VA VISN 4 Mental Illness Research, Education, and Clinical Center. Dr Zickmund is currently receiving research support from the VA HSR&D. Dr Tirado has received honoraria from Rickett-Benckiser, Alkermes, and has received payments for educational presentations from the Texas Department of State Health Services. Dr Weinrieb is currently receiving research support from National Institutes of Health (NIH), has given legal testimony, and has given lectures to the University of Pennsylvania and received payment. The remaining authors have no conflicts of interest to declare. NR 39 TC 6 Z9 6 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-0620 J9 J ADDICT MED JI J. Addict. Med. PD SEP PY 2012 VL 6 IS 3 BP 233 EP 239 DI 10.1097/ADM.0b013e31825f491b PG 7 WC Substance Abuse SC Substance Abuse GA 993CS UT WOS:000307833400009 PM 22790464 ER PT J AU Tanner, ACR Sonis, AL Holgerson, PL Starr, JR Nunez, Y Kressirer, CA Paster, BJ Johansson, I AF Tanner, A. C. R. Sonis, A. L. Holgerson, P. Lif Starr, J. R. Nunez, Y. Kressirer, C. A. Paster, B. J. Johansson, I. TI White-spot Lesions and Gingivitis Microbiotas in Orthodontic Patients SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE orthodontic; adolescents; white-spot lesions; microbial ecology; Scardovia wiggsiae; HOMIM ID EARLY-CHILDHOOD CARIES; FIXED APPLIANCES; PERMANENT TEETH; CHILDREN; PCR; ADOLESCENTS; PREVALENCE; MICROFLORA; BRACKETS AB White-spot lesions (WSL) associated with orthodontic appliances are a cosmetic problem and increase risk for cavities. We characterized the microbiota of WSL, accounting for confounding due to gingivitis. Participants were 60 children with fixed appliances, aged between 10 and 19 yrs, half with WSL. Plaque samples were assayed by a 16S rRNA-based microarray (HOMIM) and by PCR. Mean gingival index was positively associated with WSL (p = 0.018). Taxa associated with WSL by microarray included Granulicatella elegans (p = 0.01), Veillonellaceae sp. HOT 155 (p < 0.01), and Bifidobacterium Cluster 1 (p = 0.11), and by qPCR, Streptococcus mutans (p = 0.008) and Scardovia wiggsiae (p = 0.04) Taxa associated with gingivitis by microarray included: Gemella sanguinis (p = 0.002), Actinomyces sp. HOT 448 (p = 0.003), Prevotella cluster IV (p = 0.021), and Streptococcus sp. HOT 071/070 (p = 0.023); and levels of S. mutans (p = 0.02) and Bifidobacteriaceae (p = 0.012) by qPCR. Species' associations with WSL were minimally changed with adjustment for gingivitis level. Partial least-squares discriminant analysis yielded good discrimination between children with and those without WSL. Granulicatella, Veillonellaceae and Bifidobacteriaceae, in addition to S. mutans and S. wiggsiae, were associated with the presence of WSL in adolescents undergoing orthodontic treatment. Many taxa showed a stronger association with gingivitis than with WSL. C1 [Tanner, A. C. R.; Kressirer, C. A.; Paster, B. J.] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Starr, J. R.] Forsyth Inst, Ctr Clin & Translat Res, Cambridge, MA USA. [Tanner, A. C. R.; Kressirer, C. A.; Paster, B. J.] Harvard Univ, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Sonis, A. L.] Harvard Univ, Dept Dev Biol, Boston, MA 02115 USA. [Starr, J. R.] Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. [Holgerson, P. Lif; Johansson, I.] Umea Univ, Fac Med, Dept Odontol, Cariol Sect, Umea, Sweden. [Starr, J. R.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Nunez, Y.] Seton Hall Univ, S Orange, NJ 07079 USA. RP Tanner, ACR (reprint author), Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. EM annetanner@forsyth.org OI Starr, Jacqueline/0000-0002-3039-2311 FU USPHS from the NIDCR (NIH) [DE-015847, DE-021796, DE-007327]; Throne-Holst's Foundation; Bingham Trust; Harvard Catalyst [UL1 RR 025758, RC1 DE020549] FX We thank Winston Kuo and Alex Trachtenberg for assistance with qPCR assays, and Ralph Kent and Natalia Chalmers in project development. This work was conducted with support from USPHS grants DE-015847, DE-021796, and DE-007327 from the NIDCR (NIH), Throne-Holst's Foundation, the Bingham Trust, and Harvard Catalyst UL1 RR 025758, RC1 DE020549. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 26 TC 14 Z9 15 U1 7 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD SEP PY 2012 VL 91 IS 9 BP 853 EP 858 DI 10.1177/0022034512455031 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 989ES UT WOS:000307543700008 PM 22837552 ER PT J AU Beverly, EA Ritholz, MD Brooks, KM Hultgren, BA Lee, Y Abrahamson, MJ Weinger, K AF Beverly, Elizabeth A. Ritholz, Marilyn D. Brooks, Kelly M. Hultgren, Brittney A. Lee, Yishan Abrahamson, Martin J. Weinger, Katie TI A Qualitative Study of Perceived Responsibility and Self-Blame in Type 2 Diabetes: Reflections of Physicians and Patients SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE physician-patient relationship; type 2 diabetes; self-care behavior; qualitative methodology ID DIAGNOSED BREAST-CANCER; GLYCEMIC CONTROL; PSYCHOLOGICAL ADJUSTMENT; PSYCHOSOCIAL ISSUES; CHRONIC ILLNESS; GLUCOSE CONTROL; CHRONIC DISEASE; CARE; DEPRESSION; ADHERENCE AB Despite new treatment therapies and the emphasis on patient activation, nearly 50 % of diabetes patients have hemoglobin A(1c) levels above target. Understanding the impact of unmet treatment goals on the physician-patient relationship is important for maintaining quality care in clinical practice. To explore physicians' and type 2 diabetes patients' views of patients' difficulty achieving diabetes treatment goals. Qualitative study using in-depth interviews with a semi-structured interview guide. Nineteen endocrinologists and primary care physicians and 34 patients diagnosed with type 2 diabetes at least two years prior. In-depth interviews with physicians and patients. A multidisciplinary research team performed content and thematic analyses. Qualitative analysis revealed two main findings, organized by physician and patient perspectives. Physician Perspective: Physicians' Perceived Responsibility for Patients' Difficulty Achieving Treatment Goals: Physicians assumed responsibility for their patients not achieving goals and expressed concern that they may not be doing enough to help their patients achieve treatment goals. Physicians' Perceptions of Patients' Reactions: Most speculated that their patients may feel guilt, frustration, or disappointment when not reaching goals. Physicians also felt that many patients did not fully understand the consequences of diabetes. Patient Perspective: Patients' Self-Blame for Difficulty Achieving Treatment Goals: Patients attributed unmet treatment goals to their inability to carry out self-care recommendations. Most patients blamed themselves for their lack of progress and directed their frustration and disappointment inwardly through self-deprecating comments. Patients' Perceptions of Physicians' Reactions: Several patients did not know how their physician felt, while others speculated that their physicians might feel disappointed or frustrated. Physicians' perceived responsibility and patients' self-blame for difficulty achieving treatment goals may serve as barriers to an effective relationship. Physicians and patients may benefit from a greater understanding of each other's frustrations and challenges in diabetes management. C1 [Abrahamson, Martin J.; Weinger, Katie] Joslin Diabet Ctr, Joslin Clin, Boston, MA 02215 USA. [Beverly, Elizabeth A.; Ritholz, Marilyn D.; Abrahamson, Martin J.; Weinger, Katie] Harvard Univ, Sch Med, Boston, MA USA. [Ritholz, Marilyn D.] Childrens Hosp, Boston, MA 02115 USA. RP Weinger, K (reprint author), Joslin Diabet Ctr, Joslin Clin, 1 Joslin Pl, Boston, MA 02215 USA. EM Katie.Weinger@joslin.harvard.edu FU Kathleen P. Welsh Fund; NIDDK [RO1-060115]; NIH [P30 DK36836, T32 DK007260]; Diabetes and Endocrinology Research Core NIH [P30 DK36836] FX Funded by Kathleen P. Welsh Fund, NIDDK RO1-060115, NIH P30 DK36836, NIH Training Grant No. T32 DK007260; This work was supported by the Kathleen P. Welsh Fund, NIDDK RO1-060115, the Diabetes and Endocrinology Research Core NIH P30 DK36836, and the NIH Training Grant No. T32 DK007260. We thank the physicians and patients who shared their experiences and perceptions with us. We also thank Dr. Nadine Palermo, Nicholas Hebert, and Ross Markello for their useful comments on the manuscript. NR 68 TC 9 Z9 9 U1 12 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2012 VL 27 IS 9 BP 1180 EP 1187 DI 10.1007/s11606-012-2070-0 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 988SP UT WOS:000307511300018 PM 22549299 ER PT J AU Spelman, JF Hunt, SC Seal, KH Burgo-Black, AL AF Spelman, Juliette F. Hunt, Stephen C. Seal, Karen H. Burgo-Black, A. Lucile TI Post Deployment Care for Returning Combat Veterans SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE combat; post-deployment; OEF/OIF; veteran; Iraq; Afghanistan ID POSTTRAUMATIC-STRESS-DISORDER; TRAUMATIC BRAIN-INJURY; MENTAL-HEALTH DIAGNOSES; PERSISTENT POSTCONCUSSIVE SYMPTOMS; CHRONIC PAIN; AFGHANISTAN VETERANS; WAR VETERANS; GULF-WAR; LONGITUDINAL ASSESSMENT; MILITARY COHORT AB Since September 11, 2001, 2.4 million military personnel have deployed to Iraq and Afghanistan. To date, roughly 1.44 million have separated from the military and approximately 772,000 of these veterans have used VA health care. Combat deployments impact the physical, psychological, and social health of veterans. Given that many veterans are receiving care from non-VA providers, it is important that all community health care workers be familiar with the unique health care needs of this patient population, which include injuries associated with blast exposures (including mild traumatic brain injury), as well as a variety of mental health conditions, such as post-traumatic stress disorder. Other important health concerns are chronic musculoskeletal pain, medically unexplained symptoms, sequelae of environmental exposures, depression, suicide, substance abuse, sleep disturbances, and impairments in family, occupational and social functioning. Elevated rates of hypertension and tobacco use remind us that deployment may result not only in immediate impacts on health, but also increase risk for chronic disease, contributing to a growing public health burden. This paper provides a comprehensive review of these health concerns and offers practical management guidelines for primary care providers. In light of relationships between physical, psychological and psychosocial concerns in this population, we recommend an interdisciplinary approach to care directed toward mitigating the long-term health impacts of combat. C1 [Spelman, Juliette F.; Burgo-Black, A. Lucile] VA Connecticut Hlth Care Syst, West Haven, CT 06511 USA. [Spelman, Juliette F.; Burgo-Black, A. Lucile] Yale Univ, Sch Med, West Haven, CT USA. [Hunt, Stephen C.] Puget Sound VA Med Ctr, Seattle, WA USA. [Hunt, Stephen C.] Univ Washington, Sch Med, Seattle, WA USA. [Seal, Karen H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Seal, Karen H.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Seal, Karen H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Spelman, JF (reprint author), VA Connecticut Hlth Care Syst, 950 Campbell Ave,11 ACSL, West Haven, CT 06511 USA. EM Juliette.spelman@va.gov FU Department of Veterans Affairs, (VA) Health Services Research and Development (HSR&D) Research Enhancement Award Program at the San Francisco VA Medical Center FX Dr. Seal was financially supported by the Department of Veterans Affairs, (VA) Health Services Research and Development (HSR&D) Research Enhancement Award Program at the San Francisco VA Medical Center. NR 53 TC 45 Z9 45 U1 4 U2 28 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2012 VL 27 IS 9 BP 1200 EP 1209 DI 10.1007/s11606-012-2061-1 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 988SP UT WOS:000307511300021 PM 22648608 ER PT J AU Ahluwalia, SC Gross, CP Chaudhry, SI Ning, YMM Leo-Summers, L Van Ness, PH Fried, TR AF Ahluwalia, Sangeeta C. Gross, Cary P. Chaudhry, Sarwat I. Ning, Yuming M. Leo-Summers, Linda Van Ness, Peter H. Fried, Terri R. TI Impact of Comorbidity on Mortality Among Older Persons with Advanced Heart Failure (vol 27, pg 513, 2012) SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Correction C1 [Ahluwalia, Sangeeta C.] VA Greater Los Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, Los Angeles, CA 90064 USA. [Gross, Cary P.; Chaudhry, Sarwat I.] Yale Univ, Sch Med, Dept Med, Sect Gen Internal Med, New Haven, CT 06510 USA. [Ning, Yuming M.; Leo-Summers, Linda; Van Ness, Peter H.] Yale Univ, Sch Med, Program Aging, New Haven, CT USA. [Van Ness, Peter H.; Fried, Terri R.] Yale Univ, Sch Med, Dept Internal Med, Sect Geriatr, New Haven, CT 06510 USA. [Fried, Terri R.] VA Connecticut Healthcare Syst, Clin Epidemiol Res Ctr, West Haven, CT USA. RP Ahluwalia, SC (reprint author), VA Greater Los Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, 11301 Wilshire Blvd,111-G, Los Angeles, CA 90064 USA. EM sangeeta.ahluwalia@va.gov NR 1 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2012 VL 27 IS 9 BP 1228 EP 1230 DI 10.1007/s11606-012-2127-0 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 988SP UT WOS:000307511300029 ER PT J AU Fang, JC DeMarco, T Givertz, MM Borlaug, BA Lewis, GD Rame, JE Gomberg-Maitland, M Murali, S Frantz, RP McGlothlin, D Horn, EM Benza, RL AF Fang, James C. DeMarco, Teresa Givertz, Michael M. Borlaug, Barry A. Lewis, Gregory D. Rame, J. Eduardo Gomberg-Maitland, Mardi Murali, Srinivas Frantz, Robert P. McGlothlin, Dana Horn, Evelyn M. Benza, Raymond L. TI World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult-a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE Pulmonary hypertension; eft heart disease; heart failure; hight heart failure; left ventricular assist device; heart transplant ID INHALED NITRIC-OXIDE; MITRAL-VALVE-REPLACEMENT; VENTRICULAR EJECTION FRACTION; RANDOMIZED CONTROLLED-TRIAL; SOLUBLE GUANYLATE-CYCLASE; CARDIOVASCULAR MAGNETIC-RESONANCE; ARTERIAL WEDGE PRESSURE; RAPID VOLUME EXPANSION; COLLEGE-OF-CARDIOLOGY; 30 YEARS EXPERIENCE AB Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council. J Heart Lung Transplant 2012;31:913-33 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Fang, James C.] Univ Hosp, Case Med Ctr, Harrington Heart & Vasc Inst, Div Cardiovasc Med, Cleveland, OH USA. [DeMarco, Teresa; McGlothlin, Dana] Univ Calif San Francisco, Div Cardiol, San Francisco, CA USA. [Givertz, Michael M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Borlaug, Barry A.] Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, Rochester, MN USA. [Lewis, Gregory D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Rame, J. Eduardo] Univ Penn, Cardiovasc Res Inst, Philadelphia, PA USA. [Gomberg-Maitland, Mardi] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Murali, Srinivas; Benza, Raymond L.] Allegheny Gen Hosp, Gerald McGinnis Cardiovasc Inst, Pittsburgh, PA 15212 USA. [Frantz, Robert P.] Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, Rochester, MN USA. [Horn, Evelyn M.] Weill Cornell Med Coll, Perkin Heart Failure Ctr, New York, NY USA. RP Fang, JC (reprint author), Case Western Reserve Univ, Div Cardiovasc, 11100 Euclid Ave,Lakeside 3001, Cleveland, OH 44120 USA. EM james.fang@uhhospitals.org FU National Heart, Lung and Blood Institute, National Institutes of Health [K23-HL091106, U01-HL084877] FX No primary funding sources supported this project. Gregory D. Lewis, MD, received support from National Heart, Lung and Blood Institute, National Institutes of Health Grants K23-HL091106 and U01-HL084877. NR 189 TC 74 Z9 75 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD SEP PY 2012 VL 31 IS 9 BP 913 EP 933 DI 10.1016/j.healun.2012.06.002 PG 21 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 996UL UT WOS:000308120200001 PM 22884380 ER PT J AU Polasek, M Fuchs, BC Uppal, R Schuhle, DT Alford, JK Loving, GS Yamada, S Wei, L Lauwers, GY Guimaraes, AR Tanabe, KK Caravan, P AF Polasek, Miloslav Fuchs, Bryan C. Uppal, Ritika Schuehle, Daniel T. Alford, Jamu K. Loving, Galen S. Yamada, Suguru Wei, Lan Lauwers, Gregory Y. Guimaraes, Alexander R. Tanabe, Kenneth K. Caravan, Peter TI Molecular MR imaging of liver fibrosis: A feasibility study using rat and mouse models SO JOURNAL OF HEPATOLOGY LA English DT Article DE Molecular imaging; Gadolinium; Type I collagen; Carbon tetrachloride; Diethylnitrosamine ID MAGNETIC-RESONANCE ELASTOGRAPHY; HEPATIC-FIBROSIS; TRANSIENT ELASTOGRAPHY; CONTRAST AGENT; DISEASE; BIOPSY; COMPLICATIONS; DIAGNOSIS; CIRRHOSIS; READY AB Background & Aims: Liver biopsy, the current clinical gold standard for fibrosis assessment, is invasive and has sampling errors, and is not optimal for screening, monitoring, or clinical decision-making. Fibrosis is characterized by excessive accumulation of extracellular matrix proteins including type I collagen. We hypothesize that molecular magnetic resonance imaging (MRI) with a probe targeted to type I collagen could provide a direct and non-invasive method of fibrosis assessment. Methods: Liver fibrosis was induced in rats with diethylnitrosamine and in mice with carbon tetrachloride. Animals were imaged prior to and immediately following i.v. administration of either collagen-targeted probe EP-3533 or non-targeted control Gd-DTPA. Magnetic resonance (MR) signal washout characteristics were evaluated from T1 maps and T1-weighted images. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. Results: EP-3533-enhanced MR showed greater signal intensity on delayed imaging (normalized signal enhancement mice: control = 0.39 +/- 0.04, fibrotic = 0.55 +/- 0.03, p <0.01) and slower signal washout in the fibrotic liver compared to controls (liver t(1/2) = 51.3 +/- 3.6 vs. 42.0 +/- 2.5 min, p <0.05 and 54.5 +/- 1.9 vs. 44.1 +/- 2.9 min, p <0.01 for fibrotic vs. controls in rat and mouse models, respectively). Gd-DTPA-enhanced MR could not distinguish fibrotic from control animals. EP-3533 gadolinium concentration in the liver showed strong positive correlations with hydroxyproline levels (r = 0.74 (rats), r = 0.77 (mice)) and with Ishak scoring (r = 0.84 (rats), r = 0.79 (mice)). Conclusions: Molecular MRI of liver fibrosis with a collagen-specific probe identifies fibrotic tissue in two rodent models of disease. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved. C1 [Polasek, Miloslav; Uppal, Ritika; Schuehle, Daniel T.; Alford, Jamu K.; Loving, Galen S.; Guimaraes, Alexander R.; Caravan, Peter] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Polasek, Miloslav; Uppal, Ritika; Schuehle, Daniel T.; Alford, Jamu K.; Loving, Galen S.; Guimaraes, Alexander R.; Caravan, Peter] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Fuchs, Bryan C.; Yamada, Suguru; Wei, Lan; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Fuchs, Bryan C.; Yamada, Suguru; Wei, Lan; Lauwers, Gregory Y.; Tanabe, Kenneth K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Caravan, P (reprint author), Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu RI Polasek, Miloslav/G-5949-2014 FU NIH Institutes of Health; National Cancer Institute [CA140861, CA009502, CA076183, EB009062]; National Institute of Biomedical Imaging and Bioengineering fund; Tucker Gosnell Research fund FX The underlying research reported in the study was funded by the NIH Institutes of Health.; Grant Nos. CA140861 (B. C. F.), CA009502 (G. S. L), CA076183 (K. K. T), and EB009062 (P. C.) from the National Cancer Institute and the National Institute of Biomedical Imaging and Bioengineering, and Tucker Gosnell Research funds (K.K.T.) NR 43 TC 28 Z9 28 U1 2 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD SEP PY 2012 VL 57 IS 3 BP 549 EP 555 DI 10.1016/j.jhep.2012.04.035 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 994LU UT WOS:000307933100014 PM 22634342 ER PT J AU Huang, JV Greyson, CR Schwartz, GG AF Huang, Janice V. Greyson, Clifford R. Schwartz, Gregory G. TI PPAR-gamma as a therapeutic target in cardiovascular disease: evidence and uncertainty SO JOURNAL OF LIPID RESEARCH LA English DT Review DE peroxisome proliferator-activated receptor gamma; diabetes; insulin resistance; fatty acids; atherosclerosis; randomized clinical trials ID ACTIVATED-RECEPTOR-GAMMA; TYPE-2 DIABETES-MELLITUS; IMPAIRED GLUCOSE-TOLERANCE; ENDOTHELIAL PROGENITOR CELLS; RANDOMIZED-CONTROLLED-TRIAL; DENSITY-LIPOPROTEIN-CHOLESTEROL; CORONARY-ARTERY-DISEASE; INTIMA-MEDIA THICKNESS; K-ATP CHANNEL; ALL-CAUSE MORTALITY AB Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-gamma has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-gamma activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-gamma activation, or off-target effects of thiazolidinedione agents.(jlr) This review addresses these issues from a clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-gamma activators in cardiovascular disease.-Huang, J. V., C. R. Greyson, and G. G. Schwartz. PPAR-gamma as a therapeutic target in cardiovascular disease: evidence and uncertainty. J. Lipid Res. 2012. 53: 1738-1754. C1 [Schwartz, Gregory G.] US Dept Vet Affairs, Denver VA Med Ctr, Cardiol Sect, Denver, CO USA. Univ Colorado, Sch Med, Denver, CO USA. RP Schwartz, GG (reprint author), US Dept Vet Affairs, Denver VA Med Ctr, Cardiol Sect, Denver, CO USA. EM Gregory.Schwartz@va.gov FU Medical Research Service, US Department of Veterans Affairs; National Institutes of Health Grant [5-R01-HL-049944]; Roche Laboratories FX This work was supported by the Medical Research Service, US Department of Veterans Affairs and by National Institutes of Health Grant 5-R01-HL-049944 (to G.G.S.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. G. G. Schwartz received research grant support from Roche Laboratories. NR 217 TC 29 Z9 30 U1 0 U2 19 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD SEP PY 2012 VL 53 IS 9 BP 1738 EP 1754 DI 10.1194/jlr.R024505 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 991ZN UT WOS:000307743500003 PM 22685322 ER PT J AU Aronson, JP Mitha, AP Hoh, BL Auluck, PK Pomerantseva, I Vacanti, JP Ogilvy, CS AF Aronson, Joshua P. Mitha, Alim P. Hoh, Brian L. Auluck, Pavan K. Pomerantseva, Irina Vacanti, Joseph P. Ogilvy, Christopher S. TI A novel tissue engineering approach using an endothelial progenitor cell-seeded biopolymer to treat intracranial saccular aneurysms Laboratory investigation SO JOURNAL OF NEUROSURGERY LA English DT Article DE intracranial aneurysm; tissue engineering; rabbit endothelial progenitor cell; vascular disorders ID GUGLIELMI DETACHABLE COILS; ENDOVASCULAR TREATMENT; BIFURCATION ANEURYSMS; CEREBRAL ANEURYSMS; GROWTH-FACTOR; NATURAL-HISTORY; PLATINUM COILS; RABBIT MODEL; EMBOLIZATION; EXPERIENCE AB Object. Recurrence after endovascular coiling of intracranial aneurysms is reported in up to 42% of cases and is attributed to the lack of endothelialization across the neck. In this study the authors used a novel tissue engineering approach to promote endothelialization by seeding endothelial progenitor cells (EPCs) within a fibrin polymer injected endovascularly into the aneurysm. Methods. Experimental aneurysms were created in New Zealand White rabbits and were left untreated, surgically clipped, or embolized with platinum coils, fibrin biopolymer alone, or fibrin combined with autologous cultured EPCs. Results. In aneurysms treated with EPCs, a confluent monolayer of endothelial cells with underlying neointima was demonstrated across the neck at 16 weeks posttreatment, which was not observed with aneurysms treated using the other methods. Conclusions. This novel technique may address reasons for the limited durability of standard coil embolization and provides further avenues for the development of improved devices for the care of patients with aneurysms. (http://thejns.org/doi/abs/10.3171/2012.5.JNS091308) C1 [Aronson, Joshua P.; Mitha, Alim P.; Hoh, Brian L.; Ogilvy, Christopher S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Auluck, Pavan K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Pomerantseva, Irina; Vacanti, Joseph P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Lab Tissue Engn & Organ Fabricat, Boston, MA 02114 USA. [Mitha, Alim P.] Foothills Med Ctr, Div Neurosurg, Calgary, AB, Canada. [Hoh, Brian L.] Univ Florida, Dept Neurosurg, Gainesville, FL USA. RP Ogilvy, CS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,Wang Bldg,Room 745, Boston, MA 02114 USA. EM cogilvy@partners.org FU Alberta Heritage Fund for Medical Research Clinical Fellowship Award; AANS/CNS Resident Research Award in Cerebrovascular Disease; Centre for Integration of Medicine; Howard Hughes Medical Institute Medical Fellows Program FX This work was supported by an Alberta Heritage Fund for Medical Research Clinical Fellowship Award (A.P.M.), an AANS/CNS Resident Research Award in Cerebrovascular Disease (A.P.M.), a Centre for Integration of Medicine with Innovative Technologies New Concept Award (C.S.O.), and the Howard Hughes Medical Institute Medical Fellows Program (J.P.A.). NR 37 TC 11 Z9 11 U1 1 U2 10 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2012 VL 117 IS 3 BP 546 EP 554 DI 10.3171/2012.5.JNS091308 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 990JP UT WOS:000307627100018 PM 22746379 ER PT J AU Song, JQ Finnerty, CC Herndon, DN Kraft, R Boehning, D Brooks, NC Tompkins, RG Jeschke, MG AF Song, Juquan Finnerty, Celeste C. Herndon, David N. Kraft, Robert Boehning, Darren Brooks, Natasha C. Tompkins, Ronald G. Jeschke, Marc G. TI Thermal Injury Activates the eEF2K-Dependent eEF2 Pathway in Pediatric Patients SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE burn; muscle; skin; protein synthesis; hypermeta-bolism ID SKELETAL-MUSCLE; BURN INJURY; TRANSLATION INITIATION; PROTEIN-METABOLISM; AMINO-ACIDS; KINASE; CATABOLISM; DYSFUNCTION; CHILDREN; STRESS AB Background: Burn induces a hypermetabolic state characterized by alterations in protein metabolism, which is associated with increased morbidity and mortality. Eukaryotic elongation factor 2 (eEF2) plays a crucial role in regulating protein synthesis in many diseases, but whether it participates in burn-induced hypermetabolism is unclear. The aim of this study was to determine the expression of eEF2 and the upstream eEF2-inactivating kinase, eEF2K, in severely burned pediatric patients. Methods: Eight pediatric patients (> 40% total body surface area) and 3 nonburned pediatric volunteers were enrolled. Muscle and skin biopsies were collected at early (0-10 days postburn [dpb]), middle (11-49 dpb), and late (50-365 dpb) time points. Resting energy expenditure (REE), body composition, and muscle protein fractional synthesis rate (FSR) were measured. Proteins were extracted and analyzed by Western blotting. To further investigate the protein synthesis pathway, microarray data from muscle and skin were examined from 22 nonburned and 20 burned children. Results: Burn patients exhibited a profound hypermetabolic response, as seen by a significant increase in REE (P < .05) and loss of lean body mass without altered muscle FSR, indicating a shift to catabolism after thermal injury. In muscle, the phosphorylation of eEF2K-dependent eEF2 was down regulated early and middle postburn. Similar changes in eEF2K and eEF2 levels occurred in skin at the early time point. Total amounts of eEF2 and eEF2K were not altered. Conclusion: Burn induces prolonged activation of eEF2K and eEF2. Alterations in these mediators may contribute to profound hypermetabolism in severely burned patients. (JPEN J Parenter Enteral Nutr. 2012;36:596-602) C1 [Jeschke, Marc G.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Surg & Plast Surg, Toronto, ON M4N 3M5, Canada. [Song, Juquan] Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, San Antonio, TX 78229 USA. [Finnerty, Celeste C.; Boehning, Darren] Shriners Hosp Children, Galveston, TX 77550 USA. [Finnerty, Celeste C.; Herndon, David N.; Kraft, Robert] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX USA. [Finnerty, Celeste C.; Herndon, David N.; Kraft, Robert] Univ Texas Med Branch, Sealy Ctr Mol Med, Galveston, TX USA. [Finnerty, Celeste C.; Herndon, David N.; Kraft, Robert] Univ Texas Med Branch, Dept Surg, Galveston, TX USA. [Boehning, Darren] Univ Texas Med Branch, Dept Neurosci & Cell Biol, Galveston, TX USA. [Brooks, Natasha C.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX USA. [Tompkins, Ronald G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Jeschke, MG (reprint author), Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Surg & Plast Surg, 2075 Bayview Ave,Room D704, Toronto, ON M4N 3M5, Canada. EM Marc.Jeschke@sunnybrook.ca RI Boehning, Darren/I-8539-2015 OI Boehning, Darren/0000-0001-7920-6922 FU Shriners Hospitals for Children [8460, 8640, 8660, 8740, 8760, 8480, 8507]; Inflammation and the Host Response to Injury Glue Grant; NIGMS [U54 GM062119]; National Institutes of Health [GM056687, GM081685, GM087285, NIH T32-GM08256, NIH P50-GM60338, NIDRRH133A070026]; NIH [KL2RR029875, NIH UL1RR029876] FX This work was supported by grants from Shriners Hospitals for Children (8460, 8640, 8660, 8740, 8760, 8480, and 8507), the Inflammation and the Host Response to Injury Glue Grant funded by the NIGMS (U54 GM062119), and the National Institutes of Health (GM056687, GM081685, GM087285, NIH T32-GM08256, NIH P50-GM60338, NIDRRH133A070026). Celeste C. Finnerty is an Institute for Translational Sciences Career Development Scholar supported, in part, by NIH KL2RR029875 and NIH UL1RR029876. NR 37 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD SEP PY 2012 VL 36 IS 5 BP 596 EP 602 DI 10.1177/0148607111422234 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 989CV UT WOS:000307538700017 PM 22269896 ER PT J AU Aversa, LH Stoddard, JA Doran, NM Au, S Chow, B McFall, M Saxon, A Baker, DG AF Aversa, Laura H. Stoddard, Jill A. Doran, Neal M. Au, Selwyn Chow, Bruce McFall, Miles Saxon, Andrew Baker, Dewleen G. TI PTSD and depression as predictors of physical health-related quality of life in tobacco-dependent veterans SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE Health-related quality of life; PTSD; Depression; Smoking; Tobacco; SF-36 ID POSTTRAUMATIC-STRESS-DISORDER; COMORBID ANXIETY DISORDERS; EXPOSURE THERAPY; PSYCHIATRIC-DISORDERS; SMOKING-CESSATION; PRIMARY-CARE; PSYCHOMETRIC PROPERTIES; RISK-FACTOR; PRIME-MD; MORTALITY AB Objective: Smoking, depression and PTSD are related to poor physical health outcomes and health-related quality of life (HRQoL). Previous studies examining the effects of quitting smoking on HRQoL have been mixed. This study aimed to examine the effects of PTSD, depressive symptoms and smoking cessation on HRQoL in a sample receiving treatment for PTSD. Method: This study utilized archival interview and self-report data from a clinical trial (VA Cooperative Study 519) that recruited tobacco dependent veterans with chronic FTSD (N=943). Results: Analyses were conducted using hierarchical linear modeling and indicated that PTSD and depressive symptoms differentially affected the various physical health status domains. Additionally, quitting smoking was associated with better self-perceived health status and social functioning. Conclusion: Our findings further explain the interrelationships of PTSD, depression, and smoking in the prediction of physical HRQoL and advocate the importance of integrated care. (C) 2012 Elsevier Inc. All rights reserved. C1 [Aversa, Laura H.; Baker, Dewleen G.] VA San Diego Healthcare Syst, San Diego, CA 92161 USA. [Aversa, Laura H.; Stoddard, Jill A.] Alliant Int Univ, Calif Sch Profess Psychol, San Diego, CA USA. [Doran, Neal M.; Baker, Dewleen G.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Au, Selwyn; Chow, Bruce] Vet Affairs Palo Alto Hlth Care Syst, Cooperat Studies Program, Mountain View, CA USA. [McFall, Miles; Saxon, Andrew] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [McFall, Miles; Saxon, Andrew] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Baker, Dewleen G.] Vet Affairs Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. RP Aversa, LH (reprint author), VA San Diego Healthcare Syst, 3350 La Jolla Village Dr 151, San Diego, CA 92161 USA. EM laura.harder@gmail.com RI Doran, Neal/E-5653-2013 FU Cooperative Studies Program of the Clinical Science Research and Development Service, U.S. Department of Veterans Affairs (DVA) (CSP) [519, NCT00118534]; Tobacco-Related Disease Research Program [19DT-0003]; Department of Defense [PTO 090738]; DVA HSRD [SDR09-128]; VA Center of Excellence for Stress and Mental Health; VA Merit [821]; DVA; NIAAA [1 P20 AA017839-01]; NIDA [5 U10 DA013714-08]; VA HSRD [1 101 HX000616-01] FX Funding was provided by the Cooperative Studies Program of the Clinical Science Research and Development Service, U.S. Department of Veterans Affairs (DVA) (CSP #519, NCT00118534) and the Tobacco-Related Disease Research Program 19DT-0003. Dr. Baker receives research support from the Department of Defense (Navy BUMED and CDMRP) (PTO 090738) and the DVA HSR&D (SDR09-128) and is supported in part by the VA Center of Excellence for Stress and Mental Health. Dr. McFall receives research support from VA Merit #821 and DVA. Dr. Saxon receives research support from NIAAA (1 P20 AA017839-01), NIDA (5 U10 DA013714-08), and from VA HSR&D (1 101 HX000616-01). The views expressed herein are those of the authors and not necessarily those of the U.S. Department of Veterans Affairs. The authors have no competing interests to report. NR 82 TC 13 Z9 13 U1 7 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD SEP PY 2012 VL 73 IS 3 BP 185 EP 190 DI 10.1016/j.jpsychores.2012.06.010 PG 6 WC Psychiatry SC Psychiatry GA 986UW UT WOS:000307372100006 PM 22850258 ER PT J AU Bonawitz, SC Duvvuri, U AF Bonawitz, Steven C. Duvvuri, Umamaheswar TI Robot-Assisted Oropharyngeal Reconstruction with Free Tissue Transfer SO JOURNAL OF RECONSTRUCTIVE MICROSURGERY LA English DT Article DE robotic; TORS; free tissue transfer ID NECK-CANCER; SURGERY TORS; HEAD; CARCINOMA AB The surgical robot has been demonstrated to have useful applications in urologic, gynecologic, cardiac, general, and endocrine surgery. The development of robotic surgery has enhanced the precision and control of the surgeon in minimally invasive surgical situations specific to these specialties and, more recently, has been applied to the treatment of oropharyngeal tumors in the form of transoral robotic surgery (TORS). The elimination of the need for lip- and mandible-splitting approaches has allowed a reassessment of surgical options for the treatment of tumors that have until recently been primarily addressed nonoperatively with chemoradiation. The TORS approach has created the need to adapt current reconstructive options to robotic technology to manage the resultant tissue defects and to assess and compare the effectiveness of these procedures. This report details our early experience with the use of robot-assisted free tissue transfer for management of soft tissue defects of the oropharynx. C1 [Duvvuri, Umamaheswar] Univ Pittsburgh, Dept Otolaryngol, VA Pittsburgh Hlth Syst, Med Ctr,Eye & Ear Inst, Pittsburgh, PA 15213 USA. [Bonawitz, Steven C.] Johns Hopkins Univ, Sch Med, Dept Plast & Reconstruct Surg, Baltimore, MD USA. RP Duvvuri, U (reprint author), Univ Pittsburgh, Dept Otolaryngol, VA Pittsburgh Hlth Syst, Med Ctr,Eye & Ear Inst, Suite 500,200 Lothrop St, Pittsburgh, PA 15213 USA. EM duvvuriu@upmc.edu NR 12 TC 5 Z9 5 U1 0 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0743-684X J9 J RECONSTR MICROSURG JI J. Reconstr. Microsurg. PD SEP PY 2012 VL 28 IS 7 BP 485 EP 490 DI 10.1055/s-0032-1313758 PG 6 WC Surgery SC Surgery GA 990KR UT WOS:000307630200010 PM 22638875 ER PT J AU Baibergenova, AT Weinstock, MA AF Baibergenova, A. T. Weinstock, M. A. CA VATTC Trial Grp TI Oral prednisone use and risk of keratinocyte carcinoma in non-transplant population. The VATTC trial SO JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY LA English DT Article ID TRETINOIN CHEMOPREVENTION TRIAL; SKIN-CANCER; TOPICAL TRETINOIN; IMMUNOSUPPRESSIVE THERAPY; GLUCOCORTICOID-RECEPTOR; TRANSPLANT RECIPIENTS; LYMPHOMA; CYCLOSPORINE; INFLAMMATION; ASSOCIATION AB Background Glucorticosteroids (GC) are potent anti-inflammatory medications with immunosuppressive property. Few retrospective studies have reported the increased risk of development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with GC use. Objective We aimed to assess the effect of oral GC use on the risk of BCC and SCC using prospective data. Methods We analysed data from the Veterans Affairs Topical Tretinoin Chemoprevention Trial, which followed up patients from 1998 to 2004. Exposure to oral GCs was defined as (1) use of any oral GCs at any point during follow-up and (2) use of GCs for a month or longer. Outcome was occurrence of new BCC or SCC. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results Among the 1051 study participants, 148 patients (14%) had prednisone prescription filled during study period, and 63 (6%) used prednisone for over a month. A total of 472 patients (45%) developed at least one BCC during study: 394 (44%) among non-users of prednisone and 78 (53%) among any time users. The total number of new SCC was 309 (29%): 258 (29%) among non-users of prednisone and 51 (34%) among users. Among any time prednisone users, the adjusted HR was 1.11 (95% CI, 0.871.42) for BCC, and 1.05 (95% CI, 0.761.45) for SCC. Among those who used prednisone for 30 or more days, the HR was 1.26 (95% CI, 0.901.78) for BCC, and 1.03 (95% CI, 0.661.60) for SCC. Conclusion This study does not support the existence of association between use of oral GCs and risk of BCC or SCC. C1 [Baibergenova, A. T.] Univ Toronto, Fac Med, Div Dermatol, Toronto, ON, Canada. [Weinstock, M. A.] Rhode Isl Hosp, Dept Dermatol, Providence, RI USA. [Weinstock, M. A.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [VATTC Trial Grp] US Dept Vet Affairs, Cooperat Studies Program, Washington, DC USA. [Weinstock, M. A.] VA Med Ctr Providence, Dermatoepidemiol Unit, Providence, RI USA. RP Baibergenova, AT (reprint author), Univ Toronto, Fac Med, Div Dermatol, Toronto, ON, Canada. EM akerke_b@yahoo.com FU Medical Dermatology Society FX We thank the Medical Dermatology Society for their mentorship program grant that allowed Dr A. Baibergenova to conduct this research under the mentorship of Dr M. Weinstock. NR 29 TC 7 Z9 7 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0926-9959 J9 J EUR ACAD DERMATOL JI J. Eur. Acad. Dermatol. Venereol. PD SEP PY 2012 VL 26 IS 9 BP 1109 EP 1115 DI 10.1111/j.1468-3083.2011.04226.x PG 7 WC Dermatology SC Dermatology GA 989JF UT WOS:000307555400008 PM 21923839 ER PT J AU Beuling, E Aronson, BE Tran, LMD Stapleton, KA ter Horst, EN Vissers, LATM Verzi, MP Krasinski, SD AF Beuling, Eva Aronson, Boaz E. Tran, Luc M. D. Stapleton, Kelly A. ter Horst, Ellis N. Vissers, Laurens A. T. M. Verzi, Michael P. Krasinski, Stephen D. TI GATA6 Is Required for Proliferation, Migration, Secretory Cell Maturation, and Gene Expression in the Mature Mouse Colon SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA-6; HISTONE MODIFICATIONS; NA+/H+ EXCHANGER; SMALL-INTESTINE; PEPTIDE YY; MUCIN GENE; DIFFERENTIATION; MICE; HNF-1-ALPHA; ISOFORM AB Controlled renewal of the epithelium with precise cell distribution and gene expression patterns is essential for colonic function. GATA6 is expressed in the colonic epithelium, but its function in the colon is currently unknown. To define GATA6 function in the colon, we conditionally deleted Gata6 throughout the epithelium of small and large intestines of adult mice. In the colon, Gata6 deletion resulted in shorter, wider crypts, a decrease in proliferation, and a delayed crypt-to-surface epithelial migration rate. Staining techniques and electron microscopy indicated deficient maturation of goblet cells, and coimmunofluorescence demonstrated alterations in specific hormones produced by the endocrine L cells and serotonin-producing cells. Specific colonocyte genes were significantly downregulated. In LS174T, the colonic adenocarcinoma cell line, Gata6 knockdown resulted in a significant downregulation of a similar subset of goblet cell and colonocyte genes, and GATA6 was found to occupy active loci in enhancers and promoters of some of these genes, suggesting that they are direct targets of GATA6. These data demonstrate that GATA6 is necessary for proliferation, migration, lineage maturation, and gene expression in the mature colonic epithelium. C1 [Beuling, Eva; Aronson, Boaz E.; Tran, Luc M. D.; Stapleton, Kelly A.; ter Horst, Ellis N.; Vissers, Laurens A. T. M.; Krasinski, Stephen D.] Childrens Hosp Boston, Dept Med, Div Gastroenterol & Nutr, Boston, MA USA. [Aronson, Boaz E.] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands. [Verzi, Michael P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Verzi, Michael P.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Verzi, Michael P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Krasinski, Stephen D.] Tufts Univ, Gerald J & Dorothy R Friedman Sch Nutr Sci & Poli, Boston, MA 02111 USA. RP Krasinski, SD (reprint author), Childrens Hosp Boston, Dept Med, Div Gastroenterol & Nutr, Boston, MA USA. EM stephen.krasinski@childrens.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [RO1-DK-061382, K01-DK-088868]; Crohn's and Colitis Foundation of America [1987]; Harvard Digestive Disease Center [5P30-DK-34854]; Nutricia Research Foundation; Foundation De Drie Lichten; Foundation Doctor Catharine van Tussenbroek; KWF Kankerbestrijding; Prins Bernhard Cultuurfonds in The Netherlands; European Society for Pediatric Research in Switzerland FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants RO1-DK-061382 (S. D. K.) and K01-DK-088868 (M. P. V.), fellowship no. 1987 from the Crohn's and Colitis Foundation of America (M. P. V.), the Harvard Digestive Disease Center (grant 5P30-DK-34854), the Nutricia Research Foundation (E. B. and B. E. A.), the Foundation De Drie Lichten (E. B.), the Foundation Doctor Catharine van Tussenbroek (E. B.), KWF Kankerbestrijding (B. E. A.), Prins Bernhard Cultuurfonds (B. E. A.) in The Netherlands, and the European Society for Pediatric Research (B. E. A.) in Switzerland. NR 38 TC 20 Z9 21 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2012 VL 32 IS 17 BP 3392 EP 3402 DI 10.1128/MCB.00070-12 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 992WM UT WOS:000307810900003 PM 22733991 ER PT J AU Janssens, T Keil, B Farivar, R Mcnab, JA Polimeni, JR Gerits, A Arsenault, JT Wald, LL Vanduffel, W AF Janssens, T. Keil, B. Farivar, R. McNab, J. A. Polimeni, J. R. Gerits, A. Arsenault, J. T. Wald, L. L. Vanduffel, W. TI An implanted 8-channel array coil for high-resolution macaque MRI at 3 T SO NEUROIMAGE LA English DT Article DE fMRI; Macaque; Parallel imaging; Implanted coil; High resolution ID VISUAL-CORTEX; BEHAVING MACAQUES; TEMPORAL CORTEX; CONTRAST AGENT; PHASED-ARRAY; HEAD COIL; MONKEYS; RESONANCE; BRAIN; FMRI AB An 8-channel receive coil array was constructed and implanted adjacent to the skull in a male rhesus monkey in order to improve the sensitivity of (functional) brain imaging. The permanent implant was part of an acrylic headpost assembly and only the coil element loop wires were implanted. The tuning, matching, and preamplifier circuitry was connected via a removable external assembly. Signal-to-noise ratio (SNR) and noise amplification for parallel imaging were compared to single-, 4-, and 8-channel external receive-only coils routinely used for macaque fMRI. In vivo measurements showed significantly improved SNR within the brain for the implanted versus the external coils. Within a region-of-interest covering the cerebral cortex, we observed a 5.4-, 3.6-fold, and 3.4-fold increase in SNR compared to the external single-, 4-, and 8-channel coils, respectively. In the center of the brain, the implanted array maintained a 2.4x, 2.5x, and 2.1x higher SNR, respectively compared to the external coils. The array performance was evaluated for anatomical, diffusion tensor and functional brain imaging. This study suggests that a stable implanted phased-array coil can be used in macaque MRI to substantially increase the spatial resolution for anatomical, diffusion tensor, and functional imaging. (C) 2012 Elsevier Inc. All rights reserved. C1 [Janssens, T.; Keil, B.; Farivar, R.; McNab, J. A.; Polimeni, J. R.; Gerits, A.; Arsenault, J. T.; Wald, L. L.; Vanduffel, W.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Keil, B.; Farivar, R.; McNab, J. A.; Polimeni, J. R.; Gerits, A.; Arsenault, J. T.; Wald, L. L.; Vanduffel, W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Keil, B.; Wald, L. L.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Janssens, T.; Gerits, A.; Arsenault, J. T.; Vanduffel, W.] KU Leuven Med Sch, Lab Neuro & Psychophysiol, Louvain, Belgium. RP Vanduffel, W (reprint author), MGH, HMS, Dept Radiol, Bldg 149,Room 2301,13th St, Charlestown, MA 02129 USA. EM wim@nmr.mgh.harvard.edu RI Keil, Boris/P-1411-2014; Polimeni, Jonathan/P-1395-2014; Wald, Lawrence/D-4151-2009 OI Polimeni, Jonathan/0000-0002-1348-1179; FU Inter University Attraction Pole [6/29]; Program Financing [PFV/10/008]; Geconcerteerde Onderzoeks Actie [10/19]; Fonds Wetenschappelijk Onderzoek (FWO)-Vlaanderen; Hercules funding; NSF [BCS-0745436]; National Center for Research Resources grant [P41RR14075]; [G062208N10]; [G083111N10]; [G043912N] FX The authors thank H. Deng for the technical support during the scans. This work received support from Inter University Attraction Pole 6/29, Program Financing PFV/10/008, Geconcerteerde Onderzoeks Actie 10/19, Hercules funding, Fonds Wetenschappelijk Onderzoek (FWO)-Vlaanderen, G062208N10, G083111N10, and G043912N, and NSF grant BCS-0745436. TJ is an aspirant of the FWO-Vlaanderen. The Martinos Center is supported by National Center for Research Resources grant P41RR14075. NR 43 TC 9 Z9 10 U1 3 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1529 EP 1536 DI 10.1016/j.neuroimage.2012.05.028 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000021 PM 22609793 ER PT J AU Ganis, G Smith, D Schendan, HE AF Ganis, Giorgio Smith, Daniel Schendan, Haline E. TI The N170, not the P1, indexes the earliest time for categorical perception of faces, regardless of interstimulus variance SO NEUROIMAGE LA English DT Article DE Face perception; Object perception; Event-related potentials; N170; Interstimulus variance ID EVENT-RELATED POTENTIALS; HUMAN BRAIN; NEUROPHYSIOLOGICAL EVIDENCE; UNFAMILIAR FACES; NAME RECOGNITION; OBJECTS LEADS; REPETITION; MEMORY; EXPERTISE; RESPONSES AB A negative event-related potential (ERP) at occipito-temporal sites peaking around 150-170 ms after stimulus onset (N170) is typically larger for faces than other object categories. Most theories interpret this finding as due to face-selective processing in occipito-temporal and temporal cortex. However, a controversial account recently attributed the N170 effect to differences in interstimulus variance (ISV) among the images typically used for face and object conditions and proposed that the earlier P1 instead indexes the categorical processes generally attributed to the N170. This ERP study aimed to test this account definitively by using conditions in which the same face and object were shown repeatedly, eliminating both physical and perceptual ISV. Fourier amplitude spectra of faces and objects were matched to equate basic low-level visual properties that may affect early ERPs such as the P1. Results demonstrate that i) face selectivity of the N170 is largely preserved across many object categories after abolishing ISV, and ii) stimulus category does not modulate the P1. This conclusively refutes the ISV account while strongly supporting category as a critical factor driving N170 face selectivity. (C) 2012 Elsevier Inc. All rights reserved. C1 [Ganis, Giorgio; Smith, Daniel; Schendan, Haline E.] Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. [Ganis, Giorgio; Schendan, Haline E.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ganis, Giorgio] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Smith, Daniel] UCL, London WC1E 6BT, England. RP Ganis, G (reprint author), Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. EM giorgio.ganis@plymouth.ac.uk OI Ganis, Giorgio/0000-0001-6175-2618; Schendan, Haline/0000-0001-8925-5605 NR 55 TC 21 Z9 21 U1 1 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1563 EP 1574 DI 10.1016/j.neuroimage.2012.05.043 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000024 PM 22634853 ER PT J AU Wilcox, T Stubbs, J Hirshkowitz, A Boas, DA AF Wilcox, Teresa Stubbs, Jessica Hirshkowitz, Amy Boas, David A. TI Functional activation of the infant cortex during object processing SO NEUROIMAGE LA English DT Article DE Object processing; Temporal cortex; Parietal cortex; Infants; Near-infrared spectroscopy ID NEAR-INFRARED SPECTROSCOPY; SPATIOTEMPORAL INFORMATION; RECOGNITION; SHAPE; INDIVIDUATION; PERCEPTION; MONKEYS; HUMANS; COLOR; AREAS AB A great deal is known about the functional organization of the neural structures that mediate visual object processing in the adult observer. These findings have contributed significantly to our conceptual models of object recognition and identification and provided unique insight into the nature of object representations extracted from visual input. In contrast, little is known about the neural basis of object processing in the infant. The current research used near-infrared spectroscopy (NIRS) as a neuroimaging tool to investigate functional activation of the infant cortex during an object processing task that has been used extensively with infants. The neuroimaging data revealed that the infant cortex is functionally specialized for object processing (i.e., individuation-by-feature) early in the first year but that patterns of activation also change between 3 and 12 months. These changes may reflect functional reorganization of the immature cortex or age-related differences in the cognitive processes engaged during the task. (c) 2012 Elsevier Inc. All rights reserved. C1 [Wilcox, Teresa; Stubbs, Jessica; Hirshkowitz, Amy] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. RP Wilcox, T (reprint author), Texas A&M Univ, Dept Psychol, 4235 TAMU, College Stn, TX 77843 USA. EM twilcox@tamu.edu FU [R21-HD048943]; [R01-HD057999]; [P41-RR14075] FX We thank Tracy Smith Brower, Lesley Wheeler, Kayla Boone Upshaw, Jennifer Moore Norvell, and the staff of the infant Cognition Lab at Texas A&M University for help with data collection and management, Lesley Wheeler and Mariam Massoud for preparation of figures, and the infants and parents who so graciously participated in the research. This work was support by grants R21-HD048943 and R01-HD057999 to TW and grant P41-RR14075 to DAB. NR 31 TC 14 Z9 15 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1833 EP 1840 DI 10.1016/j.neuroimage.2012.05.039 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000051 PM 22634218 ER PT J AU Lu, HB Chefer, S Kurup, PK Guillem, K Vaupel, DB Ross, TJ Moore, A Yang, YH Peoples, LL Stein, EA AF Lu, Hanbing Chefer, Svetlana Kurup, Pradeep K. Guillem, Karine Vaupel, D. Bruce Ross, Thomas J. Moore, Anna Yang, Yihong Peoples, Laura L. Stein, Elliot A. TI fMRI response in the medial prefrontal cortex predicts cocaine but not sucrose self-administration history SO NEUROIMAGE LA English DT Article DE Neuroadaptation; Self-administration; Abstinence; Pharmacological MRI ID CEREBRAL BLOOD-VOLUME; NUCLEUS-ACCUMBENS; DRUG-SEEKING; FUNCTIONAL CONNECTIVITY; GLUTAMATE TRANSMISSION; INDUCED REINSTATEMENT; MEDIODORSAL NUCLEUS; REWARD REGIONS; IN-VIVO; ADDICTION AB Repeated cocaine exposure induces long-lasting neuroadaptations that alter subsequent responsiveness to the drug. However, systems-level investigation of these neuroplastic consequences is limited. We employed a rodent model of drug addiction to investigate neuroadaptations associated with prolonged forced abstinence after long-term cocaine self-administration (SA). Since natural rewards also activate the mesolimbic reward system in a partially overlapping fashion as cocaine, our design also included a sucrose SA group. Rats were trained to self-administer cocaine or sucrose using a fixed-ratio one, long-access schedule (6 h/day for 20 days). A third group of naive, sedentary rats served as a negative control. After 30 days of abstinence, the reactivity of the reward system was assessed with functional magnetic resonance imaging (fMRI) following an intravenous cocaine injection challenge. A strong positive fMRI response, as measured by fractional cerebral blood volume changes relative to baseline (CBV%), was seen in the sedentary control group in such cortico-limbic regions as medial prefrontal cortex and anterior cingulate cortex. In contrast, both the cocaine and sucrose SA groups demonstrated a very similar initial negative fMRI response followed by an attenuated positive response. The magnitude of the mPFC response was significantly correlated with the total amount of reinforcer intake during the training sessions for the cocaine SA but not for the sucrose SA group. Given that the two SA groups had identical histories of operant training and handling, this region-specific group difference revealed by regression analysis may reflect the development of neuroadaptive mechanisms specifically related to the emergence of addiction-like behavior that occurs only in cocaine SA animals. Published by Elsevier Inc. C1 [Lu, Hanbing; Chefer, Svetlana; Kurup, Pradeep K.; Vaupel, D. Bruce; Ross, Thomas J.; Yang, Yihong; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Guillem, Karine; Peoples, Laura L.] Univ Penn, Dept Psychiat, TRL, Philadelphia, PA 19104 USA. [Moore, Anna] Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Dept Radiol, Mol Imaging Lab, Boston, MA 02129 USA. [Peoples, Laura L.] Univ Penn, Neurosci Grad Grp, Philadelphia, PA 19104 USA. [Guillem, Karine] Univ Bordeaux, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France. [Peoples, Laura L.] Drexel Univ, Dept Physiol & Pharmacol, Coll Med, Philadelphia, PA 19102 USA. [Guillem, Karine] CNRS, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France. RP Stein, EA (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200,RM7A711, Baltimore, MD 21224 USA. EM estein@mail.nih.gov RI Ross, Thomas/B-7469-2008 OI Ross, Thomas/0000-0002-7745-3572 FU Intramural Research Program of the National Institute on Drug Abuse (NIDA); NIH Director's Bench-to-Bedside grant; Institute for Translational Medicine and Therapeutics of the University of Pennsylvania; National Center for Research Resources [UL1RR024134]; [P50DA012756]; [R01 552981] FX We thank William Rea for his excellent technical assistance. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA) and by an NIH Director's Bench-to-Bedside grant to L. L. Peoples and E. A Stein. It was also partially supported by P50DA012756, and R01 552981 (L.L.P.), Institute for Translational Medicine and Therapeutics of the University of Pennsylvania, and grant UL1RR024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 70 TC 8 Z9 10 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1857 EP 1866 DI 10.1016/j.neuroimage.2012.05.076 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000054 PM 22664568 ER PT J AU Cooper, RJ Caffini, M Dubb, J Fang, QQ Custo, A Tsuzuki, D Fischl, B Wells, W Dan, I Boas, DA AF Cooper, Robert J. Caffini, Matteo Dubb, Jay Fang, Qianqian Custo, Anna Tsuzuki, Daisuke Fischl, Bruce Wells, William, III Dan, Ippeita Boas, David A. TI Validating atlas-guided DOT: A comparison of diffuse optical tomography informed by atlas and subject-specific anatomies SO NEUROIMAGE LA English DT Article DE Diffuse optical tomography; NIRS; MRI; Anatomical atlas; Registration ID SURFACE-BASED ANALYSIS; SPATIAL REGISTRATION; BRAIN-FUNCTION; MNI SPACE; MRI; RECONSTRUCTION; SEGMENTATION; SYSTEM; IMAGES; EEG AB We describe the validation of an anatomical brain atlas approach to the analysis of diffuse optical tomography (DOT). Using MRI data from 32 subjects, we compare the diffuse optical images of simulated cortical activation reconstructed using a registered atlas with those obtained using a subject's true anatomy. The error in localization of the simulated cortical activations when using a registered atlas is due to a combination of imperfect registration, anatomical differences between atlas and subject anatomies and the localization error associated with diffuse optical image reconstruction. When using a subject-specific MRI, any localization error is due to diffuse optical image reconstruction only. In this study we determine that using a registered anatomical brain atlas results in an average localization error of approximately 18 mm in Euclidean space. The corresponding error when the subject's own MRI is employed is 9.1 mm. In general, the cost of using atlas-guided DOT in place of subject-specific MRI-guided DOT is a doubling of the localization error. Our results show that despite this increase in error, reasonable anatomical localization is achievable even in cases where the subject-specific anatomy is unavailable. (C) 2012 Elsevier Inc. All rights reserved. C1 [Cooper, Robert J.; Dubb, Jay; Fang, Qianqian; Fischl, Bruce; Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. [Caffini, Matteo] Univ Aquila, Dept Hlth Sci, I-67100 Laquila, Italy. [Custo, Anna] Univ Geneva, Funct Brain Mapping Lab, Ctr Med Univ, Geneva, Switzerland. [Tsuzuki, Daisuke; Dan, Ippeita] Jichi Med Univ, Ctr Dev Adv Med Technol, Funct Brain Sci Lab, Shimotsuke, Tochigi 3290498, Japan. [Wells, William, III] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Wells, William, III] Brigham & Womens Hosp, Boston, MA 02115 USA. [Caffini, Matteo] Politecn Milan, Dipartimento Fis, Milan, Italy. RP Cooper, RJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. EM rcooper@nmr.mgh.harvard.edu OI Cooper, Robert/0000-0001-6696-8020 FU NIH [P41-RR14075, P41-RR13218, R01-EB006385, P41-RR-013218, P41-EB-015902]; Comprehensive Research on Disability, Health and Welfare from Health and Labour Sciences Research Grants; Japan Society for Promotion of Science [23390354, 23650217] FX This work was supported by NIH P41-RR14075, P41-RR13218, and R01-EB006385 (to D.A.B.), NIH P41-RR-013218 and P41-EB-015902 (to W.W.), Comprehensive Research on Disability, Health and Welfare from Health and Labour Sciences Research Grants (to I.D.), and the Grants-in-Aid for Scientific Research from the Japan Society for Promotion of Science (23390354, and 23650217 to I.D.). NR 30 TC 29 Z9 29 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1999 EP 2006 DI 10.1016/j.neuroimage.2012.05.031 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000067 PM 22634215 ER PT J AU Oosterwijk, S Lindquist, KA Anderson, E Dautoff, R Moriguchi, Y Barrett, LF AF Oosterwijk, Suzanne Lindquist, Kristen A. Anderson, Eric Dautoff, Rebecca Moriguchi, Yoshiya Barrett, Lisa Feldman TI States of mind: Emotions, body feelings, and thoughts share distributed neural networks SO NEUROIMAGE LA English DT Article DE Constructionist; Emotion; Thought; Body feelings; Intrinsic networks ID TEMPORO-PARIETAL JUNCTION; MEDIAL PREFRONTAL CORTEX; INTRINSIC FUNCTIONAL CONNECTIVITY; NUCLEUS-ACCUMBENS DOPAMINE; BILATERAL AMYGDALA DAMAGE; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; EVENT-RELATED FMRI; CORTICAL SURFACE; ANTERIOR INSULA AB Scientists have traditionally assumed that different kinds of mental states (e.g., fear, disgust, love, memory, planning, concentration, etc.) correspond to different psychological faculties that have domain-specific correlates in the brain. Yet, growing evidence points to the constructionist hypothesis that mental states emerge from the combination of domain-general psychological processes that map to large-scale distributed brain networks. In this paper, we report a novel study testing a constructionist model of the mind in which participants generated three kinds of mental states (emotions, body feelings, or thoughts) while we measured activity within large-scale distributed brain networks using fMRI. We examined the similarity and differences in the pattern of network activity across these three classes of mental states. Consistent with a constructionist hypothesis, a combination of large-scale distributed networks contributed to emotions, thoughts, and body feelings, although these mental states differed in the relative contribution of those networks. Implications for a constructionist functional architecture of diverse mental states are discussed. (c) 2012 Elsevier Inc. All rights reserved. C1 [Oosterwijk, Suzanne] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Oosterwijk, Suzanne] Univ Amsterdam, Dept Psychol, NL-1018 XA Amsterdam, Netherlands. [Lindquist, Kristen A.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Dautoff, Rebecca; Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Moriguchi, Yoshiya] Natl Inst Mental Hlth Multimodal Neuroimaging Sec, Dept Psychophysiol, Natl Ctr Neurol & Psychiat, Kodaira, Tokyo 1878551, Japan. RP Oosterwijk, S (reprint author), Northeastern Univ, Dept Psychol, 114 Lake Hall, Boston, MA 02115 USA. EM s.oosterwijk@neu.edu OI Anderson, Eric/0000-0002-4215-6308 FU National Institutes of Health Director's Pioneer award [DP1OD003312]; Marie Curie International Outgoing Fellowship; Seventh Framework Program of the European Commission; Harvard University Mind/Brain/Behavior Postdoctoral Fellowship FX Many thanks to Thomas Yeo, Fenna Krienen, and the Buckner lab for making the Yeo et al. (2011) network parcellation available. This research was supported by a National Institutes of Health Director's Pioneer award (DP1OD003312) to Lisa Feldman Barrett. The writing of this manuscript was supported by a Marie Curie International Outgoing Fellowship awarded by the Seventh Framework Program of the European Commission to Suzanne Oosterwijk and a Harvard University Mind/Brain/Behavior Postdoctoral Fellowship to Kristen Lindquist. NR 153 TC 34 Z9 34 U1 2 U2 36 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 2110 EP 2128 DI 10.1016/j.neuroimage.2012.05.079 PG 19 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000076 PM 22677148 ER PT J AU Cleveland, RH Gordon, LB Kleinman, ME Miller, DT Gordon, CM Snyder, BD Nazarian, A Giobbie-Hurder, A Neuberg, D Kieran, MW AF Cleveland, Robert H. Gordon, Leslie B. Kleinman, Monica E. Miller, David T. Gordon, Catherine M. Snyder, Brian D. Nazarian, Ara Giobbie-Hurder, Anita Neuberg, Donna Kieran, Mark W. TI A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome SO PEDIATRIC RADIOLOGY LA English DT Article DE Progeria; Phenotype; Skeletal findings; Frequency; Children ID FIBROBLASTS; DYSPLASIA; PHENOTYPE AB Progeria is a rare segmental premature aging disease with significant skeletal abnormalities. Defining the full scope of radiologic abnormalities requires examination of a large proportion of the world's progeria population (estimated at 1 in 4 million). There has been no comprehensive prospective study describing the skeletal abnormalities associated with progeria. To define characteristic radiographic features of this syndrome. Thirty-nine children with classic progeria, ages 2-17 years, from 29 countries were studied at a single site. Comprehensive radiographic imaging studies were performed. Sample included 23 girls and 16 boys-the largest number of patients with progeria evaluated prospectively to date. Eight new and two little known progeria-associated radiologic findings were identified (frequencies of 3-36%). Additionally, 23 commonly reported findings were evaluated. Of these, 2 were not encountered and 21 were present and ranked according to their frequency. Nine abnormalities were associated with increasing patient age (P = 0.02-0.0001). This study considerably expands the radiographic morphological spectrum of progeria. A better understanding of the radiologic abnormalities associated with progeria and improved understanding of the biology of progerin (the molecule responsible for this disease), will improve our ability to treat the spectrum of bony abnormalities. C1 [Cleveland, Robert H.] Harvard Univ, Sch Med, Dept Radiol, Childrens Hosp Boston, Boston, MA 02115 USA. [Gordon, Leslie B.; Kleinman, Monica E.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Anesthesia, Boston, MA 02115 USA. [Gordon, Leslie B.] Brown Univ, Dept Pediat, Hasbro Childrens Hosp, Warren Alpert Med Sch, Providence, RI 02912 USA. [Miller, David T.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Genet, Boston, MA 02115 USA. [Gordon, Catherine M.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Endocrinol & Adolescent Med, Boston, MA 02115 USA. [Snyder, Brian D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Orthoped Surg, Boston, MA 02115 USA. [Giobbie-Hurder, Anita; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Neuberg, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Kieran, Mark W.] Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Kieran, Mark W.] Childrens Hosp, Boston, MA 02115 USA. RP Cleveland, RH (reprint author), Harvard Univ, Sch Med, Dept Radiol, Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM robert.cleveland@childrens.harvard.edu OI Kieran, Mark/0000-0003-2184-7692 FU Progeria Research Foundation [PRFCLIN2007-01, PRFCLINTRIAL003-080109]; National Heart, Lung and Blood Institute [1RC2HL101631-01]; Dana-Farber Cancer Institute Stop&Shop Pediatric Brain Tumor Program; National Center for Research Resources [MO1-RR02172]; National Center for Research Resources, National Institutes of Health [UL1 RR025758-01] FX We are grateful to the children with progeria and their families for their participation in this study. We thank the Family Inn (Cambridge, MA) and Devon Nicole House (Boston, MA) for housing families; Susan Campbell, MS, Nancy Wolf-Jenssen, and Nancy Grossman for medical records coordination; and Kyra Johnson, Kelly Littlefield, Kiera McKendrick, Angela Kraybill, and William Fletcher for coordinator services. This project was funded by The Progeria Research Foundation (PRFCLIN2007-01 and Grant #PRFCLINTRIAL003-080109), the National Heart, Lung and Blood Institute (1RC2HL101631-01), the Dana-Farber Cancer Institute Stop&Shop Pediatric Brain Tumor Program, by a National Center for Research Resources to the Children's Hospital Boston General Clinical Research Center (MO1-RR02172), and a grant from the National Center for Research Resources, National Institutes of Health, to the Harvard Catalyst Clinical & Translational Science Center (Harvard Catalyst) (UL1 RR025758-01). NR 31 TC 6 Z9 7 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD SEP PY 2012 VL 42 IS 9 BP 1089 EP 1098 DI 10.1007/s00247-012-2423-1 PG 10 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 991RB UT WOS:000307717800007 PM 22752073 ER PT J AU Kogai, T Brent, GA AF Kogai, Takahiko Brent, Gregory A. TI The sodium iodide symporter (NIS): Regulation and approaches to targeting for cancer therapeutics SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Sodium iodide symporter; Thyroid cancer; Breast cancer; Transcriptional regulation; Posttranslational regulation ID MCF-7 BREAST-CANCER; RAT-THYROID CELLS; TRANS-RETINOIC ACID; GROWTH-FACTOR-BETA; RECOMBINANT HUMAN THYROTROPIN; PAIRED-DOMAIN TRANSCRIPTION; PROTEIN-KINASE-A; ADENOSINE-3',5'-MONOPHOSPHATE SIGNAL ACTION; ACUTE PROMYELOCYTIC LEUKEMIA; SYSTEMIC NONVIRAL DELIVERY AB Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, beta-emitting radioactive iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS. Published by Elsevier Inc. C1 [Kogai, Takahiko] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, David Geffen Sch Med,Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, David Geffen Sch Med,Dept Physiol, Los Angeles, CA 90073 USA. RP Kogai, T (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, David Geffen Sch Med,Dept Med, Bldg 114,Room 229,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM tkogai@ucla.edu; gbrent@ucla.edu FU NIH [R01 CA089364] FX We would like to thank Drs. Jerome Hershman, Masahiro Sugawara, and Yan-Yun Liu for helpful discussions. This study was supported by NIH R01 CA089364 and VA merit review funds. NR 208 TC 47 Z9 51 U1 1 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD SEP PY 2012 VL 135 IS 3 BP 355 EP 370 DI 10.1016/j.pharmthera.2012.06.007 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 988ZD UT WOS:000307529100007 PM 22750642 ER PT J AU Sneag, DB Krajewski, KM Howard, S Jagannathan, JP Star, KV Ramaiya, N AF Sneag, Darryl B. Krajewski, Katherine M. Howard, Stephanie Jagannathan, Jyothi P. Star, Kremena V. Ramaiya, Nikhil TI Sclerotic osseous metastases from renal cell carcinoma SO SKELETAL RADIOLOGY LA English DT Article DE Renal cell carcinoma; Sclerotic; Osseous; Metastases ID BONE METASTASES; OSTEOBLASTIC METASTASES; PROGNOSTIC IMPACT; TUMOR; MECHANISMS; FEATURES; SUBTYPE; PATTERN AB This case series describes and illustrates three cases of sclerotic osseous metastases from untreated renal cell carcinoma (RCC). RCC is commonly metastatic to the skeleton but almost always produces lytic metastases, with only three prior reports of sclerotic metastases identified in the literature. Sclerotic metastasis causing low back pain was the initial disease presentation in two of the three patients in this case series and the first manifestation of metastatic disease in one. The most common metastatic sites of RCC, i.e., retroperitoneal lymph nodes, lung, and liver, were not identified in any of the cases, and skeletal involvement with epidural extension was the only site of metastasis in two. Pathologic specimens from all three cases revealed RCC of high nuclear grade. C1 [Sneag, Darryl B.; Krajewski, Katherine M.; Howard, Stephanie; Jagannathan, Jyothi P.; Ramaiya, Nikhil] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, Boston, MA 02115 USA. [Sneag, Darryl B.; Krajewski, Katherine M.; Howard, Stephanie; Jagannathan, Jyothi P.; Star, Kremena V.; Ramaiya, Nikhil] Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Star, Kremena V.] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. RP Sneag, DB (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM dsneag@partners.org; kmkrajewski@partners.org; sahoward@partners.org; jjagannathan@partners.org; kstar@partners.org; nramaiya@partners.org NR 19 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD SEP PY 2012 VL 41 IS 9 BP 1169 EP 1175 DI 10.1007/s00256-012-1424-3 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 991SB UT WOS:000307720700021 PM 22576970 ER PT J AU Sharma, SM Fuchsluger, T Ahmad, S Katikireddy, KR Armant, M Dana, R Jurkunas, UV AF Sharma, Sandhya M. Fuchsluger, Thomas Ahmad, Sajjad Katikireddy, Kishore R. Armant, Myriam Dana, Reza Jurkunas, Ula V. TI Comparative Analysis of Human-Derived Feeder Layers with 3T3 Fibroblasts for the Ex Vivo Expansion of Human Limbal and Oral Epithelium SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE Cornea; Limbal stem cells; Oral mucosa; Feeder layer; Human dermal fibroblasts; Human mesenchymal stem cells; 3T3; Ex vivo expansion; Xenobiotic-free corneal equivalents; Amniotic membrane ID OCULAR SURFACE RECONSTRUCTION; STEM-CELL DEFICIENCY; CULTIVATED CORNEAL EPITHELIUM; AMNIOTIC MEMBRANE; SUCCESSFUL TRANSPLANTATION; AUTOLOGOUS SERUM; BASAL CELLS; CULTURE; DISEASE; EQUIVALENTS AB Corneal transplantation with cultivated limbal or oral epithelium is a feasible treatment option for limbal stem cell deficiency (LSCD). Currently utilized co-culture of stem cells with murine 3T3 feeder layer renders the epithelial constructs as xenografts. To overcome the potential risks involved with xenotransplantation, we investigated the use of human-derived feeder layers for the ex vivo expansion of epithelial (stem) cells. Human limbal and oral epithelium was co-cultured with mouse 3T3 fibroblasts, human dermal fibroblasts (DF), human mesenchymal stem cells (MSC), and with no feeder cells (NF). Cell morphology was monitored with phase-contrast microscopy, and stem cell characteristics were assessed by immunohistochemistry, real-time PCR for p63 and ABCG2, (stem cell markers), and by colony-forming efficiency (CFE) assay. Immunohistochemical analysis detected positive staining for CK3 (cornea specific marker) and I beta 1 and p63 (putative stem cell markers) in all culture conditions. The level of I beta 1 and p63 was significantly higher in both limbal and oral cells cultured on the 3T3 feeder, as compared to the MSC or NF group (p < 0.01). This level was comparable to the cells cultured on DF. Expression of p63 and ABCG2 in limbal and oral epithelial cells in the 3T3 and DF groups was significantly higher than that in the MSC or NF group (p < 0.01). No statistical difference was detected between 3T3 and DF groups. The CFE of both limbal and oral cells co-cultured on 3T3 fibroblasts was comparable to cells grown on DF, and was significantly higher than that of cells co-cultured with MSC or NF (p < 0.01). Epithelial cells grown on a DF feeder layer maintained a stem cell-like phenotype, comparable to cells grown on a 3T3 feeder layer. In conclusion, DF provides a promising substitute for 3T3 feeder cells during cultivation of xenobiotic-free corneal equivalents. C1 [Sharma, Sandhya M.; Fuchsluger, Thomas; Katikireddy, Kishore R.; Dana, Reza; Jurkunas, Ula V.] Schepens Eye Res Inst, Boston, MA 02114 USA. [Dana, Reza; Jurkunas, Ula V.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Sharma, Sandhya M.; Fuchsluger, Thomas; Katikireddy, Kishore R.; Dana, Reza; Jurkunas, Ula V.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Ahmad, Sajjad] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Armant, Myriam] Immune Dis Inst, Ctr Human Cell Therapy, Boston, MA 02115 USA. RP Jurkunas, UV (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM ula.jurkunas@schepens.harvard.edu FU Center of Excellence in Women's Health Award; Harvard Medical School; New England Corneal Transplant Research Award; Massachusetts Lions Eye Research Fund; Cornea Donor Research Fund FX We thank Dr. Shigeru Kinoshita, Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan, for his mentorship in this project and allowing us to adopt his cell cultivation protocols. This work was supported by Center of Excellence in Women's Health Award, Harvard Medical School (UVJ), New England Corneal Transplant Research Award (UVJ), Massachusetts Lions Eye Research Fund (UVJ), Cornea Donor Research Fund (UVJ and RD). NR 45 TC 23 Z9 23 U1 2 U2 14 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD SEP PY 2012 VL 8 IS 3 BP 696 EP 705 DI 10.1007/s12015-011-9319-6 PG 10 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 986HQ UT WOS:000307333100008 PM 21964568 ER PT J AU Kraft, S Mackler, E Schlickman, P Welch, K DePestel, DD AF Kraft, Shawna Mackler, Emily Schlickman, Peter Welch, Kathy DePestel, Daryl D. TI Outcomes of therapy vancomycin-resistant enterococcal bacteremia in hematology and bone marrow transplant patients SO SUPPORTIVE CARE IN CANCER LA English DT Letter C1 [Kraft, Shawna; DePestel, Daryl D.] Univ Michigan Hlth Syst, Ann Arbor, MI 48109 USA. [Mackler, Emily] Univ Michigan, Ctr Canc, Ann Arbor, MI 48109 USA. [DePestel, Daryl D.] Univ Michigan, Coll Pharm, Ann Arbor, MI 48109 USA. [Schlickman, Peter] Denver VA Med Ctr, Eastern Colorado Hlth Care Syst, Denver, CO 80220 USA. [Welch, Kathy] Univ Michigan, Ctr Stat Consultat & Res, Ann Arbor, MI 48109 USA. RP Kraft, S (reprint author), Univ Michigan Hlth Syst, 1500 E Med Ctr Dr,UH B2D301,Box 0008, Ann Arbor, MI 48109 USA. EM svandeko@umich.edu NR 1 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD SEP PY 2012 VL 20 IS 9 BP 1935 EP 1936 DI 10.1007/s00520-012-1440-9 PG 2 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 985RE UT WOS:000307285800002 PM 22447367 ER PT J AU Walling, AM Asch, SM Lorenz, KA Malin, J Roth, CP Barry, T Wenger, NS AF Walling, Anne M. Asch, Steven M. Lorenz, Karl A. Malin, Jennifer Roth, Carol P. Barry, Tod Wenger, Neil S. TI The quality of supportive care among inpatients dying with advanced cancer SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Quality of care; Supportive care; Advanced cancer ID PALLIATIVE CARE; LIFE; END; DEATH; PHYSICIANS; PROVIDERS; FAMILIES AB Managing symptoms and communicating effectively are essential aspects of providing high-quality cancer care, especially among patients with advanced cancer. The purpose of this study is to apply novel quality indicators to measure the quality of supportive care provided to patients with advanced cancer who died in a large university medical center. Cancer quality ASSIST is a comprehensive quality indicator (QI) set that includes 92 symptom and care planning indicators, of which we piloted 15 applicable to persons with advanced cancer who died in the hospital setting. We evaluated medical records of all adult terminal hospitalizations with lengths of stay a parts per thousand yen3 days at one university medical center between April 2005 and April 2006. Of 496 decedents, 118 had advanced cancer (mean age 60, 54 % male). Forty-five percent received chemotherapy or radiation in the month prior to or during admission. During the hospitalization, 56 % of the patients spent time in the ICU (median length of stay 8 days), one in five received first-time hemodialysis, and 23 % had a ventilator withdrawn anticipating death. The 118 patients triggered 596 quality indicators of which 476 passed (QI level pass rate 80 %, range 50-100 %). Pain assessment and management were consistently performed; however, other cancer supportive care needed improvement: 26 % of patients not receiving cancer therapy who had nausea and vomiting received inadequate follow-up, more than one quarter of patients with dyspnea had this symptom inadequately addressed, and 29 % of patients taking long-acting opioids were not prescribed a bowel regimen. Timely discussion of patient preferences upon admission to the ICU or initiation of mechanical ventilation occurred in 64 and 69 % of cases, respectively. This set of quality indicators can evaluate the quality of supportive and end-of-life care provided to inpatients dying with advanced cancer and identify aspects of care that need improvement. C1 [Walling, Anne M.; Wenger, Neil S.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Wenger, Neil S.] UCLA Hlth Syst Eth Ctr, Los Angeles, CA USA. [Walling, Anne M.; Lorenz, Karl A.; Malin, Jennifer] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. [Lorenz, Karl A.; Roth, Carol P.; Wenger, Neil S.] RAND Hlth, Santa Monica, CA USA. [Barry, Tod] UCLA Ctr Patient Safety & Qual, Los Angeles, CA USA. [Asch, Steven M.] VA Palo Alto Healthcare Syst, Palo Alto, CA 94304 USA. [Asch, Steven M.] Stanford Sch Med, Stanford, CA 94305 USA. RP Walling, AM (reprint author), Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, David Geffen Sch Med, 911 Broxton Plaza, Los Angeles, CA 90024 USA. EM awalling@mednet.ucla.edu FU National Research Service Award Training Grant [T32 PE19001]; UCLA; NIH; National Palliative Care Research Center FX This project was supported by a donation from Mary Kay Farley to RAND Health. Dr. Walling was supported by National Research Service Award Training Grant T32 PE19001, the UCLA Specialty Training & Advanced Research Program, the NIH Loan Repayment Program, and a National Palliative Care Research Center Career Development Award. NR 21 TC 11 Z9 11 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD SEP PY 2012 VL 20 IS 9 BP 2189 EP 2194 DI 10.1007/s00520-012-1462-3 PG 6 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 985RE UT WOS:000307285800032 PM 22544290 ER PT J AU Offner, H Hurn, PD AF Offner, Halina Hurn, Patricia D. TI A Novel Hypothesis: Regulatory B Lymphocytes Shape Outcome from Experimental Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Experimental stroke; Bregs; IL-10; PD-1; Immunotherapy ID ACUTE ISCHEMIC-STROKE; MURINE EXPERIMENTAL STROKE; T-CELLS; INDUCED IMMUNODEPRESSION; NEUROLOGIC DEFICITS; IMMUNE PATHOLOGY; BRAIN ISCHEMIA; PD-1; AUTOIMMUNITY; INFLAMMATION AB Although inflammatory immune cells clearly contribute to the development of middle cerebral artery occlusion (MCAO) in mice, the failure to block neutrophil-associated injury in clinical stroke trials has discouraged further development of immunotherapeutic approaches. However, there is renewed interest in a possible protective role for regulatory T and B cells that can suppress inflammation and limit central nervous system damage induced by infiltrating pro-inflammatory cells. Our failure to implicate CD4(+)FoxP3(+) T cells in limiting brain lesion volume after MCAO turned our focus towards regulatory B cells known to mediate protection against other inflammatory CNS conditions. Our results clearly demonstrated that B cell-deficient mice developed larger infarct volumes, higher mortality, and more severe functional deficits compared to wild-type mice and had increased numbers of activated T cells, macrophages, microglial cells, and neutrophils in the affected brain hemisphere. These MCAO-induced changes were completely prevented in B cell-restored mice after transfer of highly purified WT B cells but not IL-10-deficient B cells. Our novel observations are the first to implicate IL-10-secreting B cells as a major regulatory cell type in stroke and suggest that enhancement of regulatory B cells might have application as a novel therapy for this devastating neurologic condition. C1 [Offner, Halina] Portland VA Med Ctr, Neuroimmunol Res R&D 31, Portland, OR 97239 USA. [Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Hurn, Patricia D.] Univ Texas Syst, Off Hlth Affairs, Austin, TX USA. RP Offner, H (reprint author), Portland VA Med Ctr, Neuroimmunol Res R&D 31, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU NIH [NS075887, NR003521] FX The authors wish to thank Ms. Eva Niehaus for assistance with manuscript preparation. This work was supported by NIH grants NS075887 (HO) and NR003521 (PDH). This material is the result of work supported with resources and the use of facilities at the Portland VA Medical Center, Portland, OR. The contents do not represent the views of the Department of Veterans Affairs or the US government. NR 48 TC 23 Z9 23 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 J9 TRANSL STROKE RES JI Transl. Stroke Res. PD SEP PY 2012 VL 3 IS 3 SI SI BP 324 EP 330 DI 10.1007/s12975-012-0187-4 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 992FK UT WOS:000307760800005 PM 23175646 ER PT J AU Tang, XN Zheng, Z Yenari, MA AF Tang, Xian Nan Zheng, Zhen Yenari, Midori A. TI Bone Marrow Chimeras in the Study of Experimental Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Bone marrow; Chimera; Inflammation; Stroke ID FOCAL CEREBRAL-ISCHEMIA; BLOOD-BRAIN-BARRIER; PROTEIN-KINASE-C; NADPH OXIDASE; IN-VIVO; REPERFUSION INJURY; REACTIVE OXYGEN; ACTIVATION; MATRIX-METALLOPROTEINASE-9; CELLS AB Inflammation is known to contribute to stroke evolution, and poststroke immune responses have been documented to emanate from the brain via microglia. However, circulating immune cells are increasingly recognized to play a significant role as well. Recent work has demonstrated the importance of the peripheral circulation and stroke pathogenesis. Understanding how the peripheral circulation contributes to ischemic brain injury may reveal important therapeutic targets and strategies. The use of bone marrow chimeras can be a useful tool in understanding the relative contributions of brain resident and peripheral inflammatory responses. C1 [Zheng, Zhen; Yenari, Midori A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Tang, Xian Nan; Zheng, Zhen; Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Tang, Xian Nan] Stanford Univ, Dept Anesthesia, Sch Med, Stanford, CA 94305 USA. RP Yenari, MA (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM yenari@alum.mit.edu FU NIH [R01 NS40516, P50 NS014543]; VA Merit Award; Veterans Affairs Medical Center, San Francisco, California FX This work was supported by NIH grants R01 NS40516 (MAY), P50 NS014543 (MAY) and a VA Merit Award (MAY). Grants to MAY were administered by the Northern California Institute for Research and Education and supported by resources of the Veterans Affairs Medical Center, San Francisco, California. NR 58 TC 4 Z9 4 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 J9 TRANSL STROKE RES JI Transl. Stroke Res. PD SEP PY 2012 VL 3 IS 3 SI SI BP 341 EP 347 DI 10.1007/s12975-012-0169-6 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 992FK UT WOS:000307760800007 PM 24323809 ER PT J AU Kim, MC Kim, KH Jang, JS Kwon, HC Kim, BG Rattner, DW AF Kim, Min-Chan Kim, Ki-Han Jang, Jin-Seok Kwon, Hyuk-Chan Kim, Byoung-Gwon Rattner, David W. TI Patient Perception of Natural Orifice Transluminal Endoscopic Surgery in an Endoscopy Screening Program in Korea SO YONSEI MEDICAL JOURNAL LA English DT Article DE NOTES; endoscopy; surgery; patient perception; survey ID CHOLECYSTECTOMY; SURVIVAL AB Purpose: Natural orifice transluminal endoscopic surgery (NOTES) is a new method of accessing intracavitary organs in order to minimize pain by avoiding incisions in the body wall. The aim of this study is to determine patients' acceptance of NOTES in Korea and to compare their views about laparoscopic surgery and NOTES for benign and malignant diseases. Materials and Methods: The target number of total subjects was calculated to be 540. The subjects were classified into 18 sub-groups based on age groups, gender, and history of prior surgery. The questionnaire elicited information about demographic characteristics, medical check-ups, diseases, endoscopic and surgical histories, marital status and childbirth, the acceptance of NOTES, and the preferred routes for NOTES. In addition, the subjects chose laparoscopic surgery or NOTES for a hypothetical cholecystectomy and rectal cancer surgery, and responded to questions regarding the acceptable complication rate of NOTES, the appropriate cost of NOTES, and the reason(s) why they did not select NOTES. Results: 486 of 540 patients (90.0%) who agreed to participate in this study completed the questionnaire. NOTES was preferred by the following patients: elderly; a history of treatment due to a disease; having regular cheek-ups; and a history of an endoscopic procedure (p<0.05). The most preferred route for NOTES was the stomach (67.1%). Eighty-four percent of the patients choosing NOTES responded that the complication rate of the new surgical method should be the same or lower than laparoscopic surgery. Vague anxiety over a new surgical method was the most common reason why NOTES was not selected in benign and malignant diseases (64% and 73%), respectively. Conclusion: Patients appear to be interested in the potential benefits of NOTES and would embrace it if their concerns about safety are met. We believe that qualified surgical endoscopists can meet these safety concerns, and that NOTES development has the potential to flourish. C1 [Rattner, David W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kim, Min-Chan; Kim, Ki-Han] Dong A Univ, Coll Med, Dept Surg, Pusan, South Korea. [Jang, Jin-Seok; Kwon, Hyuk-Chan] Dong A Univ, Coll Med, Dept Internal Med, Pusan, South Korea. [Kim, Byoung-Gwon] Dong A Univ, Coll Med, Dept Prevent Med, Pusan, South Korea. RP Rattner, DW (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM drattner@partners.org FU Dong-A University research fund FX This work was supported by the Dong-A University research fund. NR 13 TC 6 Z9 6 U1 1 U2 2 PU YONSEI UNIV COLL MEDICINE PI SEOUL PA 50-1 YONSEI-RO, SEODAEMUN-GU, SEOUL 120-752, SOUTH KOREA SN 0513-5796 EI 1976-2437 J9 YONSEI MED J JI Yonsei Med. J. PD SEP 1 PY 2012 VL 53 IS 5 BP 960 EP 967 DI 10.3349/ymj.2012.53.5.960 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 995DA UT WOS:000307986900012 PM 22869479 ER PT J AU Masland, RH AF Masland, Richard H. TI The Retina: An Approachable Part of the Brain SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Book Review ID CELL C1 [Masland, Richard H.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Masland, RH (reprint author), Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. NR 4 TC 0 Z9 0 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD SEP-OCT PY 2012 VL 24 IS 5 BP 719 EP 719 DI 10.1002/ajhb.22305 PG 1 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 986WV UT WOS:000307377800022 ER PT J AU Rask-Madsen, C Kahn, CR AF Rask-Madsen, Christian Kahn, C. Ronald TI Tissue-Specific Insulin Signaling, Metabolic Syndrome, and Cardiovascular Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE adhesion molecules; atherosclerosis; diabetes mellitus; endothelial function; insulin resistance ID SKELETAL-MUSCLE; ENDOTHELIAL-CELLS; GLUCOSE-UPTAKE; RECEPTOR SUBSTRATE-1; BETA-CELLS; BLOOD-FLOW; RESISTANCE; MICE; ATHEROSCLEROSIS; DYSFUNCTION AB Impaired insulin signaling is central to development of the metabolic syndrome and can promote cardiovascular disease indirectly through development of abnormal glucose and lipid metabolism, hypertension, and a proinflammatory state. However, insulin's action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications of diabetes mellitus. Recent advances in our understanding of the complex pathophysiology of insulin's effects on vascular tissues offer new opportunities for preventing these cardiovascular disorders. (Arterioscler Thromb Vasc Biol. 2012;32:2052-2059.) C1 [Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU National Institutes of Health (NIH) grant [EY018677]; NIH [DK31036, DK33201, DK55545, DK82659, R24DK085610] FX Dr Rask-Madsen is supported by National Institutes of Health (NIH) grant EY018677 and Dr Kahn by NIH grants DK31036, DK33201, DK55545, DK82659, and R24DK085610, as well as the Mary K. Iacocca Professorship. NR 55 TC 81 Z9 89 U1 2 U2 15 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 2012 VL 32 IS 9 BP 2052 EP 2059 DI 10.1161/ATVBAHA.111.241919 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 992JZ UT WOS:000307773100006 PM 22895666 ER PT J AU He, MA Wolpin, B Rexrode, K Manson, JE Rimm, E Hu, FB Qi, L AF He, Meian Wolpin, Brian Rexrode, Kathy Manson, JoAnn E. Rimm, Eric Hu, Frank B. Qi, Lu TI ABO Blood Group and Risk of Coronary Heart Disease in Two Prospective Cohort Studies SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE ABO; coronary heart disease; cohort study; meta-analysis ID MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; PANCREATIC-CANCER; SELECTIN LEVELS; METAANALYSIS; ASSOCIATION; CYTOKINES; SYSTEM; FUTURE AB Objective-Epidemiological data regarding the association between ABO blood groups and risk of coronary heart disease (CHD) have been inconsistent. We sought to investigate the associations between ABO blood group and CHD risk in prospective cohort studies. Methods and Results-Two large, prospective cohort studies (the Nurses' Health Study [NHS] including 62 073 women and the Health Professionals Follow-up Study [HPFS] including 27 428 men) were conducted with more than 20 years of follow-up (26 years in NHS and 24 years in HPFS). A meta-analysis was performed to summarize the associations from the present study and previous studies. In NHS, during 1 567 144 person-years of follow-up, 2055 participants developed CHD; in HPFS, 2015 participants developed CHD during 517 312 person-years of follow-up. ABO blood group was significantly associated with the risk of developing CHD in both women and men (log-rank test; P=0.0048 and 0.0002, respectively). In the combined analysis adjusted for cardiovascular risk factors, compared with participants with blood group O, those with blood groups A, B, or AB were more likely to develop CHD (adjusted hazard ratios [95% CI] for incident CHD were 1.06 [0.99-1.15], 1.15 [1.04-1.26], and 1.23 [1.11-1.36], respectively). Overall, 6.27% of the CHD cases were attributable to inheriting a non-O blood group. Meta-analysis indicated that non-O blood group had higher risk of CHD (relative risk =1.11; 95% CI, 1.05-1.18; P=0.001) compared with O blood group. Conclusion-These data suggest that ABO blood group is significantly associated with CHD risk. Compared with other blood groups, those with the blood type O have moderately lower risk of developing CHD. (Arterioscler Thromb Vasc Biol. 2012;32:2314-2320.) C1 [He, Meian; Rimm, Eric; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [He, Meian] Huazhong Univ Sci & Technol, Inst Occupat Med, Union Hosp, Tongji Med Coll, Wuhan 430074, Peoples R China. [He, Meian] Huazhong Univ Sci & Technol, Dept Cardiol, Union Hosp, Tongji Med Coll, Wuhan 430074, Peoples R China. [Wolpin, Brian] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rimm, Eric; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. [Rexrode, Kathy; Manson, JoAnn E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu OI Rexrode, Kathryn/0000-0003-3387-8429 FU National Institutes of Health [R01 HL71981, HL034594, P01 HL34594, CA87969]; American Heart Association Scientist Development Award; Boston Obesity Nutrition Research Center [DK46200] FX This study was supported, in part, by National Institutes of Health grants R01 HL71981 and HL034594, P01 HL34594, and CA87969, an American Heart Association Scientist Development Award, and the Boston Obesity Nutrition Research Center (DK46200 to Dr Qi). NR 39 TC 58 Z9 63 U1 0 U2 10 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 2012 VL 32 IS 9 BP 2314 EP 2320 DI 10.1161/ATVBAHA.112.248757 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 992JZ UT WOS:000307773100035 PM 22895671 ER PT J AU McNeill, LH Stoddard, A Bennett, GG Wolin, KY Sorensen, GG AF McNeill, Lorna H. Stoddard, Anne Bennett, Gary G. Wolin, Kathleen Y. Sorensen, Glorian G. TI Influence of individual and social contextual factors on changes in leisure-time physical activity in working-class populations: results of the Healthy Directions-Small Businesses Study SO CANCER CAUSES & CONTROL LA English DT Article DE Health disparities; Multivitamin; Nutrition; Physical activity; Race/ethnicity; Social context ID AFRICAN-AMERICAN WOMEN; CAROLINA LATINA IMMIGRANTS; SOCIOECONOMIC-STATUS; CANCER PREVENTION; UNITED-STATES; MULTIETHNIC POPULATIONS; ACTIVITY QUESTIONNAIRE; COLLECTIVE EFFICACY; BUILT ENVIRONMENT; BEHAVIOR-CHANGE AB As part of the Harvard Cancer Prevention Program Project, we sought to address disparities reflected in social class and race/ethnicity by developing and testing a behavioral intervention model that targeted fruit and vegetable consumption, red meat consumption, multivitamin intake, and physical activity in working-class, multiethnic populations. This paper examined the associations between change in leisure-time physical activity and individual and social contextual factors in participants employed in small businesses (n = 850) at both baseline and at 18-month final. In bivariate analyses, age, language acculturation, social ties, and workplace social capital were significantly associated with physical activity at final. In multivariable analyses, being younger and having high language acculturation were significantly associated with greater leisure-time physical activity at final; high workplace social capital was significantly associated with a decline in physical activity at final. These findings have implications for understanding factors that are integral to promoting change in physical activity among working-class, multiethnic populations. C1 [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Houston, TX 77030 USA. [Stoddard, Anne] New England Res Inst, Watertown, MA 02172 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Wolin, Kathleen Y.] Washington Univ, Sch Med, Dept Surg, Div Canc Prevent & Control, St Louis, MO 63110 USA. [Sorensen, Glorian G.] Ctr Community Based Res, Dana Farber Canc Inst, Boston, MA USA. [Sorensen, Glorian G.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP McNeill, LH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Unit 125,1100 Holcombe Blvd, Houston, TX 77030 USA. EM lmcneill@mdanderson.org RI Wolin, Kathleen/I-2154-2014 OI Wolin, Kathleen/0000-0001-7950-9042 FU National Institutes of Health [5 POl CA75308]; Dana-Farber Cancer Institute by Liberty Mutual, National Grid; Patterson Fellowship Fund FX This research was supported by the National Institutes of Health (grant 5 POl CA75308) and the Dana-Farber Cancer Institute by Liberty Mutual, National Grid, and the Patterson Fellowship Fund. The authors thank the numerous investigators and staff members who contributed to this study, including Jennifer Dacey Allen, Elizabeth Alvarez, Jamie Baron, Joyce Gheatham, Tracy Liwen Ghen, Graham Golditz, Karen Ertel, Martha Fay, Robert Fletcher, Gaitlin Gutheil, Elizabeth Gonzalez Suarez, Elizabeth Harden, Laura Jay, Ichiro Kawachi, Kerry Kokkinogenis, Nancy Krieger, Karen Kuntz, Ruth Lederman, Nancy Lightman, Simone Pinheiro, Kathleen Scafidi, Tatyana Pinchuk, George Moseley, Lorraine Wallace, Jane Weeks, Milton Weinstein, and Richard Youngstrom. In addition, this work could not have been completed without the participation of 26 small manufacturing businesses and employees participating in the Healthy Directions-Small Business Study and the participation of Harvard Vanguard Medical Associates and members in the Healthy Directions-Health Centers Study. NR 99 TC 2 Z9 2 U1 4 U2 20 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2012 VL 23 IS 9 BP 1475 EP 1487 DI 10.1007/s10552-012-0021-z PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 987FD UT WOS:000307401400008 PM 22806257 ER PT J AU Van den Stock, J de Gelder, B De Winter, FL Van Laere, K Vandenbulcke, M AF Van den Stock, Jan de Gelder, Beatrice De Winter, Francois-Laurent Van Laere, Koen Vandenbulcke, Mathieu TI A strange face in the mirror. Face-selective self-misidentification in a patient with right lateralized occipito-temporal hypo-metabolism SO CORTEX LA English DT Letter ID DELUSIONAL BELIEF; RECOGNITION C1 [Van den Stock, Jan; de Gelder, Beatrice; De Winter, Francois-Laurent; Vandenbulcke, Mathieu] Katholieke Univ Leuven, Brain & Emot Lab Leuven BELL, Div Psychiat, Dept Neurosci, B-3000 Louvain, Belgium. [de Gelder, Beatrice] Tilburg Univ, Cognit & Affect Neurosci Lab, Tilburg, Netherlands. [de Gelder, Beatrice] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Sch Med, Charlestown, MA USA. [Van Laere, Koen] Katholieke Univ Leuven, Div Nucl Med, UZ Gasthuisberg, B-3000 Louvain, Belgium. RP Van den Stock, J (reprint author), Katholieke Univ Leuven, Brain & Emot Lab Leuven BELL, Div Psychiat, Dept Neurosci, O&N 2,Herestr 49,Bus 1022, B-3000 Louvain, Belgium. EM jan.vandenstock@med.kuleuven.be RI Van den Stock, Jan/F-1906-2014 OI Van den Stock, Jan/0000-0001-5756-3195 NR 15 TC 14 Z9 14 U1 0 U2 8 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD SEP PY 2012 VL 48 IS 8 BP 1088 EP 1090 DI 10.1016/j.cortex.2012.03.003 PG 3 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 978EZ UT WOS:000306724700020 PM 22480403 ER PT J AU Langer, JE Lopes, MBS Fountain, NB Pranzatelli, MR Thiele, EA Rust, RS Goodkin, HP AF Langer, Jennifer E. Lopes, M. Beatriz S. Fountain, Nathan B. Pranzatelli, Michael R. Thiele, Elizabeth A. Rust, Robert S. Goodkin, Howard P. TI An unusual presentation of anti-Hu-associated paraneoplastic limbic encephalitis SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article ID ENCEPHALOMYELITIS SENSORY NEURONOPATHY; LUNG-CANCER; NEUROBLASTOMA; ANTIBODIES; TUMOR AB Paraneoplastic limbic encephalitis is a rare disorder characterized by personality changes, seizures, memory loss, and psychiatric symptoms often associated with antineuronal antibodies. It is well described in the adult literature but is still underreported in the pediatric literature. Symptoms are usually multifocal and subacute in presentation, occurring over days to weeks; however, in rare cases, symptom onset can be more gradual. We report the case of a 9-year-old male with anti-Hu-associated paraneoplastic limbic encephalitis that presented as episodic ataxia and behavioral changes evolving to intractable epilepsy and worsening behavioral changes over the course of a year. This case highlights the importance of considering a paraneoplastic disorder in the differential diagnosis for unexplained multifocal neurological symptoms of subacute or chronic onset as earlier detection and treatment may result in an improved outcome. C1 [Langer, Jennifer E.; Fountain, Nathan B.; Rust, Robert S.; Goodkin, Howard P.] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA 22908 USA. [Lopes, M. Beatriz S.] Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA 22908 USA. [Pranzatelli, Michael R.] So Illinois Univ, Sch Med, Dept Neurol, Springfield, IL USA. [Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Rust, Robert S.; Goodkin, Howard P.] Univ Virginia Hlth Syst, Dept Pediat, Charlottesville, VA 22908 USA. RP Goodkin, HP (reprint author), Univ Virginia Hlth Syst, Dept Neurol, POB 800394, Charlottesville, VA 22908 USA. EM hpg9v@virginia.edu NR 11 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD SEP PY 2012 VL 54 IS 9 BP 863 EP 866 DI 10.1111/j.1469-8749.2012.04221.x PG 4 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 988DP UT WOS:000307468700020 PM 22320677 ER PT J AU Bledsoe, JR Sadow, PM Stephen, A Nielsen, GP Faquin, WC AF Bledsoe, Jacob R. Sadow, Peter M. Stephen, Antonia Nielsen, G. Petur Faquin, William C. TI Fine Needle Aspiration Biopsy of an Unusual Follicular Adenoma with Sebaceous-Like Features SO ENDOCRINE PATHOLOGY LA English DT Article ID CLEAR-CELL-CHANGE; THYROID-GLAND; CARCINOMA; CYTOLOGY C1 [Bledsoe, Jacob R.; Sadow, Peter M.; Nielsen, G. Petur; Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stephen, Antonia] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. [Bledsoe, Jacob R.; Sadow, Peter M.; Stephen, Antonia; Nielsen, G. Petur; Faquin, William C.] Harvard Univ, Sch Med, Boston, MA USA. RP Faquin, WC (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 219,55 Fruit St, Boston, MA 02114 USA. EM wfaquin@partners.org NR 19 TC 0 Z9 0 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 J9 ENDOCR PATHOL JI Endocr. Pathol. PD SEP PY 2012 VL 23 IS 3 BP 177 EP 180 DI 10.1007/s12022-012-9205-z PG 4 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA 988VI UT WOS:000307518400008 PM 22527948 ER PT J AU Bosak, T Liang, B Wu, TD Templer, SP Evans, A Vali, H Guerquin-Kern, JL Klepac-Ceraj, V Sim, MS Mui, J AF Bosak, T. Liang, B. Wu, T. -D. Templer, S. P. Evans, A. Vali, H. Guerquin-Kern, J. -L. Klepac-Ceraj, V. Sim, M. S. Mui, J. TI Cyanobacterial diversity and activity in modern conical microbialites SO GEOBIOLOGY LA English DT Article ID YELLOWSTONE-NATIONAL-PARK; RIBOSOMAL-RNA GENES; BACTERIAL STROMATOLITES; OXYGENIC PHOTOSYNTHESIS; SPATIAL-RESOLUTION; MAT COMMUNITY; NORTH-ISLAND; HOT-SPRINGS; NEW-ZEALAND; SP-NOV AB Modern conical microbialites are similar to some ancient conical stromatolites, but growth, behavior and diversity of cyanobacteria in modern conical microbialites remain poorly characterized. Here, we analyze the diversity of cyanobacterial 16S rRNA gene sequences in conical microbialites from 14 ponds fed by four thermal sources in Yellowstone National Park and compare cyanobacterial activity in the tips of cones and in the surrounding topographic lows (mats), respectively, by high-resolution mapping of labeled carbon. Cones and adjacent mats contain similar 16S rRNA gene sequences from genetically distinct clusters of filamentous, non-heterocystous cyanobacteria from Subsection III and unicellular cyanobacteria from Subsection I. These sequences vary among different ponds and between two sampling years, suggesting that coniform mats through time and space contain a number of cyanobacteria capable of vertical aggregation, filamentous cyanobacteria incapable of initiating cone formation and unicellular cyanobacteria. Unicellular cyanobacteria are more diverse in topographic lows, where some of these organisms respond to nutrient pulses more rapidly than thin filamentous cyanobacteria. The densest active cyanobacteria are found below the upper 50 similar to mu m of the cone tip, whereas cyanobacterial cells in mats are less dense, and are more commonly degraded or encrusted by silica. These spatial differences in cellular activity and density within macroscopic coniform mats imply a strong role for diffusion limitation in the development and the persistence of the conical shape. Similar mechanisms may have controlled the growth, morphology and persistence of small coniform stromatolites in shallow, quiet environments throughout geologic history. C1 [Bosak, T.; Liang, B.; Templer, S. P.; Evans, A.; Sim, M. S.] MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA. [Liang, B.] Acad Sinica, Inst Earth Sci, Taipei 115, Taiwan. [Wu, T. -D.; Guerquin-Kern, J. -L.] Univ Paris 11, INSERM, F-91405 Orsay, France. [Wu, T. -D.; Guerquin-Kern, J. -L.] Inst Curie, Lab Microscopie Ion, F-91405 Orsay, France. [Templer, S. P.] Roche Mol Diagnost, Basel, Switzerland. [Vali, H.; Mui, J.] McGill Univ, Facil Electron Microscopy Res, Montreal, PQ, Canada. [Vali, H.] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada. [Klepac-Ceraj, V.] Forsyth Inst, Cambridge, MA USA. [Klepac-Ceraj, V.] Wellesley Coll, Dept Biol Sci, Wellesley, MA 02181 USA. RP Bosak, T (reprint author), MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA. EM tbosak@mit.edu RI Liang, Biqing/J-2799-2012; Vali, Hojatollah/F-3511-2012; Templer, Stefanie/D-6515-2012; OI Sim, Min Sub/0000-0002-3491-9002; Liang, Biqing/0000-0003-3634-5556; Vali, Hojatollah/0000-0003-3464-9943; Templer, Stefanie/0000-0003-2134-0699; Klepac-Ceraj, Vanja/0000-0001-5387-5706 FU Natural Sciences and Engineering Research Council (NSERC) of Canada FX We thank G. Geesey (U. Montana), S. Gunther (NPS), J. Thompson (MIT), L. Casillas (Univ. PR), D. Newman Lab (MIT), J. Holz and N. Watson (Keck Biological Imaging Facility, Whitehead Institute, MIT), members of the MIT Laboratory for Geomicrobiology and Microbial Sedimentology and Dr. S. K. Sears (McGill Univ.). H. V. acknowledges financial support from the Natural Sciences and Engineering Research Council (NSERC) of Canada. We also thank the PICT-IBiSA imaging facility in the Institut Curie for NanoSIMS analyses. Thoughtful comments by three anonymous reviewers improved the manuscript. NR 76 TC 17 Z9 17 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1472-4677 J9 GEOBIOLOGY JI Geobiology PD SEP PY 2012 VL 10 IS 5 BP 384 EP 401 DI 10.1111/j.1472-4669.2012.00334.x PG 18 WC Biology; Environmental Sciences; Geosciences, Multidisciplinary SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Geology GA 989FK UT WOS:000307545500002 PM 22713108 ER PT J AU Oh, S Go, GW Mylonakis, E Kim, Y AF Oh, S. Go, G. W. Mylonakis, E. Kim, Y. TI The bacterial signalling molecule indole attenuates the virulence of the fungal pathogen Candida albicans SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE biofilms; C; albicans; C; elegans; indole signalling; virulence ID ENTERICA SEROVAR TYPHIMURIUM; ESCHERICHIA-COLI; CAENORHABDITIS-ELEGANS; BIOFILM FORMATION; GENE-EXPRESSION; MUTANTS; SYSTEM; HOST; NRG1; PCR AB Aims Indole is a signalling molecule, produced by a number of Gram-positive and Gram-negative bacteria both in nature as well as clinical environments. Here, we explored the effect of bacterial indole and one of its main derivatives on the virulence of the fungal pathogen Candida albicans. Methods and Results We found that indole and its derivate indole-3-acetonitrile (IAN) did not affect the viability of C. albicans. Interestingly, indole and IAN repressed C. albicans biofilm formation as well as the attachment of C. albicans to intestinal epithelial HT-29 cells and inhibited the ability of the yeast to make filaments that are the main virulence factor of C. albicans. In addition, we used the heterologous model host Caenorhabditis elegans to demonstrate in vivo that the presence of indole or IAN attenuates C. albicans infection (P = 0.0188 and P < 0.0001 for indole and IAN, respectively, compared to worms exposed to C. albicans DAY185 alone) and decreases fungal colonization in the nematode gut. Importantly, quantitative real-time polymerase chain reaction (qRT-PCR) results showed that in C. albicans, indole and IAN strongly stimulated the transcription of NRG1. Conclusions Indole and IAN attenuates fungal virulence by regulating the transcription of NRG1, a transcriptional factor that influences filamentation and biofilm formation in C. albicans. Significance and Impact of the Study Our findings indicate that the bacterial signalling molecules indole and its derivatives play an inter-kingdom role in dynamic network of microbiota and directly modulate the virulence of fungal C. albicans via NRG1. C1 [Oh, S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Gastroenterol, Boston, MA USA. [Go, G. W.] Yale Univ, Sch Med, Cardiovasc Res Ctr, New Haven, CT USA. [Mylonakis, E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. [Kim, Y.] Chonbuk Natl Univ, Dept Anim Sci, Jeonju, South Korea. RP Kim, Y (reprint author), 567 Baekje Daero, Jeonju 561756, South Korea. EM ykeys2584@jbnu.ac.kr RI Go, Gwang-woong/H-2733-2013 FU Chonbuk National University FX This study was supported by research funds of Chonbuk National University in 2012. NR 39 TC 16 Z9 18 U1 4 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1364-5072 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD SEP PY 2012 VL 113 IS 3 BP 622 EP 628 DI 10.1111/j.1365-2672.2012.05372.x PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 989KN UT WOS:000307558800016 PM 22726313 ER PT J AU Hollak, CEM Kuter, D Giraldo, P Hughes, D Belmatoug, N Brand, M Muller, A Schaaf, B Giorgino, R Zimran, A AF Hollak, C. E. M. Kuter, D. Giraldo, P. Hughes, D. Belmatoug, N. Brand, M. Muller, A. Schaaf, B. Giorgino, R. Zimran, A. TI MIGLUSTAT THERAPY IN TYPE 1 GAUCHER DISEASE: LONG-TERM TREATMENT EXPERIENCE FROM A MULTICENTER, RETROSPECTIVE COHORT STUDY SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Hollak, C. E. M.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Kuter, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Giraldo, P.] Hosp Univ Miguel Servet, CIBERER, Zaragoza, Spain. [Hughes, D.] Royal Free Hosp, London NW3 2QG, England. [Hughes, D.] Univ Coll Med Sch, London, England. [Belmatoug, N.] Hop Beaujon, Clichy, France. [Brand, M.; Muller, A.; Giorgino, R.] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Schaaf, B.] Factum, Offenbach, Germany. [Zimran, A.] Shaare Zedek Med Ctr, Jerusalem, Israel. RI Hughes, Derralynn/J-8012-2013 OI Hughes, Derralynn/0000-0003-4531-9173 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD SEP PY 2012 VL 35 SU 1 BP S97 EP S97 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 988TH UT WOS:000307513100341 ER PT J AU Watanabe, R Tawa, M Fisher, DC Kupper, T Clark, RA AF Watanabe, R. Tawa, M. Fisher, D. C. Kupper, T. Clark, R. A. TI Human skin lesion morphology reflects and predicts the recirculation patterns of pathogenic T cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [Watanabe, R.; Tawa, M.; Fisher, D. C.; Kupper, T.; Clark, R. A.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 141 BP S25 EP S25 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000142 ER PT J AU Hawkins, EJ Malte, CA Baer, JS Kivlahan, DR AF Hawkins, Eric J. Malte, Carol A. Baer, John S. Kivlahan, Daniel R. TI Prevalence, predictors, and service utilization of patients with recurrent use of Veterans Affairs substance use disorder specialty care SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Chronic; Recurrent; Prevalence; Predictors; Utilization ID ABUSE TREATMENT; ADDICTION TREATMENT; FOLLOW-UP; MANAGEMENT CHECKUPS; ALCOHOL DEPENDENCE; COLLABORATIVE CARE; TREATMENT REENTRY; MENTAL-HEALTH; DRUG; RECOVERY AB Although substance use disorders (SUDs) are chronic conditions for many patients, the prevalence, predictors, and health care utilization patterns of those who reenter SUD specialty care are understudied. We identified 1,640 patients who initiated SUD specialty care at 1 Veterans Affairs (VA) medical center and categorized them, using their subsequent 24 and prior 60 months receipt of VA SUD care, as index episode only (35.7%, 33.5-38.1), index and prior episode(s) (24.6%, 22.5-22.7), and index and postindex episodes (39.6%, 37.3-42.0). Compared with the index episode-only group, the postindex episode(s) group had modestly higher percentages of men, divorced/separated, and alcohol use, cocaine use, bipolar disorder, and psychotic disorders. Patients with postindex episodes averaged 2 times more postindex emergency visits and mental health hospitalizations than patients with an index only episode. Results document the prevalence, overall health care utilization, and limited predictability of SUD treatment reentry and support development of new models of care for these complex patients. Published by Elsevier Inc. C1 [Hawkins, Eric J.; Malte, Carol A.; Kivlahan, Daniel R.] VA Puget Sound Hlth Care Syst, Seattle Div S116ATC, Hlth Serv Res & Dev, Seattle, WA 98108 USA. [Hawkins, Eric J.; Malte, Carol A.; Baer, John S.; Kivlahan, Daniel R.] VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98108 USA. [Baer, John S.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Hawkins, Eric J.; Kivlahan, Daniel R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Hawkins, EJ (reprint author), VA Puget Sound Hlth Care Syst, Seattle Div S116ATC, Hlth Serv Res & Dev, 1660 S Columbian Way, Seattle, WA 98108 USA. EM Eric.Hawkins@va.gov NR 41 TC 7 Z9 7 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD SEP PY 2012 VL 43 IS 2 BP 221 EP 230 DI 10.1016/j.jsat.2011.11.002 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 984QV UT WOS:000307207100009 PM 22197302 ER PT J AU Santa-Maria, I Diaz-Ruiz, C Ksiezak-Reding, H Chen, A Ho, L Wang, J Pasinetti, GM AF Santa-Maria, Ismael Diaz-Ruiz, Carmen Ksiezak-Reding, Hanna Chen, Alice Ho, Lap Wang, Jun Pasinetti, Giulio Maria TI GSPE interferes with tau aggregation in vivo: implication for treating tauopathy SO NEUROBIOLOGY OF AGING LA English DT Article DE GSPE; JNPL3 mouse model; tauopathy; hyperphosphorylation ID NANOELECTROSPRAY MASS-SPECTROMETRY; P301L HUMAN-TAU; ALZHEIMERS-DISEASE; FILAMENT FORMATION; TRANSGENIC MICE; NEURODEGENERATIVE DISEASES; PHOSPHORYLATION SITES; MOUSE MODEL; INHIBITION; PROTEIN AB Tauopathies are characterized by progressive neurodegeneration caused by intracellular accumulation of hyperphosphorylated tau protein aggregates in the brain. The present study was designed to test whether a grape seed polyphenolic extract (GSPE) previously shown to inhibit tau protein aggregation in vitro could benefit tau-mediated neuropathology and behavior deficits in JNPL3 transgenic mice expressing a human tau protein containing the P301L mutation. Nine-month-old JNPL3 mice were treated with GSPE delivered through their drinking water for 6 months. We found that GSPE treatment significantly reduced the number of motor neurons immunoreactive for hyperphosphorylated and conformationally-modified tau in the ventral horns of the spinal cord identified using AT100, PHF-1, AT8, and Alz50 tau antibodies. This coincided with a drastically reduced level of hyperphosphorylated and sarcosyl-insoluble tau in spinal cord fractions. Furthermore, the reduction of tau pathology was accompanied by an improvement in the motor function assessed by a wire hang test. Collectively, our results suggest that GSPE can interfere with tau-mediated neurodegenerative mechanisms and ameliorate neurodegenerative phenotype in an animal model of tauopathy. Our studies support further evaluation of GSPE for preventing and/or treating of tauopathies in humans. (C) 2012 Elsevier Inc. All rights reserved. C1 [Santa-Maria, Ismael; Diaz-Ruiz, Carmen; Ksiezak-Reding, Hanna; Chen, Alice; Ho, Lap; Wang, Jun; Pasinetti, Giulio Maria] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Santa-Maria, Ismael] Queen Sofia Fdn, CIEN Fdn, Alzheimer Dis Res Unit, Madrid, Spain. [Ksiezak-Reding, Hanna; Chen, Alice; Ho, Lap; Pasinetti, Giulio Maria] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. RP Pasinetti, GM (reprint author), Mt Sinai Sch Med, Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu OI Diaz-Ruiz, Carmen/0000-0002-0112-0595 FU Polyphenolics Inc.; Division of Constellation Wine U.S. Inc.; Society for Progressive Supranuclear Palsy; NIH [PO1 AT004511]; Veterans Administration FX This work is supported by Polyphenolics Inc., Division of Constellation Wine U.S. Inc., the Society for Progressive Supranuclear Palsy, NIH PO1 AT004511, and in part from a MERIT Review grant from Veterans Administration to G.M.P. NR 36 TC 11 Z9 11 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2012 VL 33 IS 9 BP 2072 EP 2081 DI 10.1016/j.neurobiolaging.2011.09.027 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 981TW UT WOS:000306994600020 PM 22054871 ER PT J AU Bekris, LM Lutz, F Li, G Galasko, DR Farlow, MR Quinn, JF Kaye, JA Leverenz, JB Tsuang, DW Montine, TJ Peskind, ER Yu, CE AF Bekris, Lynn M. Lutz, Franziska Li, Gail Galasko, Douglas R. Farlow, Martin R. Quinn, Joseph F. Kaye, Jeffrey A. Leverenz, James B. Tsuang, Debby W. Montine, Thomas J. Peskind, Elaine R. Yu, Chang-En TI ADAM10 expression and promoter haplotype in Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE ADAM10; Haplotype; sAPP alpha; Alzheimer's disease; Reporter assay; Neuritic plaques; Brain; Hippocampus; Cerebrospinal fluid ID AMYLOID PRECURSOR PROTEIN; ALPHA-SECRETASE ADAM10; UP-REGULATION; MOUSE MODEL; ADAM-10; MUTATIONS; BACE AB Alzheimer's disease is confirmed at autopsy according to the accumulation of brain neuritic plaques and neurofibrillary tangles in the brain. Neuritic plaques contain amyloid-beta (A beta) and lower levels of A beta correspond to an increase in ADAM10 alpha-secretase activity. ADAM10 alpha-secretase activity produces a soluble amyloid precursor protein (APP) alpha (sAPP alpha) product and negates the pathological production of A beta. In this investigation, it was hypothesized that genetic variation with the ADAM10 promoter is associated with ADAM10 expression levels as well as cerebrospinal fluid sAPP alpha levels. Results from this investigation suggest that the ADAM10 rs514049-rs653765 C-A promoter haplotype is associated with: (1) higher CSF sAPP alpha levels in cognitively normal controls compared with Alzheimer's disease (AD) patients, (2) higher postmortem brain hippocampus, but not cerebellum, ADAM10 protein levels in subjects with low plaque scores compared with those with high plaque scores, and (3) higher promoter activity for promoter-only reporter constructs compared with promoter 3' untranslated region (3' UTR) constructs in the human neuroblastoma SHSY5Y cell line, but not in HepG2 or U118 cell lines. Taken together, these findings suggest that ADAM10 expression is modulated according to a promoter haplotype that is influenced in a brain region-and cell type-specific manner. (C) 2012 Elsevier Inc. All rights reserved. C1 [Bekris, Lynn M.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98108 USA. [Bekris, Lynn M.; Lutz, Franziska; Tsuang, Debby W.; Yu, Chang-En] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Leverenz, James B.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Galasko, Douglas R.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Galasko, Douglas R.] VA Med Ctr San Diego, San Diego, CA USA. [Farlow, Martin R.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN USA. [Quinn, Joseph F.; Kaye, Jeffrey A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Quinn, Joseph F.; Kaye, Jeffrey A.] Portland VA Med Ctr, Portland, OR USA. [Leverenz, James B.] VA Puget Sound Hlth Care Syst, MIRECC, NW Network VISN 20, Seattle, WA USA. [Leverenz, James B.] Parkinsons Dis Res Educ & Clin Ctr PADRECC, NW Network VISN 20, Philadelphia, PA USA. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Bekris, LM (reprint author), Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Box 358280,VAPSHCS GRECC S182,1660 S Columbian Wa, Seattle, WA 98108 USA. EM lbekris@u.washington.edu RI Tsuang, Debby/L-7234-2016; OI Tsuang, Debby/0000-0002-4716-1894; Kaye, Jeffrey/0000-0002-9971-3478 FU U.S. Department of Veterans Affairs, Office of Research and Development; Biomedical Laboratory; NIH [2P50AG005136-27, 1P50NS062684-01A1, K99AG034214-02] FX This work is supported in part by the U.S. Department of Veterans Affairs, Office of Research and Development Clinical Research and Development Program, the Biomedical Laboratory Research Program, and NIH Grants 2P50AG005136-27, 1P50NS062684-01A1, and K99AG034214-02. Additional support includes University of Washington Alzheimer's Disease Research Center NIH P50-AB005136 and University of California San Diego Alzheimer's Disease Research Center AGO 5131. NR 32 TC 4 Z9 4 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2012 VL 33 IS 9 AR 2229.e1 DI 10.1016/j.neurobiolaging.2012.03.013 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 981TW UT WOS:000306994600036 PM 22572541 ER PT J AU Sanna-Cherchi, S Burgess, KE Nees, SN Papeta, N Choi, M Sampogna, RV Bodria, M Perry, BJ Weng, PL Lozanovski, VJ Materna-Kiryluk, A Ristoska-Bojkovska, N Gesualdo, L Gucev, Z Allegri, L Latos-Bielenska, A Scolari, F Ravazzolo, R Kiryluk, K Drummond, I Al-Awqati, Q D'Agati, VD Tasic, V Lifton, RP Ghiggeri, GM Gharavi, AG AF Sanna-Cherchi, Simone Burgess, Katelyn E. Nees, Shannon N. Papeta, Natalia Choi, Murim Sampogna, Rosemary V. Bodria, Monica Perry, Brittany J. Weng, Patricia L. Lozanovski, Vladimir J. Materna-Kiryluk, Anna Ristoska-Bojkovska, Nadica Gesualdo, Loreto Gucev, Zoran Allegri, Landino Latos-Bielenska, Anna Scolari, Francesco Ravazzolo, Roberto Kiryluk, Krzysztof Drummond, Iain Al-Awqati, Qais D'Agati, Vivette D. Tasic, Velibor Lifton, Richard P. Ghiggeri, Gian Marco Gharavi, Ali G. TI Exome sequencing identifies dominant alleles causing obstructive uropathy and other congenital anomalies SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Sanna-Cherchi, Simone; Burgess, Katelyn E.; Nees, Shannon N.; Papeta, Natalia; Sampogna, Rosemary V.; Perry, Brittany J.; Weng, Patricia L.; Kiryluk, Krzysztof; Al-Awqati, Qais; Gharavi, Ali G.] Columbia Univ, Div Nephrol, New York, NY USA. [Choi, Murim; Lifton, Richard P.] Yale Univ, Dept Genet, New Haven, CT USA. [Bodria, Monica; Ghiggeri, Gian Marco] G Gaslini Inst Children, Div Pediat Nephrol, Genoa, Italy. [Lozanovski, Vladimir J.; Ristoska-Bojkovska, Nadica; Gucev, Zoran; Tasic, Velibor] Univ Childrens Hosp, Div Pediat Nephrol, Skopje, Macedonia. [Materna-Kiryluk, Anna; Latos-Bielenska, Anna] Polish Registry Congenital Malformat, Poznan, Poland. [Gesualdo, Loreto] Univ Foggia, Dept Biomed Sci, Foggia, Italy. [Allegri, Landino] Univ Parma, Div Nephrol, I-43100 Parma, Italy. [Ravazzolo, Roberto] G Gaslini Inst Children, Mol Genet Lab, Genoa, Italy. [Drummond, Iain] Massachusetts Gen Hosp, Dept Genet, Boston, MA 02114 USA. [D'Agati, Vivette D.] Columbia Univ, Dept Pathol, New York, NY USA. RI Ghiggeri, Gian Marco/N-4712-2015; bodria, monica/K-2115-2016 OI Ghiggeri, Gian Marco/0000-0003-3659-9062; bodria, monica/0000-0001-9690-9945 NR 0 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2012 VL 27 IS 9 BP 1623 EP 1624 PG 2 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 985NT UT WOS:000307274100061 ER PT J AU Aparici, CM Seo, Y AF Aparici, Carina Mari Seo, Youngho TI Functional Imaging for Prostate Cancer: Therapeutic Implications SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; LYMPH-NODE DISSECTION; ANDROGEN-DEPRIVATION THERAPY; MODULATED RADIATION-THERAPY; MEMBRANE ANTIGEN-EXPRESSION; RADICAL RETROPUBIC PROSTATECTOMY; DOMINANT INTRAPROSTATIC LESIONS; EXTERNAL-BEAM RADIOTHERAPY; MONOCLONAL-ANTIBODY J591; WHOLE-PELVIC IRRADIATION AB Functional radionuclide imaging modalities, now commonly combined with anatomical imaging modalities computed tomography (CT) or magnetic resonance imaging (single photon emission computed tomography [SPECT]/CT, positron emission tomography [PET]/CT, and PET/magnetic resonance imaging), are promising tools for the management of prostate cancer, particularly for therapeutic implications. Sensitive detection capability of prostate cancer using these imaging modalities is one issue; however, the treatment of prostate cancer using the information that can be obtained from functional radionuclide imaging techniques is another challenging area. There are not many SPECT or PET radiotracers that can cover the full spectrum of the management of prostate cancer from initial detection to staging, prognosis predictor, and all the way to treatment response assessment. However, when used appropriately, the information from functional radionuclide imaging improves, and sometimes significantly changes, the whole course of the cancer management. The limitations of using SPECT and PET radiotracers with regard to therapeutic implications are not so much different from their limitations solely for the task of detecting prostate cancer; however, the specific imaging target and how this target is reliably imaged by SPECT and PET can potentially make significant impact in the treatment of prostate cancer. Finally, although the localized prostate cancer is considered manageable, there is still significant need for improvement in noninvasive imaging of metastatic prostate cancer, in treatment guidance, and in response assessment from functional imaging, including radionuclide-based techniques. In this review article, we present the rationale of using functional radionuclide imaging and the therapeutic implications for each of radionuclide imaging agent that have been studied in human subjects. Semin Nucl Med 42:328-342 (c) 2012 Elsevier Inc. All rights reserved. C1 [Seo, Youngho] UCSF, Phys Res Lab, Dept Radiol & Biomed Imaging, San Francisco, CA 94107 USA. [Aparici, Carina Mari] San Francisco VA Med Ctr, Nucl Med Serv, San Francisco, CA USA. [Seo, Youngho] Univ Calif San Francisco, Dept Radiat Oncol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94107 USA. [Seo, Youngho] Univ Calif San Francisco, UCSF Grad Program Bioengn, UC Berkeley, San Francisco, CA 94107 USA. RP Seo, Y (reprint author), UCSF, Phys Res Lab, Dept Radiol & Biomed Imaging, 185 Berry St,Suite 350, San Francisco, CA 94107 USA. EM youngho.seo@ucsf.edu FU National Institutes of Health (NIH) [K25 CA114254]; American Recovery and Reinvestment Act (ARRA) through NIH [K25 CA114254-04S1]; UCSF Research Evaluation and Allocation Committee; UCSF Department of Radiation Oncology FX This work was supported by grants K25 CA114254 from the National Institutes of Health (NIH); K25 CA114254-04S1 American Recovery and Reinvestment Act (ARRA) of 2009 through NIH; and from UCSF Research Evaluation and Allocation Committee and UCSF Department of Radiation Oncology. NR 214 TC 13 Z9 13 U1 1 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0001-2998 EI 1558-4623 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD SEP PY 2012 VL 42 IS 5 BP 328 EP 342 DI 10.1053/j.semnuclmed.2012.04.004 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 986TO UT WOS:000307368700006 ER PT J AU Lehavot, K Molina, Y Simoni, JM AF Lehavot, Keren Molina, Yamile Simoni, Jane M. TI Childhood Trauma, Adult Sexual Assault, and Adult Gender Expression among Lesbian and Bisexual Women SO SEX ROLES LA English DT Article DE Childhood abuse; Sexual assault; Lesbian; Bisexual; Gender expression; Gender identity; Butch/femme ID PHYSICAL ABUSE; SUBSTANCE USE; BUTCH/FEMME DIFFERENCES; IDENTITY DEVELOPMENT; INITIAL RELIABILITY; ATYPICAL BEHAVIOR; EATING-DISORDER; MENTAL-HEALTH; UNITED-STATES; VICTIMIZATION AB Several studies have demonstrated that lesbian and bisexual women are more likely than heterosexual women to report childhood abuse and adult sexual assault. It is unknown, however, which sexual minority women are most likely to experience such abuse. We recruited adult sexual minority women living in the US through electronic fliers sent to listservs and website groups inviting them to complete an online survey (N = 1,243). We examined differences in both childhood abuse and adult sexual assault by women's current gender identity (i.e., butch, femme, androgynous, or other) and a continuous measure of gender expression (from butch/masculine to femme/feminine), adjusting for sexual orientation identity, age, education, and income. Results indicated that a more butch/masculine current self-assessment of gender expression, but not gender identity, was associated with more overall reported childhood trauma. Although one aspect of gender expression, a more butch/masculine gender role, was associated with adult sexual assault, feminine appearance and a femme gender identity also significantly predicted adult sexual assault. These findings highlight the significance of gender identity and expression in identifying women at greater risk for various abuse experiences. C1 [Lehavot, Keren] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Lehavot, Keren] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Molina, Yamile] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Simoni, Jane M.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. RP Lehavot, K (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. EM klehavot@u.washington.edu OI Simoni, Jane/0000-0002-8711-1576 FU NCI NIH HHS [P50 CA148143]; NIMH NIH HHS [K24 MH093243]; ODCDC CDC HHS [R36 CD000996] NR 58 TC 10 Z9 10 U1 1 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-0025 J9 SEX ROLES JI Sex Roles PD SEP PY 2012 VL 67 IS 5-6 BP 272 EP 284 DI 10.1007/s11199-012-0171-1 PG 13 WC Psychology, Developmental; Psychology, Social; Women's Studies SC Psychology; Women's Studies GA 985LU UT WOS:000307268800002 PM 24003263 ER PT J AU de Silva, PSA Nguyen, DD Sauk, J Korzenik, J Yajnik, V Ananthakrishnan, AN AF de Silva, P. S. A. Nguyen, D. D. Sauk, J. Korzenik, J. Yajnik, V. Ananthakrishnan, A. N. TI Long-term outcome of a third anti-TNF monoclonal antibody after the failure of two prior anti-TNFs in inflammatory bowel disease SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CROHNS-DISEASE; RANDOMIZED-TRIAL; MAINTENANCE INFLIXIMAB; DOSE INTENSIFICATION; CERTOLIZUMAB PEGOL; ADALIMUMAB; THERAPY; IMMUNOMODULATORS; NATALIZUMAB; INDUCTION AB Background A significant proportion of patients with IBD lose response to anti-TNF therapies. There is limited knowledge of the long-term outcomes of those who have failed two anti-TNF agents and commenced a third. Aim To examine the safety and efficacy of third anti-TNF treatment after failure of two prior anti-TNF agents in patients with inflammatory bowel disease. Methods This was a retrospective study of all IBD patients [Crohn's disease (CD), ulcerative colitis (UC)] treated with a third anti-TNF agent after loss of response or intolerance to two prior anti-TNF agents at a single tertiary North American centre. Disease activity, drug therapy and Montreal phenotypes were noted at disease onset and commencement of the third anti-TNF agent. KaplanMeier estimates were used to calculate the probability of remaining on the third anti-TNF agent and to identify predictors of long-term clinical response. Results A total of 63 patients (64% women, 57 CD and 6 UC) were included in the analysis. The mean disease duration at initiation of third anti-TNF was 12 years. Thirty-five (55.6%) patients discontinued the third anti-TNF after a mean of 13.2 months. Probability of remaining on the third anti-TNF was 0.69, 0.55, 0.37 and 0.25 at 6, 12, 24 and 36 months respectively. Prior primary nonresponders to the first anti-TNF agent [hazard ratio (HR) 6.4, 95% CI 2.516.1] and persistent disease activity at 3 months after commencement of a third anti-TNF (HR 3.2, 95% CI 1.37.8) predicted poorer response. Conclusions Over half of patients with inflammatory bowel disease, initiated on a third anti-TNF agent after failure of two prior anti-TNF drugs, are able to remain on the third anti-TNF at 1 year. C1 [Ananthakrishnan, A. N.] Massachusetts Gen Hosp, Gastrointestinal Unit, Crohns & Colitis Ctr, Boston, MA 02114 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org NR 19 TC 24 Z9 24 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD SEP PY 2012 VL 36 IS 5 BP 459 EP 466 DI 10.1111/j.1365-2036.2012.05214.x PG 8 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 984BV UT WOS:000307164600006 PM 22784296 ER PT J AU Novara, G Ficarra, V Mocellin, S Ahlering, TE Carroll, PR Graefen, M Guazzoni, G Menon, M Patel, VR Shariat, SF Tewari, AK Van Poppel, H Zattoni, F Montorsi, F Mottrie, A Rosen, RC Wilson, TG AF Novara, Giacomo Ficarra, Vincenzo Mocellin, Simone Ahlering, Thomas E. Carroll, Peter R. Graefen, Markus Guazzoni, Giorgio Menon, Mani Patel, Vipul R. Shariat, Shahrokh F. Tewari, Ashutosh K. Van Poppel, Hendrik Zattoni, Filiberto Montorsi, Francesco Mottrie, Alexandre Rosen, Raymond C. Wilson, Timothy G. TI Systematic Review and Meta-analysis of Studies Reporting Oncologic Outcome After Robot-assisted Radical Prostatectomy SO EUROPEAN UROLOGY LA English DT Review DE Prostatic neoplasms; Prostatectomy; Laparoscopy; Robotics ID POSITIVE SURGICAL MARGINS; LEARNING-CURVE; LAPAROSCOPIC PROSTATECTOMY; FUNCTIONAL OUTCOMES; PERIOPERATIVE OUTCOMES; CANCER CONTROL; RETROPUBIC PROSTATECTOMY; SINGLE-SURGEON; CONTINENCE OUTCOMES; FOLLOW-UP AB Context: Despite the large diffusion of robot-assisted radical prostatectomy (RARP), literature and data on the oncologic outcome of RARP are limited. Objective: Evaluate lymph node yield, positive surgical margins (PSMs), use of adjuvant therapy, and biochemical recurrence (BCR)-free survival following RARP and perform a cumulative analysis of all studies comparing the oncologic outcomes of RARP and retropubic radical prostatectomy (RRP) or laparoscopic radical prostatectomy (LRP). Evidence acquisition: A systematic review of the literature was performed in August 2011, searching Medline, Embase, and Web of Science databases. A free-text protocol using the term radical prostatectomy was applied. The following limits were used: humans; gender (male); and publications dating from January 1, 2008. A cumulative analysis was conducted using Review Manager software v. 4.2 (Cochrane Collaboration, Oxford, UK) and Stata 11.0 SE software (StataCorp, College Station, TX, USA). Evidence synthesis: We retrieved 79 papers evaluating oncologic outcomes following RARP. The mean PSM rate was 15% in all comers and 9% in pathologically localized cancers, with some tumor characteristics being the most relevant predictors of PSMs. Several surgeon-related characteristics or procedure-related issues may play a major role in PSM rates. With regard to BCR, the very few papers with a follow-up duration >5 yr demonstrated 7-yr BCR-free survival estimates of approximately 80%. Finally, all the cumulative analyses comparing RARP with RRP and comparing RARP with LRP demonstrated similar overall PSM rates (RARP vs RRP: odds ratio [OR]: 1.21; p = 0.19; RARP vs LRP: OR: 1.12; p = 0.47), pT2 PSM rates (RARP vs RRP: OR: 1.25; p = 0.31; RARP vs LRP: OR: 0.99; p = 0.97), and BCR-free survival estimates (RARP vs RRP: hazard ratio [ HR]: 0.9; p = 0.526; RARP vs LRP: HR: 0.5; p = 0.141), regardless of the surgical approach. Conclusions: PSM rates are similar following RARP, RRP, and LRP. The few data available on BCR from high-volume centers are promising, but definitive comparisons with RRP or LRP are not currently possible. Finally, significant data on cancer-specific mortality are not currently available. (C) 2012 Published by Elsevier B.V. on behalf of European Association of Urology. C1 [Novara, Giacomo] Univ Padua, Dept Surg & Oncol Sci, Urol Unit, I-35100 Padua, Italy. [Ficarra, Vincenzo; Mottrie, Alexandre] OLV Robot Surg Inst, Aalst, Belgium. [Ahlering, Thomas E.] Univ Calif Irvine, Orange, CA 92668 USA. [Carroll, Peter R.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco Helen Diller Family Comprehens Canc, San Francisco, CA 94143 USA. [Graefen, Markus] Univ Hamburg Eppendorf, Prostate Canc Ctr, Martini Clin, Hamburg, Germany. [Guazzoni, Giorgio; Montorsi, Francesco] Univ Vita Salute San Raffaele, Milan, Italy. [Menon, Mani] Henry Ford Hosp, Vattikuti Urol Inst, Detroit, MI 48202 USA. [Patel, Vipul R.] Florida Hosp Celebrat Hlth, Global Robot Inst, Celebration, FL USA. [Shariat, Shahrokh F.; Tewari, Ashutosh K.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Van Poppel, Hendrik] Katholieke Univ Leuven, Univ Hosp, Louvain, Belgium. [Rosen, Raymond C.] New England Res Inst Inc, Watertown, MA USA. [Wilson, Timothy G.] City Hope Natl Canc Ctr, Duarte, CA USA. RP Novara, G (reprint author), Univ Padua, Dept Surg & Oncol Sci, Urol Unit, Via Giustiniani 2, I-35100 Padua, Italy. EM giacomonovara@gmail.com OI Ahlering, Thomas/0000-0002-6492-4910; Guazzoni, Giorgio Ferruccio/0000-0002-5713-8313 FU Astellas; Eli Lilly; Pierre Fabre; Provenge; Recordati Int.; Takeda; Intuitive Surgical, Sunnyvale, CA, USA FX Giacomo Novara certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Giacomo Novara was lecturer/advisory board member for Astellas, Eli Lilly, Pierre Fabre, Provenge, Recordati Int., Takeda. Vincenzo Ficarra was speaker for Intuitive Surgical, Sunnyvale, CA, USA. Giorgio Guazzoni, Francesco Montorsi, and Alexandre Mottrie acknowledge receiving research grants from Intuitive Surgical, Sunnyvale, CA, USA. NR 104 TC 159 Z9 165 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD SEP PY 2012 VL 62 IS 3 BP 382 EP 404 DI 10.1016/j.eururo.2012.05.047 PG 23 WC Urology & Nephrology SC Urology & Nephrology GA 981VM UT WOS:000306999400013 PM 22749851 ER PT J AU McMillan, GP Konrad-Martin, D Dille, MF AF McMillan, Garnett P. Konrad-Martin, Dawn Dille, Marilyn F. TI Accuracy of distortion-product otoacoustic emissions-based ototoxicity monitoring using various primary frequency step-sizes SO INTERNATIONAL JOURNAL OF AUDIOLOGY LA English DT Article DE Distortion-product otoacoustic emissions; ototoxicity monitoring; cisplatin; fine structure ID FINE-STRUCTURE; MODEL AB Objective: A cisplatin ototoxicity monitoring protocol was recently proposed using distortion-product otoacoustic emissions (DPOAEs) measured in 1/48th octave steps over the highest obtainable quarter octave (Dille et al, 2010). This protocol can take up to 40 minutes to complete in both ears among seriously ill patients in a potentially noisy test environment. The goal of the current study was to contrast the diagnostic accuracy of ototoxicity monitoring protocols based on changes in DPOAE levels at wider, more rapidly tested, primary frequency step sizes. Design: Measure DPOAE levels in 1/48th octave steps over the highest half-octave of obtainable DPOAEs prior to treatment and at each ototoxicity monitoring session during the course of treatment with cisplatin. Study sample: Nineteen cancer patients being treated with cisplatin at the Portland Veterans Affairs Medical Center were observed over 56 monitoring appointments. Hearing thresholds in the sensitive region for ototoxicity (SRO) were measured concurrently with DPOAE levels. Results: DPOAE levels measured in 1/24th octave steps provided comparable accuracy, and half the testing time, to the 1/48th octave step protocol previously described. Conclusions: DPOAE level shifts measured in 1/24th octave steps may provide a basis for rapid ototoxicity monitoring among adult cancer patients treated with cisplatin. C1 [McMillan, Garnett P.; Konrad-Martin, Dawn; Dille, Marilyn F.] Portland VA Med Ctr, VA RR&D Natl Ctr Rehabil Auditory Res, Portland, OR 97239 USA. [Konrad-Martin, Dawn; Dille, Marilyn F.] Oregon Hlth & Sci Univ, Dept Otolaryngol HNS, Portland, OR 97201 USA. RP McMillan, GP (reprint author), Portland VA Med Ctr, VA RR&D Natl Ctr Rehabil Auditory Res, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM garnett.mcmillan@va.gov FU Department of Veterans Affairs RRD Service [C4183R, C7113N]; VA RR&D National Center for Rehabilitative Auditory Research, Portland, Oregon, USA FX Work supported by the Department of Veterans Affairs RR&D Service (grants C4183R and C7113N) and the VA RR&D National Center for Rehabilitative Auditory Research, Portland, Oregon, USA. Helpful comments were provided by an anonymous reviewer to an early draft of this paper. NR 15 TC 3 Z9 3 U1 1 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1499-2027 J9 INT J AUDIOL JI Int. J. Audiol. PD SEP PY 2012 VL 51 IS 9 BP 689 EP 696 DI 10.3109/14992027.2012.688143 PG 8 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 986QY UT WOS:000307360500006 PM 22676700 ER PT J AU Brito, LCN Sobrinho, APR Teles, RP Socransky, SS Haffajee, AD Vieira, LQ Teles, FRF AF Brito, L. C. N. Ribeiro Sobrinho, A. P. Teles, R. P. Socransky, S. S. Haffajee, A. D. Vieira, L. Q. Teles, F. R. F. TI Microbiologic profile of endodontic infections from HIV- and HIV plus patients using Multiple-Displacement Amplification and Checkerboard DNA-DNA Hybridization SO ORAL DISEASES LA English DT Article DE endodontic infections; HIV-positive patients; MDA; checkerboard ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUBGINGIVAL MICROBIAL PROFILES; HELICOBACTER-PYLORI INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; CHRONIC PERIODONTITIS; RESPIRATORY PATHOGENS; APICAL PERIODONTITIS; ORAL COLONIZATION; POSITIVE PATIENTS; PLAQUE AB Oral Diseases (2012) 18, 558567 Objective: To compare the microbiota of endodontic infections in necrotic pulp from HIV-negative and HIV-positive subjects. Materials and Methods: Root canal samples from necrotic pulp were collected from 40 HIV- and 20 HIV+ subjects. Pulps were amplified using multiple displacement amplification (MDA). Then, checkerboard DNADNA hybridization was employed to assess the levels of 107 microbial taxa. The percentage of DNA probe count and the percentage of teeth colonized by each test species were investigated. Significant differences between groups regarding proportions of taxa and prevalence of the test species were sought using the MannWhitney test and the Chi-square analysis, respectively. Results: The most prevalent taxa detected were Dialister pneumosintes, Stenotrophomonas maltophilia, Streptococcus sobrinus, Corynebacterium diphteriae, and Helicobacter pylori among HIV- subjects and D. pneumosintes, Prevotella tannerae, Porphyromonas gingivalis, Parvimonas micra, Prevotella nigrescens, and Corynebacterium diphtheriae among HIV+ individuals. D. pneumosintes, C. diphtheria, and C. albicans were the most abundant species in the HIV- group, whereas the predominant taxa in HIV+ samples were P. tannerae, D. pneumosintes and Olsenella uli. P. tannerae, O. uli, Veilonella dispar, Bacteroides fragilis, and Actinomyces meyeri were significantly more abundant in HIV+ samples. Conclusions: There were significant differences in the prevalence and proportions of specific microbial taxa between HIV- and HIV+ individuals. The root canal microbiota may represent a reservoir of important oral and medical pathogens, mainly in HIV+ individuals. C1 [Brito, L. C. N.; Ribeiro Sobrinho, A. P.] Univ Fed Minas Gerais, Dept Operat Dent, Sch Dent, BR-31270901 Belo Horizonte, MG, Brazil. [Teles, R. P.; Socransky, S. S.; Haffajee, A. D.; Teles, F. R. F.] Forsyth Inst, Dept Periodontol, Cambridge, MA USA. [Teles, R. P.; Teles, F. R. F.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Vieira, L. Q.] Univ Fed Minas Gerais, Inst Biol Sci, Dept Biochem & Immunol, BR-31270901 Belo Horizonte, MG, Brazil. RP Sobrinho, APR (reprint author), Univ Fed Minas Gerais, Fac Odontol, Dept Odontol Restauradora, BR-31270901 Belo Horizonte, MG, Brazil. EM sobrinho.bhz@terra.com.br RI Sobrinho, Antonio/H-3245-2012; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; Vieira, Leda/G-7487-2014 FU NIH/NIDCR [R03 DE021742, U01-DE021127]; Eleanor and Miles Shore Fellowship Program for Scholars in Medicine (The Forsyth Institute/Harvard Medical School) FX This work was supported in part by NIH/NIDCR grants R03 DE021742 (FRFT), U01-DE021127 (RPT), the Eleanor and Miles Shore Fellowship Program for Scholars in Medicine (The Forsyth Institute/Harvard Medical School) (FRFT). The authors wish to thank the postgraduate program at the School of Dentistry of UFMG. LCNB is a CAPES fellow; APRS and LQV are CNPq fellows. NR 66 TC 4 Z9 4 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD SEP PY 2012 VL 18 IS 6 BP 558 EP 567 DI 10.1111/j.1601-0825.2012.01908.x PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 986KM UT WOS:000307340500004 PM 22335194 ER PT J AU Luo, AH Yang, DQ Xin, BC Paster, BJ Qin, J AF Luo, A. H. Yang, D. Q. Xin, B. C. Paster, B. J. Qin, J. TI Microbial profiles in saliva from children with and without caries in mixed dentition SO ORAL DISEASES LA English DT Article DE dental caries; saliva; HOMIM; bacteria; isolated population ID BACTERIAL DIVERSITY; ORAL-CAVITY; DENTAL-CARIES; ROOT CARIES; HEALTH; LEPTOTRICHIA; POPULATIONS; MICROFLORA; CREVICE; ADULTS AB Oral Diseases (2012) 18, 595601 Objective: The purpose of this study was to determine the bacterial profiles in saliva of the isolated children for studying caries etiology. Materials and methods: Samples were collected from isolated children from 6 to 8 years old including 20 caries-free (dmfs = 0) (healthy) and 30 caries-active individuals (dmfs > 8) (patients). 16S rRNA genes were amplified by PCR from bacterial DNA of saliva sample and labeled via incorporation of Cy3-dCTP in second nested PCR. After hybridization of labeled amplicons on HOMIM, the microarray slides were scanned and original data acquired from professional software. Results: Collectively, 94 bacterial species or clusters representing six bacterial phyla and 30 genera were detected. A higher bacterial diversity was observed in patients than in healthy samples. Statistical analyses revealed eight species or clusters were detected more frequently in diseased patients than in healthy samples, while six different species were detected more frequently in healthy as compared to diseased patients. Conclusion: The diversity of microbe within saliva derived from isolated population increased in caries-active status, and there are some bacteria in salivary flora can be as candidate biomarkers for caries prognosis in mixed dentition. The imbalances in the resident microflora may be the ultimate mechanism of dental caries. C1 [Yang, D. Q.; Qin, J.] Chongqing Med Univ, Affiliated Stomatol Hosp, Chongqing 401147, Peoples R China. [Luo, A. H.; Xin, B. C.; Qin, J.] Zunyi Med Coll, Affiliated Stomatol Hosp, Zunyi, Guizhou, Peoples R China. [Yang, D. Q.] Chongqing Med Univ, Res Ctr Oral Dis & Biomed Sci, Coll Stomatol, Chongqing 401147, Peoples R China. [Paster, B. J.] Forsyth Inst, Cambridge, MA 02142 USA. [Paster, B. J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Yang, DQ (reprint author), Chongqing Med Univ, Affiliated Stomatol Hosp, Chongqing 401147, Peoples R China. EM yangdeqin@gmail.com FU National Natural Science Foundation of China [30960419, 81170950, S (2007)1044, 2008037] FX We acknowledge the assistance of Sean Cotton in microbial analyses, and that of Di-Cong Wu and Wen-Ming Huang in subject recruitment. This study was supported by the National Natural Science Foundation of China grants 30960419 and 81170950, Guizhou Qian-Ke-He [S (2007)1044], Qian-Jiao-Ke grant 2008037. NR 35 TC 30 Z9 32 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD SEP PY 2012 VL 18 IS 6 BP 595 EP 601 DI 10.1111/j.1601-0825.2012.01915.x PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 986KM UT WOS:000307340500009 PM 22458262 ER PT J AU Zanni, MV Grinspoon, SK AF Zanni, Markella V. Grinspoon, Steven K. TI HIV-Specific Immune Dysregulation and Atherosclerosis SO CURRENT HIV/AIDS REPORTS LA English DT Article DE HIV; Atherosclerosis; Immune dysregulation; Inflammation AB HIV + patients face a heightened risk of cardiovascular disease (CVD), which cannot be fully explained by traditional risk factors or antiretroviral therapy (ART)related cardiotoxicity. Increasing evidence suggests a significant contribution of HIV-specific immune dysregulation to atherosclerosis. HIV-specific immune dysregulation may have the following atherogenic effects: 1) activation of endothelial and immune cells; 2) enhancement of the percentage of circulating atherogenic immune cell subsets; and 3) modification of lipid function. Efforts are underway to link immune dysregulation markers with validated CVD endpoints and to identify genetic predispositions for HIVinduced atherogenesis. Moreover, immune suppressants are under evaluation in HIV + patients to attempt modification of immune-mediated CVD risk. Taken together, these studies will enhance understanding of CVD risk stratification and reduction strategies in HIV. C1 [Zanni, Markella V.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Div Endocrine, Program Nutr Metab, Boston, MA 02114 USA. RP Zanni, MV (reprint author), Massachusetts Gen Hosp, Div Endocrine, Program Nutr Metab, 55 Fruit St 5LON 207, Boston, MA 02114 USA. EM mzanni@partners.org; sgrinspoon@partners.org NR 63 TC 17 Z9 17 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1548-3568 EI 1548-3576 J9 CURR HIV-AIDS REP JI Curr. Hiv/Aids Rep. PD SEP PY 2012 VL 9 IS 3 BP 200 EP 205 DI 10.1007/s11904-012-0123-y PG 6 WC Infectious Diseases SC Infectious Diseases GA V32TU UT WOS:000208974300002 PM 22638983 ER PT J AU Faje, A Klibanski, A AF Faje, Alexander Klibanski, Anne TI Body Composition and Skeletal Health: Too Heavy? Too Thin? SO CURRENT OSTEOPOROSIS REPORTS LA English DT Article DE Obesity; Anorexia nervosa; Osteoporosis; Bone density; Growth hormone; IGF-1; Estrogen; Adipokines; Body composition; Skeletal health AB The relationship between body composition and skeletal metabolism has received growing recognition. Low body weight is an established risk factor for fracture. The effect of obesity on skeletal health is less well defined. Extensive studies in patients with anorexia nervosa and obesity have illuminated many of the underlying biologic mechanisms by which body composition modulates bone mass. This review examines the relationship between body composition and bone mass through data from recent research studies throughout the weight spectrum ranging from anorexia nervosa to obesity. C1 [Faje, Alexander; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, Boston, MA 02114 USA. [Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, 55 Fruit St, Boston, MA 02114 USA. EM afaje@partners.org; aklibanski@partners.org FU NIDDK NIH HHS [R01 DK052625] NR 160 TC 11 Z9 12 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA EI 1544-2241 J9 CURR OSTEOPOROS REP JI Curr. Osteoporos. Rep. PD SEP PY 2012 VL 10 IS 3 BP 208 EP 216 DI 10.1007/s11914-012-0106-3 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V35YT UT WOS:000209181700004 PM 22644889 ER PT J AU Barton, SE Najita, J Ginsburg, ES Diller, LR AF Barton, S. E. Najita, J. Ginsburg, E. S. Diller, L. R. TI INFERTILITY AND THE UTILIZATION OF INFERTILITY TREATMENT IN FEMALE SURVIVORS OF CHILDHOOD CANCER: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS). SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Barton, S. E.; Ginsburg, E. S.] Brigham & Womens Hosp, Div Reprod Med, Boston, MA 02115 USA. [Barton, S. E.; Ginsburg, E. S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Najita, J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Diller, L. R.] Dana Farber Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-25 BP S8 EP S8 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700026 ER PT J AU Colaci, DS Gaskins, AJ Wright, D Petrozza, JC Hauser, R Chavarro, JE AF Colaci, D. S. Gaskins, A. J. Wright, D. Petrozza, J. C. Hauser, R. Chavarro, J. E. TI PROTEIN INTAKE AND EARLY IN-VITRO FERTILIZATION OUTCOMES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Colaci, D. S.; Gaskins, A. J.; Hauser, R.; Chavarro, J. E.] Harvard Sch Publ Hlth, Boston, MA USA. [Wright, D.; Petrozza, J. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-411 BP S234 EP S234 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700775 ER PT J AU Gaskins, AJ Colaci, DS Wright, DL Toth, TL Hauser, R Chavarro, JE AF Gaskins, A. J. Colaci, D. S. Wright, D. L. Toth, T. L. Hauser, R. Chavarro, J. E. TI DIETARY FOLATE INTAKE AND EARLY ASSISTED REPRODUCTIVE TECHNOLOGY OUTCOMES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Gaskins, A. J.; Colaci, D. S.; Hauser, R.; Chavarro, J. E.] Harvard Sch Publ Hlth, Boston, MA USA. [Wright, D. L.; Toth, T. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-154 BP S47 EP S47 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700154 ER PT J AU Gray, KE Schiff, MA Fitzpatrick, AL Starr, JR AF Gray, K. E. Schiff, M. A. Fitzpatrick, A. L. Starr, J. R. TI LEUKOCYTE TELOMERE LENGTH AND AGE AT MENOPAUSE SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Gray, K. E.; Schiff, M. A.; Fitzpatrick, A. L.] Univ Washington, Epidemiol, Seattle, WA 98195 USA. [Starr, J. R.] Forsyth Inst, Ctr Clin & Translat Res, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-144 BP S44 EP S44 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700144 ER PT J AU Iager, AE Kocabas, AM Otu, HH Fernandez, E Cibelli, JB Crosby, JA AF Iager, A. E. Kocabas, A. M. Otu, H. H. Fernandez, E. Cibelli, J. B. Crosby, J. A. TI PREGNANCY OUTCOME FOLLOWING IVF CAN BE PREDICTED BY A GENE EXPRESSION SIGNATURE IN HUMAN CUMULUS CELLS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Iager, A. E.; Cibelli, J. B.; Crosby, J. A.] Gema Diagnost, Ann Arbor, MI USA. [Iager, A. E.; Cibelli, J. B.; Crosby, J. A.] Rockefeller Univ, Lab Dev Neurobiol, 1230 York Ave, New York, NY 10021 USA. [Otu, H. H.] Istanbul Bilgi Univ, Dept Bioengn, Istanbul, Turkey. [Otu, H. H.] Harvard Med Sch, BIDMC Genom Ctr, Dept Med, Boston, MA USA. [Fernandez, E.; Crosby, J. A.] Clin Las Condes, Unidad Med Reprod, Santiago, Chile. [Cibelli, J. B.] Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA. [Cibelli, J. B.] Michigan State Univ, Dept Anim Sci, E Lansing, MI 48824 USA. [Cibelli, J. B.] Consejeria Salud, Lab Andaluz Reprogramac Celular LARCEL, Seville, Andalucia, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-341 BP S101 EP S101 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700337 ER PT J AU Imudia, AN Awonuga, AO Kaimal, AJ Wright, DL Styer, AK Toth, TL AF Imudia, A. N. Awonuga, A. O. Kaimal, A. J. Wright, D. L. Styer, A. K. Toth, T. L. TI ELECTIVE CRYOPRESERVATION OF ALL EMBRYOS WITH INTERVAL CRYOTHAW TRANSFER IN PATIENTS AT RISK FOR OHSS REDUCES THE RISK OF SGA AND PREECLAMPSIA COMPARED TO SIMILAR GROUP OF PATIENTS WITH FRESH TRANSFER. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Imudia, A. N.; Wright, D. L.; Styer, A. K.; Toth, T. L.] Massachusetts Gen Hosp, Fertil Ctr, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Awonuga, A. O.] Wayne State Univ, Sch Med, Div Reprod Endocrinol & Infertil, Detroit, MI USA. [Kaimal, A. J.] Vincent Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-246 BP S184 EP S184 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700614 ER PT J AU Imudia, AN Dimitriadis, I Petrozza, JC Souter, I AF Imudia, A. N. Dimitriadis, I. Petrozza, J. C. Souter, I. TI A SHORTER FOLLICULAR PHASE DOES NOT HAVE A DELETERIOUS EFFECT ON THE OUTCOME OF OVULATION INDUCTION/INTRAUTERINE INSEMINATION (OI/IUI) CYCLES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Imudia, A. N.; Dimitriadis, I.; Petrozza, J. C.; Souter, I.] Massachusetts Gen Hosp, Fertil Ctr, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-12 BP S4 EP S4 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700013 ER PT J AU Souter, I Smith, KW Dimitriadis, I Williams, PL Ford, JB Hauser, R AF Souter, I. Smith, K. W. Dimitriadis, I. Williams, P. L. Ford, J. B. Hauser, R. TI ASSOCIATION OF URINARY PHTHALATE (P) METABOLITE CONCENTRATIONS WITH OVARIAN RESPONSE AMONG PATIENTS UNDERGOING OVULATION INDUCTION/INTRAUTERINE INSEMINATION (OI/IUI). SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Souter, I.; Dimitriadis, I.; Ford, J. B.; Hauser, R.] Harvard Med Sch, Massachusetts Gen Hosp, Obstet Gynecol Reprod Endocrinol & Infertil Div, Boston, MA USA. [Smith, K. W.; Dimitriadis, I.; Ford, J. B.; Hauser, R.] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Williams, P. L.] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-108 BP S33 EP S34 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700109 ER PT J AU Thakur, M Imudia, AN Shavell, VI Singh, M Diamond, MP Awonuga, AO AF Thakur, M. Imudia, A. N. Shavell, V. I. Singh, M. Diamond, M. P. Awonuga, A. O. TI SHOULD BODY MASS INDEX INFLUENCE THE DOSE OF hCG FOR OVULATION INDUCTION AFTER SUPEROVULATION IN IVF/ICSI CYCLES? SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Thakur, M.; Shavell, V. I.; Singh, M.; Diamond, M. P.; Awonuga, A. O.] Wayne State Univ, Div Reprod Endocrinol & Infertil, Detroit, MI USA. [Imudia, A. N.] Massachusetts Gen Hosp, Fertil Ctr, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-542 BP S271 EP S272 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700899 ER PT J AU Caspi, CE Sorensen, G Subramanian, SV Kawachi, I AF Caspi, Caitlin E. Sorensen, Glorian Subramanian, S. V. Kawachi, Ichiro TI The local food environment and diet: A systematic review SO HEALTH & PLACE LA English DT Review DE Food environment; Diet; Measurement; GIS; Survey; Neighborhood ID VEGETABLE CONSUMPTION; NUTRITION ENVIRONMENTS; ATHEROSCLEROSIS RISK; INFORMATION-SYSTEMS; NEIGHBORHOOD ACCESS; STORE AVAILABILITY; BUILT ENVIRONMENTS; AFRICAN-AMERICANS; FRUIT; OBESITY AB Despite growing attention to the problem of obesogenic environments, there has not been a comprehensive review evaluating the food environment-diet relationship. This study aims to evaluate this relationship in the current literature, focusing specifically on the method of exposure assessment (GIS, survey, or store audit). This study also explores 5 dimensions of "food access" (availability, accessibility, affordability, accommodation, acceptability) using a conceptual definition proposed by Penchansky and Thomas (1981). Articles were retrieved through a systematic keyword search in Web of Science and supplemented by the reference lists of included studies. Thirty-eight studies were reviewed and categorized by the exposure assessment method and the conceptual dimensions of access it captured. GIS-based measures were the most common measures, but were less consistently associated with diet than other measures. Few studies examined dimensions of affordability, accommodation, and acceptability. Because GIS-based measures on their own may not capture important non-geographic dimensions of access, a set of recommendations for future researchers is outlined. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Caspi, Caitlin E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02114 USA. [Caspi, Caitlin E.; Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Caspi, CE (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Kresge 7th Floor,677 Huntington Ave, Boston, MA 02114 USA. EM caitlincaspi@gmail.com FU NCI NIH HHS [K05 CA108663] NR 67 TC 170 Z9 172 U1 16 U2 85 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 EI 1873-2054 J9 HEALTH PLACE JI Health Place PD SEP PY 2012 VL 18 IS 5 BP 1172 EP 1187 DI 10.1016/j.healthplace.2012.05.006 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 991VH UT WOS:000307730300030 PM 22717379 ER PT J AU Emmons, KM Puleo, E Viswanath, V Gillman, MW Bennett, GG Haines, J Sprunck-Harrild, K Greaney, M AF Emmons, K. M. Puleo, E. Viswanath, V. Gillman, M. W. Bennett, G. G. Haines, J. Sprunck-Harrild, K. Greaney, M. TI COMPARATIVE EFFECTIVENESS OF HEALTHY DIRECTIONS-2, A MULTIPLE RISK FACTOR INTERVENTION FOR PRIMARY CARE SETTINGS SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE Cancer; Health Behavior Change C1 [Emmons, K. M.; Viswanath, V.; Sprunck-Harrild, K.; Greaney, M.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Puleo, E.] Univ Massachusetts, Sch Publ Hlth, Amherst, MA 01003 USA. [Gillman, M. W.] Harvard Sch Publ Hlth, SPH Nutr, Boston, MA USA. [Gillman, M. W.] HMS Populat, Boston, MA USA. [Bennett, G. G.] Duke Univ, Psychol & Neurosci, Durham, NC 27706 USA. [Haines, J.] Univ Guelph, Family Relat & Appl Nutr, Guelph, ON, Canada. EM karen_m_emmons@dfci.harvard.edu 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 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA O208 BP S83 EP S84 PG 2 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000203 ER PT J AU Freedland, KE Burg, MM Chait, S Steinmeyer, BC AF Freedland, K. E. Burg, M. M. Chait, S. Steinmeyer, B. C. TI EFFECTS OF DEPRESSION AND LOW PERCEIVED SOCIAL SUPPORT ON MEDICATION ADHERENCE AFTER ACUTE MYOCARDIAL INFARCTION SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE Adherence; Coronary heart disease; Depression; Social support C1 [Freedland, K. E.; Steinmeyer, B. C.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. [Burg, M. M.] Yale Univ, Sch Med, Sect Cardiovasc Med, New Haven, CT USA. [Chait, S.] VA Boston Healthcare Syst, Boston, MA USA. EM freedlak@bmc.wustl.edu 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 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA O235 BP S94 EP S95 PG 2 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000230 ER PT J AU Okvat, HA Okun, MA Davis, MC Zautra, AJ Knopf, RC AF Okvat, H. A. Okun, M. A. Davis, M. C. Zautra, A. J. Knopf, R. C. TI A PILOT STUDY OF THE BENEFITS OF TRADITIONAL AND MINDFUL COMMUNITY GARDENING FOR HEALTHY AGING AMONG URBAN OLDER ADULTS SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE aging; community intervention; health promotion; mindfulness; mood; older adults; quality of life; resilience; social support C1 [Okvat, H. A.] VA Boston Healthcare Syst, Behav Med, Boston, MA USA. [Okun, M. A.; Davis, M. C.; Zautra, A. J.] Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. [Knopf, R. C.] Arizona State Univ, Osher Lifelong Learning Inst, Sch Community Resources & Dev, Phoenix, AZ USA. EM heather.okvat@asu.edu 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 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA P23 BP S13 EP S13 PG 1 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000033 ER PT J AU Tercyak, K Patenaude, A AF Tercyak, K. Patenaude, A. TI PRELIMINARY OUTCOMES OF A RANDOMIZED CONTROLLED TRIAL TO INFORM MATERNAL DECISIONS ABOUT COMMUNICATING CANCER GENETIC TEST RESULTS TO CHILDREN SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE Decision making; Genetics; Children; Family C1 [Tercyak, K.] Georgetown Univ, Dept Oncol, Washington, DC USA. [Patenaude, A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM tercyakk@georgetown.edu 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 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA S252 BP S101 EP S102 PG 2 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000246 ER PT J AU Anaya, HD Bokhour, B Feld, J Golden, JF Asch, SM Knapp, H AF Anaya, Henry D. Bokhour, Barbara Feld, Jamie Golden, Joya F. Asch, Steven M. Knapp, Herschel TI Implementation of Routine Rapid HIV Testing Within the US Department of Veterans Affairs Healthcare System SO JOURNAL FOR HEALTHCARE QUALITY LA English DT Article DE rapid HIV testing; nurse-initiated health interventions; implementation; evaluation AB Current HIV testing methods can be ineffective; patients often do not return for results. HIV rapid testing (RT) provides accurate results in 20 min. Patients find nurse-initiated HIV rapid testing (NRT) more acceptable than current testing methods and increases receipt of test results. Translating research findings into sustainable practice poses widely recognized implementation challenges. To ascertain effectiveness of NRT implementation, formative and process evaluations were conducted within the U. S. Department of Veterans Affairs Healthcare System (VA). Nurses and physicians at 2 VA medical centers were trained to administer RT. A preimplementation formative evaluation was conducted at Site 1. Process evaluations of ongoing RT activities were conducted at Site 2. Interviews were conducted with key informants. Content and thematic analysis was conducted on the field notes. A variety of barriers and facilitators were discovered that impacted the implementation of NRT. Findings indicate concerns regarding training and incorporating NRT into workflow. Process interviews indicated that training concerns could be alleviated through various means. Finally, interviewees highlighted that other clinic settings might be a more preferred setting for NRT than primary care. Findings are currently being used for the implementation of additional NRT interventions, and can also guide NRT adoption in other facilities. C1 [Anaya, Henry D.] US Dept Vet Affairs VA, West Los Angeles, CA USA. [Anaya, Henry D.] Univ Calif Los Angeles, Dept Biobehav Sci, Neuropsychiat Inst, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Ctr HIV Prevent & Treatment Serv, Los Angeles, CA 90024 USA. [Anaya, Henry D.; Golden, Joya F.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bokhour, Barbara] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Bokhour, Barbara] US Dept Vet Affairs, Ctr Hlth Qual, Bedford, MA USA. [Feld, Jamie; Golden, Joya F.; Asch, Steven M.] US Dept Vet Affairs, West Los Angeles, CA USA. [Feld, Jamie] United Nations Observ Urbano, Cordoba, Argentina. [Asch, Steven M.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Asch, Steven M.] Robert Wood Johnson Clin Scholars Program, Chapel Hill, NC USA. RP Anaya, HD (reprint author), US Dept Vet Affairs VA, West Los Angeles, CA USA. EM henry.anaya@va.gov OI Bokhour, Barbara/0000-0001-8238-0745 FU VHA FX The authors would like to thank B. Lane Turzan, Brenda Rue, Rebecca Jones, and Alicia Alcantara for their assistance on this project. We would also like to acknowledge Jaimi Butler for her substantive review and editorial suggestions and comments. The views and opinions expressed in this article are those of the author(s) and do not necessarily represent the views of the U.S. Department of Veterans Affairs. The VHA supported this study but had no input in the design or reporting, or decision to submit this paper for publication. This study was reviewed and sanctioned by a U.S. Department of Veterans Affairs Internal Review Board (IRB) process. NR 18 TC 11 Z9 11 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1062-2551 EI 1945-1474 J9 J HEALTHC QUAL JI J. Healthc. Qual. PD SEP-OCT PY 2012 VL 34 IS 5 BP 7 EP 14 DI 10.1111/j.1945-1474.2011.00151.x PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA V36OP UT WOS:000209221300001 PM 22060061 ER PT J AU Keuthen, NJ Rothbaum, BO Fama, J Altenburger, E Falkenstein, MJ Sprich, SE Kearns, M Meunier, S Jenike, MA Welch, SS AF Keuthen, Nancy J. Rothbaum, Barbara O. Fama, Jeanne Altenburger, Erin Falkenstein, Martha J. Sprich, Susan E. Kearns, Megan Meunier, Suzanne Jenike, Michael A. Welch, Stacy S. TI DBT-enhanced cognitive-behavioral treatment for trichotillomania: A randomized controlled trial SO JOURNAL OF BEHAVIORAL ADDICTIONS LA English DT Article DE trichotillomania; hair pulling; cognitive-behavioral treatment; dialectical behavior therapy AB Background and aims: Limited treatment options are available for trichotillomania (TTM) and most have modest outcomes. Suboptimal treatment results may be due to the failure of existing approaches to address all TTM styles. Methods: Thirty-eight DSM-IV TTM participants were randomly assigned across two study sites to Dialectical Behavior Therapy (DBT) -enhanced cognitive-behavioral treatment (consisting of an 11-week acute treatment and 3-month maintenance treatment) or a minimal attention control (MAC) condition. MAC participants had active treatment after the 11-week control condition. Follow-up study assessments were conducted three and six months after the maintenance period. Results: Open trial treatment resulted in significant improvement in TTM severity, emotion regulation (ER) capacity, experiential avoidance, anxiety and depression with changes generally maintained over time. In the randomized controlled trial, those with active treatment had greater improvement than those in the MAC condition for both TTM severity and ER capacity. Correlations between changes in TTM severity and ER capacity were not reported at post-treatment but did occur in maintenance and follow-up indicating reduced TTM severity with improved ER capacity. Conclusions: DBT-enhanced cognitive-behavioral treatment is a promising treatment for TTM. Future studies should compare this approach to other credible treatment interventions and investigate the efficacy of this approach in more naturalistic samples with greater comorbidity. C1 [Keuthen, Nancy J.; Fama, Jeanne; Altenburger, Erin; Sprich, Susan E.; Jenike, Michael A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Rothbaum, Barbara O.; Kearns, Megan] Emory Univ, Sch Med, Atlanta, GA USA. [Falkenstein, Martha J.] Amer Univ, Washington, DC 20016 USA. [Meunier, Suzanne] Anxiety Treatment Ctr Northwest Arkansas, Fayetteville, AR USA. [Welch, Stacy S.] Univ Washington, Anxiety & Stress Reduct Ctr, Seattle, WA 98195 USA. RP Keuthen, NJ (reprint author), Massachusetts Gen Hosp, Trichotillomania Clin & Res Unit, Simches Res Bldg,Fl 2,185 Cambridge St, Boston, MA 02114 USA. EM nkeuthen@partners.org OI Falkenstein, Martha/0000-0001-5074-3409 FU David Judah Fund FX We gratefully acknowledge the David Judah Fund for its financial support of this research. We wish to recognize study staff including Michelle Hammond-Susten and Mary Heekin who assisted with clinical assessments and Amanda Allen, Mark Burton, Elizabeth Loerke, Lillian Reuman, Anne Wilson, as well as Cole Youngner, who helped with data collection and entry. We greatly appreciate the helpful comments of Dr. Martin Franklin in the early stages of study development. Lastly, we express our heartfelt thanks to all study participants and to Christina Pearson, Jennifer Raikes, Leslie Lee and other staff at the Trichotillomania Learning Center for their assistance with study recruitment. NR 27 TC 22 Z9 22 U1 1 U2 7 PU AKADEMIAI KIADO RT PI BUDAPEST PA PRIELLE K U 19, PO BOX 245,, H-1117 BUDAPEST, HUNGARY SN 2062-5871 EI 2063-5303 J9 J BEHAV ADDICT JI J. Behav. Addict. PD SEP PY 2012 VL 1 IS 3 BP 106 EP 114 DI 10.1556/JBA.1.2012.003 PG 9 WC Psychiatry SC Psychiatry GA V32YJ UT WOS:000208986200003 PM 26165460 ER PT J AU Burney, BO Garcia, JM AF Burney, Basil O. Garcia, Jose M. TI Hypogonadism in male cancer patients SO JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE LA English DT Review DE Inflammation; Leptin; Ghrelin; Cachexia; Sarcopenia ID GONADOTROPIN-RELEASING-HORMONE; ANDROGEN REPLACEMENT THERAPY; QUALITY-OF-LIFE; LUTEINIZING-HORMONE; SEXUAL FUNCTION; TESTOSTERONE LEVELS; BODY-COMPOSITION; ORAL OPIOIDS; AGING MALES; HEALTHY-MEN AB Prevalence of hypogonadism in men with cancer has been reported between 40% and 90%, which is significantly higher than in the general population. Hypogonadism is likely to affect the quality of life in these patients by contributing to non-specific symptoms, including decreased energy, anorexia, sarcopenia, weight loss, depression, insomnia, fatigue, weakness, and sexual dysfunction. Pathogenesis of hypogonadism in cancer patients is thought to be multi-factorial. Inflammation may play an important role, but leptin, opioids, ghrelin, and high-dose chemotherapy through different mechanisms have all been implicated as the cause. Hypogonadism is also associated with poor survival in cancer patients. Data looking into the treatment of hypogonadal male cancer patients with testosterone are limited. However, improvements in body weight, muscle strength, lean body mass, and quality of life have been shown in hypogonadal men with other chronic diseases on testosterone replacement therapy. Prospective and interventional trials are needed to test the efficacy and safety of testosterone treatment in improving quality of life of these patients. C1 [Burney, Basil O.; Garcia, Jose M.] Baylor Coll Med, Div Endocrinol Diabet & Metab, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Garcia, JM (reprint author), Baylor Coll Med, Div Endocrinol Diabet & Metab, Michael E DeBakey Vet Affairs Med Ctr, 2002 Holcombe Blvd,Bldg 109,Rm 210, Houston, TX 77030 USA. EM jgarcia1@bcm.edu FU Abbott FX JMG receives research support from and is a consultant with Abbott. NR 60 TC 12 Z9 12 U1 0 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2190-5991 J9 J CACHEXIA SARCOPENI JI J. Caxhexia Sarcopenia Muscle PD SEP PY 2012 VL 3 IS 3 BP 149 EP 155 DI 10.1007/s13539-012-0065-7 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 218WO UT WOS:000324463400002 PM 22528986 ER PT J AU Mifflin, J AF Mifflin, Jeffrey TI DECOLONIZING INDIGENOUS HISTORIES: Exploring Prehistoric/Colonial Transitions in Archaeology SO JOURNAL OF THE WEST LA English DT Book Review C1 [Mifflin, Jeffrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mifflin, J (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ABC-CLIO PI SANTA BARBARA PA 130 CREMONA DR, SANTA BARBARA, CA 93117 USA SN 0022-5169 EI 1930-0115 J9 J WEST JI J. West PD FAL PY 2012 VL 51 IS 4 BP 92 EP 92 PG 1 WC History SC History GA V35UY UT WOS:000209174600026 ER PT J AU Ratcliffe, TA Durning, SJ Jena, AB Grau, T Artino, AR Arora, VM Hauer, KE Borges, N Oriol, N Elnicki, DM Fagan, MJ Harrell, HE Torre, DM Prochaska, M Meltzer, DO Reddy, S AF Ratcliffe, Temple A. Durning, Steven J. Jena, Anupam B. Grau, Thomas Artino, Anthony R., Jr. Arora, Vineet M. Hauer, Karen E. Borges, Nicole Oriol, Nancy Elnicki, D. Michael Fagan, Mark J. Harrell, Heather E. Torre, Dario M. Prochaska, Meryl Meltzer, David O. Reddy, Shalini TI Postinterview Communication Between Military Residency Applicants and Training Programs SO MILITARY MEDICINE LA English DT Article AB Purpose: Each year military medical students participate in a separate, military match culminating with the Joint Services Graduate Medical Education Selection Board (JSGMESB). Prior studies have explored postinterview communication that occurs during the National Resident Matching Program (NRMP), but not during the JSGMESB. examined the frequency and nature of communication during the JSGMESB and compared it with the NRMP. Methods: Cross-sectional survey study of senior students conducted at Uniformed Services University of the Health Sciences (USU) and seven civilian U.S. medical schools during March to May 2010. Respondents answered questions regarding communication with residency programs during the match. Results: Significantly fewer USU respondents communicated with programs compared with the civilian cohort (54.1% vs. 86.4%, p < 0.01). Specific inquiries regarding rank order were more commonly experienced by USU respondents compared with civilians (17.5% vs. 4.8%, p = 0.02). USU respondents found postinterview communication both helpful (41.3%) and stressful (41.3%). 11.1% of USU respondents indicated that they moved a program higher on their final rank lists because of further communication with these programs. Conclusions: Postinterview communication during the JSGMESB process is less common and less stressful than that reported in the NRMP. USU respondents are more likely to be asked directly about their rank list and occasionally do change their lists. Uniform guidance mirroring the NRMP's dealing with direct inquiries about rank lists could potentially improve the process. C1 [Ratcliffe, Temple A.; Durning, Steven J.; Grau, Thomas; Artino, Anthony R., Jr.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Jena, Anupam B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Arora, Vineet M.; Prochaska, Meryl; Meltzer, David O.; Reddy, Shalini] Univ Chicago, Pritzker Sch Med, Dept Med, Chicago, IL 60637 USA. [Hauer, Karen E.] Univ San Francisco, Sch Med, San Francisco, CA 94122 USA. [Borges, Nicole] Wright State Univ, Acad Affairs, Boonshoft Sch Med, Dept Community Hlth, Dayton, OH 45435 USA. [Oriol, Nancy] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Elnicki, D. Michael; Torre, Dario M.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA. [Fagan, Mark J.] Brown Univ, Warren Alpert Sch Med, Dept Med, Providence, RI 02912 USA. [Harrell, Heather E.] Univ Florida, Coll Med, Dept Med, Gainesville, FL 32603 USA. RP Ratcliffe, TA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. RI Meltzer, David/C-2926-2009; OI Meltzer, David/0000-0003-2790-7393; Artino, Anthony/0000-0003-2661-7853 FU Department of Medicine at the University of Chicago FX This study was funded by the Department of Medicine at the University of Chicago. NR 5 TC 3 Z9 3 U1 0 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD SEP PY 2012 VL 177 IS 9 SU S SI SI BP 54 EP 60 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA V33OD UT WOS:000209027200013 PM 23029863 ER PT J AU Gadermann, AM Gilman, SE McLaughlin, KA Nock, MK Petukhova, M Sampson, NA Kessler, RC AF Gadermann, Anne M. Gilman, Stephen E. McLaughlin, Katie A. Nock, Matthew K. Petukhova, Maria Sampson, Nancy A. Kessler, Ronald C. TI Projected Rates of Psychological Disorders and Suicidality Among Soldiers Based on Simulations of Matched General Population Data SO MILITARY MEDICINE LA English DT Article AB Limited data are available on lifetime prevalence and age-of-onset distributions of psychological disorders and suicidal behaviors among Army personnel. We used simulation methods to approximate such estimates based on analysis of data from a U.S. national general population survey with the sociodemographic profile of U.S. Army personnel. Estimated lifetime prevalence of any Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) anxiety, mood, behavior, or substance disorder in this sample was 53.1% (17.7% for mood disorders, 27.2% for anxiety disorders, 22.7% for behavior disorders, and 14.4% for substance disorders). The vast majority of cases had onsets before the expected age of enlistment if they were in the Army (91.6%). Lifetime prevalence was 14.2% for suicidal ideation, 5.4% for suicide plans, and 4.5% for suicide attempts. The proportion of estimated pre-enlistment onsets was between 68.4% (suicide plans) and 82.4% (suicidal ideation). Externalizing disorders with onsets before expected age of enlistment and internalizing disorders with onsets after expected age of enlistment significantly predicted postenlistment suicide attempts, with population attributable risk proportions of 41.8% and 38.8%, respectively. Implications of these findings are discussed for interventions designed to screen, detect, and treat psychological disorders and suicidality in the Army. C1 [Gadermann, Anne M.] Univ British Columbia, St Pauls Hosp, Ctr Hlth Evaluat & Outcome Sci, Vancouver, BC V6Z 1Y6, Canada. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [McLaughlin, Katie A.] Childrens Hosp Boston, Div Gen Pediat, Boston, MA 02115 USA. [McLaughlin, Katie A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Petukhova, Maria; Sampson, Nancy A.; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Gadermann, AM (reprint author), Univ British Columbia, St Pauls Hosp, Ctr Hlth Evaluat & Outcome Sci, 620B-1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. RI Gilman, Stephen/E-7632-2010; OI Gilman, Stephen/0000-0002-8331-6419; McLaughlin, Katie/0000-0002-1362-2410 FU Department of the Army [U01MH087981]; U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) FX This study was supported by the Department of the Army and funded under cooperative agreement number U01MH087981 with the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). NR 30 TC 9 Z9 9 U1 1 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD SEP PY 2012 VL 177 IS 9 BP 1002 EP 1010 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA V33OC UT WOS:000209027100002 PM 23025127 ER PT J AU Sheth, RA Kunin, A Stangenberg, L Sinnamon, M Hung, KE Kucherlapati, R Mahmood, U AF Sheth, Rahul A. Kunin, Alexandra Stangenberg, Lars Sinnamon, Mark Hung, Kenneth E. Kucherlapati, Raju Mahmood, Umar TI In Vivo Optical Molecular Imaging of Matrix Metalloproteinase Activity following Celecoxib Therapy for Colorectal Cancer SO MOLECULAR IMAGING LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MULTIPLE INTESTINAL NEOPLASIA; COLON-CARCINOMA CELLS; MIN MOUSE MODEL; CYCLOOXYGENASE-2 INHIBITOR; ADENOMATOUS POLYPOSIS; ASPIRIN USE; PREVENTION; GROWTH; CHEMOPREVENTION AB We present an optical molecular imaging approach to measure the efficacy of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on tumor growth rate through its effect on matrix metalloproteinase (MMP) activity. A xenograft model of colorectal cancer was generated in nude mice, which were then randomized to receive celecoxib versus vehicle. MMP activity was measured by an enzyme-activatable optical molecular probe. A novel genetically engineered mouse (GEM) model of colorectal cancer was also used to assess celecoxib's effect on MMP activity, which was measured by quantitative fluorescence colonoscopy. Subcutaneously implanted xenograft tumors were 84% (SD 20.2%) smaller in volume in the treatment group versus the control group. Moreover, treated animals exhibited only a 7.6% (SEM 9%) increase in MMP activity versus 106% (SEM 8%) for untreated animals. There was an apparent linear relationship (r = .91) between measured MMP activity and tumor growth rate. Finally, in the GEM model experiment, treated murine tumors remained relatively unchanged in volume and MMP activity; however, untreated tumors grew significantly and showed an increase in MMP activity. This method may provide for the improved identification of patients for whom COX-2 inhibition therapy is indicated by allowing one to balance the patient's cardiovascular risk with the cancer's responsiveness to celecoxib. C1 [Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Tufts Med Sch, Dept Gastroenterol, Boston, MA USA. RP Mahmood, U (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, 55 Fruit St,White 427, Boston, MA 02114 USA. EM mahmood@helix.mgh.harvard.edu FU National Institute of Health [P50CA127003, U01CA084301] FX This work was supported by National Institute of Health Grants P50CA127003 and U01CA084301. NR 42 TC 7 Z9 7 U1 0 U2 4 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 J9 MOL IMAGING JI Mol. Imaging PD SEP-OCT PY 2012 VL 11 IS 5 BP 417 EP 425 DI 10.2310/7290.2012.00003 PG 9 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA 220JT UT WOS:000324579900008 PM 22954186 ER PT J AU Erickson, JI Ditomassi, M Adams, JM AF Erickson, Jeanette Ives Ditomassi, Marianne Adams, Jeffrey M. TI Attending Registered Nurse: An Innovative Role to Manage Between the Spaces SO NURSING ECONOMICS LA English DT Article AB Massachusetts General Hospital embarked on the implementation of a new model that redesigned the role of selected staff nurses, advanced standardized processes, improved workflow, and introduced technology to enhance communication. These efforts included selecting 12 inpatient units to function as "Innovation Units." These units were specifically designated to support rapid change and test initiatives that would reduce costs and improve quality. The work of the Innovation Units allows nurse leaders to understand if the goals for improvement could be adopted by all inpatient units and beyond the walls of the hospital. The high-leverage intervention of introducing the role of the "Attending Nurse" in coordinating the work of the interdisciplinary team in addressing overuse, underuse, and misuse of services has been a significant staffing innovation. The Attending Nurse, while just one strategy, has placed the nurse at the center of the care team. C1 [Erickson, Jeanette Ives; Ditomassi, Marianne; Adams, Jeffrey M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Erickson, JI (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 9 TC 4 Z9 4 U1 0 U2 0 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD SEP-OCT PY 2012 VL 30 IS 5 BP 282 EP 287 PG 6 WC Nursing SC Nursing GA V35RQ UT WOS:000209166400008 PM 23198611 ER PT J AU Sayegh, RR Pineda, R AF Sayegh, Rony R. Pineda, Roberto, II TI Practical Applications of Anterior Segment Optical Coherence Tomography Imaging Following Corneal Surgery SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Corneal surgery; Cornea; Ocular imaging; Optical coherence tomography ID IN-SITU KERATOMILEUSIS; COLLAGEN CROSS-LINKING; DESCEMET MEMBRANE DETACHMENT; SWEPT SOURCE OCT; PENETRATING KERATOPLASTY; LAMELLAR KERATOPLASTY; LASIK FLAP; ENDOTHELIAL KERATOPLASTY; SECONDARY GLAUCOMA; INTERFACE FLUID AB Anterior segment optical coherence tomography (AS-OCT) has recently emerged as an important modality for imaging of the cornea. Since its introduction less than a decade ago, it has been clinically used for the diagnosis and management of an expanding number of corneal conditions. In this review, we will discuss the applications of anterior segment optical coherence tomography after corneal surgery, focusing on penetrating and lamellar keratoplasty, keratoprosthesis, intracorneal ring segments, collagen cross-linking and refractive surgery. Anterior segment optical coherence tomography is useful in evaluating outcomes, detecting adverse events, determining prognosis, guiding management decisions, and surgical planning. C1 [Sayegh, Rony R.; Pineda, Roberto, II] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Pineda, R (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Roberto_Pineda@meei.harvard.edu RI Sayegh, Rony/G-8777-2013 OI Sayegh, Rony/0000-0002-0119-4201 NR 82 TC 7 Z9 7 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 125 EP 132 DI 10.3109/08820538.2012.707274 PG 8 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600007 PM 23163266 ER PT J AU Luo, ZHK Jacobs, DS AF Luo, Zhonghui K. Jacobs, Deborah S. TI Current and Potential Applications of Anterior Segment Optical Coherence Tomography in Contact Lens Fitting SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Anterior segment OCT; Topography; Scleral lens; Contact lens; Ocular surface ID DOMAIN MODE-LOCKING; VERSUS-HOST-DISEASE; BOSTON SCLERAL LENS; SWEPT SOURCE OCT; CORNEAL TOPOGRAPHY; IN-VIVO; LASER; EYE; GLAUCOMA; REFLECTOMETRY AB Optical coherence tomography (OCT) is a non-invasive, high-resolution and high-speed imaging modality that has enjoyed rapid growth in ophthalmology since its development 20 years ago. Contact lens fitting is traditionally based on trial lenses, which is expensive and time-consuming. Modern anterior segment OCT is capable of generating three-dimensional ocular surface maps of the cornea and sclera with potential application in contact lens fitting. This paper reviewed the history, the ophthalmic applications, and the most recent advancement in three-dimensional anterior segment OCT. There is very limited literature of OCT in contact lens fitting to date. This review anticipates an increase in this application in the near future. C1 [Jacobs, Deborah S.] Boston Fdn Sight, Needham, MA 02494 USA. [Luo, Zhonghui K.; Jacobs, Deborah S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Jacobs, DS (reprint author), Boston Fdn Sight, 464 Hillside Ave,Suite 205, Needham, MA 02494 USA. EM djacobs@bostonsight.org NR 59 TC 4 Z9 4 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 133 EP 137 DI 10.3109/08820538.2012.708814 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600008 PM 23163267 ER PT J AU Alhatem, A Cavalcanti, B Hamrah, P AF Alhatem, Albert Cavalcanti, Bernardo Hamrah, Pedram TI In Vivo Confocal Microscopy in Dry Eye Disease and Related Conditions SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Ocular surface; Meibomian gland; Nerves; Dry eye disease; In vivo confocal microscopy ID MEIBOMIAN GLAND DYSFUNCTION; PRIMARY SJOGRENS-SYNDROME; CORNEAL NERVES; DIABETIC-PATIENTS; MORPHOLOGY; LASIK; REGENERATION; SENSITIVITY; INVOLVEMENT; DIAGNOSIS AB A new era of ocular imaging has recently begun with the advent of in vivo confocal microscopy (IVCM), shedding more light on the pathophysiology, diagnosis, and potential treatment strategies for dry eye disease. IVCM is a noninvasive and powerful tool that allows detection of changes in ocular surface epithelium, immune and inflammatory cells, corneal nerves, keratocytes, and meibomian gland structures on a cellular level. Ocular surface structures in dry eye-related conditions have been assessed and alterations have been quantified using IVCM. IVCM may aid in the assessment of dry eye disease prognosis and treatment, as well as lead to improved understanding of the pathophysiological mechanisms in this complex disease. Further, due to visualization of subclinical findings, IVCM may allow detection of disease at much earlier stages and allow stratification of patients for clinical trials. Finally, by providing an objective methodology to monitor treatment efficacy, image-guided therapy may allow the possibility of tailoring treatment based on cellular changes, rather than on clinical changes alone. C1 [Alhatem, Albert; Cavalcanti, Bernardo; Hamrah, Pedram] Harvard Univ, Massachusetts Eye & Ear Infirm, Ocular Surface Imaging Ctr, Cornea & Refract Surg Serv,Dept Ophthalmol,Med Sc, Boston, MA USA. RP Hamrah, P (reprint author), Massachusetts Eye & Ear Infirm, Ocular Surface Imaging Ctr, Cornea Serv, 243 Charles St, Boston, MA 02114 USA. EM pedram_hamrah@meei.harvard.edu FU NEI NIH HHS [L30 EY021919, K08 EY020575] NR 36 TC 29 Z9 29 U1 0 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 138 EP 148 DI 10.3109/08820538.2012.711416 PG 11 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600009 PM 23163268 ER PT J AU Kronberg, BP Rhee, DJ AF Kronberg, Benjamin P. Rhee, Douglas J. TI Anterior Segment Imaging and the Intraocular Pressure Lowering Effect of Cataract Surgery for Open and Narrow Angle Glaucoma SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Anterior segment optical coherence tomography (OCT); Cataract extraction; Intraocular pressure; Narrow angle glaucoma; Open angle glaucoma; Plateau iris syndrome; Ultrasound biomicroscopy (UBM) ID OPTICAL COHERENCE TOMOGRAPHY; CLEAR CORNEAL PHACOEMULSIFICATION; CHAMBER LENS IMPLANTATION; PLATEAU IRIS SYNDROME; ULTRASOUND BIOMICROSCOPY; NONGLAUCOMATOUS EYES; PSEUDOEXFOLIATION SYNDROME; CLOSURE GLAUCOMA; FOLLOW-UP; EXTRACTION AB Anterior segment imaging modalities including anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) are increasingly widespread, and can quantify several parameters of the anterior segment, such as anterior chamber depth and angle anatomy. These parameters are important to assess, particularly in patients with forms of narrow angle glaucoma. In many cases of open and narrow angle glaucoma, cataract extraction has been shown to result in favorable modification of these parameters, and a lasting decrease in intraocular pressure. Anterior segment imaging has the ability to enable the development of predictive models regarding the potential intraocular pressure lowering effect of cataract extraction in a given individual. C1 [Kronberg, Benjamin P.; Rhee, Douglas J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02115 USA. RP Kronberg, BP (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02115 USA. EM bkronberg@gmail.com NR 55 TC 2 Z9 2 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 149 EP 154 DI 10.3109/08820538.2012.708810 PG 6 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600010 PM 23163269 ER PT J AU Golez, E Latina, M AF Golez, Ernesto, III Latina, Mark TI The Use of Anterior Segment Imaging after Trabeculectomy SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Anterior segment optical coherence tomography; Eye; Glaucoma; Ultrasound biomicroscopy ID OPTICAL COHERENCE TOMOGRAPHY; ANGLE-CLOSURE GLAUCOMA; LASER SUTURE LYSIS; ULTRASOUND BIOMICROSCOPY; FILTERING BLEBS; SUPRACILIOCHOROIDAL FLUID; INTRAOCULAR-PRESSURE; MALIGNANT GLAUCOMA; EYES; SURGERY AB Evaluation of patients after trabeculectomy can be aided by the use of anterior segment imaging. Two commonly used forms of imaging are ultrasound biomicroscopy (UBM) and optical coherence tomography (OCT). Both modalities can be used to assess bleb morphology and how it affects treatment outcome, measure anterior chamber biometry, identify the presence of supraciliochoroidal fluid, cyclodialysis clefts and malignant glaucoma, and evaluate treatment modalities after trabeculectomy such as in laser suture lysis and needling. OCT, with its finer resolution, is able to view the bleb wall anatomy in detail and because of its non-contact nature can examine the eye sooner after trabeculectomy. UBM, on the other hand, is superior for the visualization of deeper structures such as the ciliary body and posterior chamber essential to identify malignant glaucoma. C1 [Golez, Ernesto, III; Latina, Mark] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Golez, E (reprint author), Massachusetts Eye & Ear Infirm, 20 Pondmeadow Dr,Suite 203, Reading, MA 01867 USA. EM docernie3g@hotmail.com NR 50 TC 3 Z9 3 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 155 EP 159 DI 10.3109/08820538.2012.707275 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600011 PM 23163270 ER PT J AU Wong, JJ Chen, TC Shen, LQ Pasquale, LR AF Wong, Jessica J. Chen, Teresa C. Shen, Lucy Q. Pasquale, Louis R. TI Macular Imaging for Glaucoma Using Spectral-domain Optical Coherence Tomography: A Review SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Glaucoma; Optical Coherence Tomography; Macula; Imaging; Spectral-Domain ID NERVE-FIBER LAYER; GANGLION-CELL COMPLEX; VISUAL-FIELD SENSITIVITY; OPEN-ANGLE GLAUCOMA; RETINAL-THICKNESS; EYES; OCT; DIAGNOSIS; VOLUME AB Since its introduction, optical coherence tomography (OCT) has become widely used and accepted as an imaging modality to detect and follow glaucoma, with measurement of the peripapillary retinal nerve fiber layer (pRNFL) being the most utilized parameter. Up until recently, macular thickness parameters have not been commonly used in glaucoma due to results of earlier studies with time-domain OCT (TD-OCT) that revealed macular imaging to be inferior to pRNFL in the diagnosis of glaucoma. The recent advent of spectral-domain OCT (SD-OCT) has renewed interest in the potential uses of macular imaging in glaucoma due to its ability to better segment and measure individual retinal layers. Multiple studies have been performed in the last few years to investigate the diagnostic ability, reproducibility, and limitations of these new SD-OCT macular parameters. The purpose of this paper is to review the findings of those studies to assess the current utility of macular SD-OCT in glaucoma. Overall, SD-OCT has been shown to have higher reproducibility than TD-OCT, and though there have been some conflicting reports, the majority of studies seem to concur that the diagnostic sensitivity of SD-OCT macular parameters is at least comparable to TD-OCT and other SD-OCT parameters. C1 [Wong, Jessica J.; Chen, Teresa C.; Shen, Lucy Q.; Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Glaucoma Serv, Boston, MA USA. RP Wong, JJ (reprint author), 808 Greenridge Dr, La Canada Flintridge, CA 91011 USA. EM Jessica.J.Wong@gmail.com NR 45 TC 12 Z9 12 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 160 EP 166 DI 10.3109/08820538.2012.712734 PG 7 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600012 PM 23163271 ER PT J AU De Castro, DK Hadlock, T Fay, A AF De Castro, Dawn K. Hadlock, Tessa Fay, Aaron TI Dynamic Imaging of Paralytic Eyelid Disorders SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Blink; Cranial nerve palsy; Eyelid imaging; Eyelid kinematics; Facial paralysis; Ptosis ID SPONTANEOUS BLINKING; SURFACE COIL; SEARCH COIL; MOVEMENTS; SACCADES; HUMANS; REFLEX; RETRACTION; EYEBLINK; ANATOMY AB Purpose: Eyelid dysmotility may result from trauma, tumors, inflammation, infection, and a variety of other conditions. In these cases, a mechanical effect is disrupting a normal neuromuscular apparatus. Dysmotility can also be caused by paralytic eyelid disorders; included in this broad category are neurologic and myogenic disorders of eyelid opening and/or closure. Secondary effects include spastic eyelid closure and synkinesis syndromes. These conditions, by definition, are disorders of movement, and can only be studied adequately using dynamic imaging techniques. Methods: A comprehensive literature search was performed on PubMed. Ninety abstracts were reviewed. Results: Dynamic eyelid imaging has evolved dramatically over the past two decades, at least partially due to the rise of inexpensive digital technology. Magnetic search coil imaging, high-and low-speed videography, electromyography, and high-resolution microscopy coil magnetic resonance imaging each has its advantages and disadvantages, an understanding of which will guide appropriate selection of technology in any given clinical situation. Conclusions: Dynamic eyelid imaging is useful to study dysmotility. The optimal technique depends upon the clinical setting and the physiologic or pathologic topic of interest. To our knowledge, a report of this type has not been previously summarized. C1 [De Castro, Dawn K.; Fay, Aaron] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Hadlock, Tessa] Massachusetts Eye & Ear Infirm, Facial Nerve Ctr, Boston, MA 02114 USA. [Hadlock, Tessa] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Fay, A (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Aaron_Fay@meei.harvard.edu NR 40 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 167 EP 174 DI 10.3109/08820538.2012.708804 PG 8 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600013 PM 23163272 ER PT J AU Lefebvre, DR Freitag, SK AF Lefebvre, Daniel R. Freitag, Suzanne K. TI Update on Imaging of the Lacrimal Drainage System SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Dacryocystography; Dacryoendoscopy; Dacryoscintigraphy; Lacrimal drainage system imaging; Lacrimal ultrasound ID COMPUTED TOMOGRAPHIC DACRYOCYSTOGRAPHY; NASOLACRIMAL DUCT OBSTRUCTION; INFERIOR MEATAL DACRYORHINOTOMY; CONGENITAL DACRYOCYSTOCELE; MR DACRYOCYSTOGRAPHY; ENDONASAL DACRYOCYSTORHINOSTOMY; RESPIRATORY-DISTRESS; MALIGNANT-MELANOMA; CONTRAST-MEDIA; CLINICAL-VALUE AB Epiphora is a common problem seen by the ophthalmologist. There are numerous etiologies of a watering eye, and the underlying diagnosis is not always clear. A variety of in-office examination techniques and procedures exist to aid with diagnosis and determination of appropriate therapy, but sometimes the diagnosis remains elusive, or an instituted therapy fails. Lacrimal imaging, particularly in these cases, can be helpful in assessing the function and anatomy of the lacrimal drainage system. This review serves to examine the literature of the last 10 years concerning imaging of the lacrimal drainage system. C1 [Lefebvre, Daniel R.; Freitag, Suzanne K.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Div Ophthalm Plast Surg, Boston, MA 02114 USA. [Lefebvre, Daniel R.; Freitag, Suzanne K.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Lefebvre, DR (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Div Ophthalm Plast Surg, 243 Charles St,10th Floor, Boston, MA 02114 USA. EM daniel_lefebvre@meei.harvard.edu NR 106 TC 5 Z9 7 U1 2 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 175 EP 186 DI 10.3109/08820538.2012.711413 PG 12 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600014 PM 23163273 ER PT J AU Oliveira, C Cestari, DM Rizzo, JF AF Oliveira, Cristiano Cestari, Dean M. Rizzo, Joseph F., III TI The Use of Fourth-generation Optical Coherence Tomography in Multiple Sclerosis: A Review SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Axonal loss; Fourier domain; Multiple sclerosis; Optic neuritis; Optical coherence tomography; Retinal nerve fiber layer ID NERVE-FIBER LAYER; CIRRUS-HD-OCT; AXONAL LOSS; VISUAL DYSFUNCTION; NEURITIS; THICKNESS; ATROPHY; REPRODUCIBILITY; DISABILITY; LESIONS AB Optical coherence tomography (OCT) has been routinely used to obtain high spatial resolution images of the retina and choroid non-invasively. Within the past decade, a fourth-generation OCT device using Fourier domain (FD) analysis has been developed that provides higher velocity and higher axial resolution images with better reproducibility than the previous generation time domain (TD) OCT technology. This review addresses the use of fourth-generation, FD ocular OCT in patients with multiple sclerosis. C1 [Oliveira, Cristiano; Cestari, Dean M.; Rizzo, Joseph F., III] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Neuroophthalmol Serv, Boston, MA 02114 USA. RP Rizzo, JF (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Joseph_Rizzo@meei.harvard.edu NR 35 TC 3 Z9 3 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 187 EP 191 DI 10.3109/08820538.2012.708808 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600015 PM 23163274 ER PT J AU Kruger, JM Lessell, S Cestari, DM AF Kruger, Joshua M. Lessell, Simmons Cestari, Dean M. TI Neuro-imaging: A Review for the General Ophthalmologist SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Neuro-ophthalmology; Neuro-imaging; MRI; CT ID ISCHEMIC OPTIC NEUROPATHY; MAGNETIC-RESONANCE; NERVE PALSY; ANEURYSMS; NEURITIS; ANGIOGRAPHY; TOMOGRAPHY; ADULTS; ARTERY AB The diagnosis of many neuro-ophthalmic conditions is facilitated with neuro-imaging. The two main modalities are Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Clinicians who refer patients for either of these techniques must not only know which of them to choose, but also where the imaging should be performed (e. g. brain, orbit), whether or not contrast is indicated, and if angiography should be supplemented. These complexities often result in imaging studies that are either unneeded or unhelpful. The goal of this manuscript is to provide a practical set of guidelines for the general ophthalmologist of how to choose the correct parameters for neuro-imaging studies. C1 [Cestari, Dean M.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Neuroophthalmol Serv, Boston, MA USA. RP Cestari, DM (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Dean_Cestari@meei.harvard.edu NR 31 TC 0 Z9 0 U1 4 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 192 EP 196 DI 10.3109/08820538.2012.708815 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600016 PM 23163275 ER PT J AU Nandakumar, N Buzney, S Weiter, JJ AF Nandakumar, Namrata Buzney, Sheldon Weiter, John J. TI Lipofuscin and the Principles of Fundus Autofluorescence: A Review SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Fundus autofluorescence; Age-related macular degeneration; Geographic atrophy; Lipofuscin ID RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; HUMAN RPE; GEOGRAPHIC ATROPHY; CONE PHOTOPIGMENT; OUTER SEGMENTS; MELANIN; PHAGOCYTOSIS; PHAGOSOME; CELLS AB Fundus autofluorescence is a non-invasive imaging modality that measures lipofuscin that has accumulated in the retinal pigment epithelium (RPE). Excessive lipofuscin in the RPE is a common pathway found in several diseases including Stargardt's disease and age-related macular degeneration. This review discusses the role of photooxidative damage in the development of lipofuscin and the principles of fundus autofluorescence. C1 [Nandakumar, Namrata; Buzney, Sheldon; Weiter, John J.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Nandakumar, N (reprint author), 243 Charles St, Boston, MA 02114 USA. NR 41 TC 8 Z9 10 U1 1 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 197 EP 201 DI 10.3109/08820538.2012.711415 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600017 PM 23163276 ER PT J AU Skondra, D Papakostas, TD Hunter, R Vavvas, DG AF Skondra, Dimitra Papakostas, Thanos D. Hunter, Rebecca Vavvas, Demetrios G. TI Near Infrared Autofluorescence Imaging of Retinal Diseases SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Enhanced imaging chorioretinal melanin ID KOYANAGI-HARADA-DISEASE; CENTRAL SEROUS CHORIORETINOPATHY; INDOCYANINE GREEN ANGIOGRAPHY; FUNDUS AUTOFLUORESCENCE; PSEUDOXANTHOMA ELASTICUM; MACULAR DEGENERATION; FLUORESCENCE; LIPOFUSCIN; MELANIN; ABNORMALITIES AB Near infrared autofluorescence (excitation 787 nm, emission > 800 nm) is a non-invasive imaging technology that provides information on the distribution of melanin within the retinal pigment epithelial cell/choroid complex. This review contains an introduction to near infrared autofluorescence imaging methods. Characteristics of near infrared imaging in a variety of retinal diseases, including age-related macular degeneration, choroidal nevus, retinal degenerations, retinal dystrophies, central serous chorioretinopathy, pseudoxanthoma elasticum and chloroquine retinopathy, are summarized. C1 [Skondra, Dimitra; Papakostas, Thanos D.; Hunter, Rebecca; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA 02114 USA. RP Vavvas, DG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 NR 40 TC 2 Z9 3 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 202 EP 208 DI 10.3109/08820538.2012.708806 PG 7 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600018 PM 23163277 ER PT J AU Skondra, D Papakostas, T Vavvas, DG AF Skondra, Dimitra Papakostas, Thanos Vavvas, Demetrios G. TI Enhanced Depth Imaging Optical Coherence Tomography in Age-related Macular Degeneration SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE AMD; Choroidal thickness; Imaging ID POLYPOIDAL CHOROIDAL VASCULOPATHY; RETICULAR PSEUDODRUSEN; MORPHOMETRIC-ANALYSIS; BRUCHS MEMBRANE; IN-VIVO; THICKNESS; FREQUENCY; THERAPY; RETINA; EDEMA AB Imaging of the choroidal layer has been limited with the conventional commercial SD-OCTs. Enhanced depth imaging optical coherence tomography (EDI-OCT) is a modification of the standard spectral-domain OCT (SD-OCT) technique that enables better non-invasive imaging of the choroid. This review contains an introduction of EDI imaging technique and principles and summarizes the findings of EDI-OCT imaging in age-related macular degeneration. C1 [Skondra, Dimitra; Papakostas, Thanos; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA 02114 USA. RP Vavvas, DG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 NR 27 TC 3 Z9 3 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 209 EP 212 DI 10.3109/08820538.2012.708807 PG 4 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600019 PM 23163278 ER PT J AU Huang, LL Hirose, T AF Huang, Lynn L. Hirose, Tatsuo TI Portable Optical Coherence Tomography in Management of Vitreoretinal Diseases: Current Developments, Indications, and Implications SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Hand-held; Intraoperative; Pediatric; Portable; Optical coherence tomography; OCT; Vitreoretinal diseases ID THICKNESS MACULAR HOLE; SURGERY; PREMATURITY; RETINOPATHY; MORPHOLOGY; INFANTS; EDEMA; OCT AB The advent of optical coherence tomography (OCT) technology has greatly enhanced our understanding of vitreoretinal diseases; it has become a routine diagnostic imaging method for the evaluation of vitreoretinal abnormalities and injuries in adult and pediatric patients. The use of OCT has recently been extended beyond the offices and clinics to perioperative and intraoperative settings. The new development in high-resolution and high-speed spectral domain OCT, along with the improvement in portability, has made the device more valuable than ever before. Our article summarizes the current development of the portable OCT devices in clinical, perioperative, and intraoperative settings in the management of vitreoretinal diseases. C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. RP Huang, LL (reprint author), 1101 Beacon St, Brookline, MA 02446 USA. EM Lynn.huang05@post.harvard.edu NR 28 TC 5 Z9 7 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 213 EP 220 DI 10.3109/08820538.2012.708811 PG 8 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600020 PM 23163279 ER PT J AU Hunter, RS Skondra, D Papaliodis, G Sobrin, L AF Hunter, Rebecca S. Skondra, Dimitra Papaliodis, George Sobrin, Lucia TI Role of OCT in the Diagnosis and Management of Macular Edema from Uveitis SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Optical coherence tomography; Uveitis; Macular edema ID OPTICAL COHERENCE TOMOGRAPHY; FLUORESCEIN ANGIOGRAPHY; QUANTITATIVE ASSESSMENT; EPIRETINAL MEMBRANES; VISUAL-ACUITY; TIME-DOMAIN; PATTERNS; RETINITIS; THERAPY AB Uveitis is a potentially visually threatening disease accounting for 10% of vision loss in the developed world. 1 The most common cause of vision loss in patients with uveitis has been shown to be macular edema (ME). 1 The early detection and management of ME is critical to preserve vision in these patients. Optical coherence tomography (OCT) is a valuable tool in the management of many ocular diseases. The use of OCT has revolutionized the diagnosis and management of macular edema from a wide variety of ophthalmological diseases, including uveitis. 2 In this review, we evaluate the role of OCT in the diagnosis and management of uveitic macular edema. C1 [Hunter, Rebecca S.; Skondra, Dimitra; Papaliodis, George; Sobrin, Lucia] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Hunter, RS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM rebecca_hunter@meei.harvard.edu NR 38 TC 6 Z9 6 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 236 EP 241 DI 10.3109/08820538.2012.708813 PG 6 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600023 PM 23163282 ER PT J AU Kohanim, S Daniels, AB Huynh, N Eliott, D Chodosh, J AF Kohanim, Sahar Daniels, Anthony B. Huynh, Nancy Eliott, Dean Chodosh, James TI Utility of Ocular Ultrasonography in Diagnosing Infectious Endophthalmitis in Patients with Media Opacities SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE B-scan; Ocular ultrasound; Infectious endophthalmitis; Diagnostic utility ID BACTERIAL ENDOPHTHALMITIS AB Assessment of patients with infectious endophthalmitis is frequently limited by media opacities, and ocular ultrasonography is routinely performed in this setting. We examined the literature to assess the level of evidence for the utility of ocular ultrasonography in these patients. Common ultrasonographic findings reported include low amplitude mobile echoes, vitreous membranes, and thickening of the retina and choroid. Based on the available evidence, we conclude that ocular ultrasound may be a useful adjunct in guiding treatment and minimizing complications. While positive findings may be confirmatory in cases in which the clinical suspicion is high, ocular ultrasound alone cannot be used to prove or to exclude the diagnosis of infectious endophthalmitis. C1 [Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv,Dept Ophthalmol, Boston, MA 02114 USA. RP Chodosh, J (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu NR 18 TC 1 Z9 1 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 242 EP 245 DI 10.3109/08820538.2012.711417 PG 4 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600024 PM 23163283 ER PT J AU Huang, YW Chung, RT AF Huang, Yi-Wen Chung, Raymond T. TI Management of hepatitis B reactivation in patients receiving cancer chemotherapy SO THERAPEUTIC ADVANCES IN GASTROENTEROLOGY LA English DT Review DE cancer; chemotherapy; HBV reactivation; hepatitis B virus; lamivudine; prophylaxis AB Hepatitis B virus (HBV) reactivation is well documented in previously resolved or inactive HBV carriers who receive cancer chemotherapy. The consequences of HBV reactivation range from self-limited conditions to fulminant hepatic failure and death. HBV reactivation also leads to premature termination of chemotherapy or delay in treatment schedules. This review summarizes current knowledge of management of HBV reactivation in patients receiving cancer chemotherapy. HBV surface antigen (HBsAg) testing should be performed in patients who require cancer chemotherapy. Four meta-analyses support lamivudine prophylaxis for HBV reactivation during chemotherapy in HBsAg-positive patients. Randomized controlled trials to compare different HBV antiviral agents are needed to define optimal regimens for the prevention and treatment of HBV reactivation in patients receiving cancer chemotherapy. C1 [Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Boston, MA 02114 USA. [Huang, Yi-Wen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA USA. [Huang, Yi-Wen] Cathay Gen Hosp, Med Ctr, Ctr Liver, Taipei, Taiwan. [Huang, Yi-Wen] Taipei Med Univ, Sch Med, Taipei, Taiwan. [Huang, Yi-Wen] Natl Taiwan Univ Coll Med & Hosp, Dept Internal Med, Div Gastroenterol, Taipei, Taiwan. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Warren 1007,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org OI Huang, Yi-Wen/0000-0002-5196-7030 FU National Science Council of Taiwan, Republic of China; Cathay General Hospital Medical Center, Taipei, Taiwan; NIH [DK078772, DK082919] FX Yi-Wen Huang is a research fellow at Massachusetts General Hospital and Harvard Medical School sponsored by National Science Council of Taiwan, Republic of China and Cathay General Hospital Medical Center, Taipei, Taiwan. Dr. Chung was supported by NIH DK078772 and DK082919. NR 79 TC 7 Z9 8 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1756-283X EI 1756-2848 J9 THER ADV GASTROENTER JI Ther. Adv. Gastroenterol. PD SEP PY 2012 VL 5 IS 5 BP 359 EP 370 DI 10.1177/1756283X12450245 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V31ZQ UT WOS:000208921900006 PM 22973419 ER PT J AU Hussain, M Corn, P Michaelson, D Hammers, H Alumkal, J Ryan, C Bruce, J Moran, S Lee, S Borgstein, N Webb, I Mortimer, P George, D AF Hussain, M. Corn, P. Michaelson, D. Hammers, H. Alumkal, J. Ryan, C. Bruce, J. Moran, S. Lee, S. Borgstein, N. Webb, I Mortimer, P. George, D. TI Safety and Efficacy of the Investigational Agent Orteronel (TAK-700) Without Prednisone in Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC) Patients with Rising Prostate-Specific Antigen (PSA): Updated Results from a Phase 2 Study SO UROLOGY LA English DT Meeting Abstract C1 [Hussain, M.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Corn, P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Michaelson, D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Hammers, H.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Alumkal, J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Ryan, C.] UCSF, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Bruce, J.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53706 USA. [Moran, S.; Lee, S.; Borgstein, N.; Webb, I] Millennium Pharmaceut Inc, Cambridge, MA USA. [Mortimer, P.] Takeda Global Res & Dev Ctr Europe Ltd, London, England. [George, D.] Duke Univ, Med Ctr, Durham, NC 27706 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA POD-09.01 BP S29 EP S29 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800063 ER PT J AU Mulders, P Scher, H Fizazi, K Saad, F Taplin, M Sternberg, C Miller, K De Wit, R Hirmand, M Selby, B De Bono, J AF Mulders, P. Scher, H. Fizazi, K. Saad, F. Taplin, M. Sternberg, C. Miller, K. De Wit, R. Hirmand, M. Selby, B. De Bono, J. CA AFFIRM Investigators TI MDV3100, an Androgen Receptor Signaling Inhibitor, Improves Overall Survival in Patients with Prostate Cancer Post Docetaxel: Results from the Phase 3 AFFIRM Study SO UROLOGY LA English DT Meeting Abstract C1 [Mulders, P.] Radboud Univ Nijmegen, Nijmegen Med Ctr, Nijmegen, Netherlands. [Scher, H.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Saad, F.] Univ Montreal, Ctr Hosp, Montreal, PQ, Canada. [Taplin, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sternberg, C.] San Camillo Forlanini Hosp, Rome, Italy. [Miller, K.] Charite Univ Med Berlin, Berlin, Germany. [Hirmand, M.; Selby, B.] Medivat Inc, San Francisco, CA USA. [Fizazi, K.] Univ Paris Sud, Villejuif, France. [De Wit, R.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [De Bono, J.] Inst Canc Res, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA POD-09.04 BP S30 EP S30 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800066 ER PT J AU Santiago-Lastra, Y Talab, SS Bachmann, A Muir, G Choi, B Tabatabaei, S AF Santiago-Lastra, Y. Talab, Shafaat S. Bachmann, A. Muir, G. Choi, B. Tabatabaei, S. TI Ejaculation Preserving Photoselective Vaporization of the Prostate SO UROLOGY LA English DT Meeting Abstract C1 [Santiago-Lastra, Y.; Talab, Shafaat S.; Tabatabaei, S.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Bachmann, A.] Univ Hosp, Dept Urol, Basel, Switzerland. [Muir, G.] Kings Coll Hosp London, Dept Urol, London, England. [Choi, B.] Weill Cornell Univ, Dept Urol, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA VID-04 BP S179 EP S179 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800433 ER PT J AU Zareba, P Fiorentino, M Flavin, R Martin, N Andersson, S Andren, O Fall, K Rider, J Mucci, L AF Zareba, P. Fiorentino, M. Flavin, R. Martin, N. Andersson, S. Andren, O. Fall, K. Rider, J. Mucci, L. TI Perineural Invasion and Lethal Prostate Cancer SO UROLOGY LA English DT Meeting Abstract C1 [Zareba, P.] McMaster Univ, Div Urol, Hamilton, ON, Canada. [Fiorentino, M.; Flavin, R.; Rider, J.] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Fiorentino, M.] St Orsola Marcello Malpighi Hosp, Addarii Inst, Pathol Unit, Bologna, Italy. [Martin, N.; Mucci, L.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Martin, N.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Andersson, S.; Andren, O.; Fall, K.; Rider, J.] Orebro Univ Hosp, Dept Urol, Orebro, Sweden. [Fall, K.] Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. [Rider, J.; Mucci, L.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA MP-07.16 BP S84 EP S84 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800199 ER PT J AU Zareba, P Pettersson, A Gerke, T Fiorentino, M Flavin, R Rider, J Giovannucci, E Finn, S Loda, M Mucci, L AF Zareba, P. Pettersson, A. Gerke, T. Fiorentino, M. Flavin, R. Rider, J. Giovannucci, E. Finn, S. Loda, M. Mucci, L. TI Immunohistochemical Expression of BRCA1 and Prostate Cancer Progression in a Large Radical Prostatectomy Cohort SO UROLOGY LA English DT Meeting Abstract C1 [Zareba, P.] McMaster Univ, Div Urol, Hamilton, ON, Canada. [Pettersson, A.; Gerke, T.; Giovannucci, E.; Mucci, L.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Fiorentino, M.; Flavin, R.; Rider, J.; Finn, S.; Loda, M.] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Fiorentino, M.] St Orsola Marcello Malpighi Hosp, Addarii Inst, Patbol Unit, Bologna, Italy. [Rider, J.; Giovannucci, E.; Mucci, L.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Giovannucci, E.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Loda, M.] Broad Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA POD-09.02 BP S29 EP S29 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800064 ER PT J AU Cohen, BE Maguen, S Bertenthal, D Shi, Y Jacoby, V Seal, KH AF Cohen, Beth E. Maguen, Shira Bertenthal, Daniel Shi, Ying Jacoby, Vanessa Seal, Karen H. TI Reproductive and Other Health Outcomes in Iraq and Afghanistan Women Veterans Using VA Health Care: Association with Mental Health Diagnoses SO WOMENS HEALTH ISSUES LA English DT Article AB Background: An increasing number of women serve in the military and are exposed to trauma during service that can lead to mental health problems. Understanding how these mental health problems affect reproductive and physical health outcomes will inform interventions to improve care for women veterans. Methods: We analyzed national Department of Veterans Affairs (VA) data from women Iraq and Afghanistan veterans who were new users of VA healthcare from October 7, 2001, through December 31, 2010 (n = 71,504). We used ICD-9 codes to categorize veterans into five groups by mental health diagnoses (MH Dx): Those with no MH Dx, posttraumatic stress disorder (PTSD), depression, comorbid PTSD and depression, and a MH Dx other than PTSD and depression. We determined the association between mental health category and reproductive and other physical health outcomes defined by ICD-9 codes. Categories included sexually transmitted infections, other infections (e. g., urinary tract infections), pain-related conditions (e. g., dysmenorrhea and dsypareunia), and other conditions (e. g., polycystic ovarian syndrome, infertility, sexual dysfunction). Models were adjusted for sociodemographic and military service factors. Results: There were 31,481 patients (44%) who received at least one mental health diagnosis. Women veterans with any mental health diagnosis had significantly higher prevalences of nearly all categories of reproductive and physical disease diagnoses (p < .0001 for adjusted prevalences). There was a trend of increasing prevalence of disease outcomes in women with PTSD, depression, and comorbid PTSD and depression (p for trend <.0001 for all outcomes). Conclusions: Iraq and Afghanistan women veterans with mental health diagnoses had significantly greater prevalences of several important reproductive and physical health diagnoses. These results provide support for VA initiatives to address mental and physical health concerns and improve comprehensive care for women veterans. Published by Elsevier Inc. C1 [Cohen, Beth E.; Maguen, Shira; Bertenthal, Daniel; Shi, Ying; Seal, Karen H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Cohen, Beth E.; Maguen, Shira; Bertenthal, Daniel; Jacoby, Vanessa; Seal, Karen H.] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Jacoby, Vanessa] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bertenthal, Daniel; Seal, Karen H.] San Francisco VA Med Ctr, Hlth Serv Res & Dev Res Enhancement Award Program, San Francisco, CA USA. RP Cohen, BE (reprint author), 4150 Clement St, San Francisco, CA 94121 USA. EM beth.cohen@va.gov FU NHLBI NIH HHS [K23 HL 094765-01, K23 HL094765] NR 63 TC 17 Z9 17 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD SEP-OCT PY 2012 VL 22 IS 5 BP E461 EP E471 DI 10.1016/j.whi.2012.06.005 PG 11 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA V33ST UT WOS:000209039200007 PM 22944901 ER PT J AU Katon, J Maynard, C Reiber, G AF Katon, Jodie Maynard, Charles Reiber, Gayle TI Attempts at Weight Loss in US Women with and without a History of Gestational Diabetes Mellitus SO WOMENS HEALTH ISSUES LA English DT Article AB Background and Objective: Gestational diabetes mellitus (GDM) is a risk factor for type 2 diabetes. Relatively modest weight loss can delay or prevent the onset of type 2 diabetes. The objective of this study was to determine, using a nationally representative survey, whether among women without diabetes, those with a history of GDM (hGDM) were more likely than those without hGDM to be currently attempting weight loss. Methods: This study used data from the 2003 Behavioral Risk Factor Surveillance System, a national, population-based, random-sample telephone survey. Women aged 18 to 44 years without diabetes who answered questions related to current weight loss activity were included in the analysis. The primary outcome was currently attempting weight loss. Logistic regression was used to analyze the association between hGDM and currently attempting weight loss. Results: We included 53,608 women without diabetes: 1,260 (2%) with hGDM, and 52,348 (98%) without hGDM. Among women with hGDM, 53% were currently attempting weight loss compared with 47% of women without hGDM. Overall, after adjusting for age, race/ethnicity, education, marital status, and medical insurance, compared with women without hGDM, those with hGDM had 20% higher odds of currently attempting weight loss (95% confidence interval [CI], 0.97-1.49); however, among obese women (body mass index >= 30 kg/m(2)), compared with women without hGDM, those with hGDM had 46% lower odds of currently attempting weight loss (95% CI, 0.35-0.82). Conclusions: Obese women with hGDM are less likely to be currently attempting weight loss compared with those without hGDM. Effective interventions for obese women with hGDM are needed. Published by Elsevier Inc. C1 [Katon, Jodie; Reiber, Gayle] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Maynard, Charles; Reiber, Gayle] VA Puget Sound Hlth Care Syst, HSR&D, Seattle, WA USA. [Maynard, Charles; Reiber, Gayle] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. RP Katon, J (reprint author), Univ Washington, Sch Publ Hlth, Dept Epidemiol, Box 357236, Seattle, WA 98195 USA. EM jkaton@u.washington.edu RI Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 FU NICHD NIH HHS [T32 HD052462] NR 23 TC 2 Z9 2 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD SEP-OCT PY 2012 VL 22 IS 5 BP E447 EP E453 DI 10.1016/j.whi.2012.07.004 PG 7 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA V33ST UT WOS:000209039200005 PM 22944900 ER PT J AU Bromley, E AF Bromley, Elizabeth TI Building patient-centeredness: Hospital design as an interpretive act SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Patient-centeredness; Hospital design; USA; Medical professionalism; Consumerism; Patienthood ID HEALTH-CARE; MEDICAL PROFESSIONALISM; THERAPEUTIC LANDSCAPES; SATISFACTION; TECHNOLOGY; COMMUNICATION; PHYSICIAN; ENCOUNTER; ILLNESS; ISSUES AB Hospital designs reflect the sociocultural, economic, professional, and aesthetic priorities prevalent at a given time. As such, hospital buildings concretize assumptions about illness, care and healing, patienthood, and medical providers' roles. Trends in hospital design have been attributed to the increasing influence of consumerism on healthcare, the influx of business-oriented managers, and technological changes. This paper describes the impact of the concept of patient-centeredness on the design of a new hospital in the USA. Data come from 35 interviews with planners, administrators, and designers of the new hospital, as well as from public documents about the hospital design. Thematic content analysis was used to identify salient design principles and intents. For these designers, administrators, and planners, an interpretation of patient-centeredness served as a heuristic, guiding the most basic decisions about space, people, and processes in the hospital. 1 detail the particular interpretation of patient-centeredness used to build and manage the new hospital space and the roles and responsibilities of providers working within it. Three strategies were central to the implementation of patient-centeredness: an onstage/offstage layout; a concierge approach to patients; and the scripting of communication. I discuss that this interpretation of patient-centeredness may challenge medical professionals' roles, may construct medical care as a product that should sate the patient's desire, and may distance patients from the realities of medical care. By describing the ways in which hospital designs reflect and reinforce contemporary concepts of patienthood and caring, this paper raises questions about the implementation of patient-centeredness that deserve further empirical study by medical social scientists. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Bromley, Elizabeth] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Ctr Hlth Serv & Soc, Los Angeles, CA 90024 USA. [Bromley, Elizabeth] W Los Angeles VA Healthcare Ctr, VA Desert Pacific Mental Illness Res Educ & Clin, Los Angeles, CA USA. RP Bromley, E (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Ctr Hlth Serv & Soc, Los Angeles, CA 90024 USA. EM ebromley@ucla.edu FU UniHealth Foundation FX This study was funded by the UniHealth Foundation. An earlier version of this paper was presented to the American Anthropological Association annual meeting November 2010 in New Orleans, LA. The author wishes to thank Lisa Mikesell, Marian Katz, Susan Stockdale, Joseph Mango, Elizabeth O'Toole, Stefan Timmermans, Kenneth B. Wells, Peter Whybrow, Joel T. Braslow, Neil Wenger, and James B. Atkinson for invaluable contributions to this research. The author also gratefully acknowledges anonymous reviewers for their insightful comments. NR 101 TC 16 Z9 16 U1 6 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD SEP PY 2012 VL 75 IS 6 BP 1057 EP 1066 DI 10.1016/j.socscimed.2012.04.037 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 979LQ UT WOS:000306821900013 PM 22703887 ER PT J AU Vogt, DS Shipherd, JC Resick, PA AF Vogt, Dawne S. Shipherd, Jillian C. Resick, Patricia A. TI Posttraumatic Maladaptive Beliefs Scale: Evolution of the Personal Beliefs and Reactions Scale SO ASSESSMENT LA English DT Article DE cognition; PTSD; measurement; maladaptive beliefs; coping; trauma ID COGNITIVE-PROCESSING THERAPY; ADMINISTERED PTSD SCALE; SEXUAL-ABUSE SURVIVORS; STRESS-DISORDER; ASSUMPTIONS SCALE; QUICK TEST; VICTIMS; TRAUMA; CLINICIAN; VICTIMIZATION AB The Posttraumatic Maladaptive Beliefs Scale (PMBS) was developed to measure maladaptive beliefs about current life circumstances that may occur following trauma exposure. This scale assesses maladaptive beliefs within three domains: (a) Threat of Harm, (b) Self-Worth and Judgment, and (c) Reliability and Trustworthiness of Others. Items for the PMBS were drawn from a larger preexisting measure that assesses a wide range of personal beliefs and reactions associated with trauma exposure. The construct validity of the PMBS was assessed in two independent samples of interpersonal trauma survivors. This article provides data to support the reliability and validity of the PMBS as an instrument to assess general, rather than trauma-specific, maladaptive beliefs that have relevance for functioning in the aftermath of a traumatic event. Moreover, the measure is sensitive to changes that occur in treatment, and the length of the measure (15 items) is practical for use in clinical settings. C1 [Vogt, Dawne S.; Shipherd, Jillian C.; Resick, Patricia A.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Vogt, Dawne S.; Shipherd, Jillian C.; Resick, Patricia A.] Boston Univ, Sch Med, Div Psychiat, Boston, MA 02118 USA. RP Vogt, DS (reprint author), VA Boston Healthcare Syst 116B 3, Womens Hlth Sci Div, 150 S Huntington Ave, Boston, MA 02130 USA. EM Dawne.Vogt@va.gov NR 57 TC 7 Z9 7 U1 1 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1911 J9 ASSESSMENT JI Assessment PD SEP PY 2012 VL 19 IS 3 BP 308 EP 317 DI 10.1177/1073191110376161 PG 10 WC Psychology, Clinical SC Psychology GA 978HS UT WOS:000306732000005 PM 20660470 ER PT J AU Yang, JA Kim, ES Kwon, JH Kim, H Shin, JH Yun, SH Choi, KY Hahn, SK AF Yang, Jeong-A Kim, Eung-Sam Kwon, Jung Hee Kim, Hyemin Shin, Ji Hye Yun, Seok Hyun Choi, Kwan Yong Hahn, Sei Kwang TI Transdermal delivery of hyaluronic acid - Human growth hormone conjugate SO BIOMATERIALS LA English DT Article DE Hyaluronic acid; Human growth hormone; Conjugate; Receptors; Transdermal delivery ID DRUG-DELIVERY; HUMAN SKIN; CELL-PROLIFERATION; PENETRATION ENHANCERS; RECEPTOR; CD44; FIBROBLASTS; MICRONEEDLES; ADHESION; CULTURE AB Hyaluronic acid (HA) is one of the major components of extracellular matrix (ECM). Keratinocyte and fibroblast are known to have HA receptors in the skin. Fibroblast also has human growth hormone (hGH) receptors. In this work, HA hGH conjugate was developed as a receptor mediated transdermal delivery system of protein drugs. HA hGH conjugate was synthesized by specific coupling reaction between aldehyde modified HA and the N-terminal amine group of hGH. We could confirm the proliferative effect of HA on keratinocyte and fibroblast, and the biological activity of HA hGH conjugate in fibroblast with an elevated expression level of phosphorylated Janus kinase 2 (p-JAK2). Interestingly, fluorescence microscopy clearly visualized the dramatically enhanced penetration of HA hGH conjugate through the dorsal skin of mice after topical treatment with FITC labeled HA hGH conjugate. According to pharmacokinetic analysis, HA hGH conjugate appeared to be delivered through the skin into the blood stream possibly by the receptor mediated transdermal delivery. This work confirms the feasibility of using the HA hGH conjugate as a model system for the receptor mediated transdermal delivery of protein drugs and their further exploitation for various cosmetic and tissue engineering applications. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Yang, Jeong-A; Kim, Hyemin; Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, Pohang 790784, Kyungbuk, South Korea. [Kim, Eung-Sam; Choi, Kwan Yong; Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Sch Interdisciplinary Biosci & Bioengn, Pohang 790784, Kyungbuk, South Korea. [Kwon, Jung Hee; Shin, Ji Hye; Choi, Kwan Yong] Pohang Univ Sci & Technol POSTECH, Div Mol & Life Sci, Dept Life Sci, Pohang 790784, Kyungbuk, South Korea. [Yun, Seok Hyun; Hahn, Sei Kwang] Harvard Univ, Sch Med, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Yun, Seok Hyun; Hahn, Sei Kwang] Massachusetts Gen Hosp, Cambridge, MA 02139 USA. RP Hahn, SK (reprint author), Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, San 31, Pohang 790784, Kyungbuk, South Korea. EM kchoi@postech.ac.kr; skhanb@postech.ac.kr FU Converging Research Center through National Research Foundation of Korea (NRF); Ministry of Education. Science and Technology [2009-0081871, 2011K000801]; Ministry of Health & Welfare, Republic of Korea [A080711]; Rural Development Administration, Republic of Korea [PJ007974] FX This research was supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education. Science and Technology (2009-0081871 and 2011K000801). This study was also supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A080711). This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ007974), Rural Development Administration, Republic of Korea. We also thank Yong Ryoul Yang for embedding the skin tissue into OCT compound and Hyuntae Jung for fluorescence microscopic images. NR 30 TC 34 Z9 35 U1 5 U2 51 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD SEP PY 2012 VL 33 IS 25 BP 5947 EP 5954 DI 10.1016/j.biomaterials.2012.05.003 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 979KY UT WOS:000306820100007 PM 22632765 ER PT J AU Lillis, KP Kramer, MA Mertz, J Staley, KJ White, JA AF Lillis, Kyle P. Kramer, Mark A. Mertz, Jerome Staley, Kevin J. White, John A. TI Pyramidal cells accumulate chloride at seizure onset SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Epilepsy; Ictogenesis; Chloride accumulation; Ion imaging; Calcium; Seizure; GABA; Chloride transport; Interneuron; Targeted path scanning ID TEMPORAL-LOBE EPILEPSY; GAMMA-AMINOBUTYRIC-ACID; GABA-MEDIATED POTENTIALS; ENTORHINAL CORTEX; IN-VITRO; EXTRACELLULAR POTASSIUM; FLUORESCENT INDICATORS; GABAERGIC INTERNEURONS; EPILEPTIFORM ACTIVITY; HIPPOCAMPAL-NEURONS AB Seizures are thought to originate from a failure of inhibition to quell hyperactive neural circuits, but the nature of this failure remains unknown. Here we combine high-speed two-photon imaging with electrophysiological recordings to directly evaluate the interaction between populations of interneurons and principal cells during the onset of seizure-like activity in mouse hippocampal slices. Both calcium imaging and dual patch clamp recordings reveal that in vitro seizure-like events (SLEs) are preceded by pre-ictal bursts of activity in which interneurons predominate. Corresponding changes in intracellular chloride concentration were observed in pyramidal cells using the chloride indicator Clomeleon. These changes were measurable at SLE onset and became very large during the SLE. Pharmacological manipulation of GABAergic transmission, either by blocking GABA(A) receptors or by hyperpolarizing the GABA(A) reversal potential, converted SLEs to short interictal-like bursts. Together, our results support a model in which pre-ictal GABA(A) receptor-mediated chloride influx shifts E-GABA to produce a positive feedback loop that contributes to the initiation of seizure activity. (C) 2012 Elsevier Inc. All rights reserved. C1 [White, John A.] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. [Lillis, Kyle P.; Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Lillis, Kyle P.; Staley, Kevin J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Mertz, Jerome] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP White, JA (reprint author), Univ Utah, Dept Bioengn, 20 S 2030 E, Salt Lake City, UT 84112 USA. EM lillis.kyle@mgh.harvard.edu; mak@bu.edu; jmertz@bu.edu; staley.kevin@mgh.harvard.edu; john.white@utah.edu RI Kramer, Mark/A-1291-2014; OI White, John/0000-0003-1073-2638 FU NIH; Epilepsy Foundation; Burroughs Wellcome Fund FX This work was supported by grants from the NIH, the Epilepsy Foundation and the Burroughs Wellcome Fund. We thank G. Feng, T. Kuner, and G.J. Augustine for generously providing us with the Clomeleon mice. NR 62 TC 31 Z9 31 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD SEP PY 2012 VL 47 IS 3 BP 358 EP 366 DI 10.1016/j.nbd.2012.05.016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 976YC UT WOS:000306622300007 PM 22677032 ER PT J AU Mai, CL Young, MJ Quraishi, SA AF Mai, Christine L. Young, Mark J. Quraishi, Sadeq A. TI Clinical implications of the transversus abdominis plane block in pediatric anesthesia SO PEDIATRIC ANESTHESIA LA English DT Review DE transversus abdominis plane; TAP; nerve block; regional anesthesia; pediatric ID PROSPECTIVE RANDOMIZED-TRIAL; POSTOPERATIVE ANALGESIA; TAP BLOCK; LIVER TRAUMA; CHILDREN; SURGERY; INFANTS; NERVES; AUDIT; WALL AB Optimal perioperative analgesia for infants and children after major abdominal surgery poses a challenge when central neuraxial techniques are contraindicated. As a regional anesthesia technique, the transversus abdominis plane (TAP) block has been shown to reduce opioid consumption and improve pain scores compared to traditional perioperative pain strategies. Accordingly, TAP blocks may be considered as an alternative to central neuraxial analgesia to optimize perioperative pain control. Advancements in ultrasound technology have further improved the reliability and safety profile of this technique. Despite growing recognition of the diverse clinical scenarios where TAP blocks may be of benefit, its use among pediatric anesthesiologists remains limited. This article describes the history, anatomy, and a review of the current literature on TAP blocks with an emphasis on outcomes in pediatric patients. C1 [Quraishi, Sadeq A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Quraishi, SA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRJ 402, Boston, MA 02114 USA. EM squraishi@partners.org FU Harvard Anaesthesia Center [5T32GM007592-33] FX Harvard Anaesthesia Center (5T32GM007592-33) supported SAQ. NR 46 TC 12 Z9 12 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1155-5645 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD SEP PY 2012 VL 22 IS 9 BP 831 EP 840 DI 10.1111/j.1460-9592.2012.03916.x PG 10 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA 980NP UT WOS:000306900400001 PM 22834467 ER PT J AU Smith, KA Tong, X Abu-Yousif, AO Mikulec, CC Gottardi, CJ Fischer, SM Pelling, JC AF Smith, Kimberly A. Tong, Xin Abu-Yousif, Adnan O. Mikulec, Carol C. Gottardi, Cara J. Fischer, Susan M. Pelling, Jill C. TI UVB radiation-induced beta-catenin signaling is enhanced by COX-2 expression in keratinocytes SO MOLECULAR CARCINOGENESIS LA English DT Article DE UVB; ss-catenin; COX-2; PGE2 ID SQUAMOUS-CELL CARCINOMA; NONMELANOMA SKIN-CANCER; GROWTH-FACTOR RECEPTOR; CYCLOOXYGENASE-2 EXPRESSION; ULTRAVIOLET-RADIATION; INDUCED APOPTOSIS; MOUSE SKIN; E-CADHERIN; ACTIVATION; CARCINOGENESIS AB UVB radiation is the major carcinogen responsible for skin carcinogenesis, thus elucidation of the molecular pathways altered in skin in response to UVB would reveal novel targets for therapeutic intervention. It is well established that UVB leads to upregulation of cyclooxygenase 2 (COX-2) in the skin which contributes to skin carcinogenesis. Overexpression of COX-2 has been shown to promote colon cancer cell growth through beta-catenin signaling, however, little is known about the connection between UVB, COX-2, and beta-catenin in the skin. In the present study, we have identified a novel pathway in which UVB induces beta-catenin signaling in keratinocytes, which is modulated by COX-2 expression. Exposure of the mouse 308 keratinocyte cell line (308 cells) and primary normal human epidermal keratinocytes (NHEKs) to UVB resulted in increased protein levels of both N-terminally unphosphorylated and total beta-catenin. In addition, we found that UVB-enhanced beta-catenin-dependent TOPflash reporter activity and expression of a downstream beta-catenin target gene. We demonstrated that UVB-induced beta-catenin signaling is modulated by COX-2, as treatment of keratinocytes with the specific COX-2 inhibitor NS398 blocked UVB induction of beta-catenin. Additionally, beta-catenin target gene expression was reduced in UVB-treated COX-2 knockout (KO) MEFs compared to wild-type (WT) MEFs. Furthermore, epidermis from UVB-exposed SKH-1 mice exhibited increased N-terminally unphosphorylated and total beta-catenin protein levels and increased staining for total beta-catenin, and both responses were reduced in COX-2 heterozygous mice. Taken together, these results suggest a novel pathway in which UVB induces beta-catenin signaling in keratinocytes which is enhanced by COX-2 expression. (c) 2011 Wiley Periodicals, Inc. C1 [Smith, Kimberly A.; Tong, Xin; Pelling, Jill C.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Smith, Kimberly A.; Tong, Xin; Pelling, Jill C.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. [Gottardi, Cara J.] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Pulm & Crit Care, Chicago, IL 60611 USA. [Abu-Yousif, Adnan O.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Mikulec, Carol C.; Fischer, Susan M.] Univ Texas Dallas, MD Anderson Canc Ctr, Sci Pk Res Div, Smithville, TX USA. RP Pelling, JC (reprint author), Northwestern Univ, Dept Pathol, Feinberg Sch Med, 303 E Super St,Lurie Bldg 3-115, Chicago, IL 60611 USA. OI Smith, Kimberly/0000-0002-2621-0052 FU NIH [CA104768, AR057579, CA09560]; Zell Foundation; Malkin Scholars Award; Robert H. Lurie Comprehensive Cancer Center; Northwestern Skin Disease Research Center, Chicago, IL [5P30AR057216]; NIH/NIAMS FX This work was supported by NIH grant CA104768 and AR057579 to J.C.P., the Zell Foundation (J.C.P was a Zell Scholar), NIH T32 grant CA09560 to K. A. S., a Malkin Scholars Award to K. A. S, in part by the Robert H. Lurie Comprehensive Cancer Center and in part by resources provided by the Northwestern Skin Disease Research Center 5P30AR057216, Chicago, IL with support from the NIH/NIAMS. NR 44 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD SEP PY 2012 VL 51 IS 9 BP 734 EP 745 DI 10.1002/mc.20840 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 976GU UT WOS:000306569700005 PM 21853475 ER PT J AU Liu, XH Joshi, SK Samagh, SP Dang, YX Laron, D Lovett, DH Bodine, SC Kim, HT Feeley, BT AF Liu, Xuhui Joshi, Sunil K. Samagh, Sanjum P. Dang, Yu-Xuan Laron, Dominique Lovett, David H. Bodine, Sue C. Kim, Hubert T. Feeley, Brian T. TI Evaluation of Akt/mTOR activity in muscle atrophy after rotator cuff tears in a rat model SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE muscle atrophy; rotator cuff tear; Akt; mTOR; denervation ID FOXO TRANSCRIPTION FACTORS; SKELETAL-MUSCLE; UBIQUITIN LIGASES; FATTY INFILTRATION; EXPRESSION; PATHWAY; SUPRASPINATUS; HYPERTROPHY; ATROGIN-1; REVEALS AB Atrophy of the rotator cuff muscles is a factor that complicates the treatment of a massive rotator cuff tear (RCT). However, the molecular mechanisms that govern the development of muscle atrophy after RCTs have not been well defined. The Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in maintaining muscle mass in response to mechanical loading. The role of this pathway in the development of muscle atrophy after a massive RCT remains unknown. The purpose of this study was to investigate the regulation of the Akt/mTOR pathway in the development of muscle atrophy after a RCT and suprascapular nerve (SSN) injury. We evaluated the activity of the Akt/mTOR signaling pathway and how this pathway interacts with two atrophy-related genes, MuRF-1 and MAFbx, in supraspinatus muscles of rats that underwent unilateral complete rotator cuff tendon transection or SSN transection. Akt/mTOR activity was significantly reduced after tendon rupture, but increased after nerve injury. MuRF-1 and MAFbx were only up-regulated following denervation. These results suggest that tendon transection leads to a decrease in protein synthesis with down-regulation of the Akt/mTOR signaling pathway, whereas denervation leads to an increase in protein degradation via up-regulation of expression of MuRF-1 and MAFbx. (C) 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:14401446, 2012 C1 [Liu, Xuhui; Joshi, Sunil K.; Dang, Yu-Xuan; Lovett, David H.; Kim, Hubert T.; Feeley, Brian T.] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. [Liu, Xuhui; Samagh, Sanjum P.; Laron, Dominique; Kim, Hubert T.; Feeley, Brian T.] Univ Calif San Francisco, Dept Orthoped Surg, San Francisco, CA 94143 USA. [Lovett, David H.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bodine, Sue C.] Univ Calif Davis, Dept Physiol & Membrane Biol, Davis, CA 95616 USA. RP Feeley, BT (reprint author), San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. EM feeleyb@orthosurg.ucsf.edu FU Orthopaedic Research & Education Foundation (OREF); VA RRD [RX000195] FX This work was supported by the Orthopaedic Research & Education Foundation (OREF) and VA RR&D (grant #: RX000195). NR 24 TC 15 Z9 15 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD SEP PY 2012 VL 30 IS 9 BP 1440 EP 1446 DI 10.1002/jor.22096 PG 7 WC Orthopedics SC Orthopedics GA 972WH UT WOS:000306311400013 PM 22378614 ER PT J AU Hasserjian, RP Preffer, FI AF Hasserjian, Robert P. Preffer, Frederic I. TI Flow cytometry to distinguish myelodysplastic syndromes from non-neoplastic causes of cytopenia: Ready for prime time? SO LEUKEMIA RESEARCH LA English DT Editorial Material DE Myelodysplastic syndrome; Therapy-related; Flow cytometry; Cytopenia; Chemotherapy ID BONE-MARROW; MUTATIONS; DYSPLASIA; CELLS C1 [Hasserjian, Robert P.; Preffer, Frederic I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM rhasserjian@partners.org NR 19 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD SEP PY 2012 VL 36 IS 9 BP 1089 EP 1090 DI 10.1016/j.leukres.2012.03.029 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 975PP UT WOS:000306523600010 PM 22727507 ER PT J AU George, RE Perez-Atayde, AR Yao, XP London, WB Shamberger, RC Neuberg, D Diller, L AF George, Rani E. Perez-Atayde, Antonio R. Yao, Xiaopan London, Wendy B. Shamberger, Robert C. Neuberg, Donna Diller, Lisa TI Tumor histology during induction therapy in patients with high-risk neuroblastoma SO PEDIATRIC BLOOD & CANCER LA English DT Article DE histology; induction; mitosis; neuroblastoma; persistent neuroblastic cells ID BONE-MARROW-TRANSPLANTATION; SCHWANNIAN STROMA-POOR; STAGE-IV NEUROBLASTOMA; HIGH-DOSE THERAPY; PATHOLOGY CLASSIFICATION; PROGNOSTIC-FACTORS; UNSELECTED GROUP; SURVIVAL; CHEMOTHERAPY; DIAGNOSIS AB Background In high-risk neuroblastoma patients, response to induction chemotherapy is emerging as an important determinant of overall survival. We sought to determine whether histological changes in the primary tumor following induction therapy could be used as a marker of response. Procedure Second-look primary tumor specimens from 43 patients were reviewed according to specific morphological features. Results In the majority, induction therapy resulted in a shift from an intermediate/high to low mitosis-karyorrhexis index (MKI) (P?=?0.0009) and from undifferentiated/poorly differentiated to differentiating tumors (P? C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-kappa B signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenstrom's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenstrom's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced I kappa B alpha and NF-kappa B p65 phosphorylation, as well as NF-kappa B nuclear staining, in Waldenstrom's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenstrom's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. CONCLUSIONS MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom's macroglobulinemia that can be useful in differentiating Waldenstrom's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.) C1 [Treon, Steven P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Pinkus, Geraldine S.; Rodig, Scott J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Sohani, Aliyah R.; Harris, Nancy Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. [Hunter, Zachary R.] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. [Arcaini, Luca] Univ Pavia, Sch Med, Dept Hematol Oncol, I-27100 Pavia, Italy. [Arcaini, Luca] Policlin San Matteo, Fdn Ist Ricovero & Cura Carattere Sci IRCCS, I-27100 Pavia, Italy. [Laramie, Jason M.; Skifter, Donald A.; Lincoln, Stephen E.] Complete Genom, Mountain View, CA USA. RP Treon, SP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,450 Brookline Ave, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu RI Hunter, Zachary/H-3018-2013; Arcaini, Luca/P-8913-2015 OI Hunter, Zachary/0000-0002-1689-1691; Arcaini, Luca/0000-0002-9504-991X FU Peter and Helen Bing Foundation; International Waldenstrom's Macroglobulinemia Foundation; Coyote Fund for Waldenstrom's Macroglobulinemia; Waldenstrom's Cancer Fund; Bailey Family Fund for Waldenstrom's Macroglobulinemia; D'Amato Family Fund for Genomic Discovery; Edward and Linda Nelson Fund for Waldenstrom's Macroglobulinemia Research; Bauman Family Trust; Tannenhauser Family Foundation FX Funded by the Peter and Helen Bing Foundation and others.; Supported by the Peter and Helen Bing Foundation, the International Waldenstrom's Macroglobulinemia Foundation, the Coyote Fund for Waldenstrom's Macroglobulinemia, the Waldenstrom's Cancer Fund, the Bailey Family Fund for Waldenstrom's Macroglobulinemia, the D'Amato Family Fund for Genomic Discovery, the Edward and Linda Nelson Fund for Waldenstrom's Macroglobulinemia Research, the Bauman Family Trust, and the Tannenhauser Family Foundation. NR 35 TC 327 Z9 344 U1 1 U2 21 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 30 PY 2012 VL 367 IS 9 BP 826 EP 833 DI 10.1056/NEJMoa1200710 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 996EN UT WOS:000308067400004 PM 22931316 ER PT J AU Byrne, TN Isakoff, SJ Rincon, SP Gudewicz, TM AF Byrne, Thomas N. Isakoff, Steven Jay Rincon, Sandra P. Gudewicz, Thomas M. TI Case 27-2012: A 60-Year-Old Woman with Painful Muscle Spasms and Hyperreflexia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STIFF-PERSON SYNDROME; PRIMARY BREAST-CANCER; AMPHIPHYSIN; CARCINOMA; METASTASES; ANTIBODIES C1 [Byrne, Thomas N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Isakoff, Steven Jay] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Rincon, Sandra P.] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Gudewicz, Thomas M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Byrne, Thomas N.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Isakoff, Steven Jay] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Rincon, Sandra P.] Harvard Univ, Sch Med, Dept Neuroradiol, Boston, MA 02115 USA. [Gudewicz, Thomas M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Byrne, TN (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 21 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 30 PY 2012 VL 367 IS 9 BP 851 EP 861 DI 10.1056/NEJMcpc1114036 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 996EN UT WOS:000308067400009 PM 22931320 ER PT J AU Barth, RF Vicente, MGH Harling, OK Kiger, WS Riley, KJ Binns, PJ Wagner, FM Suzuki, M Aihara, T Kato, I Kawabata, S AF Barth, Rolf F. Vicente, M. Graca H. Harling, Otto K. Kiger, W. S., III Riley, Kent J. Binns, Peter J. Wagner, Franz M. Suzuki, Minoru Aihara, Teruhito Kato, Itsuro Kawabata, Shinji TI Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer SO RADIATION ONCOLOGY LA English DT Review DE Boron neutron capture therapy; Gliomas; Head and neck cancer; Radiation therapy ID NEWLY-DIAGNOSED GLIOBLASTOMA; INTERNATIONAL DOSIMETRY EXCHANGE; EPIDERMAL-GROWTH-FACTOR; CERVICAL LYMPH-NODE; TSUKUBA BNCT TRIAL; I CLINICAL-TRIAL; EPITHERMAL NEUTRON; BRAIN-TUMORS; AMINO-ACIDS; COMPUTATIONAL DOSIMETRY AB Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 mu g/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or "BPA", and sodium borocaptate or "BSH" (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options. C1 [Barth, Rolf F.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Vicente, M. Graca H.] Louisiana State Univ, Dept Chem, Baton Rouge, LA 70803 USA. [Harling, Otto K.] MIT, Dept Nucl Sci & Engn, Cambridge, MA 02139 USA. [Kiger, W. S., III] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Riley, Kent J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Binns, Peter J.] Mt Auburn Hosp, Dept Radiat Oncol, Cambridge, MA 02138 USA. [Wagner, Franz M.] Tech Univ Munich, Forsch Neutronenquelle Heinz Maier Leibnitz FRM 2, D-8046 Garching, Germany. [Suzuki, Minoru] Kyoto Univ, Particle Radiat Oncol Res Ctr, Osaka, Japan. [Aihara, Teruhito] Kawasaki Med Univ, Dept Otolaryngol & Head & Neck Surg, Okayama, Japan. [Kato, Itsuro] Osaka Univ, Grad Sch Dent, Dept Oral & Maxillofacial Surg 2, Osaka, Japan. [Kawabata, Shinji] Osaka Med Coll, Dept Neurosurg, Takatsuki, Osaka 569, Japan. RP Barth, RF (reprint author), Ohio State Univ, Dept Pathol, 165 Hamilton Hall,1645 Neil Ave, Columbus, OH 43210 USA. EM rolf.barth@osumc.edu FU United States Department of Energy; National Institutes of Health; Ministry of Health, Labor and Welfare (MONBUSHO) from the government of Japan; BNCT Committee of Kyoto University Research Reactor Institute, Japan Atomic Energy Agency FX This paper is dedicated to Professor Emeritus Albert H. Soloway in celebration of his 87th birthday. Dr. Barth thanks Mrs. Heidi Bosworth for expert secretarial assistance in the preparation of this manuscript. Research of Drs. Barth, Binns, Harling, Kiger, Riley and Vicente has been supported by numerous grants from the United States Department of Energy and the National Institutes of Health. Animal studies described in this review were carried out under protocols approved by the respective Institutional Animal Care and Use Committees and in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Dr. Kawabata's clinical studies have been supported by grants from the Ministry of Health, Labor and Welfare (MONBUSHO) from the government of Japan and were approved by the Ethical Committee of Osaka Medical College (No. 98, 218, 260) and by the BNCT Committee of Kyoto University Research Reactor Institute, Japan Atomic Energy Agency. Clinical studies that were carried out at Osaka University, Department of Oral and Maxillofacial Surgery II, were approved by the Ethics Committee of Osaka University Dental Hospital under approved Protocol H19-C1. Clinical studies carried out at Kawasaki Medical School, Okayama, Japan, were approved by the Institutional Ethical Committee. NR 127 TC 64 Z9 66 U1 4 U2 71 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD AUG 29 PY 2012 VL 7 AR 146 DI 10.1186/1748-717X-7-146 PG 21 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 007UN UT WOS:000308914000001 PM 22929110 ER PT J AU Karmacharya, D Yu, DM Dixit, S Rajbhandari, R Subedi, B Shrestha, S Manandhar, S Santangelo, SL AF Karmacharya, Dibesh Yu, Dongmei Dixit, Sameer Rajbhandari, Rajesh Subedi, Bhawana Shrestha, Sonu Manandhar, Sulochana Santangelo, Susan L. TI A study of the prevalence and risk factors leading to HIV infection among a sample of street children and youth of Kathmandu SO AIDS RESEARCH AND THERAPY LA English DT Article DE HIV prevalence; Behavioural risk factors; Intravenous drug use; Street children; Kathmandu; Nepal ID SEROPREVALENCE; DRUG; SEX AB Background: The true prevalence of HIV and other sexually transmitted diseases among street children in Nepal is virtually unknown while information on related behavioural risk factors in this population is non-existent. The risk of HIV infection among street children and adolescents may be especially high due to their marginalized social and economic conditions. This study was conducted to determine the prevalence of HIV infection among a sample of street children and youth of Kathmandu and to identify risk factors associated with HIV infection in this group. A sample of street children and youth was recruited based on the purposive sampling of ten streets in Kathmandu, Nepal, known to have a high density of street children and youth. A total of 251 street children (aged 11-16 years) and youth (aged 17-24 years) were enrolled, with informed consent, from November, 2008 through June, 2009. Most of the participants (95%) were male. Case status was determined by serological assessment of HIV status; data on risk factors were obtained using structured survey interviews. HIV prevalence and rates of a number of behavioural risk factors suspected to play a role in HIV transmission among street children and youth were determined, including unprotected sex, intravenous drug use, and other risky sex and substance use behaviours. Results: Among the 251 children and youth, we found an overall HIV prevalence of 7.6%. As the sample size of females was small (n = 13) and the behavioural risk factors are likely to be quite different for boys and girls, we conducted separate analyses by gender. As our small sample of females is unlikely to be representative and lacks power for statistical testing, our report focuses on the results for the males surveyed. The strongest behavioural risk factor to emerge from this study was intravenous drug use; 30% of the male subjects were injecting drug users and 20% of those were HIV positive. Furthermore, frequency of drug injection was a highly significant predictor with a dose-response relationship; males reporting occasional injection drug use were nearly 9 times more likely to be HIV positive than never users, while weekly drug injectors had over 46 times the risk of non-users, controlling for exposure to group sex, the only other significant risk factor in the multivariate model. Conclusions: This sample of street children and youth of Kathmandu has a nearly 20-fold higher prevalence of HIV infection than the general population of Nepal (0.39%). The children and youth engage in number of high risk behaviours, including intravenous drug use, putting them at significant risk of contracting HIV and other sexually transmitted infections. C1 [Karmacharya, Dibesh; Dixit, Sameer; Rajbhandari, Rajesh; Subedi, Bhawana; Shrestha, Sonu; Manandhar, Sulochana] Ctr Mol Dynam Nepal, Kathmandu, Nepal. [Yu, Dongmei; Santangelo, Susan L.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Santangelo, Susan L.] Harvard Univ, Sch Publ Hlth, Sch Med, Boston, MA 02115 USA. RP Karmacharya, D (reprint author), Ctr Mol Dynam Nepal, Thapathali 11, Kathmandu, Nepal. EM dibesh@cmdn.org FU NRN (Non-Nepalese Residents) Community of North America; Friends of Nepal-Los Angeles, Friends of Nepal-New Jersey; UNICEF/Nepal; District AIDS Coordination Committee (DACC) of Kathmandu City FX This study was supported by financial contributions from the NRN (Non-Nepalese Residents) Community of North America, Friends of Nepal-Los Angeles, Friends of Nepal-New Jersey and UNICEF/Nepal. We will be forever grateful for their support, and for the participation of the street children and youth of Kathmandu, without which this study would not have been possible. We would also like to thank the District AIDS Coordination Committee (DACC) of Kathmandu City for their support, the National Center for AIDS and STD Control (NCASC) for technical and logistical support and all the stakeholders that are involved in the fight against HIV/AIDS in Nepal. We would also like to thank Ms. Rupa Sharma of the Arkansas Department of Health (USA) and Mr. Ganesh Sharma for their valuable input on the study design and analysis. NR 15 TC 4 Z9 4 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PD AUG 28 PY 2012 VL 9 AR 25 DI 10.1186/1742-6405-9-25 PG 7 WC Infectious Diseases SC Infectious Diseases GA 072UX UT WOS:000313699800001 PM 22929124 ER PT J AU Campos, F Perez-Mato, M Agulla, J Blanco, M Barral, D Almeida, A Brea, D Waeber, C Castillo, J Ramos-Cabrer, P AF Campos, Francisco Perez-Mato, Maria Agulla, Jesus Blanco, Miguel Barral, David Almeida, Angeles Brea, David Waeber, Christian Castillo, Jose Ramos-Cabrer, Pedro TI Glutamate Excitoxicity Is the Key Molecular Mechanism Which Is Influenced by Body Temperature during the Acute Phase of Brain Stroke SO PLOS ONE LA English DT Article ID ACUTE ISCHEMIC-STROKE; FOCAL CEREBRAL-ISCHEMIA; MILD HYPOTHERMIA; BLOOD-FLOW; RAT-BRAIN; OXALOACETATE; METABOLISM; LACTATE; SPECTROSCOPY; COMBINATION AB Glutamate excitotoxicity, metabolic rate and inflammatory response have been associated to the deleterious effects of temperature during the acute phase of stroke. So far, the association of temperature with these mechanisms has been studied individually. However, the simultaneous study of the influence of temperature on these mechanisms is necessary to clarify their contributions to temperature-mediated ischemic damage. We used non-invasive Magnetic Resonance Spectroscopy to simultaneously measure temperature, glutamate excitotoxicity and metabolic rate in the brain in animal models of ischemia. The immune response to ischemia was measured through molecular serum markers in peripheral blood. We submitted groups of animals to different experimental conditions (hypothermia at 33 degrees C, normothermia at 37 degrees C and hyperthermia at 39 degrees C), and combined these conditions with pharmacological modulation of glutamate levels in the brain through systemic injections of glutamate and oxaloacetate. We show that pharmacological modulation of glutamate levels can neutralize the deleterious effects of hyperthermia and the beneficial effects of hypothermia, however the analysis of the inflammatory response and metabolic rate, demonstrated that their effects on ischemic damage are less critical than glutamate excitotoxity. We conclude that glutamate excitotoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke. C1 [Campos, Francisco; Perez-Mato, Maria; Agulla, Jesus; Blanco, Miguel; Barral, David; Brea, David; Castillo, Jose; Ramos-Cabrer, Pedro] Univ Santiago de Compostela, IDIS, Hosp Univ Santiago, Clin Neurosci Res Lab,Dept Neurol, Santiago De Compostela, Spain. [Almeida, Angeles] Hosp Univ Salamanca, Res Unit, Salamanca, Spain. [Almeida, Angeles] Inst Hlth Sci Castilla & Leon, Salamanca, Spain. [Almeida, Angeles] Univ Salamanca, Dept Biochem & Mol Biol, E-37008 Salamanca, Spain. [Waeber, Christian] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. RP Campos, F (reprint author), Univ Santiago de Compostela, IDIS, Hosp Univ Santiago, Clin Neurosci Res Lab,Dept Neurol, Santiago De Compostela, Spain. EM francampos@linc-stg.eu; pedro.ramos@usc.es RI Waeber, Christian/A-8333-2009; Brea Lopez, David/M-1128-2015; Ramos-Cabrer, Pedro/J-5306-2014; OI Waeber, Christian/0000-0001-6078-0027; Brea Lopez, David/0000-0003-2365-7374; Ramos-Cabrer, Pedro/0000-0003-0368-7031; Castillo, Jose/0000-0002-6685-3001 FU Spanish Ministry of Science and Innovation [SAF2011-30517]; Fondo de Investigaciones Sanitarias, Instituto Salud Carlos III [RETICS-RD06/0026]; Xunta de Galicia (Conselleria de Innovacion, Industria e Comercio) [09CSA057918PR]; Xunta de Galicia (Conselleria de Sanidade) [PS09/32]; Xunta de Galicia (Fundacion Mutua Madrilena); Red de Investigacion Cooperativa Neurovascular FX This project has been partially supported by grants from the Spanish Ministry of Science and Innovation SAF2011-30517 and Fondo de Investigaciones Sanitarias, Instituto Salud Carlos III, RETICS-RD06/0026; Xunta de Galicia (Conselleria de Innovacion, Industria e Comercio: 09CSA057918PR; Conselleria de Sanidade: PS09/32 and; Fundacion Mutua Madrilena and by Red de Investigacion Cooperativa Neurovascular. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 18 Z9 20 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 28 PY 2012 VL 7 IS 8 AR e44191 DI 10.1371/journal.pone.0044191 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998CA UT WOS:000308213600090 PM 22952923 ER PT J AU Huang, S Belliveau, JW Tengshe, C Ahveninen, J AF Huang, Samantha Belliveau, John W. Tengshe, Chinmayi Ahveninen, Jyrki TI Brain Networks of Novelty-Driven Involuntary and Cued Voluntary Auditory Attention Shifting SO PLOS ONE LA English DT Article ID EVENT-RELATED FMRI; MEDIAL FRONTAL-CORTEX; SCALE NEURAL-NETWORK; SPATIAL ATTENTION; MISMATCH NEGATIVITY; CORTICAL NETWORK; PREFRONTAL CORTEX; PARIETAL CORTEX; ACOUSTIC NOISE; INCREASED DISTRACTIBILITY AB In everyday life, we need a capacity to flexibly shift attention between alternative sound sources. However, relatively little work has been done to elucidate the mechanisms of attention shifting in the auditory domain. Here, we used a mixed event-related/sparse-sampling fMRI approach to investigate this essential cognitive function. In each 10-sec trial, subjects were instructed to wait for an auditory "cue" signaling the location where a subsequent "target" sound was likely to be presented. The target was occasionally replaced by an unexpected "novel" sound in the uncued ear, to trigger involuntary attention shifting. To maximize the attention effects, cues, targets, and novels were embedded within dichotic 800-Hz vs. 1500-Hz pure-tone "standard" trains. The sound of clustered fMRI acquisition (starting at t = 7.82 sec) served as a controlled trial-end signal. Our approach revealed notable activation differences between the conditions. Cued voluntary attention shifting activated the superior intra-parietal sulcus (IPS), whereas novelty-triggered involuntary orienting activated the inferior IPS and certain subareas of the precuneus. Clearly more widespread activations were observed during voluntary than involuntary orienting in the premotor cortex, including the frontal eye fields. Moreover, we found -evidence for a frontoinsular-cingular attentional control network, consisting of the anterior insula, inferior frontal cortex, and medial frontal cortices, which were activated during both target discrimination and voluntary attention shifting. Finally, novels and targets activated much wider areas of superior temporal auditory cortices than shifting cues. C1 [Huang, Samantha; Belliveau, John W.; Tengshe, Chinmayi; Ahveninen, Jyrki] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Belliveau, John W.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Huang, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM samhuang@nmr.mgh.harvard.edu FU National Institutes of Health [R01MH083744, R21DC010060, R01HD040712, R01NS037462, P41RR14075]; [S10RR014978]; [S10RR021110]; [S10RR019307]; [S10RR023401] FX This work was supported by National Institutes of Health awards R01MH083744, R21DC010060, R01HD040712, R01NS037462, and P41RR14075. The research environment was supported by Shared Instrumentation grants S10RR014978, S10RR021110, S10RR019307, and S10RR023401. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 115 TC 24 Z9 24 U1 2 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 28 PY 2012 VL 7 IS 8 AR e44062 DI 10.1371/journal.pone.0044062 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998CA UT WOS:000308213600073 PM 22937153 ER PT J AU Lage, K Greenway, SC Rosenfeld, JA Wakimoto, H Gorham, JM Segre, AV Roberts, AE Smoot, LB Pu, WT Pereira, AC Mesquita, SM Tommerup, N Brunak, S Ballif, BC Shaffer, LG Donahoe, PK Daly, MJ Seidman, JG Seidman, CE Larsen, LA AF Lage, Kasper Greenway, Steven C. Rosenfeld, Jill A. Wakimoto, Hiroko Gorham, Joshua M. Segre, Ayellet V. Roberts, Amy E. Smoot, Leslie B. Pu, William T. Pereira, Alexandre C. Mesquita, Sonia M. Tommerup, Niels Brunak, Soren Ballif, Blake C. Shaffer, Lisa G. Donahoe, Patricia K. Daly, Mark J. Seidman, Jonathan G. Seidman, Christine E. Larsen, Lars A. TI Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genetics; transcriptional profiles; systems biology; developmental biology ID DE-NOVO MUTATIONS; EXPRESSION; DISORDERS; MORPHOGENESIS; COMPLEXES; SPECTRUM; DEFECTS; MODEL; GATA4 AB Congenital heart disease (CHD) occurs in similar to 1% of newborns. CHD arises from many distinct etiologies, ranging from genetic or genomic variation to exposure to teratogens, which elicit diverse cell and molecular responses during cardiac development. To systematically explore the relationships between CHD risk factors and responses, we compiled and integrated comprehensive datasets from studies of CHD in humans and model organisms. We examined two alternative models of potential functional relationships between genes in these datasets: direct convergence, in which CHD risk factors significantly and directly impact the same genes and molecules and functional convergence, in which risk factors significantly impact different molecules that participate in a discrete heart development network. We observed no evidence for direct convergence. In contrast, we show that CHD risk factors functionally converge in protein networks driving the development of specific anatomical structures (e.g., outflow tract, ventricular septum, and atrial septum) that are malformed by CHD. This integrative analysis of CHD risk factors and responses suggests a complex pattern of functional interactions between genomic variation and environmental exposures that modulate critical biological systems during heart development. C1 [Lage, Kasper; Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Roberts, Amy E.; Smoot, Leslie B.; Pu, William T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lage, Kasper; Donahoe, Patricia K.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Greenway, Steven C.; Wakimoto, Hiroko; Gorham, Joshua M.; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Daly, Mark J.; Seidman, Christine E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Seidman, Christine E.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Lage, Kasper; Segre, Ayellet V.; Donahoe, Patricia K.; Daly, Mark J.] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Lage, Kasper; Brunak, Soren] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Lage, Kasper; Segre, Ayellet V.; Donahoe, Patricia K.; Daly, Mark J.] Univ Copenhagen, Ctr Prot Res, Fac Hlth Sci, DK-2200 Copenhagen, Denmark. [Rosenfeld, Jill A.; Ballif, Blake C.; Shaffer, Lisa G.] PerkinElmer Inc, Signature Genom Labs, Spokane, WA 99207 USA. [Wakimoto, Hiroko; Segre, Ayellet V.] Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Roberts, Amy E.] Partners HealthCare Ctr Genet & Genom, Boston, MA 02139 USA. [Pu, William T.; Donahoe, Patricia K.] Harvard Stem Cell Inst, Boston, MA 02138 USA. [Smoot, Leslie B.; Pereira, Alexandre C.; Mesquita, Sonia M.] Univ Sao Paulo, Sch Med, Heart Inst InCor, Lab Genet & Mol Cardiol, BR-05403000 Sao Paulo, Brazil. [Tommerup, Niels; Larsen, Lars A.] Univ Copenhagen, Dept Cellular & Mol Med, Wilhelm Johannsen Ctr Funct Genome Res, DK-2200 Copenhagen, Denmark. RP Lage, K (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. EM lage.kasper@mgh.harvard.edu; cseidman@genetics.med.harvard.edu; larsal@sund.ku.dk FU Danish Heart Foundation; Forskningsradet for Sundhed og Sygdom; Eleanor and Miles Shore Fellowship; Pediatric Scientist Developmental Program; National Institutes of Health [NICHD HD055150-03, 1P01HD068250-01, NHLBI UO1 HL098166, U01 HL098147]; Howard Hughes Medical Institute FX This work was supported by grants from the Danish Heart Foundation (L.A.L.), Forskningsradet for Sundhed og Sygdom and the Eleanor and Miles Shore Fellowship (K.L.), the Pediatric Scientist Developmental Program (S.C.G.), the National Institutes of Health (NICHD HD055150-03 and 1P01HD068250-01 to K.L. and P.K.D. and NHLBI UO1 HL098166 and U01 HL098147 to A.E.R., W.T.P., H.W., J.M.G., C.E.S. and J.G.S.), and the Howard Hughes Medical Institute (C.E.S). NR 28 TC 32 Z9 33 U1 0 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2012 VL 109 IS 35 BP 14035 EP 14040 DI 10.1073/pnas.1210730109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300038 PM 22904188 ER PT J AU Larman, TC DePalma, SR Hadjipanayis, AG Protopopov, A Zhang, JH Gabriel, SB Chin, L Seidman, CE Kucherlapati, R Seidman, JG AF Larman, Tatianna C. DePalma, Steven R. Hadjipanayis, Angela G. Protopopov, Alexei Zhang, Jianhua Gabriel, Stacey B. Chin, Lynda Seidman, Christine E. Kucherlapati, Raju Seidman, J. G. CA Canc Genome Atlas Res Network TI Spectrum of somatic mitochondrial mutations in five cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE deleterious mutations; colon adenocarcinoma; rectal adenomcarcinoma; acute myeloid leukemia; ovarian serous cystadenocarcinoma ID DNA MUTATIONS; CELL-METABOLISM; GENOME; SELECTION; DISEASE; TUMORS; MTDNA; DEHYDROGENASE; GENERATION; PROSTATE AB Somatic mtDNA mutations have been reported in some human tumors, but their spectrum in different malignancies and their role in cancer development remain incompletely understood. Here, we describe the breadth of somatic and inherited mutations across the mitochondrial genome by sequence analyses of paired tumor and normal tissue samples from 226 individuals with five types of cancer using whole-genome data generated by The Cancer Genome Atlas Research Network. The frequencies of deleterious tumor-specific somatic mutations found in mtDNA varied across tumor types, ranging from 13% of glioblastomas to 63% of rectal adenocarcinomas. Compared with inherited mtDNA variants, somatic mtDNA mutations were enriched for nonsynonymous vs. synonymous changes (93 vs. 15; P < 2.2E-16) and were predicted to functionally impact the encoded protein. Somatic missense mutations in tumors were distributed uniformly among the mitochondrial protein genes, but 65% of somatic truncating mutations occurred in NADH dehydrogenase 5. Analysis of staging data in colon and rectal cancers revealed that the frequency of damaging mitochondrial mutations is the same in stages I and IV tumors. In summary, these data suggest that damaging somatic mtDNA mutations occur frequently (13-63%) in these five tumor types and likely confer a selective advantage in oncogenesis. C1 [Larman, Tatianna C.; DePalma, Steven R.; Hadjipanayis, Angela G.; Seidman, Christine E.; Kucherlapati, Raju; Seidman, J. G.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Larman, Tatianna C.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Larman, Tatianna C.; DePalma, Steven R.; Seidman, Christine E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Gabriel, Stacey B.] Broad Inst, Cambridge, MA 02142 USA. [Protopopov, Alexei; Zhang, Jianhua; Chin, Lynda] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Seidman, Christine E.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Seidman, JG (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM seidman@genetics.med.harvard.edu FU Howard Hughes Medical Institute; National Cancer Institute, National Institutes of Health; LeDucq Foundation; National Heart, Lung and Blood Institute, National Institutes of Health; SysCODE FX We thank the genome sequencing centers at the Broad Institute, Washington University, and Baylor College of Medicine for sequencing data production. We also thank Kai Wang (Children's Hospital, Philadelphia) and Yevgeniy Antipin (Memorial Sloan-Kettering Cancer Center) for assistance with variant calling and computational analyses. Studies were supported by The Howard Hughes Medical Institute (T.C.L. and C.E.S.), National Cancer Institute, National Institutes of Health (T.C.L., R.K., and J.G.S.), LeDucq Foundation (C.E.S. and J.G.S.), National Heart, Lung and Blood Institute, National Institutes of Health (J.G.S.), and SysCODE (J.G.S.). NR 42 TC 63 Z9 64 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2012 VL 109 IS 35 BP 14087 EP 14091 DI 10.1073/pnas.1211502109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300047 PM 22891333 ER PT J AU Fenton, TR Nathanson, D de Albuquerque, CP Kuga, D Iwanami, A Dang, J Yang, HJ Tanaka, K Oba-Shinjo, SM Uno, M Inda, MD Wykosky, J Bachoo, RM James, CD DePinho, RA Vandenberg, SR Zhou, HL Marie, SKN Mischel, PS Cavenee, WK Furnari, FB AF Fenton, Tim R. Nathanson, David de Albuquerque, Claudio Ponte Kuga, Daisuke Iwanami, Akio Dang, Julie Yang, Huijun Tanaka, Kazuhiro Oba-Shinjo, Sueli Mieko Uno, Miyuki Inda, Maria del Mar Wykosky, Jill Bachoo, Robert M. James, C. David DePinho, Ronald A. Vandenberg, Scott R. Zhou, Huilin Marie, Suely K. N. Mischel, Paul S. Cavenee, Webster K. Furnari, Frank B. TI Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glioma; phosphatase; erlotinib; gefitinib ID PROTEIN PHOSPHATASE-ACTIVITY; GROWTH-FACTOR RECEPTOR; TRASTUZUMAB RESISTANCE; FUNCTIONAL-ANALYSIS; CRYSTAL-STRUCTURE; MEK/ERK PATHWAY; NUCLEAR PTEN; IN-VIVO; GLIOMA; SRC AB Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM. C1 [Fenton, Tim R.; de Albuquerque, Claudio Ponte; Inda, Maria del Mar; Wykosky, Jill; Zhou, Huilin; Cavenee, Webster K.; Furnari, Frank B.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Vandenberg, Scott R.; Cavenee, Webster K.; Furnari, Frank B.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Vandenberg, Scott R.; Cavenee, Webster K.; Furnari, Frank B.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Vandenberg, Scott R.; Furnari, Frank B.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Zhou, Huilin] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Nathanson, David; Mischel, Paul S.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Kuga, Daisuke; Iwanami, Akio; Dang, Julie; Yang, Huijun; Tanaka, Kazuhiro; Mischel, Paul S.] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90095 USA. [Oba-Shinjo, Sueli Mieko; Uno, Miyuki; Marie, Suely K. N.] Univ Sao Paulo, Sch Med, Dept Neurol, Sao Paulo, Brazil. [Bachoo, Robert M.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Bachoo, Robert M.] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [James, C. David] Univ Calif San Francisco, Brain Tumor Res Ctr, Dept Neurol Surg, San Francisco, CA 94143 USA. [DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA. RP Cavenee, WK (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. EM wcavenee@ucsd.edu; ffurnari@ucsd.edu RI Oba-Shinjo, Sueli /C-4017-2012; Marie, Suely/D-1870-2012; OI Fenton, Tim/0000-0002-4737-8233 FU Goldhirsh Foundation; National Institutes of Health [P01-CA95616, P50-CA097257]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo Grant [04/12433-6] FX We thank Cameron Brennan (Memorial Sloan-Kettering Cancer Center) for the TS543 GBM tumor sphere line, Daniel Donoghue (University of California, San Diego) for the plasmid encoding FGFR3 K650E, Richard Kolodner (University of California, San Diego) and Rob de Bruin [Medical Research Council (MRC) Laboratory for Molecular Cell Biology, United Kingdom] for yeast reagents, and Stephen Henderson (University College London, United Kingdom) for assistance with bioinformatics. This work was supported by an award from the Goldhirsh Foundation (to F.B.F.), National Institutes of Health Grants P01-CA95616 (to R.A.D., W.K.C., and F.B.F.) and P50-CA097257 (to C.D.J. and P.S.M.), and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo Grant 04/12433-6 (to S.K.N.M). W.K.C. is a fellow of the National Foundation for Cancer Research. NR 45 TC 47 Z9 49 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2012 VL 109 IS 35 BP 14164 EP 14169 DI 10.1073/pnas.1211962109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300060 PM 22891331 ER PT J AU Baker, BM Shah, RP Silverstein, AM Esterhai, JL Burdick, JA Mauck, RL AF Baker, Brendon M. Shah, Roshan P. Silverstein, Amy M. Esterhai, John L. Burdick, Jason A. Mauck, Robert L. TI Sacrificial nanofibrous composites provide instruction without impediment and enable functional tissue formation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anisotropy; electrospinning; nanofiber; tissue engineering; meniscus fibrocartilage ID ENGINEERING SCAFFOLDS; ELECTROSPUN SCAFFOLDS; CELLULAR INFILTRATION; MENISCUS; ANISOTROPY; CELLS; ALIGNMENT; FIBERS; MATRIX; REPAIR AB The fibrous tissues prevalent throughout the body possess an ordered structure that underlies their refined and robust mechanical properties. Engineered replacements will require recapitulation of this exquisite architecture in three dimensions. Aligned nanofibrous scaffolds can dictate cell and matrix organization; however, their widespread application has been hindered by poor cell infiltration due to the tight packing of fibers during fabrication. Here, we develop and validate an enabling technology in which tunable composite nanofibrous scaffolds are produced to provide instruction without impediment. Composites were formed containing two distinct fiber fractions: slow-degrading poly(e-caprolactone) and water-soluble, sacrificial poly(ethylene oxide), which can be selectively removed to increase pore size. Increasing the initial fraction of sacrificial poly(ethylene oxide) fibers enhanced cell infiltration and improved matrix distribution. Despite the removal of >50% of the initial fibers, the remaining scaffold provided sufficient instruction to align cells and direct the formation of a highly organized ECM across multiple length scales, which in turn led to pronounced increases in the tensile properties of the engineered constructs (nearly matching native tissue). This approach transforms what is an interesting surface phenomenon (cells on top of nanofibrous mats) into a method by which functional, 3D tissues (>1 mm thick) can be formed, both in vitro and in vivo. As such, this work represents a marked advance in the engineering of load-bearing fibrous tissues, and will find widespread applications in regenerative medicine. C1 [Baker, Brendon M.; Shah, Roshan P.; Silverstein, Amy M.; Esterhai, John L.; Mauck, Robert L.] Univ Penn, McKay Orthopaed Res Lab, Dept Orthopaed Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Baker, Brendon M.; Silverstein, Amy M.; Burdick, Jason A.; Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Esterhai, John L.] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. RP Mauck, RL (reprint author), Univ Penn, McKay Orthopaed Res Lab, Dept Orthopaed Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. EM lemauck@mail.med.upenn.edu FU National Institutes of Health [R01 AR056624]; Department of Veterans Affairs [I01 RX000174]; National Science Foundation FX This work was supported by National Institutes of Health Grant R01 AR056624 and Department of Veterans Affairs Grant I01 RX000174. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. Additional support was provided by the Penn Center for Musculoskeletal Disorders and a National Science Foundation Graduate Research Fellowship (to B.M.B.). NR 33 TC 55 Z9 55 U1 4 U2 56 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2012 VL 109 IS 35 BP 14176 EP 14181 DI 10.1073/pnas.1206962109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300062 PM 22872864 ER PT J AU Wu, SM Milan, DJ AF Wu, Sean M. Milan, David J. TI Reprogramming the Beat Kicking It Up a Notch SO CIRCULATION LA English DT Editorial Material ID CARDIAC CONDUCTION SYSTEM; PURKINJE-FIBER DIFFERENTIATION; ENDOTHELIN-CONVERTING ENZYME-1; CONGENITAL HEART-DISEASE; EMBRYONIC STEM-CELLS; IN-VIVO; DEFINED FACTORS; DIRECT CONVERSION; HUMAN FIBROBLASTS; CARDIOMYOCYTES C1 [Milan, David J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Cambridge, MA USA. [Wu, Sean M.] Harvard Stem Cell Inst, Cambridge, MA USA. [Wu, Sean M.; Milan, David J.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Cardiovasc Res Ctr, Cambridge, MA USA. RP Milan, DJ (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Div Cardiol, Dept Med, 55 Fruit St, Boston, MA 02115 USA. EM DMilan@Partners.org FU NHLBI NIH HHS [U01 HL100408, HL109004, U01 HL099776, R01 HL109004, HL100408]; NIDA NIH HHS [R21 DA026982, DA026982]; NIH HHS [OD004411, DP2 OD004411] NR 38 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 28 PY 2012 VL 126 IS 9 BP 1009 EP 1011 DI 10.1161/CIRCULATIONAHA.112.126482 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 999ZK UT WOS:000308355100008 PM 22837161 ER PT J AU Kiefer, FW Cohen, P Plutzky, J AF Kiefer, Florian W. Cohen, Paul Plutzky, Jorge TI Fifty Shades of Brown Perivascular Fat, Thermogenesis, and Atherosclerosis SO CIRCULATION LA English DT Editorial Material DE Editorials; adipose tissue, brown; muscle, smooth; obesity; peroxisome proliferator-activated receptors; thermogenesis; atherosclerosis; adipose tissue, white ID ADIPOSE-TISSUE; CARDIOVASCULAR-DISEASE; INFLAMMATION; COLD; ADIPOCYTES; HUMANS; MOUSE; MEN C1 [Kiefer, Florian W.; Cohen, Paul; Plutzky, Jorge] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kiefer, Florian W.; Cohen, Paul; Plutzky, Jorge] Brigham & Womens Hosp, Div Cardiovasc, Vasc Dis Prevent Program, Boston, MA 02115 USA. [Cohen, Paul] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Plutzky, J (reprint author), Harvard Univ, Sch Med, 77 Ave Louis Pasteur,NRB 742, Boston, MA 02115 USA. EM jplutzky@rics.bwh.harvard.edu FU Austrian Science Fund FWF [J 3107]; NHLBI NIH HHS [P01 HL048743, HL048743,]; NIAMS NIH HHS [AR0546040351]; NIDDK NIH HHS [5P30DK057521] NR 22 TC 7 Z9 7 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 28 PY 2012 VL 126 IS 9 BP 1012 EP 1015 DI 10.1161/CIRCULATIONAHA.112.123521 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 999ZK UT WOS:000308355100009 PM 22927471 ER PT J AU Bonaca, MP Wiviott, SD Braunwald, E Murphy, SA Ruff, CT Antman, EM Morrow, DA AF Bonaca, Marc P. Wiviott, Stephen D. Braunwald, Eugene Murphy, Sabina A. Ruff, Christian T. Antman, Elliott M. Morrow, David A. TI Response to Letter Regarding Articles, "Long-Term Cardiovascular Mortality After Procedure-Related or Spontaneous Myocardial Infarction in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: A Collaborative Analysis of Individual Patient Data From the FRISC II, ICTUS, and RITA-3 Trials (FIR)" and "American College of Cardiology/American Heart Association/European Society of Cardiology/World Heart Federation Universal Definition of Myocardial Infarction Classification System and the Risk of Cardiovascular Death: Observations From the TRITON-TIMI 38 Trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38)" SO CIRCULATION LA English DT Letter C1 [Bonaca, Marc P.; Wiviott, Stephen D.; Braunwald, Eugene; Murphy, Sabina A.; Ruff, Christian T.; Antman, Elliott M.; Morrow, David A.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RP Bonaca, MP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 28 PY 2012 VL 126 IS 9 BP E138 EP E138 DI 10.1161/CIRCULATIONAHA.112.114496 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 999ZK UT WOS:000308355100005 ER PT J AU Fellin, T Ellenbogen, JM De Pitta, M Ben-Jacob, E Halassa, MM AF Fellin, Tommaso Ellenbogen, Jeffery M. De Pitta, Maurizio Ben-Jacob, Eshel Halassa, Michael M. TI Astrocyte regulation of sleep circuits: experimental and modeling perspectives SO FRONTIERS IN COMPUTATIONAL NEUROSCIENCE LA English DT Review DE glia; astrocytes; sleep; ATP; adenosine; neuronal networks; slow oscillations; computational models ID SLOW-WAVE SLEEP; GLIAL TNF-ALPHA; IN-VIVO; D-SERINE; SYNAPTIC PLASTICITY; NMDA RECEPTORS; LOCAL SLEEP; NEURONAL EXCITABILITY; NETWORK MECHANISMS; THALAMIC NETWORKS AB Integrated within neural circuits, astrocytes have recently been shown to modulate brain rhythms thought to mediate sleep function. Experimental evidence suggests that local impact of astrocytes on single synapses translates into global modulation of neuronal networks and behavior. We discuss these findings in the context of current conceptual models of sleep generation and function, each of which have historically focused on neural mechanisms. We highlight the implications and the challenges introduced by these results from a conceptual and computational perspective. We further provide modeling directions on how these data might extend our knowledge of astrocytic properties and sleep function. Given our evolving understanding of how local cellular activities during sleep lead to functional outcomes for the brain, further mechanistic and theoretical understanding of astrocytic contribution to these dynamics will undoubtedly be of great basic and translational benefit. C1 [Fellin, Tommaso] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. [Ellenbogen, Jeffery M.] Massachusetts Gen Hosp, Dept Neurol, Sleep Div, Boston, MA 02114 USA. [Ellenbogen, Jeffery M.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [De Pitta, Maurizio; Ben-Jacob, Eshel] Tel Aviv Univ, Sch Phys & Astron, Ramat Aviv, Israel. [Ben-Jacob, Eshel] Univ Calif San Diego, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA. [Halassa, Michael M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Halassa, Michael M.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Fellin, T (reprint author), Ist Italiano Tecnol, Dept Neurosci & Brain Technol, Via Morego 30, I-16163 Genoa, Italy. EM tommaso.fellin@iit.it; mhalassa@partners.org FU National Institute of Neurological Disorders and Stroke (NINDS) [K99 NS078115]; Telethon-Italy [GGP10138]; San Paolo "Programma in Neuroscienze"; FIRB [RBAP11X42L]; Tauber Family Fund; Maguy-Glass Chair in Physics of Complex Systems at Tel Aviv University FX We thank R. Beltramo and A. M. De Stasi for the pictures shown in Figure 1, and members of the Tommaso Fellin laboratory for helpful discussion. Maurizio De Pitta and Eshel Ben-Jacob are also grateful to H. Berry for insightful comments on modeling aspects discussed in this paper. This work was supported by K99 NS078115 from National Institute of Neurological Disorders and Stroke (NINDS) to Michael M. Halassa, Telethon-Italy (GGP10138), San Paolo "Programma in Neuroscienze" and FIRB (RBAP11X42L) to Tommaso Fellin, and the Tauber Family Fund and the Maguy-Glass Chair in Physics of Complex Systems at Tel Aviv University to Maurizio De Pitta and Eshel Ben-Jacob. NR 109 TC 10 Z9 10 U1 1 U2 17 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5188 J9 FRONT COMPUT NEUROSC JI Front. Comput. Neurosci. PD AUG 28 PY 2012 VL 6 AR 65 DI 10.3389/fncom.2012.00065 PG 10 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 995AK UT WOS:000307977700002 PM 22973222 ER PT J AU Ahmed, MI Aban, I Lloyd, SG Gupta, H Howard, G Inusah, S Peri, K Robinson, J Smith, P McGiffin, DC Schiros, CG Denney, T Dell'Italia, LJ AF Ahmed, Mustafa I. Aban, Inmaculada Lloyd, Steven G. Gupta, Himanshu Howard, George Inusah, Seidu Peri, Kalyani Robinson, Jessica Smith, Patty McGiffin, David C. Schiros, Chun G. Denney, Thomas, Jr. Dell'Italia, Louis J. TI A Randomized Controlled Phase IIb Trial of Beta(1)-Receptor Blockade for Chronic Degenerative Mitral Regurgitation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE beta blockade; medical therapy; mitral regurgitation; mitral valve disease ID CARDIAC-HYPERTROPHY; VOLUME-OVERLOAD; CARDIOCYTE; FRACTION; EJECTION; DOG AB Objectives The purpose of the study was to evaluate the effect of long-term beta(1)-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR). Background Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function. Methods Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or beta(1)-AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end-systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate. Results Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the beta(1)-AR blockade group required mitral valve surgery (p = 0.23). Conclusions beta(1)-AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload-Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428) (J Am Coll Cardiol 2012;60:833-8) (C) 2012 by the American College of Cardiology Foundation C1 [Dell'Italia, Louis J.] Univ Alabama Birmingham, Dept Med & Cardiovasc Dis, Div Cardiol, Birmingham, AL 35294 USA. [Aban, Inmaculada; Howard, George; Inusah, Seidu; Peri, Kalyani] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Lloyd, Steven G.; Gupta, Himanshu; Dell'Italia, Louis J.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [McGiffin, David C.] Univ Alabama Birmingham, Dept Cardiovasc Surg, Birmingham, AL 35294 USA. [Schiros, Chun G.; Denney, Thomas, Jr.] Auburn Univ, Samuel Ginn Coll Engn, Auburn, AL 36849 USA. RP Dell'Italia, LJ (reprint author), Univ Alabama Birmingham, Dept Med & Cardiovasc Dis, Div Cardiol, 901 19th St S,434 BMR2, Birmingham, AL 35294 USA. EM loudell@uab.edu FU National Heart, Lung and Blood Institute Specialized Center for Clinically Oriented Research (SCCOR) in Cardiac Dysfunction; National Institutes of Health, Bethesda, Maryland [P50HL077100] FX From the Department of Medicine and Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama; Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; Birmingham Veteran Affairs Medical Center, Birmingham, Alabama; Department of Cardiovascular Surgery, University of Alabama at Birmingham, Birmingham, Alabama; and the Samuel Ginn College of Engineering, Auburn University, Auburn, Alabama. This study was funded by the National Heart, Lung and Blood Institute Specialized Center for Clinically Oriented Research (SCCOR) in Cardiac Dysfunction, National Institutes of Health, Bethesda, Maryland (grant no.: P50HL077100). Drugs and placebos were supplied by AstraZeneca. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 19 TC 28 Z9 28 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 28 PY 2012 VL 60 IS 9 BP 833 EP 838 DI 10.1016/j.jacc.2012.04.029 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 997AY UT WOS:000308137600008 PM 22818065 ER PT J AU Abu-Yousif, AO Moor, ACE Zheng, X Savellano, MD Yu, WP Selbo, PK Hasan, T AF Abu-Yousif, Adnan O. Moor, Anne C. E. Zheng, Xiang Savellano, Mark D. Yu, Weiping Selbo, Pal K. Hasan, Tayyaba TI Epidermal growth factor receptor-targeted photosensitizer selectively inhibits EGFR signaling and induces targeted phototoxicity in ovarian cancer cells SO CANCER LETTERS LA English DT Article DE Ovarian cancer; Photodynamic therapy; Cetuximab; Verteporfin; Immunoconjugate ID DISSEMINATED INTRAPERITONEAL TUMORS; PHASE-II TRIAL; PHOTODYNAMIC THERAPY; IN-VIVO; MONOCLONAL-ANTIBODY; COLORECTAL-CANCER; DEBULKING SURGERY; MALIGNANT GLIOMA; CARCINOMA-CELLS; EX-VIVO AB Targeted photosensitizer delivery to EGFR-expressing cells was achieved in the present study using a high purity, targeted photoimmunoconjugate (PIC). When the PDT agent, benzoporphyrin derivative monoacid ring A (BPD) was coupled to an EGFR-targeting antibody (cetuximab), we observed altered cellular localization and selective phototoxicity of EGFR-positive cells, but no phototoxicity of EGFR-negative cells. Cetuximab in the PIC formulation blocked EGF-induced activation of the EGFR and downstream signaling pathways. Our results suggest that photoimmunotargeting is a useful dual strategy for the selective destruction of cancer cells and also exerts the receptor-blocking biological function of the antibody. (c) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Abu-Yousif, Adnan O.; Moor, Anne C. E.; Zheng, Xiang; Savellano, Mark D.; Yu, Weiping; Selbo, Pal K.; Hasan, Tayyaba] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. RP Hasan, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Bartlett Hall 314,40 Blossom St, Boston, MA 02114 USA. EM thasan@partners.org OI Selbo, Pal/0000-0002-5310-057X FU National Institutes of Health [RO1AR40352, 5R01CA160998, PO1CA84203]; Massachusetts Department of Public Health [34081126112]; Whitaker Foundation FX This study was supported by the National Institutes of Health Grant RO1AR40352, 5R01CA160998, PO1CA84203, a Grant from the Massachusetts Department of Public Health, (34081126112), and the Whitaker Foundation (MS). We thank Drs. Tara Heitner and James Marks (UCSF) for providing the transfected cell lines, and Drs. Jonathan P. Celli, Imran Rizvi, Klaas W. Mulder, Mr. Nathaniel Sznycer-Taub, and Ms. Divya Errabelli for superb technical advice. NR 58 TC 31 Z9 31 U1 0 U2 15 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 AUG 28 PY 2012 VL 321 IS 2 BP 120 EP 127 DI 10.1016/j.canlet.2012.01.014 PG 8 WC Oncology SC Oncology GA 953UV UT WOS:000304899600003 PM 22266098 ER PT J AU Gaber, AO Matas, AJ Henry, ML Brennan, DC Stevens, RB Kapur, S Ilsley, JN Kistler, KD Cosimi, AB AF Gaber, A. Osama Matas, Arthur J. Henry, Mitchell L. Brennan, Daniel C. Stevens, R. Brian Kapur, Sandip Ilsley, Jillian N. Kistler, Kristen D. Cosimi, A. Benedict CA Thymoglobulin Antibody TI Antithymocyte Globulin Induction in Living Donor Renal Transplant Recipients: Final Report of the TAILOR Registry SO TRANSPLANTATION LA English DT Article DE Antithymocyte globulin; Immunosuppression; Live donor transplantation; Renal transplantation ID FREE MAINTENANCE IMMUNOSUPPRESSION; RANDOMIZED-TRIAL; CORTICOSTEROID CESSATION; KIDNEY-TRANSPLANTATION; ACUTE REJECTION; UNITED-STATES; THERAPY; THYMOGLOBULIN; CYCLOSPORINE; TACROLIMUS AB Background. The Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry was established to assess clinical experience with rabbit antithymocyte globulin (rATG; Thymoglobulin) in living donor renal transplant recipients. Methods. From 2003 to 2008, US transplant centers prospectively entered information on patients who received rATG induction. In addition to standard United Network for Organ Sharing registry data elements, information was collected regarding immunosuppression, viral prophylaxis, acute rejection, and adverse events. Results. Data on 2322 patients from 49 transplant centers were enrolled and met inclusion criteria for analysis. Patient and graft survival were 99.3% and 99.0% at 6 months and 98.4% and 98.2% at 12 months as recorded in Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry and were 91.5% and 83.2% at 5 years by Kaplan-Meier estimates based on linked United Network for Organ Sharing registry records. Freedom from rejection was 93.6% through 5 years. Mean rATG cumulative dose was 5.29 mg/kg. More than one-third of patients (37.6%) were steroid-free at discharge, and nearly half of patients (48%) were steroid-free at 12 months. Before discharge, 3.2% experienced serious adverse events, with 11 events (0.005%) reported as possibly or probably related to rATG. Incidence of cytomegalovirus infection was 4.2% at 12 months, and 99.1% of patients were posttransplant lymphoproliferative disorder-free through 5 years. Conclusions. rATG induction in living donor renal transplantation is safe and associated with a low incidence of acute rejection and posttransplantation complications. C1 [Gaber, A. Osama] Methodist Hosp Syst, Methodist Hosp Phys Org, Dept Surg, Weill Cornell Med Coll, Houston, TX 77030 USA. [Matas, Arthur J.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. [Henry, Mitchell L.] Ohio State Univ, Wexner Med Ctr, Div Transplantat, Columbus, OH 43210 USA. [Brennan, Daniel C.] Washington Univ, Sch Med, Dept Med, Barnes Jewish Hosp,Renal Div, St Louis, MO 63110 USA. [Stevens, R. Brian] Univ Nebraska Med Ctr, Dept Surg, Omaha, NE USA. [Kapur, Sandip] NewYork Presbyterian Hosp, Weill Cornell Med Ctr, Div Transplant Surg, New York, NY USA. [Ilsley, Jillian N.] Sanofi Rech, Med Affairs, Cambridge, MA USA. [Kistler, Kristen D.] United BioSource Corp, Lexington, MA USA. [Cosimi, A. Benedict] Massachusetts Gen Hosp, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. RP Gaber, AO (reprint author), Methodist Hosp Syst, Methodist Hosp Phys Org, Dept Surg, Weill Cornell Med Coll, 6550 Fannin St,Suite SM1661, Houston, TX 77030 USA. EM aogaber@tmhs.org FU Genzyme Corporation; Novartis; Wyeth; Astellas; Roche FX The authors did not receive financial support for their participation in article development. Enrolling centers received per patient funds to offset the costs associated with additional data entry beyond the requirements of the United Network for Organ Sharing. J.N.I. is an employee of Sanofi (formerly Genzyme Corporation). K. D. K. is an employee of United BioSource Corporation (formerly Prosanos Corporation), which has received research support and/or consulting fees from Genzyme Corporation. Authors declare receiving research support and consulting fees from Genzyme Corporation (A.J.M, M. L. H., D. C. B., R. B. S, and S. K.), Novartis (A.J.M, D. C. B, R. B. S, and M. L. H), Wyeth (A.O.G, A.J.M, D. C. B, R. B. S, and M. L. H.), Astellas (A.J.M and D. C. B.), and Roche (A.J.M, D. C. B, M. L. H). A. B. C. has no conflicts of interest to declare. NR 31 TC 13 Z9 14 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 27 PY 2012 VL 94 IS 4 BP 331 EP 337 DI 10.1097/TP.0b013e31825a7d1f PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 997CE UT WOS:000308141000006 PM 22850297 ER PT J AU Schlenner, SM Weigmann, B Ruan, QG Chen, YH von Boehmer, H AF Schlenner, Susan M. Weigmann, Benno Ruan, Qingguo Chen, Youhai von Boehmer, Harald TI Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TGF-BETA; MEDIATED REGULATION; RETINOIC-ACID; EXPRESSION; MECHANISMS; GENE; DNA; GENERATION AB Regulatory T cells (T reg cells) are essential for the prevention of autoimmunity throughout life. T reg cell development occurs intrathymically but a subset of T reg cells can also differentiate from naive T cells in the periphery. In vitro, Smad signaling facilitates conversion of naive T cells into T reg cells but results in unstable Foxp3 expression. The TGF-beta-Smad response element in the foxp3 locus is located in the CNS1 region in close proximity to binding sites for transcription factors implicated in TCR and retinoic acid signaling. From in vitro experiments it was previously postulated that foxp3 transcription represents a hierarchical process of transcription factor binding in which Smad3 would play a central role in transcription initiation. However, in vitro conditions generate T reg cells that differ from T reg cells encountered in vivo. To address the relevance of Smad3 binding to the CNS1 enhancer in vivo, we generated mice that exclusively lack the Smad binding site (foxp3(CNS1mut)). We show that binding of Smad3 to the foxp3 enhancer is dispensable for T reg cell development in newborn and adult mice with the exception of the gut. C1 [Schlenner, Susan M.; von Boehmer, Harald] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Lab Lymphocyte Biol, Boston, MA 02115 USA. [Schlenner, Susan M.; von Boehmer, Harald] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Schlenner, Susan M.] Univ Leuven VIB, Dept Microbiol & Immunol, B-3000 Louvain, Belgium. [Weigmann, Benno] Univ Erlangen Nurnberg, Med Clin 1, D-91052 Erlangen, Germany. [Ruan, Qingguo; Chen, Youhai] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [von Boehmer, Harald] Harvard Univ, Harvard Fac Arts & Sci, Cambridge, MA 02138 USA. RP von Boehmer, H (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Lab Lymphocyte Biol, Boston, MA 02115 USA. EM harald_von_boehmer@dfci.harvard.edu FU National Institutes of Health [NIH-5R37AI053102-09]; German Research Foundation (DFG) [Schl 1897/1-1] FX This paper was supported by the National Institutes of Health (NIH-5R37AI053102-09 to H. von Boehmer) and the German Research Foundation (DFG, Schl 1897/1-1 to S.M. Schlenner). NR 26 TC 43 Z9 47 U1 2 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 27 PY 2012 VL 209 IS 9 BP 1529 EP 1535 DI 10.1084/jem.20112646 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 000XK UT WOS:000308423900002 PM 22908322 ER PT J AU Gupta, VA Kawahara, G Myers, JA Chen, AT Hall, TE Manzini, MC Currie, PD Zhou, Y Zon, LI Kunkel, LM Beggs, AH AF Gupta, Vandana A. Kawahara, Genri Myers, Jennifer A. Chen, Aye T. Hall, Thomas E. Manzini, M. Chiara Currie, Peter D. Zhou, Yi Zon, Leonard I. Kunkel, Louis M. Beggs, Alan H. TI A Splice Site Mutation in Laminin-alpha 2 Results in a Severe Muscular Dystrophy and Growth Abnormalities in Zebrafish SO PLOS ONE LA English DT Article ID LAMININ ALPHA-2; LAMA2 GENE; MEROSIN; MODEL; MUTANT; POPULATION; PHENOTYPE; MICE AB Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A) is a form of CMD caused by a defect in the laminin-alpha 2 gene (LAMA2). Laminin-alpha 2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC) complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2(cl501/cl501), exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8-15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-alpha 2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-alpha 2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD. C1 [Gupta, Vandana A.; Kawahara, Genri; Myers, Jennifer A.; Manzini, M. Chiara; Kunkel, Louis M.; Beggs, Alan H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Genom Program,Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Gupta, Vandana A.; Kawahara, Genri; Myers, Jennifer A.; Manzini, M. Chiara; Kunkel, Louis M.; Beggs, Alan H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Genet,Manton Ctr Orphan Dis Res, Boston, MA USA. [Chen, Aye T.; Zhou, Yi; Zon, Leonard I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Chen, Aye T.; Zhou, Yi; Zon, Leonard I.] Harvard Univ, Sch Med, Boston Childrens Hosp, Stem Cell Program, Boston, MA USA. [Currie, Peter D.] Monash Univ, Australian Regenerat Med Inst, Clayton, Vic 3800, Australia. [Zon, Leonard I.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA. RP Gupta, VA (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Genom Program,Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. EM beggs@enders.tch.harvard.edu RI Hall, Thomas/J-2125-2014 OI Hall, Thomas/0000-0002-7718-7614 FU Muscular Dystrophy Association [MDA201302]; National Institute of Health (NIH) grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR044345]; Lee and Penny Anderson Family Foundation; William Randolph Hearst Fund; NIH from the National Institute of Arthritis and Musculoskeletal and Skin Diseases [K01 AR062601-01]; National Institute of Child Health and Human Development [P30HD18655] FX This work was supported by the Muscular Dystrophy Association (MDA201302); National Institute of Health (NIH) grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR044345); by the Lee and Penny Anderson Family Foundation; and the William Randolph Hearst Fund. VAG was supported by NIH K01 AR062601-01 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. DNA sequencing was performed by the Children's Hospital Boston Genomics Program Molecular Genetics Core supported in part by National Institute of Child Health and Human Development grant (P30HD18655). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 15 Z9 15 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 27 PY 2012 VL 7 IS 8 AR e43794 DI 10.1371/journal.pone.0043794 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 995WH UT WOS:000308044800060 PM 22952766 ER PT J AU Hulgan, T Robbins, GK Kalams, SA Samuels, DC Grady, B Shafer, R Murdock, DG Selph, D Haas, DW Pollard, RB AF Hulgan, Todd Robbins, Gregory K. Kalams, Spyros A. Samuels, David C. Grady, Benjamin Shafer, Robert Murdock, Deborah G. Selph, Doug Haas, David W. Pollard, Richard B. CA AIDS Clinical Trials Grp TI T Cell Activation Markers and African Mitochondrial DNA Haplogroups among Non-Hispanic Black Participants in AIDS Clinical Trials Group Study 384 SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; BLOOD MONONUCLEAR-CELLS; SEQUENTIAL 3-DRUG REGIMENS; HIV-INFECTED PATIENTS; IMMUNE ACTIVATION; COUNT RECOVERY; IMMUNOLOGICAL SYNAPSE; PERIPHERAL NEUROPATHY; VIROLOGICAL RESPONSE; INITIAL THERAPY AB Introduction: Mitochondrial function influences T cell dynamics and is affected by mitochondrial DNA (mtDNA) variation. We previously reported an association between African mtDNA haplogroup L2 and less robust CD4 cell recovery on antiretroviral therapy (ART) in non-Hispanic black ACTG 384 subjects. We explored whether additional T cell parameters in this cohort differed by mtDNA haplogroup. Methods: ACTG 384 randomized ART-naive subjects to two different nucleoside regimens with efavirenz, nelfinavir, or both. CD4 and CD8 memory and activation markers were available at baseline and week 48 on most subjects. mtDNA sequencing was performed on whole blood DNA, and haplogroups were determined. We studied non-Hispanic black subjects with HIV RNA <400 copies/mL at week 48. Analyses included Wilcoxon ranksum test and linear regression. Results: Data from 104 subjects were included. Major African mtDNA haplogroups included L1 (N = 25), L2 (N = 31), and L3 (N = 32). Baseline age, HIV RNA, and CD4 cells did not differ between L2 and non-L2 haplogroups. Compared to non-L2 haplogroups, L2 subjects had lower baseline activated CD4 cells (median 12% vs. 17%; p = 0.03) and tended toward lower activated CD8 cells (41% vs. 47%; p = 0.06). At 48 weeks of ART, L2 subjects had smaller decreases in activated CD4 cells (-4% vs. -11%; p = 0.01), and smaller CD4 cell increases (+95 vs. +178; p = 0.002). In models adjusting for baseline age, CD4 cells, HIV RNA, and naive-to-memory CD4 cell ratio, haplogroup L2 was associated with lower baseline (p = 0.04) and 48-week change in (p = 0.01) activated CD4 cells. Conclusions: Among ART-naive non-Hispanic blacks, mtDNA haplogroup L2 was associated with baseline and 48-week change in T cell activation, and poorer CD4 cell recovery. These data suggest mtDNA variation may influence CD4 T cell dynamics by modulating T cell activation. Further study is needed to replicate these associations and identify mechanisms. C1 [Hulgan, Todd; Kalams, Spyros A.; Samuels, David C.; Grady, Benjamin; Murdock, Deborah G.; Selph, Doug; Haas, David W.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Robbins, Gregory K.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Shafer, Robert] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Pollard, Richard B.] Univ Calif Davis, Sacramento, CA 95817 USA. RP Hulgan, T (reprint author), Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. EM todd.hulgan@vanderbilt.edu RI Samuels, David/A-5393-2008; Murdock, Deborah/C-3483-2012; Samuels, David/C-1365-2012; Hulgan, Todd/B-3947-2014; Vella, Stefano/D-4912-2015 OI Samuels, David/0000-0003-3529-7791; Hulgan, Todd/0000-0002-3339-067X; Vella, Stefano/0000-0003-2347-5984 FU National Institutes of Health (NIH)/National Institute of Neurological Diseases and Stroke [NS059330]; National Institute of Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); Agouron/Pfizer; Bristol Myers Squibb; GlaxoSmithKline; NIH [AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, AI32782, AI27661, AI25859, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR000445]; Merck; Gilead Sciences; Schering-Plough; Boehringer-Ingelheim; National Institutes of Health [AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI069502, AI069419, AI077505, AI54999, HL087726, AI69495, 5T32GM80178, AI062435]; [AI38858] FX Funding for the genomic sequencing was provided by the National Institutes of Health (NIH)/National Institute of Neurological Diseases and Stroke grant NS059330. The project described was also supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), and National Institute of Dental and Craniofacial Research (NIDCR). AIDS Clinical Trials Group (ACTG) Study 384 was also supported by grant AI38858, and by Agouron/Pfizer, Bristol Myers Squibb, and GlaxoSmithKline. The ACTG sites contributing DNA for these analyses were funded by NIH grants AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, AI32782, AI27661, AI25859, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853, AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI069502, and AI069419. The ACTG Human DNA Repository is also supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1 TR000445. Additional NIH grant support included: AI077505, AI54999, HL087726, AI69495, 5T32GM80178 and AI062435. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors have read the journal's policy and have the following conflicts: TH has received research support from Merck. GKR has received research support from Gilead Sciences, Schering-Plough. DWH has received research grants from Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, and Merck, and has served as a consultant for Boehringer-Ingelheim. AIDS Clinical Trials Group (ACTG) Study 384 was also supported in part by Agouron/Pfizer, Bristol Myers Squibb, and GlaxoSmithKline. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 61 TC 2 Z9 2 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 27 PY 2012 VL 7 IS 8 AR e43803 DI 10.1371/journal.pone.0043803 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 995WH UT WOS:000308044800061 PM 22970105 ER PT J AU Lechene, CP Lee, GY Poczatek, JC Toner, M Biggers, JD AF Lechene, Claude P. Lee, Gloria Y. Poczatek, J. Collin Toner, Mehmet Biggers, John D. TI 3D Multi-isotope Imaging Mass Spectrometry Reveals Penetration of O-18-Trehalose in Mouse Sperm Nucleus SO PLOS ONE LA English DT Article ID SPERMATOZOA; PORE; CELLS AB The prevalence of genetically engineered mice in medical research has led to ever increasing storage costs. Trehalose has a significant beneficial effect in preserving the developmental potential of mouse sperm following partial desiccation and storage at temperatures above freezing. Using multi-isotope imaging mass spectrometry, we are able to image and measure trehalose in individual spermatozoa. We provide the first evidence that trehalose penetrates the nucleus of a mammalian cell, permitting tolerance to desiccation. These results have broad implications for long-term storage of mammalian cells. C1 [Lechene, Claude P.; Poczatek, J. Collin] Harvard Univ, Sch Med, Div Genet, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Lee, Gloria Y.; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Biggers, John D.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. RP Lechene, CP (reprint author), Harvard Univ, Sch Med, Div Genet, Brigham & Womens Hosp, Cambridge, MA 02138 USA. EM cpl@harvard.edu FU NIH/NIBIB [5P41 EB001974-10]; NIH/NIA [1R21AG034641-01]; NIH/NCRR [5 R24 RR018934] FX This work was funded through the following grants: NIH/NIBIB 5P41 EB001974-10, NIH/NIA 1R21AG034641-01 and NIH/NCRR 5 R24 RR018934. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 8 Z9 8 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 27 PY 2012 VL 7 IS 8 AR e42267 DI 10.1371/journal.pone.0042267 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 995WH UT WOS:000308044800006 PM 22952592 ER PT J AU Danzer, KM Kranich, LR Ruf, WP Cagsal-Getkin, O Winslow, AR Zhu, LY Vanderburg, CR McLean, PJ AF Danzer, Karin M. Kranich, Lisa R. Ruf, Wolfgang P. Cagsal-Getkin, Ozge Winslow, Ashley R. Zhu, Liya Vanderburg, Charles R. McLean, Pamela J. TI Exosomal cell-to-cell transmission of alpha synuclein oligomers SO MOLECULAR NEURODEGENERATION LA English DT Article DE Alpha synuclein; Oligomers; Exosomes; Parkinson's disease; Aggregation; Secretion ID CHAPERONE-MEDIATED AUTOPHAGY; PARKINSONS-DISEASE; NEURODEGENERATIVE DISORDERS; TRANSCRIPTION FACTOR; INCLUSION FORMATION; HUMAN MICRORNAS; EXPRESSION; PROTEIN; BODY; IDENTIFICATION AB Background: Aggregation of alpha-synuclein (asyn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinson's disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of asyn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted asyn across membranes. The aim of this study is to characterize the transcellular spread of asyn oligomers and determine their extracellular location. Results: Using a novel protein fragment complementation assay where asyn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that asyn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated asyn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free asyn oligomers. Specifically, we determine that asyn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of asyn oligomers is strongly influenced by autophagic activity. Conclusions: Our data suggest that asyn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of asyn oligomers is a mechanism whereby cells clear toxic asyn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in asyn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies. C1 [Danzer, Karin M.; Kranich, Lisa R.; Ruf, Wolfgang P.; Cagsal-Getkin, Ozge; Winslow, Ashley R.; Zhu, Liya; Vanderburg, Charles R.; McLean, Pamela J.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA USA. [Cagsal-Getkin, Ozge; Vanderburg, Charles R.] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr, Adv Tissue Resource Ctr, Boston, MA USA. RP McLean, PJ (reprint author), Mayo Clin, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM mclean.pamela@mayo.edu FU NIH [NS063963] FX This work was supported by NIH NS063963 to PJM. We thank Harvard Medical School EM core for electron microscopy assistance. NR 105 TC 174 Z9 174 U1 6 U2 61 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD AUG 24 PY 2012 VL 7 AR 42 DI 10.1186/1750-1326-7-42 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 028ZI UT WOS:000310464100001 PM 22920859 ER PT J AU Carroll, MC Isenman, DE AF Carroll, Michael C. Isenman, David E. TI Regulation of Humoral Immunity by Complement SO IMMUNITY LA English DT Review ID FOLLICULAR DENDRITIC CELLS; SUBCAPSULAR SINUS MACROPHAGES; EPSTEIN-BARR-VIRUS; RECEPTOR 2; B-CELLS; STAPHYLOCOCCUS-AUREUS; GERMINAL-CENTERS; LYMPH-NODES; AFFINITY MATURATION; ACQUIRED-IMMUNITY AB The complement system of innate immunity is important in regulating humoral immunity largely through the complement receptor CR2, which forms a coreceptor on B cells during antigen-induced activation. However, CR2 also retains antigens on follicular dendritic cells (FDCs). Display of antigen on FDCs is critical for clonal selection and affinity maturation of activated B cells. This review will discuss the role of complement in adaptive immunity in general with a focus on the interplay between CR2-associated antigen on B cells with CR2 expressed on FDCs. This latter interaction provides an opportunity for memory B cells to sample antigen over prolonged periods. The cocrystal structure of CR2 with its ligand C3d provides insight into how the complement system regulates access of antigen by B cells with implications for therapeutic manipulations to modulate aberrant B cell responses in the case of autoimmunity. C1 [Carroll, Michael C.] Harvard Univ, Childrens Hosp, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Childrens Hosp, Sch Med, Program Mol & Cellular Med, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Dept Pediat, Sch Med, Boston, MA 02115 USA. [Isenman, David E.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Isenman, David E.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. RP Carroll, MC (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM carroll@idi.harvard.edu FU NIAID NIH HHS [R01 AI039246] NR 73 TC 86 Z9 88 U1 1 U2 29 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 24 PY 2012 VL 37 IS 2 BP 199 EP 207 DI 10.1016/j.immuni.2012.08.002 PG 9 WC Immunology SC Immunology GA 998SX UT WOS:000308261800006 PM 22921118 ER PT J AU Acton, SE Astarita, JL Malhotra, D Lukacs-Kornek, V Franz, B Hess, PR Jakus, Z Kuligowski, M Fletcher, AL Elpek, KG Bellemare-Pelletier, A Sceats, L Reynoso, ED Gonzalez, SF Graham, DB Chang, J Peters, A Woodruff, M Kim, YA Swat, W Morita, T Kuchroo, V Carroll, MC Kahn, ML Wucherpfennig, KW Turley, SJ AF Acton, Sophie E. Astarita, Jillian L. Malhotra, Deepali Lukacs-Kornek, Veronika Franz, Bettina Hess, Paul R. Jakus, Zoltan Kuligowski, Michael Fletcher, Anne L. Elpek, Kutlu G. Bellemare-Pelletier, Angelique Sceats, Lindsay Reynoso, Erika D. Gonzalez, Santiago F. Graham, Daniel B. Chang, Jonathan Peters, Anneli Woodruff, Matthew Kim, Young-A. Swat, Wojciech Morita, Takashi Kuchroo, Vijay Carroll, Michael C. Kahn, Mark L. Wucherpfennig, Kai W. Turley, Shannon J. TI Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2 SO IMMUNITY LA English DT Article ID SECONDARY LYMPHOID ORGANS; IN-VIVO; LYMPHATIC VESSELS; RHO; MIGRATION; RAC; NEUTROPHILS; INVASION; GTPASES; ROLES AB To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces. C1 [Acton, Sophie E.; Astarita, Jillian L.; Malhotra, Deepali; Lukacs-Kornek, Veronika; Franz, Bettina; Fletcher, Anne L.; Elpek, Kutlu G.; Bellemare-Pelletier, Angelique; Sceats, Lindsay; Reynoso, Erika D.; Chang, Jonathan; Wucherpfennig, Kai W.; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Acton, Sophie E.] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England. [Astarita, Jillian L.; Malhotra, Deepali; Chang, Jonathan; Woodruff, Matthew] Harvard Univ, Sch Med, Div Med Sci, Boston, MA 02115 USA. [Hess, Paul R.; Jakus, Zoltan; Kahn, Mark L.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Hess, Paul R.; Jakus, Zoltan; Kahn, Mark L.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Kuligowski, Michael; Gonzalez, Santiago F.; Kim, Young-A.; Carroll, Michael C.] Harvard Univ, Immune Dis Inst, Sch Med, Boston, MA 02115 USA. [Kuligowski, Michael; Gonzalez, Santiago F.; Kim, Young-A.; Carroll, Michael C.] Harvard Univ, Program Cellular & Mol Med, Sch Med, Childrens Hosp,Dept Pediat, Boston, MA 02115 USA. [Kuligowski, Michael; Gonzalez, Santiago F.; Kim, Young-A.; Carroll, Michael C.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp,Dept Pathol, Boston, MA 02115 USA. [Graham, Daniel B.; Swat, Wojciech] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Peters, Anneli; Kuchroo, Vijay] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Morita, Takashi] Meiji Pharmaceut Univ, Dept Biochem, Kiyose, Tokyo 2048588, Japan. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Turley, SJ (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM shannon_turley@dfci.harvard.edu RI Acton, Sophie/G-9784-2012; Jakus, Zoltan/O-1762-2015; OI Acton, Sophie/0000-0003-2704-716X; Jakus, Zoltan/0000-0002-6304-2369; Malhotra, Deepali/0000-0002-8215-7639 FU National Institutes of Health [R01 DK074500, P01 AI045757, R01AI073718, AI061077]; LLS; Wellcome Trust; National Science Foundation; Benacerraf Postdoctoral Fellowship; National Health Medical Research Council; European Union [220044] FX The authors are grateful to J. Campbell and B. Vander Lugt for CCR7 knockout mice; to L.-H. Ang, Y. Zheng, and S. Hagen for assistance with microscopy; and to R. Gelman for assistance with statistical analysis. They are also grateful to E. Sahai for critical reading of the manuscript. This work was supported by National Institutes of Health grants R01 DK074500 and P01 AI045757 (to S.J.T.), R01AI073718 and AI061077 (W.S.), and LLS (W.S., D.B.G.); a Wellcome Trust Henry Wellcome Postdoctoral Fellowship (to S.E.A.); a National Science Foundation Graduate Research Fellowship (to J.L.A.); a Benacerraf Postdoctoral Fellowship (to V.L.K.); a National Health Medical Research Council Postdoctoral Biomedical Training Fellowship (to A.L.F.); and a Seventh Framework Programme of the European Union (Marie Curie International Outgoing Fellowship 220044, to S.F.G.). NR 31 TC 86 Z9 94 U1 2 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 24 PY 2012 VL 37 IS 2 BP 276 EP 289 DI 10.1016/j.immuni.2012.05.022 PG 14 WC Immunology SC Immunology GA 998SX UT WOS:000308261800012 PM 22884313 ER PT J AU Miller, E Yang, JY DeRan, M Wu, CL Su, AI Bonamy, GMC Liu, J Peters, EC Wu, X AF Miller, Eric Yang, Jiayi DeRan, Michael Wu, Chunlei Su, Andrew I. Bonamy, Ghislain M. C. Liu, Jun Peters, Eric C. Wu, Xu TI Identification of Serum-Derived Sphingosine-1-Phosphate as a Small Molecule Regulator of YAP SO CHEMISTRY & BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR PATHWAY; HIPPO SIGNALING PATHWAY; ORGAN SIZE CONTROL; CELL SELF-RENEWAL; SPHINGOSINE 1-PHOSPHATE; TISSUE-GROWTH; PROMOTES APOPTOSIS; CONTACT INHIBITION; TEAD/TEF FAMILY; CYCLE EXIT AB Hippo signaling represents a tumor suppressor pathway that regulates organ size and tumorigenesis through phosphorylation and inhibition of the transcription coactivator YAP. Here, we show that serum deprivation dramatically induces YAP Ser127 phosphorylation and cytoplasmic retention, independent of cell-cell contact. Through chemical isolation and activity profiling, we identified serum-derived sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) as small molecule activators of YAP. S1P induces YAP nuclear localization through S1P(2) receptor, Rho GTPase activation, and F-actin polymerization, independent of the core Hippo pathway kinases. Bioinformatics studies also showed that S1P stimulation induces YAP target gene expression in mouse liver and human embryonic stem cells. These results revealed potent small molecule regulators of YAP and suggest that Si P and LPA might modulate cell proliferation and tumorigenesis through YAP activation. C1 [DeRan, Michael; Wu, Xu] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Miller, Eric; Yang, Jiayi; Bonamy, Ghislain M. C.; Liu, Jun; Peters, Eric C.] Genom Inst Novartis Res Fdn, San Diego, CA 92121 USA. [Wu, Chunlei; Su, Andrew I.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. RP Wu, X (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM xwu@cbrc2.mgh.harvard.edu OI Su, Andrew I./0000-0002-9859-4104 FU Genomics Institute of the Novartis Research Foundation; Massachusetts General Hospital institutional fund; Harvard Stem Cell Institute; Children's Tumor Foundation; Novartis Research Foundation FX This work is supported by the Genomics Institute of the Novartis Research Foundation postdoctoral program (EM, and J.Y.), Massachusetts General Hospital institutional fund, Harvard Stem Cell Institute, and Children's Tumor Foundation (X.W.). We thank Drs. Charles Cho, Kun-Liang Guan, and Nabeel Bardeesy for discussions and reagents; Daniel Mason for assistance with mass spectrometry; and Richard Brusch III for assistance with imaging analyses and confocal microscopy. J.Y., E.M., and X.W. conceived the concepts and designed the experiments; E.M. performed isolation and analytical experiments; J.Y., M.D., and E.M. performed the cell biology and biochemistry experiments; C.W. performed bioinformatics analysis and G.B. performed imaging analysis; all authors analyzed the data; and E.M. and X.W. wrote the manuscript. E.M., J.Y., G.B., J.L. and E.P. are employees of Novartis. Part of this work was supported by the Novartis Research Foundation postdoctoral program (E.M. and J.Y.). NR 52 TC 86 Z9 88 U1 4 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD AUG 24 PY 2012 VL 19 IS 8 BP 955 EP 962 DI 10.1016/j.chembiol.2012.07.005 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 011GH UT WOS:000309152500007 PM 22884261 ER PT J AU Tolstorukov, MY Goldman, JA Gilbert, C Ogryzko, V Kingston, RE Park, PJ AF Tolstorukov, Michael Y. Goldman, Joseph A. Gilbert, Cristele Ogryzko, Vasily Kingston, Robert E. Park, Peter J. TI Histone Variant H2A.Bbd Is Associated with Active Transcription and mRNA Processing in Human Cells SO MOLECULAR CELL LA English DT Article ID HUMAN GENOME; U2 SNRNP; NUCLEOSOME; CHROMATIN; RECOGNITION; DEPOSITION; RESOLUTION; REGULATOR; BINDING; PROTEIN AB Variation in chromatin composition and organization often reflects differences in genome function. Histone variants, for example, replace canonical histones to contribute to regulation of numerous nuclear processes including transcription, DNA repair, and chromosome segregation. Here we focus on H2A.Bbd, a rapidly evolving variant found in mammals but not in invertebrates. We report that in human cells, nucleosomes bearing H2A.Bbd form unconventional chromatin structures enriched within actively transcribed genes and characterized by shorter DNA protection and nucleosome spacing. Analysis of transcriptional profiles from cells depleted for H2A.Bbd demonstrated widespread changes in gene expression with a net downregulation of transcription and disruption of normal mRNA splicing patterns. In particular, we observed changes in exon inclusion rates and increased presence of intronic sequences in mRNA products upon H2A.Bbd depletion. Taken together, our results indicate that H2A.Bbd is involved in formation of a specific chromatin structure that facilitates both transcription and initial mRNA processing. C1 [Goldman, Joseph A.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Tolstorukov, Michael Y.; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Gilbert, Cristele; Ogryzko, Vasily] Univ Paris 11, CNRS, UMR 8126, Inst Cancerol Gustave Roussy, F-94805 Villejuif, France. [Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Tolstorukov, Michael Y.; Park, Peter J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kingston@molbio.mgh.harvard.edu; peter_park@harvard.edu RI Ogryzko, Vasily/M-6665-2015 OI Ogryzko, Vasily/0000-0002-8548-1389 FU NIH grants [R01GM082798, U01HG00425, R37GM048405] FX We are grateful to Drs. Douglas Black, Erica Larschan, Artyom Alekseyenko, and Andrey Gortchakov for critical reading of the manuscript and many insightful comments. This work was supported by NIH grants R01GM082798 and U01HG00425 to P.J.P. and R37GM048405 to R.E.K. NR 41 TC 36 Z9 40 U1 1 U2 11 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 AUG 24 PY 2012 VL 47 IS 4 BP 596 EP 607 DI 10.1016/j.molcel.2012.06.011 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 996CH UT WOS:000308061100011 PM 22795134 ER PT J AU Bock, C Beerman, I Lien, WH Smith, ZD Gu, HC Boyle, P Gnirke, A Fuchs, E Rossi, DJ Meissner, A AF Bock, Christoph Beerman, Isabel Lien, Wen-Hui Smith, Zachary D. Gu, Hongcang Boyle, Patrick Gnirke, Andreas Fuchs, Elaine Rossi, Derrick J. Meissner, Alexander TI DNA Methylation Dynamics during In Vivo Differentiation of Blood and Skin Stem Cells SO MOLECULAR CELL LA English DT Article ID HEMATOPOIETIC STEM; LINEAGE COMMITMENT; GENE-THERAPY; EXPRESSION; PLURIPOTENT; METHYLOME; STATES; MAPS; HYPERMETHYLATION; MULTIPOTENCY AB DNA methylation is a mechanism of epigenetic regulation that is common to all vertebrates. Functional studies underscore its relevance for tissue homeostasis, but the global dynamics of DNA methylation during in vivo differentiation remain underexplored. Here we report high-resolution DNA methylation maps of adult stem cell differentiation in mouse, focusing on 19 purified cell populations of the blood and skin lineages. DNA methylation changes were locus specific and relatively modest in magnitude. They frequently overlapped with lineage-associated transcription factors and their binding sites, suggesting that DNA methylation may protect cells from aberrant transcription factor activation. DNA methylation and gene expression provided complementary information, and combining the two enabled us to infer the cellular differentiation hierarchy of the blood lineage directly from genome-scale data. In summary, these results demonstrate that in vivo differentiation of adult stem cells is associated with small but informative changes in the genomic distribution of DNA methylation. C1 [Lien, Wen-Hui; Fuchs, Elaine] Rockefeller Univ, Lab Mammalian Cell Biol & Dev, Howard Hughes Med Inst, New York, NY 10065 USA. [Bock, Christoph; Smith, Zachary D.; Gu, Hongcang; Boyle, Patrick; Gnirke, Andreas; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Bock, Christoph; Beerman, Isabel; Smith, Zachary D.; Rossi, Derrick J.; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Bock, Christoph; Beerman, Isabel; Smith, Zachary D.; Rossi, Derrick J.; Meissner, Alexander] Harvard Stem Cell Inst, Cambridge, MA 02318 USA. [Beerman, Isabel; Rossi, Derrick J.] Boston Childrens Hosp, Program Cellular & Mol Med, Immune Dis Inst, Boston, MA 02116 USA. RP Fuchs, E (reprint author), Rockefeller Univ, Lab Mammalian Cell Biol & Dev, Howard Hughes Med Inst, New York, NY 10065 USA. EM fuchslb@rockefeller.edu; rossi@idi.harvard.edu; alexander_meissner@harvard.edu RI Bock, Christoph/B-6723-2008; OI Bock, Christoph/0000-0001-6091-3088; Lien, Wen-Hui/0000-0002-2282-3169 FU Feodor Lynen Fellowship (Alexander von Humboldt Foundation); Charles A. King Trust Postdoctoral Fellowship (Charles A. King Trust, N.A., Bank of America, Co-Trustee); Harvey L. Karp Postdoctoral Fellowship; Jane Coffin Child Postdoctoral Fellowship; Massachusetts Life Science Center; Pew Charitable Trusts; New York Stem Cell Foundation; Harvard Stem Cell Institute; NIH/NIAMS [R01AR31737] FX We would like to thank other members of the Meissner, Rossi, and Fuchs labs for their support. From Rockefeller University, we also thank S. Maizel at the flow cytometry facility, as well as Nicole Stokes and the Comparative Biology Center animal facility. Furthermore, we thank Tarjei S. Mikkelsen for his contributions to the early parts of the project and Fontina Kelley for supporting the sequencing efforts. C.B. was supported by a Feodor Lynen Fellowship (Alexander von Humboldt Foundation) and a Charles A. King Trust Postdoctoral Fellowship (Charles A. King Trust, N.A., Bank of America, Co-Trustee). W.-H.L. was supported by a Harvey L. Karp Postdoctoral Fellowship and a Jane Coffin Child Postdoctoral Fellowship. E.F. is a Howard Hughes Medical Institute Investigator. A.M. was supported by the Massachusetts Life Science Center and the Pew Charitable Trusts. D.R. was supported by the New York Stem Cell Foundation. This work was funded by the Harvard Stem Cell Institute (to D.R. and A.M.) and partially supported by a grant (to E.F.) from the NIH/NIAMS (R01AR31737). NR 35 TC 139 Z9 139 U1 2 U2 24 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 AUG 24 PY 2012 VL 47 IS 4 BP 633 EP 647 DI 10.1016/j.molcel.2012.06.019 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 996CH UT WOS:000308061100014 PM 22841485 ER PT J AU Yuan, MS Pino, E Wu, LF Kacergis, M Soukas, AA AF Yuan, Minsheng Pino, Elizabeth Wu, Lianfeng Kacergis, Michael Soukas, Alexander A. TI Identification of Akt-independent Regulation of Hepatic Lipogenesis by Mammalian Target of Rapamycin (mTOR) Complex 2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED INSULIN-RESISTANCE; MOTIF PHOSPHORYLATION; TRANSCRIPTION FACTORS; DIABETES-MELLITUS; LIPID-METABOLISM; KINASE-B; RICTOR; MICE; AKT/PKB; LIVER AB Mammalian target of rapamycin complex 2 (mTORC2) is a key activator of protein kinases that act downstream of insulin and growth factor signaling. Here we report that mice lacking the essential mTORC2 component rictor in liver (Lrictor(KO)) are unable to respond normally to insulin. In response to insulin, Lrictor(KO) mice failed to inhibit hepatic glucose output. Lrictor(KO) mice also fail to develop hepatic steatosis on a high fat diet and manifest half-normal serum cholesterol levels. This is accompanied by lower levels of expression of SREBP-1c and SREBP-2 and genes of fatty acid and cholesterol biosynthesis. Lrictor(KO) mice had defects in insulin-stimulated Akt Ser-473 and Thr-308 phosphorylation, leading to decreased phosphorylation of Akt substrates FoxO, GSK-3 beta, PRAS40, AS160, and Tsc2. Lrictor(KO) mice also manifest defects in insulin-activated mTORC1 activity, evidenced by decreased S6 kinase and Lipin1 phosphorylation. Glucose intolerance and insulin resistance of Lrictor(KO) mice could be fully rescued by hepatic expression of activated Akt2 or dominant negative FoxO1. However, in the absence of mTORC2, forced Akt2 activation was unable to drive hepatic lipogenesis. Thus, we have identified an Akt-independent relay from mTORC2 to hepatic lipogenesis that separates the effects of insulin on glucose and lipid metabolism. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet & Diabet Unit,Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Soukas, AA (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN6224, Boston, MA 02114 USA. EM asoukas@chgr.mgh.harvard.edu FU National Institutes of Health Career Development Award through NIDDK [K08DK087941]; Charles H. Hood Foundation FX This research was supported, in whole or in part, by National Institutes of Health Career Development Award K08DK087941 through the NIDDK ( to A. A. S.). This work was also supported by a Child Health Research Award from the Charles H. Hood Foundation ( to A. A. S). NR 41 TC 59 Z9 60 U1 2 U2 17 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 24 PY 2012 VL 287 IS 35 BP 29579 EP 29588 DI 10.1074/jbc.M112.386854 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 999CO UT WOS:000308286900033 PM 22773877 ER PT J AU Penniston, JT Caride, AJ Strehler, EE AF Penniston, John T. Caride, Ariel J. Strehler, Emanuel E. TI Alternative Pathways for Association and Dissociation of the Calmodulin-binding Domain of Plasma Membrane Ca2+-ATPase Isoform 4b (PMCA4b) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TARGETED MOLECULAR-DYNAMICS; LIGHT-CHAIN KINASE; CA2+ PUMP; CALCIUM-PUMP; ACTIVATION; MECHANISM; ENZYME; RECOGNITION; SIMULATIONS; COMPLEXES AB The calmodulin (CaM)-binding domain of isoform 4b of the plasma membrane Ca2+-ATPase (PMCA) pump is represented by peptide C28. CaM binds to either PMCA or C28 by a mechanism in which the primary anchor residue Trp-1093 binds to the C-terminal lobe of the extended CaM molecule, followed by collapse of CaM with the N-terminal lobe binding to the secondary anchor Phe-1110 (Juranic, N., Atanasova, E., Filoteo, A. G., Macura, S., Prendergast, F. G., Penniston, J. T., and Strehler, E. E. (2010) J. Biol. Chem. 285, 4015-4024). This is a relatively rapid reaction, with an apparent half-time of similar to 1 s. The dissociation of CaM from PMCA4b or C28 is much slower, with an overall half-time of similar to 10 min. Using targeted molecular dynamics, we now show that dissociation of Ca2+-CaM from C28 may occur by a pathway in which Trp-1093, although deeply embedded in a pocket in the C-terminal lobe of CaM, leaves first. The dissociation begins by relatively rapid release of Trp-1093, followed by very slow release of Phe-1110, removal of C28, and return of CaM to its conformation in the free state. Fluorescence measurements and molecular dynamics calculations concur in showing that this alternative path of release of the PMCA4b CaM-binding domain is quite different from that of binding. The intermediate of dissociation with exposed Trp-1093 has a long lifetime (minutes) and may keep the PMCA primed for activation. C1 [Caride, Ariel J.; Strehler, Emanuel E.] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Penniston, John T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Strehler, EE (reprint author), Mayo Clin, Coll Med, Dept Biochem & Mol Biol, 200 1st St SW, Rochester, MN 55905 USA. EM strehler.emanuel@mayo.edu FU National Institutes of Health [NS51769]; Mayo Foundation for Medical Research and Education FX This work was supported, in whole or in part, by National Institutes of Health Grant NS51769 ( to E. E. S.). This work was also supported by the Mayo Foundation for Medical Research and Education. NR 30 TC 3 Z9 3 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 24 PY 2012 VL 287 IS 35 BP 29664 EP 29671 DI 10.1074/jbc.M112.377556 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 999CO UT WOS:000308286900042 PM 22767601 ER PT J AU Steffan, JJ Koul, S Meacham, RB Koul, HK AF Steffan, Joshua J. Koul, Sweaty Meacham, Randall B. Koul, Hari K. TI The Transcription Factor SPDEF Suppresses Prostate Tumor Metastasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GELATINASE B EXPRESSION; ETS FACTOR; CANCER-CELLS; BREAST-CANCER; MATRIX METALLOPROTEINASES; AGGRESSIVE PHENOTYPE; PROGNOSTIC MARKER; GENE-EXPRESSION; CARCINOMA CELLS; FACTOR PDEF AB Emerging evidence suggests that the SAM pointed domain containing ETS transcription factor (SPDEF) plays a significant role in tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there are no in vivo studies with respect to the role of SPDEF in tumor metastasis. The present study examined the effects of SPDEF on tumor cell metastasis using prostate tumor cells as a model. Utilizing two experimental metastasis models, we demonstrate that SPDEF inhibits cell migration and invasion in vitro and acts a tumor metastasis suppressor in vivo. Using stable expression of SPDEF in PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we demonstrate for the first time that SPDEF diminished the ability of disseminated tumors cells to survive at secondary sites and establish micrometastases. These effects on tumor metastasis were not a result of the effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth in vitro or subcutaneous tumor xenograft-growth in vivo. Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. Further analysis indicated that forced MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3 cells in vitro, suggesting that the effects of SPDEF on tumor invasion are mediated, in part, through the suppression of MMP9 and MMP13 expression. These results demonstrate for the first time, in any system, that SPDEF functions as a tumor metastasis suppressor in vivo. C1 [Steffan, Joshua J.; Koul, Sweaty; Meacham, Randall B.; Koul, Hari K.] Univ Colorado, Sch Med, Dept Surg, Program Urosci,Div Urol, Aurora, CO 80045 USA. [Steffan, Joshua J.; Koul, Sweaty; Koul, Hari K.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. [Koul, Hari K.] Univ Colorado, Ctr Comprehens Canc, Aurora, CO 80045 USA. RP Koul, HK (reprint author), 12700 E 19th Ave,RC2-6001,MS-C317, Aurora, CO 80045 USA. EM hari.koul@ucdenver.edu FU Department of Surgery (School of Medicine Academic Enrichment Funds); Veterans Affairs Merit Award [01BX001258]; National Institutes of Health [DK54084]; National Institutes of Health/NCI [R01CA161880] FX This work was supported in part by chair commitment (to H. K. K.) and Department of Surgery (School of Medicine Academic Enrichment Funds) (to H. K. K.).; Supported in part by Veterans Affairs Merit Award 01BX001258, National Institutes of Health Grant DK54084, and National Institutes of Health/NCI Grant R01CA161880. To whom correspondence should be addressed: 12700 E. 19th Ave, RC2-6001; MS-C317, Aurora, CO 80045. Tel.: 303-724-6300; Fax: 303-724-6330; E-mail: hari.koul@ucdenver.edu. NR 44 TC 20 Z9 20 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 24 PY 2012 VL 287 IS 35 BP 29968 EP 29978 DI 10.1074/jbc.M112.379396 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 999CO UT WOS:000308286900070 PM 22761428 ER PT J AU Mattaini, KR Vander Heiden, MG AF Mattaini, Katherine R. Vander Heiden, Matthew G. TI Glycosylation to Adapt to Stress SO SCIENCE LA English DT Editorial Material ID RABBIT MUSCLE PHOSPHOFRUCTOKINASE; CANCER-CELLS; METABOLISM; PHOSPHORYLATION; REGULATOR C1 [Mattaini, Katherine R.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Mattaini, Katherine R.; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Mattaini, KR (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mvh@mit.edu NR 14 TC 5 Z9 5 U1 0 U2 22 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 24 PY 2012 VL 337 IS 6097 BP 925 EP 926 DI 10.1126/science.1227513 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VI UT WOS:000307807600034 PM 22923571 ER PT J AU Lee, E Iskow, R Yang, LX Gokcumen, O Haseley, P Luquette, LJ Lohr, JG Harris, CC Ding, L Wilson, RK Wheeler, DA Gibbs, RA Kucherlapati, R Lee, C Kharchenko, PV Park, PJ AF Lee, Eunjung Iskow, Rebecca Yang, Lixing Gokcumen, Omer Haseley, Psalm Luquette, Lovelace J., III Lohr, Jens G. Harris, Christopher C. Ding, Li Wilson, Richard K. Wheeler, David A. Gibbs, Richard A. Kucherlapati, Raju Lee, Charles Kharchenko, Peter V. Park, Peter J. CA Canc Genome Atlas Res Network TI Landscape of Somatic Retrotransposition in Human Cancers SO SCIENCE LA English DT Article ID HUMAN GENOMES; ELEMENTS; CELLS; DISRUPTION; MECHANISMS; GENE AB Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis. C1 [Lee, Eunjung; Yang, Lixing; Haseley, Psalm; Luquette, Lovelace J., III; Kharchenko, Peter V.; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Lee, Eunjung; Haseley, Psalm; Kucherlapati, Raju; Park, Peter J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Iskow, Rebecca; Gokcumen, Omer; Lee, Charles] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Lohr, Jens G.] Eli & Edythe Broad Inst, Cambridge, MA 02412 USA. [Lohr, Jens G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Harris, Christopher C.; Ding, Li; Wilson, Richard K.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA. [Wheeler, David A.; Gibbs, Richard A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kharchenko, Peter V.; Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. RP Kharchenko, PV (reprint author), Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. EM peter.kharchenko@post.harvard.edu; peter_park@harvard.edu RI Yang, Lixing/A-7073-2013; OI Gokcumen, Omer/0000-0003-4371-679X FU NIH [R01GM082798, RC1HG005482, K25AG037596, U01HG005209, U01HG005725, F32AG039979, U24CA144025] FX We thank A. Langdon and U. Samarakoon for technical assistance and T. Golub and the Broad Institute for a myeloma sample obtained under a materials transfer agreement (MTA) from the Multiple Myeloma Research Consortium. This work was supported by NIH grants R01GM082798 and RC1HG005482 (P.J.P.), K25AG037596 (P. V. K.), U01HG005209 and U01HG005725 (C. L.), F32AG039979 (R. I.), and U24CA144025 (R. K.). P.J.P. is a Sloan Research Fellow. R. K. is on the board of directors of AVEO, Metamark, Enlight, and KEW Group. The sequencing data are available at dbGaP (www.ncbi.nlm.nih.gov/gap) with the following accessions: TCGA ovarian cancer, glioblastoma multiforme, and colorectal cancer (phs000178.v5.p5); multiple myeloma (phs000348.v1.p1); and prostate cancer (phs000330.v1.p1). The Tea software is available at http://compbio.med.harvard.edu/Tea. NR 23 TC 222 Z9 225 U1 6 U2 34 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 24 PY 2012 VL 337 IS 6097 BP 967 EP 971 DI 10.1126/science.1222077 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VI UT WOS:000307807600046 PM 22745252 ER PT J AU Hu, ZT Hom, S Kudze, T Tong, XJ Choi, S Aramuni, G Zhang, WQ Kaplan, JM AF Hu, Zhitao Hom, Sabrina Kudze, Tambudzai Tong, Xia-Jing Choi, Seungwon Aramuni, Gayane Zhang, Weiqi Kaplan, Joshua M. TI Neurexin and Neuroligin Mediate Retrograde Synaptic Inhibition in C. elegans SO SCIENCE LA English DT Article ID SPECTRUM DISORDERS; AUTISM; MATURATION; MUTATIONS; CELL AB The synaptic adhesion molecules neurexin and neuroligin alter the development and function of synapses and are linked to autism in humans. Here, we found that Caenorhabditis elegans neurexin (NRX-1) and neuroligin (NLG-1) mediated a retrograde synaptic signal that inhibited neurotransmitter release at neuromuscular junctions. Retrograde signaling was induced in mutants lacking a muscle microRNA (miR-1) and was blocked in mutants lacking NLG-1 or NRX-1. Release was rapid and abbreviated when the retrograde signal was on, whereas release was slow and prolonged when retrograde signaling was blocked. The retrograde signal adjusted release kinetics by inhibiting exocytosis of synaptic vesicles (SVs) that are distal to the site of calcium entry. Inhibition of release was mediated by increased presynaptic levels of tomosyn, an inhibitor of SV fusion. C1 [Hu, Zhitao; Hom, Sabrina; Kudze, Tambudzai; Tong, Xia-Jing; Choi, Seungwon; Kaplan, Joshua M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Hu, Zhitao; Hom, Sabrina; Tong, Xia-Jing; Choi, Seungwon; Kaplan, Joshua M.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Hom, Sabrina; Choi, Seungwon; Kaplan, Joshua M.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Aramuni, Gayane] Max Planck Inst Neurobiol, D-82152 Martinsried, Germany. [Zhang, Weiqi] Univ Munster, Dept Psychiat, D-48149 Munster, Germany. RP Kaplan, JM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kaplan@molbio.mgh.harvard.edu FU NSF; NIH [NS32196]; Simons Foundation for Autism Research [SF177948] FX We thank the following for strains, advice, reagents, and comments on the manuscript: C. elegans stock center, S. Mitani, S. Sassi, B. Seed, and members of the Kaplan and Ruvkun labs. This work was supported by an NSF predoctoral fellowship (S. H.) and by research grants to J.M.K. from the NIH (NS32196) and from the Simons Foundation for Autism Research (SF177948). Additional data described in the manuscript are presented in the supplementary materials. NR 24 TC 34 Z9 38 U1 1 U2 20 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 24 PY 2012 VL 337 IS 6097 BP 980 EP 984 DI 10.1126/science.1224896 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VI UT WOS:000307807600049 PM 22859820 ER PT J AU Zhang, Y Roccaro, AM Rombaoa, C Flores, L Obad, S Fernandes, SM Sacco, A Liu, Y Ngo, H Quang, P Azab, AK Azab, F Maiso, P Reagan, M Brown, JR Thai, TH Kauppinen, S Ghobrial, IM AF Zhang, Yong Roccaro, Aldo M. Rombaoa, Christopher Flores, Ludmilla Obad, Susanna Fernandes, Stacey M. Sacco, Antonio Liu, Yang Ngo, Hai Quang, Phong Azab, Abdel Kareem Azab, Feda Maiso, Patricia Reagan, Michaela Brown, Jennifer R. Thai, To-Ha Kauppinen, Sakari Ghobrial, Irene M. TI LNA-mediated anti-miR-155 silencing in low-grade B-cell lymphomas SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; INDUCED CYTIDINE DEAMINASE; MULTIPLE-MYELOMA; WALDENSTROMS MACROGLOBULINEMIA; IN-VIVO; BREAST-CANCER; C-MAF; MICRORNA-155; EXPRESSION; MICROENVIRONMENT AB miR-155 acts as an oncogenic miR in B-cell lymphoproliferative disorders, including Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia, and is therefore a potential target for therapeutic intervention. However, efficient targeting of miRs in tumor cells in vivo remains a significant challenge for the development of miR-155-based therapeutics for the treatment of B-cell malignancies. In the present study, we show that an 8-mer locked nucleic acid anti-miR-155 oligonucleotide targeting the seed region of miR-155 inhibits WM and chronic lymphocytic leukemia cell proliferation in vitro. Moreover, anti-miR-155 delivered systemically showed uptake in the BM CD19(+) cells of WM-engrafted mice, resulting in the up-regulation of several miR-155 target mRNAs in these cells, and decreased tumor growth significantly in vivo. We also found miR-155 levels to be elevated in stromal cells from WM patients compared with control samples. Interestingly, stromal cells from miR-155-knockout mice led to significant inhibition of WM tumor growth, indicating that miR-155 may also contribute to WM proliferation through BM microenvironmental cells. The results of the present study highlight the therapeutic potential of anti-miR-155-mediated inhibition of miR-155 in the treatment of WM. (Blood. 2012;120(8):1678-1686) C1 [Zhang, Yong; Roccaro, Aldo M.; Rombaoa, Christopher; Flores, Ludmilla; Fernandes, Stacey M.; Sacco, Antonio; Liu, Yang; Ngo, Hai; Quang, Phong; Azab, Abdel Kareem; Azab, Feda; Maiso, Patricia; Reagan, Michaela; Brown, Jennifer R.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Obad, Susanna; Kauppinen, Sakari] Santaris Pharma, Horsholm, Denmark. [Thai, To-Ha] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Kauppinen, Sakari] Aalborg Univ, Copenhagen, Denmark. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; Reagan, Michaela/E-3549-2017; OI Sacco, Antonio/0000-0003-2945-9416; Maiso, Patricia/0000-0003-3745-1924; Roccaro, Aldo/0000-0002-1872-5128; Reagan, Michaela/0000-0003-2884-6481 FU Leukemia & Lymphoma Society; Kirsch Laboratory for Waldenstrom; Heje Fellowship FX This work was supported in part by research grants from the Leukemia & Lymphoma Society, The Kirsch Laboratory for Waldenstrom, and the Heje Fellowship. mCherry-Luc+-BCWM1 cells were a kind gift from Dr Andrew Kung (Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA). NR 48 TC 64 Z9 67 U1 2 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 23 PY 2012 VL 120 IS 8 BP 1678 EP 1686 DI 10.1182/blood-2012-02-410647 PG 9 WC Hematology SC Hematology GA 009DK UT WOS:000309005600023 PM 22797699 ER PT J AU Chiyomaru, T Yamamura, S Zaman, MS Majid, S Deng, GR Shahryari, V Saini, S Hirata, H Ueno, K Chang, I Tanaka, Y Tabatabai, ZL Enokida, H Nakagawa, M Dahiya, R AF Chiyomaru, Takeshi Yamamura, Soichiro Zaman, Mohd Saif Majid, Shahana Deng, Guoren Shahryari, Varahram Saini, Sharanjot Hirata, Hiroshi Ueno, Koji Chang, Inik Tanaka, Yuichiro Tabatabai, Z. Laura Enokida, Hideki Nakagawa, Masayuki Dahiya, Rajvir TI Genistein Suppresses Prostate Cancer Growth through Inhibition of Oncogenic MicroRNA-151 SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; JAPANESE MEN; CHROMOSOMAL-ABERRATIONS; RISK; ISOFLAVONES; CARCINOMA; FAMILY; CELLS; CONSUMPTION; INVASION AB Genistein has been shown to suppress the growth of several cancers through modulation of various pathways. However, the effects of genistein on the regulation of oncogenic microRNA-151 (miR-151) have not been reported. In this study, we investigated whether genistein could alter the expression of oncogenic miR-151 and its target genes that are involved in the progression and metastasis of prostate cancer (PCa). Real-time RT-PCR showed that the expression of miR-151 was higher in PC3 and DU145 cells compared with RWPE-1 cells. Treatment of PC3 and DU145 cells with 25 mu M genistein down-regulated the expression of miR-151 compared with vehicle control. Inhibition of miR-151 in PCa cells by genistein significantly inhibited cell migration and invasion. In-silico analysis showed that several genes (CASZ1, IL1RAPL1, SOX17, N4BP1 and ARHGDIA) suggested to have tumor suppressive functions were target genes of miR-151. Luciferase reporter assays indicated that miR-151 directly binds to specific sites on the 3'UTR of target genes. Quantitative real-time PCR analysis showed that the mRNA expression levels of the five target genes in PC3 and DU145 were markedly changed with miR-151 mimics and inhibitor. Kaplan-Meier curves and log-rank tests revealed that high expression levels of miR-151 had an adverse effect on survival rate. This study suggests that genistein mediated suppression of oncogenic miRNAs can be an important dietary therapeutic strategy for the treatment of PCa. C1 [Chiyomaru, Takeshi; Yamamura, Soichiro; Zaman, Mohd Saif; Majid, Shahana; Deng, Guoren; Shahryari, Varahram; Saini, Sharanjot; Hirata, Hiroshi; Ueno, Koji; Chang, Inik; Tanaka, Yuichiro; Dahiya, Rajvir] San Francisco VA Med Ctr, Dept Urol, San Francisco, CA USA. [Chiyomaru, Takeshi; Yamamura, Soichiro; Zaman, Mohd Saif; Majid, Shahana; Deng, Guoren; Shahryari, Varahram; Saini, Sharanjot; Hirata, Hiroshi; Ueno, Koji; Chang, Inik; Tanaka, Yuichiro; Dahiya, Rajvir] San Francisco VA Med Ctr, Dept Pathol, San Francisco, CA USA. [Chiyomaru, Takeshi; Yamamura, Soichiro; Zaman, Mohd Saif; Majid, Shahana; Deng, Guoren; Shahryari, Varahram; Saini, Sharanjot; Hirata, Hiroshi; Ueno, Koji; Chang, Inik; Tanaka, Yuichiro; Tabatabai, Z. Laura; Dahiya, Rajvir] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Enokida, Hideki; Nakagawa, Masayuki] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Urol, Kagoshima 890, Japan. RP Chiyomaru, T (reprint author), San Francisco VA Med Ctr, Dept Urol, San Francisco, CA USA. EM rdahiya@urology.ucsf.edu RI Jackson, Benjamin/C-4297-2012 FU National Center for Research Resources of the National Institutes of Health [R01CA160079, R01CA138642, T32DK007790]; VA Merit Review and VA Program Project FX This research was supported by the National Center for Research Resources of the National Institutes of Health through Grant Numbers R01CA160079, R01CA138642, T32DK007790 and VA Merit Review and VA Program Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 39 Z9 42 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 23 PY 2012 VL 7 IS 8 AR e43812 DI 10.1371/journal.pone.0043812 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998GE UT WOS:000308224700028 PM 22928040 ER PT J AU Drapkin, MS Kamath, RS Kim, JY AF Drapkin, Mark S. Kamath, Ravi S. Kim, Ji Yeon TI Case 26-2012: A 70-Year-Old Woman with Fever and Back Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LUMBAR SPINE MIMICKING; EPIDURAL ABSCESS; CAMEL BRUCELLOSIS; TOPHACEOUS GOUT; OSTEOMYELITIS; SPONDYLODISCITIS; SPONDYLITIS; INFECTION; REGIMENS C1 [Drapkin, Mark S.] Newton Wellesley Hosp, Infect Dis Serv, Newton, MA USA. [Kamath, Ravi S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kim, Ji Yeon] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Drapkin, Mark S.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Kamath, Ravi S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kim, Ji Yeon] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Drapkin, MS (reprint author), Newton Wellesley Hosp, Infect Dis Serv, Newton, MA USA. NR 27 TC 3 Z9 3 U1 3 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 23 PY 2012 VL 367 IS 8 BP 754 EP 762 DI 10.1056/NEJMcpc1200087 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 992CX UT WOS:000307754200012 PM 22913686 ER PT J AU Goldfine, AB AF Goldfine, Allison B. TI Reassessing Benefits and Risks of Statins REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Joslin Diabet Ctr, Boston, MA 02215 USA. RP Goldfine, AB (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 23 PY 2012 VL 367 IS 8 BP 776 EP 776 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 992CX UT WOS:000307754200026 ER PT J AU Schroyens, W O'Connell, C Sykes, DB AF Schroyens, Wilfried O'Connell, Casey Sykes, David B. TI Complete and Partial Responses of the TEMPI Syndrome to Bortezomib SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Schroyens, Wilfried] Univ Antwerp Hosp, Antwerp, Belgium. [O'Connell, Casey] Univ So Calif, Los Angeles, CA USA. [Sykes, David B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Schroyens, W (reprint author), Univ Antwerp Hosp, Antwerp, Belgium. EM dbsykes@partners.org NR 2 TC 9 Z9 9 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 23 PY 2012 VL 367 IS 8 BP 778 EP 780 DI 10.1056/NEJMc1205806 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 992CX UT WOS:000307754200030 PM 22913703 ER PT J AU Bourgier, C Acevedo-Henao, C Dunant, A Rossier, C Levy, A El Nemr, M Dumas, I Delaloge, S Mathieu, MC Garbay, JR Taghian, A Marsiglia, H AF Bourgier, Celine Acevedo-Henao, Catalina Dunant, Ariane Rossier, Christine Levy, Antonin El Nemr, Mohamed Dumas, Isabelle Delaloge, Suzette Mathieu, Marie-Christine Garbay, Jean-Remi Taghian, Alphonse Marsiglia, Hugo TI Higher toxicity with 42 Gy in 10 fractions as a total dose for 3D-conformal accelerated partial breast irradiation: results from a dose escalation phase II trial SO RADIATION ONCOLOGY LA English DT Article DE 3D-conformal accelerated partial breast irradiation; Dose escalation ID CONFORMAL EXTERNAL-BEAM; LUMPECTOMY CAVITY; RADIATION-THERAPY AB Objective: Recent recommendations regarding indications of accelerated partial breast irradiation (APBI) have been put forward for selected breast cancer (BC) patients. However, some treatment planning parameters, such as total dose, are not yet well defined. The Institut Gustave Roussy has initiated a dose escalation trial at the 40 Gy/10 fractions/5 days and at a further step of total dose (TD) of 42 Gy/10 fractions/5 days. Here, we report early results of the latest step compared with the 40 Gy dose level. Methods and materials: From October 2007 to March 2010, a total of 48 pT1N0 BC patients were enrolled within this clinical trial: 17 patients at a TD of 42 Gy/10f/5d and 31 at a TD of 40 Gy/10f/5d. Median follow-up was 19 months (min-max, 12-26). All the patients were treated by APBI using a technique with 2 minitangents and an "enface" electrons delivering 20% of the total dose. Toxicities were systematically assessed at 1; 2; 6 months and then every 6 months. Results: Patients' recruitment of 42 Gy step was ended owing to persistent grade 3 toxicity 6 months after APBI completion (n = 1). Early toxicities were statistically higher after a total dose of 42 Gy regarding grade >= 2 dry (p = 0.01) and moist (p = 0.05) skin desquamation. Breast pain was also statistically higher in the 42 Gy step compared to 40 Gy step (p = 0.02). Other late toxicities (grade >= 2 fibrosis and telangectasia) were not statistically different between 42 Gy and 40 Gy. Conclusions: Early toxicities were more severe and higher rates of late toxicities were observed after 42 Gy/10 fractions/5 days when compared to 40 Gy/10 fractions/5 days. This data suggest that 40 Gy/10 fractions/5 days could potentially be the maximum tolerance for PBI although longer follow-up is warranted to better assess late toxicities. C1 [Bourgier, Celine; Dumas, Isabelle] Inst Gustave Roussy, Dept Radiat Oncol, Phys Unit, F-94805 Villejuif, France. [Dunant, Ariane] Inst Gustave Roussy, Biostat & Epidemiol Unit, F-94805 Villejuif, France. [El Nemr, Mohamed] Univ Alexandria, Alexandria, Egypt. [Delaloge, Suzette] Inst Gustave Roussy, Dept Breast Oncol, F-94805 Villejuif, France. [Mathieu, Marie-Christine] Inst Gustave Roussy, Dept Pathol, F-94805 Villejuif, France. [Garbay, Jean-Remi] Inst Gustave Roussy, Dept Breast Surg, F-94805 Villejuif, France. [Taghian, Alphonse] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Marsiglia, Hugo] Grp Imo, Madrid, Spain. RP Bourgier, C (reprint author), Inst Gustave Roussy, Dept Radiat Oncol, Phys Unit, 114 Rue Edouard Vaillant, F-94805 Villejuif, France. EM bourgier@igr.fr OI , Antonin/0000-0003-4798-8899 NR 19 TC 8 Z9 8 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD AUG 22 PY 2012 VL 7 AR 141 DI 10.1186/1748-717X-7-141 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 041QO UT WOS:000311416500001 PM 22913640 ER PT J AU Powner, MW Zheng, SL Szostak, JW AF Powner, Matthew W. Zheng, Shao-Liang Szostak, Jack W. TI Multicomponent Assembly of Proposed DNA Precursors in Water SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEIC-ACID STRUCTURE; AMINO-ACIDS; PRIMITIVE EARTH; CHEMICAL ETIOLOGY; AMMONIUM CYANIDE; RNA; GLYCOLALDEHYDE; SYSTEM; CARBON; SUGARS AB We propose a novel pathway for the prebiotic synthesis of 2'-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and beta-mercapto-acetaldehyde, and the corresponding proteinogenic amino acids, serine and cysteine, led us to explore the consequences of the corresponding sulfur substitution for our previously proposed pathways leading to the canonical ribonucleotides. We demonstrate that just as 2-aminooxazole-an important prebiotic ribonucleotide precursor-is readily formed from glycolaldehyde and cyanamide, so is 2-aminothiazole formed from beta-mercapto-acetaldehyde and cyanamide in water at neutral pH. Indeed, both the oxazole and the thiazole can be formed together in a one-pot reaction, and can be co-purified by crystallization or sublimation. We then show that 2-aminothiazole can take part in a 3-component carbon-carbon bond-forming reaction in water that leads to the diastereoselective synthesis of masked 2'-thiosugars regiospecifically tethered to purine precursors, which would lead to 2'-deoxynucleotides upon desulfurization. The possibility of an abiotic route to the 2'-deoxynucleotides provides a new perspective on the evolutionary origins of DNA. We also show that 2-aminothiazole is able to sequester, through reversible aminal formation, the important nucleotide precursors glycolaldehyde and glyceraldehyde in a, stable, crystalline form. C1 [Powner, Matthew W.] UCL, Dept Chem, Christopher Ingold Labs, London WC1H 0AJ, England. [Zheng, Shao-Liang] Harvard Xray Crystallog Ctr, Cambridge, MA 02138 USA. [Powner, Matthew W.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Powner, Matthew W.; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Powner, Matthew W.; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Powner, MW (reprint author), UCL, Dept Chem, Christopher Ingold Labs, 20 Gordon St, London WC1H 0AJ, England. EM matthew.powner@ucl.ac.uk OI Powner, Matthew/0000-0002-6368-3190 FU Harvard Origins Initiative; Howard Hughes Medical Institute; University College London; NSF [CHE-0809413] FX M.W.P. was supported by a fellowship from the Harvard Origins Initiative, the Howard Hughes Medical Institute and University College London. This research was funded in part by Grant CHE-0809413 from the NSF. J.W.S. is an Investigator of the Howard Hughes Medical Institute. The authors thank J.C. Blain, Dr. R.B. Moreno, Dr. A. Ricardo, and Prof. J.D. Sutherland for helpful discussions and The Mass Spectrometry Facility at the FAS Center for Systems Biology for mass spectrometry support. NR 51 TC 27 Z9 28 U1 2 U2 63 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 22 PY 2012 VL 134 IS 33 BP 13889 EP 13895 DI 10.1021/ja306176n PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 991KD UT WOS:000307699000050 PM 22839703 ER PT J AU Kastman, EK Willette, AA Coe, CL Bendlin, BB Kosmatka, KJ McLaren, DG Xu, GF Canu, E Field, AS Alexander, AL Voytko, ML Beasley, TM Colman, RJ Weindruch, RH Johnson, SC AF Kastman, Erik K. Willette, Auriel A. Coe, Christopher L. Bendlin, Barbara B. Kosmatka, Kris J. McLaren, Donald G. Xu, Guofan Canu, Elisa Field, Aaron S. Alexander, Andrew L. Voytko, Mary Lou Beasley, T. Mark Colman, Ricki J. Weindruch, Richard H. Johnson, Sterling C. TI A Calorie-Restricted Diet Decreases Brain Iron Accumulation and Preserves Motor Performance in Old Rhesus Monkeys (vol 30, pg 7940, 2010) SO JOURNAL OF NEUROSCIENCE LA English DT Correction ID TRANSVERSE RELAXATION RATES; VOXEL-BASED MORPHOMETRY; ALZHEIMERS-DISEASE; SUBSTANTIA-NIGRA; PARKINSONS-DISEASE; CEREBROSPINAL-FLUID; NONHUMAN-PRIMATES; OXIDATIVE DAMAGE; HEME OXYGENASE-1; SKELETAL-MUSCLE AB Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan inmanyspecies, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using magnetic resonance imaging, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n = 24, 13 males, 11 females) and standard (n = 17, 8 males, 9 females) diets. Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. ADiet x Age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species. C1 [Kastman, Erik K.; Bendlin, Barbara B.; Kosmatka, Kris J.; McLaren, Donald G.; Xu, Guofan; Canu, Elisa; Weindruch, Richard H.; Johnson, Sterling C.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. [Kastman, Erik K.; Willette, Auriel A.; Bendlin, Barbara B.; Kosmatka, Kris J.; McLaren, Donald G.; Xu, Guofan; Canu, Elisa; Weindruch, Richard H.; Johnson, Sterling C.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Dis Res Ctr, Madison, WI 53705 USA. [Willette, Auriel A.; Coe, Christopher L.] Univ Wisconsin, Dept Psychol, Harlow Primate Lab, Madison, WI 53715 USA. [Willette, Auriel A.; Coe, Christopher L.; Alexander, Andrew L.; Johnson, Sterling C.] Univ Wisconsin, Waisman Imaging Ctr, Madison, WI 53705 USA. [McLaren, Donald G.] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [Field, Aaron S.] Univ Wisconsin, Dept Radiol, Madison, WI 53792 USA. [Voytko, Mary Lou] Wake Forest Univ, Bowman Gray Sch Med, Dept Neurobiol & Anat, Winston Salem, NC 27157 USA. [Voytko, Mary Lou] Wake Forest Univ, Bowman Gray Sch Med, Interdisciplinary Neurosci Program, Winston Salem, NC 27157 USA. [Beasley, T. Mark; Colman, Ricki J.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Weindruch, Richard H.; Johnson, Sterling C.] Wisconsin Natl Primate Res Ctr, Madison, WI 53792 USA. RP Johnson, SC (reprint author), D4225 Vet Adm Hosp, Geriatr Res Educ & Clin Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. EM scj@medicine.wisc.edu RI Kastman, Erik/N-6645-2016 OI Kastman, Erik/0000-0001-7221-9042 FU NCRR NIH HHS [P51 RR000167, RR020141-01, RR15459-01]; NIA NIH HHS [R01 AG040178, P01 AG011915, AG000213, P01 AG11915, R01 AG043125]; NIH HHS [P51 OD011106] NR 82 TC 14 Z9 14 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 22 PY 2012 VL 32 IS 34 BP 11897 EP 11904 DI 10.1523/JNEUROSCI.2553-12.2012 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 997BZ UT WOS:000308140500034 PM 23082321 ER PT J AU Takada, K Zhu, D Bird, GH Sukhdeo, K Zhao, JJ Mani, M Lemieux, M Carrasco, DE Ryan, J Horst, D Fulciniti, M Munshi, NC Xu, WQ Kung, AL Shivdasani, RA Walensky, LD Carrasco, DR AF Takada, Kohichi Zhu, Di Bird, Gregory H. Sukhdeo, Kumar Zhao, Jian-Jun Mani, Mala Lemieux, Madeleine Carrasco, Daniel E. Ryan, Jeremy Horst, David Fulciniti, Mariateresa Munshi, Nikhil C. Xu, Wenqing Kung, Andrew L. Shivdasani, Ramesh A. Walensky, Loren D. Carrasco, Daniel Ruben TI Targeted Disruption of the BCL9/beta-Catenin Complex Inhibits Oncogenic Wnt Signaling SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CATENIN-BINDING PROTEIN; BETA-CATENIN; MULTIPLE-MYELOMA; ARMADILLO/BETA-CATENIN; UP-REGULATION; IN-VIVO; CANCER; PATHWAY; ACTIVATION AB Deregulated Wnt/beta-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of beta-catenin with B cell lymphoma 9 (BCL9), a coactivator for beta-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives beta-catenin signaling through direct binding mediated by its alpha-helical homology domain 2. We developed a stabilized a helix of BCL9 (SAH-BCL9), which we show targets beta-catenin, dissociates native beta-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-beta-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling. C1 [Bird, Gregory H.; Lemieux, Madeleine; Kung, Andrew L.; Walensky, Loren D.] Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Takada, Kohichi; Zhu, Di; Sukhdeo, Kumar; Zhao, Jian-Jun; Mani, Mala; Carrasco, Daniel E.; Ryan, Jeremy; Horst, David; Fulciniti, Mariateresa; Munshi, Nikhil C.; Shivdasani, Ramesh A.; Carrasco, Daniel Ruben] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Xu, Wenqing] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Carrasco, Daniel Ruben] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. RP Walensky, LD (reprint author), Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM Loren_Walensky@dfci.harvard.edu; Ruben_Carrasco@dfci.harvard.edu OI Xu, Wenqing/0000-0002-2884-3101; Lemieux, Madeleine/0000-0001-6355-8691 FU Claudia Adams Barr Award; Multiple Myeloma Research Foundation; Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence in gastrointestinal cancer [P50CA127003]; Burroughs Welcome Career Award in the Biomedical Sciences; Todd J. Schwartz Pediatric Oncology grant; [1R01CA151391-01] FX Funding: D. R. C. is supported by a Claudia Adams Barr Award, the Multiple Myeloma Research Foundation, a P50CA127003 Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence in gastrointestinal cancer, and 1R01CA151391-01. This work was also supported by a Burroughs Welcome Career Award in the Biomedical Sciences and a Todd J. Schwartz Pediatric Oncology grant to L.D.W. NR 57 TC 60 Z9 63 U1 2 U2 27 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 22 PY 2012 VL 4 IS 148 AR 148ra117 DI 10.1126/scitranslmed.3003808 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 997GB UT WOS:000308151500008 PM 22914623 ER PT J AU Gaziano, JM Wilson, PWF AF Gaziano, J. Michael Wilson, Peter W. F. TI Cardiovascular Risk Assessment in the 21st Century SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CORONARY-HEART-DISEASE; PREDICTION C1 [Gaziano, J. Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston VA Healthcare Syst, Boston, MA 02120 USA. [Wilson, Peter W. F.] Atlanta VA Med Ctr, Atlanta, GA USA. [Wilson, Peter W. F.] Emory Clin Cardiovasc Res Inst, Atlanta, GA USA. RP Gaziano, JM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston VA Healthcare Syst, 1620 Tremont St, Boston, MA 02120 USA. EM jmgaziano@partners.org NR 10 TC 12 Z9 12 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 22 PY 2012 VL 308 IS 8 BP 816 EP 817 DI 10.1001/2012.jama.10456 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 991ML UT WOS:000307705300027 PM 22910761 ER PT J AU Uccellini, L De Giorgi, V Zhao, YD Tumaini, B Erdenebileg, N Dudley, ME Tomei, S Bedognetti, D Ascierto, ML Liu, QZ Simon, R Kottyan, L Kaufman, KM Harley, JB Wang, E Rosenberg, SA Marincola, FM AF Uccellini, Lorenzo De Giorgi, Valeria Zhao, Yingdong Tumaini, Barbara Erdenebileg, Narnygerel Dudley, Mark E. Tomei, Sara Bedognetti, Davide Ascierto, Maria Libera Liu, Qiuzhen Simon, Richard Kottyan, Leah Kaufman, Kenneth M. Harley, John B. Wang, Ena Rosenberg, Steven A. Marincola, Francesco M. TI IRF5 gene polymorphisms in melanoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INTERFERON REGULATORY FACTOR; METASTATIC MELANOMA; IMMUNOLOGICAL CONSTANT; MULTIPLE-SCLEROSIS; CELL-LINES; RISK; INTERFERON-REGULATORY-FACTOR-5; VARIANTS; THERAPY AB Background: Interferon regulatory factor (IRF)-5 is a transcription factor involved in type I interferon signaling whose germ line variants have been associated with autoimmune pathogenesis. Since relationships have been observed between development of autoimmunity and responsiveness of melanoma to several types of immunotherapy, we tested whether polymorphisms of IRF5 are associated with responsiveness of melanoma to adoptive therapy with tumor infiltrating lymphocytes (TILs). Methods: 140 TILs were genotyped for four single nucleotide polymorphisms (rs10954213, rs11770589, rs6953165, rs2004640) and one insertion-deletion in the IRF5 gene by sequencing. Gene-expression profile of the TILs, 112 parental melanoma metastases (MM) and 9 cell lines derived from some metastases were assessed by Affymetrix Human Gene ST 1.0 array. Results: Lack of A allele in rs10954213 (G > A) was associated with non-response (p < 0.005). Other polymorphisms in strong linkage disequilibrium with rs10954213 demonstrated similar trends. Genes differentially expressed in vitro between cell lines carrying or not the A allele could be applied to the transcriptional profile of 112 melanoma metastases to predict their responsiveness to therapy, suggesting that IRF5 genotype may influence immune responsiveness by affecting the intrinsic biology of melanoma. Conclusions: This study is the first to analyze associations between melanoma immune responsiveness and IRF5 polymorphism. The results support a common genetic basis which may underline the development of autoimmunity and melanoma immune responsiveness. C1 [Uccellini, Lorenzo; De Giorgi, Valeria; Erdenebileg, Narnygerel; Tomei, Sara; Bedognetti, Davide; Ascierto, Maria Libera; Liu, Qiuzhen; Wang, Ena; Rosenberg, Steven A.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Uccellini, Lorenzo; De Giorgi, Valeria; Erdenebileg, Narnygerel; Tomei, Sara; Bedognetti, Davide; Ascierto, Maria Libera; Liu, Qiuzhen; Wang, Ena; Rosenberg, Steven A.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [Uccellini, Lorenzo] Univ Milan, Inst Infect Dis, L Sacco Hosp, Milan, Italy. [Uccellini, Lorenzo] Univ Milan, Inst Trop Dis, L Sacco Hosp, Milan, Italy. [Zhao, Yingdong] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Tumaini, Barbara] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Bedognetti, Davide; Ascierto, Maria Libera] Univ Genoa, Dept Internal Med DiMI, I-16132 Genoa, Italy. [Dudley, Mark E.; Kottyan, Leah; Kaufman, Kenneth M.; Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol CAGE, Cincinnati, OH 45229 USA. [Kaufman, Kenneth M.; Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH 45229 USA. [Marincola, Francesco M.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Uccellini, L (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM uccellinilorenzo@gmail.com; fmarincola@mail.cc.nih.gov RI De Giorgi, Valeria/D-4582-2017; OI Bedognetti, Davide/0000-0002-5857-773X; Kottyan, Leah/0000-0003-3979-2220 FU Conquer Cancer Foundation of the American Society of Clinical Oncology FX DB's fellowship was supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology. NR 33 TC 17 Z9 17 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD AUG 21 PY 2012 VL 10 AR 170 DI 10.1186/1479-5876-10-170 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 033LJ UT WOS:000310797500001 PM 22909381 ER PT J AU Liu, Q Collin, RWJ Cremers, FPM den Hollander, AI van den Born, LI Pierce, EA AF Liu, Qin Collin, Rob W. J. Cremers, Frans P. M. den Hollander, Anneke I. van den Born, L. Ingeborgh Pierce, Eric A. TI Expression of Wild-Type Rp1 Protein in Rp1 Knock-in Mice Rescues the Retinal Degeneration Phenotype SO PLOS ONE LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; LEBERS CONGENITAL AMAUROSIS; GENE-THERAPY; PHOTORECEPTOR DEGENERATION; RNA SURVEILLANCE; MUTANT RHODOPSIN; TRANSGENIC MICE; MOUSE MODEL; MUTATIONS; FAMILIES AB Mutations in the retinitis pigmentosa 1 (RP1) gene are a common cause of autosomal dominant retinitis pigmentosa (adRP), and have also been found to cause autosomal recessive RP (arRP) in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39) are located in the 4th and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3rd exon of RP1 (c.686delC; p.P229QfsX35) found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated Rp1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as Rp1 transgenic mice carrying a wild-type BAC Rp1 transgene. The Rp1-Q662X allele produces a truncated Rp1 protein, and homozygous Rp1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC Rp1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled. C1 [Liu, Qin; Pierce, Eric A.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Ocular Genom Inst, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. [Collin, Rob W. J.; Cremers, Frans P. M.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Collin, Rob W. J.; den Hollander, Anneke I.] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 ED Nijmegen, Netherlands. [Collin, Rob W. J.; Cremers, Frans P. M.; den Hollander, Anneke I.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. [van den Born, L. Ingeborgh] Rotterdam Eye Hosp, Rotterdam, Netherlands. RP Liu, Q (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Ocular Genom Inst, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. EM eric_pierce@meei.harvard.edu RI Cremers, Frans/A-5625-2014; Collin, Rob/N-3575-2014; Hollander, Anneke/N-4911-2014; OI Pierce, Eric/0000-0002-2354-4102 FU NIH [EY12910]; Foundation Fighting Blindness USA; F.M. Kirby Foundation; Research to Prevent Blindness; Rosanne Silbermann Foundation; Mackall Foundation Trust; Stichting Wetenschappelijk; Onderzoek Oogziekenhuis Rotterdam Prof. dr. H.J. Flieringa Foundation, Rotterdam, the Netherlands [2005-13]; Netherlands Organisation for Scientific Research [91209047] FX This work is supported by grants from the NIH (EY12910 to EAP), the Foundation Fighting Blindness USA (EAP, QL), the F.M. Kirby Foundation, Research to Prevent Blindness, Rosanne Silbermann Foundation (EAP), the Mackall Foundation Trust, Stichting Wetenschappelijk, Onderzoek Oogziekenhuis Rotterdam Prof. dr. H.J. Flieringa Foundation (grant 2005-13 to LIvdB, AIdH and FPMC), Rotterdam, the Netherlands, and the Netherlands Organisation for Scientific Research (ZonMw Topsubsidy grant 91209047 to FPMC and AIdH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 3 Z9 3 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 21 PY 2012 VL 7 IS 8 AR e43251 DI 10.1371/journal.pone.0043251 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992PA UT WOS:000307789700029 PM 22927954 ER PT J AU Cannon, CP Kohli, P AF Cannon, Christopher P. Kohli, Payal TI Danger Ahead: Watch Out for Indirect Comparisons! SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE anticoagulation; atrial fibrillation; bleeding; stroke ID ACUTE MYOCARDIAL-INFARCTION; TISSUE PLASMINOGEN-ACTIVATOR; ATRIAL-FIBRILLATION; WARFARIN; ANISTREPLASE; THROMBOLYSIS C1 [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Kohli, Payal] Univ Calif San Francisco, Div Cardiol, San Francisco, CA USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM cpcannon@partners.org NR 10 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 21 PY 2012 VL 60 IS 8 BP 747 EP 748 DI 10.1016/j.jacc.2012.05.012 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 988BS UT WOS:000307463800007 PM 22898071 ER PT J AU Ching, SN Brown, EN Kramer, MA AF Ching, ShiNung Brown, Emery N. Kramer, Mark A. TI Distributed control in a mean-field cortical network model: Implications for seizure suppression SO PHYSICAL REVIEW E LA English DT Article ID DESYNCHRONIZING BRAIN-STIMULATION; EPILEPTIFORM ACTIVITY; ELECTRIC-FIELDS; DYNAMICS; EPILEPSY; CONNECTIVITY; OSCILLATORS; POPULATIONS; MODULATION; PARAMETERS AB Brain electrical stimulation (BES) has long been suggested as a means of controlling pathological brain activity. In epilepsy, control of a spatially localized source, the seizure focus, may normalize neuronal dynamics. Consequently, most BES research has been directed at controlling small, local, neuronal populations. At a higher level, pathological seizure activity can be viewed as a network event that may begin without a clear spatial focus or in multiple sites and spread rapidly through a distributed cortical network. In this paper, we begin to address the implications of local control in a network scenario. To do so, we explore the efficacy of local BES when deployed over a larger-scale neuronal network, for instance, using a grid of stimulating electrodes on the cortex. By introducing a mean-field model of neuronal interactions we are able to identify limitations in network controllability based on physiological constraints that suggest the need for more nuanced network control strategies. C1 [Ching, ShiNung; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ching, ShiNung; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Brown, Emery N.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Ching, SN (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM shinung@mit.edu RI Kramer, Mark/A-1291-2014 FU Burroughs Wellcome Fund; NIH [DP1-OD003646] FX M.A.K. and S.C. acknowledge support through Career Awards at the Scientific Interface from the Burroughs Wellcome Fund. S.C. and E.N.B. are supported in part by NIH DP1-OD003646. NR 35 TC 15 Z9 15 U1 0 U2 3 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD AUG 21 PY 2012 VL 86 IS 2 AR 021920 DI 10.1103/PhysRevE.86.021920 PN 1 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 992BQ UT WOS:000307750700003 PM 23005798 ER PT J AU Roseman, M Turner, EH Lexchin, J Coyne, JC Bero, LA Thombs, BD AF Roseman, Michelle Turner, Erick H. Lexchin, Joel Coyne, James C. Bero, Lisa A. Thombs, Brett D. TI Reporting of conflicts of interest from drug trials in Cochrane reviews: cross sectional study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID SYSTEMATIC REVIEWS; PHARMACEUTICAL-INDUSTRY; RANDOMIZED-TRIALS; PRISMA STATEMENT; FINANCIAL TIES; METAANALYSES; QUALITY; IMPACT; CONCLUSIONS; PUBLICATION AB Objectives To investigate the degree to which Cochrane reviews of drug interventions published in 2010 reported conflicts of interest from included trials and, among reviews that reported this information, where it was located in the review documents. Design Cross sectional study. Data sources Cochrane Database of Systematic Reviews. Selection criteria Systematic reviews of drug interventions published in 2010 in the Cochrane Database of Systematic Reviews, with review content classified as up to date in 2008 or later and with results from one or more randomised controlled trials. Results Of 151 included Cochrane reviews, 46 (30%, 95% confidence interval 24% to 38%) reported information on the funding sources of included trials, including 30 (20%, 14% to 27%) that reported information on trial funding for all included trials and 16 (11%, 7% to 17%) that reported for some, but not all, trials. Only 16 of the 151 Cochrane reviews (11%, 7% to 17%) provided any information on trial author-industry financial ties or trial author-industry employment. Information on trial funding and trial author-industry ties was reported in one to seven locations within each review, with no consistent reporting location observed. Conclusions Most Cochrane reviews of drug trials published in 2010 did not provide information on trial funding sources or trial author-industry financial ties or employment. When this information was reported, location of reporting was inconsistent across reviews. C1 [Roseman, Michelle; Thombs, Brett D.] Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E4, Canada. [Roseman, Michelle; Thombs, Brett D.] McGill Univ, Montreal, PQ H3T 1E4, Canada. [Turner, Erick H.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Turner, Erick H.] Portland VA Med Ctr, Portland, OR USA. [Lexchin, Joel] York Univ, Sch Hlth Policy & Management, Toronto, ON M3J 2R7, Canada. [Coyne, James C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hlth Sci, Hlth Psychol Sect, NL-9700 AB Groningen, Netherlands. [Bero, Lisa A.] Univ Calif San Francisco, Sch Pharm, Dept Clin Pharm, San Francisco, CA 94143 USA. [Bero, Lisa A.] Univ Calif San Francisco, Sch Med, Inst Hlth Policy Studies, San Francisco, CA 94143 USA. RP Thombs, BD (reprint author), Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E4, Canada. EM brett.thombs@mcgill.ca OI Turner, Erick/0000-0002-3522-3357; Thombs, Brett/0000-0002-5644-8432 FU Canadian Institutes of Health Research; Fonds de la Recherche en Sante Quebec; McGill University provost's graduate fellowship; McGill University principal's graduate fellowship; Etablissement de Jeunes Chercheurs award from the Fonds de la Recherche en Sante Quebec; Cochrane Collaboration Methodological Fund FX MR was supported by a Frederick Banting and Charles Best Canadian graduate scholarship-master's award from the Canadian Institutes of Health Research, a master's training award from the Fonds de la Recherche en Sante Quebec, a McGill University provost's graduate fellowship, and a McGill University principal's graduate fellowship. BDT was supported by a new investigator award from the Canadian Institutes of Health Research and an Etablissement de Jeunes Chercheurs award from the Fonds de la Recherche en Sante Quebec. This study received no funding, and no funding body had any input into any aspect of the study.; All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: no authors had any financial support for the submitted work; JL was a consultant to a law firm representing Apotex in 2007, a consultant to the Canadian federal government in a lawsuit challenging the Canadian ban on direct to consumer advertising of prescription drugs in 2007-08, and a consultant to a law firm representing a plaintiff in a case against Allergan in 2010; LAB has received a grant from the Cochrane Collaboration Methodological Fund to examine how systematic reviewers identify unpublished drug trial data, and is an active member of the Cochrane Collaboration. NR 44 TC 18 Z9 18 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD AUG 21 PY 2012 VL 345 AR e5155 DI 10.1136/bmj.e5155 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 996GP UT WOS:000308073200004 PM 22906823 ER PT J AU Wesemann, DR Portuguese, AJ Magee, JM Gallagher, MP Zhou, XL Panchakshari, RA Alt, FW AF Wesemann, Duane R. Portuguese, Andrew J. Magee, Jennifer M. Gallagher, Michael P. Zhou, Xiaolong Panchakshari, Rohit A. Alt, Frederick W. TI Reprogramming IgH isotype-switched B cells to functional-grade induced pluripotent stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MU REGION; S-MU; RECOMBINATION; GENERATION; DNA; FIBROBLASTS; LYMPHOCYTES; MICE; TRANSCRIPTION; MUTATIONS AB Induced pluripotent stem cells (iPSCs) can be formed from somatic cells by a defined set of genetic factors; however, aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster often hinders their developmental potency and ability to contribute to high-grade chimerism in mice. Here, we describe an approach that allows splenic B cells activated to undergo Ig heavy-chain (IgH) class-switch recombination (CSR) to be reprogrammed into iPSCs that contribute to high-grade chimerism in mice. Treatment of naive splenic B cells in culture with anti-CD40 plus IL-4 induces IgH CSR from IgM to IgG1 and IgE. CSR leads to irreversible IgH locus deletions wherein the IgM-producing C mu exons are permanently excised from the B-cell genome. We find that anti-CD40 plus IL-4-activated B cells produce iPSCs that are uniformly hypermethylated in the imprinted Dlk1-Dio3 gene cluster and fail to produce chimerism in mice. However, treatment of activated B cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine before and at early stages of reprogramming attenuates hypermethylation of the Dlk1-Dio3 locus in resultant iPSCs and enables them to form high-grade chimerism in mice. These conditions allowed us to produce chimeric mice in which all mature B cells were derived entirely from IgG1-expressing B-cell-derived iPSCs. We conclude that culture conditions of activated B cells before and at early stages of reprogramming influence the developmental potency of resultant iPSCs. C1 [Wesemann, Duane R.; Portuguese, Andrew J.; Magee, Jennifer M.; Gallagher, Michael P.; Zhou, Xiaolong; Panchakshari, Rohit A.; Alt, Frederick W.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Wesemann, Duane R.; Portuguese, Andrew J.; Magee, Jennifer M.; Gallagher, Michael P.; Zhou, Xiaolong; Panchakshari, Rohit A.; Alt, Frederick W.] Boston Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Wesemann, Duane R.; Portuguese, Andrew J.; Magee, Jennifer M.; Gallagher, Michael P.; Zhou, Xiaolong; Panchakshari, Rohit A.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Wesemann, Duane R.; Portuguese, Andrew J.; Magee, Jennifer M.; Gallagher, Michael P.; Zhou, Xiaolong; Panchakshari, Rohit A.; Alt, Frederick W.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Wesemann, Duane R.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. RP Wesemann, DR (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. EM wesemann@idi.harvard.edu; alt@enders.tch.harvard.edu OI Zhou, Alan/0000-0002-6177-2472 FU National Institutes of Health [AI077595, AI020047, K08AI89972]; American Academy of Allergy, Asthma Immunology; Burroughs Wellcome Fund FX We thank Drs. Hidde Ploegh, Juan Lafaille, and David Schatz for critical review of the manuscript. We thank K. Hochedlinger and M. Stadtfeld for the doxycycline-inducible reprogrammable OKSM transgenic mice and for technical advice in the reprogramming procedure. This work was supported by National Institutes of Health Grants AI077595 and AI020047 (to F.W.A.) and K08AI89972 (to D.R.W.). D.R.W. was also supported by an award from the American Academy of Allergy, Asthma & Immunology and CSL Behring and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. F.W.A. is an Investigator of the Howard Hughes Medical Institute. NR 44 TC 8 Z9 8 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 21 PY 2012 VL 109 IS 34 BP 13745 EP 13750 DI 10.1073/pnas.1210286109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996KJ UT WOS:000308085200061 PM 22869756 ER PT J AU Thon, JN Peters, CG Machlus, KR Aslam, R Rowley, J Macleod, H Devine, MT Fuchs, TA Weyrich, AS Semple, JW Flaumenhaft, R Italiano, JE AF Thon, Jonathan N. Peters, Christopher G. Machlus, Kellie R. Aslam, Rukhsana Rowley, Jesse Macleod, Hannah Devine, Matthew T. Fuchs, Tobias A. Weyrich, Andrew S. Semple, John W. Flaumenhaft, Robert Italiano, Joseph E., Jr. TI T granules in human platelets function in TLR9 organization and signaling SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PROTEIN-DISULFIDE-ISOMERASE; BACTERIAL-DNA; ACTIVATED PLATELETS; BLOOD-PLATELETS; PLASMA-MEMBRANE; IN-VIVO; RECOGNITION; SURFACE; MEGAKARYOCYTES; LOCALIZATION AB Human and murine platelets (PLTs) variably express toll-like receptors (TLRs), which link the innate and adaptive immune responses during infectious inflammation and atherosclerotic vascular disease. In this paper, we show that the TLR9 transcript is specifically up-regulated during pro-PLT production and is distributed to a novel electron-dense tubular system-related compartment we have named the T granule. TLR9 colocalizes with protein disulfide isomerase and is associated with either VAMP 7 or VAMP 8, which regulates its distribution in PLTs on contact activation (spreading). Preincubation of PLTs with type IV collagen specifically increased TLR9 and CD62P surface expression and augmented oligodeoxy-nucleotide (ODN) sequestration and PLT clumping upon addition of bacterial/viral ODNs. Collectively, this paper (a) tracks TLR9 to a new intracellular compartment in PLTs and (b) describes a novel mechanism of TLR9 organization and signaling in human PLTs. C1 [Thon, Jonathan N.; Machlus, Kellie R.; Macleod, Hannah; Devine, Matthew T.; Italiano, Joseph E., Jr.] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Thon, Jonathan N.; Peters, Christopher G.; Machlus, Kellie R.; Flaumenhaft, Robert; Italiano, Joseph E., Jr.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Fuchs, Tobias A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Aslam, Rukhsana; Semple, John W.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto Platelet Immunobiol Grp, Toronto, ON M5B 1W8, Canada. [Rowley, Jesse; Weyrich, Andrew S.] Univ Utah, Program Mol Med, Salt Lake City, UT 84112 USA. [Peters, Christopher G.; Fuchs, Tobias A.] Immune Dis Inst, Boston, MA 02115 USA. [Fuchs, Tobias A.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Flaumenhaft, Robert] Beth Israel Deaconess Med Ctr, Dept Med, Div Hemostasis & Thrombosis, Boston, MA 02115 USA. [Italiano, Joseph E., Jr.] Childrens Hosp, Dept Surg, Vasc Biol Program, Boston, MA 02115 USA. RP Italiano, JE (reprint author), Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. EM jitaliano@rics.bwh.harvard.edu RI Fuchs, Tobias/F-1189-2013; OI Machlus, Kellie/0000-0002-2155-1050 FU National Institutes of Health [Hl68130]; National Institutes of Health NHLBI [HL102101] FX This work was supported in part by the National Institutes of Health grant Hl68130 (to J.E. Italiano Jr.). J.E. Italiano Jr. is an American Society of Hematology Junior Faculty Scholar. J.N. Thon is an American Society of Hematology Scholar. T. A. Fuchs is supported by the National Institutes of Health NHLBI R01 grant HL102101 (to D.D. Wagner). NR 41 TC 50 Z9 50 U1 1 U2 11 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 20 PY 2012 VL 198 IS 4 BP 561 EP 574 DI 10.1083/jcb.201111136 PG 14 WC Cell Biology SC Cell Biology GA 994LL UT WOS:000307932200010 PM 22908309 ER PT J AU Garraway, LA AF Garraway, Levi A. TI Concordance and Discordance in Tumor Genomic Profiling SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID MUTATIONS; CANCER; SAMPLES C1 [Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Garraway, Levi A.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Garraway, Levi A.] MIT, Cambridge, MA 02139 USA. RP Garraway, LA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 7 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2012 VL 30 IS 24 BP 2937 EP 2939 DI 10.1200/JCO.2011.41.3138 PG 3 WC Oncology SC Oncology GA 996JR UT WOS:000308082300005 PM 22826272 ER PT J AU Ligibel, JA Winer, EP AF Ligibel, Jennifer A. Winer, Eric P. TI Aromatase Inhibition in Obese Women: How Much Is Enough? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ADVANCED BREAST-CANCER; PLASMA ESTROGEN-LEVELS; BODY-MASS INDEX; ADJUVANT ENDOCRINE THERAPY; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; MEGESTROL-ACETATE; DOUBLE-BLIND; FASTING INSULIN; PHASE-III C1 [Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ligibel, JA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 32 TC 9 Z9 9 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 AUG 20 PY 2012 VL 30 IS 24 BP 2940 EP 2942 DI 10.1200/JCO.2012.43.7244 PG 3 WC Oncology SC Oncology GA 996JR UT WOS:000308082300006 PM 22802318 ER PT J AU McElligott, S Field, RI Bristol-Demeter, M Domchek, SM Asch, DA AF McElligott, Sean Field, Robert I. Bristol-Demeter, Mirar Domchek, Susan M. Asch, David A. TI How Genetic Variant Libraries Effectively Extend Gene Testing Patents: Implications for Intellectual Property and Good Clinical Care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID UNCERTAIN SIGNIFICANCE; SEQUENCE VARIATION; BRCA2 VARIANTS; RISK C1 [McElligott, Sean; Bristol-Demeter, Mirar; Asch, David A.] Univ Penn, Philadelphia, PA 19104 USA. [Field, Robert I.] Drexel Univ, Philadelphia, PA 19104 USA. [Domchek, Susan M.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP McElligott, S (reprint author), Univ Penn, Philadelphia, PA 19104 USA. OI Asch, David/0000-0002-7970-286X FU NCI NIH HHS [UC2 CA148310] NR 10 TC 1 Z9 2 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2012 VL 30 IS 24 BP 2943 EP 2945 DI 10.1200/JCO.2012.42.7757 PG 3 WC Oncology SC Oncology GA 996JR UT WOS:000308082300007 PM 22802312 ER PT J AU Chan, JA Stuart, K Earle, CC Clark, JW Bhargava, P Miksad, R Blaszkowsky, L Enzinger, PC Meyerhardt, JA Zheng, H Fuchs, CS Kulke, MH AF Chan, Jennifer A. Stuart, Keith Earle, Craig C. Clark, Jeffrey W. Bhargava, Pankaj Miksad, Rebecca Blaszkowsky, Lawrence Enzinger, Peter C. Meyerhardt, Jeffrey A. Zheng, Hui Fuchs, Charles S. Kulke, Matthew H. TI Prospective Study of Bevacizumab Plus Temozolomide in Patients With Advanced Neuroendocrine Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PANCREATIC ENDOCRINE CARCINOMAS; ISLET-CELL-CARCINOMA; PHASE-II TRIAL; STREPTOZOCIN; FLUOROURACIL; DOXORUBICIN; ONCOLOGY; THERAPY; DACARBAZINE AB Purpose Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs. Patients and Methods Thirty-four patients (56% with carcinoid, 44% with pancreatic NETs) were treated with temozolomide 150 mg/m(2) orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle. All patients received prophylaxis against Pneumocystis carinii and varicella zoster. Patients were followed for toxicity, biochemical and radiologic response, and survival. Results The combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 toxicities, including lymphopenia (53%) and thrombocytopenia (18%). Although the overall radiographic response rate was 15% (five of 34), response rates differed between patients with pancreatic NETs (33%; five of 15) and those with carcinoid tumors (zero of 19). The median progression-free survival was 11.0 months (14.3 months for pancreatic NETs v 7.3 months for carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic NETs v 18.8 months for carcinoid tumors). Conclusion Temozolomide and bevacizumab can be safely administered together in patients with advanced NETs, and the combination regimen appears promising for patients with pancreatic NETs. Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted. C1 [Chan, Jennifer A.; Earle, Craig C.; Bhargava, Pankaj; Enzinger, Peter C.; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA USA. [Chan, Jennifer A.; Earle, Craig C.; Bhargava, Pankaj; Enzinger, Peter C.; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Kulke, Matthew H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Stuart, Keith; Miksad, Rebecca] Deaconess Med Ctr, Boston, MA USA. [Clark, Jeffrey W.; Blaszkowsky, Lawrence] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Chan, Jennifer A.; Stuart, Keith; Earle, Craig C.; Clark, Jeffrey W.; Bhargava, Pankaj; Miksad, Rebecca; Blaszkowsky, Lawrence; Enzinger, Peter C.; Meyerhardt, Jeffrey A.; Zheng, Hui; Fuchs, Charles S.; Kulke, Matthew H.] Harvard Univ, Sch Med, Boston, MA USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM jang@partners.org OI Miksad, Rebecca/0000-0003-3194-5122 FU Schering-Plough/Merck; Genentech; Merck; Novartis; Onyx Pharmaceuticals; Bayer FX Supported by Genentech and Schering-Plough/Merck.; Research Funding: Jennifer A. Chan, Bayer, Merck, Novartis, Onyx Pharmaceuticals NR 18 TC 92 Z9 94 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2012 VL 30 IS 24 BP 2963 EP 2968 DI 10.1200/JCO.2011.40.3147 PG 6 WC Oncology SC Oncology GA 996JR UT WOS:000308082300010 PM 22778320 ER PT J AU Basch, E Oliver, TK Vickers, A Thompson, I Kantoff, P Parnes, H Loblaw, DA Roth, B Williams, J Nam, RK AF Basch, Ethan Oliver, Thomas K. Vickers, Andrew Thompson, Ian Kantoff, Philip Parnes, Howard Loblaw, D. Andrew Roth, Bruce Williams, James Nam, Robert K. TI Screening for Prostate Cancer With Prostate-Specific Antigen Testing: American Society of Clinical Oncology Provisional Clinical Opinion SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SERVICES-TASK-FORCE; FOLLOW-UP; CONSERVATIVE MANAGEMENT; MORTALITY; COMPLICATIONS; STATISTICS; OUTCOMES; BIOPSY; RISK AB Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to the ASCO membership after publication or presentation of potentially practice-changing data from major studies. This PCO addresses the role of prostate-specific antigen (PSA) testing in the screening of men for prostate cancer. Clinical Context Prostate cancer is the second leading cause of cancer deaths among men in the United States. The rationale for screening men for prostate cancer is the potential to reduce the risk of death through early detection. Recent Data Evidence from a 2011 Agency for Healthcare Research and Quality systematic review primarily informs this PCO on the benefits and harms of PSA-based screening. An update search was conducted to March 16, 2012, for additional evidence related to the topic. Results In one randomized trial, PSA testing in men who would not otherwise have been screened resulted in reduced death rates from prostate cancer, but it is uncertain whether the size of the effect was worth the harms associated with screening and subsequent unnecessary treatment. Although there are limitations to the existing data, there is evidence to suggest that men with longer life expectancy may benefit from PSA testing. Adverse events associated with prostate biopsy are low for the majority of men; however, several population-based studies have shown increasing rates of infectious complications after prostate biopsy, which is a concern. C1 [Oliver, Thomas K.; Nam, Robert K.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Basch, Ethan; Vickers, Andrew] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Thompson, Ian] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Kantoff, Philip] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Parnes, Howard] NCI, Rockville, MD USA. [Loblaw, D. Andrew; Nam, Robert K.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Odette Canc Ctr, Toronto, ON, Canada. [Roth, Bruce] Washington Univ, St Louis, MO USA. [Williams, James] Penn Prostate Canc Coalit, Camp Hill, PA USA. RP Nam, RK (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org OI Vickers, Andrew/0000-0003-1525-6503 NR 46 TC 65 Z9 69 U1 0 U2 15 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2012 VL 30 IS 24 BP 3020 EP 3025 DI 10.1200/JCO.2012.43.3441 PG 6 WC Oncology SC Oncology GA 996JR UT WOS:000308082300018 PM 22802323 ER PT J AU Hardin, C Tambe, D Zhou, EH Krishnan, R Butler, JP Fredberg, J AF Hardin, Corey Tambe, Dhananjay Zhou, Enhua Krishnan, Ramachandran Butler, James P. Fredberg, Jeffrey TI Jamming and glass transitions in cell mechanics: From single cells to tissues SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc, Amer Chem Soc, Div Chem Educ, Amer Chem Soc, Div Inorgan Chem, Soc Biol Inorgan Chem, Amer Chem Soc, Div Polymer Chem Inc C1 [Tambe, Dhananjay; Zhou, Enhua; Butler, James P.; Fredberg, Jeffrey] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hardin, Corey] Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02114 USA. [Krishnan, Ramachandran] Beth Israel Deaconess Med Ctr, Ctr Vasc Biol, Boston, MA 02115 USA. EM chardin@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 103-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807266 ER PT J AU Lin, LL Tiemann, K Li, YL Heo, GS Lim, Y Pinkner, J Walker, J Hultgren, S Hunstad, D Wooley, K AF Lin, Lily Tiemann, Kristin Li, Yali Heo, Gyu Seong Lim, Young Pinkner, Jerome Walker, Jennifer Hultgren, Scott Hunstad, David Wooley, Karen TI Bacterial adhesin protein-conjugated polymer nanoparticles as antimicrobial nanodevices that utilize bacterial modes of epithelial cell entry for effective treatment strategies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Lin, Lily; Heo, Gyu Seong; Lim, Young; Wooley, Karen] Texas A&M Univ, Dept Chem, College Stn, TX 77842 USA. [Tiemann, Kristin; Pinkner, Jerome; Walker, Jennifer; Hultgren, Scott; Hunstad, David] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Li, Yali] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02129 USA. EM wooley@chem.tamu.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 319-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808477 ER PT J AU Liong, M Lee, H Weissleder, R AF Liong, Monty Lee, Hakho Weissleder, Ralph TI Multiplexed labeling and signal amplification in diagnostic magnetic resonance SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Liong, Monty; Lee, Hakho; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM liong.monty@gmail.com NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 142-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621802344 ER PT J AU Liong, M AF Liong, Monty TI Inorganic nanomaterials: Functional scaffold in therapeutics and diagnostics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Liong, Monty] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM liong.monty@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 37-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800036 ER PT J AU Liu, R Rallo, R Shaw, S Cohen, Y AF Liu, Rong Rallo, Robert Shaw, Stanley Cohen, Yoram TI Nano-SAR development with application to regulatory decision making SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Liu, Rong; Rallo, Robert; Cohen, Yoram] Univ Calif Los Angeles, Ctr Environm Implicat Nanotechnol, Los Angeles, CA 90095 USA. [Shaw, Stanley] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM rongliu@ucla.edu RI Rallo, Robert/F-4703-2010 OI Rallo, Robert/0000-0003-3812-4458 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 360-ENVR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621804560 ER PT J AU Lusic, H Freedman, JD Snyder, BD Grinstaff, MW AF Lusic, Hrvoje Freedman, Jonathan D. Snyder, Brian D. Grinstaff, Mark W. TI X-ray computed tomography contrast agents for cartilage imaging SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Lusic, Hrvoje; Freedman, Jonathan D.; Grinstaff, Mark W.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Lusic, Hrvoje; Freedman, Jonathan D.; Grinstaff, Mark W.] Boston Univ, Dept Chem, Boston, MA 02215 USA. [Snyder, Brian D.] Harvard Univ, Sch Med, Beth Israel Deacones Med Ctr, Boston, MA 02215 USA. EM hlusic@bu.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 534-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806734 ER PT J AU Perrault, SD Shih, WM AF Perrault, Steven D. Shih, Willam M. TI Directed assembly of lipid bilayers onto 3D DNA nanostructures SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Perrault, Steven D.; Shih, Willam M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA. [Perrault, Steven D.; Shih, Willam M.] Dana Farber Canc Inst, Boston, MA 02115 USA. EM steven.perrault@wyss.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 463-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621802646 ER PT J AU Sears, RB AF Sears, R. Bryan TI Development of novel therapeutics, combinations, and formulations of photodynamic therapy agents for the treatment of cancers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Sears, R. Bryan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. EM Sears.Bryan@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 43-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800041 ER PT J AU Tamae, D Byrns, MC Balk, SP Nelson, PS Montgomery, B Mostaghel, E Kantoff, P Taplin, ME Blair, IA Penning, TM AF Tamae, Daniel Byrns, Michael C. Balk, Steven P. Nelson, Peter S. Montgomery, Bruce Mostaghel, Elahe Kantoff, Philip Taplin, Mary-Ellen Blair, Ian A. Penning, Trevor M. TI Development of stable isotope dilution liquid chromatography tandem mass spectrometry (LS-MS/MS) methods for the determination of the androgen metabolome in serum following androgen deprivation therapy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Tamae, Daniel; Byrns, Michael C.; Blair, Ian A.; Penning, Trevor M.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Ctr Excellence Environm Toxicol, Philadelphia, PA 19104 USA. [Tamae, Daniel; Byrns, Michael C.; Blair, Ian A.; Penning, Trevor M.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Ctr Excellence Canc Pharmacol, Philadelphia, PA 19104 USA. [Balk, Steven P.; Nelson, Peter S.; Kantoff, Philip; Taplin, Mary-Ellen] Harvard Univ, Sch Med, Dana Farber Harvard Canc Ctr, Boston, MA USA. [Balk, Steven P.; Nelson, Peter S.; Kantoff, Philip; Taplin, Mary-Ellen] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Montgomery, Bruce; Mostaghel, Elahe] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. EM dtamae@mail.med.upenn.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 39-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800817 ER PT J AU Matzuk, MM McKeown, MR Filippakopoulos, P Li, QL Ma, L Agno, JE Lemieux, ME Picaud, S Yu, RN Qi, J Knapp, S Bradner, JE AF Matzuk, Martin M. McKeown, Michael R. Filippakopoulos, Panagis Li, Qinglei Ma, Lang Agno, Julio E. Lemieux, Madeleine E. Picaud, Sarah Yu, Richard N. Qi, Jun Knapp, Stefan Bradner, James E. TI Small-Molecule Inhibition of BRDT for Male Contraception SO CELL LA English DT Article ID BET BROMODOMAINS; 1ST BROMODOMAIN; BINDING; TESTIS; MYC; DIFFERENTIATION; IDENTIFICATION; INFERTILITY; EXPRESSION; CHROMATIN AB A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood: testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception. C1 [Matzuk, Martin M.; Ma, Lang; Agno, Julio E.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Ctr Drug Discovery, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Ctr Reprod Med, Houston, TX 77030 USA. [McKeown, Michael R.; Lemieux, Madeleine E.; Qi, Jun; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Filippakopoulos, Panagis; Picaud, Sarah; Knapp, Stefan] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7DQ, England. [Li, Qinglei] Texas A&M Univ, Dept Vet Integrat Biosci, Coll Vet Med & Biomed Sci, College Stn, TX 77843 USA. [Lemieux, Madeleine E.] Bioinfo, Ottawa, ON K1J 8G4, Canada. [Yu, Richard N.] Childrens Hosp, Dept Urol, Boston, MA 02115 USA. [Knapp, Stefan] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Matzuk, MM (reprint author), Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. EM mmatzuk@bcm.edu; james_bradner@dfci.harvard.edu OI Lemieux, Madeleine/0000-0001-6355-8691; Filippakopoulos, Panagis/0000-0002-1515-1317; Knapp, Stefan/0000-0001-5995-6494 FU Eunice Kennedy Shriver NICHD/NIH [U01-HD060496]; Alkek Award for Pilot Projects in Experimental Therapeutics; Fidelity Foundation; Burroughs Wellcome Fund; NIH [K08CA128972]; Smith Family Foundation; Damon-Runyon Cancer Research Foundation; CIHR [1097737]; Canada Foundation for Innovation; Genome Canada; GlaxoSmithKline; Pfizer; Eli Lilly; Abbott; Takeda; Novartis Research Foundation; Ontario Ministry of Research and Innovation; Wellcome Trust; Wellcome Trust Career Development Fellowship [095751/Z/11/Z]; NICHD (SCCPRR) [U54-HD28934] FX We are grateful to Drs. J. Brown and J. Plutzky for pharmacodynamic data; Dr. A. Roy for advice on the spermatozoa assays; Y. Vasquez and Dr. Z. Yu for technical help; J. Marineau, K. Shaw, and W. Smith for support of peptide synthesis; Dr. S. Kistler for the generous gift of the anti-TNP2 antibody; and Dr. S. Khochbin for helpful comments. These studies were supported, in part, by the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement U01-HD060496 as part of the Cooperative Program in Male Contraception; an Alkek Award for Pilot Projects in Experimental Therapeutics; and a grant from the Fidelity Foundation (to M. M. M.), the Burroughs Wellcome Fund, the NIH (K08CA128972), the Smith Family Foundation, and Damon-Runyon Cancer Research Foundation (to J. E. B.). The SGC is a registered charity (number 1097737) that receives funds from the CIHR, Canada Foundation for Innovation, Genome Canada, GlaxoSmithKline, Pfizer, Eli Lilly, Abbott, Takeda, Novartis Research Foundation, Ontario Ministry of Research and Innovation, and Wellcome Trust. P. F. is supported by a Wellcome Trust Career Development Fellowship (095751/Z/11/Z). Serum FSH, LH, and testosterone analyses were performed at the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core supported by NICHD (SCCPRR) grant U54-HD28934. Baylor College of Medicine and Dana-Farber Cancer Institute have filed patent applications on technologies relating to this work, which have been licensed to Tensha Therapeutics. NR 29 TC 142 Z9 148 U1 5 U2 73 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 17 PY 2012 VL 150 IS 4 BP 673 EP 684 DI 10.1016/j.cell.2012.06.045 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 995IT UT WOS:000308002300004 PM 22901802 ER PT J AU Nijhawan, D Zack, TI Ren, Y Strickland, MR Lamothe, R Schumacher, SE Tsherniak, A Besche, HC Rosenbluh, J Shehata, S Cowley, GS Weir, BA Goldberg, AL Mesirov, JP Root, DE Bhatia, SN Beroukhim, R Hahn, WC AF Nijhawan, Deepak Zack, Travis I. Ren, Yin Strickland, Matthew R. Lamothe, Rebecca Schumacher, Steven E. Tsherniak, Aviad Besche, Henrike C. Rosenbluh, Joseph Shehata, Shyemaa Cowley, Glenn S. Weir, Barbara A. Goldberg, Alfred L. Mesirov, Jill P. Root, David E. Bhatia, Sangeeta N. Beroukhim, Rameen Hahn, William C. TI Cancer Vulnerabilities Unveiled by Genomic Loss SO CELL LA English DT Article ID COPY-NUMBER ALTERATION; OVARIAN-CANCER; PROTEASOMAL ATPASES; ONCOGENE ADDICTION; DRUG-SENSITIVITY; LUNG-CANCER; CELLS; GENE; IDENTIFICATION; THERAPY AB Due to genome instability, most cancers exhibit loss of regions containing tumor suppressor genes and collateral loss of other genes. To identify cancer-specific vulnerabilities that are the result of copy number losses, we performed integrated analyses of genome-wide copy number and RNAi profiles and identified 56 genes for which gene suppression specifically inhibited the proliferation of cells harboring partial copy number loss of that gene. These CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes are enriched for spliceosome, proteasome, and ribosome components. One CYCLOPS gene, PSMC2, encodes an essential member of the 19S proteasome. Normal cells express excess PSMC2, which resides in a complex with PSMC1, PSMD2, and PSMD5 and acts as a reservoir protecting cells from PSMC2 suppression. Cells harboring partial PSMC2 copy number loss lack this complex and die after PSMC2 suppression. These observations define a distinct class of cancer-specific liabilities resulting from genome instability. C1 [Nijhawan, Deepak; Zack, Travis I.; Strickland, Matthew R.; Lamothe, Rebecca; Schumacher, Steven E.; Rosenbluh, Joseph; Shehata, Shyemaa; Beroukhim, Rameen; Hahn, William C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Nijhawan, Deepak; Zack, Travis I.; Strickland, Matthew R.; Lamothe, Rebecca; Schumacher, Steven E.; Rosenbluh, Joseph; Shehata, Shyemaa; Beroukhim, Rameen; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Nijhawan, Deepak; Zack, Travis I.; Schumacher, Steven E.; Tsherniak, Aviad; Rosenbluh, Joseph; Cowley, Glenn S.; Weir, Barbara A.; Mesirov, Jill P.; Root, David E.; Bhatia, Sangeeta N.; Beroukhim, Rameen; Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Zack, Travis I.] Harvard Univ, Biophys Program, Boston, MA 02115 USA. [Besche, Henrike C.; Goldberg, Alfred L.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Ren, Yin; Bhatia, Sangeeta N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Nijhawan, Deepak; Rosenbluh, Joseph; Bhatia, Sangeeta N.; Beroukhim, Rameen; Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Bhatia, Sangeeta N.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Beroukhim, R (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM rameen_beroukhim@dfci.harvard.edu; william_hahn@dfci.harvard.edu RI Schumacher, Steven/E-9821-2013 OI Schumacher, Steven/0000-0002-6819-5647 FU NIH/NCI [RC2 CA148268, U54 CA143798, K08 CA122833, T32 GM008313, RO1 GM051923-17, U54 CA112962]; H.L. Snyder Medical Foundation; V Foundation; Conquer Cancer Foundation Young Investigator Award; Sass Foundation Fellowship; Marie D. & Pierre Casimir-Lambert Fund FX We would like to thank Leslie Gaffney and Lauren Solomon for support in generating illustrations and graphics and Jesse Boehm, Scott Carter, George Demartino, and members of the Goldberg and Hahn lab for helpful discussion. This work was supported in part by NIH/NCI grants RC2 CA148268 (W. C. H.), U54 CA143798, K08 CA122833 (R. B.), T32 GM008313 (T.I.Z.), RO1 GM051923-17 (A. L. G and H. C. B.), and U54 CA112962 (A. T., J.P.M., W. C. H.), the H.L. Snyder Medical Foundation (W. C. H.), the V Foundation (R. B.), a Conquer Cancer Foundation Young Investigator Award (D.N.), Sass Foundation Fellowship (D.N.), and the Marie D. & Pierre Casimir-Lambert Fund. S.N.B. is a Howard Hughes Investigator. W. C. H. and R. B. are consultants for Novartis Pharmaceuticals. NR 35 TC 64 Z9 65 U1 1 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 17 PY 2012 VL 150 IS 4 BP 842 EP 854 DI 10.1016/j.cell.2012.07.023 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 995IT UT WOS:000308002300017 PM 22901813 ER PT J AU Hom, JK Wang, BX Chetty, S Giddy, J Mazibuko, M Allen, J Walensky, RP Losina, E Freedberg, KA Bassett, IV AF Hom, Jeffrey K. Wang, Bingxia Chetty, Senica Giddy, Janet Mazibuko, Matilda Allen, Jenny Walensky, Rochelle P. Losina, Elena Freedberg, Kenneth A. Bassett, Ingrid V. TI Drug-Resistant Tuberculosis among HIV-Infected Patients Starting Antiretroviral Therapy in Durban, South Africa SO PLOS ONE LA English DT Article ID MULTIDRUG-RESISTANT; EPIDEMIC AB Objective: To estimate the prevalence of drug-resistant tuberculosis (TB) and describe the resistance patterns in patients commencing antiretroviral therapy (ART) in an HIV clinic in Durban, South Africa. Design: Cross-sectional cohort study. Methods: Consecutive HIV-infected adults (>= 18y/o) initiating HIV care were enrolled from May 2007-May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium). Positive cultures were tested for susceptibility to first-and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed. Results: 1,035 subjects had complete culture results. Median CD4 count was 92/mu l (IQR 42-150/mu l). 267 subjects (26%) reported a prior history of TB and 210 (20%) were receiving TB treatment at enrollment; 191 (18%) subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0-12.4). Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9-30.5) compared to 5.2% (95% CI 2.1-8.9) among those with no prior TB. 5.1% (95% CI 2.4-9.5) had rifampin or rifampin plus INH resistance. Conclusions: The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence. C1 [Hom, Jeffrey K.; Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.; Bassett, Ingrid V.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Bingxia; Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Chetty, Senica; Giddy, Janet; Mazibuko, Matilda] McCord Hosp, Durban, South Africa. [Allen, Jenny] Univ KwaZulu Natal, Microbiol Lab, Durban, South Africa. [Allen, Jenny] MRC, Durban, South Africa. [Walensky, Rochelle P.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped, Boston, MA 02115 USA. [Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.; Bassett, Ingrid V.] Harvard Univ, Harvard Ctr AIDS Res CFAR, Boston, MA 02115 USA. RP Hom, JK (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM ibassett@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU Infectious Disease Society of America Education and Research Foundation; National Institute of Allergy and Infectious Disease [K23 AI 068458, R01 AI058736, K24 AI062476]; National Institute of Mental Health [R01 MH073445, R01MH90326]; Claflin Distinguished Scholar Award; Burke Global Health Fellowship; Doris Duke Charitable Foundation; ORACTA Award FX This work was supported in part by: The Infectious Disease Society of America Education and Research Foundation (JKH) (http://www.idsociety.org/Index.aspx); The National Institute of Allergy and Infectious Disease: K23 AI 068458 (IVB) (http://www.niaid.nih.gov/Pages/default.aspx); A PEPFAR supplement to R01 AI058736 (KAF); K24 AI062476 (KAF) (http://www.pepfar.gov/); The National Institute of Mental Health: R01 MH073445 (RPW); R01MH90326 (IVB) (http://www.nimh.nih.gov/index.shtml); The Claflin Distinguished Scholar Award (IVB) (http://www.massgeneral.org/digestive/news/newsarticle.aspx?id=2850); The Burke Global Health Fellowship (IVB) (http://globalhealth.harvard.edu/icb/icb.do?keyword=k16925&pageid=icb.pa ge240155) and the Doris Duke Charitable Foundation Clinical Scientist Development Award (RPW) and ORACTA Award (KAF) (http://www.ddcf.org/Grants-Awarded/). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 1 Z9 1 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 17 PY 2012 VL 7 IS 8 AR e43281 DI 10.1371/journal.pone.0043281 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996DG UT WOS:000308063700074 PM 22912845 ER PT J AU Zhang, GT Liu, RJ Zhong, YF Plotnikov, AN Zhang, WJ Zeng, L Rusinova, E Gerona-Nevarro, G Moshkina, N Joshua, J Chuang, PY Ohlmeyer, M He, JC Zhou, MM AF Zhang, Guangtao Liu, Ruijie Zhong, Yifei Plotnikov, Alexander N. Zhang, Weijia Zeng, Lei Rusinova, Elena Gerona-Nevarro, Guillermo Moshkina, Natasha Joshua, Jennifer Chuang, Peter Y. Ohlmeyer, Michael He, John Cijiang Zhou, Ming-Ming TI Down-regulation of NF-kappa B Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUBULAR EPITHELIAL-CELLS; PROBE LEVEL DATA; DIABETIC-NEPHROPATHY; TRANSGENIC MICE; APOPTOSIS; ACTIVATION; INFECTION; THERAPY; NMR; GLOMERULOSCLEROSIS AB NF-kappa B-mediated inflammation is the major pathology in chronic kidney diseases, including HIV-associated nephropathy (HIVAN) that ultimately progresses to end stage renal disease. HIV infection in the kidney induces NF-kappa B activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-kappa B transcriptional activity by small molecule blocking NF-kappa B binding to the transcriptional cofactor BRD4, which is required for the assembly of the productive transcriptional complex comprising positive transcription elongation factor b and RNA polymerase II. We showed that our BET (Bromodomain and Extra-Terminal domain)-specific bromodomain inhibitor MS417, designed to block BRD4 binding to the acetylated NF-kappa B, effectively attenuates NF-kappa B transcriptional activation of proinflammatory genes in kidney cells treated with TNF alpha or infected by HIV. MS417 ameliorates inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIVAN. Our study suggests that BET bromodomain inhibition, targeting at the proinflammatory activity of NF-kappa B, represents a new therapeutic approach for treating NF-kappa B-mediated inflammation and kidney injury in HIVAN. C1 [Zhang, Guangtao; Plotnikov, Alexander N.; Zeng, Lei; Rusinova, Elena; Gerona-Nevarro, Guillermo; Moshkina, Natasha; Joshua, Jennifer; Ohlmeyer, Michael; Zhou, Ming-Ming] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY 10029 USA. [Liu, Ruijie; Zhang, Weijia; Chuang, Peter Y.; He, John Cijiang] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Liu, Ruijie; He, John Cijiang] James J Peters Vet Affairs Med Ctr, Dept Med, Bronx, NY 10486 USA. [Zhong, Yifei] Shanghai Univ Tradit Chinese Med, Longhua Hosp, Dept Nephrol, Shanghai 201203, Peoples R China. RP He, JC (reprint author), 1425 Madison Ave,Box 1677, New York, NY 10029 USA. EM cijiang.he@mssm.edu; ming-ming.zhou@mssm.edu RI Zhang, Guangtao/C-7341-2011 FU National Institutes of Health [HG004508, DK088541]; Veterans Affairs Merit Award [1I01BX000345] FX This work was supported, in whole or in part, by National Institutes of Health Grants HG004508 (to M.-M. Z.) and DK088541 (to J. C. H.). This work was also supported by Veterans Affairs Merit Award 1I01BX000345 (to J. C. H.). NR 53 TC 82 Z9 89 U1 2 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 AUG 17 PY 2012 VL 287 IS 34 BP 28840 EP 28851 DI 10.1074/jbc.M112.359505 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 996HD UT WOS:000308074600056 PM 22645123 ER PT J AU Jeon, J Leibiger, I Moede, T Walter, B Faul, C Maiguel, D Villarreal, R Guzman, J Berggren, PO Mundel, P Ricordi, C Merscher-Gomez, S Fornoni, A AF Jeon, Jongmin Leibiger, Ingo Moede, Tilo Walter, Britta Faul, Christian Maiguel, Dony Villarreal, Rodrigo Guzman, Johanna Berggren, Per-Olof Mundel, Peter Ricordi, Camillo Merscher-Gomez, Sandra Fornoni, Alessia TI Dynamin-mediated Nephrin Phosphorylation Regulates Glucose-stimulated Insulin Release in Pancreatic Beta Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SLIT DIAPHRAGM; TYROSINE PHOSPHORYLATION; ACTIN REORGANIZATION; GLOMERULAR PODOCYTES; KIDNEY PODOCYTES; PROTEIN; SECRETION; KINASE; COMPLEX; POLYMERIZATION AB We have previously demonstrated a role for Nephrin in glucose stimulated insulin release (GSIR). We now hypothesize that Nephrin phosphorylation is required for GSIR and that Dynamin influences Nephrin phosphorylation and function. MIN6-C3 Nephrin-deficient pancreatic beta cells and human islets were transfected with WT-Nephrin or with a mutant Nephrin in which the tyrosine residues responsible for SH2 domain binding were substituted with phenylalanine (3YF-Nephrin). GSIR and live images of Nephrin and vesicle trafficking were studied. Immunoprecipitation experiments and overexpression of WT-Dynamin or dominant negative Dynamin mutant (K44A-Dynamin) in WT-Nephrin, 3YF-Nephrin, or Nephrin siRNA-transfected cells were utilized to study Nephrin-Dynamin interaction. In contrast to WT-Nephrin or to single tyrosine mutants, 3YF-Nephrin did not positively affect GSIR and led to impaired cell-cell contacts and vesicle trafficking. K44A-Dynamin prevented the effect of Nephrin on GSIR in the absence of protein-protein interaction between Nephrin and Dynamin. Nephrin gene silencing abolished the positive effects of WT-Dynamin on GSIR. The effects of protamine sulfate and vanadate on Nephrin phosphorylation and GSIR were studied in MIN6 cells and human islets. WT-Nephrin phosphorylation after glucose occurred at Tyr-1176/1193 and resulted in improved GSIR. On the contrary, protamine sulfate-induced phosphorylation at Tyr-1176/1193/1217 was associated with Nephrin degradation and impaired GSIR. Vanadate, which prevented Nephrin dephosphorylation after glucose stimulation, improved GSIR in human islets and MIN6 cells. In conclusion, Dynamin-dependent Nephrin phosphorylation occurs in response to glucose and is necessary for Nephrin-mediated augmentation of GSIR. Pharmacological modulation of Nephrin phosphorylation may thus facilitate pancreatic beta cell function. C1 [Jeon, Jongmin; Maiguel, Dony; Villarreal, Rodrigo; Guzman, Johanna; Berggren, Per-Olof; Ricordi, Camillo; Fornoni, Alessia] Univ Miami, L Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Jeon, Jongmin; Walter, Britta; Faul, Christian; Maiguel, Dony; Villarreal, Rodrigo; Guzman, Johanna; Merscher-Gomez, Sandra; Fornoni, Alessia] Univ Miami, L Miller Sch Med, Div Nephrol & Hypertens, Dept Med, Miami, FL 33136 USA. [Leibiger, Ingo; Moede, Tilo; Berggren, Per-Olof] Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, SE-17177 Stockholm, Sweden. [Mundel, Peter] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mundel, Peter] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Fornoni, A (reprint author), Univ Miami, Miller Sch Med, Diabet Res Inst, 1450 NW 10th Ave, Miami, FL 33136 USA. EM afornoni@med.miami.edu RI Fornoni, Alessia/F-8350-2013; OI Moede, Tilo/0000-0002-2045-9244; Ricordi, Camillo/0000-0001-8092-7153 FU National Institutes of Health [DK82636, DK70460, U42 RR016603]; American Diabetes Association [7-09-JF-23]; Forest County Potawatomi Community Foundation; Max and Yetta Karasik Family Foundation; Diabetes Research Institute Foundation; Swedish Research Council; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg's Foundation; Swedish Diabetes Association; Family Erling-Persson Foundation; Peggy and Harold Katz Family Foundation; City of Hope, Duarte, CA FX This work was supported, in whole or in part, by National Institutes of Health Grants DK82636, DK70460, and U42 RR016603. This work was also supported by American Diabetes Association Grant 7-09-JF-23, the Forest County Potawatomi Community Foundation, the Max and Yetta Karasik Family Foundation, the Diabetes Research Institute Foundation, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Torsten and Ragnar Soderberg's Foundation, the Swedish Diabetes Association, the Family Erling-Persson Foundation, the Peggy and Harold Katz Family Foundation, and the City of Hope, Duarte, CA. NR 52 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2012 VL 287 IS 34 BP 28932 EP 28942 DI 10.1074/jbc.M112.389452 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 996HD UT WOS:000308074600062 PM 22718751 ER PT J AU Wang, JX Bair, AM King, SL Shnayder, R Huang, YF Shieh, CC Soberman, RJ Fuhlbrigge, RC Nigrovic, PA AF Wang, Jun-Xia Bair, Angela M. King, Sandra L. Shnayder, Ruslan Huang, Ya-Fang Shieh, Chi-Chang Soberman, Roy J. Fuhlbrigge, Robert C. Nigrovic, Peter A. TI Ly6G ligation blocks recruitment of neutrophils via a beta 2-integrin-dependent mechanism SO BLOOD LA English DT Article ID AUTOANTIBODY-MEDIATED ARTHRITIS; INFL AMMATORY ARTHRITIS; MAST-CELLS CONTRIBUTE; B-4 RECEPTORS BLT1; MOUSE BONE-MARROW; INFLAMMATORY ARTHRITIS; RHEUMATOID-ARTHRITIS; LEUKOTRIENE B-4; MEMBRANE ORGANIZATION; MONOCLONAL-ANTIBODY AB Ly6G is a glycosylphosphatidylinositol (GPI)-anchored protein of unknown function that is commonly targeted to induce experimental neutrophil depletion in mice. In the present study, we found that doses of anti-Ly6G Abs too low to produce sustained neutropenia remained capable of inhibiting experimental arthritis, leaving joint tissues free of infiltrating neutrophils. Thioglycollate-stimulated peritonitis was also attenuated. No alteration in neutrophil apoptosis was observed, implicating impaired recruitment. Indeed, Ly6G ligation abrogated neutrophil migration toward LTB4 and other chemoattractants in a transwell system. Exploring the basis for this blockade, we identified colocalization of Ly6G and beta 2-integrins by confocal microscopy and confirmed close association by both coimmunoprecipitation and fluorescence lifetime imaging microscopy. Anti-Ly6G Ab impaired surface expression of beta 2-integrins in LTB4-stimulated neutrophils and mimicked CD11a blockade in inhibiting both ICAM-1 binding and firm adhesion to activated endothelium under flow conditions. Correspondingly, migration of beta 2-integrin-deficient neutrophils was no longer inhibited by anti-Ly6G. These results demonstrate that experimental targeting of Ly6G has functional effects on the neutrophil population and identify a previously unappreciated role for Ly6G as a modulator of neutrophil migration to sites of inflammation via a beta 2-integrin-dependent mechanism. (Blood. 2012;120(7):1489-1498) C1 [Wang, Jun-Xia; Shnayder, Ruslan; Nigrovic, Peter A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Bair, Angela M.; Soberman, Roy J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Nephrol, Boston, MA 02115 USA. [King, Sandra L.; Fuhlbrigge, Robert C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Huang, Ya-Fang; Shieh, Chi-Chang] Natl Cheng Kung Univ, Inst Clin Med, Tainan 70101, Taiwan. [Huang, Ya-Fang; Shieh, Chi-Chang] Natl Cheng Kung Univ, Dept Pediat, Tainan 70101, Taiwan. [Fuhlbrigge, Robert C.; Nigrovic, Peter A.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Med,Div Immunol, Boston, MA 02115 USA. RP Nigrovic, PA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Rheumatol Immunol & Allergy, Smith Bldg,Rm 516C,1 Jimmy Fund Way, Boston, MA 02115 USA. EM pnigrovic@partners.org FU Arthritis National Research Foundation; Charles H. Hood Foundation; Harvard Skin Disease Research Center; Cogan Family Foundation; National Science Council, Taiwan; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [P30 AR42689]; [5RO1-AI068871]; [3RO1AI068871-04S]; [1S10RR027931]; [1R01HL097796]; [K01 DK089145] FX This work was supported by grants from the Arthritis National Research Foundation, the Charles H. Hood Foundation, the Harvard Skin Disease Research Center, and the Cogan Family Foundation (to P.A.N.); the National Science Council, Taiwan (to C.-C.S.); and the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR42689 to R.C.F.; 5RO1-AI068871, 3RO1AI068871-04S, 1S10RR027931, and 1R01HL097796 to R.J.S.; and K01 DK089145 to A.B.). NR 50 TC 24 Z9 24 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 AUG 16 PY 2012 VL 120 IS 7 BP 1489 EP 1498 DI 10.1182/blood-2012-01-404046 PG 10 WC Hematology SC Hematology GA 009CA UT WOS:000309001900023 PM 22661700 ER PT J AU Quintin, J Saeed, S Martens, JHA Giamarellos-Bourboulis, EJ Ifrim, DC Logie, C Jacobs, L Jansen, T Kullberg, BJ Wijmenga, C Joosten, LAB Xavier, RJ van der Meer, JWM Stunnenberg, HG Netea, MG AF Quintin, Jessica Saeed, Sadia Martens, Joost H. A. Giamarellos-Bourboulis, Evangelos J. Ifrim, Daniela C. Logie, Colin Jacobs, Liesbeth Jansen, Trees Kullberg, Bart-Jan Wijmenga, Cisca Joosten, Leo A. B. Xavier, Ramnik J. van der Meer, Jos W. M. Stunnenberg, Hendrik G. Netea, Mihai G. TI Candida albicans Infection Affords Protection against Reinfection via Functional Reprogramming of Monocytes SO CELL HOST & MICROBE LA English DT Article ID NATURAL-KILLER-CELLS; EPIGENETIC REGULATION; DENDRITIC CELLS; IMMUNE-RESPONSE; CROHNS-DISEASE; MEMORY; TRANSCRIPTION; ACTIVATION; IMMUNOSUPPRESSION; POLARIZATION AB Immunological memory in vertebrates is often exclusively attributed to T and B cell function. Recently it was proposed that the enhanced and sustained innate immune responses following initial infectious exposure may also afford protection against reinfection. Testing this concept of "trained immunity," we show that mice lacking functional T and B lymphocytes are protected against reinfection with Candida albicans in a monocyte-dependent manner. C. albicans and fungal cell wall beta-glucans induced functional reprogramming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the beta-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. Monocyte training by beta-glucans was associated with stable changes in histone trimethylation at H3K4, which suggests the involvement of epigenetic mechanisms in this phenomenon. The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of "trained immunity" and may be employed for the design of improved vaccination strategies. C1 [Quintin, Jessica; Ifrim, Daniela C.; Jacobs, Liesbeth; Jansen, Trees; Kullberg, Bart-Jan; Joosten, Leo A. B.; van der Meer, Jos W. M.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands. [Quintin, Jessica; Ifrim, Daniela C.; Jacobs, Liesbeth; Jansen, Trees; Kullberg, Bart-Jan; Joosten, Leo A. B.; van der Meer, Jos W. M.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Inst Infect Inflammat & Immun N4i, NL-6525 GA Nijmegen, Netherlands. [Saeed, Sadia; Martens, Joost H. A.; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. [Saeed, Sadia; Martens, Joost H. A.; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Fac Med, Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Giamarellos-Bourboulis, Evangelos J.] Univ Athens, Sch Med, Dept Internal Med 4, Athens 12462, Greece. [Giamarellos-Bourboulis, Evangelos J.] Jena Univ Hosp, Ctr Sepsis Control & Care, D-07747 Jena, Germany. [Wijmenga, Cisca] Univ Med Ctr Groningen, Dept Genet, NL-9713 EX Groningen, Netherlands. [Wijmenga, Cisca] Univ Groningen, NL-9713 EX Groningen, Netherlands. [Xavier, Ramnik J.] Harvard Univ, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Harvard Univ, Cambridge, MA 02142 USA. RP Netea, MG (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands. EM m.netea@aig.umcn.nl RI Logie, Colin/A-1528-2010; van der Meer, Jos/C-8521-2013; Kullberg, Bart Jan/C-8520-2013; Wijmenga, Cisca/D-2173-2009; Stunnenberg, Hendrik/D-6875-2012; Joosten, Leo/H-3138-2015; Netea, Mihai/N-5155-2014; OI Logie, Colin/0000-0002-8534-6582; van der Meer, Jos/0000-0001-5120-3690; Jansen, Tim/0000-0003-3026-3154; Wijmenga, Cisca/0000-0002-5635-1614; Giamarellos-Bourboulis, Evangelos/0000-0003-4713-3911 FU Vici Grant of the Netherlands Organization for Scientific Research; Higher Education Commission of Pakistan; Vidi Grant of the Netherlands Organization for Scientific Research; All-Fun EU-FP7 grant; "DNA-in-action" consortium; Foundation for Fundamental Research on Matter (FOM); Netherlands Organisation for Scientific Research (NWO); US National Institutes of Health [AI 062773, DK 043351, DK 83756]; Helmsley Trust FX J.Q. and M.G.N. were supported by a Vici Grant of the Netherlands Organization for Scientific Research (to M.G.N.). S.S. was supported by the Higher Education Commission of Pakistan and J.H.A.M. by a Vidi Grant of the Netherlands Organization for Scientific Research. D.C.I was supported by the All-Fun EU-FP7 grant. C.L. was supported by the "DNA-in-action" consortium, Foundation for Fundamental Research on Matter (FOM), Netherlands Organisation for Scientific Research (NWO). R.J.X. was supported by grants (AI 062773, DK 043351 DK 83756) from the US National Institutes of Health and the Helmsley Trust. J.Q., S.S., C.W., J.H.A.M., C.L., J.W.M.v.d.M., and M.G.N. designed and analyzed the experiments. J.Q., S.S., M.G.N., E.J.G.-B., L.A.B.J., and T.J. performed the experiments. D.C.I. contributed to some of the experiments. J.Q., S.S., R.J.X., J.W.M.v.d.M., H.G.S., and M.G.N. wrote the manuscript, and all authors contributed to the manuscript preparation. M.G.N. supervised the project. NR 40 TC 149 Z9 151 U1 3 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD AUG 16 PY 2012 VL 12 IS 2 BP 223 EP 232 DI 10.1016/j.chom.2012.06.006 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 998UM UT WOS:000308265900012 PM 22901542 ER PT J AU Smith, LR Chambers, HG Subramaniam, S Lieber, RL AF Smith, Lucas R. Chambers, Henry G. Subramaniam, Shankar Lieber, Richard L. TI Transcriptional Abnormalities of Hamstring Muscle Contractures in Children with Cerebral Palsy SO PLOS ONE LA English DT Article ID GROSS MOTOR FUNCTION; SKELETAL-MUSCLE; EXTRACELLULAR-MATRIX; MEDIAL GASTROCNEMIUS; SPASTIC DIPLEGIA; GENE ONTOLOGY; STIFFNESS; HYPOEXTENSIBILITY; DIFFERENTIATION; ARCHITECTURE AB Cerebral palsy (CP) is an upper motor neuron disease that results in a spectrum of movement disorders. Secondary to the neurological lesion, muscles from patients with CP are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in CP is a response to aberrant complex neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response in CP using transcriptional profiling correlated with functional measures to broadly investigate muscle adaptations leading to mechanical deficits. Biospsies were obtained from both the gracilis and semitendinosus muscles from a cohort of patients with CP (n = 10) and typically developing patients (n = 10) undergoing surgery. Biopsies were obtained to define the unique expression profile of the contractures and passive mechanical testing was conducted to determine stiffness values in previously published work. Affymetrix HG-U133A 2.0 chips (n = 40) generated expression data, which was validated for selected transcripts using quantitative real-time PCR. Chips were clustered based on their expression and those from patients with CP clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n = 1,398). Significantly altered genes were analyzed for over-representation among gene ontologies and muscle specific networks. The majority of altered transcripts were related to increased extracellular matrix expression in CP and a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and development of novel therapies. C1 [Smith, Lucas R.; Subramaniam, Shankar; Lieber, Richard L.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Chambers, Henry G.] Rady Childrens Hosp, Dept Orthoped Surg, San Diego, CA USA. [Chambers, Henry G.; Lieber, Richard L.] Univ Calif San Diego, Dept Orthoped Surg, La Jolla, CA 92093 USA. [Lieber, Richard L.] US Dept Vet Affairs, Med Ctr, San Diego, CA USA. RP Smith, LR (reprint author), Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. EM rlieber@ucsd.edu FU National Institutes of Health [AR057393] FX This work was supported by the National Institutes of Health [grant number AR057393]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 8 Z9 8 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 16 PY 2012 VL 7 IS 8 AR e40686 DI 10.1371/journal.pone.0040686 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 993AN UT WOS:000307824300004 PM 22956992 ER PT J AU Muller, FL Colla, S Aquilanti, E Manzo, VE Genovese, G Lee, J Eisenson, D Narurkar, R Deng, PN Nezi, L Lee, MA Hu, BL Hu, J Sahin, E Ong, D Fletcher-Sananikone, E Ho, D Kwong, L Brennan, C Wang, YA Chin, L DePinho, RA AF Muller, Florian L. Colla, Simona Aquilanti, Elisa Manzo, Veronica E. Genovese, Giannicola Lee, Jaclyn Eisenson, Daniel Narurkar, Rujuta Deng, Pingna Nezi, Luigi Lee, Michelle A. Hu, Baoli Hu, Jian Sahin, Ergun Ong, Derrick Fletcher-Sananikone, Eliot Ho, Dennis Kwong, Lawrence Brennan, Cameron Wang, Y. Alan Chin, Lynda DePinho, Ronald A. TI Passenger deletions generate therapeutic vulnerabilities in cancer SO NATURE LA English DT Article ID ENOLASE DEFICIENCY; GENETIC REDUNDANCY; BREAST-CANCER; GLIOBLASTOMA; INHIBITION; REGIONS; GENOME; TUMORS; CELLS; LUNG AB Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events. C1 [Muller, Florian L.; Colla, Simona; Aquilanti, Elisa; Manzo, Veronica E.; Genovese, Giannicola; Lee, Jaclyn; Eisenson, Daniel; Narurkar, Rujuta; Deng, Pingna; Nezi, Luigi; Lee, Michelle A.; Hu, Baoli; Hu, Jian; Sahin, Ergun; Ong, Derrick; Fletcher-Sananikone, Eliot; Ho, Dennis; Kwong, Lawrence; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Muller, Florian L.; Colla, Simona; Genovese, Giannicola; Deng, Pingna; Nezi, Luigi; Hu, Baoli; Hu, Jian; Ong, Derrick; Fletcher-Sananikone, Eliot; Kwong, Lawrence; Wang, Y. Alan; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Muller, Florian L.; Colla, Simona; Hu, Jian; Sahin, Ergun; Ong, Derrick; Ho, Dennis; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet & Med, Boston, MA 02115 USA. [Lee, Michelle A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hu, Baoli; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Brennan, Cameron] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM rdepinho@mdanderson.org OI Brennan, Cameron/0000-0003-4064-8891; Colla, Simona/0000-0001-6583-8910 FU National Institutes of Health (NIH) [T32-CA009361, P01CA95616]; American Cancer Society [115992-PF-08-261-01-TBE]; Dana-Farber Cancer Institute/Harvard Cancer Center Myeloma SPORE career development grant; Howard Hughes Medical Institute Medical Research Fellowship [57006984]; Harvard PRISE fellowship; Diversity in Health-Related research award [3 P01 CA095616-08S1]; Ben and Catherine Ivy Foundation FX We thank K. Ligon, C. Maire, D. N. Louis, J. Kimand G. Mohapatra for sharing bioinformatics data from their tumour neurosphere banks. We also thank D. Bigner for sharing the D423-MG and D502-MG cell lines and D. N. Louis and J. Kim for sharing the Gli56 cell line. We thank G. Chu and D. Jakubosky for assistance with necropsy and histopathological analysis. F. L. M. was supported by a training grant from the National Institutes of Health (NIH T32-CA009361) and a fellowship from the American Cancer Society (115992-PF-08-261-01-TBE). S. C. was supported by a Dana-Farber Cancer Institute/Harvard Cancer Center Myeloma SPORE career development grant. E. A. was supported by a Howard Hughes Medical Institute Medical Research Fellowship (57006984). V. M. was supported by a Harvard PRISE fellowship. M. A. L. was supported by a Diversity in Health-Related research award (3 P01 CA095616-08S1). F. L. M. thanks J. Mohr for assistance with figure preparations. We also thank K. Muller for assistance with manuscript editing. We thank all members of the DePinho and Chin laboratories for suggestions and discussions. This work is supported by the NIH (P01CA95616 to C. B., L. C. and R. A. D.) and by the Ben and Catherine Ivy Foundation (to R. A. D. and L.C.). NR 37 TC 79 Z9 82 U1 0 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 16 PY 2012 VL 488 IS 7411 BP 337 EP + DI 10.1038/nature11331 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OS UT WOS:000307501000033 PM 22895339 ER PT J AU Reich, D Patterson, N Campbell, D Tandon, A Mazieres, S Ray, N Parra, MV Rojas, W Duque, C Mesa, N Garcia, LF Triana, O Blair, S Maestre, A Dib, JC Bravi, CM Bailliet, G Corach, D Hunemeier, T Bortolini, MC Salzano, FM Petzl-Erler, ML Acuna-Alonzo, V Aguilar-Salinas, C Canizales-Quinteros, S Tusie-Luna, T Riba, L Rodriguez-Cruz, M Lopez-Alarcon, M Coral-Vazquez, R Canto-Cetina, T Silva-Zolezzi, I Fernandez-Lopez, JC Contreras, AV Jimenez-Sanchez, G Gomez-Vazquez, MJ Molina, J Carracedo, A Salas, A Gallo, C Poletti, G Witonsky, DB Alkorta-Aranburu, G Sukernik, RI Osipova, L Fedorova, SA Vasquez, R Villena, M Moreau, C Barrantes, R Pauls, D Excoffier, L Bedoya, G Rothhammer, F Dugoujon, JM Larrouy, G Klitz, W Labuda, D Kidd, J Kidd, K Di Rienzo, A Freimer, NB Price, AL Ruiz-Linares, A AF Reich, David Patterson, Nick Campbell, Desmond Tandon, Arti Mazieres, Stephane Ray, Nicolas Parra, Maria V. Rojas, Winston Duque, Constanza Mesa, Natalia Garcia, Luis F. Triana, Omar Blair, Silvia Maestre, Amanda Dib, Juan C. Bravi, Claudio M. Bailliet, Graciela Corach, Daniel Huenemeier, Tabita Bortolini, Maria Catira Salzano, Francisco M. Petzl-Erler, Maria Luiza Acuna-Alonzo, Victor Aguilar-Salinas, Carlos Canizales-Quinteros, Samuel Tusie-Luna, Teresa Riba, Laura Rodriguez-Cruz, Maricela Lopez-Alarcon, Mardia Coral-Vazquez, Ramon Canto-Cetina, Thelma Silva-Zolezzi, Irma Fernandez-Lopez, Juan Carlos Contreras, Alejandra V. Jimenez-Sanchez, Gerardo Gomez-Vazquez, Maria Jose Molina, Julio Carracedo, Angel Salas, Antonio Gallo, Carla Poletti, Giovanni Witonsky, David B. Alkorta-Aranburu, Gorka Sukernik, Rem I. Osipova, Ludmila Fedorova, Sardana A. Vasquez, Rene Villena, Mercedes Moreau, Claudia Barrantes, Ramiro Pauls, David Excoffier, Laurent Bedoya, Gabriel Rothhammer, Francisco Dugoujon, Jean-Michel Larrouy, Georges Klitz, William Labuda, Damian Kidd, Judith Kidd, Kenneth Di Rienzo, Anna Freimer, Nelson B. Price, Alkes L. Ruiz-Linares, Andres TI Reconstructing Native American population history SO NATURE LA English DT Article ID COLONIZATION; SETTLEMENT; DISPERSAL; DIVERSITY; PATTERNS; ORIGIN; MODEL; ASIA AB The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved(1-5). One contentious issue is whether the settlement occurred by means of a single(6-8) migration or multiple streams of migration from Siberia(9-15). The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call `First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America. C1 [Reich, David; Tandon, Arti] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Reich, David; Patterson, Nick; Tandon, Arti; Price, Alkes L.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Reich, David; Patterson, Nick; Tandon, Arti] MIT, Cambridge, MA 02142 USA. [Campbell, Desmond; Mazieres, Stephane; Parra, Maria V.; Rojas, Winston; Duque, Constanza; Mesa, Natalia; Bravi, Claudio M.; Huenemeier, Tabita; Ruiz-Linares, Andres] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. Univ Hong Kong, Dept Psychiat, Pokfulam, Hong Kong, Peoples R China. [Campbell, Desmond] Univ Hong Kong, Ctr Genom Sci, Pokfulam, Hong Kong, Peoples R China. [Mazieres, Stephane] Aix Marseille Univ, CNRS, EFS, ADES,UMR7268, F-13344 Marseille, France. [Ray, Nicolas] Univ Geneva, Inst Environm Sci, CH-1227 Geneva, Switzerland. [Ray, Nicolas] Univ Geneva, Forel Inst, CH-1227 Geneva, Switzerland. [Parra, Maria V.; Rojas, Winston; Duque, Constanza; Mesa, Natalia; Garcia, Luis F.; Triana, Omar; Blair, Silvia; Maestre, Amanda; Bedoya, Gabriel] Univ Antioquia, Medellin, Colombia. [Dib, Juan C.] Fdn Salud Trop, Santa Marta, Colombia. [Bravi, Claudio M.; Bailliet, Graciela] Consejo Nacl Invest Cient & Tecn, CICPCA, CCT La Plata, Inst Multidisciplinario Biol Celular, RA-1900 La Plata, Argentina. [Corach, Daniel] Univ Buenos Aires, Serv Huellas Digitales Genet, RA-1053 Buenos Aires, DF, Argentina. [Corach, Daniel] Univ Buenos Aires, CONICET, RA-1053 Buenos Aires, DF, Argentina. [Huenemeier, Tabita; Bortolini, Maria Catira; Salzano, Francisco M.] Univ Fed Rio Grande do Sul, Inst Biociencias, Dept Genet, BR-91501970 Porto Alegre, RS, Brazil. [Petzl-Erler, Maria Luiza] Univ Fed Parana, Dept Genet, BR-81531980 Curitiba, Parana, Brazil. [Acuna-Alonzo, Victor] Natl Inst Anthropol & Hist, Mexico City 06100, DF, Mexico. [Aguilar-Salinas, Carlos] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Endocrinol & Metab, Mexico City 14100, DF, Mexico. [Canizales-Quinteros, Samuel; Tusie-Luna, Teresa; Riba, Laura] Univ Nacl Autonoma Mexico, Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Unidad Biol Mol & Med Genom, Mexico City 14100, DF, Mexico. [Canizales-Quinteros, Samuel] Univ Nacl Autonoma Mexico, Fac Quim, Dept Biol, Mexico City 04510, DF, Mexico. [Rodriguez-Cruz, Maricela; Lopez-Alarcon, Mardia] Hosp Pediat Mexico City, Inst Mexicano Seguro Social, CMNSXXI, Unidad Invest Med Nutr, Mexico City 06720, DF, Mexico. [Coral-Vazquez, Ramon] Inst Politecn Nacl, Escuela Super Med, Secc Posgrado, Mexico City 11340, DF, Mexico. [Canto-Cetina, Thelma] Ctr Invest Reg, Dept Salud Reprod & Genet, Lab Biol Reproducc, Merida 97000, Mexico. [Silva-Zolezzi, Irma; Fernandez-Lopez, Juan Carlos; Contreras, Alejandra V.; Jimenez-Sanchez, Gerardo] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico. [Gomez-Vazquez, Maria Jose] Univ Autonoma Nuevo Leon, San Nicolas De Los Garza 66451, Nuevo Leon, Mexico. [Molina, Julio] Ctr Invest Biomed Guatemala, Guatemala City, Guatemala. [Carracedo, Angel; Salas, Antonio] Univ Santiago de Compostela, Fdn Med Xenom SERGAS, Inst Ciencias Forenses, Santiago De Compostela, Spain. [Gallo, Carla; Poletti, Giovanni] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Labs Invest & Desarrollo, Lima 15102, Peru. [Witonsky, David B.; Alkorta-Aranburu, Gorka; Di Rienzo, Anna] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Sukernik, Rem I.] Russian Acad Sci, Siberian Branch, Inst Mol & Cellular Biol, Lab Human Mol Genet, Novosibirsk 630090, Russia. [Osipova, Ludmila] Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, Novosibirsk 630090, Russia. [Fedorova, Sardana A.] Yakut Res Ctr Complex Med Problems, Dept Mol Genet, Sakha 677010, Yakutia, Russia. [Fedorova, Sardana A.] NE Fed Univ, Sakha 677010, Yakutia, Russia. [Vasquez, Rene; Villena, Mercedes] Univ Autonoma Tomas Frias, Inst Boliviano Biol Altura, Potosi, Bolivia. [Moreau, Claudia; Labuda, Damian] Univ Montreal, Dept Pediat, Ctr Rech, CHU St Justine, Montreal, PQ H3T 1C5, Canada. [Barrantes, Ramiro] Univ Costa Rica, Escuela Biol, San Jose, Costa Rica. [Pauls, David] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Excoffier, Laurent] Univ Bern, Inst Ecol & Evolut, Computat & Mol Populat Genet Lab, CH-3012 Bern, Switzerland. [Excoffier, Laurent] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Rothhammer, Francisco] Univ Chile, Fac Med, Programa Genet Humana ICBM, Inst Alta Invest ,Univ Tarapaca, Arica 1001236, Chile. [Rothhammer, Francisco] Ctr Invest Hombre El Desierto, Arica 1001236, Chile. [Dugoujon, Jean-Michel; Larrouy, Georges] Univ Toulouse 3, CNRS, UMR 5288, F-31000 Toulouse, France. [Klitz, William] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Kidd, Judith; Kidd, Kenneth] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Freimer, Nelson B.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Reich, D (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM reich@genetics.med.harvard.edu; a.ruizlin@ucl.ac.uk RI Contreras, Alejandra Virginia/E-7815-2013; Ray, Nicolas/C-8988-2009; Fernandez, Juan Carlos/C-4976-2013; Excoffier, Laurent/D-3498-2013; Acuna Alonzo, Victor/E-2312-2013; Mazieres, Stephane/G-1702-2010; Osipova, Ludmila/O-6480-2014; Salas, Antonio/E-3977-2012; Salzano, Francisco/L-7916-2015; Sukernik, Rem/N-6990-2015; Petzl-Erler, Maria-Luiza/H-8221-2012 OI Corach, Daniel/0000-0002-0662-7424; Contreras, Alejandra Virginia/0000-0003-3653-5958; Triana, Omar/0000-0001-8031-0225; Ray, Nicolas/0000-0002-4696-5313; Fernandez, Juan Carlos/0000-0003-3680-4193; Gallo, Carla/0000-0001-8348-0473; Campbell, Desmond/0000-0003-1085-714X; Excoffier, Laurent/0000-0002-7507-6494; Acuna Alonzo, Victor/0000-0003-2205-7625; Osipova, Ludmila/0000-0001-7602-1156; Salas, Antonio/0000-0002-2336-702X; Petzl-Erler, Maria-Luiza/0000-0002-0345-5276 FU National Institutes of Health [NS043538, NS037484, MH075007, GM079558, GM079558-S1, GM057672, HG006399]; Biotechnology and Biological Sciences Research Council [BB/1021213/1]; National Science Foundation HOMINID [BCS-1032255]; Canadian Institutes of Health Research grant; Universidad de Antioquia CODI grant; Fondo de Investigacion Sanitaria grant [PS 09/2368]; Ministerio de Ciencia e Innovacion [SAF2011-26983]; Wenner-Gren Foundation [ICRG-65]; Russian Foundation for Basic Research [06-04-048182, 02-06-80524a]; Siberian Branch Russian Academy of Sciences field grant; Centre National de la Recherche Scientifique Programme Interdisciplinaire de Recherche Amazonie grant; Harvard Medical School; Harvard School of Public Health FX We thank the volunteers who provided the samples that made this study possible. We thank E. D. Ruiz for assistance in the collection involving the Mixtec, Zapotec and Mixe; and P. Herrera for assistance in the collection involving the Quechua; A. Carnevale, M. Crawford, M. Metspalu, F. C. Nielsen, X. Soberon, R. Villems and E. Willerslev for facilitating sharing of data from Mexican, Siberian and Arctic populations; C. Stevens and A. Crenshaw for assistance with genotyping; and P. Bellwood, D. Bolnick, K. Bryc, J. Diamond, T. Dillehay, R. Gonzalez-Jose, M. Hammer, J. Hill, B. Kemp, S. LeBlanc, D. Meltzer, P. Moorjani, A. Moreno-Estrada, B. Pakendorf, J. Pickrell, M. Ruhlen, D. G. Smith, M. Stoneking, N. Tuross and A. Williams for critiques and discussions. Support was provided by National Institutes of Health grants NS043538 (A. R.-L.), NS037484 and MH075007 (N. B. F.), GM079558 (A. D.), GM079558-S1 (A. D.), GM057672 (K. K. K. and J. R. K.), and HG006399 (D. R., N. P. & A. L. P); by a Biotechnology and Biological Sciences Research Council grant BB/1021213/1; by a National Science Foundation HOMINID grant BCS-1032255 (D. R. and N. P.); by a Canadian Institutes of Health Research grant (D. L.); by a Universidad de Antioquia CODI grant (G. B.); by a Fondo de Investigacion Sanitaria grant PS 09/2368 (A. C.); by a Ministerio de Ciencia e Innovacion grant SAF2011-26983 (A. S.); by a Wenner-Gren Foundation grant ICRG-65 (A. D. and R. S.); by Russian Foundation for Basic Research grants 06-04-048182 (R. S.) and 02-06-80524a (L.O.); by a Siberian Branch Russian Academy of Sciences field grant (L.O.); by a Centre National de la Recherche Scientifique Programme Interdisciplinaire de Recherche Amazonie grant (J.-M.D.); and by startup funds from Harvard Medical School (D. R.) and the Harvard School of Public Health (A.L.P.). NR 37 TC 204 Z9 212 U1 5 U2 168 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 16 PY 2012 VL 488 IS 7411 BP 370 EP + DI 10.1038/nature11258 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OS UT WOS:000307501000040 PM 22801491 ER PT J AU Zella, GC Gee, MS Badizadegan, K AF Zella, Garrett C. Gee, Michael S. Badizadegan, Kamran TI Case 25-2012: A 15-Year-Old Boy with Abdominal Pain, Hematochezia, and Anemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PEUTZ-JEGHERS-SYNDROME; ADULT INTUSSUSCEPTION; CYSTIC-FIBROSIS; COLONIC POLYPS; GASTRIC-MUCOSA; CHILDREN; MANAGEMENT; DIAGNOSIS; RECURRENT; ADENOMAS C1 [Zella, Garrett C.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Gee, Michael S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Badizadegan, Kamran] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zella, Garrett C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Gee, Michael S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Badizadegan, Kamran] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Zella, GC (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 27 TC 1 Z9 1 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 16 PY 2012 VL 367 IS 7 BP 659 EP 667 DI 10.1056/NEJMcpc1111578 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600011 PM 22894579 ER PT J AU Jaff, MR White, CJ AF Jaff, Michael R. White, Christopher J. TI Secondary Prevention after Ischemic Stroke SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [White, Christopher J.] Alton Ochsner Med Fdn & Ochsner Clin, New Orleans, LA 70121 USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mjaff@partners.org RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 NR 5 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 16 PY 2012 VL 367 IS 7 BP 675 EP 676 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600021 PM 22894587 ER PT J AU Coyle, C Venna, N AF Coyle, Christina Venna, Nagagopal TI THE DISCUSSANTS REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID FOLLOW-UP; NEUROCYSTICERCOSIS; SERUM; DIAGNOSIS; ANTIGEN C1 [Coyle, Christina] Albert Einstein Coll Med, New York, NY USA. [Venna, Nagagopal] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Coyle, C (reprint author), Albert Einstein Coll Med, New York, NY USA. EM christina.coyle@einstein.yu.edu NR 5 TC 0 Z9 0 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 16 PY 2012 VL 367 IS 7 BP 679 EP 680 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600028 ER PT J AU D'Amico, AV Smith, MR AF D'Amico, Anthony V. Smith, Matthew R. TI Screening for Prostate Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RADICAL PROSTATECTOMY; FOLLOW-UP; MORTALITY C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 10 TC 0 Z9 0 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 AUG 16 PY 2012 VL 367 IS 7 DI 10.1056/NEJMclde1209426 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600013 ER PT J AU Kaddurah-Daouk, R McEvoy, J Baillie, R Zhu, HJ Yao, JK Nimgaonkar, VL Buckley, PF Keshavan, MS Georgiades, A Nasrallah, HA AF Kaddurah-Daouk, Rima McEvoy, Joseph Baillie, Rebecca Zhu, Hongjie Yao, Jeffrey K. Nimgaonkar, Vishwajit L. Buckley, Peter F. Keshavan, Matcheri S. Georgiades, Anastasia Nasrallah, Henry A. TI Impaired plasmalogens in patients with schizophrenia SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Drug-naive; Metabolomics; Lipidomics; Plasmalogen; Phospholipids ID POLYUNSATURATED FATTY-ACIDS; GLOBAL BIOCHEMICAL APPROACH; BLOOD-CELL MEMBRANE; ETHANOLAMINE PLASMALOGEN; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; ENDOTHELIAL-CELLS; ARACHIDONIC-ACID; SURROGATE MARKER; ION-TRANSPORT AB Plasmalogens are a subclass of glycerophospholipids and ubiquitous constituents of cellular membranes and serum lipoproteins. Several neurological disorders show decreased level of plasmogens. An earlier study found differences in plasma phospholipids between unmedicated patients with schizophrenia and matched healthy control subjects. We here report a comparison of plasma plasmalogen levels across 20 drug-naive patients experiencing first psychotic episodes, 20 recently unmedicated patients experiencing psychotic relapses after failing to comply with prescribed medications, and 17 matched healthy control subjects. Multiple plasma phosphatidylcholine and phosphatidylethanolamine plasmalogen levels were significantly lower in first episode patients and patients with recurrent disease compared to healthy controls. Reduced plasmalogen levels appear to be a trait evident at the onset of psychotic illness and after multiple psychotic relapses. It is implied that reductions in plasmalogen levels are not related to antipsychotic treatment but due to the illness itself. Reduced plasmalogen levels suggest impairments in membrane structure and function in patients with schizophrenia that might happen early in development This may serve as a clue to the neurobiology of schizophrenia and should be studied as a potential biomarker for individuals at risk for schizophrenia. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Kaddurah-Daouk, Rima; McEvoy, Joseph; Georgiades, Anastasia] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Baillie, Rebecca] Rosa & Co LLC, San Carlos, CA 94070 USA. [Zhu, Hongjie] N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Zhu, Hongjie] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Yao, Jeffrey K.; Nimgaonkar, Vishwajit L.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Nimgaonkar, Vishwajit L.] Western Psychiat Inst & Clin, Dept Human Genet, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Buckley, Peter F.] Med Coll Georgia, Dept Psychiat, Augusta, GA 30912 USA. [Keshavan, Matcheri S.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Nasrallah, Henry A.] Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH 45219 USA. RP Kaddurah-Daouk, R (reprint author), Duke Univ, Med Ctr, Dept Psychiat, Box 3950, Durham, NC 27710 USA. EM kaddu001@mc.duke.edu NR 67 TC 23 Z9 23 U1 3 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2012 VL 198 IS 3 BP 347 EP 352 DI 10.1016/j.psychres.2012.02.019 PG 6 WC Psychiatry SC Psychiatry GA 050HQ UT WOS:000312044800002 PM 22513041 ER PT J AU Zhang, Q Liu, Q Austin, C Drummond, I Pierce, EA AF Zhang, Qi Liu, Qin Austin, Chrissy Drummond, Iain Pierce, Eric A. TI Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID BARDET-BIEDL SYNDROME; RETINITIS-PIGMENTOSA; PROTEOMIC ANALYSIS; SENSORY ORGANELLE; PRIMARY CILIUM; CAENORHABDITIS-ELEGANS; IN-VITRO; DISEASE; MUTATIONS; GENES AB In our effort to understand genetic disorders of the photoreceptor cells of the retina, we have focused on intraflagellar transport in photoreceptor sensory cilia. From previous mouse proteomic data we identified a cilia protein Ttc26, orthologue of dyf-13 in Caenorhabditis elegans, as a target. We localized Ttc26 to the transition zone of photoreceptor and to the transition zone of cilia in cultured murine inner medullary collecting duct 3 (mIMCD3) renal cells. Knockdown of Ttc26 in mIMCD3 cells produced shortened and defective primary cilia, as revealed by immunofluorescence and scanning electron microscopy. To study Ttc26 function in sensory cilia in vivo, we utilized a zebrafish vertebrate model system. Morpholino knockdown of ttc26 in zebrafish embryos caused ciliary defects in the pronephric kidney at 27 h postfertilization and distension/dilation of pronephros at 5 d postfertilization (dpf). In the eyes, the outer segments of photoreceptor cells appeared shortened or absent, whereas cellular lamination appeared normal in retinas at 5 dpf. This suggests that loss of ttc26 function prevents normal ciliogenesis and differentiation in the photoreceptor cells, and that ttc26 is required for normal development and differentiation in retina and pronephros. Our studies support the importance of Ttc26 function in ciliogenesis and suggest that screening for TTC26 mutations in human ciliopathies is justified. C1 [Zhang, Qi; Liu, Qin; Pierce, Eric A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst,Dept Ophthalmol, Boston, MA 02114 USA. [Austin, Chrissy; Drummond, Iain] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit CNY 8, Charlestown, MA 02129 USA. [Zhang, Qi; Liu, Qin; Pierce, Eric A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Berman Gund Lab, Boston, MA 02114 USA. RP Pierce, EA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst,Dept Ophthalmol, Boston, MA 02114 USA. EM eric_pierce@meei.harvard.edu OI Pierce, Eric/0000-0002-2354-4102 FU National Institutes of Health [R01-EY012910]; Foundation Fighting Blindness USA; F. M. Kirby Foundation; Research to Prevent Blindness; Rosanne Silbermann Foundation FX We thank Gregory Pazour for providing the SSTR-3 mIMCD3 cell line and Michael Pack and Jie He of the Zebrafish Core at Penn Medicine for their assistance. This work was supported by grants from the National Institutes of Health (R01-EY012910 to E.A.P.), the Foundation Fighting Blindness USA, the F. M. Kirby Foundation, Research to Prevent Blindness, and the Rosanne Silbermann Foundation. We also acknowledge the contribution of medical editing by David Titus. NR 51 TC 10 Z9 14 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 AUG 15 PY 2012 VL 23 IS 16 BP 3069 EP 3078 DI 10.1091/mbc.E12-01-0019 PG 10 WC Cell Biology SC Cell Biology GA 052SX UT WOS:000312219900006 PM 22718903 ER PT J AU Baas, D Caussanel-Boude, S Guiraud, A Calhabeu, F Delaune, E Pilot, F Chopin, E Machuca-Gayet, I Vernay, A Bertrand, S Rual, JF Jurdic, P Hill, DE Vidal, M Schaeffer, L Goillot, E AF Baas, Dominique Caussanel-Boude, Sabine Guiraud, Alexandre Calhabeu, Frederico Delaune, Emilie Pilot, Fanny Chopin, Emilie Machuca-Gayet, Irma Vernay, Aurelia Bertrand, Stephanie Rual, Jean-Francois Jurdic, Pierre Hill, David E. Vidal, Marc Schaeffer, Laurent Goillot, Evelyne TI CKIP-1 regulates mammalian and zebrafish myoblast fusion SO JOURNAL OF CELL SCIENCE LA English DT Article DE CKIP-1; Arp2/3; Actin cytoskeleton; Myoblast fusion; Zebrafish muscle development ID PLECKSTRIN HOMOLOGY DOMAIN; CONTAINING PROTEIN CKIP-1; MUSCLE-CELL MIGRATION; ACTIN-CAPPING PROTEIN; ARP2/3 COMPLEX; PLASMA-MEMBRANE; DANIO-RERIO; KINASE CK2; IN-VIVO; SLOW AB Multinucleated muscle fibres arise by fusion of precursor cells called myoblasts. We previously showed that CKIP-1 ectopic expression in C2C12 myoblasts increased cell fusion. In this work, we report that CKIP-1 depletion drastically impairs C2C12 myoblast fusion in vitro and in vivo during zebrafish muscle development. Within developing fast-twich myotome, Ckip-1 localises at the periphery of fast precursor cells, closed to the plasma membrane. Unlike wild-type myoblasts that form spatially arrayed multinucleated fast myofibres, Ckip-1-deficient myoblasts show a drastic reduction in fusion capacity. A search for CKIP-1 binding partners identified the ARPC1 subunit of Arp2/3 actin nucleation complex essential for myoblast fusion. We demonstrate that CKIP-1, through binding to plasma membrane phosphoinositides via its PH domain, regulates cell morphology and lamellipodia formation by recruiting the Arp2/3 complex at the plasma membrane. These results establish CKIP-1 as a regulator of cortical actin that recruits the Arp2/3 complex at the plasma membrane essential for muscle precursor elongation and fusion. C1 [Baas, Dominique; Caussanel-Boude, Sabine; Guiraud, Alexandre; Calhabeu, Frederico; Delaune, Emilie; Pilot, Fanny; Chopin, Emilie; Vernay, Aurelia; Schaeffer, Laurent; Goillot, Evelyne] Univ Lyon, CNRS UMR 5239, Equipe Differenciat Neuromusculaire,ENS Lyon, Lab Biol Mol Cellule,Biosci Lyon Gerland IFR128, F-69364 Lyon 07, France. [Machuca-Gayet, Irma; Jurdic, Pierre] UCB Lyon 1, Equipe Biol Cellulaire & Physiopathol Osseuse, UMR CNRS 5242, IGFL,ENS Lyon,INRA 1288, F-69364 Lyon 07, France. [Bertrand, Stephanie] Univ Paris 06, CNRS UMR 7628, Observ Oceanog, F-66651 Banyuls Sur Mer, France. [Rual, Jean-Francois; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Rual, Jean-Francois; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Rual, Jean-Francois; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Goillot, E (reprint author), Univ Lyon, CNRS UMR 5239, Equipe Differenciat Neuromusculaire,ENS Lyon, Lab Biol Mol Cellule,Biosci Lyon Gerland IFR128, 46 Allee Italie, F-69364 Lyon 07, France. EM evelyne.goillot@ens-lyon.fr RI Hill, David/B-6617-2011; Bertrand, Stephanie/D-8482-2014; OI Bertrand, Stephanie/0000-0002-0689-0126; Rual, Jean-Francois/0000-0003-4465-8819 FU NICHD; Association francaise contre les Myopathies [AFM-12130]; Ministere de la Recherche et de l'Enseignement Superieur; Fondation pour la Recherche Medicale [FDT20101221104]; Association pour la Recherche contre le Cancer [ARC-3853]; Ministere de la Recherche et de la Technologie [ANR-11-BSV2-017-01] FX We are grateful to M. D. Welch (Department of Molecular and Cell Biology, University of California) for providing Arp2/3 subunit antibodies. The (MAb 5B12.3) (MAb 3F2.3), (MAb F59) (MAb F310) were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242. We thank the zebrafish (PRECI) and microscopy (Plateau Technique Imagerie/Microscopie) facilities of the IFR128 Biosciences.; This work was supported by the Association francaise contre les Myopathies [grant number AFM-12130 to F. C. and E. G.]; the Ministere de la Recherche et de l'Enseignement Superieur; Fondation pour la Recherche Medicale [grant number FDT20101221104 to A. G.]; the Association pour la Recherche contre le Cancer [grant number ARC-3853 to E. G.]; and the Ministere de la Recherche et de la Technologie [grant number ANR-11-BSV2-017-01 to L.S.]. NR 50 TC 6 Z9 6 U1 0 U2 12 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 15 PY 2012 VL 125 IS 16 BP 3790 EP 3800 DI 10.1242/jcs.101048 PG 11 WC Cell Biology SC Cell Biology GA 016NJ UT WOS:000309525300011 PM 22553210 ER PT J AU Sepucha, KR Feibelmann, S Abdu, WA Clay, CF Cosenza, C Kearing, S Levin, CA Atlas, SJ AF Sepucha, Karen R. Feibelmann, Sandra Abdu, William A. Clay, Catharine F. Cosenza, Carol Kearing, Stephen Levin, Carrie A. Atlas, Steven J. TI Psychometric Evaluation of a Decision Quality Instrument for Treatment of Lumbar Herniated Disc SO SPINE LA English DT Article DE shared decision making; patient-centered care; decision quality; quality measurement; lumbar herniated disc ID INTERACTIVE VIDEO PROGRAM; BACK SURGERY; PATIENT; PREFERENCES; AIDS; CARE; PAIN AB Study Design. Retrospective and prospective patient surveys and a physician survey using a sample from American Medical Association master file. Objective. To evaluate the performance of a new instrument designed to measure the quality of decisions about treatment of herniated disc. Summary of Background Data. There is growing consensus on the importance of engaging and informing patients to improve the quality of significant medical decisions, yet there are no instruments currently available to measure decision quality. Methods. The herniated disc-decision quality instrument (HD-DQI) was developed with input from clinical experts, survey research experts, and patients. The HD-DQI produces 2 scores each scaled to 0% to 100%, with higher scores indicating better quality: (1) a total knowledge score and (2) a concordance score (indicating the percentage of patients who received treatments that matched their goals). We examined hypotheses relating to the acceptability, feasibility, validity, and reliability of the instrument, using data from 3 samples. Results. The HD-DQI survey was feasible to implement and acceptable to patients, with good response rates and low missing data. The knowledge score discriminated between patients who had seen a decision aid or no decision aid (55% vs. 38%, P < 0.001) and between providers and patients (73% vs. 46%, P < 0.001). The knowledge score also had good retest reliability (intraclass correlation coefficient = 0.85). Most patients (78%) received treatments that matched their goals. Patients who received treatments that matched their goals were less likely to regret the decision than those who did not (13% vs. 39%, P = 0.004). Conclusion. The HD-DQI met several criteria for high-quality patient-reported survey instruments. It can be used to determine the quality of decisions for treatment of herniated disc. More work is needed to examine acceptability for use as part of routine patient care. C1 [Sepucha, Karen R.] Harvard Univ, Massachusetts Gen Hosp, Div Gen Med, Hlth Decis Sci Ctr,Med Sch, Boston, MA 02114 USA. [Abdu, William A.] Dartmouth Hitchcock Med Ctr, Dept Orthopaed Surg, Lebanon, NH 03766 USA. [Clay, Catharine F.; Kearing, Stephen] Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Cosenza, Carol] Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. [Levin, Carrie A.] Informed Med Decis Fdn, Boston, MA USA. RP Sepucha, KR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Gen Med, Hlth Decis Sci Ctr,Med Sch, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM ksepucha@partners.org FU Informed Medical Decisions Foundation FX The work was supported by two grants from the Informed Medical Decisions Foundation, one to Massachusetts General Hospital (MGH) and one to Dartmouth. The authors thank the patients and providers whose participation made this research possible. The research involved collaboration between the MGH research team, the Dartmouth research team, and representatives from the funder (CL). The research grant was awarded in compliance with MGH's policies which bar funder interference in scholarly work. NR 24 TC 5 Z9 5 U1 4 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD AUG 15 PY 2012 VL 37 IS 18 BP 1609 EP 1616 DI 10.1097/BRS.0b013e3182532924 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 992OJ UT WOS:000307787300021 PM 22426449 ER PT J AU Vaid, M Prasad, R Singh, T Jones, V Katiyar, SK AF Vaid, Mudit Prasad, Ram Singh, Tripti Jones, Virginia Katiyar, Santosh K. TI Grape seed proanthocyanidins reactivate silenced tumor suppressor genes in human skin cancer cells by targeting epigenetic regulators SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Grape seed proanthocyanidins; DNA methylation; Skin cancer cells; Histone acetylation; Tumor suppressor genes and proteins ID SKH-1 HAIRLESS MICE; DNA METHYLATION; HISTONE ACETYLATION; OXIDATIVE STRESS; MECHANISMS; PREVENTION; REPAIR; PHOTOCARCINOGENESIS; HYPERMETHYLATION; INACTIVATION AB Grape seed proanthocyanidins (GSPs) have been shown to have anti-skin carcinogenic effects in in vitro and in vivo models. However, the precise epigenetic molecular mechanisms remain unexplored. This study was designed to investigate whether GSPs reactivate silenced tumor suppressor genes following epigenetic modifications in skin cancer cells. For this purpose, A431 and SCC13 human squamous cell carcinoma cell lines were used as in vitro models. The effects of GSPs on DNA methylation, histone modifications and tumor suppressor gene expressions were studied in these cell lines using enzyme activity assays, western blotting, dot-blot analysis and real-time polymerase chain reaction (RT-PCR). We found that treatment of A431 and SCC13 cells with GSPs decreased the levels of: ( i) global DNA methylation, (ii) 5-methylcytosine, (iii) DNA methyltransferase (DNMT) activity and (iv) messenger RNA (mRNA) and protein levels of DNMT1, DNMT3a and DNMT3b in these cells. Similar effects were noted when these cancer cells were treated identically with 5-aza-2'-deoxycytidine, an inhibitor of DNA methylation. GSPs decreased histone deacetylase activity, increased levels of acetylated lysines 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysines 5, 12 and 16 on histone H4, and reduced the levels of methylated H3-Lys 9. Further, GSP treatment resulted in re-expression of the mRNA and proteins of silenced tumor suppressor genes, RASSF1A, p16(INK4a) and Cip1/p21. Together, this study provides a new insight into the epigenetic mechanisms of GSPs and may have significant implications for epigenetic therapy in the treatment/prevention of skin cancers in humans. (C) 2012 Elsevier Inc. All rights reserved. C1 [Vaid, Mudit; Prasad, Ram; Singh, Tripti; Jones, Virginia; Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. RP Katiyar, SK (reprint author), Univ Alabama Birmingham, Dept Dermatol, 1670 Univ Blvd,Volker Hall 557, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU Veterans Administration Merit Review Award [ONCA-029-11S]; National Institutes of Health [CA140832] FX This work was supported by funds from the Veterans Administration Merit Review Award (ONCA-029-11S, S.K.K.) and the National Institutes of Health (CA140832, S.K.K.). The human keratinocytes were obtained from the UAB Skin Diseases Research Center (AR050948). Editorial assistance from Dr. Fiona Hunter is gratefully acknowledged. The content of this manuscript does not necessarily reflect the views or policies of the funding sources. NR 33 TC 18 Z9 19 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 15 PY 2012 VL 263 IS 1 BP 122 EP 130 DI 10.1016/j.taap.2012.06.013 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 984RK UT WOS:000307208900015 PM 22749965 ER PT J AU Heist, EK Chalhoub, F Barrett, C Danik, S Ruskin, JN Mansour, M AF Heist, E. Kevin Chalhoub, Fadi Barrett, Conor Danik, Stephan Ruskin, Jeremy N. Mansour, Moussa TI Predictors of Atrial Fibrillation Termination and Clinical Success of Catheter Ablation of Persistent Atrial Fibrillation SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LONG-LASTING PERSISTENT; PULMONARY VEIN ISOLATION; PROCEDURAL END-POINT; FOLLOW-UP; FRACTIONATED ELECTROGRAMS; RADIOFREQUENCY ABLATION; SUBSTRATE; REGULARIZATION; MULTICENTER; ARRHYTHMIAS AB The termination of persistent atrial fibrillation (AF) during catheter ablation has been associated in some, but not all, studies with reduced arrhythmia during clinical follow-up. We sought to determine the rate of persistent AF termination achievable with a stepwise ablation strategy, the predictors of AF termination, and the clinical outcomes associated with termination and nontermination. A total of 143 consecutive patients (age 62 +/- 9 years, AF duration 5.7 +/- 5.2 years) with persistent and longstanding persistent AF resistant to antiarrhythmic medication who presented in AF for catheter ablation were studied. Ablation was done with a stepwise approach, including pulmonary vein isolation, followed by complex fractionated atrial electrogram ablation and ablation of resultant atrial tachycardias. Clinical follow-up was then performed after a 2-month blanking period to assess arrhythmia recurrence, defined as AF or atrial tachycardia lasting >= 30 seconds. AF termination by ablation was achieved in 95 (66%) of the 143 patients. Multivariate predictors of AF termination included longer baseline AF cycle length (p < 0.001) and smaller left atrial size (p = 0.002). AF termination by ablation was associated with both a lower incidence of arrhythmia recurrence after a single procedure without antiarrhythmic drugs (p = 0.01) and overall clinical success (single or multiple procedures, with or without antiarrhythmic drugs; p = 0.005). On multivariate analysis, the predictors of overall clinical success included AF termination by ablation (p = 0.001), a shorter ablation duration (p = 0.002), younger age (p = 0.02), male gender (p = 0.03), and the presence of hypertension (p = 0.03). In conclusion, among patients with persistent AF, termination of AF by ablation can be achieved in most patients and is associated with reduced recurrence of arrhythmia. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:545-551) C1 [Mansour, Moussa] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Mansour, M (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. EM mmansour@partners.org FU Deane Institute for Integrative Research in Stroke and Atrial Fibrillation (Massachusetts General Hospital, Boston, Massachusetts) FX This work has been partially supported by the Deane Institute for Integrative Research in Stroke and Atrial Fibrillation (Massachusetts General Hospital, Boston, Massachusetts). NR 28 TC 19 Z9 20 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2012 VL 110 IS 4 BP 545 EP 551 DI 10.1016/j.amjcard.2012.04.028 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 993LK UT WOS:000307861000014 PM 22591670 ER PT J AU Muller, LUW Schlaeger, TM DeVine, AL Williams, DA AF Mueller, Lars U. W. Schlaeger, Thorsten M. DeVine, Alexander L. Williams, David A. TI Induced pluripotent stem cells as a tool for gaining new insights into Fanconi anemia SO CELL CYCLE LA English DT Article DE Fanconi anemia; bone marrow failure; induced pluripotent stem cells; hematopoietic differentiation; drug discovery ID REVERSE MOSAICISM; IFN-GAMMA; TNF-ALPHA; KNOCKDOWN; REVEALS; VIVO AB Induced pluripotent stem cells (iPSC) hold significant promise for advancing biomedical research. In the case of monogenic diseases, patient-iPSC and their derivatives contain the disease-causing mutation, suggesting the possibility of recapitulating salient disease features in vitro. Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. The etiology of bone marrow failure in FA remains largely unclear, but limited studies on patient bone marrow cells indicate cell intrinsic defects as causative. We examined the feasibility of modeling FA in a system based on hematopoietic differentiation of patient-specific iPSC. An informative iPSC-based model is predicated on the ability to derive disease-specific (uncorrected) patient iPSC that contain the disease-causing mutation, are pluripotent, maintain a normal karyotype and are capable of hematopoietic differentiation. Careful analysis of hematopoietic differentiation of such iPSC holds the promise of uncovering new insights into bone marrow failure and may enable high-throughput screening with the goal of identifying compounds that ameliorate hematopoietic failure. Ultimately, genetic correction, molecular characterization and successful engraftment of iPSC-derived cells may provide an attractive alternative to current hematopoietic stem cell-targeted gene therapy in some monogenic diseases, including FA. C1 [Mueller, Lars U. W.; Williams, David A.] Harvard Univ, Sch Med, Div Pediat Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA. [Mueller, Lars U. W.; Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Schlaeger, Thorsten M.; DeVine, Alexander L.] Boston Childrens Hosp, Stem Cell Program, Boston, MA USA. RP Williams, DA (reprint author), Harvard Univ, Sch Med, Div Pediat Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA. EM DAWilliams@childrens.harvard.edu FU St. Baldrick's Foundation; Harvard Stem Cell Institute; Hood Foundation; [NIH1RC4DK090913-01] FX We would like to thank the Dana Farber/Harvard Cancer Center Rodent Histopathology Core for assisting with teratoma histology. We appreciate the assistance with DNA sequence analysis provided by Bai-Lin Wu, Va Lip and Yiping Shen of the Genetics Diagnostic Lab at Boston Children's Hospital. Grant support: Supported by a fellowship grant from the St. Baldrick's Foundation (L. M.), Harvard Stem Cell Institute (L. M.), Hood Foundation (L. M.) and NIH1RC4DK090913-01 (D.A.W.). NR 28 TC 9 Z9 9 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD AUG 15 PY 2012 VL 11 IS 16 BP 2985 EP 2990 DI 10.4161/cc.21109 PG 6 WC Cell Biology SC Cell Biology GA 995JJ UT WOS:000308004000015 PM 22825249 ER PT J AU Stumpfova, M Janne, PA AF Stumpfova, Magda Jaenne, Pasi A. TI Zeroing in on ROS1 Rearrangements in Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID GLIOBLASTOMA; FUSION AB Rimkunas and colleagues report on the development and validation of an immunohistochemical assay evaluating non-small cell lung cancers (NSCLC) for the presence of ROS1 fusions. The diagnostic was validated in a screen of 556 NSCLCs, identifying 9 (1.6%) tumors with oncogenic ROS1 rearrangements. These patients are candidates for ROS1-targeted therapies. Clin Cancer Res; 18(16); 4222-4. (C) 2012 AACR. C1 [Stumpfova, Magda; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Stumpfova, Magda; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, HIM223,450 Brookline Ave, Boston, MA 02215 USA. EM pjanne@partners.org NR 9 TC 12 Z9 13 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2012 VL 18 IS 16 BP 4222 EP 4224 DI 10.1158/1078-0432.CCR-12-1812 PG 3 WC Oncology SC Oncology GA 988PY UT WOS:000307504200002 PM 22859716 ER PT J AU Heinrich, MC Griffith, D McKinley, A Patterson, J Presnell, A Ramachandran, A Debiec-Rychter, M AF Heinrich, Michael C. Griffith, Diana McKinley, Arin Patterson, Janice Presnell, Ajia Ramachandran, Abhijit Debiec-Rychter, Maria TI Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-Resistant Gastrointestinal Stromal Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; KINASE INHIBITORS; PHASE-II; KIT; MUTANT; CANCER; MECHANISMS; SORAFENIB; ONCOLOGY; MESYLATE AB Purpose: To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA. Experimental Design: The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth. Results: Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC50 of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency. Conclusions: Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5% of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated. Clin Cancer Res; 18(16); 4375-84. (C) 2012 AACR. C1 [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Dept Med, Div Hematol Oncol, Portland, OR 97239 USA. [Heinrich, Michael C.; Griffith, Diana; McKinley, Arin; Patterson, Janice; Presnell, Ajia] Oregon Hlth & Sci Univ, OHSU Knight Canc Inst, Portland, OR 97239 USA. [Ramachandran, Abhijit] AROG Pharmaceut LLC, Dallas, TX USA. [Debiec-Rychter, Maria] Katholieke Univ Leuven, Dept Human Genet, Louvain, Belgium. Univ Hosp, Louvain, Belgium. RP Heinrich, MC (reprint author), Oregon Hlth & Sci Univ, Portland VA Med Ctr, Dept Med, Div Hematol Oncol, R&D-19 3710 US Vet Hosp Rd, Portland, OR 97239 USA. EM Heinrich@ohsu.edu OI Patterson, Janice/0000-0002-8969-2933 FU AROG; Novartis; Imclone; Ariad; Veterans Affairs Merit Review Grant; AROG Pharmaceuticals LLC; Life Raft Group; GIST Cancer Research Fund FX M.C. Heinrich has received commercial research grants from AROG, Novartis, Imclone, and Ariad, and honoraria from speakers bureau of Novartis. He also has ownership interest (including patents) from MolecularMD and is a consultant and an advisory board member of Novartis, Pfizer, and MolecularMD. No potential conflicts of interest were disclosed by the other authors.; The work was supported in part from funding from a Veterans Affairs Merit Review Grant (M. C. Heinrich), AROG Pharmaceuticals LLC, the Life Raft Group (M. C. Heinrich, M. Debiec-Rychter), and the GIST Cancer Research Fund (M.C. Heinrich). NR 34 TC 56 Z9 57 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2012 VL 18 IS 16 BP 4375 EP 4384 DI 10.1158/1078-0432.CCR-12-0625 PG 10 WC Oncology SC Oncology GA 988PY UT WOS:000307504200020 PM 22745105 ER PT J AU Heon, S Yeap, BY Lindeman, NI Joshi, VA Butaney, M Britt, GJ Costa, DB Rabin, MS Jackman, DM Johnson, BE AF Heon, Stephanie Yeap, Beow Y. Lindeman, Neal I. Joshi, Victoria A. Butaney, Mohit Britt, Gregory J. Costa, Daniel B. Rabin, Michael S. Jackman, David M. Johnson, Bruce E. TI The Impact of Initial Gefitinib or Erlotinib versus Chemotherapy on Central Nervous System Progression in Advanced Non-Small Cell Lung Cancer with EGFR Mutations SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; BRAIN METASTASES; RESISTANCE; TRIAL; RISK; ADENOCARCINOMA; CLASSIFICATION; CARBOPLATIN; PACLITAXEL; CRIZOTINIB AB Purpose: This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous system (CNS) progression in advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Experimental Design: Patients with stage IV or relapsed NSCLC with a sensitizing EGFR mutation initially treated with gefitinib, erlotinib, or chemotherapy were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. Results: One hundred and fifty-five patients were eligible (EGFR-TKI: 101, chemotherapy: 54). Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P 1.000); 32 of the 36 received CNS therapy before initiating systemic treatment. Thirty-three patients (33%) in the EGFR-TKI group and 26 patients (48%) in the chemotherapy group developed CNS progression after a median follow-up of 25 months. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% in the EGFR-TKI group compared with corresponding rates of 7%, 19%, and 32% in the chemotherapy group (P = 0.026). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 [95% confidence interval (CI), 0.34-0.94]. Conclusions: Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR-TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC. Clin Cancer Res; 18(16); 4406-14. (C) 2012 AACR. C1 [Heon, Stephanie; Butaney, Mohit; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, Boston, MA 02215 USA. [Heon, Stephanie; Yeap, Beow Y.; Britt, Gregory J.; Costa, Daniel B.; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Heon, Stephanie; Lindeman, Neal I.; Joshi, Victoria A.; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lindeman, Neal I.; Joshi, Victoria A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Britt, Gregory J.; Costa, Daniel B.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, 450 Brookline Ave,Dana Bldg 1234, Boston, MA 02215 USA. EM bejohnson@partners.org OI Costa, Daniel/0000-0002-0689-395X FU American Society of Clinical Oncology (ASCO) Cancer Foundation Translational Research Professorship; NIH [5R01-CA114465]; ASCO Conquer Cancer Foundation; Dana-Farber Cancer Institute FX This work was funded in part by the American Society of Clinical Oncology (ASCO) Cancer Foundation Translational Research Professorship (to B. E. Johnson), NIH grant 5R01-CA114465 (to B. E. Johnson and B.Y. Yeap), ASCO Conquer Cancer Foundation Career Development Award (to D. B. Costa), the Alice and Stephen D. Cutler Investigator Fund in Thoracic Oncology at Dana-Farber Cancer Institute (to D. M. Jackman and S. Heon), and the Elaine Promisel Siegel Fund in Thoracic Oncology at Dana-Farber Cancer Institute (to S. Heon). 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 37 TC 62 Z9 65 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2012 VL 18 IS 16 BP 4406 EP 4414 DI 10.1158/1078-0432.CCR-12-0357 PG 9 WC Oncology SC Oncology GA 988PY UT WOS:000307504200023 PM 22733536 ER PT J AU Zhu, JH Lee, HP Lim, KM Gordon, BR Wang, DY AF Zhu, Jian Hua Lee, Heow Pueh Lim, Kian Meng Gordon, Bruce R. Wang, De Yun TI Effect of accessory ostia on maxillary sinus ventilation: A computational fluid dynamics (CFD) study SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Article DE Accessory ostium; Maxillary sinus ventilation; Maxillary sinus airflow; Ostiomeatal complex; CFD simulation ID HUMAN NASAL CAVITY; AIR-FLOW; NUMERICAL-SIMULATION; HUMAN NOSE; PARANASAL SINUSES; NITRIC-OXIDE; MUCUS; PATTERNS; MODEL; RECIRCULATION AB We evaluated, by CFD simulation, effects of accessory ostium (AO) on maxillary sinus ventilation. A three-dimensional nasal model was constructed from an adult CT scan with two left maxillary AOs (sinus I) and one right AO (sinus II), then compared to an identical control model with all AOs sealed (sinuses III and IV). Transient simulations of quiet inspiration and expiration at 15 L/min, and nasal blow at 48 L/min, were calculated for both models using low-Reynolds-number turbulent analysis. At low flows, ventilation rates in sinuses with AOs (I approximate to 0.46 L/min, II approximate to 0.54 L/min), were both more than a magnitude higher than sinuses without AOs (III approximate to 0.019 L/min, IV approximate to 0.020 L/min). Absence of AO almost completely prevented sinus ventilation. Increased ventilation of sinuses with AOs is complex. Under high flow conditions mimicking nose blowing, in sinuses II. HI, and IV, the sinus flow rate increased. In contrast, the airflow direction through sinus I reversed between inspiration and expiration, while it remained almost constant throughout the respiration cycle in sinus II. CFD simulation demonstrated that AOs markedly increase maxillary sinus airflow rates and alter sinus air circulation patterns. Whether these airflow changes impact maxillary sinus physiology or pathophysiology is unknown. (c) 2012 Elsevier B.V. All rights reserved. C1 [Zhu, Jian Hua] Natl Univ Singapore, Fac Engn, Dept Mech Engn, Singapore 117576, Singapore. [Gordon, Bruce R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Gordon, Bruce R.] Cape Cod Hosp, Div Otolaryngol, Hyannis, MA USA. [Wang, De Yun] Natl Univ Singapore, Dept Otolaryngol, Singapore 117576, Singapore. RP Zhu, JH (reprint author), Natl Univ Singapore, Fac Engn, Dept Mech Engn, 1 Engn Dr 2, Singapore 117576, Singapore. EM jhzhu.me@gmail.com RI Lim, Kian-Meng/B-2556-2010; Lee, Heow Pueh/I-7834-2014 OI Lim, Kian-Meng/0000-0003-4311-9223; Lee, Heow Pueh/0000-0002-4380-3888 FU Academic Research Grant from the Ministry of Education, Singapore [T208A3103] FX The authors would like to acknowledge the support by the Academic Research Grant (T208A3103) from the Ministry of Education, Singapore. This research has been approved by the relevant Institutional Review Board. NR 32 TC 9 Z9 12 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 EI 1878-1519 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD AUG 15 PY 2012 VL 183 IS 2 BP 91 EP 99 DI 10.1016/j.resp.2012.06.026 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 993NU UT WOS:000307867200005 PM 22750570 ER PT J AU Ren, Y Cheung, HW von Maltzhan, G Agrawal, A Cowley, GS Weir, BA Boehm, JS Tamayo, P Karst, AM Liu, JF Hirsch, MS Mesirov, JP Drapkin, R Root, DE Lo, J Fogal, V Ruoslahti, E Hahn, WC Bhatia, SN AF Ren, Yin Cheung, Hiu Wing von Maltzhan, Geoffrey Agrawal, Amit Cowley, Glenn S. Weir, Barbara A. Boehm, Jesse S. Tamayo, Pablo Karst, Alison M. Liu, Joyce F. Hirsch, Michelle S. Mesirov, Jill P. Drapkin, Ronny Root, David E. Lo, Justin Fogal, Valentina Ruoslahti, Erkki Hahn, William C. Bhatia, Sangeeta N. TI Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4 SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID IN-VIVO; CELLS; NANOPARTICLES; EXPRESSION; DELIVERY; PEPTIDE; INTERFERENCE; INHIBITION; PROTEINS; BARRIERS AB The comprehensive characterization of a large number of cancer genomes will eventually lead to a compendium of genetic alterations in specific cancers. Unfortunately, the number and complexity of identified alterations complicate endeavors to identify biologically relevant mutations critical for tumor maintenance because many of these targets are not amenable to manipulation by small molecules or antibodies. RNA interference provides a direct way to study putative cancer targets; however, specific delivery of therapeutics to the tumor parenchyma remains an intractable problem. We describe a platform for the discovery and initial validation of cancer targets, composed of a systematic effort to identify amplified and essential genes in human cancer cell lines and tumors partnered with a novel modular delivery technology. We developed a tumor-penetrating nanocomplex (TPN) that comprised small interfering RNA (siRNA) complexed with a tandem tumor-penetrating and membrane-translocating peptide, which enabled the specific delivery of siRNA deep into the tumor parenchyma. We used TPN in vivo to evaluate inhibitor of DNA binding 4 (ID4) as a novel oncogene. Treatment of ovarian tumor-bearing mice with ID4-specific TPN suppressed growth of established tumors and significantly improved survival. These observations not only credential ID4 as an oncogene in 32% of high-grade ovarian cancers but also provide a framework for the identification, validation, and understanding of potential therapeutic cancer targets. C1 [Cheung, Hiu Wing; Karst, Alison M.; Liu, Joyce F.; Drapkin, Ronny; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ren, Yin; von Maltzhan, Geoffrey; Agrawal, Amit; Lo, Justin; Bhatia, Sangeeta N.] MIT, Cambridge, MA 02139 USA. [Cheung, Hiu Wing; Cowley, Glenn S.; Weir, Barbara A.; Boehm, Jesse S.; Tamayo, Pablo; Mesirov, Jill P.; Root, David E.; Hahn, William C.; Bhatia, Sangeeta N.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Hirsch, Michelle S.; Drapkin, Ronny] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hirsch, Michelle S.; Drapkin, Ronny; Hahn, William C.; Bhatia, Sangeeta N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mesirov, Jill P.; Bhatia, Sangeeta N.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Fogal, Valentina; Ruoslahti, Erkki] Univ Calif Santa Barbara, Ctr Nanomed, Sanford Burnham Med Res Inst, Santa Barbara, CA 93106 USA. [Fogal, Valentina; Ruoslahti, Erkki] Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA. [Hahn, William C.; Bhatia, Sangeeta N.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Bhatia, Sangeeta N.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM william_hahn@dfci.harvard.edu; sbhatia@mit.edu RI Drapkin, Ronny/E-9944-2016; OI Drapkin, Ronny/0000-0002-6912-6977; Boehm, Jesse/0000-0002-6795-6336 FU Howard Hughes Medical Institute; National Cancer Institute (NCI) [U54 CA119349, U54 CA119335, R01 CA124427, R33 CA128625, RC2 CA148268, U54 CA112962, RO1 CA152327, P50 CA105009]; NIH [U01 CA152990]; Starr Cancer Consortium; Marie D. and Pierre Casimir-Lambert Fund; Mary Kay Foundation; Sandy Rollman Ovarian Cancer Foundation; Canadian Institutes of Health Research Fellowship; Cancer Center Support (Core) from NCI [P30 CA14051] FX Supported by the Howard Hughes Medical Institute (S.N.B.); National Cancer Institute (NCI) grants U54 CA119349 (S.N.B.), U54 CA119335 (S.N.B.), R01 CA124427 (S.N.B.), R33 CA128625 (W.C.H.), RC2 CA148268 (W.C.H.), U54 CA112962 (W.C.H.), RO1 CA152327 (E.R.), and P50 CA105009 (R.D.); NIH grant U01 CA152990 (R.D.); the Starr Cancer Consortium (W.C.H. and S.N.B.); the Marie D. and Pierre Casimir-Lambert Fund (S.N.B.); The Mary Kay Foundation (R.D.); the Sandy Rollman Ovarian Cancer Foundation (R.D.); Canadian Institutes of Health Research Fellowship (A.M.K.); and in part by Cancer Center Support (Core) Grant P30 CA14051 from the NCI. NR 42 TC 63 Z9 63 U1 3 U2 40 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 15 PY 2012 VL 4 IS 147 AR 147ra112 DI 10.1126/scitranslmed.3003778 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 994UR UT WOS:000307958800006 PM 22896676 ER PT J AU Bouldin, SD Darch, MA Hart, PJ Outten, CE AF Bouldin, Samantha D. Darch, Maxwell A. Hart, P. John Outten, Caryn E. TI Redox properties of the disulfide bond of human Cu,Zn superoxide dismutase and the effects of human glutaredoxin 1 SO BIOCHEMICAL JOURNAL LA English DT Article DE Cu,Zn superoxide dismutase (SOD); disulfide; glutaredoxin; monothiol; redox potential; yeast ID AMYOTROPHIC-LATERAL-SCLEROSIS; COPPER CHAPERONE CCS; MUTANT CU,ZN-SUPEROXIDE DISMUTASE; INTERMEMBRANE SPACE; FAMILIAL ALS; BINDING-SITE; REDUCED FORM; MOUSE MODEL; WILD-TYPE; SOD1 AB The intramolecular disulfide bond in hSOD1 [human SOD1 (Cu,Zn superoxide dismutase 1)] plays a key role in maintaining the protein's stability and quaternary structure. In mutant forms of SOD1 that cause familial ALS (amyotrophic lateral sclerosis), this disulfide bond is more susceptible to chemical reduction, which may lead to destabilization of the dimer and aggregation. During hSOD1 maturation, disulfide formation is catalysed by CCS1 (copper chaperone for SOD1). Previous studies in yeast demonstrate that the yeast GSH/Grx (glutaredoxin) redox system promotes reduction of the hSOD1 disulfide in the absence of CCS1. In the present study, we probe further the interaction between hSOD1, GSH and Grxs to provide mechanistic insight into the redox kinetics and thermodynamics of the hSOD1 disulfide. We demonstrate that hGrx1 (human Grx1) uses a monothiol mechanism to reduce the hSOD1 disulfide, and the GSH/hGrx1 system reduces ALS mutant SOD1 at a faster rate than WT (wild-type) hSOD1. However, redox potential measurements demonstrate that the thermodynamic stability of the disulfide is not consistently lower in ALS mutants compared with WT hSOD1. Furthermore, the presence of metal cofactors does not influence the disulfide redox potential. Overall, these studies suggest that differences in the GSH/hGrx1 reaction rate with WT compared with ALS mutant hSOD1 and not the inherent thermodynamic stability of the hSOD1 disulfide bond may contribute to the greater pathogenicity of ALS mutant hSOD1. C1 [Bouldin, Samantha D.; Darch, Maxwell A.; Outten, Caryn E.] Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. [Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Outten, CE (reprint author), Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. EM outten@mailbox.sc.edu OI Outten, Caryn/0000-0003-0335-6531 FU National Institutes of Health [K22 ES013780, R01 GM086619, R01 NS039112]; Judith and Jean Pape Adams Charitable Foundation FX This work was supported by the National Institutes of Health [grant numbers K22 ES013780 and R01 GM086619 (to C.E.O.), and R01 NS039112 (to P.J.H.)] and the Judith and Jean Pape Adams Charitable Foundation (to P.J.H.). NR 65 TC 13 Z9 13 U1 0 U2 9 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 15 PY 2012 VL 446 BP 59 EP 67 DI 10.1042/BJ20120075 PN 1 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 990JH UT WOS:000307626300006 PM 22651090 ER PT J AU Kronenberg, G Balkaya, M Prinz, V Gertz, K Ji, S Kirste, I Heuser, I Kampmann, B Hellmann-Regen, J Gass, P Sohr, R Hellweg, R Waeber, C Juckel, G Hortnagl, H Stumm, R Endres, M AF Kronenberg, Golo Balkaya, Mustafa Prinz, Vincent Gertz, Karen Ji, Shengbo Kirste, Imke Heuser, Isabella Kampmann, Bjoern Hellmann-Regen, Julian Gass, Peter Sohr, Reinhard Hellweg, Rainer Waeber, Christian Juckel, Georg Hoertnagl, Heide Stumm, Ralf Endres, Matthias TI Exofocal Dopaminergic Degeneration as Antidepressant Target in Mouse Model of Poststroke Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE BDNF; depression; dopamine; mesolimbic reward system; serotonin reuptake inhibition; stroke ID SEROTONIN REUPTAKE INHIBITORS; IPSILATERAL SUBSTANTIA-NIGRA; LESION LOCATION; PARKINSONS-DISEASE; CEREBRAL INFARCTION; RECEPTOR ACTIVATION; TRANSIENT ISCHEMIA; NUCLEUS-ACCUMBENS; CONTROLLED-TRIAL; FOCAL ISCHEMIA AB Background: Although poststroke depression (PSD) is a frequent chronic complication of stroke with high relevance for outcome and survival, underlying pathomechanisms remain inadequately understood. This may be because suitable animal models are largely lacking and existing models are poorly characterized. Methods: Male 129/SV mice were subjected to 30-min middle cerebral artery occlusion (MCAo)/reperfusion and serial magnetic resonance imaging scans. A subset of animals received selective serotonin reuptake inhibitor citalopram starting 7 days after MCAo. Behavioral assessment was performed at 14 weeks. To identify biological correlates of PSD, we quantified corticosterone levels in serum and brain-derived neurotrophic factor levels in brain. The integrity of the mesolimbic dopaminergic system was assessed using tyrosine hydroxylase and dynorphin in situ hybridizations as well as dopamine transporter autoradiography. Results: Left, but not right, MCAo, elicited anhedonia and increased anxiety and despair. This depression-like syndrome was associated with alterations in the mesolimbic reward system. MCAo resulted in delayed degeneration of dopaminergic neurons in ipsilateral midbrain, which was accompanied by reduced dopamine concentrations and decreased levels of dopamine transporter density along with increased brain-derived neurotrophic factor protein levels in ischemic striatum and increased dynorphin messenger RNA expression in nucleus accumbens. Chronic antidepressant treatment initiated as late as 7 days after stroke reversed the behavioral phenotype, prevented degeneration of dopaminergic midbrain neurons, and attenuated striatal atrophy at 4 months. Conclusions: Our results highlight the importance of the dopaminergic system for the development of PSD. Prevention of secondary neurodegeneration by antidepressants may provide a novel target for subacute stroke therapy. C1 [Kronenberg, Golo; Balkaya, Mustafa; Prinz, Vincent; Gertz, Karen; Ji, Shengbo; Endres, Matthias] Charite Univ Med Berlin, Klin & Poliklin Neurol, D-10117 Berlin, Germany. [Kronenberg, Golo; Balkaya, Mustafa; Prinz, Vincent; Gertz, Karen; Ji, Shengbo; Endres, Matthias] Charite Univ Med Berlin, Ctr Stroke Res Berlin, D-10117 Berlin, Germany. [Kampmann, Bjoern; Sohr, Reinhard; Hoertnagl, Heide] Charite Univ Med Berlin, Inst Pharmakol & Toxikol, D-10117 Berlin, Germany. [Hellweg, Rainer] Charite Univ Med Berlin, Klin Psychiat & Psychotherapie, D-10117 Berlin, Germany. [Kronenberg, Golo; Kirste, Imke; Heuser, Isabella; Hellmann-Regen, Julian] Charite Univ Med Berlin, Klin & Hsch Ambulanz Psychiat & Psychotherapie, D-10117 Berlin, Germany. [Kronenberg, Golo] Max Delbruck Ctr, Expt & Clin Res Ctr, Berlin, Germany. [Kronenberg, Golo] Humboldt Univ, Fac Med Charite, Inst Pharmacol & Toxicol, D-10098 Berlin, Germany. [Gass, Peter] Univ Heidelberg, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-6800 Mannheim, Germany. [Waeber, Christian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Stroke & Neurovasc Regulat Lab, Charlestown, MA USA. [Juckel, Georg] Ruhr Univ Bochum, Dept Psychiat, Bochum, Germany. [Stumm, Ralf] Otto von Guericke Univ, Res Grp Mol & Syst Neuropharmacol, Ctr Behav Brain Sci, Magdeburg, Germany. RP Endres, M (reprint author), Charite Univ Med Berlin, Klin & Poliklin Neurol, Campus Mitte,Charitepl 1, D-10117 Berlin, Germany. EM matthias.endres@charite.de RI Kronenberg, Golo/F-8772-2010; Waeber, Christian/A-8333-2009; Gertz, Karen/J-1603-2015 OI Waeber, Christian/0000-0001-6078-0027; FU Deutsche Forschungsgemeinschaft; Sonderforschungsbereich [TR 43]; Cluster of Excellence [257]; VolkswagenStiftung (Lichtenberg Program); Bundesministerium fur Bildung und Forschung (Center for Stroke Research Berlin); European Union [201024, 202213] FX This work was supported by individual grants by the Deutsche Forschungsgemeinschaft (to RH, RSt, ME) as well as through Sonderforschungsbereich TR 43 and Cluster of Excellence 257 (NeuroCure), VolkswagenStiftung (Lichtenberg Program to ME), the Bundesministerium fur Bildung und Forschung (Center for Stroke Research Berlin), and the European Union's Seventh Framework Program (Grant No. FP7/2008-2013) under grant Agreement Nos. 201024 and 202213 (European Stroke Network). NR 78 TC 28 Z9 31 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2012 VL 72 IS 4 BP 273 EP 281 DI 10.1016/j.biopsych.2012.02.026 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 980NA UT WOS:000306898800010 PM 22464799 ER PT J AU Dutta, C Day, T Kopp, N van Bodegom, D Davids, MS Ryan, J Bird, L Kommajosyula, N Weigert, O Yoda, A Fung, H Brown, JR Shapiro, GI Letai, A Weinstock, DM AF Dutta, Chaitali Day, Tovah Kopp, Nadja van Bodegom, Diederik Davids, Matthew S. Ryan, Jeremy Bird, Liat Kommajosyula, Naveen Weigert, Oliver Yoda, Akinori Fung, Hua Brown, Jennifer R. Shapiro, Geoffrey I. Letai, Anthony Weinstock, David M. TI BCL2 Suppresses PARP1 Function and Nonapoptotic Cell Death SO CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; HOMOLOGOUS RECOMBINATION; TRANSCRIPTIONAL ACTIVITY; MISMATCH REPAIR; DNA-DAMAGE; APOPTOSIS; ABT-737; MITOCHONDRIAL; INHIBITOR; FAMILY AB BCL2 suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating outer mitochondrial membrane permeabilization. Many tumor types, including B-cell lymphomas and chronic lymphocytic leukemia, are dependent on BCL2 for survival but become resistant to apoptosis after treatment. Here, we identified a direct interaction between the antiapoptotic protein BCL2 and the enzyme PARP1, which suppresses PARP1 enzymatic activity and inhibits PARP1-dependent DNA repair in diffuse large B-cell lymphoma cells. The BH3 mimetic ABT-737 displaced PARP1 from BCL2 in a dose-dependent manner, reestablishing PARP1 activity and DNA repair and promoting nonapoptotic cell death. This form of cell death was unaffected by resistance to single-agent ABT-737 that results from upregulation of antiapoptotic BCL2 family members. On the basis of the ability of BCL2 to suppress PARP1 function, we hypothesized that ectopic BCL2 expression would kill PARP inhibitor-sensitive cells. Strikingly, BCL2 expression reduced the survival of PARP inhibitor-sensitive breast cancer and lung cancer cells by 90% to 100%, and these effects were reversed by ABT-737. Taken together, our findings show that a novel interaction between BCL2 and PARP1 blocks PARP1 enzymatic activity and suppresses PARP1-dependent repair. Targeted disruption of the BCL2-PARP1 interaction therefore may represent a potential therapeutic approach for BCL2-expressing tumors resistant to apoptosis. Cancer Res; 72(16); 4193-203. (C) 2012 AACR. C1 [Weinstock, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Weinstock, DM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 510B, Boston, MA 02115 USA. EM davidm_weinstock@dfci.harvard.edu FU Burroughs-Wellcome Fund Career Award in the Biomedical Sciences [6150801]; Claudia Adams Barr Program in Cancer Research; John Stellato Fund; American Cancer Society; DF/HCC SPORE in Lung Cancer [P50 CA90578] FX This work was supported by a Burroughs-Wellcome Fund Career Award in the Biomedical Sciences (6150801), the Claudia Adams Barr Program in Cancer Research, and the John Stellato Fund. T. Day is supported by an American Cancer Society Fellowship. N. Kommajosyula and G. I. Shapiro are supported by the DF/HCC SPORE in Lung Cancer P50 CA90578. NR 47 TC 17 Z9 17 U1 0 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 AUG 15 PY 2012 VL 72 IS 16 BP 4193 EP 4203 DI 10.1158/0008-5472.CAN-11-4204 PG 11 WC Oncology SC Oncology GA 993SY UT WOS:000307881100030 PM 22689920 ER PT J AU Beker, S Kellner, V Kerti, L Stern, EA AF Beker, Shlomit Kellner, Vered Kerti, Lucia Stern, Edward A. TI Interaction between Amyloid-beta Pathology and Cortical Functional Columnar Organization SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MOUSE BARREL CORTEX; LAYER-IV BARRELS; ALZHEIMERS-DISEASE; TRANSGENIC MICE; IN-VIVO; VISUAL-CORTEX; SPATIOTEMPORAL CONVERGENCE; VIBRISSAL INFORMATION; BRAIN-DEVELOPMENT; RECEPTIVE-FIELDS AB Amyloid-beta plaques are one of the major neuropathological features in Alzheimer's disease (AD). Plaques are found in the extracellular space of telencephalic structures, and have been shown to disrupt neuronal connectivity. Since the disruption of connectivity may underlie a number of the symptoms of AD, understanding the distribution of plaques in the neuropil in relation to the connectivity pattern of the neuronal network is crucial. We measured the distribution and clustering patterns of plaques in the vibrissae-receptive primary sensory cortex (barrel cortex), in which the cortical columnar structure is anatomically demarcated by boundaries in Layer IV. We found that the plaques are not distributed randomly with respect to the barrel structures in Layer IV; rather, they are more concentrated in the septal areas than in the barrels. This difference was not preserved in the supragranular extensions of the functional columns. When comparing the degree of clustering of plaques between primary sensory cortices, we found that the degree of plaques clustering is significantly higher in somatosensory cortex than in visual cortex, and these differences are preserved in Layers II/III. The degree of areal discontinuity is therefore correlated with the patterns of neuropathological deposits. The discontinuous anatomical structure of this area allows us to make predictions about the functional effects of plaques on specific patterns of computational disruption in the AD brain. C1 [Beker, Shlomit; Kellner, Vered; Kerti, Lucia; Stern, Edward A.] Bar Ilan Univ, Brain Res Ctr, Fac Life Sci, IL-52900 Ramat Gan, Israel. [Stern, Edward A.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Boston, MA 02129 USA. [Stern, Edward A.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Kerti, Lucia] Univ Freiburg, Fac Biol, Bernstein Ctr Freiburg, D-79104 Freiburg, Germany. RP Stern, EA (reprint author), Bar Ilan Univ, Brain Res Ctr, Fac Life Sci, IL-52900 Ramat Gan, Israel. EM sterned@mail.biu.ac.il FU National Institute on Aging [AG024238]; Israel Science Foundation [688/10] FX This work was supported by the National Institute on Aging (Grant AG024238) and the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (Grant 688/10). NR 73 TC 4 Z9 4 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 15 PY 2012 VL 32 IS 33 BP 11241 EP 11249 DI 10.1523/JNEUROSCI.2426-12.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 994OJ UT WOS:000307940000008 PM 22895708 ER PT J AU Choi, HG Zhang, JM Weisberg, E Griffin, JD Sim, T Gray, NS AF Choi, Hwan Geun Zhang, Jianming Weisberg, Ellen Griffin, James D. Sim, Taebo Gray, Nathanael S. TI Development of 'DFG-out' inhibitors of gatekeeper mutant kinases SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE T315I Bcr-Abl; Kinase inhibitor; Gatekeeper mutant; Type II inhibitor; Thiazolo[5,4-b]pyridine ID CHRONIC MYELOID-LEUKEMIA; ABL TYROSINE KINASE; BCR-ABL; SELECTIVE INHIBITOR; RESISTANCE; DISCOVERY; IMATINIB; SRC; AMN107; CELLS AB HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I-Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Choi, Hwan Geun; Zhang, Jianming; Sim, Taebo; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Weisberg, Ellen; Griffin, James D.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sim, Taebo] Korea Inst Sci & Technol, Life Sci Res Div, Seoul 136791, South Korea. [Choi, Hwan Geun; Zhang, Jianming; Sim, Taebo; Gray, Nathanael S.] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Sch Med, Boston, MA 02115 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu FU Novartis; NIH [R01 CA130876-02] FX We thank Nam Doo Kim for assistance with molecular modeling and Sara Buhrlage for critical reading of the manuscript. We acknowledge research funding from Novartis and NIH (R01 CA130876-02). NR 19 TC 3 Z9 3 U1 0 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2012 VL 22 IS 16 BP 5297 EP 5302 DI 10.1016/j.bmcl.2012.06.036 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 981JJ UT WOS:000306962800028 PM 22819762 ER PT J AU O'Horo, JC Thompson, D Safdar, N AF O'Horo, John C. Thompson, Deb Safdar, Nasia TI Is the Gram Stain Useful in the Microbiologic Diagnosis of VAP? A Meta-analysis SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID VENTILATOR-ASSOCIATED PNEUMONIA; BRONCHOALVEOLAR LAVAGE FLUID; APPROPRIATE ANTIBIOTIC-THERAPY; PROTECTED SPECIMEN BRUSH; INTRACELLULAR ORGANISMS; RANDOMIZED-TRIAL; PREDICTIVE-VALUE; MICROSCOPIC EXAMINATION; NOSOCOMIAL PNEUMONIA; INJURED PATIENTS AB In a meta-analysis examining respiratory specimen Gram stain for diagnosis of ventilator-associated pneumonia, absence of bacteria on Gram stain had a high negative predictive value, but a positive Gram stain correlated poorly with organisms recovered in culture. Rapid and accurate diagnosis of ventilator-associated pneumonia (VAP) is a major challenge and no generally accepted gold standard exists for VAP diagnosis. We conducted a meta-analysis to examine the role of respiratory specimen Gram stain to diagnose VAP, and the correlation with final culture results. In 21 studies, pooled sensitivity of Gram stain for VAP was 0.79 (95% confidence interval [CI],.77-0.81; P < .0001) and specificity was 0.75 (95% CI,.73-.78; P < .0001). Negative predictive value of Gram stain for a VAP prevalence of 20%-30% was 91%, suggesting that VAP is unlikely with a negative Gram stain but the positive predictive value of Gram stain was only 40%. Pooled kappa was 0.42 for gram-positive organisms and 0.34 for gram-negative organisms, suggesting fair concordance between organisms on Gram stain and recovery by culture. Therefore, a positive Gram stain should not be used to narrow anti-infective therapy until culture results become available. C1 [O'Horo, John C.] Aurora Healthcare Metro, Dept Grad Med Educ, Milwaukee, WI USA. [Thompson, Deb] Infect Dis Associates, Milwaukee, WI USA. [Safdar, Nasia] Univ Wisconsin, Sch Med & Publ Hlth, William S Middleton Mem Vet Hosp, Madison, WI 53706 USA. [Safdar, Nasia] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. RP Safdar, N (reprint author), Hlth Sci Learning Ctr, Sect Infect Dis, MFCB 5221,1685 Highland Ave, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu RI O'Horo, John/A-8787-2013; O'Horo, John/N-8681-2013 OI O'Horo, John/0000-0002-0880-4498; O'Horo, John/0000-0002-0880-4498 NR 52 TC 19 Z9 23 U1 1 U2 27 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2012 VL 55 IS 4 BP 551 EP 561 DI 10.1093/cid/cis512 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 977RQ UT WOS:000306682500014 PM 22677711 ER PT J AU Coutinho, A Roxo, U Epino, H Muganzi, A Dorward, E Pick, B AF Coutinho, Alex Roxo, Uchechi Epino, Henry Muganzi, Alex Dorward, Emily Pick, Billy TI The Expanding Role of Civil Society in the Global HIV/AIDS Response: What Has The President's Emergency Program For AIDS Relief's Role Been? SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE civil society; PEPFAR ID HEALTH SYSTEMS; SCALE-UP; HIV; SERVICES AB Civil society has been part of the HIV/AIDS response from the very beginning of the epidemic, often becoming engaged before national governments. Traditional roles of civil society-advocacy, activism, serving as government watchdog, and acting as community caretaker-have been critical to the response. In addition, civil society organizations (CSOs) play an integral part in providing world-class HIV prevention and treatment services and helping to ensure continuity of care. The President's Emergency Program for AIDS Relief (PEPFAR) has significantly increased the global scale-up of combination antiretroviral therapy reaching for more than 5 million people in developing countries, as well as implementation of effective evidence-based combination prevention approaches. PEPFAR databases in 5 countries and annual reports from a centrally managed initiative were mined and analyzed to determine the numbers and types of CSOs funded by PEPFAR over a 5-year period (2006-2011). Data are also presented from Uganda showing the overall resource growth in CSO working for HIV. Case studies document the evolution of 3 indigenous CSOs that increased the capacity to implement activities with PEPFAR funding. A legacy of PEPFAR has been the growth of civil society to address social and health issues as well as recognition by governments that partnerships with beneficiaries and civil society result in better outcomes. Scale-up of the global response could not have happened without the involvement of civil society and people living with HIV. This game changing partnership to jointly tackle the problems that countries face may well be the greatest benefit emerging from the HIV epidemic. C1 [Coutinho, Alex; Muganzi, Alex] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Roxo, Uchechi; Dorward, Emily; Pick, Billy] US Agcy Int Dev, Washington, DC 20523 USA. [Epino, Henry] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Epino, Henry] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. RP Coutinho, A (reprint author), Makerere Univ, Infect Dis Inst, POB 22418, Kampala, Uganda. EM acoutinho@idi.co.ug FU PEPRAR FX AC and AM both work for The Infectious Diseases Institute, which receives funding from PEPRAR. NR 26 TC 5 Z9 5 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2012 VL 60 SU 3 BP S152 EP S157 DI 10.1097/QAI.0b013e31825d0383 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TR UT WOS:000306994100015 PM 22797737 ER PT J AU Zhi, L Ustyugova, IV Chen, XY Zhang, Q Wu, MX AF Zhi, Liang Ustyugova, Irina V. Chen, Xinyuan Zhang, Qi Wu, Mei X. TI Enhanced Th17 Differentiation and Aggravated Arthritis in IEX-1-Deficient Mice by Mitochondrial Reactive Oxygen Species-Mediated Signaling SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HELPER T-CELLS; NF-KAPPA-B; OXIDATIVE STRESS; RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSES; GLUCOSE-OXIDASE; ROR-GAMMA; INTERLEUKIN-17 AB CD4(+) Th1 and Th17 cells both can cause autoimmune diseases, either alone or collaboratively, if left unchecked. However, what determines the dominant Th effector phenotype in a specific autoimmune disease remains poorly understood. Our present investigation shows that null mutation of IEX-1 promotes differentiation of Th17 cells but compromises the survival of Th1 cells. The differential effect gave rise to a greater number of Th17 cells, a higher level of IL-17 production, and more severe arthritis in IEX-1 knockout mice than in wild-type mice after immunizations with collagen. IEX-1 deficiency-facilitated Th17 cell differentiation was mediated by the increased formation of reactive oxygen species (ROS) at mitochondria following T cell activation, as suggested by marked inhibition of Th17 induction with ROS scavenger N-acetylcysteine or mitoquinone, a specific inhibitor for mitochondrial ROS production. Mitochondrial ROS augmented the expression of B cell-activating transcription factor, which may contribute to increased IL-17 production in the absence of IEX-1, in light of its importance in IL-17 transcription. The results demonstrate that mitochondrial ROS contribute significantly to the dominant Th effector phenotype in autoimmunity in addition to the cytokine milieu. The Journal of Immunology, 2012, 189: 1639-1647. C1 [Zhi, Liang; Ustyugova, Irina V.; Chen, Xinyuan; Zhang, Qi; Wu, Mei X.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Boston, MA 02114 USA. [Zhi, Liang; Ustyugova, Irina V.; Chen, Xinyuan; Zhang, Qi; Wu, Mei X.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Wu, Mei X.] Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA. RP Wu, MX (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Edwards 222,50 Blossom St, Boston, MA 02114 USA. EM mwu2@partners.org FU National Institutes of Health [AI050822, AI070785]; Senior Research Award from the Crohn's and Colitis Foundation of America FX This work was supported in part by National Institutes of Health Grants AI050822 and AI070785 and a Senior Research Award from the Crohn's and Colitis Foundation of America (to M.X.W.). NR 52 TC 19 Z9 21 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2012 VL 189 IS 4 BP 1639 EP 1647 DI 10.4049/jimmunol.1200528 PG 9 WC Immunology SC Immunology GA 984TW UT WOS:000307216000015 PM 22798682 ER PT J AU Lin, T Sammy, F Yang, H Thundivalappil, S Hellman, J Tracey, KJ Warren, HS AF Lin, Tian Sammy, Fatima Yang, Huan Thundivalappil, Sujatha Hellman, Judith Tracey, Kevin J. Warren, H. Shaw TI Identification of Hemopexin as an Anti-Inflammatory Factor That Inhibits Synergy of Hemoglobin with HMGB1 in Sterile and Infectious Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INNATE IMMUNE-RESPONSE; DENDRITIC CELLS; BIOLOGICAL-ACTIVITY; PRETERM INFANTS; HEME; TRANSFUSION; PROTEIN; LPS; ENDOTOXIN; TOLL-LIKE-RECEPTOR-4 AB Hemoglobin is released from lysed RBCs in numerous clinical settings. High mobility group box 1 (HMGB1) is a nuclear and cytosolic DNA-binding protein released from injured cells that has been shown to play an important role in inducing inflammation. Because both of these endogenous molecules are frequently present in sites of necrosis and inflammation, we studied their interaction on the activation of macrophages. We report in this article that hemoglobin and HMGB1 synergize to activate mouse macrophages to release significantly increased proinflammatory cytokines. Addition of microbial ligands that activate through TLR2 or TLR4 resulted in further significant increases, in a "three-way" synergy between endogenous and microbial ligands. The synergy was strongly suppressed by hemopexin (Hx), an endogenous heme-binding plasma protein. The findings suggest that hemoglobin may play an important role in sterile and infectious inflammation, and that endogenous Hx can modulate this response. Administration of Hx may be beneficial in clinical settings characterized by elevated extracellular hemoglobin and HMGB1. The Journal of Immunology, 2012, 189: 2017-2022. C1 [Lin, Tian; Sammy, Fatima; Thundivalappil, Sujatha; Warren, H. Shaw] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02129 USA. [Yang, Huan; Tracey, Kevin J.] Feinstein Inst Med Res, Lab Biomed Sci, Manhasset, NY 11030 USA. [Hellman, Judith] Univ Calif San Francisco, Div Crit Care Med, Dept Anesthesia, San Francisco, CA 94143 USA. RP Lin, T (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, Room 5234,149 13th St, Boston, MA 02129 USA. EM tlin7@partners.org OI Tracey, Kevin J/0000-0003-1884-6314 FU Shriners Hospital for Crippled Children [8720]; National Institutes of Health [AI059010, GM59694, GM62508, GM098446]; Defense Advanced Research Planning Agency [W911NF-10-1-0271] FX This work was supported by the Shriners Hospital for Crippled Children (Grant 8720), the National Institutes of Health (Grants AI059010 and GM59694 to H.S.W., Grant GM62508 to K.J.T., and Grant GM098446 to J.H.), and the Defense Advanced Research Planning Agency (Grant W911NF-10-1-0271 to H.S.W.). NR 40 TC 25 Z9 27 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2012 VL 189 IS 4 BP 2017 EP 2022 DI 10.4049/jimmunol.1103623 PG 6 WC Immunology SC Immunology GA 984TW UT WOS:000307216000055 PM 22772444 ER PT J AU Simoni, JM Huh, D Wilson, IB Shen, J Goggin, K Reynolds, NR Remien, RH Rosen, MI Bangsberg, DR Liu, HH AF Simoni, Jane M. Huh, David Wilson, Ira B. Shen, Jie Goggin, Kathy Reynolds, Nancy R. Remien, Robert H. Rosen, Marc I. Bangsberg, David R. Liu, Honghu TI Racial/Ethnic Disparities in ART Adherence in the United States: Findings From the MACH14 Study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV/AIDS; race/ethnicity; antiretroviral treatment; medication adherence ID ACTIVE ANTIRETROVIRAL THERAPY; MULTICENTER AIDS COHORT; HIV-INFECTED PATIENTS; HEALTH LITERACY; DRUG-USERS; DEPRESSION; SAMPLE; CARE; MEN; DISCRIMINATION AB Background: Minority race/ethnicity is generally associated with antiretroviral therapy nonadherence in US-based studies. Limitations of the existing literature include small samples, subjective adherence measures, and inadequate control for potential confounders such as mental health and substance use, which have been consistently associated with poorer adherence. Methods: Individual-level data were pooled from 13 US-based studies employing electronic drug monitoring to assess adherence. Adherence was operationalized as percent of prescribed doses taken from the first 12 (monthly) waves of data in each study. Depression symptoms were aggregated from several widely used assessments, and substance use was operationalized as any use of cocaine/stimulants, heroin/opiates, ecstasy, hallucinogens, or sedatives in the 30-365 days preceding baseline. Results: The final analytic sample of 1809 participants ranged in age from 18 to 72 years and was 67% male. Participants were 53% African American, 14% Latino, and 34% White. In a logistic regression adjusting for age, gender, income, education, and site, race/ethnicity was significantly associated with adherence (P, 0.001) and persisted in a model that also controlled for depression and substance use (P < 0.001), with African Americans having significantly lower adherence than Latinos [odds ratio (OR) = 0.72, P = 0.04] and whites (OR = 0.60, P < 0.001). Adherence did not differ between whites and Latinos (OR = 0.84, P = 0.27). Conclusions: Racial/ethnic differences in demographics, depression, and substance abuse do not explain the lower level of antiretroviral therapy adherence in African Americans observed in our sample. Further research is needed to explain the persistent disparity and might examine factors such as mistrust of providers, health literacy, and inequities in the health care system. C1 [Simoni, Jane M.; Huh, David; Bangsberg, David R.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Wilson, Ira B.] Brown Univ, Alpert Med Sch, Dept Hlth Serv Policy & Practice, Providence, RI 02912 USA. [Shen, Jie] Univ Calif Los Angeles, Sch Dent, Div Publ Hlth & Community Dent, Los Angeles, CA 90024 USA. [Goggin, Kathy] Univ Missouri, Dept Psychol, Kansas City, MO 64110 USA. [Reynolds, Nancy R.] Yale Univ, Sch Nursing, New Haven, CT 06536 USA. [Remien, Robert H.] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. [Rosen, Marc I.] Yale Univ, Sch Med, West Haven, CT 06516 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA 02138 USA. [Liu, Honghu] Univ Calif Los Angeles, Dept Med, Div Publ Hlth & Community Dent, Los Angeles, CA 90024 USA. [Liu, Honghu] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. RP Simoni, JM (reprint author), Univ Washington, Dept Psychol, Box 351525, Seattle, WA 98195 USA. EM jsimoni@uw.edu RI Wilson, Ira/F-9190-2016; OI Wilson, Ira/0000-0002-0246-738X; Simoni, Jane/0000-0002-8711-1576 FU National Institute of Mental Health (NIMH), Office on AIDS [R01MH078773]; [R01DA11869]; [R01MH54907]; [R01NR04749]; [R01MH68197]; [R01DA13826]; [K23MH01862]; [R01MH01584]; [R01AI41413]; [R01 MH61173]; [NIH/NIAID AI38858]; [AI069419]; [K02DA017277]; [R01DA15215]; [NIMH P01MH49548]; [R01MH58986]; [R01MH61695]; [CC99-SD003]; [CC02-SD-003]; [R01DA015679] FX Supported by the multisite adherence collaboration in HIV (MACH14) grant R01MH078773 from the National Institute of Mental Health (NIMH), Office on AIDS. The original grants of individual participating studies are: R01DA11869, R01MH54907, R01NR04749, R01NR04749, R01MH68197, R01DA13826, K23MH01862, R01MH01584, R01AI41413, R01 MH61173, NIH/NIAID AI38858, AI069419, K02DA017277, R01DA15215, NIMH P01MH49548, R01MH58986, R01MH61695, CC99-SD003, CC02-SD-003, and R01DA015679. NR 43 TC 44 Z9 44 U1 2 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2012 VL 60 IS 5 BP 466 EP 472 DI 10.1097/QAI.0b013e31825db0bd PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TV UT WOS:000306994500006 PM 22595873 ER PT J AU Hempel, S Miles, JNV Shekelle, PG AF Hempel, Susanne Miles, Jeremy N. V. Shekelle, Paul G. TI Probiotics for Antibiotic-Associated Diarrhea Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID THERAPY; BLIND C1 [Hempel, Susanne] RAND Hlth, So Calif Evidence Based Practice Ctr, Santa Monica, CA USA. [Miles, Jeremy N. V.] RAND Corp, Santa Monica, CA USA. [Shekelle, Paul G.] W Los Angeles VA Med Ctr, Los Angeles, CA USA. RP Hempel, S (reprint author), RAND Hlth, So Calif Evidence Based Practice Ctr, Santa Monica, CA USA. EM Susanne_hempel@rand.org NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 15 PY 2012 VL 308 IS 7 BP 665 EP 666 DI 10.1001/jama.2012.8738 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 988NC UT WOS:000307496700013 ER PT J AU Monson, CM Fredman, SJ Macdonald, A Pukay-Martin, ND Resick, PA Schnurr, PP AF Monson, Candice M. Fredman, Steffany J. Macdonald, Alexandra Pukay-Martin, Nicole D. Resick, Patricia A. Schnurr, Paula P. TI Effect of Cognitive-Behavioral Couple Therapy for PTSD A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PSYCHOTHERAPY; METAANALYSIS; CLINICIAN; SYMPTOMS; MARRIAGE; QUALITY; SCALES AB Context Posttraumatic stress disorder (PTSD) is a prevalent condition associated with intimate relationsh