FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Stuart, GL Shorey, RC Moore, TM Ramsey, SE Kahler, CW O'Farrell, TJ Strong, DR Temple, JR Monti, PM AF Stuart, Gregory L. Shorey, Ryan C. Moore, Todd M. Ramsey, Susan E. Kahler, Christopher W. O'Farrell, Timothy J. Strong, David R. Temple, Jeff R. Monti, Peter M. TI Randomized clinical trial examining the incremental efficacy of a 90-minute motivational alcohol intervention as an adjunct to standard batterer intervention for men SO ADDICTION LA English DT Article DE Batterer intervention; brief alcohol intervention; intimate partner violence; motivational interviewing; partner abuse; randomized clinical trial; treatment outcome ID INTIMATE PARTNER VIOLENCE; SUBSTANCE USE; METAANALYSIS; AGGRESSION; CONSUMPTION AB Aims The efficacy of batterer intervention programs to reduce intimate partner violence (IPV) is questionable, with individuals with alcohol problems particularly unlikely to benefit. We examined whether adding adjunctive alcohol intervention to batterer intervention reduced the likelihood of substance use and violence relative to batterer intervention alone. Design Randomized clinical trial. Setting Batterer intervention programs in Rhode Island, USA. Participants A total of 252 hazardous drinking men in batterer intervention programs. Participants were randomized to receive 40 hours of standard batterer program (SBP) or the SBP plus a 90-minute alcohol intervention (SBP+BAI). None withdrew due to adverse effects. Data were collected at baseline, 3-, 6- and 12-month follow-up, with follow-up rates of 95, 89 and 82%, respectively. Measurements Substance use was measured with a well-validated calendar-assisted interview. Violence was measured with a validated questionnaire. Arrest records were obtained for all participants. The primary substance use outcome was drinks per drinking day (DPDD) and the primary violence outcome was frequency of any physical IPV. Findings Relative to SBP alone, men receiving SBP+BAI reported consuming fewer DPDD at 3-month follow-up [B=-1.36, 95% confidence interval (CI):-2.65, -0.04, P=0.04] but not 6- or 12-month follow-up. In secondary analyses, men receiving SBP+BAI reported significantly greater abstinence at 3- (B=0.09, 95% CI:0.03, 0.14, P=0.002) and 6-month (B=0.06, 95% CI:0.01, 0.11, P=0.01) follow-up but not 12-month follow-up. There were no significant differences in physical IPV between men receiving SBP and men receiving SBP+BAI. In secondary analyses, men receiving SBP+BAI reported less severe physical aggression at 3-month (IRR=0.18, 95% CI:0.05, 0.65, P=0.009) but not 6- or 12-month follow-up. Men receiving SBP+BAI reported less severe psychological aggression (B=-1.24, 95% CI:-2.47, -0.02, P=0.04) and fewer injuries to partners at 3- and 6-month follow-up (IRR=0.33, 95% CI:0.12, 0.92, P=0.03), with differences fading by 12 months. Conclusions Men with a history of intimate partner violence and hazardous drinking who received a batterer intervention plus an alcohol intervention showed improved alcohol and violence outcomes initially, but improvements faded by 12 months. C1 [Stuart, Gregory L.; Shorey, Ryan C.; Moore, Todd M.] Univ Tennessee, Knoxville, TN 37996 USA. [Stuart, Gregory L.; Shorey, Ryan C.; Moore, Todd M.] Butler Hosp, Knoxville, TN USA. [Ramsey, Susan E.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Ramsey, Susan E.] Rhode Isl Hosp, Providence, RI USA. [Kahler, Christopher W.; Monti, Peter M.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [O'Farrell, Timothy J.] VA Boston Healthcare Syst, Dept Psychiat, Brockton, MA USA. [O'Farrell, Timothy J.] Harvard Univ, Sch Med, Brockton, MA 02401 USA. [Strong, David R.] Brown Univ, Warren Alpert Med Sch, San Diego, CA USA. [Strong, David R.] Butler Hosp, San Diego, CA USA. [Temple, Jeff R.] UTMB Hlth, Galveston, TX USA. RP Stuart, GL (reprint author), Univ Tennessee, Dept Psychol, 310C Austin Peay Bldg, Knoxville, TN 37996 USA. EM gstuart@utk.edu RI Temple, Jeff/A-7666-2009 OI Temple, Jeff/0000-0003-3193-0510 FU National Institute on Alcohol Abuse and Alcoholism [R01AA014193, K24AA019707, K05AA019681] FX This work was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (R01AA014193 and K24AA019707, Stuart, Principal Investigator; K05AA019681, Monti, Principal Investigator). There were no contractual constraints on publishing. All authors report no competing interests. NR 41 TC 17 Z9 17 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2013 VL 108 IS 8 BP 1376 EP 1384 DI 10.1111/add.12142 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 180SN UT WOS:000321616800005 PM 23414253 ER PT J AU Pine-Abata, H McNeill, A Raw, M Bitton, A Rigotti, N Murray, R AF Pine-Abata, Hembadoon McNeill, Ann Raw, Martin Bitton, Asaf Rigotti, Nancy Murray, Rachael TI A survey of tobacco dependence treatment guidelines in 121 countries SO ADDICTION LA English DT Article DE Article 14; Article 14 guidelines; FCTC; national treatment guidelines; survey; tobacco dependence treatment AB Aims To report progress among Parties to the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) in developing national tobacco treatment guidelines in accordance with FCTC Article 14 guideline recommendations. Design Cross-sectional study. Setting Electronic survey from December 2011 to August 2012; participants were asked to complete either an online or attached Microsoft Word questionnaire. Participants One hundred and sixty-three of the 173 Parties to the FCTC at the time of our survey. Measurements The 51-item questionnaire contained 30 items specifically on guidelines. Questions covered the areas of guidelines writing process, content, key recommendations and other characteristics. Findings One hundred and twenty-one countries (73%) responded. Fifty-three countries (44%) had guidelines, ranging from 75% among high-income countries to 11% among low-income countries. Nearly all guidelines recommended brief advice (93%), intensive specialist support (93%) and medications (96%), while 66% recommended quitlines. Fifty-seven percent had a dissemination strategy, 76% stated funding source and 68% had professional endorsement. Conclusion Fewer than half of the Parties to the WHO FCTC have developed national tobacco treatment guidelines, but, where guidelines exist, they broadly follow FCTC Article 14 guideline recommendations. C1 [Pine-Abata, Hembadoon; Raw, Martin; Murray, Rachael] Univ Nottingham, UK Ctr Tobacco Control Studies, Div Epidemiol & Publ Hlth, Nottingham NG5 1PB, England. [McNeill, Ann] Kings Coll London, UK Ctr Tobacco Control Studies, Inst Psychiat, Natl Addict Ctr, London, England. [Bitton, Asaf] Harvard Univ, Brigham & Womens Hosp, Dept Hlth Care Policy, Div Gen Med,Med Sch, Boston, MA 02115 USA. [Rigotti, Nancy] Harvard Univ, Sch Med, Boston, MA USA. [Rigotti, Nancy] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Div Gen Med, Boston, MA 02114 USA. RP Pine-Abata, H (reprint author), Univ Nottingham, UK Ctr Tobacco Control Studies, Div Epidemiol & Publ Hlth, City Hosp, Clin Sci Bldg, Nottingham NG5 1PB, England. EM mcxhp@nottingham.ac.uk FU University of Nottingham; UK Centre for Tobacco Control Studies (UKCTCS), a centre for public health research excellence; British Heart Foundation; Cancer Research UK; Economic and Social Research Council; Medical Research Council; National Institute of Health Research; Society for the Study of Addiction; Framework Convention Alliance FX This study was funded jointly by the University of Nottingham and the UK Centre for Tobacco Control Studies (UKCTCS), a centre for public health research excellence funded by the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Medical Research Council and the National Institute of Health Research. This funding is gratefully acknowledged. MR's time on this project was funded by the Society for the Study of Addiction and the Framework Convention Alliance, to whom we are extremely grateful. We thank Jacques Le Houezec and Vicky Baldi for translating the questionnaire into French and Spanish respectively. Finally, we sincerely thank the country contacts who completed the survey, and the many other organisations and people who helped us identify them. NR 9 TC 8 Z9 8 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2013 VL 108 IS 8 BP 1470 EP 1475 DI 10.1111/add.12158 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 180SN UT WOS:000321616800017 PM 23437892 ER PT J AU Pine-Abata, H McNeill, A Murray, R Bitton, A Rigotti, N Raw, M AF Pine-Abata, Hembadoon McNeill, Ann Murray, Rachael Bitton, Asaf Rigotti, Nancy Raw, Martin TI A survey of tobacco dependence treatment services in 121 countries SO ADDICTION LA English DT Article DE FCTC; Article 14; Article 14 guidelines; survey; tobacco dependence treatment; treatment systems ID SMOKING-CESSATION SUPPORT; TRIAL; GUIDELINES; CYTISINE; COST AB Aims To report progress among Parties to the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) in developing tobacco dependence treatment systems in accordance with FCTC Article 14 and the Article 14 guidelines recommendations. Design Cross-sectional study. Setting Electronic survey from December 2011 to August 2012. Participants One hundred and sixty-three of the 174 Parties to the FCTC at the time of our survey. Measurements The 51-item questionnaire contained 21 items specifically on treatment systems. Questions covered the availability of basic treatment infrastructure and national cessation support systems. Findings We received responses from 121 (73%) of the 166 countries surveyed. Fewer than half of the countries had national treatment guidelines (n=53, 44%), a government official responsible for tobacco dependence treatment (n=49, 41%), an official national treatment strategy (n=53, 44%) or provided tobacco cessation support for health workers (n=55, 46%). More than half encouraged brief advice in existing health care services (n=68, 56%), while only 44 (36%) had quitlines and only 20 (17%) had a network of treatment support covering the whole country. Low- and middle-income countries had less tobacco dependence treatment provision than high-income countries. Conclusion Most countries, especially low- and middle-income countries, have not yet implemented the recommendations of FCTC Article 14 or the FCTC Article 14 guidelines. C1 [Pine-Abata, Hembadoon; Murray, Rachael; Raw, Martin] Univ Nottingham, UK Ctr Tobacco Control Studies, Div Epidemiol & Publ Hlth, Nottingham NG5 1PB, England. [McNeill, Ann] Kings Coll London, UK Ctr Tobacco Control Studies, Natl Addict Ctr, Inst Psychiat, London, England. [Bitton, Asaf] Harvard Univ, Brigham & Womens Hosp, Div Gen Med, Dept Hlth Care Policy,Med Sch, Boston, MA 02115 USA. [Rigotti, Nancy] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rigotti, Nancy] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Div Gen Med, Boston, MA 02114 USA. RP Pine-Abata, H (reprint author), Univ Nottingham, UK Ctr Tobacco Control Studies, Div Epidemiol & Publ Hlth, City Hosp, Clin Sci Bldg, Nottingham NG5 1PB, England. EM mcxhp@nottingham.ac.uk FU University of Nottingham; UK Centre for Tobacco Control Studies (UKCTCS), a centre for public health research excellence; British Heart Foundation; Cancer Research UK; Economic and Social Research Council; Medical Research Council; National Institute of Health Research; Society for the Study of Addiction; Framework Convention Alliance FX This study was funded jointly by the University of Nottingham and the UK Centre for Tobacco Control Studies (UKCTCS), a centre for public health research excellence which is funded by the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Medical Research Council and the National Institute of Health Research. This funding is gratefully acknowledged. M.R.'s time on this project was funded by the Society for the Study of Addiction and the Framework Convention Alliance, to whom we are extremely grateful. We thank Jacques Le Houezec and Vicky Baldi for translating the questionnaire into French and Spanish, respectively. Finally, we sincerely thank the country contacts who completed the survey, and the many other organizations and people who helped us identify them. NR 27 TC 37 Z9 37 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2013 VL 108 IS 8 BP 1476 EP 1484 DI 10.1111/add.12172 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 180SN UT WOS:000321616800018 PM 23451932 ER PT J AU Mimiaga, MJ Reisner, SL Closson, EF Perry, N Perkovich, B Nguyen, T Trang, NNN Lan, HX Thien, DD Mayer, KH Colby, D AF Mimiaga, Matthew J. Reisner, Sari L. Closson, Elizabeth F. Perry, Nicholas Perkovich, Brandon Thi Nguyen Trang, Nguyen N. N. Lan, Hang X. Dinh Duc Thien Mayer, Kenneth H. Colby, Donn TI Self-perceived HIV risk and the use of risk reduction strategies among men who engage in transactional sex with other men in Ho Chi Minh City, Vietnam SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE HIV; Vietnam; prevention; male sex workers; transactional sex ID PREVENTION; PREVALENCE AB An emerging HIV epidemic can be seen among men who have sex with men (MSM) in Vietnam, with prevalence as high as 18%. Transactional sex represents a risk factor for HIV transmission/acquisition among MSM globally, particularly in urban contexts, but remains largely underinvestigated in Ho Chi Minh City (HCMC), Vietnam. In 2010, 23 MSM who reported exchanging sex for money in the last month completed a brief survey and semistructured qualitative interview at The Life Centre, a non-governmental organization in HCMC, to assess sociodemographics, individual- and structural-level HIV risk factors and explore acceptable future prevention interventions. Participants' mean age was 24 years. Equal proportions of respondents self-identified as heterosexual/straight, homosexual/gay, and bisexual. Participants had a mean of 158 male clients in the past year, with a median of 60 male clients in the past year (interquartile range [IQR]=70) and reported inconsistent condom use and inaccurate perceptions of HIV risk. Nearly half of the sample reported engaging in unprotected anal sex with a male partner in the past 12 months and one-third with a male client. Major themes that emerged for HIV prevention interventions with male sex workers were those that: (1) focused on individual factors (drug and alcohol use, barriers to condom use, knowledge of asymptomatic STIs, enhancement of behavioral risk-reduction skills, and addressing concomitant mental health issues); (2) incorporated interpersonal and relational contexts (led by peer educators, built interpersonal skills, attended to partner type and intimacy dynamics); and (3) considered the exogenous environments in which individual choices/relationships operate (stigma of being MSM in Vietnam, availability of alternative economic opportunities, and varied sexual venues). HIV prevention efforts are needed that address the specific needs of MSM who engage in transactional sex in HCMC. Universally, MSM endorsed HIV prevention interventions, suggesting a need and desire for efforts in this context. C1 [Mimiaga, Matthew J.; Perry, Nicholas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Mimiaga, Matthew J.; Reisner, Sari L.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mimiaga, Matthew J.; Reisner, Sari L.; Closson, Elizabeth F.; Perkovich, Brandon; Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Perkovich, Brandon] Harvard Univ, Cambridge, MA USA. [Thi Nguyen; Colby, Donn] Harvard Med Sch AIDS Initiat Vietnam HAIVN, Ho Chi Minh City, Vietnam. [Trang, Nguyen N. N.; Lan, Hang X.; Dinh Duc Thien] Ctr Promot Qual Life, Life Ctr, Ho Chi Minh City, Vietnam. [Mayer, Kenneth H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Mimiaga, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. EM mmimiaga@partners.org OI colby, donn/0000-0003-3931-5926 FU NCATS NIH HHS [UL1 TR000170]; NCRR NIH HHS [1 UL1 RR 025758-02, UL1 RR025758] NR 16 TC 10 Z9 10 U1 2 U2 10 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD AUG 1 PY 2013 VL 25 IS 8 BP 1039 EP 1044 DI 10.1080/09540121.2012.748873 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 184JU UT WOS:000321886700015 PM 23252673 ER PT J AU Sonnenberg, A AF Sonnenberg, A. TI Review article: historic changes of Helicobacter pylori-associated diseases SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Review ID GASTROESOPHAGEAL-REFLUX DISEASE; PERFORATED PEPTIC-ULCER; COLORECTAL-CANCER; DUODENAL-ULCER; UNITED-STATES; TIME TRENDS; BIRTH-COHORT; HOSPITAL ADMISSIONS; GASTRIC-CANCER; ESOPHAGEAL ADENOCARCINOMA AB BackgroundThe long-term time trends of multiple gastrointestinal diseases are characterised by a striking rise and fall. These temporal changes provide important clues about disease aetiology. AimTo highlight the importance of Helicobacter pylori infection in shaping the temporal trends of many common gastrointestinal diseases. MethodsLiterature review of the time trends associated with common digestive diseases. ResultsThe general trends of gastric ulcer, duodenal ulcer, gastric cancer, colon cancer, rectum cancer have all been shaped by a similar underlying birth-cohort phenomenon. Mortality associated with these diagnoses increased in all generations born during the nineteenth century. It peaked among generations born shortly before the turn of the century and then decreased in all subsequent generations born throughout the twentieth century. These patterns can be observed in the incidence, hospitalisation and mortality data from many different countries. They reflect similar rising and falling trends of H. pylori infection in the general population. Diseases that are inversely associated with H. pylori, such as reflux disease, erosive oesophagitis, Barrett's oesophagus, and oesophageal adenocarcinoma, have seen a striking rise during the recent decline of H. pylori infection. ConclusionThe temporal variations of H. pylori infection have affected the occurrence of gastroenterology's most common disorders. C1 [Sonnenberg, A.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97201 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr, P3 GI,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 105 TC 18 Z9 18 U1 0 U2 9 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 AUG PY 2013 VL 38 IS 4 BP 329 EP 342 DI 10.1111/apt.12380 PG 14 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 182VU UT WOS:000321773700001 PM 23786250 ER PT J AU Monach, PA Warner, RL Tomasson, G Specks, U Stone, JH Ding, L Fervenza, FC Fessler, BJ Hoffman, GS Ikle, D Kallenberg, CGM Krischer, J Langford, CA Mueller, M Seo, P St Clair, EW Spiera, R Tchao, N Ytterberg, SR Johnson, KJ Merkel, PA AF Monach, Paul A. Warner, Roscoe L. Tomasson, Gunnar Specks, Ulrich Stone, John H. Ding, Linna Fervenza, Fernando C. Fessler, Barri J. Hoffman, Gary S. Ikle, David Kallenberg, Cees G. M. Krischer, Jeffrey Langford, Carol A. Mueller, Mark Seo, Philip St Clair, E. William Spiera, Robert Tchao, Nadia Ytterberg, Steven R. Johnson, Kent J. Merkel, Peter A. TI Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article DE Autoimmune Diseases; Chemokines; Cytokines ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; SOLUBLE ADHESION MOLECULES; ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; C-REACTIVE PROTEIN; B-CELL CHEMOKINE; WEGENERS-GRANULOMATOSIS; FOLLOW-UP; E-SELECTIN; MATRIX METALLOPROTEINASES; ELEVATED PRODUCTION AB Objective To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation. Methods Twenty-eight serum proteins representing diverse aspects of the biology of AAV were measured before and 6months after treatment in a large clinical trial of AAV. Subjects (n=186) enrolled in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were studied. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were available for comparison. The primary outcome was the ability of markers to distinguish severe AAV (Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS/WG)3 at screening) from remission (BVAS/WG=0 at month 6), using areas under receiver operating characteristic (ROC) curve (AUC). Results All subjects had severe active vasculitis (median BVAS/WG=8) at screening. In the 137 subjects in remission at month 6, 24 of the 28 markers showed significant declines. ROC analysis indicated that levels of CXCL13 (BCA-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinases-1 (TIMP-1) best discriminated active AAV from remission (AUC>0.8) and from healthy controls (AUC>0.9). Correlations among these markers and with ESR or CRP were low. Conclusions Many markers are elevated in severe active AAV and decline with treatment, but CXCL13, MMP-3 and TIMP-1 distinguish active AAV from remission better than the other markers studied, including ESR and CRP. These proteins are particularly promising candidates for future studies to address unmet needs in the assessment of patients with AAV. C1 [Monach, Paul A.; Tomasson, Gunnar; Merkel, Peter A.] Boston Univ, Sch Med, Vasculitis Ctr, Rheumatol Sect, Boston, MA USA. [Monach, Paul A.; Tomasson, Gunnar; Merkel, Peter A.] Boston Univ, Sch Med, Clin Epidemiol Unit, Boston, MA USA. [Warner, Roscoe L.; Johnson, Kent J.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Specks, Ulrich] Mayo Clin, Coll Med, Div Pulm & Crit Care Med, Rochester, MN USA. [Stone, John H.] Massachusetts Gen Hosp, Rheumatol Unit, Boston, MA 02114 USA. [Ding, Linna] Natl Inst Allergy & Infect Dis, Bethesda, MD USA. [Fervenza, Fernando C.] Mayo Clin, Coll Med, Div Nephrol & Hypertens, Rochester, MN USA. [Fessler, Barri J.] Univ Alabama, Div Clin Immunol & Rheumatol, Birmingham, MN USA. [Hoffman, Gary S.] Cleveland Clin, Ctr Vasculitis Care & Res, Cleveland, OH 44106 USA. [Ikle, David] Rho, Chapel Hill, NC USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, Groningen, Netherlands. [Krischer, Jeffrey] Univ S Florida, Coll Med, Dept Pediat, Tampa, FL 33612 USA. [Mueller, Mark] Immune Tolerance Network, Bethesda, MD USA. [Seo, Philip] Johns Hopkins Univ, Div Rheumatol, Baltimore, MD USA. [St Clair, E. William] Duke Univ, Div Rheumatol & Immunol, Durham, NC USA. [Spiera, Robert] Hosp Special Surg, Div Rheumatol, New York, NY 10021 USA. [Tchao, Nadia] Immune Tolerance Network, San Francisco, CA USA. [Ytterberg, Steven R.] Mayo Clin, Coll Med, Div Rheumatol, Rochester, MN USA. [Merkel, Peter A.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. RP Merkel, PA (reprint author), Univ Penn, Div Rheumatol, 8th Floor Penn Tower,3400 Spruce St, Philadelphia, PA 19104 USA. EM pmerkel@upenn.edu FU Vasculitis Clinical Research Consortium; National Institute of Arthritis and Musculoskeletal and Skin Diseases [U54AR057319, RC1 AR058303, P60 AR047785]; National Center for Research Resources [U54 RR019497]; National Institute of Neurological Disorders and Stroke [NS064808]; Office of Rare Diseases Research; Immune Tolerance Network (NIH) [N01 AI15416]; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation; Genentech; Biogen Idec; National Center for Research Resources (NCRR), at Johns Hopkins University [RR024150-01]; NCRR [RR025005]; Boston University; National Institutes of Health [M01 RR00533]; Arthritis Foundation; [K24 AR049185]; [K23 AR052820]; [K24 AR02224] FX This work was sponsored by the Vasculitis Clinical Research Consortium which has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319, RC1 AR058303 and P60 AR047785), the National Center for Research Resources (U54 RR019497), the National Institute of Neurological Disorders and Stroke (NS064808), and the Office of Rare Diseases Research. The RAVE Trial was performed with the support of the Immune Tolerance Network (NIH Contract N01 AI15416), an international clinical research consortium supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation (see online appendix for the list of all members of the RAVE-ITN Research Group). Genentech and Biogen Idec provided the study medications and partial funding. At the Mayo Clinic and Foundation, the trial was supported by a Clinical and Translational Science Award from the National Center for Research Resources (NCRR) (RR024150-01), at Johns Hopkins University, by grants from the NCRR (RR025005) and career development awards (K24 AR049185 to JHS, and K23 AR052820 to PS), and at Boston University, by a Clinical and Translational Science Award (RR 025771), grants from the National Institutes of Health (M01 RR00533) and a career development award (K24 AR02224 to Dr Peter A Merkel). Dr Paul A Monach was supported by an Arthritis Investigator Award from the Arthritis Foundation. NR 54 TC 22 Z9 24 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD AUG PY 2013 VL 72 IS 8 BP 1342 EP 1350 DI 10.1136/annrheumdis-2012-201981 PG 9 WC Rheumatology SC Rheumatology GA 176WW UT WOS:000321338400015 PM 22975753 ER PT J AU Kwak, YG Jacoby, GA Hooper, DC AF Kwak, Yee Gyung Jacoby, George A. Hooper, David C. TI Induction of Plasmid-Carried qnrS1 in Escherichia coli by Naturally Occurring Quinolones and Quorum-Sensing Signal Molecules SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PSEUDOMONAS-AERUGINOSA; SALMONELLA-ENTERICA; VIBRIO-SPLENDIDUS; RESISTANCE; SYSTEM; COMMUNICATION; DETERMINANTS; AUTOINDUCER; EXPRESSION; MECHANISM AB Naturally occurring quinolone and quinolone-like compounds, such as quinine, 2-hydroxyquinoline, 4-hydroxyquinoline, and 2-heptyl-3-hydroxy-4(1H)-quinolone, increased expression of qnrS1 in Escherichia coli 2.3- to 11.2-fold, similar to the synthetic quinolone ciprofloxacin. In contrast, chromosomal qnrVS1 of Vibrio splendidus was not induced by these compounds. Molecules associated with quorum sensing, such as N-3-hydroxybutyryl-homoserine lactone (HSL), N-hexanoyl-HSL, and N-3-(oxododecanoyl)-HSL, did not show an induction effect on either qnrS1 or qnrVS1 at the tested concentrations. C1 [Kwak, Yee Gyung; Hooper, David C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Kwak, Yee Gyung; Hooper, David C.] Harvard Univ, Sch Med, Boston, MA USA. [Kwak, Yee Gyung] Inje Univ, Coll Med, Pusan, South Korea. [Jacoby, George A.] Lahey Hosp & Med Ctr, Burlington, MA USA. RP Hooper, DC (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM dhooper@partners.org OI Kwak, Yee Gyung/0000-0002-4713-8045 FU Inje Research and Scholarship Foundation of the Inje University College of Medicine; National Institutes of Health, U.S. Public Health Service [R01 AI057576] FX This work was supported by the Inje Research and Scholarship Foundation (to Y.G.K. in 2011) of the Inje University College of Medicine and by grant R01 AI057576 (to D.C.H. and G.A.J.) from the National Institutes of Health, U.S. Public Health Service. NR 23 TC 5 Z9 5 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2013 VL 57 IS 8 BP 4031 EP 4034 DI 10.1128/AAC.00337-13 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 182RO UT WOS:000321761800074 PM 23689721 ER PT J AU Beard, CJ Travis, LB Chen, MH Arvold, ND Nguyen, PL Martin, NE Kuban, DA Ng, AK Hoffman, KE AF Beard, Clair J. Travis, Lois B. Chen, Ming-Hui Arvold, Nils D. Nguyen, Paul L. Martin, Neil E. Kuban, Deborah A. Ng, Andrea K. Hoffman, Karen E. TI Outcomes in stage I testicular seminoma: A population-based study of 9193 patients SO CANCER LA English DT Article DE testicular cancer; seminoma; radiotherapy; survivor; second malignant neoplasm; cardiovascular disease; suicide; all-cause mortality ID LONG-TERM SURVIVORS; GERM-CELL TUMORS; CARDIOVASCULAR-DISEASE; CANCER-PATIENTS; 2ND CANCERS; MORTALITY; RADIOTHERAPY; LIFE; SURVEILLANCE; CHEMOTHERAPY AB BACKGROUND Few studies have quantified temporal patterns of cause-specific mortality in contemporary cohorts of men with early-stage seminoma. Given that several management strategies can be applied in these patients, each resulting in excellent long-term survival, it is important to evaluate associated long-term sequelae. In particular, data describing long-term risks of cardiovascular disease (CVD) are conflicting. METHODS We identified 9193 men diagnosed with stage I seminoma (ages 15-70 years) in the population-based SEER registries (1973-2001). We calculated survival estimates, standardized mortality ratios (SMRs), and adjusted hazard rates (AHRs). RESULTS During 121,037 person-years of follow-up (median, 12.3 years), 915 deaths (SMR, 1.23; 95% CI, 1.16-1.32) were reported, with significant excesses for suicide (n=39; SMR, 1.45; 95% CI, 1.06-1.98), infection (n=58; SMR, 2.32; 95% CI, 1.80-3.00), and second malignant neoplasms (SMNs; n=291; SMR, 1.81; 95% CI, 1.61-2.03), but not CVD (n=201; SMR, 0.91; 95% CI, 0.80-1.05). After radiotherapy (78% patients), CVD deaths were not increased (n=158; SMR, 0.89; 95% CI, 0.76-1.04), in contrast to SMN deaths (n=246; SMR, 1.89; 95% CI, 1.67-2.14). SMN mortality was higher among patients administered radiotherapy than among those not given radiotherapy (AHR, 1.36; 95% CI, 0.99-1.88; P=.059), with a cumulative 15-year risk of 2.64% (95% CI, 2.19-3.16). Suicide, although rare, accounted for 1 in 230 deaths. CONCLUSIONS Modern radiotherapy as applied in this large population-based study is not associated with excess CVD mortality. Although increased all-cause mortality exists, cumulative SMN risk is considerably smaller than reported in historical series, but additional follow-up will be required to characterize long-term trends. The increased risk of suicide, previously unreported in men with stage I seminoma, requires confirmation. Cancer 2013;119:2771-2777. (c) 2013 American Cancer Society. C1 [Beard, Clair J.; Arvold, Nils D.; Nguyen, Paul L.; Martin, Neil E.; Ng, Andrea K.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Travis, Lois B.] Univ Rochester, Med Ctr, Dept Radiat Oncol, Rubin Ctr Canc Survivorship, Rochester, NY 14642 USA. [Travis, Lois B.] Univ Rochester, Med Ctr, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Kuban, Deborah A.; Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. RP Beard, CJ (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM cbeard@lroc.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU National Cancer Institute [R01-CA157823-01A1-NCI] FX Dr. Travis was supported by National Cancer Institute R01-CA157823-01A1-NCI. NR 38 TC 22 Z9 22 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 1 PY 2013 VL 119 IS 15 BP 2771 EP 2777 DI 10.1002/cncr.28086 PG 7 WC Oncology SC Oncology GA 185OB UT WOS:000321977500017 PM 23633409 ER PT J AU de Groot, NL van Haalen, HGM Spiegel, BMR Laine, L Lanas, A Focks, JJ Siersema, PD van Oijen, MGH AF de Groot, N. L. van Haalen, H. G. M. Spiegel, B. M. R. Laine, L. Lanas, A. Focks, J. Jaspers Siersema, P. D. van Oijen, M. G. H. TI Gastroprotection in Low-Dose Aspirin Users for Primary and Secondary Prevention of ACS: Results of a Cost-Effectiveness Analysis Including Compliance SO CARDIOVASCULAR DRUGS AND THERAPY LA English DT Article DE Cost-effectiveness; QALY; Aspirin; Proton pump inhibitor; Dyspepsia; Gastrointestinal bleeding; Compliance ID PROTON PUMP INHIBITORS; CORONARY-ARTERY-DISEASE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ST-SEGMENT ELEVATION; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIALS; ISCHEMIC-HEART-DISEASE; LONG-TERM ADHERENCE; ESOMEPRAZOLE 20 MG; ACETYLSALICYLIC-ACID AB Low-dose aspirin (ASA) increases the risk of upper gastrointestinal (GI) complications. Proton pump inhibitors (PPIs) reduce these upper GI side effects, yet patient compliance to PPIs is low. We determined the cost-effectiveness of gastroprotective strategies in low-dose ASA users considering ASA and PPI compliance. Using a Markov model we compared four strategies: no medication, ASA monotherapy, ASA+PPI co-therapy and a fixed combination of ASA and PPI for primary and secondary prevention of ACS. The risk of acute coronary syndrome (ACS), upper GI bleeding and dyspepsia was modeled as a function of compliance and the relative risk of developing these events while using medication. Costs, quality adjusted life years and number of ACS events were evaluated, applying a variable risk of upper GI bleeding. Probabilistic sensitivity analyses were performed. For our base case patients using ASA for primary prevention of ACS no medication was superior to ASA monotherapy. PPI co-therapy was cost-effective (incremental cost-effectiveness ratio [ICER] a,not sign10,314) compared to no medication. In secondary prevention, PPI co-therapy was cost-effective (ICER a,not sign563) while the fixed combination yielded an ICER < a,not sign20,000 only in a population with elevated risk for upper GI bleeding or moderate PPI compliance. PPI co-therapy had the highest probability to be cost-effective in all scenarios. PPI use lowered the overall number of ACS. Considering compliance, PPI co-therapy is likely to be cost-effective in patients taking low dose ASA for primary and secondary prevention of ACS, given low PPI prices. In secondary prevention, a fixed combination seems cost-effective in patients with elevated risk for upper GI bleeding or in those with moderate PPI compliance. Both strategies reduced the number of ACS compared to ASA monotherapy. C1 [de Groot, N. L.; van Haalen, H. G. M.; Siersema, P. D.; van Oijen, M. G. H.] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, NL-3508 GA Utrecht, Netherlands. [Spiegel, B. M. R.] Vet Affairs Greater Los Angeles Hlth Care Syst, Div Gastroenterol & Hepatol, Los Angeles, CA USA. [Spiegel, B. M. R.; van Oijen, M. G. H.] Univ Calif Los Angeles, Vet Affairs Ctr Outcomes Res & Educ CORE, Los Angeles, CA USA. [Laine, L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Lanas, A.] Univ Zaragoza, Sch Med, Aragon Hlth Res Inst IIS Aragon, CIBERehd, Zaragoza, Spain. [Focks, J. Jaspers] Radboud Univ Nijmegen, Med Ctr, Dept Cardiol, NL-6525 ED Nijmegen, Netherlands. RP de Groot, NL (reprint author), Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, POB 85500 Internal Code F02-618, NL-3508 GA Utrecht, Netherlands. EM n.l.degroot-3@umcutrecht.nl FU AstraZeneca FX This study was sponsored by an unrestricted educational grant from AstraZeneca. NR 68 TC 6 Z9 6 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-3206 J9 CARDIOVASC DRUG THER JI Cardiovasc. Drugs Ther. PD AUG PY 2013 VL 27 IS 4 BP 341 EP 357 DI 10.1007/s10557-013-6448-y PG 17 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 183AS UT WOS:000321786600010 PM 23417566 ER PT J AU Calderone, DJ Hoptman, MJ Martinez, A Nair-Collins, S Mauro, CJ Bar, M Javitt, DC Butler, PD AF Calderone, Daniel J. Hoptman, Matthew J. Martinez, Antgona Nair-Collins, Sangeeta Mauro, Cristina J. Bar, Moshe Javitt, Daniel C. Butler, Pamela D. TI Contributions of Low and High Spatial Frequency Processing to Impaired Object Recognition Circuitry in Schizophrenia SO CEREBRAL CORTEX LA English DT Article DE cortical circuitry; magnocellular; object recognition; schizophrenia; visual ID LATERAL OCCIPITAL COMPLEX; TOP-DOWN FACILITATION; HUMAN VISUAL-CORTEX; NMDA-RECEPTOR ACTIVITY; PERCEPTUAL ORGANIZATION; HUMAN BRAIN; SENSORY CONTRIBUTIONS; CONTRAST SENSITIVITY; PARVOCELLULAR CONTRIBUTIONS; INFEROTEMPORAL CORTEX AB Patients with schizophrenia exhibit cognitive and sensory impairment, and object recognition deficits have been linked to sensory deficits. The frame and fill model of object recognition posits that low spatial frequency (LSF) information rapidly reaches the prefrontal cortex (PFC) and creates a general shape of an object that feeds back to the ventral temporal cortex to assist object recognition. Visual dysfunction findings in schizophrenia suggest a preferential loss of LSF information. This study used functional magnetic resonance imaging (fMRI) and resting state functional connectivity (RSFC) to investigate the contribution of visual deficits to impaired object framing circuitry in schizophrenia. Participants were shown object stimuli that were intact or contained only LSF or high spatial frequency (HSF) information. For controls, fMRI revealed preferential activation to LSF information in precuneus, superior temporal, and medial and dorsolateral PFC areas, whereas patients showed a preference for HSF information or no preference. RSFC revealed a lack of connectivity between early visual areas and PFC for patients. These results demonstrate impaired processing of LSF information during object recognition in schizophrenia, with patients instead displaying increased processing of HSF information. This is consistent with findings of a preference for local over global visual information in schizophrenia. C1 [Calderone, Daniel J.; Hoptman, Matthew J.; Martinez, Antgona; Nair-Collins, Sangeeta; Mauro, Cristina J.; Javitt, Daniel C.; Butler, Pamela D.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Calderone, Daniel J.; Hoptman, Matthew J.; Butler, Pamela D.] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Calderone, Daniel J.; Hoptman, Matthew J.; Nair-Collins, Sangeeta; Javitt, Daniel C.; Butler, Pamela D.] CUNY, Dept Psychol, New York, NY 10021 USA. [Martinez, Antgona] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Mauro, Cristina J.] Yeshiva Univ, Ferkauf Grad Sch Psychol, Bronx, NY USA. [Bar, Moshe] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr, Charlestown, MA USA. [Bar, Moshe] Bar Ilan Univ, Gonda Ctr Brain Res, IL-52100 Ramat Gan, Israel. [Javitt, Daniel C.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. RP Calderone, DJ (reprint author), 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA. EM dcalderone@nki.rfmh.org RI Hoptman, Matthew/N-1035-2014 OI Hoptman, Matthew/0000-0003-4485-6102 FU National Institutes of Health [RO1 MH084848, R21 MH084031, R37 MH049334, P50 MH086385]; NCRR High End Instrumentation grant [S10 RR022972]; Graduate Center of the City University of New York FX This work was supported by the National Institutes of Health (RO1 MH084848 to P. D. B. and M.J.H., R21 MH084031 to M.J. H., and R37 MH049334 and P50 MH086385 to D.C.J.), and the scanner used in this study was funded in part by S10 RR022972 NCRR High End Instrumentation grant to Craig A. Branch, PhD) and the Graduate Center of the City University of New York (Doctoral Student Research Grant to D.J.C. NR 118 TC 19 Z9 20 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2013 VL 23 IS 8 BP 1849 EP 1858 DI 10.1093/cercor/bhs169 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 182OS UT WOS:000321754200008 PM 22735157 ER PT J AU Kamba, A Lee, IA Mizoguchi, E AF Kamba, A. Lee, I. -A. Mizoguchi, E. TI Potential Association Between TLR4 and Chitinase 3-Like 1 (CHI3L1/YKL-40) Signaling on Colonic Epithelial Cells in Inflammatory Bowel Disease and Colitis-Associated Cancer SO CURRENT MOLECULAR MEDICINE LA English DT Article DE Autoimmunity; chitinase; colitis-associated cancer; mammalian inflammation; microbiota ID TOLL-LIKE RECEPTOR-4; NECROSIS-FACTOR-ALPHA; COLORECTAL-CANCER; NEGATIVE REGULATOR; DROSOPHILA TOLL; GENE-EXPRESSION; INTESTINAL INFLAMMATION; ARTICULAR CHONDROCYTES; ULCERATIVE-COLITIS; HUMAN MACROPHAGES AB Inflammatory bowel disease (IBD) is a group of inflammatory disorders in the small and large intestines. Several studies have proved that persistent and disregulated host/microbial interactions are required for the development of IBD. It is well known that chronic IBD is strongly associated with an increased risk of developing colorectal cancer by 0.5-1% annually, 8-10 years after the initial diagnosis. To detect the tiny dysplasia or early stage of cancer in chronic IBD patients, a tremendous amount of effort is currently directed for improving colonoscopic technology and noninvasive serological marker development. However, there is only a limited amount of data available to understand the exact mechanism of how long term chronic colitis is connected to the development of colorectal tumors. Recently, our group has identified significantly increased expression of chitinase 3-like 1 (CHI3L1) molecule in non-dysplastic mucosa from patients with IBD and remote dysplasia/cancer, compared to patients with IBD without dysplasia or healthy controls. CHI3L1 seems to contribute to the proliferation, migration, and neoplastic progression of colonic epithelial cells (CECs) under inflammatory conditions. Furthermore, the TLR4-mediated intracellular signaling cascade is likely to interact with CHI3L1 signaling in CECs. In this review article, we have concisely summarized the cellular and molecular mechanisms underlining the development of IBD and colitis-associated cancer, with particular focus on the TLR4- and CHI3L1-signaling pathways in CECs. C1 [Kamba, A.; Lee, I. -A.; Mizoguchi, E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA 02114 USA. [Mizoguchi, E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Mizoguchi, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, GRJ 825D,55 Fruit St, Boston, MA 02114 USA. EM emizoguchi@partners.org FU National Institute of Health [DK 80070, DK74454, DK64289, DK43351]; Eli and Edythe L. Broad Medical Foundation; American Gastroenterological Association Foundation; National Research Foundation of Korea Fellowship Award FX We would like to thank Mr. Terry Danford Lott for his excellent assistance in preparing this manuscript. This work has been supported by National Institute of Health (DK 80070, DK74454, DK64289 and DK43351), and grants from the Eli and Edythe L. Broad Medical Foundation and American Gastroenterological Association Foundation to E. Mizoguchi. I.A. Lee has been supported by the National Research Foundation of Korea Fellowship Award. NR 112 TC 8 Z9 11 U1 1 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD AUG PY 2013 VL 13 IS 7 BP 1110 EP 1121 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 180UJ UT WOS:000321623900006 PM 23170831 ER PT J AU Cotman, SL Karaa, A Staropoli, JF Sims, KB AF Cotman, Susan L. Karaa, Amel Staropoli, John F. Sims, Katherine B. TI Neuronal Ceroid Lipofuscinosis: Impact of Recent Genetic Advances and Expansion of the Clinicopathologic Spectrum SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Neuronal ceroid lipofuscinosis; NCL; Batten disease; Kufs disease; Parkinson's disease; Parkinsonism; Frontotemporal lobar degeneration; FTLD; Endosome; Lysosome; Lysosomal disease; Subunit c; Saposin; Progranulin; DNAJC5; CSP alpha; CLN6; Cathepsin F; KCTD7; ATP13A2 ID PALMITOYL-PROTEIN THIOESTERASE; PROGRESSIVE MYOCLONIC EPILEPSY; CATHEPSIN-D DEFICIENCY; P-TYPE ATPASE; BATTEN-DISEASE; TRANSMEMBRANE PROTEIN; KUFS-DISEASE; CSP-ALPHA; NEURODEGENERATIVE DISORDER; FRONTOTEMPORAL DEMENTIA AB Neuronal ceroid lipofuscinosis (NCL), first clinically described in 1826 and pathologically defined in the 1960s, refers to a group of disorders mostly diagnosed in the childhood years that involve the accumulation of lysosomal storage material with characteristic ultrastructure and prominent neurodegenerative features including vision loss, seizures, motor and cognitive function deterioration, and often times, psychiatric disturbances. All NCL disorders evidence early morbidity and treatment options are limited to symptomatic and palliative care. While distinct genetic forms of NCL have long been recognized, recent genetic advances are considerably widening the NCL genotypic and phenotypic spectrum, highlighting significant overlap with other neurodegenerative diseases. This review will discuss these recent advances and the expanded potential for increased awareness and new research that will ultimately lead to effective treatments for NCL and related disorders. C1 [Cotman, Susan L.; Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Karaa, Amel] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Staropoli, John F.] Massachusetts Gen Hosp, Dept Pathol, Ctr Human Genet Res, Boston, MA 02114 USA. [Karaa, Amel] Harvard Univ, Sch Med, Clin Genet Program, Boston, MA 02115 USA. RP Cotman, SL (reprint author), Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. EM cotman@helix.mgh.harvard.edu FU NINDS NIH HHS [K08 NS079359, R01 NS073813] NR 93 TC 21 Z9 22 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD AUG PY 2013 VL 13 IS 8 AR 366 DI 10.1007/s11910-013-0366-z PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 188DA UT WOS:000322171000003 PM 23775425 ER PT J AU Mathisen, DJ AF Mathisen, Douglas J. TI Challenging conventional wisdom SO EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY LA English DT Editorial Material DE 'Routine' chest tube; Thoracoscopic; Pulmonary resection C1 Massachusetts Gen Hosp, Dept Gen Thorac Surg, Boston, MA 02114 USA. RP Mathisen, DJ (reprint author), Massachusetts Gen Hosp, Dept Gen Thorac Surg, 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM dmathisen@partners.org NR 1 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1010-7940 EI 1873-734X J9 EUR J CARDIO-THORAC JI Eur. J. Cardio-Thorac. Surg. PD AUG PY 2013 VL 44 IS 2 BP 230 EP 230 DI 10.1093/ejcts/ezs706 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 183PD UT WOS:000321828300020 PM 23324795 ER PT J AU Faje, A Nachtigall, L AF Faje, Alexander Nachtigall, Lisa TI Current treatment options for hyperprolactinemia SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE dopamine agonist; hyperprolactinemia; prolactinoma ID SECRETING PITUITARY-ADENOMAS; ENDOTHELIAL GROWTH-FACTOR; PLASMA PROLACTIN CONCENTRATIONS; METASTATIC BREAST-CANCER; BROMOCRIPTINE-RESISTANT PROLACTINOMAS; SOMATOSTATIN RECEPTOR SUBTYPES; GLYCOSYLATED HUMAN-PROLACTIN; CARDIAC-VALVE REGURGITATION; DOPAMINE AGONIST THERAPY; VALVULAR HEART-DISEASE AB Introduction: Hyperprolactinemia is a prevalent cause of oligo-amenorrhea, and prolactinomas are the most common type of functional pituitary tumor. Untreated hyperprolactinemia can lead to bone loss and impair gonadal function and fertility. Normalization of prolactin improves bone mass and restores gonadal function in a majority of patients. Areas covered: This article contains an overview of hyperprolactinemia with an emphasis on pharmacologic, surgical and radiation treatment options. Discussion focuses on the efficacy and safety of available treatments and comments on new and emerging therapies. Expert opinion: Dopamine agonists, usually cabergoline, remain the primary choice for initial treatment of hyperprolactinemia. Surgery may also be an appropriate alternative in certain circumstances. Monotherapy with dopamine agonists is often successful at controlling prolactin levels and tumor size, but adjunctive treatments may be necessary for resistant or aggressive prolactinomas. C1 [Faje, Alexander] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Nachtigall, Lisa] Massachusetts Gen Hosp, Neuroendocrine Clin Ctr, Boston, MA 02114 USA. RP Nachtigall, L (reprint author), Massachusetts Gen Hosp, Neuroendocrine Clin Ctr, 0 Emerson Pl, Boston, MA 02114 USA. EM lnachtigall@partners.org NR 191 TC 1 Z9 2 U1 3 U2 23 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 EI 1744-7666 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD AUG PY 2013 VL 14 IS 12 BP 1611 EP 1625 DI 10.1517/14656566.2013.806488 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 183OE UT WOS:000321825400005 PM 23738973 ER PT J AU Sullivan, JL Meterko, M Baker, E Stolzmann, K Adjognon, O Ballah, K Parker, VA AF Sullivan, Jennifer L. Meterko, Mark Baker, Errol Stolzmann, Kelly Adjognon, Omonyele Ballah, Konique Parker, Victoria A. TI Reliability and Validity of a Person-Centered Care Staff Survey in Veterans Health Administration Community Living Centers SO GERONTOLOGIST LA English DT Article DE Person-centered care; Long-term care; Measurement ID QUALITY-OF-LIFE; NURSING-HOME; VALIDATION; OUTCOMES; PROGRAM AB Purpose: The objective of this study was to test and revise a staff assessment of person-centered care (PCC) within the Veterans Health Administration (VA) Community Living Center (CLC) setting. Design and Methods: Starting with measures of PCC initially developed through the Better Jobs Better Care (BJBC) study, we conducted cognitive interviews with CLC staff to assess applicability to the VA setting. We then (a) modified the questionnaire based on respondent feedback, (b) administered the revised survey via Internet to 265 staff at 8 VA CLCs, and (c) examined the psychometric properties of the revised 50-item BJBC PCC instrument using multitrait analysis. Results: Scale reliabilities met the criterion for group comparisons (alpha levels ranged from 0.84 to 0.91). The pattern of item correlations and intra- and interscale correlations indicating convergent and discriminant validity, respectively, were both 100%. Implications: Our results support the broader use of the BJBC survey within VA. In addition, given the high levels of internal consistency reliability of the current scales, it is likely that a psychometrically sound short form of the instrument could be created. Further research on construct and convergent validity are warranted to support the broader application of the instrument. C1 [Sullivan, Jennifer L.; Meterko, Mark; Baker, Errol; Stolzmann, Kelly; Adjognon, Omonyele; Ballah, Konique; Parker, Victoria A.] VA Boston Healthcare Syst, COLMR, Boston, MA 02130 USA. [Sullivan, Jennifer L.; Meterko, Mark; Parker, Victoria A.] Boston Univ, Sch Publ Hlth Hlth Policy & Management, Boston, MA 02215 USA. [Ballah, Konique] Brigham & Womens Hosp, Transplant Adm, Boston, MA 02115 USA. RP Sullivan, JL (reprint author), VA Boston Healthcare Syst, COLMR, 150 South Huntington Ave 152M, Boston, MA 02130 USA. EM jennifer.sullivan@va.gov OI Parker, Victoria/0000-0002-7632-9174 NR 29 TC 5 Z9 5 U1 17 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD AUG PY 2013 VL 53 IS 4 BP 596 EP 607 DI 10.1093/geront/gns140 PG 12 WC Gerontology SC Geriatrics & Gerontology GA 182CF UT WOS:000321717400007 PM 23197392 ER PT J AU Seyyedi, M Eddington, DK Nadol, JB AF Seyyedi, Mohammad Eddington, Donald K. Nadol, Joseph B., Jr. TI Effect of monopolar and bipolar electric stimulation on survival and size of human spiral ganglion cells as studied by postmortem histopathology SO HEARING RESEARCH LA English DT Article ID NEONATALLY DEAFENED CATS; COCHLEAR IMPLANTATION; AUDITORY-NERVE; GUINEA-PIG; NEUROTROPHIC FACTOR; HEARING-LOSS; INNER-EAR; NEURONS; DEGENERATION; PATTERNS AB The spiral ganglion cell (SGC) is the target of electrical stimulation in cochlear implants. This study is designed to test the hypothesis that chronic electrical stimulation tends to preserve SGCs in implanted hearing-impaired ears. A total of 26 pairs of temporal bones were studied from 26 individuals who in life suffered bilateral profound hearing impairment that was symmetric (in degree of impairment and etiology) across ears and then underwent unilateral cochlear implantation. The subjects were divided in two groups by stimulus configuration: bipolar (n = 16) or monopolar (n = 10). The temporal bones were prepared for histological review by standard methods and two measures of SGC status were made by cochlear segment: count and maximal cross-sectional area. Within-subject comparison of the measures between the implanted-stimulated and the unimplanted ears showed: (1) for both stimulus configurations, the mean (across subjects and segments) of the count difference (implanted ear - unimplanted ear) was significantly less than zero; (2) the mean (across subject) count difference for cochlear segments I, II and III (segments with electrode contacts in the implanted ear) was significantly less negative than the mean difference for cochlear segment IV (no electrode in implanted ear) for bipolar but not for monopolar stimulation; (3) neither implantation-stimulation nor stimulus configuration significantly influenced the measures of maximum cross-sectional cell area. The SGC count results are consistent with the hypothesis that implantation results in a propensity across the whole cochlea for SGCs to degenerate and with chronic bipolar stimulation ameliorating this propensity in those cochlear segments with electrodes present. (C) 2013 Elsevier B.V. All rights reserved. C1 [Seyyedi, Mohammad; Eddington, Donald K.; Nadol, Joseph B., Jr.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Seyyedi, Mohammad; Eddington, Donald K.; Nadol, Joseph B., Jr.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Seyyedi, Mohammad; Eddington, Donald K.; Nadol, Joseph B., Jr.] Massachusetts Eye & Ear Infirm, Cochlear Implant Res Lab, Boston, MA 02114 USA. [Eddington, Donald K.; Nadol, Joseph B., Jr.] MIT, Speech & Hearing Biosci & Technol Program, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Nadol, JB (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM joseph_nadol@meei.harvard.edu FU National Institute of Deafness and Other Communication Disorders [R01-DC000152] FX This work was supported by grant R01-DC000152 from the National Institute of Deafness and Other Communication Disorders. NR 42 TC 4 Z9 6 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD AUG PY 2013 VL 302 BP 9 EP 16 DI 10.1016/j.heares.2013.04.007 PG 8 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 186OZ UT WOS:000322055300002 PM 23660399 ER PT J AU Yakoob, MY Bateman, BT Ho, E Hernandez-Diaz, S Franklin, JM Goodman, JE Hoban, RA AF Yakoob, Mohammad Y. Bateman, Brian T. Ho, Eugenia Hernandez-Diaz, Sonia Franklin, Jessica M. Goodman, Julie E. Hoban, Rebecca A. TI The Risk of Congenital Malformations Associated With Exposure to -Blockers Early in Pregnancy: A Meta-Analysis SO HYPERTENSION LA English DT Article DE -blockers; cleft lip; palate; congenital anomalies; heart defects; congenital; neural tube defects; pregnancy; trimester; first ID ANTIHYPERTENSIVE MEDICATION USE; GESTATIONAL-AGE NEWBORNS; DIABETIC PREGNANCIES; PRECONCEPTION CARE; DRUGS; POPULATION; INFANTS; WOMEN; OUTCOMES; DEFECTS AB -blockers are commonly used during the first trimester of pregnancy. Data about risks of congenital anomalies in offspring have not been summarized. We performed a meta-analysis to determine teratogenicity of -blockers in early pregnancy. A systematic literature search was performed using PubMed, EMBASE, Cochrane Clinical Trials, and hand search. Meta-analyses were performed using random-effects models based on odds ratios (ORs). Prespecified subgroup analyses were performed to explore heterogeneity. Randomized controlled trials or observational studies examining risks of congenital malformations associated with first trimester -blocker exposure compared with no exposure were included. Thirteen population-based case-control or cohort studies were identified. Based on meta-analyses, first-trimester oral -blocker use showed no increased odds of all or major congenital anomalies (OR=1.00; 95% confidence interval, 0.91-1.10; 5 studies). However, in analyses examining organ-specific malformations, increased odds of cardiovascular defects (OR=2.01; 95% confidence interval, 1.18-3.42; 4 studies), cleft lip/palate (OR=3.11; 95% confidence interval, 1.79-5.43; 2 studies), and neural tube defects (OR=3.56; 95% confidence interval, 1.19-10.67; 2 studies) were observed. The effects on severe hypospadias were nonsignificant (1 study). Causality is difficult to interpret given the small number of heterogeneous studies and possibility of biases. Given the frequency of this exposure in pregnancy, further research is needed. C1 [Yakoob, Mohammad Y.; Hernandez-Diaz, Sonia; Goodman, Julie E.] Harvard Univ, Sch Med, Dept Epidemiol, Boston, MA USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Bateman, Brian T.; Franklin, Jessica M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02115 USA. [Ho, Eugenia] Childrens Hosp Boston, Dept Pediat Neurol, Boston, MA USA. [Hoban, Rebecca A.] Rush Univ, Sect Neonatol, Chicago, IL 60612 USA. RP Yakoob, MY (reprint author), 203 Pk Dr,Unit 223A, Boston, MA 02215 USA. EM myyakoob@mail.harvard.edu FU NIH [R01 HD059861-01A1]; Agency of Healthcare Research and Qualit [RO1 HS018533] FX IRB approval/informed consent is not applicable as this article involves a meta-analysis only of previously published articles involving de-identified data. This was an unfunded study. Sonia Hernandez-Diaz is the Principal Investigator (PI) of NIH R01 HD046595-01A1 on teratogenicity of drugs commonly used in pregnancy and NIH R01 HD059861-01A1 grant on phthalates in medications and risk of male genital malformations. She receives sponsorships from Agency of Healthcare Research and Quality (Grant RO1 HS018533) on antidepressants use in pregnancy and postpartum, and is involved in projects funded by pharmaceutical companies related to North American Antiepileptic Drug Pregnancy Registry. The other authors report no conflicts. NR 30 TC 21 Z9 23 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD AUG PY 2013 VL 62 IS 2 BP 375 EP 381 DI 10.1161/HYPERTENSIONAHA.111.00833 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 185IY UT WOS:000321962300029 PM 23753416 ER PT J AU Hess, DR Kondili, D Burns, E Bittner, EA Schmidt, UH AF Hess, Dean R. Kondili, Dhimiter Burns, Edward Bittner, Edward A. Schmidt, Ulrich H. TI A 5-year observational study of lung-protective ventilation in the operating room: A single-center experience SO JOURNAL OF CRITICAL CARE LA English DT Article DE Anesthesia; Knowledge transfer; Lung-protective ventilation; Tidal volume; Positive end-expiratory pressure ID RESPIRATORY-DISTRESS-SYNDROME; TIDAL VOLUME VENTILATION; RANDOMIZED CONTROLLED-TRIAL; MECHANICAL VENTILATION; GENERAL-ANESTHESIA; RISK-FACTOR; INJURY; ATELECTASIS; MANAGEMENT; STRATEGY AB Purpose: We assessed the evolution of lung-protective ventilation strategies during anesthesia and identified factors associated with the selection of a nonprotective ventilation strategy. Methods: This retrospective observational study covered a 5-year period from March 2006 to March 2011. It included 45 575 adult patients who underwent intubation de novo in the operating room. We considered a tidal volume (V-T) greater than 10 mL/kg of ideal body weight (IBW) and/or positive end-expiratory pressure (PEEP) less than 5 cm H2O as not lung protective. We evaluated the use of nonprotective ventilation strategies over time in men and women, by American Society of Anesthesiologists classification, and for elective vs emergent surgery. Results: Over the duration of the study, there was a significant reduction in the percentage of patients receiving a V-T greater than 10 mL/kg IBW (28.5%-16.3%, P < .001), zero PEEP (27.5%-18.2%, P < .001), and V-T greater than 10 mL/kg IBW with PEEP less than 5 cm H2O (13.4%-8.0%, P < .001). The odds of receiving nonprotective ventilation were greater for women than for men, in the first year compared with the last year, and for elective compared with emergent surgery. Conclusion: Although use of nonprotective ventilation decreased over time, an important percentage of patients continue to receive nonprotective ventilation. (c) 2013 Elsevier Inc. All rights reserved. C1 [Hess, Dean R.; Bittner, Edward A.; Schmidt, Ulrich H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Kondili, Dhimiter; Burns, Edward] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hess, DR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. EM dhess@partners.org NR 36 TC 2 Z9 3 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0883-9441 J9 J CRIT CARE JI J. Crit. Care PD AUG PY 2013 VL 28 IS 4 AR 533.e9 DI 10.1016/j.jcrc.2012.11.014 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 181UQ UT WOS:000321694900038 PM 23369521 ER PT J AU Volpp, KG Small, DS Romano, PS Itani, KMF Rosen, AK Even-Shoshan, O Wang, YL Bellini, L Halenar, MJ Korovaichuk, S Zhu, JS Silber, JH AF Volpp, Kevin G. Small, Dylan S. Romano, Patrick S. Itani, Kamal M. F. Rosen, Amy K. Even-Shoshan, Orit Wang, Yanli Bellini, Lisa Halenar, Michael J. Korovaichuk, Sophia Zhu, Jingsan Silber, Jeffrey H. TI Teaching Hospital Five-Year Mortality Trends in the Wake of Duty Hour Reforms SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE patient outcomes; mortality; duty hour reform; ACGME; administrative data ID ACUTE MYOCARDIAL-INFARCTION; QUALITY-OF-CARE; MEDICARE BENEFICIARIES; EDUCATION; IMPACT AB The Accreditation Council for Graduate Medical Education (ACGME) implemented duty hour regulations for residents in 2003 and again in 2011. While previous studies showed no systematic impacts in the first 2 years post-reform, the impact on mortality in subsequent years has not been examined. To determine whether duty hour regulations were associated with changes in mortality among Medicare patients in hospitals of different teaching intensity after the first 2 years post-reform. Observational study using interrupted time series analysis with data from July 1, 2000 to June 30, 2008. Logistic regression was used to examine the change in mortality for patients in more versus less teaching-intensive hospitals before (2000-2003) and after (2003-2008) duty hour reform, adjusting for patient comorbidities, time trends, and hospital site. Medicare patients (n = 13,678,956) admitted to short-term acute care non-federal hospitals with principal diagnoses of acute myocardial infarction (AMI), gastrointestinal bleeding, or congestive heart failure (CHF); or a diagnosis-related group (DRG) classification of general, orthopedic, or vascular surgery. All-location mortality within 30 days of hospital admission. In medical and surgical patients, there were no consistent changes in the odds of mortality at more vs. less teaching intensive hospitals in post-reform years 1-3. However, there were significant relative improvements in mortality for medical patients in the fourth and fifth years post-reform: Post4 (OR 0.88, 95 % CI [0.93-0.94]); Post5 (OR 0.87, [0.82-0.92]) and for surgical patients in the fifth year post-reform: Post5 (OR 0.91, [0.85-0.96]). Duty hour reform was associated with no significant change in mortality in the early years after implementation, and with a trend toward improved mortality among medical patients in the fourth and fifth years. It is unclear whether improvements in outcomes long after implementation can be attributed to the reform, but concerns about worsening outcomes seem unfounded. (C) Society of General Internal Medicine 2013 C1 [Volpp, Kevin G.; Halenar, Michael J.] Vet Adm Hosp, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Bellini, Lisa; Halenar, Michael J.; Zhu, Jingsan] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Silber, Jeffrey H.] Univ Penn, Wharton Sch, Dept Hlth Care Management, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Zhu, Jingsan] Univ Penn, Leonard Davis Inst, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. [Small, Dylan S.] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA. [Romano, Patrick S.] Univ Calif Davis, Sch Med, Div Gen Med, Sacramento, CA 95817 USA. [Romano, Patrick S.] Univ Calif Davis, Sch Med, Ctr Healthcare Policy & Res, Sacramento, CA 95817 USA. [Itani, Kamal M. F.] VA Boston Healthcare Syst, Dept Surg, Boston, MA USA. [Itani, Kamal M. F.] Boston Univ, Boston, MA 02215 USA. [Rosen, Amy K.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. [Rosen, Amy K.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Even-Shoshan, Orit; Wang, Yanli; Korovaichuk, Sophia; Silber, Jeffrey H.] Childrens Hosp Philadelphia, Ctr Outcomes Res, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.] Univ Penn, Dept Anesthesiol & Crit Care, Perelman Sch Med, Philadelphia, PA 19104 USA. [Even-Shoshan, Orit; Silber, Jeffrey H.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Volpp, KG (reprint author), Vet Adm Hosp, Ctr Hlth Equ Res & Promot, 1120 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM Volpp70@wharton.upenn.edu RI Romano, Patrick/N-4225-2014 OI Romano, Patrick/0000-0001-6749-3979 FU NHLBI [R01 HL094593-01] FX This work was funded by grant R01 HL094593-01 from the NHLBI. NR 36 TC 8 Z9 8 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2013 VL 28 IS 8 BP 1048 EP 1055 DI 10.1007/s11606-013-2401-9 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 184DZ UT WOS:000321869000014 PM 23592241 ER PT J AU Austad, KE Avorn, J Franklin, JM Kowal, MK Campbell, EG Kesselheim, AS AF Austad, Kirsten E. Avorn, Jerry Franklin, Jessica M. Kowal, Mary K. Campbell, Eric G. Kesselheim, Aaron S. TI Changing Interactions Between Physician Trainees and the Pharmaceutical Industry: A National Survey SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE pharmaceutical industry; undergraduate medical education; drug promotion; conflict of interest ID MEDICAL-STUDENTS EXPOSURE; RESPONSE RATES; EDUCATION; ATTITUDES; REPRESENTATIVES; BEHAVIOR; SCHOOL AB Increasingly, medical school policies limit pharmaceutical representatives' access to students and gifts from drugmakers, but little is known about how these policies affect student attitudes toward industry. To assess interactions between trainees and the pharmaceutical industry, and to determine whether learning environment characteristics influence students' practices and attitudes. We conducted a cross-sectional survey with a nationally-representative sample of first- and fourth-year medical students and third-year residents, stratified by medical school, including a parts per thousand yen 14 randomly selected trainees at each level per school. We measured frequency of industry interactions and attitudes regarding how such interactions affect medical training and the profession. Chi-squared tests assessed bivariate linear trend, and hierarchical logistic regression models were fitted to assess associations between trainees' attitudes and their schools' National Institutes of Health (NIH) funding levels and American Medical Student Association (AMSA) PharmFree Scorecard grades reflecting industry-related conflict of interest policies. Among 1,610 student (49.3 % response rate) and 739 resident (43.1 %) respondents, industry-sponsored gifts were common, rising from 33.0 % (first-year students) to 56.8 % (fourth-year students) and 54 % (residents) (p < 0.001). These gifts included meals outside the hospital (reported by 5 % first-year students, 13.4 % fourth-year students, 27.5 % residents (p < 0.001)) and free drug samples (reported by 7.4 % first-year students, 14.1 % fourth-year students, 14.3 % residents (p < 0.001)). The perception that industry interactions lead to bias was prevalent, but the belief that physicians receive valuable education through these interactions increased (64.1 % to 67.5 % to 79.8 %, p < 0.001). Students in schools receiving more NIH funding reported industry gifts less often (OR = 0.51, 95 % CI: 0.38-0.68, p < 0.001), but the strength of institutional conflict of interest policies was not associated with this variable. Despite recent policy changes, a substantial number of trainees continue to receive gifts from pharmaceutical representatives. We found no relation between these outcomes and a school's policies concerning interactions with industry. (C) Society of General Internal Medicine 2013 C1 [Austad, Kirsten E.; Avorn, Jerry; Franklin, Jessica M.; Kowal, Mary K.; Kesselheim, Aaron S.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Austad, Kirsten E.; Avorn, Jerry; Franklin, Jessica M.; Kowal, Mary K.; Campbell, Eric G.; Kesselheim, Aaron S.] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Austad, Kirsten E.; Kesselheim, Aaron S.] Harvard Univ, Edmond J Safra Ctr Eth, Cambridge, MA 02138 USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Kesselheim, AS (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM akesselheim@partners.org OI Franklin, Jessica/0000-0002-8941-4116 FU Edmond J. Safra Center for Ethics at Harvard University; Agency for Healthcare Research Quality [K08HS18465-01]; Robert Wood Johnson Foundation FX The authors would like to thank Prof. Lawrence Lessig of Harvard Law School for his helpful comments on the study, and to acknowledge useful input from members of the Research Ethics Program of the Harvard Clinical and Translational Science Center. Study funded by a grant from the Edmond J. Safra Center for Ethics at Harvard University. Dr. Kesselheim is supported by a career development award from the Agency for Healthcare Research & Quality (K08HS18465-01), and a Robert Wood Johnson Foundation Investigator Award in Health Policy Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 28 Z9 30 U1 1 U2 14 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 AUG PY 2013 VL 28 IS 8 BP 1064 EP 1071 DI 10.1007/s11606-013-2361-0 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 184DZ UT WOS:000321869000016 PM 23444007 ER PT J AU Hauer, KE Soni, K Cornett, P Kohlwes, J Hollander, H Ranji, SR ten Cate, O Widera, E Calton, B O'Sullivan, PS AF Hauer, Karen E. Soni, Krishan Cornett, Patricia Kohlwes, Jeff Hollander, Harry Ranji, Sumant R. ten Cate, Olle Widera, Eric Calton, Brook O'Sullivan, Patricia S. TI Developing Entrustable Professional Activities as the Basis for Assessment of Competence in an Internal Medicine Residency: A Feasibility Study SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE clinical competence; assessment; education; medical; graduate medical education ID CARE; ENVIRONMENT; INPATIENT; EDUCATION AB Graduate medical education programs assess trainees' performance to determine readiness for unsupervised practice. Entrustable professional activities (EPAs) are a novel approach for assessing performance of core professional tasks. To describe a pilot and feasibility evaluation of two EPAs for competency-based assessment in internal medicine (IM) residency. Post-graduate year-1 interns (PGY-1s) and attendings at a large internal medicine (IM) residency program. Two Entrustable professional activities (EPA) assessments (Discharge, Family Meeting) were piloted. Twenty-eight out of 43 (65.1 %) PGY-1 s and 32/43 (74.4 %) attendings completed surveys about the Discharge EPA experience. Most who completed the EPA assessment (10/12, 83.8 %, PGY-1s; 9/11, 83.3 %, attendings) agreed it facilitated useful feedback discussions. For the Family Meeting EPA, 16/26 (61.5 %) PGY-1s completed surveys, and most who participated (9/12 PGY1s, 75 %) reported it improved attention to family meeting education, although only half recommended continuing the EPA assessment. From piloting two EPA assessments in a large IM residency, we recognized our reminder systems and time dedicated for completing EPA requirements as inadequate. Collaboration around patient safety and palliative care with relevant clinical services has enhanced implementation and buy-in. We will evaluate how well EPA-based assessment serves the intended purpose of capturing trainees' trustworthiness to conduct activities unsupervised. (C) Society of General Internal Medicine 2013 C1 [Hauer, Karen E.; Soni, Krishan; Hollander, Harry; Ranji, Sumant R.; ten Cate, Olle; Calton, Brook; O'Sullivan, Patricia S.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Cornett, Patricia; Kohlwes, Jeff; Widera, Eric] Univ Calif San Francisco, Dept Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. [ten Cate, Olle] Univ Utrecht, Dept Med, Utrecht, Netherlands. RP Hauer, KE (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM Karen.hauer@ucsf.edu OI O'Sullivan, Patricia/0000-0002-8706-4095; ten Cate, Olle/0000-0002-6379-8780 FU American Board of Internal Medicine FX Dr. Hauer received support from the American Board of Internal Medicine. There was no additional funding specific to this project. NR 19 TC 17 Z9 17 U1 1 U2 14 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 AUG PY 2013 VL 28 IS 8 BP 1110 EP 1114 DI 10.1007/s11606-013-2372-x PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 184DZ UT WOS:000321869000022 PM 23595926 ER PT J AU Sheth, SA Eskandar, EN Dougherty, DD AF Sheth, Sameer A. Eskandar, Emad N. Dougherty, Darin D. TI Obsessive-compulsive disorder and cingulotomy RESPONSE SO JOURNAL OF NEUROSURGERY LA English DT Letter C1 [Sheth, Sameer A.] Columbia Univ, NewYork Presbyterian Hosp, New York, NY 10027 USA. [Eskandar, Emad N.; Dougherty, Darin D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Sheth, SA (reprint author), Columbia Univ, NewYork Presbyterian Hosp, New York, NY 10027 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2013 VL 119 IS 2 BP 526 EP 526 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 187CL UT WOS:000322094400042 PM 24063045 ER PT J AU Seif, F Patel, SR Walia, H Rueschman, M Bhatt, DL Gottlieb, DJ Lewis, EF Patil, SP Punjabi, NM Babineau, DC Redline, S Mehra, R AF Seif, Fadi Patel, Sanjay R. Walia, Harneet Rueschman, Michael Bhatt, Deepak L. Gottlieb, Daniel J. Lewis, Eldrin F. Patil, Susheel P. Punjabi, Naresh M. Babineau, Denise C. Redline, Susan Mehra, Reena TI Association between obstructive sleep apnea severity and endothelial dysfunction in an increased background of cardiovascular burden SO JOURNAL OF SLEEP RESEARCH LA English DT Article DE cardiovascular disease; endothelial dysfunction; sleep apnea ID OXIDATIVE STRESS; BRACHIAL-ARTERY; HEART HEALTH; NITRIC-OXIDE; RISK-FACTORS; VASODILATION; HYPERTENSION; IMPAIRMENT; REACTIVITY; AMPLITUDE AB The objective of this study is to examine whether increasing obstructive sleep apnea (OSA) severity is associated with worsening endothelial function. The design is a cross-sectional examination of the baseline assessment of a multi-centre randomized controlled clinical trial examining the effects of oxygen, continuous positive airway pressure (CPAP) therapy or lifestyle modifications on cardiovascular biomarkers. Participants were recruited from cardiology clinics at four sites. Participants with an apnea-hypopnea index (AHI) of 15-50 and known cardio/cerebrovascular disease (CVD) or CVD risk factors were included. OSA severity indices [oxygen desaturation index (ODI), AHI and percentage of sleep time below 90% oxygen saturation (total sleep time < 90)] and a measure of endothelium-mediated vasodilatation [Framingham reactive hyperaemia index (F-RHI) derived from peripheral arterial tonometry (PAT)] were assessed. The sample included 267 individuals with a mean AHI of 25.0 +/- 8.5 SD and mean F-RHI 0.44 +/- 0.38. In adjusted models, the slope of the relationship between ODI and F-RHI differed above and below an ODI of 24.6 (P = 0.04), such that above an ODI of 24.6 there was a marginally significant decline in the geometric mean of the PAT ratio by 3% [95% confidence interval (CI): 0%, 5%; P = 0.05], while below this point, there was a marginally significant incline in the geometric mean of the PAT ratio by 13% (95% CI: 0%, 27%; P = 0.05) per 5-unit increase in ODI. A similar pattern was observed between AHI and F-RHI. No relation was noted with total sleep time < 90 and F-RHI. There was evidence of a graded decline in endothelial function in association with higher levels of intermittent hypoxaemia. C1 [Seif, Fadi; Walia, Harneet; Mehra, Reena] Case Sch Med, Dept Med, Cleveland, OH USA. [Patel, Sanjay R.; Rueschman, Michael; Bhatt, Deepak L.; Gottlieb, Daniel J.; Lewis, Eldrin F.; Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Patel, Sanjay R.; Redline, Susan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Bhatt, Deepak L.; Gottlieb, Daniel J.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA USA. [Patil, Susheel P.; Punjabi, Naresh M.] Johns Hopkins Univ, Baltimore, MD USA. [Babineau, Denise C.] Case Western Reserve Univ, Ctr Clin Invest, Cleveland, OH 44106 USA. [Mehra, Reena] Case Sch Med, Case Comprehens Canc Ctr, Case Ctr Transdisciplinary Res Energet & Canc, Cleveland, OH USA. RP Mehra, R (reprint author), Case Western Reserve Univ, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM reena.mehra@case.edu OI Mehra, Reena/0000-0002-6222-2675; Patel, Sanjay/0000-0002-9142-5172 FU NIH National Heart Lung Blood Institute [RC2 HL101417, K23 HL079114]; American Heart Association [0530188N]; Central Society of Clinical Research; NHLBI [K08 HL081385]; NCI [1U54CA116867]; NIH [M01 RR00080] FX This study was supported by NIH National Heart Lung Blood Institute RC2 HL101417 and K23 HL079114, NIH M01 RR00080, American Heart Association National Scientist Development Award 0530188N, Central Society of Clinical Research, NHLBI K08 HL081385 and NCI 1U54CA116867. The project described was also supported by UL1 RR024989 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. NR 31 TC 12 Z9 13 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1105 J9 J SLEEP RES JI J. Sleep Res. PD AUG PY 2013 VL 22 IS 4 BP 443 EP 451 DI 10.1111/jsr.12026 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 182VP UT WOS:000321773200012 PM 23331757 ER PT J AU Cheng, P Casement, MD Chen, CF Hoffmann, RF Armitage, R Deldin, PJ AF Cheng, Philip Casement, Melynda D. Chen, Chiau-Fang Hoffmann, Robert F. Armitage, Roseanne Deldin, Patricia J. TI Sleep-disordered breathing in major depressive disorder SO JOURNAL OF SLEEP RESEARCH LA English DT Article DE major depressive disorder; sleep-disordered breathing AB Individuals with major depressive disorder often experience obstructive sleep apnea. However, the relationship between depression and less severe sleep-disordered breathing is unclear. This study examined the rate of sleep-disordered breathing in depression after excluding those who had clinically significant sleep apnea (>5 apneas.h(-1)). Archival data collected between 1991 and 2005 were used to assess the prevalence of sleep-disordered breathing events in 60 (31 depressed; 29 healthy controls) unmedicated participants. Respiratory events were automatically detected using a program developed in-house measuring thermal nasal air-flow and chest pressure. Results show that even after excluding participants with clinically significant sleep-disordered breathing, individuals with depression continue to exhibit higher rates of sleep-disordered breathing compared with healthy controls (depressed group: apnea-hypopnea index mean = 0.524, SE = 0.105; healthy group: apnea-hypopnea index mean = 0.179, SE = 0.108). Exploratory analyses were also conducted to assess for rates of exclusion in depression studies due to sleep-disordered breathing. Study exclusion of sleep-disordered breathing was quantified based on self-report during telephone screening, and via first night polysomnography. Results from phone screening data reveal that individuals reporting depression were 5.86 times more likely to report a diagnosis of obstructive sleep apnea than presumptive control participants. Furthermore, all of the participants excluded for severe sleep-disordered breathing detected on the first night were participants with depression. These findings illustrate the importance of understanding the relationship between sleep-disordered breathing and depression, and suggest that screening and quantification of sleep-disordered breathing should be considered in depression research. C1 [Cheng, Philip; Chen, Chiau-Fang; Hoffmann, Robert F.; Armitage, Roseanne; Deldin, Patricia J.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Casement, Melynda D.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Casement, Melynda D.] Boston Univ, Med Ctr, Boston, MA USA. RP Deldin, PJ (reprint author), Univ Michigan, 530 Church St, Ann Arbor, MI 48109 USA. EM pjdeldin@umich.edu OI Casement, Melynda/0000-0002-5906-0994 FU National Institute of Mental Health (NIMH) [R01-MH061515, T32-MH019836] FX This research was supported in part by National Institute of Mental Health (NIMH) Grant R01-MH061515, awarded to Roseanne Armitage. Support for the second author was provided by NIMH Institutional Training Grant T32-MH019836. The content of this manuscript is solely the responsibility of the authors, and does not necessarily represent the official views of NIMH or NIH. The authors would also like to thank the UM Department of Psychology, Department of Psychiatry, and the Depression Center for their continued support. NR 10 TC 4 Z9 4 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1105 J9 J SLEEP RES JI J. Sleep Res. PD AUG PY 2013 VL 22 IS 4 BP 459 EP 462 DI 10.1111/jsr.12029 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 182VP UT WOS:000321773200014 PM 23350718 ER PT J AU Roberts, DS Lin, HW Herrmann, BS Lee, DJ AF Roberts, Daniel S. Lin, Harrison W. Herrmann, Barbara S. Lee, Daniel J. TI Differential cochlear implant outcomes in older adults SO LARYNGOSCOPE LA English DT Article DE Cochlear Implant outcomes; elderly; octogenarians ID SPEECH RECOGNITION; ELDERLY-PATIENTS; PERFORMANCE; QUALITY; PREDICTORS; PERCEPTION; HEARING AB Objectives/Hypothesis The goals of this study were to analyze whether cochlear implant (CI) users over 65 years of age have different surgical and audiological outcomes when compared to younger adult CI users and to identify reasons for these possible differences. Study Design Retrospective single-institution study. Methods Records of 113 postlingually deafened adults with unilateral cochlear implants were reviewed. Preoperative and postoperative speech perception scores, and medical and epidemiological data were recorded and analyzed. Results Speech perception ability was significantly poorer in CI users over 65 years of age compared to younger adult patients (P = .012). Patients over the age of 80 years accounted for these findings (P = .017). Older patients were less likely to have a family history of hearing deficits. A history of noise exposure and idiopathic cause of hearing loss did not correlate with audiological outcomes. A family history of hearing loss was associated with a trend toward better speech recognition (P = .062). Older patients did not experience more vestibular symptoms or other complications compared to younger patients. Conclusions Patients over the age of 80 years had lower speech perception scores than other adult CI recipients but did not have higher rates of dizziness or vertigo after surgery. A family history of hearing loss was associated with a trend toward better speech recognition, possibly representing a new prognostic variable. These findings provide important information that will aid clinicians in counseling older CI candidates. C1 [Roberts, Daniel S.; Lin, Harrison W.; Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Herrmann, Barbara S.] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Roberts, Daniel S.; Lin, Harrison W.; Herrmann, Barbara S.; Lee, Daniel J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Lee, DJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM daniel_lee@meei.harvard.edu FU Massachusetts Eye and Ear Department of Otolaryngology FX Support for this research was from the Massachusetts Eye and Ear Department of Otolaryngology fund for resident research. NR 22 TC 18 Z9 19 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2013 VL 123 IS 8 BP 1952 EP 1956 DI 10.1002/lary.23676 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 185XN UT WOS:000322004400024 PM 23737286 ER PT J AU Davids, MS Letai, A Brown, JR AF Davids, Matthew S. Letai, Anthony Brown, Jennifer R. TI Overcoming stroma-mediated treatment resistance in chronic lymphocytic leukemia through BCL-2 inhibition SO LEUKEMIA & LYMPHOMA LA English DT Article DE Chronic lymphocytic leukemia; apoptosis; B cell lymphoma/leukemia 2 (BCL-2); microenvironment ID NAVITOCLAX; PATHWAY AB Despite recent advances in the treatment of chronic lymphocytic leukemia (CLL) with chemoimmunotherapy, many patients with CLL are older or frail and cannot tolerate aggressive chemotherapy. Even those who can inevitably develop resistance due to factors such as deletion of pro-apoptotic factors like TP53 or the support of pro-survival signals from the stromal microenvironment. Using BH3 profiling, we found that CLL cells co-cultured with stroma are less primed to undergo apoptosis in response to BCL-2 inhibition. Currently, several approaches to BCL-2 inhibition with well-tolerated oral agents are in development in the clinic. Dosing of navitoclax (ABT-263) was complicated by thrombocytopenia due to BCL-XL inhibition, but the BCL-2 specific inhibitor ABT-199 (GDC-0199) should avoid this issue, and may overcome stroma-mediated resistance to apoptosis. We are developing BH3 profiling as a biomarker to predict response to novel therapies such as ABT-199, and to identify resistance mechanisms to new agents being studied in CLL. C1 [Davids, Matthew S.; Letai, Anthony; Brown, Jennifer R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Davids, MS (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave,M232, Boston, MA 02215 USA. EM matthew_davids@dfci.harvard.edu FU NCI NIH HHS [T32 CA009172] NR 13 TC 12 Z9 11 U1 0 U2 4 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 AUG PY 2013 VL 54 IS 8 BP 1823 EP 1825 DI 10.3109/10428194.2013.796051 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA 182SG UT WOS:000321763800048 PM 23614795 ER PT J AU Jambunathan, K Watson, DS Najvar, LK Wiederhold, NP Kirkpatrick, WR Patterson, TF Askew, DS Kodukula, K Galande, AK AF Jambunathan, Kalyani Watson, Douglas S. Najvar, Laura K. Wiederhold, Nathan P. Kirkpatrick, William R. Patterson, Thomas F. Askew, David S. Kodukula, Krishna Galande, Amit K. TI Prolyl endopeptidase activity in bronchoalveolar lavage fluid: a novel diagnostic biomarker in a guinea pig model of invasive pulmonary aspergillosis SO MEDICAL MYCOLOGY LA English DT Article DE fluorogenic probes; invasive aspergillosis; proteolytic enzymes; combinatorial library; broncheoalveolar lavage fluid ID NEUTROPENIC PATIENTS; FUNGAL-INFECTIONS; FUMIGATUS; ENZYME; GALACTOMANNAN; IDENTIFICATION; IMMUNOASSAY; MANAGEMENT; SUBSTRATE; PROTEASES AB Improved diagnostics are needed to detect invasive pulmonary aspergillosis, a life-threatening infection caused by the pathogenic fungus Aspergillus fumigatus. We are investigating secreted fungal proteases as novel biomarkers for the diagnosis of this disease. Although the A. fumigatus genome encodes a multitude of secreted proteases, few have been experimentally characterized. Here, we employed an unbiased combinatorial library of internally quenched fluorogenic probes to detect infection-associated proteolysis in the lungs of guinea pigs experimentally infected with A. fumigatus. Comparative protease activity profiling revealed a prolyl endopeptidase activity that is reproducibly induced during infection but is not observed in healthy animals. This proteolytic activity was found in four independent animal experiments involving two A. fumigatus isolates. We synthesized a small, focused fluorogenic probe library to define the substrate specificity of the prolyl endopeptidase substrate motif and to identify optimal Probe sequences. These efforts resulted in the identification of a panel of six individual substrate-based fluorescent probes capable of detecting infection in guinea pigs with high statistical significance (P < 0.005 in most cases). Receiver operating characteristic analyses demonstrated that this fluorogenic assay could detect A. fumigatus infection-associated proteolysis with comparable sensitivity and specificity as existing diagnostic procedures, suggesting that further optimization of the methodology may lead to improved diagnostics options for invasive pulmonary aspergillosis. C1 [Jambunathan, Kalyani; Watson, Douglas S.; Kodukula, Krishna; Galande, Amit K.] SRI Int, Biosci Div, Harrisonburg, VA 22802 USA. [Najvar, Laura K.; Wiederhold, Nathan P.; Kirkpatrick, William R.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Askew, David S.] Univ Cincinnati, Coll Med, Dept Pathol & Lab Med, Cincinnati, OH 45267 USA. [Najvar, Laura K.; Kirkpatrick, William R.; Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Wiederhold, Nathan P.] Univ Texas Austin, Coll Pharm, Austin, TX USA. RP Galande, AK (reprint author), SRI Int, Biosci Div, 140 Res Dr, Harrisonburg, VA 22802 USA. EM amit.galande@sri.com OI Wiederhold, Nathan/0000-0002-2225-5122 FU National Institute of Allergy and Infectious Diseases (NIAID) [R21AI08502, N01AI30041, HHSN2722010000381]; Commonwealth of Virginia FX The authors wish to acknowledge the encouragement and guidance of Dr Joe Perrone, Director of Diagnostics at SRI Biosciences, and Dr Walter Moos, Vice President of SRI Biosciences. This work was supported by grant R21AI08502 and contract N01AI30041 and HHSN2722010000381 from the National Institute of Allergy and Infectious Diseases (NIAID). SRI International's Center for Advanced Drug Research was established through funding support from the Commonwealth of Virginia. NR 43 TC 3 Z9 4 U1 0 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD AUG PY 2013 VL 51 IS 6 BP 592 EP 602 DI 10.3109/13693786.2012.761360 PG 11 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 183CG UT WOS:000321790600006 PM 23356446 ER PT J AU Sheedy, FJ Grebe, A Rayner, KJ Kalantari, P Ramkhelawon, B Carpenter, SB Becker, CE Ediriweera, HN Mullick, AE Golenbock, DT Stuart, LM Latz, E Fitzgerald, KA Moore, KJ AF Sheedy, Frederick J. Grebe, Alena Rayner, Katey J. Kalantari, Parisa Ramkhelawon, Bhama Carpenter, Susan B. Becker, Christine E. Ediriweera, Hasini N. Mullick, Adam E. Golenbock, Douglas T. Stuart, Lynda M. Latz, Eicke Fitzgerald, Katherine A. Moore, Kathryn J. TI CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation SO NATURE IMMUNOLOGY LA English DT Article ID SCAVENGER-RECEPTOR-A; AMYLOID-BETA; ALZHEIMERS-DISEASE; CHOLESTEROL CRYSTALS; NALP3 INFLAMMASOME; MICE; CELLS; PROTEIN; MACROPHAGES; PEPTIDE AB Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1 beta (IL-1 beta) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-beta and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1 beta production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1 beta and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation. C1 [Sheedy, Frederick J.; Rayner, Katey J.; Ramkhelawon, Bhama; Ediriweera, Hasini N.; Moore, Kathryn J.] NYU, Sch Med, Marc & Ruti Bell Program Vasc Biol & Dis, Dept Med,Leon H Charney Div Cardiol, New York, NY 10012 USA. [Grebe, Alena; Latz, Eicke] Univ Bonn, Inst Innate Immun, Bonn, Germany. [Kalantari, Parisa; Carpenter, Susan B.; Golenbock, Douglas T.; Latz, Eicke; Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Dept Infect Dis & Immunol, Worcester, MA USA. [Becker, Christine E.; Stuart, Lynda M.] Harvard Univ, Sch Med, Dept Pediat, Lab Dev Immunol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Mullick, Adam E.] ISIS Pharmaceut, Carlsbad, CA 92008 USA. [Latz, Eicke] German Ctr Neurodegenerat Dis, Bonn, Germany. RP Moore, KJ (reprint author), NYU, Sch Med, Marc & Ruti Bell Program Vasc Biol & Dis, Dept Med,Leon H Charney Div Cardiol, New York, NY 10012 USA. EM kathryn.moore@nyumc.edu RI Latz, Eicke/H-3951-2014; OI Latz, Eicke/0000-0003-1488-5666; Mullick, Adam/0000-0003-4600-961X; Moore, kathryn/0000-0003-2505-2547; Sheedy, Frederick/0000-0003-2645-8493 FU US National Institutes of Health [R01HL117334, R01AG032349, U24 AI082660, R01 AI079198, 5R01HL093262-02, 1R01HL112661-01, AI083713]; American Heart Association [11POST7400075] FX We thank F. Maxfield (Weill Cornell Medical College) for Lalistat. Supported by the US National Institutes of Health (R01HL117334 and R01AG032349 to K.J.M.; U24 AI082660 to L.M.S. and K.J.M.; R01 AI079198 to L.M.S.; 5R01HL093262-02 and 1R01HL112661-01 to E.L.; and AI083713 to K.A.F. and E.L.) and the American Heart Association (11POST7400075 to F.J.S.). NR 54 TC 161 Z9 172 U1 3 U2 40 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 AUG PY 2013 VL 14 IS 8 BP 812 EP + DI 10.1038/ni.2639 PG 11 WC Immunology SC Immunology GA 185ZN UT WOS:000322010600010 PM 23812099 ER PT J AU A-Gonzalez, N Guillen, JA Gallardo, G Diaz, M de la Rosa, JV Hernandez, IH Casanova-Acebes, M Lopez, F Tabraue, C Beceiro, S Hong, C Lara, PC Andujar, M Arai, S Miyazaki, T Li, SL Corbi, AL Tontonoz, P Hidalgo, A Castrillo, A AF A-Gonzalez, Noelia Guillen, Jose A. Gallardo, German Diaz, Mercedes de la Rosa, Juan V. Hernandez, Irene H. Casanova-Acebes, Maria Lopez, Felix Tabraue, Carlos Beceiro, Susana Hong, Cynthia Lara, Pedro C. Andujar, Miguel Arai, Satoko Miyazaki, Toru Li, Senlin Corbi, Angel L. Tontonoz, Peter Hidalgo, Andres Castrillo, Antonio TI The nuclear receptor LXR alpha controls the functional specialization of splenic macrophages SO NATURE IMMUNOLOGY LA English DT Article ID LIVER-X-RECEPTORS; DENDRITIC CELLS; MARGINAL-ZONE; IMMUNE-RESPONSE; GENE-EXPRESSION; MYELOID CELLS; B-CELLS; MONOCYTES; SPLEEN; INFLAMMATION AB Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXR alpha was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXR alpha or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXR alpha-deficient mice. Our results demonstrate that signaling via LXR alpha in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets. C1 [A-Gonzalez, Noelia; Guillen, Jose A.; Diaz, Mercedes; Hernandez, Irene H.; Beceiro, Susana; Castrillo, Antonio] Univ Autonoma Madrid, Consejo Super Invest Cient, Inst Invest Biomed Alberto Sols Madrid, Madrid, Spain. [A-Gonzalez, Noelia; Guillen, Jose A.; Gallardo, German; Diaz, Mercedes; de la Rosa, Juan V.; Hernandez, Irene H.; Lopez, Felix; Tabraue, Carlos; Beceiro, Susana; Castrillo, Antonio] Univ Las Palmas Gran Canaria, Consejo Super Invest Cient, Inst Invest Biomed Alberto Sols Madrid, Unidad Asociada Biomed, Las Palmas Gran Canaria, Spain. [Casanova-Acebes, Maria; Hidalgo, Andres] Ctr Nacl Invest Cardiovasc, Dept Epidemiol Atherothrombosis & Imaging, Madrid, Spain. [Hong, Cynthia; Tontonoz, Peter] Univ Calif Los Angeles, Howard Hughes Med Inst, Dept Pathol & Lab Med, Los Angeles, CA 90024 USA. [Lara, Pedro C.] Hosp Univ Gran Canaria Dr Negrin, Serv Oncol Radioterap, Las Palmas Gran Canaria, Spain. [Andujar, Miguel] Hosp Univ Materno Infantil Las Palmas, Serv Patol, Las Palmas Gran Canaria, Spain. [Arai, Satoko; Miyazaki, Toru] Univ Tokyo, Fac Med, Ctr Dis Biol & Integrat Med, Lab Mol Biomed Pathogenesis, Tokyo 113, Japan. [Li, Senlin] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Li, Senlin] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Li, Senlin] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Corbi, Angel L.] CSIC, Ctr Invest Biol, Madrid, Spain. RP Castrillo, A (reprint author), Univ Autonoma Madrid, Consejo Super Invest Cient, Inst Invest Biomed Alberto Sols Madrid, Madrid, Spain. EM acastrillo@iib.uam.es RI Corbi, Angel/B-7194-2011; Tabraue, Carlos/D-7126-2015; Alonso Gonzalez , Noelia/H-4488-2015; Hidalgo, Andres/L-5643-2014 OI Corbi, Angel/0000-0003-1980-5733; Tabraue, Carlos/0000-0001-9920-8116; Alonso Gonzalez , Noelia/0000-0003-0533-5216; Hidalgo, Andres/0000-0001-5513-555X FU Spanish Ministry of Research and Innovation [SAF2008-00057]; Ministry of Economy and Competitiveness [SAF2011-29244, SAF2009-11037]; European Union [IRG246655]; Howard Hughes Medical Institute; US National Institutes of Health [HL-066088, HL-030568]; Subprograma Ramon y Cajal [RYC-2007-00697]; Formacion de Personal Investigador [BES-2010-032828, BES-2009-012191]; Universidad Las Palmas de Gran Canaria FX We thank D. Mangelsdorf (University of Texas Southwestern Medical Center) for LXR alpha- and LXR beta-sufficient wild-type (Nr1h3+/+ Nr1h2+/+) mice, LXR alpha-deficient (Nr1h3-/-) mice, LXR alpha-deficient (Nr1h2-/-) mice and LXR-deficient (Nr1h3-/-Nr1h2-/-) mice; the Institut Clinique de la Souris for Nr1h3fl/fl mice; D. Kioussis (Medical Research Council) and S. Gonzalez (Centro Nacional de Investigaciones Cardiovasculares) for Vav-Cre mice; S. Gordon and M. Stacey (University of Oxford) for antibody to F4/80 (anti-F4/80) and anti-CD169; G. Randolph (Washington University St. Louis) for discussions and anti-TREML4 from the R. Steinman laboratory (Rockefeller University); M. Kosco-Vilbois (NovImmune) for anti-FDC-M1 and anti-FDC-M2; J. Collins and T. Willson (GlaxoSmithKline) for the synthetic ligands of LXR (GW3965) and retinoid X receptor (LG268); N. Ruddle, C. Glass, N. Spann, A. Chawla, G. Lemke, D. Hume, L. Hedrick, A. Lazarus and L. Bosca for comments; and Servicio Microscopia Electronica (University of Las Palmas de Gran Canaria) for electron microscopy. Supported by the Spanish Ministry of Research and Innovation (SAF2008-00057 to A.C.), the Ministry of Economy and Competitiveness (SAF2011-29244 to A.C. and SAF2009-11037 to A.H.), Framework Programme 7 of the European Union (International Reintegration Grant IRG246655 to A. H.), the Howard Hughes Medical Institute (P.T.), the US National Institutes of Health (HL-066088 and HL-030568 to P.T.), Subprograma Ramon y Cajal (RYC-2007-00697 to A. H.), Formacion de Personal Investigador (BES-2010-032828 to M. C.-A. and BES-2009-012191 to I.H.H.) and Universidad Las Palmas de Gran Canaria (J.V.d.l.R.). NR 47 TC 32 Z9 34 U1 3 U2 20 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 AUG PY 2013 VL 14 IS 8 BP 831 EP + DI 10.1038/ni.2622 PG 11 WC Immunology SC Immunology GA 185ZN UT WOS:000322010600012 PM 23770640 ER PT J AU Posthuma, R Weinstein, MM Iyer, S Alperin, M Wakamatsu, MM Pulliam, SJ AF Posthuma, R. Weinstein, M. M. Iyer, S. Alperin, M. Wakamatsu, M. M. Pulliam, S. J. TI CLINICAL APPLICATION OF THE IUGA/ICS CLASSIFICATION SYSTEM FOR MESH-RELATED COMPLICATIONS SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT 43rd Annual Meeting of the International-Continence-Society (ICS) CY AUG 26-30, 2013 CL Barcelona, SPAIN SP Int Continence Soc (ICS) C1 [Posthuma, R.; Weinstein, M. M.; Iyer, S.; Wakamatsu, M. M.; Pulliam, S. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Alperin, M.] Univ Calif San Diego, San Diego, CA 92103 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0733-2467 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD AUG PY 2013 VL 32 IS 6 MA 253 BP 876 EP 877 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 178HP UT WOS:000321437700254 ER PT J AU Limaye, S Riley, S Zhao, SH O'Neill, A Posner, M Adkins, D Jaffa, Z Clark, J Haddad, R AF Limaye, Sewanti Riley, Sarah Zhao, Sihai O'Neill, Anne Posner, Marshall Adkins, Douglas Jaffa, Zachary Clark, John Haddad, Robert TI A randomized phase II study of docetaxel with or without vandetanib in recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN) SO ORAL ONCOLOGY LA English DT Article DE Recurrent/metastatic; Head and neck cancer; Palliative chemotherapy; Targeted therapy ID LUNG-CANCER; COMBINATION CHEMOTHERAPY; PLUS DOCETAXEL; ACTIVE-DRUG; ANGIOGENESIS; BEVACIZUMAB; CISPLATIN; TRIAL; ERLOTINIB; THERAPY AB Objectives: There are limited chemotherapeutic options for advanced recurrent or metastatic SCCHN. The efficacy and toxicity of docetaxel with or without vandetanib was investigated in these patients. Materials and Methods: Patients with pathologically confirmed, recurrent or metastatic SCCHN who had progressed on platinum based therapy given as definitive or palliative treatment, were randomized in this open label, multicenter phase II study of docetaxel (75 mg/m2 IV Q3 weeks) with or without vandetanib (100 mg PO daily). The primary objective was response rate (RR) and secondary objectives were progression free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DOR). Results: 29 analyzable patients were enrolled, 14 in docetaxel arm and 15 in combined arm. PR was achieved in 1 patient in the docetaxel arm and 2 patients in the combined arm. The objective RR was 7% (1/14) (95% CI 0.2-33.8%) in the single and 13% (2/15) (95% CI 1.6-40.4%) combined arm. The median PFS was 3.21 (95% CI 3.0-22.0) and 9 (95% CI (5.86-18.1) weeks; median OS was 26.8(95% CI 17.7-100.7+) and 24.1 (95% CI, 16.4-171.1+) weeks. Most common adverse events were fatigue, dysphagia, diarrhea or constipation, cytopenias and alopecia. Conclusions: Although an initial benefit in response was noted and statistical criteria met there was only a minor trend towards improved PFS for the combined arm. The study was designed with low threshold for activity in each arm and results were deemed not to be of enough clinical significance in this group of patients to continue accrual. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Limaye, Sewanti; Riley, Sarah; Jaffa, Zachary; Haddad, Robert] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Limaye, Sewanti; Riley, Sarah; Jaffa, Zachary; Haddad, Robert] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Zhao, Sihai; O'Neill, Anne] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Posner, Marshall] Mt Sinai Sch Med, New York, NY 10029 USA. [Adkins, Douglas] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Clark, John] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Limaye, S (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM SewantiA_limaye@dfci.harvard.edu FU AstraZeneca FX AstraZeneca. NR 30 TC 13 Z9 14 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD AUG PY 2013 VL 49 IS 8 BP 835 EP 841 DI 10.1016/j.oraloncology.2013.04.010 PG 7 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 178HS UT WOS:000321438100020 PM 23727257 ER PT J AU Snorrason, I Olafsson, RP Flessner, CA Keuthen, NJ Franklin, ME Woods, DW AF Snorrason, Ivar Olafsson, Ragnar P. Flessner, Christopher A. Keuthen, Nancy J. Franklin, Martin E. Woods, Douglas W. TI The Skin Picking Impact Scale: Factor structure, validity and development of a short version SO SCANDINAVIAN JOURNAL OF PSYCHOLOGY LA English DT Article DE Skin picking impact scale; pathological skin picking; psychogenic excoriation; factor analysis; validity; reliability; psychosocial impact ID CLINICAL CHARACTERISTICS; ECONOMIC-IMPACT; FIT INDEXES; SAMPLE; TRICHOTILLOMANIA; PHENOMENOLOGY; POPULATION; TESTS AB In the present study, we examined the psychometric properties of the Skin Picking Impact Scale (SPIS; Keuthen, Deckersbach, Wilhelm etal., 2001), a 10 item self-report questionnaire designed to assess the psychosocial impact of skin picking disorder (SPD). Participants were 650 individuals who met criteria for SPD in an online survey. Exploratory and confirmatory factor analyses demonstrated a unitary factor structure with high internal consistency (alpha = 0.94). Consequently, we constructed an abbreviated 4-item version that retained good internal consistency (alpha = 0.87) and a robust factor structure. Both the short and the full versions demonstrated discriminant and convergent/concurrent validity. In conclusion, the findings indicate that both versions are psychometrically sound measures of SPD related psychosocial impact; however, some potential limitations of the full scale are discussed. C1 [Snorrason, Ivar; Woods, Douglas W.] Univ Wisconsin Milwaukee, Dept Psychol, Milwaukee, WI 53211 USA. [Olafsson, Ragnar P.] Univ Iceland, Sch Hlth Sci, Landspitali Univ Hosp, Div Psychiat, IS-101 Reykjavik, Iceland. [Olafsson, Ragnar P.] Univ Iceland, Sch Hlth Sci, Fac Psychol, IS-101 Reykjavik, Iceland. [Flessner, Christopher A.] Kent State Univ, Dept Psychol, Kent, OH USA. [Keuthen, Nancy J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Cambridge, MA 02138 USA. [Franklin, Martin E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Snorrason, I (reprint author), Univ Wisconsin Milwaukee, Dept Psychol, 2441 East Hartford Ave, Milwaukee, WI 53211 USA. EM ivarsnorrason@gmail.com RI Flessner, Christopher/K-1483-2015 NR 24 TC 5 Z9 6 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0036-5564 J9 SCAND J PSYCHOL JI Scand. J. Psychol. PD AUG PY 2013 VL 54 IS 4 BP 344 EP 348 DI 10.1111/sjop.12057 PG 5 WC Psychology, Multidisciplinary SC Psychology GA 182PM UT WOS:000321756200011 PM 23682651 ER PT J AU Pugh, TD Conklin, MW Evans, TD Polewski, MA Barbian, HJ Pass, R Anderson, BD Colman, RJ Eliceiri, KW Keely, PJ Weindruch, R Beasley, TM Anderson, RM AF Pugh, Thomas D. Conklin, Matthew W. Evans, Trent D. Polewski, Michael A. Barbian, Hannah J. Pass, Rachelle Anderson, Bradley D. Colman, Ricki J. Eliceiri, Kevin W. Keely, Patricia J. Weindruch, Richard Beasley, T. Mark Anderson, Rozalyn M. TI A shift in energy metabolism anticipates the onset of sarcopenia in rhesus monkeys SO AGING CELL LA English DT Article DE aging; metabolism; mitochondria; NAD; PGC-1; skeletal muscle; rhesus monkeys ID TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; SKELETAL-MUSCLE; FLUORESCENCE MICROSCOPY; CALORIE RESTRICTION; BODY-COMPOSITION; IN-VIVO; AGE; SIRT1; ADAPTATION; BIOLOGY AB Age-associated skeletal muscle mass loss curtails quality of life and may contribute to defects in metabolic homeostasis in older persons. The onset of sarcopenia occurs in middle age in rhesusmacaques although the trigger has yet to be identified. Here, we show that a shift in metabolism occurs in advance of the onset of sarcopenia in rhesus vastuslateralis. Multiphoton laser-scanning microscopy detects a shift in the kinetics of photon emission from autofluorescent metabolic cofactors NADH and FAD. Lifetime of both fluorophores is shortened at mid-age, and this is observed in both free and bound constituent pools. Levels of FAD and free NADH are increased and the NAD/NADH redox ratio is lower. Concomitant with this, expression of fiber-type myosin isoforms is altered resulting in a shift in fiber-type distribution, activity of cytochrome c oxidase involved in mitochondrial oxidative phosphorylation is significantly lower, and the subcellular organization of mitochondria in oxidative fibers is compromised. A regulatory switch involving the transcriptional coactivator PGC-1 directs metabolic fuel utilization and governs the expression of structural proteins. Age did not significantly impact total levels of PGC-1; however, its subcellular localization was disrupted, suggesting that PGC-1 activities may be compromised. Consistent with this, intracellular lipid storage is altered and there is shift to larger lipid droplet size that likely reflects a decline in lipid turnover or a loss in efficiency of lipid metabolism. We suggest that changes in energy metabolism contribute directly to skeletal muscle aging in rhesus monkeys. C1 [Pugh, Thomas D.; Evans, Trent D.; Polewski, Michael A.; Barbian, Hannah J.; Pass, Rachelle; Anderson, Bradley D.; Weindruch, Richard; Anderson, Rozalyn M.] Univ Wisconsin, Dept Med, Madison, WI 53706 USA. [Conklin, Matthew W.; Eliceiri, Kevin W.] Univ Wisconsin, Lab Opti& Computat Instrumen, Madison, WI 53706 USA. [Colman, Ricki J.; Anderson, Rozalyn M.] Univ Wisconsin, Natl Primate Res Ctr, Madison, WI 53715 USA. [Keely, Patricia J.] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53706 USA. [Weindruch, Richard; Anderson, Rozalyn M.] William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI 53705 USA. [Beasley, T. Mark] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. RP Anderson, RM (reprint author), VA Hosp, GRECC D5214,2500 Overlook Terrace, Madison, WI 53705 USA. EM rmanderson@medicine.wisc.edu OI Eliceiri, Kevin/0000-0001-8678-670X FU NIA [P01AG011915]; NIH [UL1RR025011, R01CA13659, R01AG037000]; Department of Medicine, School of Medicine and Public Health, UW Madison FX We would like to acknowledge Scott Baum and Susan McKiernan for assistance with sample procurement. We also thank staff at LOCI for assistance with imaging instrumentation. Funding for this study was provided by NIA grant P01AG011915, NIH UL1RR025011, NIH R01CA13659, NIH R01AG037000, and the Department of Medicine, School of Medicine and Public Health, UW Madison. The study was conducted with the use of resources and facilities at the William S. Middleton Memorial Veterans Hospital, Madison WI. NR 48 TC 14 Z9 14 U1 2 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD AUG PY 2013 VL 12 IS 4 BP 672 EP 681 DI 10.1111/acel.12091 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 182WP UT WOS:000321775800015 PM 23607901 ER PT J AU Trickett, EJ Beehler, S AF Trickett, Edison J. Beehler, Sarah TI The Ecology of Multilevel Interventions to Reduce Social Inequalities in Health SO AMERICAN BEHAVIORAL SCIENTIST LA English DT Article DE multilevel; interventions; inequality; health ID PUBLIC-HEALTH; TRANSDISCIPLINARY RESEARCH; PROMOTION PROGRAMS; NETWORK ANALYSIS; COMMUNITY; DISPARITIES; SCIENCE; OBESITY; EQUITY; IMPACT AB Health inequities persist and, in some cases, are increasing. Multilevel interventions involve efforts to change aspects of social contexts related to the creation and maintenance of health inequities among varied groups. Momentum for conducting multilevel interventions to achieve health equity is found across professional fields as well as scientific and funding organizations. This article discusses the rationale for multilevel interventions, briefly reviews their evolution over time with respect to health inequities, and provides an ecological way of thinking about some of the conceptual and pragmatic challenges they raise for social science. This perspective frames community interventions as multilevel, ecologically based, collaboratively conducted, culturally situated, and designed to increase community capacity. Implications of this perspective are drawn for the development, implementation, and evaluation of multilevel interventions. C1 [Trickett, Edison J.] Univ Illinois, Chicago, IL 60607 USA. [Trickett, Edison J.] Univ Illinois, Dept Psychol, Community & Prevent Res Div, Chicago, IL 60607 USA. [Beehler, Sarah] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Jamaica Plain, MA USA. RP Trickett, EJ (reprint author), Univ Illinois, 1007 West Harrison St, Chicago, IL 60607 USA. EM trickett@uic.edu NR 93 TC 14 Z9 14 U1 1 U2 33 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0002-7642 J9 AM BEHAV SCI JI Am. Behav. Sci. PD AUG PY 2013 VL 57 IS 8 SI SI BP 1227 EP 1246 DI 10.1177/0002764213487342 PG 20 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA 181XR UT WOS:000321704500011 ER PT J AU Harte, CB Liverant, GI Sloan, DM Kamholz, BW Rosebrock, LE Fava, M Kaplan, GB AF Harte, Christopher B. Liverant, Gabrielle I. Sloan, Denise M. Kamholz, Barbara W. Rosebrock, Laina E. Fava, Maurizio Kaplan, Gary B. TI Association Between Smoking and Heart Rate Variability Among Individuals with Depression SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Smoking; Depression; Heart rate variability; Cardiac autonomic regulation; Autonomic nervous system ID ACUTE MYOCARDIAL-INFARCTION; COMORBIDITY SURVEY REPLICATION; CORONARY-ARTERY DISEASE; CIGARETTE-SMOKING; SPECTRAL-ANALYSIS; SHORT-TERM; MAJOR DEPRESSION; MORTALITY; POPULATION; CESSATION AB Both depression and smoking have been independently associated with lower heart rate variability (HRV), suggesting dysregulation of cardiac autonomic function. However, no studies have systematically explored the effects of smoking on HRV among depressed patients. This study examined differences in HRV based on smoking status among depressed individuals. Electrophysiological data were examined among 77 adult outpatients without a history of myocardial infarction, who met criteria for major depressive disorder or dysthymia. Frequency domain [low frequency (LF), high frequency (HF), LF/HF ratio, respiratory sinus arrhythmia (RSA)] parameters of HRV, and heart rate and inter-beat interval (IBI) data were compared between depressed smokers (n = 34) and depressed nonsmokers (n = 44). After controlling for covariates, depressed smokers, compared to depressed nonsmokers, displayed significantly lower LF, HF, and RSA. Among depressed patients, smoking is associated with significantly lower HRV, indicating dysregulated autonomic modulation of the heart. C1 [Harte, Christopher B.; Liverant, Gabrielle I.; Sloan, Denise M.; Kamholz, Barbara W.; Rosebrock, Laina E.; Kaplan, Gary B.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Harte, Christopher B.; Liverant, Gabrielle I.; Sloan, Denise M.; Kamholz, Barbara W.; Kaplan, Gary B.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Sloan, Denise M.] Natl Ctr PTSD, Boston, MA USA. [Kamholz, Barbara W.] Boston Univ, Boston, MA 02215 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fava, Maurizio] Harvard Univ, Sch Med, Boston, MA USA. RP Harte, CB (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave 116-B4, Boston, MA 02130 USA. EM christopher.harte@va.gov OI Sloan, Denise/0000-0002-0962-478X; Harte, Christopher/0000-0002-8097-7369 NR 41 TC 6 Z9 6 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD AUG PY 2013 VL 46 IS 1 BP 73 EP 80 DI 10.1007/s12160-013-9476-8 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 180GC UT WOS:000321580800011 PM 23436273 ER PT J AU Clark, DJ Kautz, SA Bauer, AR Chen, YT Christou, EA AF Clark, David J. Kautz, Steven A. Bauer, Andrew R. Chen, Yen-Ting Christou, Evangelos A. TI Synchronous EMG Activity in the Piper Frequency Band Reveals the Corticospinal Demand of Walking Tasks SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Walking; Electromyography; Motor control; Nervous system; Locomotion ID EVOKED MOTOR-RESPONSES; CORTICOMUSCULAR COHERENCE; HUMAN GAIT; DEPENDENT MODULATION; MUSCLE-ACTIVITY; SURFACE EMG; EEG-EMG; CORTEX; OSCILLATIONS; DRIVE AB Evidence indicates that the frequency-domain characteristics of surface electromyogram (EMG) signals are modulated according to the contributing sources of neural drive. Modulation of inter-muscular EMG synchrony within the Piper frequency band (30-60 Hz) during movement tasks has been linked to drive from the corticospinal tract. However, it is not known whether EMG synchrony is sufficiently sensitive to detect task-dependent differences in the corticospinal contribution to leg muscle activation during walking. We investigated this question in seventeen healthy older men and women. It was hypothesized that, relative to typical steady state walking, Piper band EMG synchrony of the triceps surae muscle group would be reduced for dual-task walking (because of competition for cortical resources), similar for fast walking (because walking speed is directed by an indirect locomotor pathway rather than by the corticospinal tract), and increased when taking a long step (because voluntary gait pattern modifications are directed by the corticospinal tract). Each of these hypotheses was confirmed. These findings support the use of frequency-domain analysis of EMG in future investigations into the corticospinal contribution to control of healthy and disordered human walking. C1 [Clark, David J.; Bauer, Andrew R.] Malcom Randall VA Med Ctr, Brain Rehabil Res Ctr, Gainesville, FL 32608 USA. [Clark, David J.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL 32610 USA. [Kautz, Steven A.] Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. [Kautz, Steven A.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Chen, Yen-Ting; Christou, Evangelos A.] Univ Florida, Dept Appl Physiol & Kinesiol, Gainesville, FL 32611 USA. RP Clark, DJ (reprint author), Malcom Randall VA Med Ctr, Brain Rehabil Res Ctr, 1601 SW Archer Rd 151A, Gainesville, FL 32608 USA. EM davidclark@ufl.edu OI Kautz, Steven/0000-0003-3151-8235 FU US Department of Veterans Affairs Rehabilitation Research and Development Service [B7176W]; National Institute on Aging [P30-AG028740-04, R01 AG-031769] FX This work was supported by the US Department of Veterans Affairs Rehabilitation Research and Development Service (B7176W to DJC) and by the National Institute on Aging (P30-AG028740-04 to DJC and R01 AG-031769 to EAC). NR 50 TC 6 Z9 7 U1 1 U2 12 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 AUG PY 2013 VL 41 IS 8 BP 1778 EP 1786 DI 10.1007/s10439-013-0832-4 PG 9 WC Engineering, Biomedical SC Engineering GA 179IT UT WOS:000321514300019 PM 23740367 ER PT J AU de Souza, P Rathkopf, D Smith, M Mulders, P Mainwaring, P North, S Griffin, T Park, Y Molina, A Ryan, C AF de Souza, Paul Rathkopf, Dana Smith, Matthew Mulders, Peter Mainwaring, Paul North, Scott Griffin, Thomas Park, Youn Molina, Arturo Ryan, Charles TI Long-term safety and efficacy analysis of abiraterone acetate (AA) plus prednisone (P) in study COU-AA-302for metastatic castration-resistant prostate cancer SO BJU INTERNATIONAL LA English DT Meeting Abstract C1 [de Souza, Paul] Univ Western Sydney, Penrith, NSW 1797, Australia. [Rathkopf, Dana] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Smith, Matthew] Massachusetts Gen Hosp Canc Ctr, Boston, MA USA. [Mulders, Peter] Radboud Univ Nijmegen Med Ctr, Nijmegen, Netherlands. [North, Scott] Cross Canc Inst, Edmonton, AB, Canada. [Griffin, Thomas; Molina, Arturo] Janssen Res & Dev, Los Angeles, CA USA. [Park, Youn] Janssen Res & Dev, Raritan, NJ USA. [Ryan, Charles] Univ Calif San Francisco, San Francisco, CA 94143 USA. RI Mulders, Peter/H-8076-2014 NR 1 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD AUG PY 2013 VL 112 SU 1 SI SI BP 13 EP 13 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 185LK UT WOS:000321969100032 ER PT J AU DeAngelo, DJ Mesa, RA Fiskus, W Tefferi, A Paley, C Wadleigh, M Ritchie, EK Snyder, DS Begna, K Ganguly, S Ondovik, MS Rine, J Bhalla, KN AF DeAngelo, Daniel J. Mesa, Ruben A. Fiskus, Warren Tefferi, Ayalew Paley, Carole Wadleigh, Martha Ritchie, Ellen K. Snyder, David S. Begna, Kebede Ganguly, Siddhartha Ondovik, Michael S. Rine, Jessica Bhalla, Kapil N. TI Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE myelofibrosis; myeloproliferative neoplasms; panobinostat; histone deacetylase inhibitors ID CHRONIC MYELOPROLIFERATIVE NEOPLASMS; JAK2 INHIBITOR; CELLS; EFFICACY; THERAPY; LBH589; EZH2 AB Myelofibrosis (MF) is a Philadelphia chromosome-negative stem cell myeloproliferative neoplasm (MPN) associated with cytopenias, splenomegaly, constitutional symptoms, and poor prognosis. MF patients commonly express JAK2 V617F mutation and activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Agents targeting the JAK/STAT pathway have demonstrated efficacy in patients with MF. This study evaluated panobinostat, a pan-deacetylase inhibitor that depletes JAK2 V617F levels and JAK/STAT signalling in MPN cells, in patients with primary MF, post-essential thrombocythaemia MF, and post-polycythaemia vera MF. Patients received panobinostat 40 mg administered three times per week. Dose reductions were permitted for toxicities. The primary endpoint was response rate at 6 months using International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) consensus criteria. Analyses of peripheral blood cells from treated patients revealed that panobinostat inhibited JAK/STAT signalling, decreased inflammatory cytokine levels, and decreased JAK2 V617F allelic burden. However, panobinostat was poorly tolerated at the dose and schedule evaluated, and only 16 of 35 patients completed 2 cycles of treatment. One patient (3%) achieved an IWG-MRT response. Common adverse events were thrombocytopenia (71 center dot 4%) and diarrhoea (80 center dot 0%). Although molecular correlative analyses suggested that panobinostat inhibits key intracellular targets, limited clinical activity was observed because of poor tolerance. C1 [DeAngelo, Daniel J.; Wadleigh, Martha] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mesa, Ruben A.] Mayo Clin, Scottsdale, AZ USA. [Fiskus, Warren; Ganguly, Siddhartha; Bhalla, Kapil N.] Methodist Hosp Res Inst, Cockrell Ctr Adv Therapeut, Houstony, TX USA. [Tefferi, Ayalew] Mayo Clin, Rochester, MN USA. [Paley, Carole; Ondovik, Michael S.; Rine, Jessica] Novartis Pharmaceut, E Hanover, NJ USA. [Ritchie, Ellen K.] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA. [Snyder, David S.] City Hope Natl Med Ctr, Duarte, CA USA. RP DeAngelo, DJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana D1B30, Boston, MA 02215 USA. EM daniel_deangelo@dfci.harvard.edu; knbhalla@tmhs.org FU Novartis Pharmaceuticals Corporation FX This study was funded by Novartis Pharmaceuticals Corporation. The authors thank Ghulam Warsi, PhD, for assistance with statistical analysis; Robyn Scherber for analysis of the MF-SAF data; and William Fazzone, PhD, for medical editorial assistance with this manuscript. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. NR 27 TC 35 Z9 35 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2013 VL 162 IS 3 BP 326 EP 335 DI 10.1111/bjh.12384 PG 10 WC Hematology SC Hematology GA 180BV UT WOS:000321568800006 PM 23701016 ER PT J AU Chasman, D Schurks, M Anttila, V Kurth, T AF Chasman, D. Schuerks, M. Anttila, V. Kurth, T. TI Preferential Association of Migraine Loci with Migraine Characterized by Specific Traits on a Population Basis SO CEPHALALGIA LA English DT Meeting Abstract CT International Headache Congress CY JUN 27-30, 2013 CL Boston, MA SP Int Headache Soc, Amer Headache Soc C1 [Chasman, D.; Kurth, T.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schuerks, M.] Univ Hosp, Essen, Germany. [Anttila, V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kurth, T.] INSERM, U708, Bordeaux, France. [Kurth, T.] Univ Bordeaux, Bordeaux, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 J9 CEPHALALGIA JI Cephalalgia PD AUG PY 2013 VL 33 IS 11 BP 986 EP 987 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 176VJ UT WOS:000321333800062 ER PT J AU Tritos, NA Hamrahian, AH King, D Greenspan, SL Cook, DM Jonsson, PJ Koltowska-Haggstrom, M Biller, BMK AF Tritos, Nicholas A. Hamrahian, Amir H. King, Donna Greenspan, Susan L. Cook, David M. Jonsson, Peter J. Koltowska-Haggstrom, Maria Biller, Beverly M. K. TI Predictors of the effects of 4years of growth hormone replacement on bone mineral density in patients with adult-onset growth hormone deficiency - a KIMS database analysis SO CLINICAL ENDOCRINOLOGY LA English DT Article ID GH REPLACEMENT; HYPOPITUITARY PATIENTS; BODY-COMPOSITION; GLUCOCORTICOID REPLACEMENT; POSTMENOPAUSAL WOMEN; METABOLISM; THERAPY; OSTEOPOROSIS; MULTICENTER; GENDER AB Objective Growth hormone (GH) replacement may increase bone mineral density (BMD) in GH-deficient (GHD) adults. The goal of this study was to identify predictors of BMD response to GH replacement in GH naive adults. Design and measurements This was a retrospective analysis of data extracted from KIMS (Pfizer International Metabolic Database), an international pharmacoepidemiological survey of adult GHD patients from 31 countries. Patients A total of 231 GH naive adults were identified (115 women and 116 men) who had BMD measured on the same densitometer in the lumbar spine (LS) and/or femoral neck (FN) both at baseline and after 4 years of GH replacement. Results After 4 years, there was a median (10th, 90th percentile) 4.6% (-5.2%, 12.2%) increase in LS BMD over baseline (P = 0.0001). There was a positive correlation between per cent change in LS BMD and age at the onset of pituitary disease (r = 0.25, P = 0.001). There was no change in FN BMD over baseline [0.0% (-7.3%, 8.5%)]. On multivariate analysis, older age at the onset of pituitary disease predicted a greater increase in LS BMD on GH replacement (r = 0.55, P < 0.0001). Conclusions In a population of GH naive adults, GH replacement led to a significant increase in LS BMD over baseline, but no change in FN BMD. The potential for greater BMD improvement on GH replacement therapy in adults with disease of later onset should be considered when making treatment decisions in this patient population. C1 [Tritos, Nicholas A.; Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Tritos, Nicholas A.; Biller, Beverly M. K.] Harvard Univ, Sch Med, Boston, MA USA. [Hamrahian, Amir H.] Cleveland Clin, Dept Diabet Endocrinol & Metab, Cleveland, OH 44106 USA. [King, Donna] Pfizer Inc, New York, NY USA. [Greenspan, Susan L.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Cook, David M.] Oregon Hlth & Sci Univ, Dept Endocrinol, Portland, OR 97201 USA. [Jonsson, Peter J.; Koltowska-Haggstrom, Maria] Pfizer Inc, Pfizer Endocrine Care, Sollentuna, Sweden. RP Tritos, NA (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, 0 Emerson Pl,Suite 112, Boston, MA 02114 USA. EM ntritos@partners.org FU Pfizer, Inc.; Pfizer; Ipsen; Novartis; Eli Lilly; Warner Chilcott; Tarsa; Novo Nordisk; Serono FX KIMS is sponsored by Pfizer, Inc. N.A.T., A.H.H., S.L.G., D.M.C. and B.M.K.B. were not compensated for their contributions to this manuscript.; N.A.T. has been a recipient of research funding from Pfizer and Ipsen, and received consulting fees from Pfizer; spouse is an employee of Pfizer. A.H.H. has been a recipient of lecture fees from Novartis, Ipsen and Pfizer, and has served as consultant to Ipsen and Pfizer. S.L.G. has been a recipient of research funding from Eli Lilly, Warner Chilcott, Tarsa, and has consulted and served on an advisory board for Amgen and Merck. D.K., P.J.J. and M.K-H. are full-time employees of Pfizer. B.M.K.B. has been a recipient of research funding from Pfizer, Novo Nordisk and Serono, has served on an advisory board with consulting fees from Pfizer and Novo Nordisk. NR 34 TC 5 Z9 5 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 AUG PY 2013 VL 79 IS 2 BP 178 EP 184 DI 10.1111/cen.12132 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 180CP UT WOS:000321570800006 PM 23278636 ER PT J AU Bredella, MA McManus, S Misra, M AF Bredella, Miriam A. McManus, Shilpa Misra, Madhusmita TI Impact of metformin monotherapy versus metformin with oestrogen-progesterone on lipids in adolescent girls with polycystic ovarian syndrome SO CLINICAL ENDOCRINOLOGY LA English DT Article ID COMBINED ORAL-CONTRACEPTIVES; INSULIN-SENSITIZING AGENTS; HYPERINSULINEMIC HYPERANDROGENISM; MYOCARDIAL-INFARCTION; FLUTAMIDE-METFORMIN; 2 FORMS; WOMEN; THERAPY; TESTOSTERONE; METAANALYSIS AB Objective Hyperinsulinaemia is an important determinant of the polycystic ovarian syndrome (PCOS). In addition to lifestyle measures, therapeutic strategies include the use of oestrogen-progesterone combination pills (EP), and insulin sensitizers such as metformin, either alone or in combination. Data are limited regarding the impact of metformin alone vs metformin with EP on cardiometabolic risk in overweight adolescents with PCOS. We hypothesized that metformin alone would lead to an improvement in HbA1C and lipid levels in overweight adolescent girls with PCOS compared with meformin with EP. Study design Retrospective clinic-based therapy. Patients and measurements We examined the effects of therapy with metformin alone (n = 14) vs metformin with EP (n = 13) on HbA1C and lipid parameters over 10-14 months in 27 overweight girls, drawn from a clinic population of adolescents with PCOS. Results The groups did not differ for age, body mass index (BMI), HbA1C or baseline lipids. After at least 10 months, the metformin only group compared with the metformin and EP group had a decrease in total cholesterol (-0.605 +/- 0.100 vs 0.170 +/- 0.348 mM, P = 0.02, nonparametric test) and triglycerides (-0.342 +/- 0.184 vs 0.262 +/- 0.133 mM, P = 0.02), despite similar changes in BMI (-1.6 +/- 0.7 vs 0.6 +/- 2.1 kg/m(2), P = 0.25) and HbA1C (0.03 +/- 0.06 vs 0.03 +/- 0.13%, P = 0.99). Differences between groups remained significant after controlling for baseline parameters and for changes in BMI. Conclusion Metformin alone more effectively improves lipid parameters than metformin with EP in adolescent PCOS, as indicated by a decrease in total cholesterol and triglycerides. This effect is not related to BMI changes. C1 [Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Bredella, Miriam A.; McManus, Shilpa; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA USA. [McManus, Shilpa; Misra, Madhusmita] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, Boston, MA 02114 USA. EM mmisra@partners.org FU NICHD NIH HHS [K24 HD071843] NR 25 TC 8 Z9 12 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD AUG PY 2013 VL 79 IS 2 BP 199 EP 203 DI 10.1111/cen.12028 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 180CP UT WOS:000321570800009 PM 22928702 ER PT J AU Wiggs, JL Howell, GR Linkroum, K Abdrabou, W Hodges, E Braine, CE Pasquale, LR Hannon, GJ Haines, JL John, SWM AF Wiggs, J. L. Howell, G. R. Linkroum, K. Abdrabou, W. Hodges, E. Braine, C. E. Pasquale, L. R. Hannon, G. J. Haines, J. L. John, S. W. M. TI Variations in COL15A1 and COL18A1 influence age of onset of primary open angle glaucoma SO CLINICAL GENETICS LA English DT Article DE collagen; glaucoma; modifying gene; myocilin ID AMINO-ACID SUBSTITUTIONS; GENETIC-HETEROGENEITY; GLN368STOP MUTATION; MYOCILIN MUTATION; COLLAGEN-XV; MOUSE MODEL; POLYMORPHISM; EXPRESSION; ENDOSTATIN; MODIFIER AB Primary open angle glaucoma (POAG) is a genetically and phenotypically complex disease that is a leading cause of blindness worldwide. Previously we completed a genome-wide scan for early-onset POAG that identified a locus on 9q22 (GLC1J). To identify potential causative variants underlying GLC1J, we used targeted DNA capture followed by high throughput sequencing of individuals from four GLC1J pedigrees, followed by Sanger sequencing to screen candidate variants in additional pedigrees. A mutation likely to cause early-onset glaucoma was not identified, however COL15A1 variants were found in the youngest affected members of 7 of 15 pedigrees with variable disease onset. In addition, the most common COL15A1 variant, R163H, influenced the age of onset in adult POAG cases. RNA in situ hybridization of mouse eyes shows that Col15a1 is expressed in the multiple ocular structures including ciliary body, astrocytes of the optic nerve and cells in the ganglion cell layer. Sanger sequencing of COL18A1, a related multiplexin collagen, identified a rare variant, A1381T, in members of three additional pedigrees with early-onset disease. These results suggest genetic variation in COL15A1 and COL18A1 can modify the age of onset of both early and late onset POAG. C1 [Wiggs, J. L.; Linkroum, K.; Abdrabou, W.; Pasquale, L. R.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Wiggs, J. L.; Linkroum, K.; Abdrabou, W.; Pasquale, L. R.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Howell, G. R.; Braine, C. E.; John, S. W. M.] Jackson Lab, Bar Harbor, ME 04609 USA. [Hodges, E.; Hannon, G. J.] Cold Spring Harbor Lab, Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA. [Hodges, E.; Hannon, G. J.] Cold Spring Harbor Lab, Howard Hughes Med Inst, Cold Spring Harbor, NY 11724 USA. [Haines, J. L.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. [John, S. W. M.] Howard Hughes Med Inst, Bar Harbor, ME USA. RP Wiggs, JL (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM janey_wiggs@meei.harvard.edu FU NIH [EY00947, EY015872, EY010886, P30 Ey014104, EY011721, EY021525]; Pew Foundation; Kathryn Davis and family FX This work was supported by NIH EY00947 (J. L. W.), EY015872 (J. L. W.), EY010886 (J. L. W.), P30 Ey014104 (J. L. W.), NIH EY011721 (S. W. M. J.), NIH EY021525 (G. R. H.), the Pew Foundation and Kathryn Davis and family. S. W. M. J. is an investigator of the Howard Hughes Medical Institute. NR 40 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD AUG PY 2013 VL 84 IS 2 BP 167 EP 174 DI 10.1111/cge.12176 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 179CN UT WOS:000321495800010 PM 23621901 ER PT J AU Branda, JA Strle, F Strle, K Sikand, N Ferraro, MJ Steere, AC AF Branda, John A. Strle, Franc Strle, Klemen Sikand, Nikhil Ferraro, Mary Jane Steere, Allen C. TI Performance of United States Serologic Assays in the Diagnosis of Lyme Borreliosis Acquired in Europe SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Lyme; Borrelia burgdorferi; VlsE; C6; diagnosis ID BURGDORFERI SENSU-LATO; LINKED IMMUNOSORBENT ASSAYS; STANDARDIZED WESTERN BLOTS; VARIABLE SURFACE-ANTIGEN; C6 PEPTIDE ELISA; INTERPRETATION CRITERIA; ANTIBODY-RESPONSE; ERYTHEMA MIGRANS; DISEASE; VLSE AB Background. Physicians in the United States sometimes need to evaluate a patient for suspected Lyme borreliosis (LB) who may have acquired the infection in Europe. Using serum samples from European LB patients, we compared the performance of European and US serodiagnostic tests, including newer-generation assays containing Vmp-like sequence, expressed or its C6 peptide. Methods. The sensitivity of each assay was determined using 64 serum samples from LB patients with early or late disease manifestations who acquired the infection in Europe. Specificity was measured using 100 sera from healthy subjects from a nonendemic area. Results. For the detection of European-acquired infection, conventional 2-tiered testing (enzyme-linked immunosorbent assay [ ELISA] followed by immunoblotting) using US assays had an overall sensitivity and specificity of 52% and 100%, compared with 81% (P = .0007) and 99% (P = 1.00) using analogous European tests. The sensitivity of a US C6 ELISA used as a stand-alone test (88% overall) was statistically comparable to that of conventional 2-tiered testing using European tests (P = .47) and was 100% specific. Similarly, an alternative 2-tiered algorithm using a standard US ELISA followed by a C6 ELISA was comparably sensitive (84% overall) compared with conventional 2-tiered testing using European assays (P = .82), and specificity remained 100%. Conclusions. European assays outperformed analogous US assays in a conventional 2-tiered testing algorithm. However, a C6 ELISA used as a stand-alone test or in the second tier of a 2-tiered algorithm performed comparably to conventional 2-tiered testing using European assays, and can be used for evaluation of any patient, regardless of travel history. C1 [Branda, John A.; Ferraro, Mary Jane] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ferraro, Mary Jane; Steere, Allen C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Strle, Klemen; Sikand, Nikhil; Steere, Allen C.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Strle, Franc] Univ Med Ctr Ljubljana, Dept Infect Dis, Ljubljana, Slovenia. RP Branda, JA (reprint author), Massachusetts Gen Hosp, Clin Microbiol Lab, GRB 526,55 Fruit St, Boston, MA 02114 USA. EM branda.john@mgh.harvard.edu FU Department of Pathology, Massachusetts General Hospital, Boston FX This work was funded by an Austin L. Vickery Jr award from the Department of Pathology, Massachusetts General Hospital, Boston. NR 40 TC 27 Z9 27 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2013 VL 57 IS 3 BP 333 EP 340 DI 10.1093/cid/cit235 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 182IA UT WOS:000321733700002 PM 23592827 ER PT J AU Demircay, E Hornicek, FJ Mankin, HJ Degroot, H AF Demircay, Emre Hornicek, Francis John, Jr. Mankin, Henry J. Degroot, Henry, III TI Malignant Lymphoma of Bone: A Review of 119 Patients SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Review ID PROGNOSTIC-FACTORS AB Lymphoma of bone is uncommon. As a result of this, many aspects of primary lymphoma of bone (PLB) are controversial: the definition, treatment strategies, response criteria, and prognostic factors. We sought to determine the following in an analysis from a single center over a four-decade period: (1) 5-year disease-free survival of patients with PLB as well as those with systemic lymphoma with bone involvement; and (2) whether prognostic factors (sex, site of tumor, age) were associated with 5-year survival. A total of 119 patients with lymphoma involving the musculoskeletal system were retrospectively evaluated. Among these, 94 patients who had a minimum followup of 6 months (mean, 67 months; range, 6 months to 34 years) were further analyzed for the skeletal site of involvement, the orthopaedic intervention(s) needed, and survival. The overall median age was 45 years (range, 7-87 years). The female-to-male ratio was 1:1.53. There were 70 (65 unifocal, five multifocal) patients with PLB. The femur was the most frequent site involved. Appendicular skeleton involvement was substantially higher in patients with PLB. Thirty-four (36%) patients had at least one surgical intervention. Fourteen patients (41%) needed more than one major surgical intervention. The disease-free 5-year survival for patients with PLB was 81% and for the patients with systemic lymphoma with bone involvement, it was 44%. The disease-free 5-year survival of the patients with PLB younger than 60 years old and 60 years old or older was 90% and 62%, respectively. Age was the only prognostic factor on survival of patients with PLB. Orthopaedic intervention was usually needed for pathologic fractures, avascular necrosis, spinal cord compression, or for the lesions of the weightbearing bones compromising stability or joint motion. The potential for long-term survival suggests the use of implants and techniques that have the best chance of long-term success. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Demircay, Emre] Baskent Univ, Dept Orthoped Surg, Sch Med, TR-34662 Istanbul, Turkey. [Hornicek, Francis John, Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Mankin, Henry J.] Harvard Univ, Sch Med, Boston, MA USA. [Degroot, Henry, III] Newton Wellesley Hosp, Newton Lower Falls, MA 02162 USA. RP Demircay, E (reprint author), Baskent Univ, Dept Orthoped Surg, Sch Med, Oymaci SN 7, TR-34662 Istanbul, Turkey. EM emredemircay@hotmail.com NR 18 TC 11 Z9 11 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD AUG PY 2013 VL 471 IS 8 BP 2684 EP 2690 DI 10.1007/s11999-013-2991-x PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 179VM UT WOS:000321549600041 PM 23591933 ER PT J AU Maahs, DM Caramori, L Cherney, DZI Galecki, AT Gao, CY Jalal, D Perkins, BA Pop-Busui, R Rossing, P Mauer, M Doria, A AF Maahs, David M. Caramori, Luiza Cherney, David Z. I. Galecki, Andrzej T. Gao, Chuanyun Jalal, Diana Perkins, Bruce A. Pop-Busui, Rodica Rossing, Peter Mauer, Michael Doria, Alessandro CA PERL Consortium TI Uric Acid Lowering to Prevent Kidney Function Loss in Diabetes: The Preventing Early Renal Function Loss (PERL) Allopurinol Study SO CURRENT DIABETES REPORTS LA English DT Article DE Uric acid; Kidney disease; Diabetes; Diabetic kidney disease; Glomerular filtration rate; Allopurinol; Diabetic nephropathy; Randomized clinical trial; Type 1 diabetes; PERL trial ID GLOMERULAR-FILTRATION-RATE; TOXIC EPIDERMAL NECROLYSIS; STEVENS-JOHNSON-SYNDROME; BLOOD-PRESSURE; ENDOTHELIAL DYSFUNCTION; METABOLIC SYNDROME; FUNCTION DECLINE; ESSENTIAL-HYPERTENSION; INDEPENDENT MECHANISM; CARDIOVASCULAR RISK AB Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages. C1 [Maahs, David M.] Univ Colorado Denver, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Maahs, David M.; Jalal, Diana] Univ Colorado Denver, Div Renal Dis & Hypertens, Aurora, CO USA. [Caramori, Luiza; Mauer, Michael] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Caramori, Luiza; Mauer, Michael] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Cherney, David Z. I.; Perkins, Bruce A.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Cherney, David Z. I.] Univ Toronto, Div Nephrol, Toronto, ON, Canada. [Galecki, Andrzej T.] Univ Michigan, Sch Med, Inst Gerontol, Div Geriatr, Ann Arbor, MI USA. [Galecki, Andrzej T.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Gao, Chuanyun] Joslin Diabet Ctr, Joslin Clin, Boston, MA 02215 USA. [Perkins, Bruce A.] Univ Toronto, Div Endocrinol, Toronto, ON, Canada. [Pop-Busui, Rodica] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. [Rossing, Peter] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Rossing, Peter] Univ Aarhus, HEALTH, Aarhus, Denmark. [Rossing, Peter] Univ Copenhagen, NNF CBMR, Copenhagen, Denmark. [Doria, Alessandro] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. [Doria, Alessandro] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Doria, A (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, 1 Joslin Pl, Boston, MA 02215 USA. EM alessandro.doria@joslin.harvard.edu OI rossing, peter/0000-0002-1531-4294 FU NIDDK [DK075360]; Juvenile Diabetes Research Foundation; NIH [R03 DK094484, R34 DK097808]; Juvenile Diabetes Research Foundation (JDRF) [17-2012-377] FX Dr. Maahs was supported by a grant from NIDDK (DK075360). Dr. Caramori is supported by a Career Development Award from the Juvenile Diabetes Research Foundation. This project was supported by NIH grants R03 DK094484 and R34 DK097808, and by grant 17-2012-377 from the Juvenile Diabetes Research Foundation (JDRF). Its contents are the authors' sole responsibility and do not necessarily represent official NIH or JDRF views. NR 81 TC 45 Z9 47 U1 1 U2 7 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD AUG PY 2013 VL 13 IS 4 BP 550 EP 559 DI 10.1007/s11892-013-0381-0 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 179JR UT WOS:000321517000011 PM 23649945 ER PT J AU Stanton, RC AF Stanton, Robert C. TI Combination Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Diabetic Kidney Disease SO CURRENT DIABETES REPORTS LA English DT Article DE Diabetic kidney disease; ACE inhibitors; Angiotensin receptor blockers ID ALDOSTERONE SYSTEM; ACE-INHIBITION; END-POINTS; NEPHROPATHY; BLOCKADE; THERAPY; HYPERTENSION; PROGRESSION; LOSARTAN; OUTCOMES AB Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) have played a major role in slowing the progression of diabetic kidney disease, since they lower urine protein levels, lower blood pressure, and slow progression. Studies have suggested that the combination of ACE-I and ARB offered greater benefits for patients with diabetic kidney disease. In 2008, the large ONTARGET study reported no benefit with combination therapy, as compared with monotherapy. This study has changed practice patterns, but few patients in this study had diabetic kidney disease. In this review, the data in favor of the combination use of these agents in patients with diabetic kidney disease and data against the combination are reviewed. At this time, there is little support for using the combination in diabetic patients with no kidney disease or early stage diabetic kidney disease. But there are patients who may benefit from combination use. C1 [Stanton, Robert C.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Joslin Diabet Ctr, Boston, MA USA. [Stanton, Robert C.] Joslin Diabet Ctr, Kidney & Hypertens Sect, Boston, MA 02215 USA. RP Stanton, RC (reprint author), Joslin Diabet Ctr, Kidney & Hypertens Sect, 1 Joslin Pl, Boston, MA 02215 USA. EM Robert.Stanton@joslin.harvard.edu NR 39 TC 0 Z9 0 U1 0 U2 5 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD AUG PY 2013 VL 13 IS 4 BP 567 EP 573 DI 10.1007/s11892-013-0391-y PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 179JR UT WOS:000321517000013 PM 23653011 ER PT J AU Lipinski, B Pretorius, E AF Lipinski, Boguslaw Pretorius, Etheresia TI Iron-Induced Fibrin in Cardiovascular Disease SO CURRENT NEUROVASCULAR RESEARCH LA English DT Article DE Cardiovascular disease; fibrinogen; free radicals; inflammation; iron; parafibrin; thrombosis ID ERYTHROCYTE SEDIMENTATION-RATE; PERIPHERAL ARTERIAL-DISEASE; ACUTE CORONARY SYNDROMES; SERUM-ALBUMIN; OXIDATIVE STRESS; HEART-DISEASE; ATHEROSCLEROSIS; RISK; MECHANISMS; INFLAMMATION AB Accumulating evidence within the last two decades indicates the association between cardiovascular disease (CVD) and chronic inflammatory state. Under normal conditions fibrin clots are gradually degraded by the fibrinolytic enzyme system, so no permanent insoluble deposits remain in the circulation. However, fibrinolytic therapy in coronary and cerebral thrombosis is ineffective unless it is installed within 3-5 hours of the onset. We have shown that trivalent iron (FeIII) initiates a hydroxyl radical-catalyzed conversion of fibrinogen into a fibrin-like polymer (parafibrin) that is remarkably resistant to the proteolytic dissolution and thus promotes its intravascular deposition. Here we suggest that the persistent presence of proteolysis-resistant fibrin clots causes chronic inflammation. We study the effects of certain amphiphilic substances on the iron-and thrombin-induced fibrinogen polymerization visualized using scanning electron microscopy. We argue that the culprit is an excessive accumulation of free iron in blood, known to be associated with CVD. The only way to prevent iron overload is by supplementation with iron chelating agents. However, administration of free radical scavengers as effective protection against persistent presence of fibrin-like deposits should also be investigated to contribute to the prevention of cardiovascular and other degenerative diseases. C1 [Lipinski, Boguslaw] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Pretorius, Etheresia] Univ Pretoria, Fac Hlth Sci, Dept Physiol, ZA-0007 Arcadia, South Africa. RP Pretorius, E (reprint author), Univ Pretoria, Fac Hlth Sci, Dept Physiol, Private Bag X323, ZA-0007 Arcadia, South Africa. EM resia.pretorius@up.ac.za NR 66 TC 14 Z9 14 U1 0 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2026 J9 CURR NEUROVASC RES JI Curr. Neurovasc. Res. PD AUG PY 2013 VL 10 IS 3 BP 269 EP 274 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 173WW UT WOS:000321114000011 PM 23721262 ER PT J AU Lancellotti, P Nkomo, VT Badano, LP Bergler, J Bogaert, J Davin, L Cosyns, B Coucke, P Dulgheru, R Edvardsen, T Gaemperli, O Galderisi, M Griffin, B Heidenreich, PA Nieman, K Plana, JC Port, SC Scherrer-Crosbie, M Schwartz, RG Sebag, IA Voigt, JU Wann, S Yang, PC AF Lancellotti, Patrizio Nkomo, Vuyisile T. Badano, Luigi P. Bergler, Jutta Bogaert, Jan Davin, Laurent Cosyns, Bernard Coucke, Philippe Dulgheru, Raluca Edvardsen, Thor Gaemperli, Oliver Galderisi, Maurizio Griffin, Brian Heidenreich, Paul A. Nieman, Koen Plana, Juan C. Port, Steven C. Scherrer-Crosbie, Marielle Schwartz, Ronald G. Sebag, Igal A. Voigt, Jens-Uwe Wann, Samuel Yang, Phillip C. CA European Soc Cardiol Working Grp N TI Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Article DE radiotherapy; echocardiography; cardiac magnetic resonance; nuclear cardiology; cardiac computed tomography; heart disease ID CORONARY-ARTERY-DISEASE; LONG-TERM SURVIVORS; SPECKLE-TRACKING ECHOCARDIOGRAPHY; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; VENTRICULAR DIASTOLIC FUNCTION; DIFFUSE MYOCARDIAL FIBROSIS; CONGESTIVE-HEART-FAILURE; BREAST-CANCER PATIENTS; NATIVE VALVE DISEASE; HODGKINS-DISEASE AB Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed. C1 [Lancellotti, Patrizio] Univ Liege Hosp, CHU Sart Tilman, Dept Cardiol, GIGA Cardiovasc Sci,Heart Valve Clin, B-4000 Liege, Belgium. [Nkomo, Vuyisile T.] Mayo Clin, Div Cardiovasc Dis & Internal Med, Rochester, MN USA. [Badano, Luigi P.] Univ Padua, Dept Cardiac Vasc & Thorac Sci, Padua, Italy. [Bergler, Jutta] Med Univ Vienna, Dept Cardiol, Vienna, Austria. [Bogaert, Jan] Catholic Univ Louvain, Dept Radiol, Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Davin, Laurent] CHU Sart Tilman, Dept Cardiovasc Imaging & Invas Cardiol, B-4000 Liege, Belgium. [Cosyns, Bernard] UZ Brussel, Ctr Voor Hart Vaatziekten CHVZ, Dept Cardiol, B-1090 Brussels, Belgium. [Coucke, Philippe] Univ Hosp, CHU Liege, Dept Radiotherapy, Liege, Belgium. [Dulgheru, Raluca] Univ Med & Pharm Carol Davila, Emergency Univ Hosp, Dept Cardiol, Bucharest, Romania. [Edvardsen, Thor] Oslo Univ Hosp, Rikshosp, Dept Cardiol, Oslo, Norway. [Gaemperli, Oliver] Univ Zurich Hosp, Ctr Cardiovasc, CH-8091 Zurich, Switzerland. [Galderisi, Maurizio] Federico II Univ Hosp, Cardioangiol CCU, Dept Clin & Expt Med, Naples, Italy. [Griffin, Brian; Plana, Juan C.] Cleveland Clin, Dept Cardiovasc Med, Sect Cardiovasc Imaging, Cleveland, OH 44106 USA. [Heidenreich, Paul A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Heidenreich, Paul A.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Nieman, Koen] Erasmus Univ, Med Ctr, Dept Cardiol, Rotterdam, Netherlands. [Nieman, Koen] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Port, Steven C.] Aurora Hlth Care, Aurora Cardiovasc Serv, Milwaukee, WI USA. [Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Schwartz, Ronald G.] Univ Rochester, Med Ctr, Dept Med, Div Cardiol, Rochester, NY 14642 USA. [Schwartz, Ronald G.] Univ Rochester, Med Ctr, Div Nucl Med, Dept Imaging Sci, Rochester, NY 14642 USA. [Sebag, Igal A.] Sir Mortimer B Davis Jewish Hosp, Dept Med, Div Cardiol, Montreal, PQ H3T 1E2, Canada. [Sebag, Igal A.] McGill Univ, Lady Davis Inst Med Res, Montreal, PQ, Canada. [Voigt, Jens-Uwe] Catholic Univ Louvain, Univ Hosp Gasthuisberg, Dept Cardiovasc Dis, B-3000 Louvain, Belgium. [Wann, Samuel] Columbia St Marys Healthcare Milwaukee, Heart Failure Program, Milwaukee, WI USA. [Yang, Phillip C.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Lancellotti, P (reprint author), Univ Liege Hosp, CHU Sart Tilman, Dept Cardiol, GIGA Cardiovasc Sci,Heart Valve Clin, B-4000 Liege, Belgium. EM plancellotti@chu.ulg.ac.be RI Edvardsen, Thor/F-4079-2012; bogaert, jan/E-6181-2012; OI Edvardsen, Thor/0000-0002-3800-765X; Heidenreich, Paul/0000-0001-7730-8490; Galderisi, Maurizio/0000-0003-0311-9069; Badano, Luigi/0000-0002-0379-3283 NR 121 TC 61 Z9 63 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD AUG PY 2013 VL 14 IS 8 BP 721 EP 740 DI 10.1093/ehjci/jet123 PG 20 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 183QV UT WOS:000321833100001 PM 23847385 ER PT J AU Martinez-Martin, P Rojo-Abuin, JM Dujardin, K Pontone, GM Weintraub, D Forjaz, MJ Starkstein, S Leentjens, AFG AF Martinez-Martin, P. Rojo-Abuin, J. M. Dujardin, K. Pontone, G. M. Weintraub, D. Forjaz, M. J. Starkstein, S. Leentjens, A. F. G. TI Designing a new scale to measure anxiety symptoms in Parkinson's disease: item selection based on canonical correlation analysis SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE anxiety; assessment; canonical correlation; Parkinson's disease; rating scales ID PSYCHOMETRIC PROPERTIES; HOSPITAL ANXIETY; DEPRESSION SCALE; RATING-SCALES; DISORDERS; INVENTORY; PREVALENCE; VALIDATION; MINI AB Background and purpose: The lack of appropriate measures has hindered the research on anxiety syndromes in Parkinson's disease (PD). The objective of the present cross-sectional, international study was to identify shared elements and grouping of components from anxiety scales as a basis for designing a new scale for use in PD. Methods: For this purpose, 342 consecutive PD patients were assessed by means of the Mini International Neuropsychiatric Inventory (depression and anxiety sections), the Clinical Global Impression of severity of the anxiety symptoms, the Hamilton Anxiety Rating Scale (HARS), the Neuropsychiatric Inventory (section E), the Beck Anxiety Inventory (BAI) and the Anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A). Results: As the HADS-A showed a weak correlation with the HARS and BAI, it was not considered for more analyses. HARS and BAI exploratory factor analysis identified nine factors (62% of the variance), with only two of them combining items from both scales. Therefore, a canonical correlation model (a method to identify relations between components of two groups of variables) was built and it showed four factors grouping items from both scales: the first factor corresponded to 'generalized anxiety'; the second factor included muscular, sensory and autonomic 'non-specific somatic symptoms'; the third factor was dominated by 'respiratory symptoms'; and the fourth factor included 'cardiovascular symptoms'. Conclusions: BAI is heavily focused on panic symptoms, whilst HARS is more focused towards generalized anxiety symptoms. The new scale should include additional components in order to assess both episodic and persistent anxiety as well as items for evaluation of avoidance behaviour. C1 [Martinez-Martin, P.; Forjaz, M. J.] Carlos III Inst Hlth, Consortium Biomed Res Neurodegenerat Dis CIBERNED, Madrid, Spain. [Rojo-Abuin, J. M.] Spanish Council Sci Res, Ctr Human & Social Sci, Dept Stat, Madrid, Spain. [Dujardin, K.] Univ Lille 2, EA 4559, Lab Neurosci Fonct & Pathol, Lille, France. [Pontone, G. M.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Weintraub, D.] Univ Penn, Pereleman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, D.] Philadelphia VA Med Ctr, PADRECC, Philadelphia, PA USA. [Weintraub, D.] Philadelphia VA Med Ctr, MIRECC, Philadelphia, PA USA. [Forjaz, M. J.] Carlos III Inst Hlth, Natl Sch Publ Hlth, Madrid, Spain. [Forjaz, M. J.] Alzheimer Ctr Reina Sofia Fdn, Madrid 28031, Spain. [Starkstein, S.] Univ Western Australia, Sch Psychiat & Clin Neurosci, Perth, WA 6009, Australia. [Starkstein, S.] Fremantle Hosp, Fremantle, WA, Australia. [Leentjens, A. F. G.] Maastricht Univ Med Ctr, Dept Psychiat, Maastricht, Netherlands. RP Martinez-Martin, P (reprint author), Alzheimer Ctr Reina Sofia Fdn, C Valderrebollo 5, Madrid 28031, Spain. EM pmartinez@fundacioncien.es OI Forjaz, Maria Joao/0000-0003-3935-962X FU Michael J. Fox Foundation for Parkinson Research FX This study was sponsored by a grant from the Michael J. Fox Foundation for Parkinson Research (MJFF; www.michaeljfox.org). NR 27 TC 9 Z9 9 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 J9 EUR J NEUROL JI Eur. J. Neurol. PD AUG PY 2013 VL 20 IS 8 BP 1198 EP 1203 DI 10.1111/ene.12160 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 176UM UT WOS:000321331100018 PM 23581431 ER PT J AU Cheng, G Kwee, TC Basu, S Alavi, A AF Cheng, Gang Kwee, Thomas C. Basu, Sandip Alavi, Abass TI Critical considerations on the combined use of F-18-FDG and F-18-fluoride for PET assessment of metastatic bone disease SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Editorial Material ID POSITRON-EMISSION-TOMOGRAPHY; FDG-PET; LUNG-CANCER; SKELETAL SCINTIGRAPHY; PROSTATE-CANCER; COMPLIMENTARY ROLE; CARCINOMA; MARROW; SCAN; MALIGNANCY C1 [Cheng, Gang] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA 19104 USA. [Kwee, Thomas C.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [Basu, Sandip] Bhabha Atom Res Ctr, Radiat Med Ctr, Tata Mem Hosp Annexe, Bombay 400012, Maharashtra, India. [Cheng, Gang; Alavi, Abass] Hosp Univ Penn, Dept Radiol, Div Nucl Med, Philadelphia, PA 19104 USA. RP Alavi, A (reprint author), Hosp Univ Penn, Dept Radiol, Div Nucl Med, 3400 Spruce St, Philadelphia, PA 19104 USA. EM abass.alavi@uphs.upenn.edu NR 43 TC 5 Z9 5 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD AUG PY 2013 VL 40 IS 8 BP 1141 EP 1145 DI 10.1007/s00259-013-2459-y PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 179LE UT WOS:000321521000002 PM 23695838 ER PT J AU Wai, B Thai, WE Brown, H Truong, QA AF Wai, Bryan Thai, Wai-ee Brown, Heather Truong, Quynh A. TI Novel phase-based noise reduction strategy for quantification of left ventricular function and mass assessment by cardiac CT: Comparison with cardiac magnetic resonance SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Left ventricular function; Left ventricular mass; Noise reduction; Computed tomography ID DUAL-SOURCE CT; PROGNOSTIC-SIGNIFICANCE; COMPUTED-TOMOGRAPHY; ECHOCARDIOGRAPHY; ANGIOGRAPHY; ASSOCIATION; INFARCTION; DEATH AB Background: Tube current modulation in retrospective ECG gated cardiac computed tomography (CT) results in increased image noise and may reduce the accuracy of left ventricular (LV) ejection fraction (EF) and mass assessment. Objective: To examine the effects of a novel CT phase-based noise reduction (NR) algorithm on LV EF and mass quantification as compared to cardiac magnetic resonance (CMR). Methods: In 40 subjects, we compared the LV EF and mass between CT and CMR. In a subset of 24 subjects with tube current modulated CT, the effect of phase-based noise reduction strategies on contrast-to-noise ratio (CNR) and the assessment of LV EF and mass was compared to CMR. Results: There was excellent correlation between CT and CMR for EF (r = 0.94) and mass (r = 0.97). As compared to CMR, the limits of agreement improved with increasing strength of NR strategy. There was a systematic underestimation of LV mass by CT compared to CMR with no NR (-10.3 +/- 10.1 g) and low NR (-10.3 +/- 12.5 g), but was attenuated with high NR (-0.5 +/- 8.3 g). Studies without NR had lower CNR compared to low and high NR at both the ES phase and ED phase (all p < 0.01). Conclusions: A high NR strategy on tube current modulated functional cardiac CT improves correlation of EF compared to CMR and reduces variability of EF and mass evaluation by increasing the CNR. In an effort to reduce radiation dose with tube current modulation, this strategy provides better image quality when LV function and mass quantification is needed. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Wai, Bryan; Thai, Wai-ee; Truong, Quynh A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol & Dept Radiol,Cardiac MR PET CT Progr, Boston, MA USA. [Brown, Heather] Qi Imaging, Redwood City, CA USA. RP Wai, B (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM bwai@partners.org FU NIH [K23HL098370, L30HL093896]; Qi Imaging FX Dr. Quynh Truong received support from NIH grant K23HL098370 and L30HL093896 and research support from Qi Imaging. NR 21 TC 3 Z9 4 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X J9 EUR J RADIOL JI Eur. J. Radiol. PD AUG PY 2013 VL 82 IS 8 BP E337 EP E341 DI 10.1016/j.ejrad.2013.02.023 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 179CV UT WOS:000321496900006 PM 23522745 ER PT J AU Perry, DJ AF Perry, Donna J. TI Transcendental Method for Research with Human Subjects: A Transformative Phenomenology for the Human Sciences SO FIELD METHODS LA English DT Article DE research; method; qualitative; Lonergan; phenomenology ID QUALITATIVE RESEARCH; CARING RESEARCH; RIGOR AB This article provides an overview of a qualitative research method called transcendental method for research with human subjects. The method employs a transformative phenomenological approach and was developed using the philosophy of Bernard Lonergan. Reflective use of this method suggests that it has both investigational and interventional qualities, with transformative potential for both researcher and study participants. C1 [Perry, Donna J.] Univ Massachusetts, Grad Sch Nursing, Worcester, MA 01655 USA. [Perry, Donna J.] Massachusetts Gen Hosp, Yvonne L Munn Ctr Nursing Res, Inst Patient Care, Boston, MA 02114 USA. RP Perry, DJ (reprint author), Univ Massachusetts, Grad Sch Nursing, 55 Lake Ave North, Worcester, MA 01655 USA. EM DonnaJ.Perry@umassmed.edu NR 26 TC 4 Z9 4 U1 3 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1525-822X J9 FIELD METHOD JI Field Methods PD AUG PY 2013 VL 25 IS 3 BP 262 EP 282 DI 10.1177/1525822X12467105 PG 21 WC Anthropology; Social Sciences, Interdisciplinary SC Anthropology; Social Sciences - Other Topics GA 184NT UT WOS:000321898700003 ER PT J AU Gorin, Y Block, K AF Gorin, Yves Block, Karen TI Nox4 and diabetic nephropathy: With a friend like this, who needs enemies? SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE Diabetic complications; Diabetic nephropathy; Hyperglycemia; Oxidative stress; NADPH oxidases of the Nox family; Nox4; Reactive oxygen species; Glomerular cell injury; Tubulointerstitial cell injury; Free radicals ID SMOOTH-MUSCLE-CELLS; INDUCED OXIDATIVE STRESS; TUBULAR EPITHELIAL-CELLS; MESSENGER-RNA TRANSLATION; DINUCLEOTIDE PHOSPHATE OXIDASE; GLOMERULAR MESANGIAL CELLS; OXYGEN SPECIES PRODUCTION; KINASE-C-BETA; NADPH-OXIDASE; NAD(P)H OXIDASE AB Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, a complication of diabetes in the kidney. NADPH oxidases of the Nox family are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current understanding of the roles of Nox catalytic and regulatory subunits in the processes that control mesangial cell, podocyte, and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin-angiotensin system and transforming growth factor-beta. The role of the Nox isoform Nox4 in the redox processes that alter renal biology in diabetes is highlighted. (C) 2013 Elsevier Inc. All rights reserved. C1 [Gorin, Yves; Block, Karen] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Block, Karen] South Texas Vet Hlth Care Syst, Audie L Murphy Mem Hosp Div, San Antonio, TX 78229 USA. RP Gorin, Y (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM gorin@uthscsa.edu; block@uthscsa.edu OI Gorin, Yves/0000-0003-4048-6925 FU Juvenile Diabetes Research Foundation Multiproject Grants; NIH [RO1 DK 079996, RO1 CA 131272]; Veterans Administration FX This work was supported by Juvenile Diabetes Research Foundation Multiproject Grants (Y.G. and K.B.), NIH RO1 DK 079996 (Y.G.), NIH RO1 CA 131272 (K.B.), and the Veterans Administration (K.B.). NR 190 TC 33 Z9 35 U1 2 U2 39 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG PY 2013 VL 61 BP 130 EP 142 DI 10.1016/j.freeradbiomed.2013.03.014 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 168EA UT WOS:000320687300014 PM 23528476 ER PT J AU Khalili, H Higuchi, LM Ananthakrishnan, AN Richter, JM Feskanich, D Fuchs, CS Chan, AT AF Khalili, Hamed Higuchi, Leslie M. Ananthakrishnan, Ashwin N. Richter, James M. Feskanich, Diane Fuchs, Charles S. Chan, Andrew T. TI Oral contraceptives, reproductive factors and risk of inflammatory bowel disease SO GUT LA English DT Article DE Inflammatory bowel disease; Crohn's disease; ulcerative colitis; oral contraceptive use; reproductive factors; Nurses' Health Study; Crohn's colitis; epidemiology; cancer epidemiology; health service research; gastrointestinal haemorrhage; IBD clinical; cancer prevention; cyclooxygenase-2; aspirin; non-steroidal anti-inflammatory drugs; chemoprevention; adenoma; inflammation; adenocarcinoma ID CROHNS-DISEASE; ULCERATIVE-COLITIS; CIGARETTE-SMOKING; BARRIER FUNCTION; OLMSTED COUNTY; WOMEN; METAANALYSIS; VALIDITY; COHORT; REPRODUCIBILITY AB Background Oral contraceptive use has been associated with risk of Crohn's disease (CD) and ulcerative colitis (UC). Objective To determine whether this association is confounded or modified by other important lifestyle and reproductive factors. Design A prospective cohort study was carried out of 117?375 US women enrolled since 1976 in the Nurses Health Study I (NHS I) and 115?077 women enrolled since 1989 in the Nurses' Health Study II (NHS II) with no prior history of UC or CD. These women had provided information every 2years, on age at menarche, oral contraceptive use, parity, menopause status and other risk factors. Diagnoses of CD and UC were confirmed by review of medical records. Cox proportional hazards models were used to calculate HRs and 95% CIs. Results Among 232?452 women with over 5?030?196 person-years of follow-up, 315 cases of CD and 392 cases of UC were recorded through 2007 in NHS II and 2008 in NHS I. Compared with never users of oral contraceptives, the multivariate-adjusted HRs for CD were 2.82 (95% CI 1.65 to 4.82) among current users and 1.39 (95% CI 1.05 to 1.85) among past users. The association between oral contraceptives and UC differed according to smoking history (p(heterogeneity)=0.04). Age at menarche, age at first birth and parity were not associated with risk of UC or CD. Conclusion In two large prospective cohorts of US women, oral contraceptive use was associated with risk of CD. The association between oral contraceptive use and UC was limited to women with a history of smoking. C1 [Khalili, Hamed; Ananthakrishnan, Ashwin N.; Richter, James M.; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Khalili, Hamed; Higuchi, Leslie M.; Ananthakrishnan, Ashwin N.; Richter, James M.; Feskanich, Diane; Fuchs, Charles S.; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Higuchi, Leslie M.] Childrens Hosp Boston, Div Gastroenterol & Nutr, Boston, MA USA. [Feskanich, Diane; Fuchs, Charles S.; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,GRJ 728A, Boston, MA 02114 USA. EM achan@partners.org FU Crohn's and Colitis Foundation of American (CCFA); National Institute of Diabetes and Digestive and Kidney Diseases [K08 DK064256]; American Gastroenterological Association; [R01 CA137178]; [R01 CA050385]; [P01 CA87969]; [P30 DK043351] FX Funded by R01 CA137178, R01 CA050385, P01 CA87969, P30 DK043351, K08 DK064256. ATC is a Damon Runyon Cancer Research Foundation clinical investigator. HK is supported by a career development award from the Crohn's and Colitis Foundation of American (CCFA). LH is supported by National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK064256). ANA is supported by a career research scholars award from the American Gastroenterological Association. NR 41 TC 48 Z9 48 U1 0 U2 15 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD AUG PY 2013 VL 62 IS 8 BP 1153 EP 1159 DI 10.1136/gutjnl-2012-302362 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 176WQ UT WOS:000321337600011 PM 22619368 ER PT J AU Tucker-Seeley, RD Harley, AE Stoddard, AM Sorensen, GG AF Tucker-Seeley, Reginald D. Harley, Amy E. Stoddard, Anne M. Sorensen, Glorian G. TI Financial Hardship and Self-Rated Health Among Low-Income Housing Residents SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE community health; health disparities; mental health; social determinants; social inequalities ID ECONOMIC HARDSHIP; LIFE-COURSE; PSYCHOLOGICAL DISTRESS; PERCEIVED STRESS; AMERICANS; STRAIN; DISPARITIES; VALIDITY; POVERTY; IMPACT AB Background. Self-rated health (SRH) has been shown to be predictive of morbidity and mortality. Evidence also shows that SRH is socioeconomically patterned, although this association differs depending on the indicator of socioeconomic status used. The purpose of this study was to determine the association between SRH and financial hardship among residents of low-income housing. Methods. We analyzed cross-sectional data from the Health in Common Study (N = 828), an observational study to investigate social and physical determinants of cancer risk-related behaviors among residents of low-income housing in three cities in the Boston metropolitan area. Modified Poisson regression models were used to obtain the relative risk of low SRH (fair or poor), adjusting for demographic and socioeconomic characteristics. Results. Unadjusted models revealed that the respondents reporting financial hardship were 53% more likely to report low SRH compared with those not reporting financial hardship. After controlling for demographic characteristics, socioeconomic characteristics, and psychological distress, the results showed that those reporting financial hardship were 44% more likely to report low SRH. Conclusion. Our results suggest that financial hardship is a robust predictor of SRH; and over and above the influence of demographic and traditional socioeconomic indicators, and even psychological distress, financial hardship remains strongly associated with low SRH. Additional research needs to be conducted to further elucidate this pathway and to better understand the determinants of variability in financial hardship among low-income housing residents to ensure the most appropriate policy levers (e.g., housing-related policy, food-related policy) are chosen to improve health outcomes in this population. C1 [Tucker-Seeley, Reginald D.; Sorensen, Glorian G.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Harley, Amy E.] Univ Wisconsin, Milwaukee, WI 53201 USA. [Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. RP Tucker-Seeley, RD (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,LW666A, Boston, MA 02215 USA. EM reginald_tucker-seeley@dfci.harvard.edu FU NCI NIH HHS [K05 CA108663, 5K05CA108663-05, 5R01CA111310-04] NR 35 TC 7 Z9 7 U1 3 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD AUG PY 2013 VL 40 IS 4 BP 442 EP 448 DI 10.1177/1090198112463021 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 185DI UT WOS:000321945000008 PM 23104979 ER PT J AU Berkowitz, SA Aragon, K Hines, J Seligman, H Lee, S Sarkar, U AF Berkowitz, Seth A. Aragon, Katherine Hines, Jonas Seligman, Hilary Lee, Sei Sarkar, Urmimala TI Do Clinical Standards for Diabetes Care Address Excess Risk for Hypoglycemia in Vulnerable Patients? A Systematic Review SO HEALTH SERVICES RESEARCH LA English DT Article DE Diabetes mellitus; quality and safety; health disparities; vulnerable populations; clinical guidelines ID QUALITY-OF-CARE; GLYCEMIC CONTROL; FOOD INSECURITY; SOCIOECONOMIC POSITION; AMERICAN-COLLEGE; PROJECT DULCE; STATEMENT; MELLITUS; MANAGEMENT; PERFORMANCE AB Objective. To determine whether diabetes clinical standards consider increased hypoglycemia risk in vulnerable patients. Data Sources. MEDLINE, the National Guidelines Clearinghouse, the National Quality Measures Clearinghouse, and supplemental sources. Study Design. Systematic review of clinical standards (guidelines, quality metrics, or pay-for-performance programs) for glycemic control in adult diabetes patients. The primary outcome was discussion of increased risk for hypoglycemia in vulnerable populations. Data Collection/Extraction Methods. Manuscripts identified were abstracted by two independent reviewers using prespecified inclusion/exclusion criteria and a standardized abstraction form. Principal Findings. We screened 1,166 titles, and reviewed 220 manuscripts in full text. Forty-four guidelines, 17 quality metrics, and 8 pay-for-performance programs were included. Five (11 percent) guidelines and no quality metrics or pay-for-performance programs met the primary outcome. Conclusions. Clinical standards do not substantively incorporate evidence about increased risk for hypoglycemia in vulnerable populations. C1 [Berkowitz, Seth A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Aragon, Katherine; Hines, Jonas; Seligman, Hilary; Lee, Sei; Sarkar, Urmimala] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Berkowitz, SA (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. EM SABerkowitz@partners.org OI Berkowitz, Seth/0000-0003-1030-4297 FU Institutional National Research Service Award [T32HP10251]; Division of General Internal Medicine at Massachusetts General Hospital; Agency for Health Care Research and Quality [K08HS017594]; National Center for Research Resources [KL2RR024130]; NIH/NCRR/OD UCSF-CTSI [KL2 RR024130]; National Center for Research Resources (a component of the NIH) [KL2RR024130]; National Institute of Aging; American Federation for Aging Research [K23AG040779] FX Dr. Berkowitz was supported by an Institutional National Research Service Award T32HP10251 and by the Division of General Internal Medicine at Massachusetts General Hospital. Dr. Sarkar is support by the Agency for Health Care Research and Quality (K08HS017594), and the National Center for Research Resources (KL2RR024130). Dr. Seligman receives support from NIH/NCRR/OD UCSF-CTSI grant number KL2 RR024130. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Dr. Lee was supported by the KL2RR024130 from the National Center for Research Resources (a component of the NIH) and the Paul Beeson Career Development Award from the National Institute of Aging and the American Federation for Aging Research (K23AG040779). The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication. NR 38 TC 9 Z9 9 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD AUG PY 2013 VL 48 IS 4 BP 1299 EP 1310 DI 10.1111/1475-6773.12048 PG 12 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 176IM UT WOS:000321297600005 PM 23445498 ER PT J AU Werner, RM Konetzka, RT Polsky, D AF Werner, Rachel M. Konetzka, R. Tamara Polsky, Daniel TI The Effect of Pay-for-Performance in Nursing Homes: Evidence from State Medicaid Programs SO HEALTH SERVICES RESEARCH LA English DT Article DE Quality of care; pay-for-performance; nursing home quality; long-term care ID RESIDENT ASSESSMENT INSTRUMENT; RISK-ADJUSTMENT; HEALTH-CARE; QUALITY; IMPROVE; MDS AB Objective. Pay-for-performance (P4P) is commonly used to improve health care quality in the United States and is expected to be frequently implemented under the Affordable Care Act. However, evidence supporting its use is mixed with few large-scale, rigorous evaluations of P4P. This study tests the effect of P4P on quality of care in a large-scale setting-the implementation of P4P for nursing homes by state Medicaid agencies. Data Sources/Study Setting. 2001-2009 nursing home Minimum Data Set and Online Survey, Certification, and Reporting (OSCAR) datasets. Study Design. Between 2001 and 2009, eight state Medicaid agencies adopted P4P programs in nursing homes. We use a difference-in-differences approach to test for changes in nursing home quality under P4P, taking advantage of the variation in timing of implementation across these eight states and using nursing homes in the 42 non-P4P states plus Washington, DC as contemporaneous controls. Principal Findings. Quality improvement under P4P was inconsistent. While three clinical quality measures (the percent of residents being physically restrained, in moderate to severe pain, and developed pressure sores) improved with the implementation of P4P in states with P4P compared with states without P4P, other targeted quality measures either did not change or worsened. Of the two structural measures of quality that were tied to payment (total number of deficiencies and nurse staffing) deficiency rates worsened slightly under P4P while staffing levels did not change. Conclusions. Medicaid-based P4P in nursing homes did not result in consistent improvements in nursing home quality. Expectations for improvement in nursing home care under P4P should be tempered. C1 [Werner, Rachel M.] Philadelphia VAMC, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Werner, Rachel M.] Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Konetzka, R. Tamara] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Polsky, Daniel] Univ Penn, Sch Med, Leonard Davis Inst Hlth Econ, Div Gen Internal Med, Philadelphia, PA 19104 USA. RP Werner, RM (reprint author), 1230 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM rwerner@upenn.edu FU National Institute on Aging [R01 AG034182-01]; VA HSR&D Career Development Award FX This research was funded by a grant from the National Institute on Aging (R01 AG034182-01). Rachel Werner was supported in part by a VA HSR&D Career Development Award. The authors gratefully thank Chris Wirtalla for his outstanding programming and research assistance. NR 38 TC 13 Z9 13 U1 3 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD AUG PY 2013 VL 48 IS 4 BP 1393 EP 1414 DI 10.1111/1475-6773.12035 PG 22 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 176IM UT WOS:000321297600010 PM 23398330 ER PT J AU Maciejewski, ML Bryson, CL Wang, V Perkins, M Liu, CF AF Maciejewski, Matthew L. Bryson, Chris L. Wang, Virginia Perkins, Mark Liu, Chuan-Fen TI Potential Bias in Medication Adherence Studies of Prevalent Users SO HEALTH SERVICES RESEARCH LA English DT Article DE Medication adherence; pharmaceutical policy; cost sharing; research design; veterans; inclusion criteria ID DRUG UTILIZATION; COPAYMENT INCREASE; RISK ADJUSTMENT; PERFORMANCE; IMPACT; EXPENDITURES; COMORBIDITY; VETERANS; HEALTH AB Purpose. We examined how the choice of historic medication use criteria for identifying prevalent users may bias estimated adherence changes associated with a medication copayment increase. Methods. From pharmacy claims data in a retrospective cohort study, we identified 6,383 prevalent users of oral diabetes medications from four VA Medical Centers. Patients were included in this prevalent cohort if they had one fill both 3 months prior and 4-12 months prior to the index date, defined as the month in which medication copayments increased. To determine whether these historic medication use criteria introduced bias in the estimated response to a $5 medication copayment increase, we compared adherence trends from cohorts defined from different medication use criteria and from different index dates of copayment change. In an attempt to validate the prior observation of an upward trend in adherence prior to the date of the policy change, we replicated time series analyses varying the index dates prior to and following the date of the policy change, hypothesizing that the trend line associated with the policy change would differ from the trend lines that were not. Results. Medication adherence trends differed when different medication use criteria were applied. Contrary to our expectations, similar adherence trends were observed when the same medication use criteria were applied at index dates when no copayment changes occurred. Conclusion. To avoid introducing bias due to study design in outcomes assessments of medication policy changes, historic medication use inclusion criteria must be chosen carefully when constructing cohorts of prevalent users. Furthermore, while pharmacy data have enormous potential for population research and monitoring, there may be inherent logical flaws that limit cohort identification solely through administrative pharmacy records. C1 [Maciejewski, Matthew L.; Wang, Virginia] Duke Univ, Dept Med, Div Gen Internal Med, Ctr Hlth Serv Res Primary Care,Durham VA Med Ctr, Durham, NC 27705 USA. [Bryson, Chris L.; Perkins, Mark; Liu, Chuan-Fen] Univ Washington, Dept Med, Div Gen Internal Med, VA Puget Sound Hlth Care Syst,Northwest Ctr Outco, Seattle, WA USA. RP Maciejewski, ML (reprint author), Duke Univ, Dept Med, Div Gen Internal Med, Ctr Hlth Serv Res Primary Care,Durham VA Med Ctr, Durham, NC 27705 USA. EM matthew.maciejewski@va.gov FU Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs [IIR 03-200]; Department of Veterans Affairs [RCS 10-391]; Takeda Pharmaceuticals; Novartis; Surgical Review Corporation; Research Data and Assistance Center (ResDAC) at the University of Minnesota FX This work was supported by the Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs, project number IIR 03-200. Dr. Maciejewski was also supported by a Research Career Scientist award from the Department of Veterans Affairs (RCS 10-391). The authors would like to acknowledge tremendously helpful comments and editorial suggestions from the editors, two reviewers, Hollis Weidenbacher and Jaclyn Lemon. Dr. Maciejewski has received consultation funds from Takeda Pharmaceuticals, Novartis, the Surgical Review Corporation, and the Research Data and Assistance Center (ResDAC) at the University of Minnesota, and owns stock in Amgen via his wife's employment at Amgen. The views expressed are those of the authors and do not reflect the views of the Department of Veterans Affairs and their affiliated institutions. NR 25 TC 4 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD AUG PY 2013 VL 48 IS 4 BP 1468 EP 1486 DI 10.1111/1475-6773.12043 PG 19 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 176IM UT WOS:000321297600014 PM 23402554 ER PT J AU Williams, VJ Leritz, EC Shepel, J McGlinchey, RE Milberg, WP Rudolph, JL Lipsitz, LA Salat, DH AF Williams, Victoria J. Leritz, Elizabeth C. Shepel, Juli McGlinchey, Regina E. Milberg, William P. Rudolph, James L. Lipsitz, Lewis A. Salat, David H. TI Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults SO HUMAN BRAIN MAPPING LA English DT Article DE DTI; serum cholesterol; aging; cerebrovascular; white matter; fractional anisotropy; diffusivity ID SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; MAGNETIC-RESONANCE IMAGES; ALZHEIMERS-DISEASE; DIFFUSION TENSOR; BLOOD-PRESSURE; COGNITIVE FUNCTION; CORTICAL SURFACE; RISK-FACTORS; GEOMETRICALLY ACCURATE AB Prior research has demonstrated links among vascular health and the occurrence of stroke, mild cognitive decline, and dementia in older adults. However, little is known about whether normal variation in vascular indicators may be related to changes in neural tissue integrity. Even less is known about how the brain is affected by cholesterol levels in the normal to moderate risk range, leading up to overt disease pathology. This study examined associations between serum lipid levels and DTI indicators of white matter (WM) structural integrity in a sample of 125 generally healthy older adults aged 43-87 years. Whole-brain voxelwise analysis, controlling for age and gender, revealed low density lipoprotein levels (LDL) as the most robust correlate of regional WM structural integrity of the measured lipids. Higher LDL was associated with decreased WM integrity in right frontal and temporal regions, the superior longitudinal fasciculus and internal/external capsules. Increasing LDL was associated with increased radial and axial diffusivity; however, more widespread statistical effects were found for radial diffusivity. These findings suggest that normal interindividual variation in lipid levels is associated with compromised regional WM integrity, even in individuals below clinical thresholds for hyperlipidemia. Given the prevalence of cholesterol-associated sequelae in older adults, and mounting evidence suggesting a vascular role in the etiology of dementia, the current data suggest that understanding the relationship between cholesterol and brain tissue microstructure may have important clinical implications for early detection of vascular-related cognitive disorders and optimal regulation of serum lipids to maintain neural health in older adults. Hum Brain Mapp, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Williams, Victoria J.; Leritz, Elizabeth C.; Shepel, Juli; Salat, David H.] VA Boston Healthcare Syst, Neuroimaging Res Vet NeRVe Ctr, Boston, MA USA. [Williams, Victoria J.; Leritz, Elizabeth C.; Shepel, Juli; McGlinchey, Regina E.; Milberg, William P.; Rudolph, James L.; Salat, David H.] VA Boston Healthcare Syst, GRECC, Boston, MA USA. [Williams, Victoria J.; Leritz, Elizabeth C.; Shepel, Juli; Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Williams, Victoria J.; Leritz, Elizabeth C.; Shepel, Juli; Lipsitz, Lewis A.; Salat, David H.] Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. [Leritz, Elizabeth C.; McGlinchey, Regina E.; Milberg, William P.; Salat, David H.] Harvard Univ, Sch Med, Boston, MA USA. [Lipsitz, Lewis A.] Beth Israel Deaconess Med Ctr, Gerontol Div, Hebrew Senior Life Inst Aging Res, Boston, MA 02215 USA. RP Salat, DH (reprint author), Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. EM salat@nmr.mgh.harvard.edu RI McGlinchey, Regina/R-1971-2016 FU National Institute of Neurologic Disorders and Stroke [K23NS062148]; National Institute of Nursing Research [R01NR010827]; National Institute on Aging [P60AG08812, P01AG004390, K01AG24898]; Medical Research Service VA Merit Review Awards FX Contract grant sponsor: National Institute of Neurologic Disorders and Stroke; Contract grant number: K23NS062148; Contract grant sponsor: National Institute of Nursing Research; Contract grant number: R01NR010827; Contract grant sponsor: National Institute on Aging; Contract grant number: P60AG08812, P01AG004390, K01AG24898; Contract grant sponsor: Medical Research Service VA Merit Review Awards. NR 80 TC 18 Z9 18 U1 0 U2 6 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 AUG PY 2013 VL 34 IS 8 BP 1826 EP 1841 DI 10.1002/hbm.22030 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 178GX UT WOS:000321435100007 PM 22438182 ER PT J AU Wong, HKA Veremeyko, T Patel, N Lemere, CA Walsh, DM Esau, C Vanderburg, C Krichevsky, AM AF Wong, Hon-Kit Andus Veremeyko, Tatiana Patel, Nehal Lemere, Cynthia A. Walsh, Dominic M. Esau, Christine Vanderburg, Charles Krichevsky, Anna M. TI De-repression of FOXO3a death axis by microRNA-132 and-212 causes neuronal apoptosis in Alzheimers disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID AMYLOID PRECURSOR PROTEIN; FORKHEAD TRANSCRIPTION FACTOR; MILD COGNITIVE IMPAIRMENT; TUMOR-SUPPRESSOR PTEN; LONG-TERM DEPRESSION; NEUROTROPHIC FACTOR; CELL-DEATH; HIPPOCAMPAL-NEURONS; CIRCADIAN-CLOCK; COCAINE INTAKE AB Alzheimers disease (AD) is a multifactorial and fatal neurodegenerative disorder for which the mechanisms leading to profound neuronal loss are incompletely recognized. MicroRNAs (miRNAs) are recently discovered small regulatory RNA molecules that repress gene expression and are increasingly acknowledged as prime regulators involved in human brain pathologies. Here we identified two homologous miRNAs, miR-132 and miR-212, downregulated in temporal cortical areas and CA1 hippocampal neurons of human AD brains. Sequence-specific inhibition of miR-132 and miR-212 induces apoptosis in cultured primary neurons, whereas their overexpression is neuroprotective against oxidative stress. Using primary neurons and PC12 cells, we demonstrate that miR-132/212 controls cell survival by direct regulation of PTEN, FOXO3a and P300, which are all key elements of AKT signaling pathway. Silencing of these three target genes by RNAi abrogates apoptosis caused by the miR-132/212 inhibition. We further demonstrate that mRNA and protein levels of PTEN, FOXO3a, P300 and most of the direct pro-apoptotic transcriptional targets of FOXO3a are significantly elevated in human AD brains. These results indicate that the miR-132/miR-212/PTEN/FOXO3a signaling pathway contributes to AD neurodegeneration. C1 [Wong, Hon-Kit Andus; Veremeyko, Tatiana; Lemere, Cynthia A.; Krichevsky, Anna M.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Wong, Hon-Kit Andus; Veremeyko, Tatiana; Lemere, Cynthia A.; Krichevsky, Anna M.] Harvard Univ, Sch Med, Harvard Inst Med, Boston, MA 02115 USA. [Patel, Nehal; Vanderburg, Charles] Massachusetts Gen Hosp, Harvard NeuroDiscovery Ctr, Charlestown, MA 02129 USA. [Patel, Nehal] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Walsh, Dominic M.] Brigham & Womens Hosp, Ctr Neurol Dis, Lab Neurodegenerat Res, Harvard Inst Med, Boston, MA 02115 USA. [Esau, Christine] Regulus Therapeut, San Diego, CA 92121 USA. RP Krichevsky, AM (reprint author), Brigham & Womens Hosp, Ctr Neurol Dis, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM akrichevsky@rics.bwh.harvard.edu RI Wong, Hon-Kit/G-3944-2014 OI Wong, Hon-Kit/0000-0003-0049-8454 FU Alzheimer's Association [NIRG-09-132844] FX This work was supported by a grant from the Alzheimer's Association (NIRG-09-132844). NR 86 TC 69 Z9 75 U1 3 U2 29 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2013 VL 22 IS 15 BP 3077 EP 3092 DI 10.1093/hmg/ddt164 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 178MR UT WOS:000321452600010 PM 23585551 ER PT J AU Motai, Y Yoshida, H AF Motai, Yuichi Yoshida, Hiroyuki TI Principal Composite Kernel Feature Analysis: Data-Dependent Kernel Approach SO IEEE TRANSACTIONS ON KNOWLEDGE AND DATA ENGINEERING LA English DT Article DE Principal component analysis; data-dependent kernel; nonlinear subspace; manifold structures ID SUPPORT VECTOR MACHINES; NEAREST-NEIGHBOR CLASSIFICATION; COMPUTER-AIDED DIAGNOSIS; PROTEIN FOLD RECOGNITION; CT-COLONOGRAPHY; COLONIC POLYPS; NEURAL-NETWORKS; CANCER; DISCRIMINANT; CLASSIFIERS AB Principal composite kernel feature analysis (PC-KFA) is presented to show kernel adaptations for nonlinear features of medical image data sets (MIDS) in computer-aided diagnosis (CAD). The proposed algorithm PC-KFA has extended the existing studies on kernel feature analysis (KFA), which extracts salient features from a sample of unclassified patterns by use of a kernel method. The principal composite process for PC-KFA herein has been applied to kernel principal component analysis [34] and to our previously developed accelerated kernel feature analysis [20]. Unlike other kernel-based feature selection algorithms, PC-KFA iteratively constructs a linear subspace of a high-dimensional feature space by maximizing a variance condition for the nonlinearly transformed samples, which we call data-dependent kernel approach. The resulting kernel subspace can be first chosen by principal component analysis, and then be processed for composite kernel subspace through the efficient combination representations used for further reconstruction and classification. Numerical experiments based on several MID feature spaces of cancer CAD data have shown that PC-KFA generates efficient and an effective feature representation, and has yielded a better classification performance for the proposed composite kernel subspace using a simple pattern classifier. C1 [Motai, Yuichi] Virginia Commonwealth Univ, Sch Engn, Sensory Intelligent Lab, Dept Elect & Comp Engn, Richmond, VA 23284 USA. [Yoshida, Hiroyuki] Harvard Univ, Sch Med, Dept Radiol, 3D Imaging Res, Boston, MA 02114 USA. [Yoshida, Hiroyuki] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Motai, Y (reprint author), Virginia Commonwealth Univ, Sch Engn, Sensory Intelligent Lab, Dept Elect & Comp Engn, POB 843068,601 West Main St, Richmond, VA 23284 USA. EM ymotai@vcu.edu; yoshida.hiro@mgh.harvard.edu FU American Cancer Society Institutional Research Grant through the Massey Cancer Center; Virginia Commonwealth University; US National Science Foundation ECCS [1054333]; USPHS from National Cancer Institute [R01CA095279] FX The authors would like to express gratitude for the support of this research by the American Cancer Society Institutional Research Grant through the Massey Cancer Center, Presidential Research Incentive Program at Virginia Commonwealth University, US National Science Foundation ECCS #1054333 (CAREER Award), and USPHS Grant R01CA095279 from National Cancer Institute. The work reported here would not be possible without the help of many of the past and present members of the laboratory, in particular, D. Ma, A. Docef, S. Myla, and L. Winter. NR 75 TC 8 Z9 8 U1 3 U2 18 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 1041-4347 J9 IEEE T KNOWL DATA EN JI IEEE Trans. Knowl. Data Eng. PD AUG PY 2013 VL 25 IS 8 BP 1863 EP 1875 DI 10.1109/TKDE.2012.110 PG 13 WC Computer Science, Artificial Intelligence; Computer Science, Information Systems; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 175VF UT WOS:000321261000014 ER PT J AU Trautner, BW Patterson, JE Petersen, NJ Hysong, S Horwitz, D Chen, GJ Grota, P Naik, AD AF Trautner, Barbara W. Patterson, Jan E. Petersen, Nancy J. Hysong, Sylvia Horwitz, Deborah Chen, G. John Grota, Patti Naik, Aanand D. TI Quality Gaps in Documenting Urinary Catheter Use and Infectious Outcomes SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID TRACT-INFECTION; CARE; PREVENTION; CONDOM AB OBJECTIVE. To describe the frequency of use of all types of urinary catheters, including but not limited to indwelling catheters, as well as positive cultures associated with the various types. We also determined the accuracy of catheter-days reporting at our institution. DESIGN. Prospective, observational trial based on patient-level review of the electronic medical record. Chart review was compared with standard methods of catheter surveillance and reporting by infection control personnel. SETTING. Ten internal medicine and 5 long-term care wards in 2 tertiary care Veterans Affairs hospitals in Texas from July 2010 through June 2011. PARTICIPANTS. The study included 7,866 inpatients. METHODS. Measurements included patient bed-days; days of use of indwelling, external, suprapubic, and intermittent urinary catheters; number of urine cultures obtained and culture results; and infection control reports of indwelling catheter-days. RESULTS. We observed 7,866 inpatients with 128,267 bed-days on acute medicine and extended care wards during the study. A urinary catheter was used on 36.9% of the total bed-days observed. Acute medicine wards collected more urine cultures per 1,000 bed-days than did the extended care wards (75.9 and 10.4 cultures per 1,000 bed-days, respectively; P < .0001). Catheter-days were divided among indwelling-catheter-days (47.8%), external-catheter-days (48.4%), and other (intermittent- and suprapubic-catheter-days, 3.8%). External catheters contributed to 376 (37.3%) of the 1,009 catheter-associated positive urine cultures. Urinary-catheter-days reported to the infection control department missed 20.1% of the actual days of indwelling catheter use, whereas 12.0% of their reported catheter-days were false. CONCLUSIONS. Urinary catheter use was extremely common. External catheters accounted for a large portion of catheter-associated bacteriuria, and standard practices for tracking urinary-catheter-days were unreliable. C1 [Trautner, Barbara W.; Petersen, Nancy J.; Hysong, Sylvia; Horwitz, Deborah; Chen, G. John; Naik, Aanand D.] Michael E DeBakey VA Med Ctr, Houston Vet Affairs Hlth Serv, Res & Dev Ctr Excellence, Houston, TX USA. [Trautner, Barbara W.; Petersen, Nancy J.; Hysong, Sylvia; Horwitz, Deborah; Chen, G. John; Naik, Aanand D.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Petersen, Nancy J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med Infect Dis, San Antonio, TX 78229 USA. [Patterson, Jan E.; Grota, Patti] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Trautner, BW (reprint author), MEDVAMC HSR&D CoE 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM trautner@bcm.edu RI Hysong, Sylvia/B-8420-2008 OI Hysong, Sylvia/0000-0002-9063-5207 FU VA Health Services Research and Development [IIR 09-104]; VA Rehabilitation Research and Development [B4623]; National Institute of Diabetes and Digestive and Kidney Diseases [DK092293]; VA Health Services Research and Development Houston Center of Excellence [HFP-090-20] FX This work was supported by the VA Health Services Research and Development (IIR 09-104); VA Rehabilitation Research and Development (B4623); and the National Institute of Diabetes and Digestive and Kidney Diseases (DK092293). This work was also partly supported by the VA Health Services Research and Development Houston Center of Excellence (HFP-090-20). B.W.T. had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of data analysis. NR 26 TC 4 Z9 4 U1 2 U2 12 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD AUG PY 2013 VL 34 IS 8 BP 793 EP 799 DI 10.1086/671267 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 180RT UT WOS:000321613900005 PM 23838219 ER PT J AU van Kollenburg, JAPAC Vrahas, MS Smith, RM Guitton, TG Ring, D AF van Kollenburg, Johan A. P. A. C. Vrahas, Mark S. Smith, R. Malcolm Guitton, Thierry G. Ring, David CA Sci Variation Grp TI Diagnosis of union of distal tibia fractures: Accuracy and interobserver reliability SO INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED LA English DT Article DE Distal tibia fracture; Open reduction and internal fixation; Radiographs; Diagnosis of union; Reliability; Accuracy; Diagnostic performance characteristics ID PLAFOND FRACTURES; PILON FRACTURES; INTERNAL-FIXATION; OPEN REDUCTION AB Decisions about return to activity and additional surgery are often made on the basis of radiographs obtained 3 months after injury. If radiographs 3 months after injury cannot reliably and accurately diagnose union, then patients may be needlessly disabled and might receive unnecessary treatments including surgery. We evaluated the accuracy and the reliability of the diagnosis of union or eventual union on radiographs obtained 3 months after open reduction and internal fixation of a fracture of the distal tibia by having 69 trauma surgeons evaluate radiographs of 33 consecutively treated patients in an online survey. Observers were also asked to judge specific criteria that are commonly used to diagnose fracture union. There was moderate interobserver reliability for the diagnosis of union or diagnosis of "eventual union". The interobserver agreement for the various specific radiographic signs of union varied between fair to moderate. The sensitivity of radiographs for diagnosis of "union or eventual union" of distal tibia fractures was 47%, the specificity was 73% and the accuracy was 68%. The prevalence adjusted positive predictive value was 25% and the negative predictive value was 88%. Diagnosis of union based on radiographs 3 months after injury is only moderately reliable and accurate but has a high negative predictive value. Decisions about activity level and additional treatment 3 months after injury should not be based on radiographs alone. (C) 2012 Elsevier Ltd. All rights reserved. C1 [van Kollenburg, Johan A. P. A. C.; Vrahas, Mark S.; Smith, R. Malcolm; Guitton, Thierry G.; Ring, David] Harvard Univ, Sch Med, Boston, MA 02114 USA. [van Kollenburg, Johan A. P. A. C.; Guitton, Thierry G.; Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. [Vrahas, Mark S.; Smith, R. Malcolm] Massachusetts Gen Hosp, Orthopaed Trauma Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Sch Med, 55 Fruit St,YAW 2100, Boston, MA 02114 USA. EM dring@partners.org OI Borris, Lars/0000-0002-0527-1518; Guitton, Thierry/0000-0002-2599-1985 FU Biomet; Skeletal Dynamics FX David Ring is a Consultant for Wright Medical and Skeletal Dynamics; has research contracts with Biomet and Skeletal Dynamics; and receives royalties from Wright Medical and has contracts for future royalties with Medartis and Skeletal Dynamics. NR 17 TC 1 Z9 1 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-1383 J9 INJURY JI Injury-Int. J. Care Inj. PD AUG PY 2013 VL 44 IS 8 BP 1073 EP 1075 DI 10.1016/j.injury.2012.10.034 PG 3 WC Critical Care Medicine; Emergency Medicine; Orthopedics; Surgery SC General & Internal Medicine; Emergency Medicine; Orthopedics; Surgery GA 179CU UT WOS:000321496700011 PM 23200031 ER PT J AU Saunders, GH Frederick, MT Silverman, S Papesh, M AF Saunders, Gabrielle H. Frederick, Melissa Teahen Silverman, Shienpei Papesh, Melissa TI Application of the health belief model: Development of the hearing beliefs questionnaire (HBQ) and its associations with hearing health behaviors SO INTERNATIONAL JOURNAL OF AUDIOLOGY LA English DT Article DE Rehabilitation of hearing impaired; health behavior; health care seeking behavior; patient acceptance of health care; patient compliance; hearing aids ID HELP-SEEKING BEHAVIOR; OLDER-ADULTS; AID USE; PEOPLE; IMPAIRMENT; REHABILITATION; POPULATION; COMPLAINTS; COMMUNITY; ATTITUDES AB Objective : To develop a hearing beliefs questionnaire (HBQ) that assesses hearing beliefs within the constructs of the health belief model, and to investigate whether HBQ scores are associated with hearing health behaviors. Design: A 60-item version of the questionnaire was developed and completed by 223 participants who also provided information about their hearing health behaviors (help seeking, hearing-aid acquisition, and hearing-aid use). Study sample: Individuals aged between 22 and 90 years recruited from a primary care waiting area at a Veterans hospital. Seventy-six percent were male, 80% were Veterans. Results: A 26-item version of the HBQ with six scales was derived using factor analysis and reliability analyses. The scales measured: perceived susceptibility, perceived severity, perceived benefits, perceived barriers, perceived self-efficacy, and cues to action. HBQ scores differed significantly between individuals with different hearing health behaviors. Logistic regression analyses resulted in robust models of hearing health behaviors that correctly classified between 59% and 100% of participant hearing health behaviors. Conclusions: The HBM appears to be an appropriate framework for examining hearing health behaviors, and the HBQ is a valuable tool for assessing hearing health beliefs and predicting hearing health behaviors. C1 [Saunders, Gabrielle H.; Frederick, Melissa Teahen; Silverman, Shienpei; Papesh, Melissa] Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, Portland, OR USA. [Saunders, Gabrielle H.] Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97201 USA. RP Saunders, GH (reprint author), Natl Ctr Rehabil Auditory Res, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM gabrielle.saunders@va.gov FU Unitron; Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service [C4844C] FX This material is based upon work supported by Unitron and by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Grant # C4844C. Aspects of these data were presented at the International Hearing Aid Research Conference (IHCON), Lake Tahoe, USA, August 8-12, 2012, at the Academy of Rehabilitative Audiology Institute, Providence, USA, September 9-11, 2012, and at the British Academy of Audiology, Manchester, UK, November 12-13, 2012. NR 41 TC 17 Z9 19 U1 2 U2 20 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 AUG PY 2013 VL 52 IS 8 BP 558 EP 567 DI 10.3109/14992027.2013.791030 PG 10 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 181UJ UT WOS:000321693900006 PM 23682849 ER PT J AU Sewell, MC Luo, XD Neugroschl, J Sano, M AF Sewell, Margaret C. Luo, Xiaodong Neugroschl, Judith Sano, Mary TI Detection of mild cognitive impairment and early stage dementia with an audio-recorded cognitive scale SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Article DE cognitive assessment; Alzheimer's disease; MCI; diagnostic accuracy ID ALZHEIMERS-DISEASE AB Background: Physicians often miss diagnosis of mild cognitive impairment (MCI) or early dementia and screening measures can be insensitive to very mild impairments. Other cognitive assessments may take too much time or be frustrating to seniors. This study examined the ability of an audio-recorded scale, developed in Australia, to detect MCI or mild Alzheimer's disease (AD) and compared cognitive domain-specific performance on the audio-recorded scale to in-person battery and common cognitive screens. Method: Seventy-six patients from the Mount Sinai Alzheimer's Disease Research Center were recruited. Patients were aged 75 years or older, with clinical diagnosis of AD or MCI (n = 51) or normal control (n = 25). Participants underwent in-person neuropsychological testing followed by testing with the audio-recorded cognitive screen (ARCS). Results: ARCS provided better discrimination between normal and impaired elderly individuals than either the Mini-Mental State Examination or the clock drawing test. The in-person battery and ARCS analogous variables were significantly correlated, most in the 0.4 to 0.7 range, including verbal memory, executive function/attention, naming, and verbal fluency. The area under the curve generated from the receiver operating characteristic curves indicated high and equivalent discrimination for ARCS and the in-person battery (0.972 vs. 0.988; p = 0.23). Conclusion: The ARCS demonstrated better discrimination between normal controls and those with mild deficits than typical screening measures. Performance on cognitive domains within the ARCS was well correlated with the in-person battery. Completion of the ARCS was accomplished despite mild difficulty hearing the instructions even in very elderly participants, indicating that it may be a useful measure in primary care settings. C1 [Sewell, Margaret C.; Luo, Xiaodong; Neugroschl, Judith; Sano, Mary] Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Sano, Mary] James J Peters VA Med Ctr, Bronx, NY USA. RP Sewell, MC (reprint author), Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, 1 Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM margaret.sewell@mssm.edu FU National Institutes of Health [NIH U01 P50-AG005138-28] FX The authors would like to express their gratitude to Talia Sandwick, BA, for her work with subject recruitment and data collection. The authors are also grateful to the National Institutes of Health for their grant no. NIH U01 P50-AG005138-28. NR 19 TC 0 Z9 0 U1 0 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD AUG PY 2013 VL 25 IS 8 SI SI BP 1325 EP 1333 DI 10.1017/S1041610213000598 PG 9 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA 175WD UT WOS:000321263400013 PM 23635663 ER PT J AU Hinton, DE Ojserkis, RA Jalal, B Peou, S Hofmann, SG AF Hinton, Devon E. Ojserkis, Rebecca A. Jalal, Baland Peou, Sonith Hofmann, Stefan G. TI Loving-Kindness in the Treatment of Traumatized Refugees and Minority Groups: A Typology of Mindfulness and the Nodal Network Model of Affect and Affect Regulation SO JOURNAL OF CLINICAL PSYCHOLOGY LA English DT Article DE acceptance; mindfulness; meditation; posttraumatic stress disorder; cross-cultural ID CULTURALLY ADAPTED CBT; EMOTION REGULATION; CAMBODIAN REFUGEES; ANXIETY DISORDER; PTSD; MEDITATION; MECHANISMS; EXAMPLES; WORRY AB This article discusses how loving-kindness can be used to treat traumatized refugees and minority groups, focusing on examples from our treatment, culturally adapted cognitive-behavioral therapy (CA-CBT). To show how we integrate loving-kindness with other mindfulness interventions and why loving-kindness should be an effective therapeutic technique, we present a typology of mindfulness states and the Nodal Network Model (NNM) of Affect and Affect Regulation. We argue that mindfulness techniques such as loving-kindness are therapeutic for refugees and minority populations because of their potential for increasing emotional flexibility, decreasing rumination, serving as emotional regulation techniques, and forming part of a new adaptive processing mode centered on psychological flexibility. We present a case to illustrate the clinical use of loving-kindness within the context of CA-CBT. C1 [Hinton, Devon E.; Ojserkis, Rebecca A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hinton, Devon E.; Ojserkis, Rebecca A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Jalal, Baland] Univ Calif San Diego, San Diego, CA USA. [Hofmann, Stefan G.] Boston Univ, Boston, MA 02215 USA. RP Hinton, DE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM devon_hinton@hms.harvard.edu RI Hofmann, Stefan/B-8769-2014 OI Hofmann, Stefan/0000-0002-3548-9681 NR 21 TC 4 Z9 4 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9762 J9 J CLIN PSYCHOL JI J. Clin. Psychol. PD AUG PY 2013 VL 69 IS 8 BP 817 EP 828 DI 10.1002/jclp.22017 PG 12 WC Psychology, Clinical SC Psychology GA 179AE UT WOS:000321487800003 PM 23784718 ER PT J AU Alshouibi, EN Kaye, EK Cabral, HJ Leone, CW Garcia, RI AF Alshouibi, E. N. Kaye, E. K. Cabral, H. J. Leone, C. W. Garcia, R. I. TI Vitamin D and Periodontal Health in Older Men SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE periodontal disease; alveolar bone; probing depth; clinical attachment loss; vitamin D intake; aging ID D DEFICIENCY; CALCIUM SUPPLEMENTATION; SERUM CONCENTRATIONS; DISEASE PROGRESSION; ASSOCIATION; POPULATION; UPDATE AB Vitamin D, an anti-inflammatory mediator, has potential benefits for physical and oral health. Although it is produced endogenously, some individuals have a greater need for dietary and supplemental sources. This repeated-measures cross-sectional study assessed associations between total vitamin D intake and periodontal health in older men. Participants were 562 members of the Department of Veterans Affairs Dental Longitudinal Study, mean age 62.9 years, who were examined 1 to 4 times between 1986 and 1998. A calibrated examiner measured probing pocket depth (PPD) and attachment loss (AL) on each tooth. Alveolar bone loss (ABL) was determined from radiographs. Severe periodontal disease was defined as PPD 5 mm on 1 tooth and AL 6 mm at 2 sites (not on same tooth), and moderate-to-severe alveolar bone loss as ABL 40% at 3 sites. Generalized estimating equations were used to compute the odds ratios (OR) and 95% confidence intervals (95% CI) of having periodontal disease by level of vitamin D intake. Total vitamin D intake 800 IU was associated with lower odds of severe periodontal disease (OR = 0.67, 95% CI = 0.55-0.81) and moderate-to-severe ABL (OR = 0.54, 95% CI = 0.30-0.96) relative to intake < 400 IU/day. Vitamin D intake may protect against periodontal disease progression. C1 [Alshouibi, E. N.] King Abdulaziz Univ, Fac Dent, Dept Prevent Sci, Jeddah 21413, Saudi Arabia. [Alshouibi, E. N.; Kaye, E. K.; Garcia, R. I.] Boston Univ, Henry M Goldman Sch Dent Med, Dept Hlth Policy & Hlth Serv Res, Boston, MA 02215 USA. [Kaye, E. K.; Garcia, R. I.] VA Boston Healthcare Syst, Boston, MA USA. [Cabral, H. J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Leone, C. W.] Boston Univ, Henry M Goldman Sch Dent Med, Dept Periodontol & Oral Biol, Boston, MA 02215 USA. RP Kaye, EK (reprint author), Boston Univ, Henry M Goldman Sch Dent Med, Dept Hlth Policy & Hlth Serv Res, Boston, MA 02215 USA. EM kralle@bu.edu OI Kaye, Elizabeth/0000-0001-7529-2501 FU National Institute of Dental and Craniofacial Research [K24 DE00419]; US Department of Veterans Affairs; VA HSRD Service FX This work was supported by the National Institute of Dental and Craniofacial Research (K24 DE00419). The Dental Longitudinal Study and Normative Aging Study are components of the Massachusetts Veterans Epidemiology Research and Information Center, supported by the US Department of Veterans Affairs Cooperative Studies Program. Dr. Garcia was a recipient of a Veterans Affairs Career Development Award in Health Services Research from the VA HSR&D Service. The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 24 TC 13 Z9 13 U1 2 U2 11 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 AUG PY 2013 VL 92 IS 8 BP 689 EP 693 DI 10.1177/0022034513495239 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 182JQ UT WOS:000321738500004 PM 23788610 ER PT J AU Nelson, DB Freeman, MP Johnson, NL McIntire, DD Leveno, KJ AF Nelson, David B. Freeman, Marlene P. Johnson, Neysa L. McIntire, Donald D. Leveno, Kenneth J. TI A prospective study of postpartum depression in 17 648 parturients SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Edinburgh postnatal depression scale; postpartum depression; prospective study ID POSTNATAL DEPRESSION; PERINATAL DEPRESSION; SCALE EPDS; WOMEN; RISK; PREGNANCY; VALIDATION; SYMPTOMS; COHORT; IMPACT AB Objective: To assess perinatal antecedents to postpartum depression (PPD). Methods: This was a prospective population-based, observational study of women screened for symptoms of depression using the Edinburgh Postnatal Depression Scale (EPDS) with scores >= 13 referred for psychiatric evaluation. Obstetric and neonatal outcomes were analyzed using univariable and multivariable analysis for associations with postpartum depressive symptoms. Results: Of 25 050 women delivered, 17 648 (71%) completed EPDS questionnaires with 1106 (6.3%) scoring >= 13. Perinatal complications most associated with EPDS scores >= 13 included major malformation (adjusted OR 1.5; 95% CI, 1.1-2.3), neonatal death (adjusted OR 5.8; 95% CI, 2.9-11.4), stillbirth (adjusted OR 9.4; 95% CI, 6.0-14.8), and necrotizing enterocolitis (adjusted OR 21.7; 95% CI, 1.9-244.3). A total of 238 (22%) women kept their psychiatric referral appointment, and 111 (47%) were diagnosed with PPD. Perinatal factors were also found to be significantly associated with PPD. Conclusions: PPD is significantly increased in women with adverse pregnancy outcomes, especially involving the infant. C1 [Nelson, David B.; McIntire, Donald D.; Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Freeman, Marlene P.] Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. [Johnson, Neysa L.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. RP Nelson, DB (reprint author), Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM davidb.nelson@utsouthwestern.edu NR 31 TC 5 Z9 6 U1 4 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD AUG PY 2013 VL 26 IS 12 BP 1155 EP 1161 DI 10.3109/14767058.2013.777698 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 183YQ UT WOS:000321853600001 PM 23421404 ER PT J AU Keith, DA Dodson, TB Kaban, LB AF Keith, David A. Dodson, Thomas B. Kaban, Leonard B. TI Historical Review: First Facial Pain Patient Admitted to Massachusetts General Hospital, February 1823 and First Case Series SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID TRIGEMINAL NEURALGIA; MICROVASCULAR DECOMPRESSION AB Founded in 1811, the Massachusetts General Hospital recently celebrated its bicentennial. The War of 1812 delayed construction of the building so the first patient actually was admitted to the hospital 10 years later, on September 3, 1821. By 1823, the 60 hospital beds were full. Patient 66 was admitted on February 28, 1823, and his hospital course, as described in the admissions book, was transcribed for the Massachusetts General Hospital bicentennial celebration. That case history is reproduced and a case series of 6 similar patients published in 1828 by Dr John Warren, surgeon-in-chief and a founder of the hospital, is presented. In this report, the authors comment on the diagnosis, treatment, and outcome of these patients in the context of the contemporaneous health care environment and in light of the current knowledge of facial pain disorders. This article was adapted from the authors' commentary for the bicentennial celebration. (C) 2013 American Association of Oral and Maxillofacial Surgeons C1 [Keith, David A.; Kaban, Leonard B.] Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02115 USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg,Ctr Appl Clin Inve, Boston, MA 02115 USA. RP Keith, DA (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St, Boston, MA 02114 USA. EM dkeith@partners.org FU Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund FX This project was supported by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund. NR 33 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2013 VL 71 IS 8 BP 1322 EP 1333 DI 10.1016/j.joms.2013.04.027 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 182IQ UT WOS:000321735300009 PM 23866949 ER PT J AU Kinard, BE Chuang, SK August, M Dodson, TB AF Kinard, Brian E. Chuang, Sung-Kiang August, Meredith Dodson, Thomas B. TI How Well Do We Manage the Odontogenic Keratocyst? SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID TERM-FOLLOW-UP; DECOMPRESSION; ENUCLEATION; RECURRENCE; MARSUPIALIZATION; CRYOTHERAPY; STRATEGY; CYSTS AB Purpose: To answer the clinical question: Among patients treated for odontogenic keratocysts (OKCs), what is the overall 5-year disease-free rate and what factors are associated with disease recurrence? Materials and Methods: The investigators implemented a retrospective cohort study and enrolled a sample composed of patients presenting for the evaluation and management of previously untreated OKCs. The predictor variables were grouped into demographic, medical, radiographic, and operative categories. The primary outcome variable was time to lesion recurrence. Data analyses were performed using univariate and bivariate or multivariate Cox proportional hazards models. Results: The study sample was composed of 31 patients (31 OKCs) with a mean age of 41.0 years. Of the 31 OKCs treated, 19 (61.3%) were treated with decompression with or without residual cystectomy and 12 (38.7%) were treated with enucleation with or without adjunctive therapy. There were 8 recurrences in 8 patients, with a median time to recurrence of 17.8 months (interquartile range, 13.4 to 26.4 months). The 5-year disease-free estimate was 51.2% (95% confidence interval, 37.2%-65.2%). Multiloculated lesions were 33.6 times more likely to recur than unilocular lesions. Conclusion: This may be the first study looking at disease recurrence after treatment of OKCs using appropriate statistical analyses for a time-dependent outcome (disease recurrence). The risk for recurrent disease is higher in this report than in many other studies and raises the issue that other reports may have underestimated the risk for recurrent disease owing to inappropriate statistical methods for assessing time-dependent outcomes. (C) 2013 American Association of Oral and Maxillofacial Surgeons C1 [Kinard, Brian E.] Emory Univ, Sch Med, Dept Oral & Maxillofacial Surg, Atlanta, GA USA. [Chuang, Sung-Kiang; August, Meredith] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Ctr Appl Clin Invest,Dept Oral Surg, Boston, MA 02115 USA. [Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Ctr Appl Clin Invest,Dept Maxillofacial Surg, Boston, MA 02115 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 Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund; Center for Applied Clinical Investigation; Massachusetts General Physicians Organization FX This project was supported in part by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund (to B. E. K.), the Center for Applied Clinical Investigation (to S.-K.C. and T.B.D.), and the Massachusetts General Physicians Organization (to S.-K.C., M.A., and T.B.D.). NR 31 TC 4 Z9 4 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2013 VL 71 IS 8 BP 1353 EP 1358 DI 10.1016/j.joms.2013.01.029 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 182IQ UT WOS:000321735300013 PM 23623200 ER PT J AU Zhang, XY Chen, DC Xiu, MH Tan, YL Yang, FD Zhang, LY Zhang, LY Haile, CN Kosten, TR AF Zhang, Xiang Yang Chen, Da Chun Xiu, Mei Hong Tan, Yun Long Yang, Fu De Zhang, Laurence Y. Zhang, Laura Y. Haile, Colin N. Kosten, Thomas R. TI Clinical symptoms and cognitive impairment associated with male schizophrenia relate to plasma manganese superoxide dismutase activity: A case-control study SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Schizophrenia; Cognition; Oxidative stress; MnSOD; Psychopathology ID NEVER-MEDICATED 1ST-EPISODE; OXIDATIVE STRESS; NEUROPSYCHOLOGICAL STATUS; ANTIOXIDANT ENZYMES; REPEATABLE BATTERY; GENDER-DIFFERENCES; FATTY-ACIDS; DEFICITS; PSYCHOSIS; BRAIN AB Several lines of evidence suggest that excessive reactive oxygen species-induced oxidative damage may underlie cognitive impairment in psychiatric disorders. A growing body of evidence show that oxidative damage may relate to the range of cognitive deficits associated with schizophrenia. In this study we examine one of the primary antioxidant defense enzymes manganese superoxide dismutase (MnSOD), and whether it relates to cognitive deficits in schizophrenia. We recruited 185 chronic male schizophrenia patients and 132 male controls and compared results from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and plasma MnSOD activity between groups. Symptom severity in patients with schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS). Our results showed that MnSOD activities were significantly lower in patients than controls (p < 0.05). Cognitive scores on the RBANS and, nearly all of its five subscales (all p < 0.001) except for the Visuospatial/Constructional index were significantly lower in schizophrenia patients than normal controls. MnSOD was negatively correlated with the general psychopathology subscale of PANSS, PANSS total score, positive symptoms and RBANS total score in patients with schizophrenia. Our findings add to growing evidence that oxidative stress may be involved in the psychopathology of male schizophrenia, and its associated cognitive impairment (C) 2013 Elsevier Ltd. All rights reserved. C1 [Zhang, Xiang Yang; Kosten, Thomas R.] Michael E DeBakey VA Med Ctr, Menninger Dept Psychiat & Behav Sci, Baylor Coll Med, Houston, TX USA. [Zhang, Xiang Yang; Chen, Da Chun; Xiu, Mei Hong; Tan, Yun Long; Yang, Fu De; Haile, Colin N.; Kosten, Thomas R.] Peking Univ, Beijing HuiLongGuan Hosp, Beijing 100871, Peoples R China. [Zhang, Laurence Y.; Zhang, Laura Y.] Bellaire High Sch, Houston, TX USA. RP Zhang, XY (reprint author), VA Med Ctr, Res Bldg 109,Room 130,2002 Holcombe Blvd, Houston, TX 77030 USA. EM xyzhang@bcm.edu; kosten@bcm.edu OI Haile, Colin/0000-0001-8293-7291 FU Stanley Medical Research Institute [03T-459, 05T-726]; Department of Veterans Affairs; VISN [16]; Mental Illness Research, Education and Clinical Center (MIRECC); United States National Institute of Health [K05-DA0454, P50-DA18827, U01-MH79639] FX This study was supported by the Stanley Medical Research Institute (03T-459 and 05T-726), and the Department of Veterans Affairs, VISN 16, Mental Illness Research, Education and Clinical Center (MIRECC), United States National Institute of Health K05-DA0454, P50-DA18827 and U01-MH79639. These sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 43 TC 7 Z9 7 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD AUG PY 2013 VL 47 IS 8 BP 1049 EP 1053 DI 10.1016/j.jpsychires.2013.03.014 PG 5 WC Psychiatry SC Psychiatry GA 173IU UT WOS:000321073500009 PM 23611682 ER PT J AU McKay, JR Van Horn, D Rennert, L Drapkin, M Ivey, M Koppenhaver, J AF McKay, James R. Van Horn, Deborah Rennert, Lior Drapkin, Michelle Ivey, Megan Koppenhaver, Janelle TI Factors in sustained recovery from cocaine dependence SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Cocaine dependence; Cocaine abstinence; Recovery; Predictors; Treatment response; Follow-up; Treatment ID SUBSTANCE-ABUSE TREATMENT; ADDICTION SEVERITY INDEX; CONTINUING CARE; FOLLOW-UP; PSYCHOMETRIC PROPERTIES; PSYCHOSOCIAL TREATMENT; DRINKING TRAJECTORIES; OUTPATIENT TREATMENT; TREATMENT ATTRITION; INITIAL ABSTINENCE AB The goal was to identify factors that predicted sustained cocaine abstinence and transitions from cocaine use to abstinence over 24 months. Data from baseline assessments and multiple follow-ups were obtained from three studies of continuing care for patients in intensive outpatient programs (IOPs). In the combined sample, remaining cocaine abstinent and transitioning into abstinence at the next follow-up were predicted by older age, less education, and less cocaine and alcohol use at baseline, and by higher self-efficacy, commitment to abstinence, better social support, lower depression, and lower scores on other problem severity measures assessed during the follow-up. In addition, higher self-help participation, self-help beliefs, readiness to change, and coping assessed during the follow-up predicted transitions from cocaine use to abstinence. These results were stable over 24 months. Commitment to abstinence, self-help behaviors and beliefs, and self-efficacy contributed independently to the prediction of cocaine use transitions. Implications for treatment are discussed. Published by Elsevier Inc. C1 [McKay, James R.; Van Horn, Deborah; Rennert, Lior; Drapkin, Michelle; Ivey, Megan; Koppenhaver, Janelle] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [McKay, James R.; Drapkin, Michelle] Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP McKay, JR (reprint author), Univ Penn, 3440 Market St,Suite 370, Philadelphia, PA 19104 USA. EM jimrache@mail.med.upenn.edu FU NIAAA NIH HHS [R01 AA014850, R01 AA14850]; NIDA NIH HHS [K24 DA029062, R01 DA020623] NR 75 TC 12 Z9 12 U1 2 U2 18 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 AUG PY 2013 VL 45 IS 2 BP 163 EP 172 DI 10.1016/j.jsat.2013.02.007 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 173IH UT WOS:000321072100002 PM 23561331 ER PT J AU McMillan, GP Hanson, TE Saunders, G Gallun, FJ AF McMillan, Garnett P. Hanson, Timothy E. Saunders, Gabrielle Gallun, Frederick J. TI A two-component circular regression model for repeated measures auditory localization data SO JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS LA English DT Article DE Angular regression; Bimodal data; B-splines; Sound localization; Symmetry models ID BAYESIAN MODEL; DISTRIBUTIONS; SPLINES; TESTS AB . Auditory localization experiments are conducted to evaluate human ability to locate the position of a source of sound, and to determine how population characteristics might affect this ability. These experiments generate data that are circular, bimodal and repeated, and have hypothesized symmetry patterns that should be included and tested within the modelling framework. We propose a two-part mixture of wrapped Cauchy densities for these bimodal angular data, with random effects to model correlation between repeated measures. The effects of signal position and types of symmetry in the signal response around the circle are modelled by using circular B-splines. The model is used to investigate the effects of age and hearing impairment on the ability to localize a low frequency signal. C1 [McMillan, Garnett P.; Saunders, Gabrielle; Gallun, Frederick J.] Natl Ctr Rehabil Auditory Res, Portland, OR USA. [Hanson, Timothy E.] Univ S Carolina, Columbia, SC 29208 USA. RP McMillan, GP (reprint author), Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM Garnett.McMillan@va.gov RI Gallun, Frederick/G-3792-2012; Hanson, Timothy/A-9127-2016 OI Gallun, Frederick/0000-0002-4145-2199; FU Department of Veterans Affairs, Veterans Health Administration 'Rehabilitation research and development' grant [3040] FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration 'Rehabilitation research and development' grant 3040. The authors thank Anna Forsline, MA, and M. Samantha Lewis, PhD, for their assistance with data collection. We are grateful to Dr David Draper and several reviewers for helpful advice on this paper. The contents of this paper do not necessarily represent the views of the US Department of Veterans Affairs or the US Government. NR 33 TC 2 Z9 2 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0035-9254 J9 J R STAT SOC C-APPL JI J. R. Stat. Soc. Ser. C-Appl. Stat. PD AUG PY 2013 VL 62 IS 4 BP 515 EP 534 DI 10.1111/rssc.12004 PG 20 WC Statistics & Probability SC Mathematics GA 181YL UT WOS:000321706600001 ER PT J AU D'Amico, AV AF D'Amico, Anthony V. TI Adjuvant Versus Salvage Post-Prostatectomy Radiation Therapy: A Critical Review of the Evidence SO JOURNAL OF UROLOGY LA English DT Editorial Material ID PROSTATE-CANCER; RISK; RADIOTHERAPY; TRIAL C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. NR 4 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2013 VL 190 IS 2 BP 450 EP 451 DI 10.1016/j.juro.2013.05.028 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 178HJ UT WOS:000321436600017 PM 23688645 ER PT J AU Avci, P Nyame, TT Gupta, GK Sadasivam, M Hamblin, MR AF Avci, Pinar Nyame, Theodore T. Gupta, Gaurav K. Sadasivam, Magesh Hamblin, Michael R. TI Low-Level Laser Therapy for Fat Layer Reduction: A Comprehensive Review SO LASERS IN SURGERY AND MEDICINE LA English DT Review DE body contouring; cellulite; cholesterol; fat; lipoplasty; LLLT; liposuction ID NEAR-IR RADIATION; ASSISTED LIPOSUCTION; DUAL-WAVELENGTH; SUBCUTANEOUS FAT; MAMMALIAN-CELLS; CELLULITE; IRRADIATION; ENERGY; LIGHT; VIABILITY AB Background and Objective Low-level laser (light) therapy (LLLT) is a noninvasive, nonthermal approach to disorders requiring reduction of pain and inflammation and stimulation of healing and tissue regeneration. Within the last decade, LLLT started being investigated as an adjuvant to liposuction, for noninvasive body contouring, reduction of cellulite, and improvement of blood lipid profile. LLLT may also aid autologous fat transfer procedures by enhancing the viability of adipocytes. However the underlying mechanism of actions for such effects still seems to be unclear. It is important, therefore, to understand the potential efficacy and proposed mechanism of actions of this new procedure for fat reduction. Materials and Methods A review of the literature associated with applications of LLLT related to fat layer reduction was performed to evaluate the findings from pre-clinical and clinical studies with respect to the mechanism of action, efficacy, and safety. Results The studies as of today suggest that LLLT has a potential to be used in fat and cellulite reduction as well as in improvement of blood lipid profile without any significant side effects. One of the main proposed mechanism of actions is based upon production of transient pores in adipocytes, allowing lipids to leak out. Another is through activation of the complement cascade which could cause induction of adipocyte apoptosis and subsequent release of lipids. Conclusion Although the present studies have demonstrated safety and efficacy of LLLT in fat layer reduction, studies demonstrating the efficacy of LLLT as a stand-alone procedure are still inadequate. Moreover, further studies are necessary to identify the mechanism of action. Lasers Surg. Med. 45:349-357, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Avci, Pinar; Gupta, Gaurav K.; Sadasivam, Magesh; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Avci, Pinar; Gupta, Gaurav K.; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA USA. [Avci, Pinar] Semmelweis Univ, Sch Med, Dept Dermatol Dermatooncol & Venerol, H-1085 Budapest, Hungary. [Nyame, Theodore T.] Harvard Univ, Sch Med, Div Plast & Reconstruct Surg, Boston, MA USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU US NIH [R01AI050875] FX Contract grant sponsor: US NIH; Grant number: R01AI050875 NR 85 TC 21 Z9 21 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD AUG PY 2013 VL 45 IS 6 BP 349 EP 357 DI 10.1002/lsm.22153 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 182NY UT WOS:000321751700001 PM 23749426 ER PT J AU Walker, SR Nelson, EA Yeh, JE Pinello, L Yuan, GC Frank, DA AF Walker, Sarah R. Nelson, Erik A. Yeh, Jennifer E. Pinello, Luca Yuan, Guo-Cheng Frank, David A. TI STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID B-CELL LYMPHOMA; BREAST-CANCER; SIGNALING PATHWAY; SERINE PHOSPHORYLATION; HUMAN TUMORS; TRANSDUCER; ACTIVATION; BINDING; AUTOREGULATION; IDENTIFICATION AB Inappropriate activation of the transcription factors STAT3 and STAT5 has been shown to drive cancer pathogenesis through dysregulation of genes involved in cell survival, growth, and differentiation. Although STAT3 and STAT5 are structurally related, they can have opposite effects on key genes, including BCL6. BCL6, a transcriptional repressor, has been shown to be oncogenic in diffuse large B cell lymphoma. BCL6 also plays an important role in breast cancer pathogenesis, a disease in which STAT3 and STAT5 can be activated individually or concomitantly. To determine the mechanism by which these oncogenic transcription factors regulate BCL6 transcription, we analyzed their effects at the levels of chromatin and gene expression. We found that STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation. STAT5, in contrast, represses BCL6 expression below basal levels and decreases the association of RNA polymerase II at the gene. Furthermore, the repression mediated by STAT5 is dominant over STAT3-mediated induction. STAT5 exerts this effect by displacing STAT3 from one of the two regulatory regions to which it binds. These findings may underlie the divergent biology of breast cancers containing activated STAT3 alone or in conjunction with activated STAT5. C1 [Walker, Sarah R.; Nelson, Erik A.; Yeh, Jennifer E.; Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Walker, Sarah R.; Nelson, Erik A.; Frank, David A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Walker, Sarah R.; Nelson, Erik A.; Yeh, Jennifer E.; Frank, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Pinello, Luca; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Pinello, Luca; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM david_frank@dfci.harvard.edu FU NIH [R01-CA160979]; Susan G. Komen for the Cure; BCRF-AACR grant for Translational Breast Cancer Research; Brent Leahey Fund; Friends of the Dana-Farber Cancer Institute FX This work was supported by NIH grant R01-CA160979, Susan G. Komen for the Cure, a BCRF-AACR grant for Translational Breast Cancer Research, the Brent Leahey Fund, and Friends of the Dana-Farber Cancer Institute. NR 33 TC 21 Z9 21 U1 0 U2 4 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 AUG PY 2013 VL 33 IS 15 BP 2879 EP 2890 DI 10.1128/MCB.01620-12 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 180SD UT WOS:000321615500007 PM 23716595 ER PT J AU Liu, H Li, WJ Ahmad, M Rose, ME Miller, TM Yu, M Chen, J Pascoe, JL Poloyac, SM Hickey, RW Graham, SH AF Liu, Hao Li, Wenjin Ahmad, Muzamil Rose, Marie E. Miller, Tricia M. Yu, Mei Chen, Jie Pascoe, Jordan L. Poloyac, Samuel M. Hickey, Robert W. Graham, Steven H. TI Increased Generation of Cyclopentenone Prostaglandins after Brain Ischemia and Their Role in Aggregation of Ubiquitinated Proteins in Neurons SO NEUROTOXICITY RESEARCH LA English DT Article DE Cyclopentenone prostaglandins; Cell death; Ubiquitinated protein; Ubiquitin proteasome system; Primary neuron; Temporary focal ischemia ID 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); PARKINSONS-DISEASE; NEURODEGENERATIVE DISEASES; THERAPEUTIC IMPLICATIONS; ENDOGENOUS ELECTROPHILE; DEGRADATION PATHWAYS; AGGRESOME FORMATION; PROTEASOME SYSTEM; HYDROLASE UCH-L1; J2 AB The cyclopentenone prostaglandin (CyPG) J(2) series, including prostaglandin J(2) (PGJ(2)), Delta(12)-PGJ(2), and 15-deoxy-a dagger(12,14)-prostaglandin J(2) (15d-PGJ(2)), are active metabolites of PGD(2), exerting multiple effects on neuronal function. However, the physiologic relevance of these effects remains uncertain as brain concentrations of CyPGs have not been precisely determined. In this study, we found that free PGD(2) and the J(2) series CyPGs (PGJ(2), Delta(12)-PGJ(2), and 15d-PGJ(2)) were increased in post-ischemic rat brain as detected by UPLC-MS/MS with 15d-PGJ(2) being the most abundant CyPG. These increases were attenuated by pre-treating with the cyclooxygenase (COX) inhibitor piroxicam. Next, effects of chronic exposure to 15d-PGJ(2) were examined by treating primary neurons with 15d-PGJ(2), CAY10410 (a 15d-PGJ(2) analog lacking the cyclopentenone ring structure), or vehicle for 24 to 96 h. Because we found that the concentration of free 15d-PGJ(2) decreased rapidly in cell culture medium, freshly prepared medium containing 15d-PGJ(2), CAY10410, or vehicle was changed twice daily to maintain steady extracellular concentrations. Incubation with 2.5 mu M 15d-PGJ(2), but not CAY10410, increased the neuronal cell death without the induction of caspase-3 or PARP cleavage, consistent with a primarily necrotic mechanism for 15d-PGJ(2)-induced cell death which was further supported by TUNEL assay results. Ubiquitinated protein accumulation and aggregation was observed after 96 h 15d-PGJ(2) incubation, accompanied by compromised 20S proteasome activity. Unlike another proteasome inhibitor, MG132, 15d-PGJ(2) treatment did not activate autophagy or induce aggresome formation. Therefore, the cumulative cytotoxic effects of increased generation of CyPGs after stroke may contribute to delayed post-ischemic neuronal injury. C1 [Liu, Hao; Li, Wenjin; Ahmad, Muzamil; Rose, Marie E.; Pascoe, Jordan L.; Graham, Steven H.] VA Pittsburgh Healthcare, Geriatr Res Educ & Clin Ctr GR H 00, Pittsburgh, PA 15206 USA. [Liu, Hao; Li, Wenjin; Ahmad, Muzamil; Rose, Marie E.; Yu, Mei; Chen, Jie; Pascoe, Jordan L.; Graham, Steven H.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Miller, Tricia M.; Poloyac, Samuel M.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Hickey, Robert W.] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. RP Graham, SH (reprint author), VA Pittsburgh Healthcare, Geriatr Res Educ & Clin Ctr GR H 00, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM sgra@pitt.edu FU National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS37459] FX This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke R01NS37459. The authors thank Pat Strickler for secretarial support. NR 53 TC 14 Z9 14 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD AUG PY 2013 VL 24 IS 2 BP 191 EP 204 DI 10.1007/s12640-013-9377-4 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 170VN UT WOS:000320882700009 PM 23355003 ER PT J AU McKenzie, T Chen, Y Shikora, S Hodin, R Moore, F Lubitz, C AF McKenzie, T. Chen, Y. Shikora, S. Hodin, R. Moore, F., Jr. Lubitz, C. TI Primary Hyperparathyroidism After Roux-en-Y Gastric Bypass: A Case Series SO OBESITY SURGERY LA English DT Meeting Abstract CT 18th World Congress of the International-Federation-for-the-Surgery-of-Obesity-and-Metabolic-Disord ers (IFSO) CY AUG 28-31, 2013 CL Istanbul, TURKEY SP Int Federat Surg Obes & Metab Disorders (IFSO) C1 [McKenzie, T.; Chen, Y.; Hodin, R.; Lubitz, C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shikora, S.; Moore, F., Jr.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 J9 OBES SURG JI Obes. Surg. PD AUG PY 2013 VL 23 IS 8 BP 1033 EP 1033 PG 1 WC Surgery SC Surgery GA 177QC UT WOS:000321389200055 ER PT J AU Lee, MK Dodson, TB Karimbux, NY Nalliah, RP Allareddy, V AF Lee, Min Kyeong Dodson, Thomas B. Karimbux, Nadeem Y. Nalliah, Romesh P. Allareddy, Veerasathpurush TI Effect of occurrence of infection-related never events on length of stay and hospital charges in patients undergoing radical neck dissection for head and neck cancer SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID CLOSTRIDIUM-DIFFICILE INFECTION; NOSOCOMIAL INFECTIONS; IMPACT; SURGERY; COMPLICATIONS; INTERVENTION; COSTS; CARE AB Objective. To estimate the impact of infection-related never events (postoperative pneumonia, Clostridium difficile infection, infection with microorganisms resistant to penicillin, postoperative infections, and decubitus ulcers) following radical neck dissections for head and neck cancers. Study Design. The 2008 Nationwide Inpatient Sample was used to select hospitalizations with HNC that underwent radical neck dissections. Predictor variables were occurrence of never events and other patient-and hospital-level factors. Outcome variables were hospitalization charges and length of stay (LOS). Regression analyses were used to measure the association between predictors and outcomes. Results. Among 10,660 hospitalizations, prevalence of never events ranged from 0.2% to 5.0%. Mean hospitalization charge and LOS were $75,654 and 6.8 days, respectively. Never events were associated with 5.6-10.0 longer LOS and $49,153-$124,057 excess charges. Conclusion. Occurrence of never events was associated with at least 5.6 longer hospital days and $49,153 charge compared with hospitalizations without a never event. C1 [Lee, Min Kyeong] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Ctr Appl Clin Invest, Boston, MA 02114 USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral Surg, Boston, MA 02114 USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Maxillofacial Surg, Boston, MA 02114 USA. [Dodson, Thomas B.; Nalliah, Romesh P.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Karimbux, Nadeem Y.] Tufts Univ, Sch Dent Med, Dept Periodontol, Boston, MA 02111 USA. [Allareddy, Veerasathpurush] Boston Childrens Hosp, Dept Dent, Boston, MA USA. RP Lee, MK (reprint author), Harvard Univ, Sch Dent Med, Dept Dev Biol, 188 Longwood Ave, Boston, MA 02115 USA. EM minkyminko@gmail.com NR 24 TC 15 Z9 15 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-4403 J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD AUG PY 2013 VL 116 IS 2 BP 147 EP 158 DI 10.1016/j.oooo.2013.02.006 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 182JL UT WOS:000321737900015 PM 23591100 ER PT J AU Nicolatou-Galitis, O Nikolaidi, A Athanassiadis, I Papadopoulou, E Sonis, S AF Nicolatou-Galitis, Ourania Nikolaidi, Adamantia Athanassiadis, Ilias Papadopoulou, Erofili Sonis, Stephen TI Oral ulcers in patients with advanced breast cancer receiving everolimus: a case series report on clinical presentation and management SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID RENAL-CELL CARCINOMA; MAMMALIAN TARGET; MTOR INHIBITORS; APHTHOUS ULCERS; STOMATITIS; RAPAMYCIN; THERAPY; TEMSIROLIMUS; INFECTION; MUCOSITIS AB Objective. We report the clinical features and management outcomes in 7 patients with everolimus-related stomatitis. Study design. Fifteen women with hormone-receptor-positive advanced breast cancer receiving everolimus combined with exemestane were prospectively evaluated to assess the development of stomatitis. Oral ulcers were diagnosed based on established criteria. Results. Seven patients developed stomatitis (46.6%). All patients were treated with topical dexamethasone solution, while everolimus was temporarily discontinued in 4 patients. Stomatitis resolved within 1-2 weeks. Two of the 4 patients, who had interrupted everolimus, developed recurrent stomatitis following drug resume and everolimus was again discontinued and restarted after 2 weeks. To date, 5 patients receive everolimus in full dose. The 2 patients, who developed recurrent stomatitis, received a reduced dose. Conclusions. Everolimus-related oral ulcers were frequent and led to dose modifications. Controlled trials, endorsing a consensus in terminology, are needed to evaluate measures on prevention and management of this unique toxicity. C1 [Nicolatou-Galitis, Ourania; Papadopoulou, Erofili] Univ Athens, Sch Dent, Clin Hosp Dent, Oral Oncol Unit, Athens 11527, Greece. [Nikolaidi, Adamantia; Athanassiadis, Ilias] Mitera Hosp Ygeia, Dept Oncol, Athens, Greece. [Sonis, Stephen] Brigham & Womens Hosp, Div Oral Med, Boston, MA 02115 USA. [Sonis, Stephen] Dana Farber Canc Inst, Div Oral Med, Boston, MA 02115 USA. RP Nicolatou-Galitis, O (reprint author), Univ Athens, Sch Dent, Clin Hosp Dent, Thivon 2, Athens 11527, Greece. EM nicolatou.galitis@hotmail.com NR 29 TC 9 Z9 10 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-4403 J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD AUG PY 2013 VL 116 IS 2 BP E110 EP E116 DI 10.1016/j.oooo.2013.02.022 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 182JL UT WOS:000321737900006 PM 23643584 ER PT J AU Carbone, LD Chin, AS Burns, SP Svircev, JN Hoenig, H Heggeness, M Weaver, F AF Carbone, L. D. Chin, A. S. Burns, S. P. Svircev, J. N. Hoenig, H. Heggeness, M. Weaver, F. TI Morbidity following lower extremity fractures in men with spinal cord injury SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Fractures; Men; Morbidity; Pressure ulcers; Spinal cord injury ID HIP FRACTURE; TRACT-INFECTION; RISK-FACTORS; SCI QUERI; VETERANS; MANAGEMENT; DISORDERS; IMPLEMENTATION; EPIDEMIOLOGY; OSTEOPOROSIS AB The Veterans Affairs Spinal Cord Dysfunction Registry from 2002 to 2007 was reviewed to determine whether men with spinal cord injury (SCI) and lower extremity fractures had an increased risk of complications compared to those without fractures. We determined that fractures are associated with significant consequences, particularly during the first month postfracture. Despite increasing longevity, patients with SCI have a substantial number of illnesses and comorbid conditions. Lower extremity fractures are frequent events in these patients. However, whether these fractures are associated with any increased risk of complications in SCI is not certain. The purpose of this report was to determine the impact of lower extremity fractures on morbidities in men with SCI. A population-based, nested, case-control (1,027 cases and 1,027 propensity-matched controls) of men enrolled in the Veterans Affairs Spinal Cord Dysfunction Registry from fiscal years 2002 to 2007 was reviewed to determine whether lower extremity fractures were associated with an increased risk for complications. In propensity score models matched for demographic (age, race) and SCI-related injury factors (level/completeness of SCI), Veterans Affairs-service connection status, and comorbidities, at 1 month following the fracture, there was an increased risk for respiratory infections, pressure ulcers, urinary tract infections, thromboembolic events, depression, and delirium (p a parts per thousand currency signaEuro parts per thousand 0.03 for all). Over 12 months, the only complication more common in fracture cases was pressure ulcers (p < 0.01), with an absolute difference of less than 2 % when compared to controls. There was no significant increased risk of cardiac arrhythmias at any time examined following fracture (a parts per thousand yen0.12). Lower extremity fractures are associated with significant consequences in men with SCI during the first month postfracture, but they do not persist for a long term, except for pressure ulcers. Targeted interventions to prevent complications should be considered following lower extremity fractures in SCI, particularly in the first month following fracture. C1 [Carbone, L. D.] Vet Affairs Med Ctr, Memphis, TN 38163 USA. [Carbone, L. D.] Univ Tennessee, Ctr Hlth Sci, Dept Med, Div Rheumatol, Memphis, TN 38163 USA. [Chin, A. S.; Weaver, F.] Edward J Hines Jr VA Hosp, Hines, IL USA. [Burns, S. P.; Svircev, J. N.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Burns, S. P.; Svircev, J. N.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Hoenig, H.] Durham Vet Affairs Med Ctr, Durham, NC USA. [Heggeness, M.] Vet Affairs Med Ctr, Houston, TX 77030 USA. [Heggeness, M.] Baylor Coll Med, Dept Orthoped, Houston, TX 77030 USA. [Weaver, F.] Loyola Univ, Stritch Sch Med, Maywood, IL 60153 USA. RP Carbone, LD (reprint author), Univ Tennessee, Ctr Hlth Sci, Dept Med, Div Rheumatol, Memphis, TN 38163 USA. EM lcarbone@uthsc.edu FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development [IIR 08-033] FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development #IIR 08-033. NR 39 TC 10 Z9 10 U1 1 U2 10 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD AUG PY 2013 VL 24 IS 8 BP 2261 EP 2267 DI 10.1007/s00198-013-2295-8 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 181GH UT WOS:000321655500013 PM 23392311 ER PT J AU Zhao, W Petit, E Gafni, RI Collins, MT Robey, PG Seton, M Miller, KK Mannstadt, M AF Zhao, W. Petit, E. Gafni, R. I. Collins, M. T. Robey, P. G. Seton, M. Miller, K. K. Mannstadt, M. TI Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Acroosteolysis; Exome sequencing; Hajdu-Cheney syndrome; NOTCH2; Osteoporosis ID OSTEOPOROSIS; ACTIVATION; DISORDER AB The Hajdu-Cheney syndrome is a very rare disease that affects several organ system, leading to severe osteoporosis and other abnormalities. We describe clinical and genetic findings of nine patients with this disease. The Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant disorder characterized by severe osteoporosis, acroosteolysis of the distal phalanges, renal cysts, and other abnormalities. Recently, heterozygous mutations in NOTCH2 were identified as the cause of HCS. Nine patients with typical presentations of HCS took part in this study: five affected patients from two small families and four sporadic cases. Peripheral blood DNA was obtained and exome sequencing performed in one affected individual per family and in all four sporadic cases. Sanger sequencing confirmed mutations in all patients. One of the identified mutations was introduced in a plasmid encoding NOTCH2. Wild-type and mutant NOTCH2 were transiently expressed in HEK293 cells to assess intracellular localization after ligand activation. Deleterious heterozygous mutations in the last NOTCH2 exon were identified in all patients; five of the six mutations were novel. Consistent with previous reports, all mutations are predicted to result in a loss of the proline/glutamic acid/serine/threonine sequence, which harbors signals for degradation, therefore suggesting activating mutations. One of the six mutations furthermore predicted disruption of the second nuclear localization signal of NOTCH2, but the mutant revealed normal nuclear localization after transfection, which is consistent with the proposed gain-of-function mechanism as the cause of this autosomal dominant disease. Our findings confirm that heterozygous NOTCH2 mutations are the cause of HCS and expand the mutational spectrum of this disorder. C1 [Zhao, W.; Petit, E.; Mannstadt, M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Seton, M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Gafni, R. I.; Collins, M. T.; Robey, P. G.] NIDCR, CSDB, NIH, Bethesda, MD USA. [Miller, K. K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Mannstadt, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Thier 10,55 Fruit St, Boston, MA 02114 USA. EM mmannstadt@partners.org RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU NHGRI [U54 HG003067]; National Institute of Diabetes and Digestive and Kidney Disease [K08-DK081669-01]; Division of Intramural Research, NIDCR, a part of the Intramural Research Program of the NIH, DHHS FX We like to thank all patients and family members who participated in this study. We thank the Broad Institute for generating high-quality sequence data supported by NHGRI funds (U54 HG003067, PI Eric Lander), Harald Juppner for support and Spyros Artavanis-Tsakonas for the Notch2 cDNA plasmid. This research was supported, in part, by grants from the National Institute of Diabetes and Digestive and Kidney Disease (K08-DK081669-01 to M. M.) and by the Division of Intramural Research, NIDCR, a part of the Intramural Research Program of the NIH, DHHS. NR 25 TC 8 Z9 8 U1 0 U2 5 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD AUG PY 2013 VL 24 IS 8 BP 2275 EP 2281 DI 10.1007/s00198-013-2298-5 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 181GH UT WOS:000321655500015 PM 23389697 ER PT J AU Kim, J Loggia, ML Edwards, RR Wasan, AD Gollub, RL Napadow, V AF Kim, Jieun Loggia, Marco L. Edwards, Robert R. Wasan, Ajay D. Gollub, Randy L. Napadow, Vitaly TI Sustained deep-tissue pain alters functional brain connectivity SO PAIN LA English DT Article DE Somatosensory; Sensorimotor network; Salience network; Dorsal attention network; Frontoparietal control network; Functional connectivity ID DIABETIC NEUROPATHIC PAIN; INDEPENDENT COMPONENT ANALYSIS; BLOOD-FLOW CHANGES; RESTING-STATE; SOMATOSENSORY CORTEX; INSULAR CORTEX; STRUCTURAL CONNECTIVITY; INDIVIDUAL-DIFFERENCES; SUBJECTIVE EXPERIENCE; SELECTIVE ATTENTION AB Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, frontoparietal control, and default mode networks: SMN, SLN, DAN, FCN, and DMN) was evaluated with functional-connectivity magnetic resonance imaging, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable, with no significant changes of subjects' pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula, and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to interindividual differences in pain sensitivity. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [Kim, Jieun; Loggia, Marco L.; Gollub, Randy L.; Napadow, Vitaly] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. [Loggia, Marco L.; Edwards, Robert R.; Wasan, Ajay D.; Napadow, Vitaly] Harvard Univ, Brigham & Womens Hosp, Med Sch HMS, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Loggia, Marco L.; Gollub, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, HMS, Boston, MA 02114 USA. [Edwards, Robert R.; Wasan, Ajay D.] Brigham & Womens Hosp, Dept Psychiat, HMS, Boston, MA 02115 USA. RP Kim, J (reprint author), Massachusetts Gen Hosp, 2301,149 13th St, Charlestown, MA 02129 USA. EM seesaw@nmr.mgh.harvard.edu OI Gollub, Randy L./0000-0002-9434-4044 FU National Institutes of Health [R01-AT004714, P01-AT002048, 1K23DA020681-01A1]; NCRR [P41RR14075, CRC 1 UL1 RR025758]; American College of Rheumatology; Arthritis Foundation FX We would like to thank the National Institutes of Health for funding support (VN: R01-AT004714, P01-AT002048; AW: 1K23DA020681-01A1), the NCRR (P41RR14075; CRC 1 UL1 RR025758, Harvard Clinical and Translational Science Center). Dr. Edwards received support for this study from the American College of Rheumatology and the Arthritis Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of our sponsors. NR 82 TC 12 Z9 12 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD AUG PY 2013 VL 154 IS 8 BP 1343 EP 1351 DI 10.1016/j.pain.2013.04.016 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 176XF UT WOS:000321339400024 PM 23718988 ER PT J AU Bortsov, AV Smith, JE Diatchenko, L Soward, AC Ulirsch, JC Rossi, C Swor, RA Hauda, WE Peak, DA Jones, JS Holbrook, D Rathlev, NK Foley, KA Lee, DC Collette, R Domeier, RM Hendry, PL McLean, SA AF Bortsov, Andrey V. Smith, Jennifer E. Diatchenko, Luda Soward, April C. Ulirsch, Jacob C. Rossi, Catherine Swor, Robert A. Hauda, William E. Peak, David A. Jones, Jeffrey S. Holbrook, Debra Rathlev, Niels K. Foley, Kelly A. Lee, David C. Collette, Renee Domeier, Robert M. Hendry, Phyllis L. McLean, Samuel A. TI Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure SO PAIN LA English DT Article DE Motor vehicle collision; Rape; Musculoskeletal pain; Single nucleotide polymorphism; Glucocorticoid receptor ID WHIPLASH-ASSOCIATED DISORDERS; SEXUAL ASSAULT HISTORY; REPEATED SOUND STRESS; EMERGENCY-DEPARTMENT; ASSOCIATION; POPULATION; AXIS; HYPERALGESIA; SYMPTOMS; RISK AB Individual vulnerability factors influencing the function of the hypothalamic-pituitary-adrenal axis may contribute to the risk of the development of persistent musculoskeletal pain after traumatic stress exposure. The objective of the study was to evaluate the association between polymorphisms in the gene encoding FK506 binding protein 51, FKBP5, a glucocorticoid receptor co-chaperone, and musculoskeletal pain severity 6 weeks after 2 common trauma exposures. The study included data from 2 prospective emergency department-based cohorts: a discovery cohort (n = 949) of European Americans experiencing motor vehicle collision and a replication cohort of adult European American women experiencing sexual assault (n = 53). DNA was collected from trauma survivors at the time of initial assessment. Overall pain and neck pain 6 weeks after trauma exposure were assessed using a 0-10 numeric rating scale. After adjustment for multiple comparisons, 6 FKBP5 polymorphisms showed significant association (minimum P < 0.0001) with both overall and neck pain in the discovery cohort. The association of rs3800373, rs9380526, rs9394314, rs2817032, and rs2817040 with neck pain and/or overall pain 6 weeks after trauma was replicated in the sexual assault cohort, showing the same direction of the effect in each case. The results of this study indicate that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced during the weeks after motor vehicle collision and sexual assault. These results suggest that glucocorticoid pathways influence the development of persistent posttraumatic pain, and that such pathways may be a target of pharmacologic interventions aimed at improving recovery after trauma. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [Bortsov, Andrey V.; Smith, Jennifer E.; Soward, April C.; Ulirsch, Jacob C.; McLean, Samuel A.] Univ N Carolina, TRYUMPH Res Program, Chapel Hill, NC 27599 USA. [Bortsov, Andrey V.; Smith, Jennifer E.; Soward, April C.; Ulirsch, Jacob C.; McLean, Samuel A.] Univ N Carolina, Dept Anesthesiol, Chapel Hill, NC 27599 USA. [Diatchenko, Luda] Univ N Carolina, Reg Ctr Neurosensory Disorders, Chapel Hill, NC 27599 USA. [Rossi, Catherine] Cone Hlth Syst, Dept Med, Forens Nursing Program, Greensboro, NC USA. [Swor, Robert A.] William Beaumont Hosp, Dept Emergency Med, Royal Oak, MI 48072 USA. [Hauda, William E.] Inova Fairfax Hosp, Forens Assessment & Consultat Teams, Falls Church, VA USA. [Peak, David A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Jones, Jeffrey S.] Spectrum Hlth Syst, Dept Emergency Med, Grand Rapids, MI USA. [Holbrook, Debra] Mercy Med Ctr, SANE Sexual Assault Nurse Examiner Program, Baltimore, MD USA. [Rathlev, Niels K.] Baystate Med Ctr, Dept Emergency Med, Springfield, MA USA. [Foley, Kelly A.] Sentara Norfolk Hosp, Dept Emergency Med, Norfolk, VA USA. [Lee, David C.] N Shore Univ Hosp, Dept Emergency Med, Manhasset, NY USA. [Collette, Renee] Mission Hlth Syst, SANE Program, Asheville, NC USA. [Domeier, Robert M.] St Joseph Mercy Hlth Syst, Dept Emergency Med, Ypsilanti, MI USA. [Hendry, Phyllis L.] Univ Florida, Dept Emergency Med, Jacksonville, FL USA. [McLean, Samuel A.] Univ N Carolina, Dept Emergency Med, Chapel Hill, NC 27599 USA. RP McLean, SA (reprint author), Univ N Carolina, Sch Med, Wing C CB 7010, Chapel Hill, NC 27599 USA. EM smclean@aims.unc.edu OI McLean, Samuel/0000-0001-9482-3582 FU National Institute of Arthritis, Musculoskeletal, and Skin Diseases [R01 AR056328]; National Center for Research Resources [UL1RR025747] FX Funding for this study was provided by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (R01 AR056328: Samuel A. McLean) and by the National Center for Research Resources (UL1RR025747: Samuel A. McLean). None of the above funding agencies had any role in the design and conduct of the study, in the collection, management, analysis and interpretation of the data, or in the preparation, review, or approval of the manuscript. NR 56 TC 20 Z9 20 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD AUG PY 2013 VL 154 IS 8 BP 1419 EP 1426 DI 10.1016/j.pain.2013.04.037 PG 8 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 176XF UT WOS:000321339400033 PM 23707272 ER PT J AU Medoff, BD AF Medoff, Benjamin D. TI Fat, fire and muscle - The role of adiponectin in pulmonary vascular inflammation and remodeling SO PULMONARY PHARMACOLOGY & THERAPEUTICS LA English DT Article DE Pulmonary hypertension; Obesity; Adiponectin; Pulmonary vascular disease ID SERUM RESPONSE FACTOR; ACTIVATED PROTEIN-KINASE; ADIPOSE-SPECIFIC PROTEIN; CORONARY-ARTERY-DISEASE; SMOOTH-MUSCLE; GROWTH-FACTOR; MYOCARDIAL-INFARCTION; PLASMA-CONCENTRATIONS; CELL DIFFERENTIATION; MOUSE MODEL AB Pulmonary hypertension is a life-threatening condition that results from a heterogeneous group of diseases, many of which demonstrate characteristic pathologic changes of pulmonary vascular inflammation and remodeling. Recent clinical studies indicate obesity to be a risk factor for the development of pulmonary hypertension; however, the mechanisms leading to this association are unknown. Adipocytes secrete multiple bioactive mediators that can influence inflammation and tissue remodeling, suggesting that adipose tissue may directly influence the pathogenesis of pulmonary hypertension. One of these mediators is adiponectin, a protein with a wide range of metabolic, anti-inflammatory, and antiproliferative activities. Paradoxically, adiponectin is present in high concentration in the serum of lean healthy individuals, but decreases in obesity. Studies suggest that relative adiponectin-deficiency may contribute to the development of inflammatory diseases in obesity, and recent animal studies implicate adiponectin in the pathogenesis of pulmonary hypertension. Most notably, experimental studies show that adiponectin can reduce lung vascular remodeling in response to inflammation and hypoxia. Moreover, mice deficient in adiponectin develop a spontaneous lung vascular phenotype characterized by age-dependent increases in pen-vascular inflammatory cells and elevated pulmonary artery pressures. Emerging evidence indicates adiponectin's effects are mediated through anti-inflammatory and anti-proliferative actions on cells in the lung. This review aims to synthesize the existing data related to adiponectin's effects on the pulmonary vasculature and to discuss how changes in adiponectin levels might contribute to the development of pulmonary hypertension. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Medoff, Benjamin D.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Medoff, Benjamin D.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Medoff, Benjamin D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Medoff, BD (reprint author), Massachusetts Gen Hosp, Crit Care Unit, 55 Fruit St,Bulfinch 148, Boston, MA 02114 USA. EM bmedoff@partners.org NR 112 TC 1 Z9 1 U1 1 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1094-5539 J9 PULM PHARMACOL THER JI Pulm. Pharmacol. Ther. PD AUG PY 2013 VL 26 IS 4 BP 420 EP 426 DI 10.1016/j.pupt.2012.06.006 PG 7 WC Pharmacology & Pharmacy; Respiratory System SC Pharmacology & Pharmacy; Respiratory System GA 177WT UT WOS:000321406800004 PM 22750271 ER PT J AU Dougan, SK Dougan, M Kim, J Turner, JA Ogata, S Cho, HI Jaenisch, R Celis, E Ploegh, HL AF Dougan, Stephanie K. Dougan, Michael Kim, Jun Turner, Jacob A. Ogata, Souichi Cho, Hyun-Il Jaenisch, Rudolf Celis, Esteban Ploegh, Hidde L. TI Transnuclear TRP1-Specific CD8 T Cells with High or Low Affinity TCRs Show Equivalent Antitumor Activity SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID CANCER-IMMUNOTHERAPY; METASTATIC MELANOMA; BINDING-PROPERTIES; VIRAL-INFECTION; TUMOR VACCINES; REGULATORY T; MICE; BLOCKADE; PEPTIDE; ACTIVATION AB We have generated, via somatic cell nuclear transfer, two independent lines of transnuclear mice, using as nuclear donors CD8 T cells, sorted by tetramer staining, that recognize the endogenous melanoma antigen tyrosinase related protein 1 (TRP1). These two lines of nominally identical specificity differ greatly in their affinity for antigen (TRP1(high) or TRP1(low)) as inferred from tetramer dissociation and peptide responsiveness. Ex vivo-activated CD8 T cells from either TRP1(high) or TRP1(low) mice show cytolytic activity in three-dimensional tissue culture and in vivo, and slow the progression of subcutaneous B16 melanoma. Although naive TRP1(low) CD8 T cells do not affect tumor growth, upon activation these cells function indistinguishably from TRP1(high) cells in vivo, limiting tumor cell growth and increasing mouse survival. The antitumor effect of both TRP1(high) and TRP1(low) CD8 T cells is enhanced in RAG-deficient hosts. However, tumor outgrowth eventually occurs, likely due to T cell exhaustion. The TRP1 transnuclear mice are an excellent model for examining the functional attributes of T cells conferred by T cell receptor (TCR) affinity, and they may serve as a platform for screening immunomodulatory cancer therapies. (C) 2013 AACR. C1 [Dougan, Stephanie K.; Dougan, Michael; Kim, Jun; Turner, Jacob A.; Ogata, Souichi; Jaenisch, Rudolf; Ploegh, Hidde L.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Kim, Jun] MIT, Cambridge, MA 02139 USA. [Dougan, Michael] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Turner, Jacob A.] Univ Cincinnati, Cincinnati, OH USA. [Ogata, Souichi] Janssen Res & Dev, Div Janssen Pharmaceut NV, Beerse, Belgium. [Cho, Hyun-Il; Celis, Esteban] H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL USA. RP Ploegh, HL (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr,Rm 361, Cambridge, MA 02142 USA. EM ploegh@wi.mit.edu FU Cancer Research Institute; Bushrod H. Campbell and Adah F. Hall Charity Fund; Harold Whitworth Pierce Charitable Trust; Janssen Pharmaceutica NV; NIH; Janssen Pharmaceuticals, Inc; AACR-Pancreatic Cancer Action Network FX S.K. Dougan was funded by the Cancer Research Institute and by the Bushrod H. Campbell and Adah F. Hall Charity Fund and Harold Whitworth Pierce Charitable Trust. S. Ogata was funded by Janssen Pharmaceutica NV.E. Celis, H.L. Ploegh, and R. Jaenisch are funded by grants from the NIH. S.K. Dougan and H.L. Ploegh are funded by Janssen Pharmaceuticals, Inc. and by the AACR-Pancreatic Cancer Action Network. NR 56 TC 9 Z9 9 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD AUG PY 2013 VL 1 IS 2 BP 99 EP 111 DI 10.1158/2326-6066.CIR-13-0047 PG 13 WC Oncology; Immunology SC Oncology; Immunology GA AM7FG UT WOS:000340029500004 PM 24459675 ER PT J AU Dolmatova, E Mahida, S Ellinor, PT Lubitz, SA AF Dolmatova, Elena Mahida, Saagar Ellinor, Patrick T. Lubitz, Steven A. TI Genetic Etiology and Evaluation of Sudden Cardiac Death SO CURRENT CARDIOLOGY REPORTS LA English DT Article DE Sudden cardiac death; Ventricular tachycardia and fibrillation; Genetics; Inherited arrhythmia ID LONG-QT SYNDROME; POLYMORPHIC VENTRICULAR-TACHYCARDIA; ST-SEGMENT-ELEVATION; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; TERM-FOLLOW-UP; GENOTYPE-PHENOTYPE CORRELATION; AMERICAN-HEART-ASSOCIATION; GENOME-WIDE ASSOCIATION; BUNDLE-BRANCH BLOCK; HYPERTROPHIC CARDIOMYOPATHY AB A wide range of inherited syndromes can result in ventricular arrhythmias and sudden cardiac death (SCD). The natural histories of inherited arrhythmia syndromes are highly variable and current risk stratification techniques are limited. Thus, the management of these conditions can be difficult and often involves a combination of risk assessment, lifestyle modification, cardiac interventions, counselling, and family screening. Recent advances in high throughput sequencing have enabled routine testing in patients with a high clinical index of suspicion for an inherited arrhythmia condition, and cascade screening in relatives of mutation carriers. Given the complexity in screening and data interpretation that has been introduced by recent genomic advances, individuals with inherited arrhythmia syndromes are encouraged to seek care at specialized centers with cardiovascular genetics expertise. In this review, we discuss the etiologies of SCD syndromes and discuss strategies for the evaluation of patients at risk for SCD with a focus on the role of genetic testing and family screening. C1 [Dolmatova, Elena; Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Mahida, Saagar] Leeds Gen Infirm, Leeds LS1 3EX, W Yorkshire, England. [Ellinor, Patrick T.; Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Lubitz, SA (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA. EM slubitz@partners.org NR 130 TC 4 Z9 4 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD AUG PY 2013 VL 15 IS 8 AR 389 DI 10.1007/s11886-013-0389-8 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT6YO UT WOS:000345083200008 PM 23812838 ER PT J AU Sanchez-Tejada, L Sanchez-Ortiga, R Moreno-Perez, O Montanana, CF Niveiro, M Tritos, NA Alfonso, AMP AF Sanchez-Tejada, Laura Sanchez-Ortiga, Ruth Moreno-Perez, Oscar Fajardo Montanana, Carmen Niveiro, Maria Tritos, Nicholas A. Pico Alfonso, Antonio M. TI Pituitary tumor transforming gene and insulin-like growth factor 1 receptor expression and immunohistochemical measurement of Ki-67 as potential prognostic markers of pituitary tumors aggressiveness SO ENDOCRINOLOGIA Y NUTRICION LA English DT Article DE Pituitary adenoma; Pituitary tumor transforming gene protein; Humans; Ki-67 antigen; Insulin-like growth factor 1 receptor AB Introduction and objective: The ability to predict recurrence of pituitary adenoma (PA) after surgery may be helpful to determine follow-up frequency and the need for adjuvant treatment. The purpose of this study was to assess the prognostic capacity of pituitary tumor transforming gene (PTTG), insulin-like growth factor 1 receptor (IGFIR), and Ki-67. Materials and methods: In this retrospective study, the normalized copy number (NCN) of PTIG and IGFIR mRNA was measured using RT-PCR, and the Ki-67 index was measured by immunohistochemistry in 46 PA samples. Clinical data, histological subtype, and radiographic characteristics were collected to assess associations between variables and tumor behavior. Progression of tumor remnants and its association to markers was also studied in 14 patients with no adjuvant treatment after surgery followed up for 46 +/- 36 months. Results: Extrasellar tumors had a lower PUG expression as compared to sellar tumors (0.065 [1st-3rd quartile: 0.000-0.089] NCN vs. 0.135 [0.105-0.159] NCN, p= 0.04). IGFIR expression changed depending on histological subtype (p= 0.014), and was greater in tumor with remnant growth greater than 20% during follow-up (10.69 +/- 3.84 NCN vs. 5.44 +/- 3.55 NCN, p= 0.014). Conclusions: Our results suggest that the IGFIR is a more helpful molecular marker than PUG in PA management. Ki-67 showed no association to tumor behavior. However, the potential of these markers should be established in future studies with standardized methods and on larger samples. (C) 2012 SEEN. Published by Elsevier Espana, S.L. All rights reserved. C1 [Sanchez-Tejada, Laura; Sanchez-Ortiga, Ruth; Moreno-Perez, Oscar; Pico Alfonso, Antonio M.] Hosp Gen Univ Alicante, Res Unit, Dept Endocrinol, Alicante, Spain. [Fajardo Montanana, Carmen] Hosp Univ La Ribera, Dept Endocrinol, La Ribera, Spain. [Niveiro, Maria] Hosp Gen Univ Alicante, Dept Pathol, Alicante, Spain. [Tritos, Nicholas A.] Massachusetts Gen Hosp, Neuroendocrin Unit, Boston, MA 02114 USA. [Tritos, Nicholas A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Alfonso, AMP (reprint author), Hosp Gen Univ Alicante, Res Unit, Dept Endocrinol, Alicante, Spain. EM antonio.pico@umh.es RI Moreno-Perez, Oscar/F-4556-2016 OI Moreno-Perez, Oscar/0000-0002-8670-6404 FU Pfizer Grant FX This work was supported by Pfizer Grant. NR 30 TC 11 Z9 16 U1 0 U2 2 PU ELSEVIER DOYMA SL PI BARCELONA PA TRAVESERA DE GARCIA, 17-21, BARCELONA, 08021, SPAIN SN 1575-0922 EI 1579-2021 J9 ENDOCRINOL NUTR JI Endocrinol. Nutr. PD AUG-SEP PY 2013 VL 60 IS 7 BP 358 EP 367 DI 10.1016/j.endoen.2013.10.001 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA V43XT UT WOS:000209714800003 PM 23416216 ER PT J AU Krim, SR Vivo, RP Krim, NR Qian, F Cox, M Ventura, H Hernandez, AF Bhatt, DL Fonarow, GC AF Krim, Selim R. Vivo, Rey P. Krim, Nassim R. Qian, Feng Cox, Margueritte Ventura, Hector Hernandez, Adrian F. Bhatt, Deepak L. Fonarow, Gregg C. TI Racial/Ethnic Differences in B-Type Natriuretic Peptide Levels and Their Association With Care and Outcomes Among Patients Hospitalized With Heart Failure Findings From Get With The Guidelines-Heart Failure SO JACC-HEART FAILURE LA English DT Article DE BNP; heart failure; outcome; quality of care; race AB Objectives This study sought to determine if there were differences in B-type natriuretic peptide (BNP) levels across racial/ethnic groups and in their association with quality of care and in-hospital outcomes among patients with heart failure (HF). Background It remains unclear whether BNP levels and their associations with quality of care and prognosis vary by race/ethnicity among patients hospitalized with HF. Methods Using Get With The Guidelines-Heart Failure (GWTG-HF), patient characteristics and BNP levels at admission were compared among 4 racial/ethnic populations: white, black, Hispanic, and Asian. The associations between BNP, quality of care, in-hospital mortality, and length of stay (LOS) across these groups were analyzed. Results A total of 92,072 patients (65,037 white, 19,092 black, 6,747 Hispanic, and 1,196 Asian) from 264 hospitals were included. Median BNP levels were higher in Asian (1,066 pg/ml) and black (866 pg/ml) patients than in white (776 pg/ml) and Hispanic (737 pg/ml) patients, and race/ethnicity was independently associated with BNP levels (p < 0.0001). Irrespective of race/ethnicity, patients in higher BNP quartiles (Q3, Q4) were more likely to be older and male and have lower body mass index, reduced ejection fraction, and renal insufficiency, whereas those in the lowest quartile (Q1) were more likely to have diabetes. With some exceptions, there were no significant racial/ethnic differences in the association of BNP levels with performance measure adherence. In multivariate analysis, elevated BNP levels remained associated with longer LOS and increased mortality in all racial/ethnic groups. Conclusions Asian and black patients with HF had higher BNP levels at admission compared with white and Hispanic patients. BNP levels at admission provided prognostic value for in-hospital mortality and hospital LOS irrespective of race/ethnicity. (C) 2013 by the American College of Cardiology Foundation C1 [Krim, Selim R.; Ventura, Hector] Ochsner Clin Fdn, John Ochsner Heart & Vasc Inst, New Orleans, LA 70121 USA. [Vivo, Rey P.] Univ Texas Med Branch, Galveston, TX 77555 USA. [Vivo, Rey P.] Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Krim, Nassim R.] Bronx Lebanon Hosp Ctr, Bronx, NY USA. [Qian, Feng] SUNY Albany, Rensselaer, NY USA. [Cox, Margueritte; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. RP Krim, SR (reprint author), Ochsner Clin Fdn, John Ochsner Heart & Vasc Inst, Div Cardiol, 1514 Jefferson Highway, New Orleans, LA 70121 USA. EM krimselim@hotmail.com RI Ventura, Hector/A-7691-2011; Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 NR 20 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD AUG PY 2013 VL 1 IS 4 BP 345 EP 352 DI 10.1016/j.jchf.2013.04.008 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V41GX UT WOS:000209535800011 PM 24621938 ER PT J AU Vaduganathan, M Fonarow, GC Gheorghiade, M AF Vaduganathan, Muthiah Fonarow, Gregg C. Gheorghiade, Mihai TI Drug Therapy to Reduce Early Readmission Risk in Heart Failure Ready for Prime Time? SO JACC-HEART FAILURE LA English DT Editorial Material DE acute heart failure; digoxin; mineralocorticoid receptor antagonists; readmissions AB Readmission for heart failure remains a major focus of policymakers, clinicians, and patients. Despite meeting key national performance measures and frequent use of evidence-based therapies, rates of 30-day post-discharge rehospitalization may be as high as 25%. Digoxin and mineralocorticoid antagonists are known to reduce admissions for heart failure, but are significantly underused in current clinical practice despite their proven benefits. (C) 2013 by the American College of Cardiology Foundation C1 [Vaduganathan, Muthiah] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, 645 North Michigan Ave,Suite 1006, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu NR 25 TC 7 Z9 7 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD AUG PY 2013 VL 1 IS 4 BP 361 EP 364 DI 10.1016/j.jchf.2013.04.010 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V41GX UT WOS:000209535800013 PM 24621940 ER PT J AU Morris, ED Kim, SJ Sullivan, JM Wang, S Normandin, MD Constantinescu, CC Cosgrove, KP AF Morris, Evan D. Kim, Su Jin Sullivan, Jenna M. Wang, Shuo Normandin, Marc D. Constantinescu, Cristian C. Cosgrove, Kelly P. TI Creating Dynamic Images of Short-lived Dopamine Fluctuations with lp-ntPET: Dopamine Movies of Cigarette Smoking SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Behavior; Issue 78; Neuroscience; Neurobiology; Molecular Biology; Biomedical Engineering; Medicine; Anatomy; Physiology; Image Processing; Computer-Assisted; Receptors; Dopamine; Dopamine; Functional Neuroimaging; Binding; Competitive; mathematical modeling (systems analysis); Neurotransmission; transient; dopamine release; PET; modeling; linear; time-invariant; smoking; F-test; ventral-striatum; clinical techniques AB We describe experimental and statistical steps for creating dopamine movies of the brain from dynamic PET data. The movies represent minute-to-minute fluctuations of dopamine induced by smoking a cigarette. The smoker is imaged during a natural smoking experience while other possible confounding effects (such as head motion, expectation, novelty, or aversion to smoking repeatedly) are minimized. We present the details of our unique analysis. Conventional methods for PET analysis estimate time-invariant kinetic model parameters which cannot capture short-term fluctuations in neurotransmitter release. Our analysis - yielding a dopamine movie - is based on our work with kinetic models and other decomposition techniques that allow for time-varying parameters(1-7). This aspect of the analysis - temporal-variation - is key to our work. Because our model is also linear in parameters, it is practical, computationally, to apply at the voxel level. The analysis technique is comprised of five main steps: pre-processing, modeling, statistical comparison, masking and visualization. Preprocessing is applied to the PET data with a unique 'HYPR' spatial filter(8) that reduces spatial noise but preserves critical temporal information. Modeling identifies the time-varying function that best describes the dopamine effect on C-11-raclopride uptake. The statistical step compares the fit of our (lp-ntPET) model (7) to a conventional model(9). Masking restricts treatment to those voxels best described by the new model. Visualization maps the dopamine function at each voxel to a color scale and produces a dopamine movie. Interim results and sample dopamine movies of cigarette smoking are presented. C1 [Morris, Evan D.; Kim, Su Jin; Sullivan, Jenna M.; Wang, Shuo; Cosgrove, Kelly P.] Yale Univ, New Haven, CT 06520 USA. [Morris, Evan D.; Kim, Su Jin; Sullivan, Jenna M.; Wang, Shuo; Cosgrove, Kelly P.] Yale Univ, Yale PET Ctr, New Haven, CT 06520 USA. [Normandin, Marc D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Constantinescu, Cristian C.] Univ Calif Irvine, Irvine, CA USA. RP Morris, ED (reprint author), Yale Univ, New Haven, CT 06520 USA. EM evan.morris@yale.edu RI Normandin, Marc/C-6728-2015 OI Normandin, Marc/0000-0003-1645-523X FU [R21 AA15077]; [K02 DA031750] FX Much of the development of the ntPET techniques was supported by R21 AA15077 to E. Morris. K. Cosgrove is supported by K02 DA031750. NR 39 TC 2 Z9 2 U1 1 U2 6 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD AUG PY 2013 IS 78 AR UNSP e50358 DI 10.3791/50358 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RH UT WOS:000209228000015 ER PT J AU Tseng, JC Kung, AL AF Tseng, Jen-Chieh Kung, Andrew L. TI In vivo Imaging Method to Distinguish Acute and Chronic Inflammation SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 78; Infection; Medicine; Cellular Biology; Molecular Biology; Biomedical Engineering; Anatomy; Physiology; Cancer Biology; Stem Cell Biology; Inflammation; Phagocytes; Phagocyte; Superoxides; Molecular Imaging; chemiluminescence; in vivo imaging; superoxide; bioluminescence; chronic inflammation; acute inflammation; phagocytes; cells; imaging; animal model AB Inflammation is a fundamental aspect of many human diseases. In this video report, we demonstrate non-invasive bioluminescence imaging techniques that distinguish acute and chronic inflammation in mouse models. With tissue damage or pathogen invasion, neutrophils are the first line of defense, playing a major role in mediating the acute inflammatory response. As the inflammatory reaction progresses, circulating monocytes gradually migrate into the site of injury and differentiate into mature macrophages, which mediate chronic inflammation and promote tissue repair by removing tissue debris and producing anti-inflammatory cytokines. Intraperitoneal injection of luminol (5-amino-2,3-dihydro-1,4-phthalazinedione, sodium salt) enables detection of acute inflammation largely mediated by tissue-infiltrating neutrophils. Luminol specifically reacts with the superoxide generated within the phagosomes of neutrophils since bioluminescence results from a myeloperoxidase (MPO) mediated reaction. Lucigenin (bis-N-methylacridinium nitrate) also reacts with superoxide in order to generate bioluminescence. However, lucigenin bioluminescence is independent of MPO and it solely relies on phagocyte NADPH oxidase (Phox) in macrophages during chronic inflammation. Together, luminol and lucigenin allow non-invasive visualization and longitudinal assessment of different phagocyte populations across both acute and chronic inflammatory phases. Given the important role of inflammation in a variety of human diseases, we believe this non-invasive imaging method can help investigate the differential roles of neutrophils and macrophages in a variety of pathological conditions. C1 [Tseng, Jen-Chieh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lurie Family Imaging Ctr, Cambridge, MA 02138 USA. [Kung, Andrew L.] Columbia Univ, Med Ctr, Div Pediat Hematol Oncol Stem Cell Transplant, New York, NY 10027 USA. RP Tseng, JC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Lurie Family Imaging Ctr, Cambridge, MA 02138 USA. EM jen-chieh_tseng@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU Nancy Lurie Marks Foundation FX This work was supported by the Nancy Lurie Marks Foundation. We thank Dr. Nancy E. Kohl for critical reading of the manuscript. We thank Kin K. Wong for his assistance in preparing this video report. NR 31 TC 0 Z9 0 U1 1 U2 5 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD AUG PY 2013 IS 78 AR UNSP e50690 DI 10.3791/50690 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RH UT WOS:000209228000050 ER PT J AU Kumar, R Korideck, H Ngwa, W Berbeco, RI Makrigiorgos, GM Sridhar, S AF Kumar, Rajiv Korideck, Houari Ngwa, Wilfred Berbeco, Ross I. Makrigiorgos, G. Mike Sridhar, Srinivas TI Third generation gold nanoplatform optimized for radiation therapy SO TRANSLATIONAL CANCER RESEARCH LA English DT Article DE Gold nanoparticles; PEGylation; multifunctional nanoparticles; clonogenic assay; radiation therapy AB We report the design and fabrication of third generation ultrasmall PEGylated gold nanoparticles based platform (AuRadTM) optimized for applications in radiation therapy. The AuRadTM nanoplatform has the following key features: (I) surface coating of hetero-bifunctional-PEG with amine, carboxyl, methoxy functional groups, which make this a versatile nanoplatform to conjugate various moieties like fluorophores, peptides, drugs, radiolabels; (II) size that is optimized for longer circulation, higher tumor uptake and modulated clearance; (III) high radiation enhancement. We have synthesized ultrasmall 2-3 nm gold nanoparticles, followed by attachment of hetero-bifunctional PEG and further conjugation of fluorophore AlexaFlour 647 for optical imaging, with a stability of more than 6 months. Confocal bioimaging with HeLa cells showed robust uptake of biocompatible nanoparticles in cells. Irradiation experiments X-rays showed greater than 2.8-fold cell kill enhancement as demonstrated by clonogenic survival assays. The results indicate that AuRad nanoplatform can act as potential theranostic agent in radiation therapy. C1 [Kumar, Rajiv; Sridhar, Srinivas] Northeastern Univ, Elect Mat Res Inst, 110 Forsyth St 111 Dana, Boston, MA 02115 USA. [Kumar, Rajiv; Sridhar, Srinivas] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Kumar, Rajiv; Korideck, Houari; Ngwa, Wilfred; Berbeco, Ross I.; Makrigiorgos, G. Mike; Sridhar, Srinivas] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiat Oncol,Dana Farber Canc Inst, Boston, MA USA. RP Sridhar, S (reprint author), Northeastern Univ, Elect Mat Res Inst, 110 Forsyth St 111 Dana, Boston, MA 02115 USA. EM s.sridhar@neu.edu FU BWH Biomedical Research Institute; [NSF-DGE-0965843]; [HHS/1U54CA151881 CORE1]; [1R03 CA164645-01] FX This work was supported partially by NSF-DGE-0965843, HHS/1U54CA151881 CORE1, 1R03 CA164645-01 and a seed grant from the BWH Biomedical Research Institute. NR 50 TC 7 Z9 8 U1 2 U2 6 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-676X EI 2219-6803 J9 TRANSL CANCER RES JI Transl. Cancer Res. PD AUG PY 2013 VL 2 IS 4 BP 228 EP + DI 10.3978/j.issn.2218-676X.2013.07.02 PG 13 WC Oncology SC Oncology GA V42WF UT WOS:000209643200002 ER PT J AU Haymond, M Kappelgaard, AM Czernichow, P Biller, BMK Takano, K Kiess, W AF Haymond, Morey Kappelgaard, Anne-Marie Czernichow, Paul Biller, Beverly M. K. Takano, Koji Kiess, Wieland CA Global Advisory Panel Meeting TI Early recognition of growth abnormalities permitting early intervention SO ACTA PAEDIATRICA LA English DT Review DE Growth failure; Growth hormone; Short stature ID IDIOPATHIC SHORT STATURE; HORMONE DEFICIENCY; WESSEX GROWTH; POOR GROWTH; WORK-UP; CHILDREN; HEIGHT; POPULATION; RELIABILITY; PREVALENCE AB Normal growth is a sign of good health. Monitoring for growth disturbances is fundamental to children's health care. Early detection and diagnosis of the causes of short stature allows management of underlying medical conditions, optimizing attainment of good health and normal adult height. Conclusion This review summarizes currently available information on monitoring for short stature in children and conditions usually associated with short stature and summarizes the authors' conclusions on the early recognition of growth disorders. C1 [Haymond, Morey] Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Kappelgaard, Anne-Marie] Novo Nordisk AS, DK-2880 Bagsvaerd, Denmark. [Czernichow, Paul] Hop Necker Enfants Malad, Paris, France. [Biller, Beverly M. K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Takano, Koji] Univ Tokyo, Tokyo, Japan. [Kiess, Wieland] Univ Leipzig, Hosp Children & Adolescents, D-04109 Leipzig, Germany. RP Kappelgaard, AM (reprint author), Novo Nordisk AS, Vandtarnsvej 108-110, DK-2860 Soborg, Denmark. EM amk@novonordisk.com NR 52 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD AUG PY 2013 VL 102 IS 8 BP 787 EP 796 DI 10.1111/apa.12266 PG 10 WC Pediatrics SC Pediatrics GA 169KA UT WOS:000320777700017 PM 23586744 ER PT J AU Vaz-Luis, I Seah, D Olson, EM Wagle, N Metzger-Filho, O Sohl, J Litsas, G Burstein, HJ Krop, IE Winer, EP Lin, NU AF Vaz-Luis, Ines Seah, Davinia Olson, Erin M. Wagle, Nikhil Metzger-Filho, Otto Sohl, Jessica Litsas, Georgia Burstein, Harold J. Krop, Ian E. Winer, Eric P. Lin, Nancy U. TI Clinicopathological Features Among Patients With Advanced Human Epidermal Growth Factore-2-Positive Breast Cancer With Prolonged Clinical Benefit to First-Line Trastuzumab-Based Therapy: A Retrospective Cohort Study SO CLINICAL BREAST CANCER LA English DT Article DE HER2-positive; Outcomes; Treatment Duration ID PHASE-II TRIAL; MOLECULAR PORTRAITS; MONOCLONAL-ANTIBODY; RECEPTOR STATUS; HER2 THERAPY; CHEMOTHERAPY; EFFICACY; SAFETY; TUMORS; VINORELBINE AB The relationship between clinicopathological features and long-term benefit to trastuzumab-based therapy was evaluated in 164 HER2-positive metastatic breast cancer patients. Treatment duration was associated with hormone receptor status and use of adjuvant trastuzumab; however, with low predictive value. With growing availability of targeted treatments for HER2-positive disease, a major clinical priority is identifying molecular predictors of benefit of anti-HER2 therapies. Background: The magnitude of benefit of trastuzumab for the treatment of advanced HER2-positive breast cancer varies widely. In this retrospective study, we investigated the clinicopathological features associated with prolonged first-line trastuzumab-based treatment duration. Patients and Methods: A total of 164 patients diagnosed with advanced HER2-positive breast cancer and treated with first-line trastuzumab-based therapy from 1999 to 2009 were identified. Duration of treatment was classified according to tertiles. Different logistic regression models including age, disease-free interval, number of metastatic sites, visceral disease, hormone receptor, and adjuvant trastuzumab were fitted to investigate associations with benefit of prolonged trastuzumab-based therapies. The predictive value of each model was assessed using C-statistics. Results: At a median follow-up of 5.8 years (range, 0.7-22.1 years), patients in the short-, intermediate-, and long-term treatment duration groups were given first-line trastuzumab-based therapy for < 7.2 months, 7.2 to 14 months, and > 14 months, respectively. In the multivariate analysis, patients with long-term clinical benefit had a higher likelihood of having hormone receptor-positive tumors (odds ratio [OR] positive vs. negative 2.39 [95% confidence interval (CI), 1.08-5.31]; P = .032); and a lower likelihood of having received adjuvant trastuzumab (ORadjuvant trastuzumab vs. no adjuvant trastuzumab 0.30 [95% CI, 0.10-0.96]; P = .043]. C-statistics varied between 0.634 and 0.699. Conclusion: Long-term benefit of trastuzumab-based therapy is associated with hormone receptor positivity and the absence of previous adjuvant trastuzumab. Nevertheless, clinicopathological features had a low predictive value for prolonged treatment duration. The validation of the current findings and the identification of molecular features associated the magnitude of trastuzumab benefit should be encouraged. C1 [Vaz-Luis, Ines; Seah, Davinia; Wagle, Nikhil; Metzger-Filho, Otto; Sohl, Jessica; Litsas, Georgia; Burstein, Harold J.; Krop, Ian E.; Winer, Eric P.; Lin, Nancy U.] Dana Farber Canc Inst, Dept Med Oncol, Breast Oncol Ctr, Boston, MA 02215 USA. [Vaz-Luis, Ines] Inst Mol Med, Clin & Translat Oncol Res Unit, Lisbon, Portugal. [Olson, Erin M.] Ohio State Univ, Dept Med Oncol, Columbus, OH 43210 USA. RP Lin, NU (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Nancy_Lin@dfci.harvard.edu FU Scholars in Clinical Science Program of Harvard Catalyst; Harvard Clinical and Translational Science Center [UL1 RR025758]; National Cancer Institute Specialized Program of Research Excellence in Breast Cancer [NIH P50 CA089393]; National Comprehensive Cancer Network, Breast Cancer Research Foundation; Nancy and Randy Berry Junior Faculty Award; Karen Webster and David Evans Research Fund; Fundacao para a Ciencia e Tecnologia [HMSP-ICS/0004/2011] FX I. Vaz-Luis is supported by the Scholars in Clinical Science Program of Harvard Catalyst, The Harvard Clinical and Translational Science Center (Award No. UL1 RR025758) and contributions from Harvard University and its affiliated academic health care centers.; The study was supported by the National Cancer Institute Specialized Program of Research Excellence in Breast Cancer (NIH P50 CA089393), the National Comprehensive Cancer Network, Breast Cancer Research Foundation (to N.U. Lin), Nancy and Randy Berry Junior Faculty Award (to N.U. Lin), the Karen Webster and David Evans Research Fund, and Fundacao para a Ciencia e Tecnologia (HMSP-ICS/0004/2011, Career development award to I. Vaz-Luis). NR 31 TC 10 Z9 10 U1 0 U2 5 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1526-8209 J9 CLIN BREAST CANCER JI Clin. Breast Cancer PD AUG PY 2013 VL 13 IS 4 BP 254 EP 263 DI 10.1016/j.clbc.2013.02.010 PG 10 WC Oncology SC Oncology GA 175OI UT WOS:000321239600005 PM 23829891 ER PT J AU Yang, L Lawson, KA Teteak, CJ Zou, JH Hacquebord, J Patterson, D Ghatan, AC Mei, Q Zielinska-Kwiatkowska, A Bain, SD Fernandes, RJ Chansky, HA AF Yang, Liu Lawson, Kevin A. Teteak, Colin J. Zou, Junhui Hacquebord, Jacques Patterson, David Ghatan, Andrew C. Mei, Qi Zielinska-Kwiatkowska, Anna Bain, Steven D. Fernandes, Russell J. Chansky, Howard A. TI ESET histone methyltransferase is essential to hypertrophic differentiation of growth plate chondrocytes and formation of epiphyseal plates SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Epigenetics; Chondrogenesis; Chondrocyte hypertrophy; Chondrocyte differentiation; Epiphyseal plate; Long bone formation; Endochondral ossification; Trabecular bone; Histone deacetylase; Indian hedgehog gene Hh ID EMBRYONIC STEM-CELLS; OSTEOBLAST DIFFERENTIATION; BONE-FORMATION; CANCER-CELLS; SET DOMAIN; INTERACTS; LINEAGE; CBFA1; RUNX2; G9A AB The ESET (also called SETDB1) protein contains an N-terminal tudor domain that mediates protein-protein interactions and a C-terminal SET domain that catalyzes methylation of histone H3 at lysine 9. We report here that ESET protein is transiently upregulated in prehypertrophic chondrocytes in newborn mice. To investigate the in vivo effects of ESET on chondrocyte differentiation, we generated conditional knockout mice to specifically eliminate the catalytic SET domain of ESET protein only in mesenchymal cells. Such deletion of the ESET gene caused acceleration of chondrocyte hypertrophy in both embryos and young animals, depleting chondrocytes that are otherwise available to form epiphyseal plates for endochondral bone growth. ESET-deficient mice are thus characterized by defective long bone growth and trabecular bone formation. To understand the underlying mechanism for ESET regulation of chondrocytes, we carried out co-expression experiments and found that ESET associates with histone deacetylase 4 to bind and inhibit the activity of Runx2, a hypertrophy-promoting transcription factor. Repression of Runx2-mediated gene transactivation by ESET is dependent on its H3-K9 methyltransferase activity as well as its associated histone deacetylase activity. In addition, knockout of ESET is associated with repression of Indian hedgehog gene in pre- and early hypertrophic chondrocytes. Together, these results provide clear evidence that ESET controls hypertrophic differentiation of growth plate chondrocytes and endochondral ossification during embryogenesis and postnatal development. Published by Elsevier Inc. C1 [Yang, Liu; Lawson, Kevin A.; Teteak, Colin J.; Zou, Junhui; Hacquebord, Jacques; Patterson, David; Ghatan, Andrew C.; Zielinska-Kwiatkowska, Anna; Bain, Steven D.; Fernandes, Russell J.; Chansky, Howard A.] Univ Washington, Dept Orthoped & Sports Med, Seattle, WA 98108 USA. [Yang, Liu; Mei, Qi; Chansky, Howard A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Yang, L (reprint author), Univ Washington, Dept Orthoped & Sports Med, 1660 S Columbian Way,GMR 151, Seattle, WA 98108 USA. EM lyang@u.washington.edu OI Lawson, Kevin/0000-0002-2931-5263 FU NIH grant [RO1 AR051455, RO1 AR057025]; VA Merit Review Award FX We thank Dr. Y. Shinkai for frozen mouse embryos harboring the foxed ESET allele, Dr. J. J. Westendorf for pOG2-Luc reporter, Dr. G. Karsenty for pCMV-HA-Runx2 plasmid, and S. L. Carey for assistance in mouse breeding. This work is supported in part by NIH grant RO1 AR051455 (to L.Y.), RO1 AR057025 (to R.J.F), and by VA Merit Review Award (to H.A.C.). NR 28 TC 16 Z9 17 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 1 PY 2013 VL 380 IS 1 BP 99 EP 110 DI 10.1016/j.ydbio.2013.04.031 PG 12 WC Developmental Biology SC Developmental Biology GA 170DC UT WOS:000320829100009 PM 23652029 ER PT J AU Socransky, SS Haffajee, AD Teles, R Wennstrom, JL Lindhe, J Bogren, A Hasturk, H van Dyke, T Wang, XS Goodson, JM AF Socransky, Sigmund S. Haffajee, Anne D. Teles, Ricardo Wennstrom, Jan L. Lindhe, Jan Bogren, Anna Hasturk, Hatice van Dyke, Thomas Wang, Xiaoshan Goodson, Jo Max TI Effect of periodontal therapy on the subgingival microbiota over a 2-year monitoring period. I. Overall effect and kinetics of change SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE chronic periodontitis; kinetics; microbiology; therapy ID CONTROLLED CLINICAL-TRIAL; GENERALIZED AGGRESSIVE PERIODONTITIS; ACTINOMYCETEMCOMITANS-ASSOCIATED PERIODONTITIS; DNA-DNA HYBRIDIZATION; ADULT PERIODONTITIS; NONSURGICAL TREATMENT; DOUBLE-BLIND; METRONIDAZOLE; AMOXICILLIN; DISEASE AB Aim To examine the 2-year post-therapy kinetics of change in the composition of subgingival biofilms. Material and Methods In this study, 178 chronic periodontitis subjects were recruited and clinically monitored at baseline, 3, 6, 12, 18 and 24months after therapy. All subjects received scaling and root planing and 156 one or more of periodontal surgery, systemically administered amoxicillin+metronidazole or local tetracycline at pockets 5mm. Subgingival biofilm samples taken from each subject at each time point were analysed for their content of 40 bacterial species using checkerboard DNA-DNA hybridization. The significance of changes in median species counts over time was sought using the Wilcoxon or Friedman tests and adjusted for multiple comparisons. Results Mean counts were significantly reduced from baseline to 2years for 30 of the 40 taxa. Marked reductions were observed for periodontal pathogens including Tannerella forsythia, Treponema denticola and Eubacterium nodatum. The kinetics of change differed from species to species. When data were subset according to baseline PD, patterns of change in the microbial profiles were generally similar. Conclusion Periodontal therapy leads to a rapid reduction in periodontal pathogens, followed by a slower reduction in other taxa that can be sustained for at least 2years. C1 [Socransky, Sigmund S.; Haffajee, Anne D.; Teles, Ricardo; Hasturk, Hatice; van Dyke, Thomas; Goodson, Jo Max] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Wennstrom, Jan L.; Lindhe, Jan; Bogren, Anna] Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Periodontol, Gothenburg, Sweden. [Wang, Xiaoshan] Forsyth Inst, Ctr Clin & Translat Res, Dept Appl Oral Sci Epidemiol & Biostat Core, Cambridge, MA 02142 USA. RP Teles, R (reprint author), Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, 245 1st St, Cambridge, MA 02142 USA. EM rteles@forsyth.org RI Wang, Xiaoshan/D-6292-2014 OI Wang, Xiaoshan/0000-0002-6760-5456 FU National Institute of Dental and Craniofacial [DE12861, RR025771]; GCRC [RR00533, RR01032] FX This study was supported by the National Institute of Dental and Craniofacial Research grants DE12861 and RR025771 and GCRC funding from RR00533 and RR01032. There are no conflicts of interest to report. NR 39 TC 12 Z9 12 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD AUG PY 2013 VL 40 IS 8 BP 771 EP 780 DI 10.1111/jcpe.12117 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 178GK UT WOS:000321433300006 PM 23710672 ER PT J AU Haslinger, R Pipa, G Lewis, LD Nikolic, D Williams, Z Brown, E AF Haslinger, Robert Pipa, Gordon Lewis, Laura D. Nikolic, Danko Williams, Ziv Brown, Emery TI Encoding Through Patterns: Regression Tree-Based Neuronal Population Models SO NEURAL COMPUTATION LA English DT Article ID NEURAL SPIKING ACTIVITY; RESPONSE VARIABILITY; CORTICAL NETWORKS; TRAIN DATA; INFORMATION; MONKEY; RELIABILITY; SYNCHRONY; DIRECTION; ENSEMBLE AB Although the existence of correlated spiking between neurons in a population is well known, the role such correlations play in encoding stimuli is not. We address this question by constructing pattern-based encoding models that describe how time-varying stimulus drive modulates the expression probabilities of population-wide spike patterns. The challenge is that large populations may express an astronomical number of unique patterns, and so fitting a unique encoding model for each individual pattern is not feasible. We avoid this combinatorial problem using a dimensionality-reduction approach based on regression trees. Using the insight that some patterns may, from the perspective of encoding, be statistically indistinguishable, the tree divisively clusters the observed patterns into groups whose member patterns possess similar encoding properties. These groups, corresponding to the leaves of the tree, are much smaller in number than the original patterns, and the tree itself constitutes a tractable encoding model for each pattern. Our formalism can detect an extremely weak stimulus-driven pattern structure and is based on maximizing the data likelihood, not making a priori assumptions as to how patterns should be grouped. Most important, by comparing pattern encodings with independent neuron encodings, one can determine if neurons in the population are driven independently or collectively. We demonstrate this method using multiple unit recordings from area 17 of anesthetized cat in response to a sinusoidal grating and show that pattern-based encodings are superior to those of independent neuron models. The agnostic nature of our clustering approach allows us to investigate encoding by the collective statistics that are actually present rather than those (such as pairwise) that might be presumed. C1 [Haslinger, Robert] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Haslinger, Robert; Lewis, Laura D.; Brown, Emery] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Pipa, Gordon] Univ Osnabruck, Dept Neuroinformat, D-49069 Osnabruck, Germany. [Nikolic, Danko] Max Planck Inst Brain Res, Dept Neurophysiol, Frankfurt, Germany. [Nikolic, Danko] Goethe Univ Frankfurt, Frankfurt Inst Adv Studies, D-60528 Frankfurt, Germany. [Nikolic, Danko] Max Planck Gesell, Ernst Strungman Inst Neurosci, Frankfurt, Germany. [Williams, Ziv] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Brown, Emery] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Haslinger, R (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM rob.haslinger@gmail.com; gpipa@uos.de; ldlewis@mit.edu; danko.nikolic@googlemail.com; ZWILLIAMS1@partners.org; enb@neurostat.mit.edu RI Pipa, Gordon/M-1813-2014 OI Pipa, Gordon/0000-0002-3416-2652 FU NIH [K25 NS052422-02, DP1 OD003646-0, MH59733-07]; Hertie Foundation; Deutsche Forschungsgemeinschaft [NI 708/2-1]; Hertie Stiftung; Max-Planck Society; Frankfurt Institute for Advanced Studies FX We thank Demba Ba, Zhe Chen, and Cosma Shalizi for helpful conversations regarding the research presented in this article. This work was supported by NIH grants K25 NS052422-02 (R.H.), DP1 OD003646-0, MH59733-07 (E.N.), and the Hertie Foundation (G.P.). Experiments with cat recordings (D.N.) were supported by a Deutsche Forschungsgemeinschaft Grant NI 708/2-1, Hertie Stiftung, Max-Planck Society, and the Frankfurt Institute for Advanced Studies. NR 54 TC 6 Z9 6 U1 0 U2 8 PU MIT PRESS PI CAMBRIDGE PA 55 HAYWARD STREET, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD AUG PY 2013 VL 25 IS 8 BP 1953 EP 1993 DI 10.1162/NECO_a_00464 PG 41 WC Computer Science, Artificial Intelligence; Neurosciences SC Computer Science; Neurosciences & Neurology GA 166XG UT WOS:000320592700001 PM 23607564 ER PT J AU Chase, MH AF Chase, Michael H. TI Motor control during sleep and wakefulness: Clarifying controversies and resolving paradoxes SO SLEEP MEDICINE REVIEWS LA English DT Review DE Motor control; Postsynaptic inhibition; REM sleep; Wakefulness; Reticular response-reversal; Hypocretin cataplexy ID EYE-MOVEMENT SLEEP; MUSCLE EMG AMPLITUDE; MEDULLARY RETICULAR NEURONS; NUCLEUS PONTIS ORALIS; IN-VIVO MICRODIALYSIS; REM-SLEEP; ACTIVE SLEEP; LUMBAR MOTONEURONS; BEHAVIOR DISORDER; POSTSYNAPTIC POTENTIALS AB Data accumulated during the last 40 years, since the discovery that there is a loss of muscle tone during REM sleep, have delineated many of the neurotransmitter systems, synaptic mechanisms and neuronal circuitries involved in the control of somatic motoneurons during sleep and waking states. Nevertheless, there are still a number of extant controversies as well as paradoxical and conflicting data. For example, the paradoxical modulation of motor activity that occurs in individuals with cataplexy during wakefulness compared to REM sleep is unresolved as are the mechanisms that are responsible for the control of hypoglossal motoneurons during normal states and those that are operative during sleep disorders such as obstructive sleep apnea. In addition, the circuitry whereby the hypocretinergic system promotes motor activation during wakefulness, and motor inhibition during REM sleep, has yet to be clarified. The use of new techniques, such those involving optogenetics and nanoparticles, will help to clarify the preceding issues and provide as a foundation for addressing a number of current critical unanswered questions such as those dealing with the differential control of motor activity in newborns and the aged. The resulting data will strengthen the foundation for the development of efficacious therapeutics to treat disorders of motor control that occur during sleep as well as wakefulness. (C) 2012 Published by Elsevier Ltd. C1 Univ Calif Los Angeles, Sch Med, VA Greater Angeles Healthcare Syst, WebSci Int, Los Angeles, CA 90095 USA. RP Chase, MH (reprint author), Univ Calif Los Angeles, Sch Med, VA Greater Angeles Healthcare Syst, WebSci Int, 1251 Westwood Blvd, Los Angeles, CA 90095 USA. EM mchase@websciences.org NR 116 TC 13 Z9 13 U1 1 U2 26 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1087-0792 J9 SLEEP MED REV JI Sleep Med. Rev. PD AUG PY 2013 VL 17 IS 4 BP 299 EP 312 DI 10.1016/j.smrv.2012.09.003 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 173QQ UT WOS:000321094400008 PM 23499211 ER PT J AU Zhang, XY Tang, W Xiu, MH Chen, DC Yang, FD Tan, YL Wang, ZR Zhang, FX Liu, JH Liu, LJ Chen, YL Wen, N Kosten, TR AF Zhang, Xiang Yang Tang, Wei Xiu, Mei Hong Chen, Da Chun Yang, Fu De Tan, Yun Long Wang, Zhi Ren Zhang, Feixue Liu, Jiahong Liu, Linjing Chen, Yuanling Wen, Na Kosten, Thomas R. TI Interleukin 18 and cognitive impairment in first episode and drug naive schizophrenia versus healthy controls SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Schizophrenia; Cognition; Interleukin-18; Immune function; Psychopathology ID NEUROPSYCHOLOGICAL STATUS; INFLAMMATORY CYTOKINES; REPEATABLE BATTERY; PRENATAL INFECTION; ALZHEIMERS-DISEASE; SIGNALING PATHWAYS; GLIAL-CELLS; BRAIN; IL-18; EXPRESSION AB Alterations in the inflammatory and immune systems have been documented to occur from the earliest stages of schizophrenia, and have been associated with neurodevelopmental changes. Cognitive impairment is a core feature in the pathology of schizophrenia, and recent studies showed a significant increase in serum IL-18 in schizophrenia, and a putative role of IL-18 in neuroprogression and thus neurocognitive defects. The purpose of this study was to examine the association of IL-18 with cognitive deficits in schizophrenia. We recruited 77 first episode and drug naive schizophrenic patients and 75 healthy control subjects and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum IL-18 in both groups. Schizophrenic symptoms were assessed using the positive and negative syndrome scale (PANSS). We found that IL-18 levels were non-significantly higher in patients than controls (206.0 +/- 92.9 pg/ml vs 193.2 +/- 41.8 pg/ml, p = 0.28). Cognitive scores on the RBANS and nearly all of its five subscales (all p < 0.05) except for the Visuospatial/Constructional index (p > 0.05) were significantly lower in schizophrenic patients than normal controls. For the patients, IL-18 was positively associated with the Visuospatial/Constructional domain of cognitive deficits in schizophrenia. Our findings suggest that cognitive deficits occur during the acute stage of a schizophrenic episode, and IL-18 may be involved in Visuospatial/Constructional deficits of these patients. (C) 2013 Elsevier Inc. All rights reserved. C1 [Zhang, Xiang Yang; Kosten, Thomas R.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Zhang, Xiang Yang; Kosten, Thomas R.] Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. [Zhang, Xiang Yang; Xiu, Mei Hong; Chen, Da Chun; Yang, Fu De; Tan, Yun Long; Wang, Zhi Ren; Kosten, Thomas R.] Peking Univ, Beijing HuiLongGuan Hosp, Ctr Biol Psychiat, Beijing 100096, Peoples R China. [Tang, Wei; Zhang, Feixue; Liu, Jiahong; Liu, Linjing; Chen, Yuanling; Wen, Na] Kangning Hosp, Wenzhou 325000, Peoples R China. RP Zhang, XY (reprint author), VA Med Ctr, Res Bldg 109,Room 130,2002 Holcombe Blvd, Houston, TX 77030 USA. EM xyzhang@bcm.edu; kosten@bcm.edu FU Wenzhou Science and Technology Bureau [Y20100324]; National Natural Science Foundation of China [81000509]; Beijing Municipal Excellent Talents Foundation [2010D003034000032]; Stanley Medical Research Institute [03T-459, 05T-726]; United States National Institute of Health [K05-DA0454, P50-DA18827, U01-MH79639] FX This study was funded by the Wenzhou Science and Technology Bureau (Y20100324), the National Natural Science Foundation of China (81000509), the Beijing Municipal Excellent Talents Foundation (2010D003034000032), the Stanley Medical Research Institute (03T-459 and 05T-726), and the United States National Institute of Health K05-DA0454, P50-DA18827 and U01-MH79639. NR 76 TC 11 Z9 11 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD AUG PY 2013 VL 32 BP 105 EP 111 DI 10.1016/j.bbi.2013.03.001 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 168YG UT WOS:000320743300013 PM 23499732 ER PT J AU Hoge, EA Chen, MM Orr, E Metcalf, CA Fischer, LE Pollack, MH DeVivo, I Simon, NM AF Hoge, Elizabeth A. Chen, Maxine M. Orr, Esther Metcalf, Christina A. Fischer, Laura E. Pollack, Mark H. DeVivo, Immaculata Simon, Naomi M. TI Loving-Kindness Meditation practice associated with longer telomeres in women SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Telomere length; Aging; Mortality; Meditation; Loving-Kindness; Metta ID CIGARETTE-SMOKING; STRESS-REDUCTION; LENGTH; MINDFULNESS; DISEASE; RISK; NEUROENDOCRINE; INTERVENTION; MORTALITY; HEALTH AB Relatively short telomere length may serve as a marker of accelerated aging, and shorter telomeres have been linked to chronic stress. Specific lifestyle behaviors that can mitigate the effects of stress might be associated with longer telomere lengths. Previous research suggests a link between behaviors that focus on the well-being of others, such as volunteering and caregiving, and overall health and longevity. We examined relative telomere length in a group of individuals experienced in Loving-Kindness Meditation (LKM), a practice derived from the Buddhist tradition which utilizes a focus on unselfish kindness and warmth towards all people, and control participants who had done no meditation. Blood was collected by venipuncture, and Genomic DNA was extracted from peripheral blood leukocytes. Quantitative real time PCR was used to measure relative telomere length (RTL) (Cawthon, 2002) in fifteen LKM practitioners and 22 control participants. There were no significant differences in age, gender, race, education, or exposure to trauma, but the control group had a higher mean body mass index (BMI) and lower rates of past depression. The LKM practitioners had longer RTL than controls at the trend level (p = .083); among women, the LKM practitioners had significantly longer RTL than controls, (p = .007), which remained significant even after controlling for BMI and past depression. Although limited by small sample size, these results offer the intriguing possibility that LKM practice, especially in women, might alter RTL, a biomarker associated with longevity. (C) 2013 Elsevier Inc. All rights reserved. C1 [Hoge, Elizabeth A.; Metcalf, Christina A.; Fischer, Laura E.; DeVivo, Immaculata; Simon, Naomi M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Hoge, Elizabeth A.; Metcalf, Christina A.; Fischer, Laura E.; DeVivo, Immaculata; Simon, Naomi M.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Maxine M.; Orr, Esther] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [DeVivo, Immaculata] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Pollack, Mark H.] Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. RP Hoge, EA (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, 1 Bowdoin Sq,6th Flr, Boston, MA 02114 USA. EM ehoge@partners.org RI Hoge, Elizabeth/H-5879-2012; OI Hoge, Elizabeth/0000-0002-5513-2292; Chen, Maxine/0000-0001-7138-6228 FU Mind and Life Institute; Highland Foundation; National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000170-05]; Harvard University FX we would like to thank the study participants, and also Pati Soule for their help in this project. This project was supported in part by the Mind and Life Institute and by the Highland Foundation (EH, NS, MP, LF, CM). This work was also conducted with nursing support from Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. NR 47 TC 22 Z9 22 U1 8 U2 57 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD AUG PY 2013 VL 32 BP 159 EP 163 DI 10.1016/j.bbi.2013.04.005 PG 5 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 168YG UT WOS:000320743300019 PM 23602876 ER PT J AU Jacob, MC Harley, R Sprich, S Prairie, EM AF Jacob, Michelle C. Harley, Rebecca Sprich, Susan Prairie, Ellen M. TI "Stay in the Game": Collecting Data on Symptom Improvement in Naturalistic Settings in Order to Increase Reimbursement Rates SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Editorial Material DE Dialectical Behavior Therapy; reimbursement rates; naturalistic settings AB An industrious approach to increasing reimbursement rates from third-party payers is reviewed. Balancing fidelity to treatment with real-world demands at a local hospital is discussed, as well as ways we were able to increase reimbursement within our own department. Data in naturalistic settings, though not always able to adhere to randomized controlled trials, offers evidence of improvement in symptoms. This reaction paper encourages other clinical programs to "stay in the game" of data collection while balancing treatment fidelity. C1 [Jacob, Michelle C.; Harley, Rebecca; Sprich, Susan; Prairie, Ellen M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. RP Jacob, MC (reprint author), Massachusetts Gen Hosp, 15 Parkman St,ACC 812, Boston, MA 02114 USA. EM mjacobo@partners.org NR 4 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 1077-7229 J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD AUG PY 2013 VL 20 IS 3 BP 331 EP 333 PG 3 WC Psychology, Clinical SC Psychology GA 170FB UT WOS:000320834700009 ER PT J AU Hammad, MA Abdel-Bakky, MS Walker, LA Ashfaq, MK AF Hammad, Mohamed A. Abdel-Bakky, Mohamed Sadek Walker, Larry A. Ashfaq, Mohammad K. TI Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice SO JOURNAL OF APPLIED TOXICOLOGY LA English DT Article DE tissue factor; fibrinogen; oxidized low-density lipoprotein; keratinocyte-derived chemokine; tissue factor antisense oligodeoxynucleotides ID RESPIRATORY-DISTRESS-SYNDROME; FACTOR-DEPENDENT COAGULATION; CHOLESTATIC LIVER-INJURY; ESCHERICHIA-COLI SEPSIS; REPERFUSION INJURY; BLOOD-COAGULATION; OXIDIZED LDL; RAT-LIVER; IN-VIVO; OLIGONUCLEOTIDES AB Tissue factor (TF) is a membranous glycoprotein that functions as a receptor for coagulation factor VII/VIIa and activates the coagulation system when blood vessels or tissues are damaged. TF was upregulated in our monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity model. We tested the hypothesis that TF-dependent fibrin deposition and lipid peroxidation in the form of oxidized low-density-lipoprotein (ox-LDL) accumulation contribute to liver inflammation induced by MCT/LPS in mice. In the present study, we blocked TF using antisense oligodeoxynucleotides against mouse TF (TF-ASO). TF-ASO (5.6mgkg-1) was given i.v. to ND4 male mice 30min after administration of MCT (200mgkg-1) p.o. followed after 3.5h by LPS i.p. (6mgkg-1). Blood alanine aminotransferase (ALT), TF, ox-LDL, platelets, hematocrit and keratinocyte-derived chemokine (KC) levels were evaluated in different treatment groups. Fibrin deposition and ox-LDL accumulation were also analyzed in the liver sections using immunofluorescent staining. The results showed that TF-ASO significantly restored blood ALT, hematocrit and KC levels, distorted after MCT/LPS co-treatment, as well as preventing the accumulation of ox-LDL and the deposition of fibrin in the liver tissues, and thereby inhibited liver injury caused by MCT/LPS. In a separate experiment, TF-ASO administration significantly prolonged animal survival. The current study demonstrates that TF is associated with MCT/LPS-induced liver injury. Administration of TF-ASO successfully prevented this type of liver injury. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Hammad, Mohamed A.; Abdel-Bakky, Mohamed Sadek; Walker, Larry A.; Ashfaq, Mohammad K.] Univ Mississippi, Sch Pharm, Natl Ctr Nat Prod Res, University, MS 38677 USA. [Hammad, Mohamed A.; Walker, Larry A.] Univ Mississippi, Sch Pharm, Dept Pharmacol, University, MS 38677 USA. [Hammad, Mohamed A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. [Abdel-Bakky, Mohamed Sadek] Al Azhar Univ, Fac Pharm, Cairo, Egypt. RP Ashfaq, MK (reprint author), Univ Mississippi, Sch Pharm, Thad Cochran Res Ctr, Room 2047, University, MS 38677 USA. EM MKASHFAQ@OLEMISS.EDU OI HAMMAD, MOHAMED/0000-0002-9684-2506 FU NSF [MRI 619774]; United States Department of Agriculture, Agricultural Research Service [58-6408-2-0009]; US Food and Drug Administration [5U01FD002071-09, 1U01FD003871-011] FX The authors acknowledge the Light Microscopy Core Facility members, Dr Zia Shariat-Madar and Mr Noah Osman (School of Pharmacy, University of Mississippi) for their assistance. The Zeiss 510-META confocal microscope service is supported through NSF grant no. MRI 619774 (ZSM). We thank Mrs. Lavanya Madgula, Mrs. Mona Haron and all the vivarium staff at the University of Mississippi for their help in completing the experiments. This work was supported in part by grants from the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative agreement (58-6408-2-0009) and the US Food and Drug Administration (5U01FD002071-09 and 1U01FD003871-011). NR 45 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0260-437X J9 J APPL TOXICOL JI J. Appl. Toxicol. PD AUG PY 2013 VL 33 IS 8 BP 774 EP 783 DI 10.1002/jat.2728 PG 10 WC Toxicology SC Toxicology GA 169KH UT WOS:000320778400008 PM 22407844 ER PT J AU Rapuano, BE Singh, H Boskey, AL Doty, SB MacDonald, DE AF Rapuano, Bruce E. Singh, Herman Boskey, Adele L. Doty, Stephen B. MacDonald, Daniel E. TI Heat and radiofrequency plasma glow discharge pretreatment of a titanium alloy: Eveidence for enhanced osteoinductive properties SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE DENTAL IMPLANT; FIBRONECTIN; OSTEOBLAST; CELL DIFFERENTIATION; BONE MINERALIZATION; HYDROXYAPATITE ID OXIDE NET CHARGE; BONE SIALOPROTEIN; IN-VITRO; OSTEOBLAST ADHESION; DENTAL IMPLANTS; CELL-LINE; FIBRONECTIN; DIFFERENTIATION; MINERALIZATION; TISSUE AB It is believed that orthopedic and implant longevity can be improved by optimizing fixation, or direct bone-implant contact, through the stimulation of new bone formation around the implant. The purpose of this study was to determine whether heat (600 degrees C) or radiofrequency plasma glow discharge (RFGD) pretreatment of Ti6Al4V stimulated calcium-phosphate mineral formation in cultures of attached MC3T3 osteoprogenitor cells with or without a fibronectin coating. Calcium-phosphate mineral was analyzed by flame atomic absorption spectrophotometry, scanning electron microscopy (SEM)/electron dispersive X-ray microanalysis (EDAX) and Fourier transformed infrared spectroscopy (FTIR). RFGD and heat pretreatments produced a general pattern of increased total soluble calcium levels, although the effect of heat pretreatment was greater than that of RFGD. SEM/EDAX showed the presence of calcium-and phosphorus-containing particles on untreated and treated disks that were more numerous on fibronectin-coated disks. These particles were observed earliest (1 week) on RFGD-pretreated surfaces. FTIR analyses showed that the heat pretreatment produced a general pattern of increased levels of apatite mineral at 2-4 weeks; a greater effect was observed for fibronectin-coated disks compared to uncoated disks. The observed findings suggest that heat pretreatment of Ti6Al4V increased the total mass of the mineral formed in MC3T3 osteoprogenitor cell cultures more than RFGD while the latter pretreatment hastened the early deposition of mineral. These findings help to support the hypothesis that the pretreatments enhance the osteoinductive properties of the alloy. J. Cell. Biochem. 114: 1917-1927, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Rapuano, Bruce E.; Singh, Herman; Boskey, Adele L.; Doty, Stephen B.; MacDonald, Daniel E.] Cornell Univ, Hosp Special Surg, Weill Med Coll, New York, NY 10021 USA. [MacDonald, Daniel E.] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [MacDonald, Daniel E.] Columbia Univ, Langmuir Ctr Colloids & Interfaces, New York, NY 10027 USA. RP MacDonald, DE (reprint author), Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. EM dem14@columbia.edu OI Boskey, Adele/0000-0002-6181-2219 FU National Center for Research Resources, NIH [C06-RR12538-01]; [NIH R01 DE017695] FX The project described was supported by Grant Number NIH R01 DE017695 (Awarded to DEM). The sponsor did not have any role in the study design; the collection, analysis and interpretation of data; the writing of the report; or the decision to submit the article for publication. This material is also the result of work supported with resources and the use of facilities at the James J. Peters VA Medical Center, Bronx, New York. This investigation was also conducted at the HSS research facility constructed with support of Grant C06-RR12538-01 from the National Center for Research Resources, NIH. We would like to acknowledge Tony Labissiere for technical assistance with the SEM/EDAX analyses. We would also like to acknowledge Hayat Taleb, Kyle Hackshaw, and Carrie Guan for assistance with FTIR and atomic absorption spectroscopy. Special thanks goes to Kevin Pun for the preparation and treatment of titanium alloy disks. NR 50 TC 6 Z9 6 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD AUG PY 2013 VL 114 IS 8 BP 1917 EP 1927 DI 10.1002/jcb.24536 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 162OZ UT WOS:000320276000023 PM 23494951 ER PT J AU Kim, SH Lu, HF Alano, C AF Kim, Sun Hee Lu, Huafei Alano, Conrad TI The mitochondrial sirtuin Sirt3 protects neurons from oxidative injury SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Meeting Abstract CT 10th International Conference on Brain Energy Metabolism - Bioenergetics of Neurological Disease and Aging CY APR 17-20, 2012 CL Pacific Grove, CA SP NINDS, NIA, Int Soc Neurochemistry (ISN) Conf Comm, NCIRE, Vet Hlth Res Inst, Wiley Blackwell, Seahorse Bioscience C1 [Kim, Sun Hee; Lu, Huafei; Alano, Conrad] UCSF, San Francisco VA Med Ctr, Dept Neurol, San Francisco, CA 94121 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG PY 2013 VL 91 IS 8 SI SI BP 1096 EP 1096 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 171MO UT WOS:000320933700037 ER PT J AU Carroll, JB Fossale, E Weston, R Deik, A Guide, J Wheeler, VC Seong, IS Lee, JM Clish, CB MacDonald, ME AF Carroll, Jeffrey B. Fossale, Elisa Weston, Rory Deik, Amy Guide, Jolene Wheeler, Vanessa C. Seong, Ihn Sik Lee, Jong-Min Clish, Clary B. MacDonald, Marcy E. TI Objective metabolic phenotyping of knock-in mice reveals novel dysfunctional pathways in Huntington's disease SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Meeting Abstract CT 10th International Conference on Brain Energy Metabolism - Bioenergetics of Neurological Disease and Aging CY APR 17-20, 2012 CL Pacific Grove, CA SP NINDS, NIA, Int Soc Neurochemistry (ISN) Conf Comm, NCIRE, Vet Hlth Res Inst, Wiley Blackwell, Seahorse Bioscience C1 [Carroll, Jeffrey B.; Fossale, Elisa; Guide, Jolene; Wheeler, Vanessa C.; Seong, Ihn Sik; Lee, Jong-Min; MacDonald, Marcy E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Deik, Amy; Clish, Clary B.; MacDonald, Marcy E.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Deik, Amy; Clish, Clary B.; MacDonald, Marcy E.] Harvard Univ, Cambridge, MA 02142 USA. [Carroll, Jeffrey B.; Weston, Rory] Western Washington Univ, Dept Psychol, Behav Neurosci Program, Bellingham, WA 98225 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG PY 2013 VL 91 IS 8 SI SI BP 1099 EP 1099 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 171MO UT WOS:000320933700045 ER PT J AU Reyes, R Kim, JE Brennan, AM Swanson, RA AF Reyes, Reno Kim, Ji-Eun Brennan, Angela M. Swanson, Raymond A. TI Malic enzyme can support neuronal superoxide production by providing NADPH SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Meeting Abstract CT 10th International Conference on Brain Energy Metabolism - Bioenergetics of Neurological Disease and Aging CY APR 17-20, 2012 CL Pacific Grove, CA SP NINDS, NIA, Int Soc Neurochemistry (ISN) Conf Comm, NCIRE, Vet Hlth Res Inst, Wiley Blackwell, Seahorse Bioscience C1 [Reyes, Reno; Kim, Ji-Eun; Brennan, Angela M.; Swanson, Raymond A.] San Francisco VA Med Ctr, Dept Neurol, San Francisco, CA USA. [Reyes, Reno; Kim, Ji-Eun; Brennan, Angela M.; Swanson, Raymond A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD AUG PY 2013 VL 91 IS 8 SI SI BP 1110 EP 1110 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 171MO UT WOS:000320933700069 ER PT J AU Elborai, Y Blanchette, A Maher, O Lehmann, L Lee, M AF Elborai, Yasser Blanchette, Andrew Maher, Ossama Lehmann, Leslie Lee, Michelle TI RENAL AND BONE MARROW TOXICITY IN PEDIATRIC HSCT PATIENTS ON ACYCLOVIR PROPHYLAXIS SO PEDIATRIC TRANSPLANTATION LA English DT Meeting Abstract C1 [Elborai, Yasser; Maher, Ossama] Cairo Univ, Natl Canc Inst, Ped Onc, Cairo, Egypt. [Elborai, Yasser; Blanchette, Andrew; Lehmann, Leslie; Lee, Michelle] Harvard Univ, Dana Farber Canc Inst, Ped HSCT, Boston, MA 02115 USA. [Maher, Ossama] Brooklyn Hosp Ctr, Brooklyn, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1397-3142 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD AUG PY 2013 VL 17 SU 1 MA 133 BP 75 EP 75 PG 1 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA 178IC UT WOS:000321439600133 ER PT J AU Nagy, AY Lehmann, LE AF Nagy, Ahmed Y. Lehmann, Leslie E. TI THE ASSOCIATION OF STEROID INDUCED CARDIAC VENTRICULAR HYPERTROPHY AND TRANSPLANT-RELATED MORTALITY IN CHILDREN WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS SO PEDIATRIC TRANSPLANTATION LA English DT Meeting Abstract C1 [Nagy, Ahmed Y.] Ain Shams Univ, Fac Med, Cairo, Egypt. [Lehmann, Leslie E.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1397-3142 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD AUG PY 2013 VL 17 SU 1 MA 134 BP 75 EP 75 PG 1 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA 178IC UT WOS:000321439600134 ER PT J AU Shulman, DS Lehmann, LE AF Shulman, David S. Lehmann, Leslie E. TI INCIDENCE AND CAUSES OF HOSPITAL READMISSION FOR PEDIATRIC PATIENTS UNDERGOING HEMATOIETIC CELL TRANSPLANT SO PEDIATRIC TRANSPLANTATION LA English DT Meeting Abstract C1 [Shulman, David S.] Harvard Univ, Sch Med, Boston, MA USA. [Lehmann, Leslie E.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1397-3142 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD AUG PY 2013 VL 17 SU 1 MA 135 BP 75 EP 76 PG 2 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA 178IC UT WOS:000321439600135 ER PT J AU Kuter, DJ Mehta, A Hollak, CEM Giraldo, P Hughes, D Belmatoug, N Brand, M Muller, A Schaaf, B Giorgino, R Zimran, A AF Kuter, David J. Mehta, Atul Hollak, Carla E. M. Giraldo, Pilar Hughes, Derralynn Belmatoug, Nadia Brand, Monika Muller, Audrey Schaaf, Berthold Giorgino, Ruben Zimran, Ari TI Miglustat therapy in type 1 Gaucher disease: Clinical and safety outcomes in a multicenter retrospective cohort study SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Gaucher disease; Miglustat; Outcomes; Safety; Tolerability ID N-BUTYLDEOXYNOJIRIMYCIN; OPEN-LABEL; PERIPHERAL NEUROPATHY; MAINTENANCE THERAPY; ENZYME REPLACEMENT; TREATED PATIENTS; OGT-918; ADULTS; 2-YEAR AB We evaluated clinical and safety outcomes in adult patients with type 1 Gaucher disease receiving miglustat in clinical practice settings. An observational, retrospective cohort study was conducted in centers across the EU and the USA. Medical chart data were collected from consecutive patients between the 20th November 2002 and 31st December 2008. A total of 115 patients were included; 34 (30%) were enzyme replacement therapy-naive ('naive') and 81(70%) were enzyme pretreated ('pretreated'). Median (range) miglustat exposures in these groups were 15.1(0.6-52.9) months and 15.2 (0.3-62.1) months, respectively. Low numbers of patients were anemic (10/101) or thrombocytopenic (21/101) at initiation of miglustat therapy. The median (range) hemoglobin concentration at miglustat initiation was 12.8 (10.2-16.4) g/dl in naive patients and 13.6(7.3-17.4) g/dl in pretreated patients; median (range) changes in hemoglobin were 0.3 (-2.5-3.6) and -0.3 (-4-4.6) g/dl, respectively. The median (range) platelet counts at miglustat initiation were 101 (37-730) x 10(9)/l in naive patients and 173 (43-382) x 10(9)/l in pretreated patients; median (range) changes in platelet count were 8 (-77-145) x 10(9)/l and -10 (-144-434) x 10(9)/l, respectively. Plasma chitotriosidase was substantially reduced in naive but not in pretreated patients. Organ volumes were not routinely monitored. Forty-nine (43%) patients discontinued miglustat; most due to gastrointestinal manifestations and some due to tremor. Overall, hemoglobin and platelet counts tended to increase in naive patients treated with miglustat and to remain stable or decrease slightly in pretreated patients. The profile of safety and tolerability observed with miglustat in the current study is similar to previous studies. (c) 2013 Elsevier Inc. All rights reserved. C1 [Kuter, David J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mehta, Atul; Hughes, Derralynn] Royal Free Hosp, London NW3 2QG, England. [Hollak, Carla E. M.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Giraldo, Pilar] Hosp Univ Miguel Servet, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Zaragoza, Spain. [Hughes, Derralynn] UCL, Sch Med, London W1N 8AA, England. [Belmatoug, Nadia] Hop Beaujon, Clichy, France. [Brand, Monika; Muller, Audrey; Giorgino, Ruben] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Schaaf, Berthold] Factum GmbH, Offenbach, Germany. [Zimran, Ari] Shaare Zedek Med Ctr, Jerusalem, Israel. RP Kuter, DJ (reprint author), Massachusetts Gen Hosp, Div Hematol, 55 Fruit St, Boston, MA 02114 USA. EM DKUTER@PARTNERS.ORG FU Actelion Pharmaceuticals Ltd FX The authors would like to thank all participating physicians for their valuable contributions to these data, and Harbajan Chadha-Boreham PhD, Senior Statistician at Actelion for providing support on the Statistical Analysis Plan. We would also like to thank Matthew Reilly PhD, associated with InTouch Medical Ltd., for medical writing assistance in the preparation of this manuscript. This study was funded by the Actelion Pharmaceuticals Ltd. NR 26 TC 21 Z9 23 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD AUG PY 2013 VL 51 IS 2 BP 116 EP 124 DI 10.1016/j.bcmd.2013.04.005 PG 9 WC Hematology SC Hematology GA 164LP UT WOS:000320411900011 PM 23683771 ER PT J AU Nivison-Smith, L Sun, D Fletcher, EL Marc, RE Kalloniatis, M AF Nivison-Smith, Lisa Sun, Daniel Fletcher, Erica L. Marc, Robert E. Kalloniatis, Michael TI Mapping kainate activation of inner neurons in the rat retina SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE kainate; kainate receptors; agmatine; AGB; rat retina; glutamate; GABA; glycine; immunocytochemistry ID CONE BIPOLAR CELLS; NITRIC-OXIDE SYNTHASE; AMINO-ACID RECEPTORS; IONOTROPIC GLUTAMATE RECEPTORS; CENTRAL-NERVOUS-SYSTEM; ZEBRAFISH OLFACTORY-BULB; NK3 NEUROKININ RECEPTORS; DEVELOPING RABBIT RETINA; AII-AMACRINE CELLS; PROTEIN KINASE-C AB Kainate receptors mediate fast, excitatory synaptic transmission for a range of inner neurons in the mammalian retina. However, allocation of functional kainate receptors to known cell types and their sensitivity remains unresolved. Using the cation channel probe 1-amino-4-guanidobutane agmatine (AGB), we investigated kainate sensitivity of neurochemically identified cell populations within the structurally intact rat retina. Most inner retinal neuron populations responded to kainate in a concentration-dependent manner. OFF cone bipolar cells demonstrated the highest sensitivity of all inner neurons to kainate. Immunocytochemical localization of AGB and macromolecular markers confirmed that type 2 bipolar cells were part of this kainate-sensitive population. The majority of amacrine (ACs) and ganglion cells (GCs) showed kainate responses with different sensitivities between major neurochemical classes (-aminobutyric acid [GABA]/glycine ACs > glycine ACs > GABA ACs; glutamate [Glu]/weakly GABA GCs > Glu GCs). Conventional and displaced cholinergic ACs were highly responsive to kainate, whereas dopaminergic ACs do not appear to express functional kainate receptors. These findings further contribute to our understanding of neuronal networks in complex multicellular tissues. J. Comp. Neurol. 521:2416-2438, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Nivison-Smith, Lisa; Kalloniatis, Michael] Univ New S Wales, Sch Optometry & Vis Sci, Sydney, NSW 2052, Australia. [Sun, Daniel; Kalloniatis, Michael] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Sun, Daniel] Univ Auckland, Dept Optometry & Vis Sci, Auckland 1142, New Zealand. [Fletcher, Erica L.; Kalloniatis, Michael] Univ Melbourne, Dept Anat & Neurosci, Parkville, Vic 3010, Australia. [Marc, Robert E.] Univ Utah, Sch Med, Dept Ophthalmol, Salt Lake City, UT 84113 USA. [Kalloniatis, Michael] Ctr Eye Hlth, Sydney, NSW 2052, Australia. RP Kalloniatis, M (reprint author), Univ New S Wales, Ctr Eye Hlth, Sydney, NSW 2052, Australia. EM m.kalloniatis@unsw.edu.au RI Fletcher, Erica/E-6364-2012; OI Fletcher, Erica/0000-0001-9412-9523; Nivison-Smith, Lisa/0000-0001-6677-1949 FU National Health and Medical Research Council of Australia [1009342, 1021042]; National Institutes of Health [EY02576, EY014800] FX Grant sponsor: the National Health and Medical Research Council of Australia; Grant numbers: 1009342 (to M. K. and E. L. F.) and 1021042 (to E. L. F. and M. K.); Grant sponsor: the National Institutes of Health; Grant numbers: EY02576 and EY014800 (to R.E.M.). NR 119 TC 10 Z9 10 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD AUG 1 PY 2013 VL 521 IS 11 BP 2416 EP 2438 DI 10.1002/cne.23305 PG 23 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 158KU UT WOS:000319970100002 PM 23348566 ER PT J AU Muller, LPD Liu, J Solomon, A Rodriguez, A Brecha, NC AF Mueller, Luis Perez De Sevilla Liu, Janelle Solomon, Alexander Rodriguez, Allen Brecha, Nicholas C. TI Expression of voltage-gated calcium channel 24 subunits in the mouse and rat retina SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE calcium channel; 24 subunit; Muller cell; photoreceptor; retina; mouse; rat ID PHOTORECEPTOR RIBBON SYNAPSE; ACID TRANSPORTER EXPRESSION; TISSUE-SPECIFIC EXPRESSION; PIG HORIZONTAL CELLS; PROTEIN KINASE-C; MAMMALIAN RETINA; FUNCTIONAL ABNORMALITIES; BIPOLAR CELLS; ALPHA(2)DELTA SUBUNIT; CELLULAR-DISTRIBUTION AB High-voltage activated Ca channels participate in multiple cellular functions, including transmitter release, excitation, and gene transcription. Ca channels are heteromeric proteins consisting of a pore-forming 1 subunit and auxiliary 2 and subunits. Although there are reports of 24 subunit mRNA in the mouse retina and localization of the 24 subunit immunoreactivity to salamander photoreceptor terminals, there is a limited overall understanding of its expression and localization in the retina. 24 subunit expression and distribution in the mouse and rat retina were evaluated by using reverse transcriptase polymerase chain reaction, western blot, and immunohistochemistry with specific primers and a well-characterized antibody to the 24 subunit. 24 subunit mRNA and protein are present in mouse and rat retina, brain, and liver homogenates. Immunostaining for the 24 subunit is mainly localized to Muller cell processes and endfeet, photoreceptor terminals, and photoreceptor outer segments. This subunit is also expressed in a few displaced ganglion cells and bipolar cell dendrites. These findings suggest that the 24 subunit participates in the modulation of L-type Ca2+ current regulating neurotransmitter release from photoreceptor terminals and Ca2+-dependent signaling pathways in bipolar and Muller cells. J. Comp. Neurol. 521:2486-2501, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Mueller, Luis Perez De Sevilla; Liu, Janelle; Solomon, Alexander; Rodriguez, Allen; Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, CURE Digest Dis Res Ctr, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Muller, LPD (reprint author), Univ Calif Los Angeles, David Geffen Sch Med Los Angeles, Dept Neurobiol, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM luisperez@mednet.ucla.edu FU U.S. Army Medical Research & Materiel Command (USAMRMC); Telemedicine & Advanced Technology Research Center (TATRC), at Fort Detrick, MD [W81XWH-10-2-0077]; National Institutes of Health [EY04067]; Veterans Administration Merit Review FX Grant sponsor: the U.S. Army Medical Research & Materiel Command (USAMRMC) and the Telemedicine & Advanced Technology Research Center (TATRC), at Fort Detrick, MD; Grant number: W81XWH-10-2-0077; Grant sponsor: National Institutes of Health; Grant number: EY04067; Grant sponsor: Veterans Administration Merit Review (to N.C.B., who is also a Veterans Administration Career Research Scientist) J.L. and A. S. contributed equally to this work. NR 95 TC 4 Z9 4 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD AUG 1 PY 2013 VL 521 IS 11 BP 2486 EP 2501 DI 10.1002/cne.23294 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 158KU UT WOS:000319970100005 ER PT J AU Knowles, JK Simmons, DA Nguyen, TVV Vander Griend, L Xie, YM Zhang, H Yang, T Pollak, J Chang, T Arancio, O Buckwalter, MS Wyss-Coray, T Massa, SM Longo, FM AF Knowles, Juliet K. Simmons, Danielle A. Nguyen, Thuy-Vi V. Vander Griend, Lilith Xie, Youmei Zhang, Hong Yang, Tao Pollak, Julia Chang, Timothy Arancio, Ottavio Buckwalter, Marion S. Wyss-Coray, Tony Massa, Stephen M. Longo, Frank M. TI A small molecule p75(NTR) ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimers' disease; p75 neurotrophin receptor; Neuritic dystrophy; LM11A-31 ID NERVE GROWTH-FACTOR; P75 NEUROTROPHIN RECEPTOR; BASAL FOREBRAIN NEURONS; LONG-TERM DEPRESSION; FACTOR GENE-THERAPY; TRANSGENIC MICE; INTRACEREBROVENTRICULAR INFUSION; ADULT-RAT; DISEASE; EXPRESSION AB The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-beta-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates. (c) 2013 Elsevier Inc. All rights reserved. C1 [Knowles, Juliet K.; Simmons, Danielle A.; Nguyen, Thuy-Vi V.; Vander Griend, Lilith; Yang, Tao; Pollak, Julia; Chang, Timothy; Buckwalter, Marion S.; Wyss-Coray, Tony; Longo, Frank M.] Stanford Univ, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA. [Knowles, Juliet K.; Xie, Youmei] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. [Zhang, Hong; Arancio, Ottavio] Columbia Univ, Dept Pathol, New York, NY USA. [Zhang, Hong; Arancio, Ottavio] Columbia Univ, Taub Inst, New York, NY USA. [Wyss-Coray, Tony] Palo Alto Vet Affairs Hlth Care Syst, Palo Alto, CA USA. [Massa, Stephen M.] San Francisco VA Med Ctr, Dept Neurol, San Francisco, CA USA. [Massa, Stephen M.] San Francisco VA Med Ctr, Lab Computat Neurochem & Drug Discovery, San Francisco, CA USA. [Massa, Stephen M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Longo, FM (reprint author), Stanford Univ, Dept Neurol & Neurol Sci, Palo Alto, CA 94304 USA. EM longo@stanford.edu FU NINDS [F30 NA051971, NIA UO1 AG032225, NS049442]; Alzheimer's Drug Discovery Foundation; Alzheimer's Association; Eastern Chapter of the North Carolina Alzheimer's Association; Jean Perkins Foundation; Horngren Family Alzheimer's Research Fund; Richard M. Lucas Foundation; Veterans Administration FX This project was supported by funding from NINDS F30 NA051971 (J.K.K.), NIA UO1 AG032225 (F.M.L.), NS049442 (O.A.), the Alzheimer's Drug Discovery Foundation (F.M.L.), Alzheimer's Association (F.M.L.), the Eastern Chapter of the North Carolina Alzheimer's Association (F.M.L.), the Jean Perkins Foundation (F.M.L.), and the Horngren Family Alzheimer's Research Fund (F.M.L.), the Richard M. Lucas Foundation (F.M.L.) and the Veterans Administration (S.M.M. and T.W.C.). The authors thank Chihiro Ishikawa and Mary Wilson for their assistance in the execution of this work. NR 65 TC 33 Z9 35 U1 0 U2 22 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 AUG PY 2013 VL 34 IS 8 BP 2052 EP 2063 DI 10.1016/j.neurobiolaging.2013.02.015 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 156ED UT WOS:000319803100013 PM 23545424 ER PT J AU Yue, XM Nasr, S Devaney, KJ Holt, DJ Tootell, RBH AF Yue, Xiaomin Nasr, Shahin Devaney, Kathryn J. Holt, Daphne J. Tootell, Roger B. H. TI FMRI analysis of contrast polarity in face-selective cortex in humans and monkeys SO NEUROIMAGE LA English DT Article DE Face recognition; FFA; Contrast polarity; Face inversion; Monkey fMRI; Face patches ID PRIMARY VISUAL-CORTEX; LATERAL OCCIPITAL COMPLEX; TEMPORAL CORTEX; FUNCTIONAL-ANALYSIS; RECOGNITION MEMORY; COORDINATE SYSTEM; CEREBRAL-CORTEX; FUSIFORM GYRUS; CORTICAL AREAS; MACAQUE AB Recognition is strongly impaired when the normal contrast polarity of faces is reversed. For instance, otherwise-familiar faces become very difficult to recognize when viewed as photographic negatives. Here, we used fMRI to demonstrate related properties in visual cortex: 1) fMRI responses in the human Fusiform Face Area (FFA) decreased strongly (26%) to contrast-reversed faces across a wide range of contrast levels (5.3-100% RMS contrast), in all subjects tested. In a whole brain analysis, this contrast polarity bias was largely confined to the Fusiform Face Area (FFA; p < 0.0001), with possible involvement of a left occipital face-selective region. 2) It is known that reversing facial contrast affects three image properties in parallel (absorbance, shading, and specular reflection). Here, comparison of FFA responses to those in V1 suggests that the contrast polarity bias is produced in FFA only when all three component properties were reversed simultaneously, which suggests a prominent non-linearity in FFA processing. 3) Across a wide range (180 degrees) of illumination source angles, 3D face shapes without texture produced response constancy in FFA, without a contrast polarity bias. 4) Consistent with psychophysics, analogous fMRI biases for normal contrast polarity were not produced by non-face objects, with image statistics similar to the face stimuli. 5) Using fMRI, we also demonstrated a contrast polarity bias in awake behaving macaque monkeys, in the cortical region considered homologous to human FFA. Thus common cortical mechanisms may underlie facial contrast processing across similar to 25 million years of primate evolution. (c) 2013 Elsevier Inc. All rights reserved. C1 [Yue, Xiaomin; Nasr, Shahin; Devaney, Kathryn J.; Holt, Daphne J.; Tootell, Roger B. H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Yue, XM (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM xiaomin@nmr.mgh.harvard.edu FU National Institute of Health [EY017081, EY022096, MH076054]; National Alliance for Research on Schizophrenia and Depression (NARSAD); Sidney J. Bear Trust; Martinos Center for Biomedical Imaging, NCRR [P41RR14075] FX This study was supported by the National Institute of Health (EY017081 and EY022096 to RBHT, MH076054 to DJH) and the National Alliance for Research on Schizophrenia and Depression (NARSAD) (RBT, DJH), with the Sidney J. Bear Trust (DJH). Additional support came from the Martinos Center for Biomedical Imaging, NCRR (P41RR14075). NR 70 TC 7 Z9 7 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 AUG 1 PY 2013 VL 76 IS 1 BP 57 EP 69 DI 10.1016/j.neuroimage.2013.02.068 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 146KP UT WOS:000319090300006 PM 23518007 ER PT J AU Lew, S Sliva, DD Choe, MS Grant, PE Okada, Y Wolters, CH Hamalainen, MS AF Lew, Seok Sliva, Danielle D. Choe, Myong-sun Grant, P. Ellen Okada, Yoshio Wolters, Carsten H. Haemaelaeinen, Matti S. TI Effects of sutures and fontanels on MEG and EEG source analysis in a realistic infant head model SO NEUROIMAGE LA English DT Article DE MEG; EEG; FEM; Source analysis; Suture; Fontanel ID SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; FINITE-ELEMENT-METHOD; CORTICAL SURFACE; SOURCE LOCALIZATION; ELECTRICAL-CONDUCTIVITY; COORDINATE SYSTEM; INVERSE PROBLEM; TERM INFANTS; HUMAN BRAIN AB In infants, the fontanels and sutures as well as conductivity of the skull influence the volume currents accompanying primary currents generated by active neurons and thus the associated electroencephalography (EEG) and magnetoencephalography (MEG) signals. We used a finite element method (FEM) to construct a realistic model of the head of an infant based on MRI images. Using this model, we investigated the effects of the fontanels, sutures and skull conductivity on forward and inverse EEG and MEG source analysis. Simulation results show that MEG is better suited than EEG to study early brain development because it is much less sensitive than EEG to distortions of the volume current caused by the fontanels and sutures and to inaccurate estimates of skull conductivity. Best results will be achieved when MEG and EEG are used in combination. (C) 2013 Elsevier Inc All rights reserved. C1 [Lew, Seok; Choe, Myong-sun; Grant, P. Ellen; Haemaelaeinen, Matti S.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sliva, Danielle D.; Choe, Myong-sun; Grant, P. Ellen; Okada, Yoshio] Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. [Okada, Yoshio] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Wolters, Carsten H.] Univ Munster, Inst Biomagnetism & Biosignalanal, D-48149 Munster, Germany. RP Lew, S (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM slew@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; Wolters, Carsten/R-4234-2016 OI Wolters, Carsten/0000-0001-6233-424X FU NIH [R01EB0009048, R21EB008547, P41RR14075]; NSF [0958669]; German DFG [WO1425/3-1] FX We would like to thank Ruopeng Wang for his support in using Freeview, Benjamin Lanfer for his support in implementing infant magnetometer coils, and Moritz Dannhauer for providing the NeuroFEM FIFF file reader. This study was supported by NIH grants R01EB0009048, R21EB008547, and P41RR14075, NSF grant 0958669, and German DFG-project WO1425/3-1. NR 73 TC 24 Z9 24 U1 0 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2013 VL 76 IS 1 BP 282 EP 293 DI 10.1016/j.neuroimage.2013.03.017 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 146KP UT WOS:000319090300027 PM 23531680 ER PT J AU Bakkour, A Morris, JC Wolk, DA Dickerson, BC AF Bakkour, Akram Morris, John C. Wolk, David A. Dickerson, Bradford C. TI The effects of aging and Alzheimer's disease on cerebral cortical anatomy: Specificity and differential relationships with cognition SO NEUROIMAGE LA English DT Article DE Magnetic resonance imaging; Cerebral cortex; Aging; Alzheimer' disease; Parietal lobe; Frontal lobe; Temporal lobe ID VOXEL-BASED MORPHOMETRY; NORMAL NEUROANATOMICAL VARIATION; SURFACE-BASED ANALYSIS; PITTSBURGH COMPOUND-B; MEDIAL TEMPORAL-LOBE; MILD AD DEMENTIA; HUMAN BRAIN; FUNCTIONAL CONNECTIVITY; AMYLOID DEPOSITION; ELDERLY SUBJECTS AB Although both normal aging and Alzheimer's disease (AD) are associated with regional cortical atrophy, few studies have directly compared the spatial patterns and magnitude of effects of these two processes. The extant literature has not addressed two important questions: 1) Is the pattern of age-related cortical atrophy different if cognitively intact elderly individuals with silent AD pathology are excluded?.and 2) Does the age- or AD-related atrophy relate to cognitive function? Here we studied 142 young controls, 87 older controls, and 28 mild AD patients. In addition, we studied 35 older controls with neuroimaging data indicating the absence of brain amyloid. Whole-cortex analyses identified regions of interest (ROIs) of cortical atrophy in aging and in AD. Results showed that some regions are predominantly affected by age with relatively little additional atrophy in patients with AD, e.g., calcarine cortex; other regions are predominantly affected by AD with much less of an effect of age, e.g., medial temporal cortex. Finally, other regions are affected by both aging and AD, e.g., dorsolateral prefrontal cortex and inferior parietal lobule. Thus, the processes of aging and AD have both differential and partially overlapping effects on specific regions of the cerebral cortex. In particular, some frontoparietal regions are affected by both processes, most temporal lobe regions are affected much more prominently by AD than aging, while sensorimotor and some prefrontal regions are affected specifically by aging and minimally more by AD. Within normal older adults, atrophy in aging-specific cortical regions relates to cognitive performance, while in AD patients atrophy in AD-specific regions relates to cognitive performance. Further work is warranted to investigate the behavioral and clinical relevance of these findings in additional detail, as well as their histological basis; ROIs generated from the present study could be used strategically in such investigations. (C) 2013 Elsevier Inc. All rights reserved. C1 [Bakkour, Akram; Dickerson, Bradford C.] Massachusetts Gen Hosp, Frontotemporal Dementia Unit, Boston, MA 02114 USA. [Bakkour, Akram; Dickerson, Bradford C.] Harvard Univ, Sch Med, Boston, MA USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bakkour, Akram; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Massachusetts Alzheimers Dis Res Ctr, Boston, MA 02114 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Morris, John C.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Morris, John C.] Washington Univ, Sch Med, Alzheimers Dis Res Ctr, St Louis, MO USA. [Wolk, David A.] Univ Penn, Dept Neurol, Alzheimers Dis Core Ctr, Penn Memory Ctr, Philadelphia, PA 19104 USA. RP Dickerson, BC (reprint author), MGH Frontotemporal Dementia Unit, 149 13th St,Suite 2691, Charlestown, MA 02129 USA. EM bradd@nmr.mgh.harvard.edu OI Bakkour, Akram/0000-0002-6070-4945 FU NIA [R01-AG29411, R21-AG29840, P50-AG05134, P50-AG05681, P01-AG03991]; NCRR [P41-RR14075, U24-RR021382]; Alzheimer's Association; Mental Illness and Neuroscience Discovery (MIND) Institute FX This study was supported by grants from the NIA R01-AG29411, R21-AG29840, P50-AG05134, P50-AG05681, and P01-AG03991, the NCRR P41-RR14075 and U24-RR021382, the Alzheimer's Association, and the Mental Illness and Neuroscience Discovery (MIND) Institute. NR 95 TC 20 Z9 20 U1 0 U2 34 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2013 VL 76 IS 1 BP 332 EP 344 DI 10.1016/j.neuroimage.2013.02.059 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 146KP UT WOS:000319090300032 PM 23507382 ER PT J AU Cassetta, L Kajaste-Rudnitski, A Coradin, T Saba, E Della Chiara, G Barbagallo, M Graziano, F Alfano, M Cassol, E Vicenzi, E Poli, G AF Cassetta, Luca Kajaste-Rudnitski, Anna Coradin, Tiziana Saba, Elisa Della Chiara, Giulia Barbagallo, Marialuisa Graziano, Francesca Alfano, Massimo Cassol, Edana Vicenzi, Elisa Poli, Guido TI M1 polarization of human monocyte-derived macrophages restricts pre and postintegration steps of HIV-1 replication SO AIDS LA English DT Article DE APOBEC3A; APOBEC3G; cytokines; HIV-1; integration; M1 polarization; macrophage; transcription ID DEAMINASE ACTIVITY; APOBEC3 PROTEINS; GENE-EXPRESSION; HUMAN-CELLS; T-CELLS; IN-VIVO; VIRUS; ACTIVATION; INFECTION; DNA AB Objective: Functional polarization of human monocyte-derived macrophages (MDMs) into M1 cells leads to inhibition of R5 HIV-1 replication and viral DNA synthesis in comparison to control, unpolarized cells together with CD4 downregulation from the cell surface and upregulation of CCR5-binding chemokine secretion. We here investigated whether a postentry restriction of virus replication is also induced by M1 polarization of MDM. Design: MDM were first polarized to M1 cells by 18 h stimulation with interferon-g and tumor necrosis factor-alpha; the cytokines were then removed and the cells were infected with vesicular stomatitis virus G-protein pseudotyped enhanced green fluorescence protein HIV-1 (HIV-GFP) generating a single-round infection cycle. Methods: HIV-1 expression was monitored in terms of eGFP expression by fluorescence activated cell sorter (FACS) analysis and real-time PCR analysis of total HIV-1 gag DNA, 2-long terminal repeat DNA, proviral DNA, and multiply spliced RNA transcripts. Expression of apolipopoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G), and APOBEC3A was tested by western blotting and FACS analysis. Results: Inhibition of HIV-GFP expression was observed in M1-MDM along with impaired viral DNA synthesis, delayed proviral integration, and reduced proviral transcription. Although APOBEC3G levels were similar in M1 and unpolarized MDM, APOBEC 3A was selectively expressed only by M1 cells. Conclusion: M1 polarization of in-vitro differentiated primary MDM determines a transient, but profound restriction of HIV-1 replication affecting multiple (entry and postentry) steps in the virus life cycle likely involving the upregulated expression of APOBEC3A. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Cassetta, Luca; Saba, Elisa; Della Chiara, Giulia; Barbagallo, Marialuisa; Graziano, Francesca; Alfano, Massimo; Cassol, Edana; Poli, Guido] Ist Sci San Raffaele, AIDS Immunopathogenesis Unit, I-20132 Milan, Italy. [Kajaste-Rudnitski, Anna; Coradin, Tiziana; Vicenzi, Elisa] Ist Sci San Raffaele, Viral Pathogens & Biosafety Unit, Div Immunol Transplantat & Infect Dis, I-20132 Milan, Italy. [Graziano, Francesca; Poli, Guido] Univ Vita Salute Salute San Raffaele, Sch Med, Milan, Italy. [Cassetta, Luca] Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10467 USA. [Coradin, Tiziana] Univ Trento, Ctr Integrat Biol, Mattarello, Trento, Italy. [Kajaste-Rudnitski, Anna] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, I-20132 Milan, Italy. [Della Chiara, Giulia] European Inst Oncol, Dept Expt Oncol, Milan, Italy. [Cassol, Edana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Poli, G (reprint author), P2-P3 Labs,DIBIT 1,Via Olgettina 58, I-20132 Milan, Italy. EM poli.guido@hsr.it OI Kajaste-Rudnitski, Anna/0000-0003-1549-2426; Vicenzi, Elisa/0000-0003-0051-3968 FU CARIPLO [2008-2230]; Ministry of Health, Italy [40H76, 40H18, 40H11] FX This study was supported by the CARIPLO grant 2008-2230 (to G. P.) and by the grants n. 40H76, 40H18, and 40H11 (to G. P., E. V., and M. A., respectively) of the Program of AIDS research 2009-2010 of the Ministry of Health, Italy. NR 40 TC 18 Z9 18 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 31 PY 2013 VL 27 IS 12 BP 1847 EP 1856 DI 10.1097/QAD.0b013e328361d059 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 301IK UT WOS:000330525800002 PM 23612004 ER PT J AU Smurzynski, M Wu, KL Schouten, JT Lok, JJ Bosch, RJ Taiwo, B Johnson, VA Collier, AC AF Smurzynski, Marlene Wu, Kunling Schouten, Jeffrey T. Lok, Judith J. Bosch, Ronald J. Taiwo, Babafemi Johnson, Victoria Anne Collier, Ann C. TI Factors associated with remaining on initial randomized efavirenz-containing regimens SO AIDS LA English DT Article DE clinical trials; cohort study; efavirenz; HAART; HIV ID COMBINATION ANTIRETROVIRAL THERAPY; HIV-INFECTED INDIVIDUALS; INJECTION-DRUG USERS; VIROLOGICAL FAILURE; TRIALS ALLRT; ADHERENCE; COHORT; PHARMACOGENETICS; DISCONTINUATION; RECOMMENDATIONS AB Objective: Efavirenz (EFV) along with two nucleoside reverse transcriptase inhibitors (NRTIs) is a recommended initial antiretroviral regimen. Understanding characteristics related to EFV success is clinically useful. Design: Data from 2220 antiretroviral-naive participants randomized to EFV and two to three NRTIs in four ACTG trials as well as a long-term cohort were analysed. Methods: Logistic regression, using inverse probability of censoring weighting to address selective-follow-up bias, was used to identify factors associated with EFV success (no treatment interruptions of >30 days, HIV RNA<200 copies/ml) 1 year post initiation and at years 2-5 if successful at year 1. Results: Pretreatment characteristics were median age 38 years, 82% male, 40% white, 10% history of IDU (HxIDU), median CD4(+) T-lymphocyte 227 cells/mu l and 33% HIV RNA more than 100 000 copies/ml. In a multivariable model, factors associated with year 1 EFV success were race [white odds ratio (OR) 1.5; P<0.001; Hispanic OR 1.5; P=0.003 vs. black], no pretreatment sign/symptom grade 3 or higher (OR 1.7; P=0.008) and no HxIDU (OR 1.7; P=0.001). Predictors of EFV success at years 2-5 were no HxIDU (years 2-5; ORs 1.9-2.2); self-reported complete (4 days prior to study visit) adherence during year 1 (years 2-4; ORs 1.6-1.9); fewer missed visits during year 1 (years 2, 4, 5; ORs 0.92-0.98/1% increase); HIV RNA less than 50 copies/ml at year 1 (years 2, 3; ORs 1.9-2.2); and older age (>50 vs. <= 30 years) (years 2-4: ORs 2.3-3.7). Conclusion: Characteristics predictive of EFV success in the short-term and longer term differed except for HxIDU. Behaviours occurring during year 1 were associated with EFV success over 5 years. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Smurzynski, Marlene; Wu, Kunling; Lok, Judith J.; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Schouten, Jeffrey T.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Schouten, Jeffrey T.; Collier, Ann C.] Univ Washington, Seattle, WA 98195 USA. [Taiwo, Babafemi] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [Johnson, Victoria Anne] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Johnson, Victoria Anne] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. RP Smurzynski, M (reprint author), George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Epidemiol & Biostat, 2100-W Penn Ave NW,8th Floor, Washington, DC 20037 USA. EM msmurzyn@e-mail.gwu.edu FU Statistical and Data Management Center of the AIDS Clinical Trials Group, under the National Institute of Allergy and Infectious Diseases [1 UM1 AI068634, 1 UM1 AI068636]; National Institute of Allergy and Infectious Diseases grant: UAB Center for AIDS Research [P30AI27767]; National Institute of Allergy and Infectious Diseases grant: Alabama Clinical Trials Unit [UM1AI069452]; National Institute of Allergy and Infectious Diseases grant: UW Clinical HIV Integrated Research Program [5 UM1 AI 69434-06, R01AI100762] FX This work was supported by the Statistical and Data Management Center of the AIDS Clinical Trials Group, under the National Institute of Allergy and Infectious Diseases grant [1 UM1 AI068634] and the Leadership grant [1 UM1 AI068636]. Members of the team were also supported under the following National Institute of Allergy and Infectious Diseases grants: UAB Center for AIDS Research [P30AI27767], Alabama Clinical Trials Unit [UM1AI069452], UW Clinical HIV Integrated Research Program [5 UM1 AI 69434-06] and [R01AI100762]. NR 41 TC 1 Z9 1 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 31 PY 2013 VL 27 IS 12 BP 1887 EP 1897 DI 10.1097/QAD.0b013e328361645f PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 301IK UT WOS:000330525800006 PM 23925417 ER PT J AU Shapiro, RL Kitch, D Ogwu, A Hughes, MD Lockman, S Powis, K Souda, S Moffat, C Moyo, S McIntosh, K van Widenfelt, E Zwerski, S Mazhani, L Makhema, J Essex, M AF Shapiro, Roger L. Kitch, Douglas Ogwu, Anthony Hughes, Michael D. Lockman, Shahin Powis, Kathleen Souda, Sajini Moffat, Claire Moyo, Sikhulile McIntosh, Kenneth van Widenfelt, Erik Zwerski, Sheryl Mazhani, Loeto Makhema, Joseph Essex, Max TI HIV transmission and 24-month survival in a randomized trial of HAART to prevent MTCT during pregnancy and breastfeeding in Botswana SO AIDS LA English DT Article DE Africa; antiretrovirals; Botswana; HIV; infant survival; maternal health; mother-to-child HIV transmission ID TO-CHILD TRANSMISSION; ANTIRETROVIRAL THERAPY; INFECTED WOMEN; INFANTS; MALAWI; PROPHYLAXIS; MORTALITY; MOTHERS; BORN; ZIDOVUDINE AB Objectives: HAART for prevention of mother-to-child HIV transmission (MTCT) may impact long-term survival of women and children. Design: Randomized clinical trial. Methods: HIV-infected pregnant women with CD4(+) cell count at least 200 cells/mu l were randomly assigned to abacavir, zidovudine, lamivudine (arm A) or lopinavir-ritonavir, zidovudine-lamivudine (arm B) from week 26 to 34 gestation through planned weaning by 6 months postpartum. Women with baseline CD4(+) cell count less than 200 cells/mu l received nevirapine-zidovudine-lamivudine indefinitely (Obs arm), as did randomized women later qualifying for treatment. Results: Among 560 randomized and 170 observational women enrolled, there were 14 deaths (1.9%) - one antenatally (Obs), three from delivery to 6 months postpartum (1 arm A, 2 Obs), and 10 from 6 to 24 months postpartum (5 arm A, 3 arm B, 2 Obs). Time to death or CD4(+) cell count below 200 cells/mu l was shorter in arm A vs. B (P=0.03). Of the 709 live-born children, 97% breastfed for a median of 5.8 months. Of 37 (5.2%) deaths by 24 months, nine were before breastfeeding initiated (3 arm A, 2 arm B, 4 Obs); six while breastfeeding (1 arm A, 2 arm B, 3 Obs); and 22 after weaning (9 arm A, 11 arm B, 2 Obs). Only eight children (1.1%) were HIV-infected at 24 months (6 arm A, 1 arm B, 1 Obs), all before 6 months. Conclusion: Low MTCT was maintained through extended follow-up in all arms. Disease progression appeared slower after discontinuing protease inhibitor-based HAART, but a concerning number of maternal deaths occurred after stopping either regimen. Strategies to improve maternal and child survival in the postintervention period are required. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Shapiro, Roger L.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Shapiro, Roger L.; Lockman, Shahin; Powis, Kathleen; Makhema, Joseph; Essex, Max] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Shapiro, Roger L.; Ogwu, Anthony; Lockman, Shahin; Powis, Kathleen; Souda, Sajini; Moffat, Claire; Moyo, Sikhulile; van Widenfelt, Erik; Makhema, Joseph; Essex, Max] Botswana Harvard AIDS Inst Partnership HIV Res &, Gaborone, Botswana. [Kitch, Douglas; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lockman, Shahin] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Powis, Kathleen] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Powis, Kathleen] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [McIntosh, Kenneth] Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Zwerski, Sheryl] NIAID, NIH, Bethesda, MD 20892 USA. [Mazhani, Loeto] Univ Botswana, Sch Med, Gaborone, Botswana. RP Shapiro, RL (reprint author), Beth Israel Deaconess Med Ctr, Div Infect Dis, 110 Francis St,Suite GB, Boston, MA 02215 USA. EM rshapiro@hsph.harvard.edu RI Moyo, Sikhulile/E-1464-2015 OI Moyo, Sikhulile/0000-0003-3821-4592 FU National Institute of Allergy and Infectious Diseases [U01-AI066454] FX National Institute of Allergy and Infectious Diseases (U01-AI066454) / clinicaltrials.-gov Identifier: NCT00270296. NR 29 TC 11 Z9 11 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 31 PY 2013 VL 27 IS 12 BP 1911 EP 1920 DI 10.1097/QAD.0b013e32836158b0 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 301IK UT WOS:000330525800008 PM 24180000 ER PT J AU Sever, S Trachtman, H Wei, CL Reiser, J AF Sever, Sanja Trachtman, Howard Wei, Changli Reiser, Jochen TI Is There Clinical Value in Measuring suPAR Levels in FSGS? SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; UROKINASE RECEPTOR C1 [Sever, Sanja] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA USA. [Trachtman, Howard] NYU, Dept Pediat, New York, NY 10016 USA. [Wei, Changli; Reiser, Jochen] Rush Univ, Dept Med, Chicago, IL 60612 USA. RP Reiser, J (reprint author), Rush Univ, Med Ctr, Dept Med, Cohn Biomed Res Bldg,Suite 724, Chicago, IL 60612 USA. EM jochen_reiser@rush.edu OI Trachtman, Howard/0000-0001-7447-9489 NR 13 TC 13 Z9 13 U1 0 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL 31 PY 2013 VL 8 IS 8 BP 1273 EP 1275 DI 10.2215/CJN.06170613 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 201EC UT WOS:000323122500001 PM 23886567 ER PT J AU O'Hare, AM AF O'Hare, Ann M. TI Vascular Access for Hemodialysis in Older Adults: A "Patient First" Approach SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; DECISION-MAKING; FISTULA 1ST; ARTERIOVENOUS-FISTULA; ELDERLY-PATIENT; REFER PATIENTS; DIALYSIS; CARE; GUIDELINE; OUTCOMES C1 Univ Washington, Vet Affairs Puget Sound Healthcare Syst, Seattle, WA 98108 USA. RP O'Hare, AM (reprint author), Univ Washington, Vet Affairs Puget Sound Healthcare Syst, 1160 South Columbian Way, Seattle, WA 98108 USA. EM ann.ohare@va.gov NR 29 TC 8 Z9 8 U1 0 U2 5 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL 31 PY 2013 VL 24 IS 8 BP 1187 EP 1190 DI 10.1681/ASN.2013050507 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 198GD UT WOS:000322909400004 PM 23813217 ER PT J AU Rhee, EP Clish, CB Ghorbani, A Larson, MG Elmariah, S McCabe, E Yang, Q Cheng, S Pierce, K Deik, A Souza, AL Farrell, L Domos, C Yeh, RW Palacios, I Rosenfield, K Vasan, RS Florez, JC Wang, TJ Fox, CS Gerszten, RE AF Rhee, Eugene P. Clish, Clary B. Ghorbani, Anahita Larson, Martin G. Elmariah, Sammy McCabe, Elizabeth Yang, Qiong Cheng, Susan Pierce, Kerry Deik, Amy Souza, Amanda L. Farrell, Laurie Domos, Carly Yeh, Robert W. Palacios, Igor Rosenfield, Kenneth Vasan, Ramachandran S. Florez, Jose C. Wang, Thomas J. Fox, Caroline S. Gerszten, Robert E. TI A Combined Epidemiologic and Metabolomic Approach Improves CKD Prediction SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; SERUM CREATININE; GENERAL-POPULATION; ARGININE SYNTHESIS; RENAL METABOLISM; KYNURENIC ACID; AMINO-ACIDS; RAT NEPHRON; DISEASE; PHOSPHATIDYLCHOLINE AB Metabolomic approaches have begun to catalog the metabolic disturbances that accompany CKD, but whether metabolite alterations can predict future CKD is unknown. We performed liquid chromatography/mass spectrometry-based metabolite profiling on plasma from 1434 participants in the Framingham Heart Study (FHS) who did not have CKD at baseline. During the following 8 years, 123 individuals developed CKD, defined by an estimated GFR of <60 ml/min per 1.73 m(2). Numerous metabolites were associated with incident CKD, including 16 that achieved the Bonferroni-adjusted significance threshold of P0.00023. To explore how the human kidney modulates these metabolites, we profiled arterial and renal venous plasma from nine individuals. Nine metabolites that predicted CKD in the FHS cohort decreased more than creatinine across the renal circulation, suggesting that they may reflect non-GFR-dependent functions, such as renal metabolism and secretion. Urine isotope dilution studies identified citrulline and choline as markers of renal metabolism and kynurenic acid as a marker of renal secretion. In turn, these analytes remained associated with incident CKD in the FHS cohort, even after adjustment for eGFR, age, sex, diabetes, hypertension, and proteinuria at baseline. Addition of a multimarker metabolite panel to clinical variables significantly increased the c-statistic (0.77-0.83, P<0.0001); net reclassification improvement was 0.78 (95% confidence interval, 0.60 to 0.95; P<0.0001). Thus, the addition of metabolite profiling to clinical data may significantly improve the ability to predict whether an individual will develop CKD by identifying predictors of renal risk that are independent of estimated GFR. C1 [Rhee, Eugene P.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. [Ghorbani, Anahita; Elmariah, Sammy; Cheng, Susan; Farrell, Laurie; Domos, Carly; Yeh, Robert W.; Palacios, Igor; Rosenfield, Kenneth; Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA 02129 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Charlestown, MA 02129 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Charlestown, MA 02129 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Rhee, Eugene P.; Clish, Clary B.; Pierce, Kerry; Deik, Amy; Souza, Amanda L.; Gerszten, Robert E.] Broad Inst, Cambridge, MA USA. [Ghorbani, Anahita; Larson, Martin G.; Cheng, Susan; Vasan, Ramachandran S.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ghorbani, Anahita; Larson, Martin G.; Cheng, Susan; Vasan, Ramachandran S.; Fox, Caroline S.] Boston Univ, Sch Med, Framingham, MA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [McCabe, Elizabeth; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cheng, Susan] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston Med Ctr, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston Med Ctr, Cardiol Sect, Boston, MA 02118 USA. [Wang, Thomas J.] Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN USA. [Wang, Thomas J.] Vanderbilt Heart & Vasc Inst, Nashville, TN USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. RP Rhee, EP (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, 149 13th St,8th Floor,8401, Charlestown, MA 02129 USA. EM eprhee@partners.org; rgerszten@partners.org RI Yang, Qiong/G-5438-2014; OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health (NIH) [N01-HC-25195, R01-DK-HL081572]; Leducq Foundation; American Heart Association; NIH [K08-DK-090142] FX This work was supported by National Institutes of Health (NIH) contract N01-HC-25195 to the Framingham Heart Study, R01-DK-HL081572 (R. E. G. and T.J.W.), the Leducq Foundation (R. E. G.), and an Established Investigator Award from the American Heart Association (R. E. G.). E. P. R. received support from NIH award K08-DK-090142. NR 35 TC 47 Z9 47 U1 4 U2 19 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL 31 PY 2013 VL 24 IS 8 BP 1330 EP 1338 DI 10.1681/ASN.2012101006 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 198GD UT WOS:000322909400021 PM 23687356 ER PT J AU Bandyopadhyay, S Cahill, C Balleidier, A Huang, CN Lahiri, DK Huang, XD Rogers, JT AF Bandyopadhyay, Sanghamitra Cahill, Catherine Balleidier, Amelie Huang, Conan Lahiri, Debomoy K. Huang, Xudong Rogers, Jack T. TI Novel 5 ' Untranslated Region Directed Blockers of Iron-Regulatory Protein-1 Dependent Amyloid Precursor Protein Translation: Implications for Down Syndrome and Alzheimer's Disease SO PLOS ONE LA English DT Article ID APP-MESSENGER-RNA; 5'-UNTRANSLATED REGION; RESPONSIVE ELEMENT; BETA PEPTIDE; EXPRESSION; MICE; IDENTIFICATION; DEGENERATION; DYSFUNCTION; INHIBITORS AB We reported that iron influx drives the translational expression of the neuronal amyloid precursor protein (APP), which has a role in iron efflux. This is via a classic release of repressor interaction of APP mRNA with iron-regulatory protein-1 (IRP1) whereas IRP2 controls the mRNAs encoding the L-and H-subunits of the iron storage protein, ferritin. Here, we identified thirteen potent APP translation blockers that acted selectively towards the uniquely configured iron-responsive element (IRE) RNA stem loop in the 5' untranslated region (UTR) of APP mRNA. These agents were 10-fold less inhibitory of 5 ' UTR sequences of the related prion protein (PrP) mRNA. Western blotting confirmed that the 'ninth' small molecule in the series selectively reduced neural APP production in SH-SY5Y cells at picomolar concentrations without affecting viability or the expression of a-synuclein and ferritin. APP blocker-9 (JTR-009), a benzimidazole, reduced the production of toxic Ab in SH-SY5Y neuronal cells to a greater extent than other well tolerated APP 5'UTR-directed translation blockers, including posiphen, that were shown to limit amyloid burden in mouse models of Alzheimer's disease (AD). RNA binding assays demonstrated that JTR-009 operated by preventing IRP1 from binding to the IRE in APP mRNA, while maintaining IRP1 interaction with the H-ferritin IRE RNA stem loop. Thus, JTR-009 constitutively repressed translation driven by APP 5'UTR sequences. Calcein staining showed that JTR-009 did not indirectly change iron uptake in neuronal cells suggesting a direct interaction with the APP 5'UTR. These studies provide key data to develop small molecules that selectively reduce neural APP and Ab production at 10-fold lower concentrations than related previously characterized translation blockers. Our data evidenced a novel therapeutic strategy of potential impact for people with trisomy of the APP gene on chromosome 21, which is a phenotype long associated with Down syndrome (DS) that can also cause familial Alzheimer's disease. C1 [Bandyopadhyay, Sanghamitra; Cahill, Catherine; Balleidier, Amelie; Huang, Conan; Huang, Xudong; Rogers, Jack T.] Massachusetts Gen Hosp, Dept Psychiat, Neurochem Lab, Charlestown, MA USA. [Bandyopadhyay, Sanghamitra; Cahill, Catherine; Balleidier, Amelie; Huang, Conan; Huang, Xudong; Rogers, Jack T.] Harvard Univ, Sch Med, Charlestown, MA USA. [Cahill, Catherine] Massachusetts Gen Hosp, Dept Pediat, Charlestown, MA USA. [Lahiri, Debomoy K.] Indiana Univ Sch Med, Dept Psychiat, Inst Psychiat Res, Mol Neurogenet Lab, Indianapolis, IN 46202 USA. RP Rogers, JT (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Neurochem Lab, Charlestown, MA USA. EM jrogers@partners.org OI Bandyopadhyay, Sanghamitra /0000-0002-1490-3599 FU Alzheimer's Association Zenith Award; Michael JFOX NADD grant; NICH; [R21 NS077079-01A1] FX JR was funded from an R21 NS077079-01A1 (Post Transcriptional Control of hemorrhagic iron damage). JR is a recipient of the Alzheimer's Association Zenith Award, and of a Michael JFOX NADD grant. CC was supported by an R01 Supplement from the NICH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 17 Z9 17 U1 0 U2 15 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 JUL 31 PY 2013 VL 8 IS 7 AR e65978 DI 10.1371/journal.pone.0065978 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 194LB UT WOS:000322633700001 PM 23935819 ER PT J AU Kong, J Spaeth, R Cook, A Kirsch, I Claggett, B Vangel, M Gollub, RL Smoller, JW Kaptchuk, TJ AF Kong, Jian Spaeth, Rosa Cook, Amanda Kirsch, Irving Claggett, Brian Vangel, Mark Gollub, Randy L. Smoller, Jordan W. Kaptchuk, Ted J. TI Are All Placebo Effects Equal? Placebo Pills, Sham Acupuncture, Cue Conditioning and Their Association SO PLOS ONE LA English DT Article ID DISPOSITIONAL OPTIMISM; EXPERIMENTAL PAIN; ANALGESIA; EXPECTANCY; TRIALS; NEEDLE; DISSOCIATION; MECHANISMS; NETWORK; BLIND AB Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditioning responses, correlate with one another. Secondarily, this study also examines whether responses to sham acupuncture correlate with responses to genuine acupuncture. Healthy subjects were recruited to participate in two sequential experiments. Experiment one is a five-session crossover study. In each session, subjects received one of four treatments: placebo pills (described as Tylenol), sham acupuncture, genuine acupuncture, or no treatment rest control condition. Before and after each treatment, paired with a verbal suggestion of positive effect, each subject's pain threshold, pain tolerance, and pain ratings to calibrated heat pain were measured. At least 14 days after completing experiment one, all subjects were invited to participate in experiment two, during which their analgesic responses to conditioned visual cues were tested. Forty-eight healthy subjects completed experiment one, and 45 completed experiment two. The results showed significantly different effects of genuine acupuncture, placebo pill and rest control on pain threshold. There was no significant association between placebo pills, sham acupuncture and cue conditioning effects, indicating that individuals may respond to unique healing rituals in different ways. This outcome suggests that placebo response may be a complex behavioral phenomenon that has properties that comprise a state, rather than a trait characteristic. This could explain the difficulty of detecting a signature for "placebo responders." However, a significant association was found between the genuine and sham acupuncture treatments, implying that the non-specific effects of acupuncture may contribute to the analgesic effect observed in genuine acupuncture analgesia. C1 [Kong, Jian; Spaeth, Rosa; Cook, Amanda; Gollub, Randy L.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Kong, Jian; Spaeth, Rosa; Cook, Amanda; Gollub, Randy L.; Smoller, Jordan W.] Harvard Univ, Sch Med, Charlestown, MA USA. [Kirsch, Irving; Kaptchuk, Ted J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Program Placebo Studies, Boston, MA 02215 USA. [Kirsch, Irving] Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. [Claggett, Brian] Harvard Univ, Sch Med, Div Cardiovasc Med, Boston, MA USA. [Claggett, Brian] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Vangel, Mark] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. RP Kong, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. EM kongj@nmr.mgh.harvard.edu OI Gollub, Randy L./0000-0002-9434-4044 FU NCCAM [KO1AT003883, R21AT004497, R01AT006364, R01AT005280, K24AT004095, P01 AT006663]; NIDA [R03AT218317]; NIMH [K24MH094614] FX This work was supported by KO1AT003883 (NCCAM), R21AT004497 (NCCAM), R03AT218317 (NIDA), and R01AT006364 (NCCAM) to Jian Kong; R01AT005280 (NCCAM) to Randy Gollub; K24AT004095 (NCCAM) to Ted Kaptchuk; K24MH094614 (NIMH) to Jordan W. Smoller, and P01 AT006663 (NCCAM) to Bruce Rosen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 21 Z9 21 U1 5 U2 36 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 JUL 31 PY 2013 VL 8 IS 7 AR e67485 DI 10.1371/journal.pone.0067485 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 194LB UT WOS:000322633700004 PM 23935833 ER PT J AU Bornigen, D Morgan, XC Franzosa, EA Ren, BY Xavier, RJ Garrett, WS Huttenhower, C AF Boernigen, Daniela Morgan, Xochitl C. Franzosa, Eric A. Ren, Boyu Xavier, Ramnik J. Garrett, Wendy S. Huttenhower, Curtis TI Functional profiling of the gut microbiome in disease-associated inflammation SO GENOME MEDICINE LA English DT Review ID RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; BOWEL-DISEASE; VITAMIN-D; ATOPIC-DERMATITIS; ANTIBIOTIC-RESISTANCE; ALLERGIC DISEASES; WIDE ASSOCIATION; PROTEIN FAMILIES; INNATE IMMUNITY AB The microbial residents of the human gut are a major factor in the development and lifelong maintenance of health. The gut microbiota differs to a large degree from person to person and has an important influence on health and disease due to its interaction with the human immune system. Its overall composition and microbial ecology have been implicated in many autoimmune diseases, and it represents a particularly important area for translational research as a new target for diagnostics and therapeutics in complex inflammatory conditions. Determining the biomolecular mechanisms by which altered microbial communities contribute to human disease will be an important outcome of current functional studies of the human microbiome. In this review, we discuss functional profiling of the human microbiome using metagenomic and metatranscriptomic approaches, focusing on the implications for inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis. Common themes in gut microbial ecology have emerged among these diverse diseases, but they have not yet been linked to targetable mechanisms such as microbial gene and genome composition, pathway and transcript activity, and metabolism. Combining these microbial activities with host gene, transcript and metabolic information will be necessary to understand how and why these complex interacting systems are altered in disease-associated inflammation. C1 [Boernigen, Daniela; Morgan, Xochitl C.; Franzosa, Eric A.; Ren, Boyu; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Boernigen, Daniela; Morgan, Xochitl C.; Franzosa, Eric A.; Xavier, Ramnik J.; Garrett, Wendy S.; Huttenhower, Curtis] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Huttenhower, C (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM chuttenh@hsph.harvard.edu OI Morgan, Xochitl/0000-0002-6264-6961; Huttenhower, Curtis/0000-0002-1110-0096 FU National Science Foundation [DBI-1053486]; Danone research grant [PLF-5972-GD]; National Institutes of Health (NIH) [1R01HG005969]; NIH [R01CA154426, K08AI078942, R01GM099531]; Burroughs Wellcome Career in Medical Sciences Award; Searle Scholars Award; NIH/NIDDK [R01DK092405]; Crohn's and Colitis Foundation of America; Juvenile Diabetes Research Foundation FX The authors would like to thank Timothy Tickle and Levi Waldron for assistance with figures, Carolyn Ingalls and Nicole Levesque for their editorial assistance, and the members of the Huttenhower laboratory for their input and thoughtful discussions. This work was supported by National Science Foundation grant DBI-1053486 (CH), Danone research grant PLF-5972-GD (WSG), National Institutes of Health (NIH) grant 1R01HG005969 (CH), NIH R01CA154426 (WSG), K08AI078942 (WSG), R01GM099531 (WSG), a Burroughs Wellcome Career in Medical Sciences Award (WSG), a Searle Scholars Award (WSG), Cancer Research Institute Investigator, NIH/NIDDK R01DK092405 (RJX), the Crohn's and Colitis Foundation of America (CH and RJX), and the Juvenile Diabetes Research Foundation (RJX). NR 127 TC 17 Z9 18 U1 2 U2 102 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD JUL 31 PY 2013 VL 5 AR 65 DI 10.1186/gm469 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 193FJ UT WOS:000322543400001 PM 23906180 ER PT J AU Corcoran, RB Rothenberg, SM Hata, AN Faber, AC Piris, A Nazarian, RM Brown, RD Godfrey, JT Winokur, D Walsh, J Mino-Kenudson, M Maheswaran, S Settleman, J Wargo, JA Flaherty, KT Haber, DA Engelman, JA AF Corcoran, Ryan B. Rothenberg, Stephen Michael Hata, Aaron N. Faber, Anthony C. Piris, Adriano Nazarian, Rosalynn M. Brown, Ronald D. Godfrey, Jason T. Winokur, Daniel Walsh, John Mino-Kenudson, Mari Maheswaran, Shyamala Settleman, Jeffrey Wargo, Jennifer A. Flaherty, Keith T. Haber, Daniel A. Engelman, Jeffrey A. TI TORC1 Suppression Predicts Responsiveness to RAF and MEK Inhibition in BRAF-Mutant Melanoma SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID VIVO ANTITUMOR-ACTIVITY; METASTATIC MELANOMA; ACQUIRED-RESISTANCE; TUBEROUS SCLEROSIS; CUTANEOUS MELANOMA; KINASE INHIBITORS; IMPROVED SURVIVAL; V600E MUTATION; HUMAN CANCER; S6 KINASE AB RAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) inhibitors are effective in treating patients with BRAF-mutant melanoma. However, most responses are partial and short-lived, and many patients fail to respond at all. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein S6 (P-S6), effectively predicted induction of cell death by the inhibitor in BRAF-mutant melanoma cell lines. In resistant melanomas, TORC1 activity was maintained after treatment with RAF or MEK inhibitors, in some cases despite robust suppression of mitogen-activated protein kinase (MAPK) signaling. In in vivo mouse models, suppression of TORC1 after MAPK inhibition was necessary for induction of apoptosis and tumor response. Finally, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression predicted significantly improved progression-free survival. Such a change in P-S6 could be readily monitored in real time by serial fine-needle aspiration biopsies, making quantitation of P-S6 a valuable biomarker to guide treatment in BRAF-mutant melanoma. C1 [Corcoran, Ryan B.; Rothenberg, Stephen Michael; Hata, Aaron N.; Faber, Anthony C.; Brown, Ronald D.; Godfrey, Jason T.; Winokur, Daniel; Walsh, John; Maheswaran, Shyamala; Wargo, Jennifer A.; Flaherty, Keith T.; Haber, Daniel A.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Corcoran, Ryan B.; Rothenberg, Stephen Michael; Hata, Aaron N.; Flaherty, Keith T.; Haber, Daniel A.; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Piris, Adriano; Nazarian, Rosalynn M.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA. [Piris, Adriano; Nazarian, Rosalynn M.; Mino-Kenudson, Mari; Wargo, Jennifer A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Settleman, Jeffrey] Genentech Inc, San Francisco, CA 94080 USA. [Wargo, Jennifer A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02129 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. EM dhaber@partners.org; jengelman@partners.org OI Nazarian, Rosalynn/0000-0003-4003-7193 FU Damon Runyon Clinical Investigator Award; NIH/National Institute of Dental and Craniofacial Research [1K08DE020139]; NIH [R01CA137008]; National Cancer Institute [CA129933] FX This work was funded by a Damon Runyon Clinical Investigator Award (to R.B.C.), NIH/National Institute of Dental and Craniofacial Research grant 1K08DE020139 (to S.M.R.), NIH grant R01CA137008 (to J.A.E.), National Cancer Institute grant CA129933 (to D.A.H.). NR 46 TC 15 Z9 16 U1 1 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 31 PY 2013 VL 5 IS 196 AR 196ra98 DI 10.1126/scitranslmed.3005753 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 193WG UT WOS:000322591600002 PM 23903755 ER PT J AU Elkabets, M Vora, S Juric, D Morse, N Mino-Kenudson, M Muranen, T Tao, J Campos, AB Rodon, J Ibrahim, YH Serra, V Rodrik-Outmezguine, V Hazra, S Singh, S Kim, P Quadt, C Liu, M Huang, A Rosen, N Engelman, JA Scaltriti, M Baselga, J AF Elkabets, Moshe Vora, Sadhna Juric, Dejan Morse, Natasha Mino-Kenudson, Mari Muranen, Taru Tao, Jessica Campos, Ana Bosch Rodon, Jordi Ibrahim, Yasir H. Serra, Violeta Rodrik-Outmezguine, Vanessa Hazra, Saswati Singh, Sharat Kim, Phillip Quadt, Cornelia Liu, Manway Huang, Alan Rosen, Neal Engelman, Jeffrey A. Scaltriti, Maurizio Baselga, Jose TI mTORC1 Inhibition Is Required for Sensitivity to PI3K p110 alpha Inhibitors in PIK3CA-Mutant Breast Cancer SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ADVANCED SOLID TUMORS; ANTITUMOR-ACTIVITY; PIK3CA MUTATIONS; 3-KINASE PATHWAY; PHASE-I; KINASE; GROWTH; RESISTANCE; CELLS; GENE AB Activating mutations of the PIK3CA gene occur frequently in breast cancer, and inhibitors that are specific for phosphatidylinositol 3-kinase (PI3K) p110 alpha, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110 alpha inhibition among PIK3CA-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORC1 signaling, although Akt phosphorylation was inhibited. Similarly, in patients, pS6 (residues 240/4) expression (a marker of mTORC1 signaling) was associated with tumor response to BYL719, and mTORC1 was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3CA-mutant cancer cell lines with persistent mTORC1 signaling despite PI3K p110 alpha blockade (that is, resistance), the addition of the allosteric mTORC1 inhibitor RAD001 to the cells along with BYL719 resulted in reversal of resistance in vitro and in vivo. Finally, we found that growth factors such as insulin-like growth factor 1 and neuregulin 1 can activate mammalian target of rapamycin (mTOR) and mediate resistance to BYL719. Our findings suggest that simultaneous administration of mTORC1 inhibitors may enhance the clinical activity of p110 alpha-targeted drugs and delay the appearance of resistance. C1 [Elkabets, Moshe; Morse, Natasha; Campos, Ana Bosch; Scaltriti, Maurizio; Baselga, Jose] Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Elkabets, Moshe; Morse, Natasha; Campos, Ana Bosch; Scaltriti, Maurizio; Baselga, Jose] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Elkabets, Moshe; Vora, Sadhna; Juric, Dejan; Tao, Jessica; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, CNY 149, Charlestown, MA 02129 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Muranen, Taru] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Rodon, Jordi; Ibrahim, Yasir H.; Serra, Violeta] Vall Hebron Inst Oncol, Expt Therapeut Grp, Barcelona 08035, Spain. [Rodrik-Outmezguine, Vanessa; Rosen, Neal] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA. [Hazra, Saswati; Singh, Sharat; Kim, Phillip] Prometheus Therapeut & Diagnost, San Diego, CA 92121 USA. [Quadt, Cornelia] Novartis Pharma AG, CH-4056 Basel, Switzerland. [Liu, Manway; Huang, Alan] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. RP Scaltriti, M (reprint author), Human Oncol & Pathogenesis Program, 1275 York Ave,Box 20, New York, NY 10065 USA. EM scaltrim@mskcc.org; baselgaj@mskcc.org OI Rodrik - Outmezguine, Vanessa/0000-0002-3024-4490 FU Stand Up To Cancer Dream Team Translational Cancer Research Grant, a program of the Entertainment Industry Foundation [SU2C-AACR-DT0209]; Breast Cancer Research Foundation; European Research Council [AdG09250244]; Instituto de Salud Carlos III [Intrasalud PSO9/00623]; Spanish Society of Medical Oncology (SEOM); ASCO YIA; American Association for Cancer Research-Genentech BioOncology Fellowship; Terri Brodeur Breast Cancer Foundation; [RO1CA137008] FX This work was funded by a Stand Up To Cancer Dream Team Translational Cancer Research Grant, a program of the Entertainment Industry Foundation (SU2C-AACR-DT0209 to J.B.), the Breast Cancer Research Foundation (to J.B.), the European Research Council (AdG09250244 to J.B.), the Instituto de Salud Carlos III (Intrasalud PSO9/00623 to J.B.), and RO1CA137008 (to J.A.E.). M.E. is an International Sephardic Education Foundation postdoctoral fellow. A.B.C. holds a Translational Research Fellowship from the Spanish Society of Medical Oncology (SEOM). S.V. is supported by an ASCO YIA, American Association for Cancer Research-Genentech BioOncology Fellowship, and Terri Brodeur Breast Cancer Foundation research grant. NR 49 TC 51 Z9 52 U1 4 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 31 PY 2013 VL 5 IS 196 AR 196ra99 DI 10.1126/scitranslmed.3005747 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 193WG UT WOS:000322591600004 PM 23903756 ER PT J AU Bonderman, D Ghio, S Felix, SB Ghofrani, HA Michelakis, E Mitrovic, V Oudiz, RJ Boateng, F Scalise, AV Roessig, L Semigran, MJ AF Bonderman, Diana Ghio, Stefano Felix, Stephan B. Ghofrani, Hossein-Ardeschir Michelakis, Evangelos Mitrovic, Veselin Oudiz, Ronald J. Boateng, Francis Scalise, Andrea-Viviana Roessig, Lothar Semigran, Marc J. CA Left Ventricular Systolic Dysfunct TI Riociguat for Patients With Pulmonary Hypertension Caused by Systolic Left Ventricular Dysfunction A Phase IIb Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging Hemodynamic Study SO CIRCULATION LA English DT Article DE clinical trial; heart failure, systolic; hypertension, pulmonary; riociguat; soluble guanylate cyclase ID CHRONIC HEART-FAILURE; SOLUBLE GUANYLATE-CYCLASE; INHALED NITRIC-OXIDE; ENDOTHELIAL DYSFUNCTION; DILATED CARDIOMYOPATHY; PROGNOSTIC VALUE; ANTAGONIST; SILDENAFIL; MORTALITY; SECONDARY AB Background-Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction. Methods and Results-Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (-6.1+/-1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L.min(-1).m(-2); 95% confidence interval, 0.2-0.5; P=0.0001) and stroke volume index (5.2 mL.m(-2);95% confidence interval, 2.0-8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (-46.6 dynes.s(-1).cm(-5); 95% confidence interval, -89.4 to -3.8; P=0.03) and systemic vascular resistance (-239.3 dynes.s(-1).cm(-5); 95% confidence interval, -363.4 to -115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups. Conclusions-Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance. C1 [Bonderman, Diana] Med Univ Vienna, Dept Internal Med 2, Vienna, Austria. [Ghio, Stefano] Univ Hosp, Fdn IRCCS Policlin San Matteo, Dept Cardiol, Pavia, Italy. [Felix, Stephan B.] Univ Med Greifswald, Dept Cardiol & Internal Med B, Greifswald, Germany. [Felix, Stephan B.] DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Ghofrani, Hossein-Ardeschir] Univ Giessen, D-35390 Giessen, Germany. [Ghofrani, Hossein-Ardeschir] Marburg Lung Ctr, Giessen, Germany. [Ghofrani, Hossein-Ardeschir] German Ctr Lung Res, Giessen, Germany. [Michelakis, Evangelos] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Mitrovic, Veselin] Forschungsgesell GmbH, Kerckhoff Klin, Bad Nauheim, Germany. [Oudiz, Ronald J.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Boateng, Francis] Bayer HealthCare Pharmaceut, New York, NY USA. [Scalise, Andrea-Viviana] Bayer Hispania, Barcelona, Spain. [Roessig, Lothar] Bayer Pharma AG, Berlin, Germany. [Semigran, Marc J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP Semigran, MJ (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Fruit St, Boston, MA 02114 USA. EM msemigran@partners.org FU Bayer HealthCare Pharmaceuticals (Berlin, Germany) FX This study was supported by Bayer HealthCare Pharmaceuticals (Berlin, Germany). NR 30 TC 83 Z9 85 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 30 PY 2013 VL 128 IS 5 BP 502 EP U95 DI 10.1161/CIRCULATIONAHA.113.001458 PG 27 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 301LE UT WOS:000330533000010 PM 23775260 ER PT J AU Weiner, RB Wang, F Isaacs, SK Malhotra, R Berkstresser, B Kim, JH Hutter, AM Picard, MH Wang, TJ Baggish, AL AF Weiner, Rory B. Wang, Francis Isaacs, Stephanie K. Malhotra, Rajeev Berkstresser, Brant Kim, Jonathan H. Hutter, Adolph M., Jr. Picard, Michael H. Wang, Thomas J. Baggish, Aaron L. TI Blood Pressure and Left Ventricular Hypertrophy During American-Style Football Participation SO CIRCULATION LA English DT Article DE blood pressure; cardiomegaly, exercise-induced; exercise; hypertension; hypertrophy, left ventricular ID CARDIOVASCULAR-DISEASE MORTALITY; RISK-FACTORS; EXERCISE; HYPERTENSION; IMPACT; ENDURANCE; RECOMMENDATIONS; METAANALYSIS; PREVALENCE; DIMENSIONS AB Background-Hypertension, a strong determinant of cardiovascular disease risk, has been documented among elite, professional American-style football (ASF) players. The risk of increased blood pressure (BP) and early adulthood hypertension among the substantially larger population of collegiate ASF athletes is not known. Methods and Results-We conducted a prospective, longitudinal study to examine BP, the incidence of hypertension, and left ventricular remodeling among collegiate ASF athletes. Resting BP and left ventricular structure were assessed before and after a single season of competitive ASF participation in 6 consecutive groups of first-year university athletes (n=113). ASF participation was associated with significant increases in systolic BP (116+/-8 versus 125+/-13 mm Hg; P<0.001) and diastolic BP (64+/-8 mm Hg versus 66+/-10 mm Hg; P<0.001). At the postseason assessment, the majority of athletes met criteria for Joint National Commission (seventh report) prehypertension (53 of 113, 47%) or stage 1 hypertension (16 of 113, 14%). Among measured characteristics, lineman field position, intraseason weight gain, and family history of hypertension were the strongest independent predictors of postseason BP. Among linemen, there was a significant increase in the prevalence of concentric left ventricular hypertrophy (2 of 64 [3%] versus 20 of 64 [31%]; P<0.001) and change in left ventricular mass correlated with intraseason change in systolic BP (R=0.46, P<0.001). Conclusions-Collegiate ASF athletes may be at risk for clinically relevant increases in BP and the development of hypertension. Enhanced surveillance and carefully selected interventions may represent important opportunities to improve later-life cardiovascular health outcomes in this population. C1 [Weiner, Rory B.; Hutter, Adolph M., Jr.; Baggish, Aaron L.] Massachusetts Gen Hosp, Cardiovasc Performance Program, Boston, MA 02114 USA. [Weiner, Rory B.; Isaacs, Stephanie K.; Malhotra, Rajeev; Kim, Jonathan H.; Hutter, Adolph M., Jr.; Picard, Michael H.; Wang, Thomas J.; Baggish, Aaron L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Wang, Francis; Berkstresser, Brant; Baggish, Aaron L.] Harvard Univ, Univ Hlth Serv, Cambridge, MA 02138 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Cardiovasc Performance Program, Yawkey Ste 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org OI Picard, Michael/0000-0002-9264-3243; Malhotra, Rajeev/0000-0003-0120-4630 FU American Heart Association [09FTF2220328] FX This work was supported by the American Heart Association (09FTF2220328 to Dr Baggish). NR 30 TC 20 Z9 21 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 30 PY 2013 VL 128 IS 5 BP 524 EP 531 DI 10.1161/CIRCULATIONAHA.113.003522 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 301LE UT WOS:000330533000012 PM 23897848 ER PT J AU Ullrich, NJ Kieran, MW Miller, DT Gordon, LB Cho, YJ Silvera, VM Giobbie-Hurder, A Neuberg, D Kleinman, ME AF Ullrich, Nicole J. Kieran, Mark W. Miller, David T. Gordon, Leslie B. Cho, Yoon-Jae Silvera, V. Michelle Giobbie-Hurder, Anita Neuberg, Donna Kleinman, Monica E. TI Neurologic features of Hutchinson-Gilford progeria syndrome after lonafarnib treatment SO NEUROLOGY LA English DT Article ID FARNESYLTRANSFERASE INHIBITOR; PHENOTYPE; DISEASE AB Objectives: The objective of this study was to retrospectively evaluate neurologic status pre-and posttreatment with the oral farnesyltransferase inhibitor lonafarnib in children with Hutchinson-Gilford progeria syndrome (HGPS), a rare, fatal disorder of segmental premature aging that results in early death by myocardial infarction or stroke. Methods: The primary outcome measure for intervention with lonafarnib was to assess increase over pretherapy in estimated annual rate of weight gain. In this study, neurologic signs and symptoms were compared pre-and posttreatment with lonafarnib. Results: Twenty-six participants were treated for a minimum of 2 years. Frequency of clinical strokes, headaches, and seizures was reduced from pretrial rates. Three patients with a history of frequent TIAs and average clinical stroke frequency of 1.75/year during the year before treatment experienced no new events during treatment. One patient with a history of stroke died due to large-vessel hemispheric stroke after 5 months on treatment. Headache prevalence and frequency were reduced. Four patients exhibited pretherapy seizures and no patients experienced recurrent or new-onset seizures Conclusions: This study provides preliminary evidence that lonafarnib therapy may improve neurologic status of children with HGPS. To address this question, we have incorporated prospective neuroimaging and neurologic assessments as measures in subsequent studies involving children with HGPS. Classification of evidence: This study provides Class IV evidence that lonafarnib 115-150 mg/m(2) for 24 to 29 months reduces the prevalence of stroke and TIA and the prevalence and frequency of headache over the treatment period. C1 [Ullrich, Nicole J.; Cho, Yoon-Jae] Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Kieran, Mark W.] Boston Childrens Hosp, Dept Hematol Oncol, Boston, MA USA. [Gordon, Leslie B.; Kleinman, Monica E.] Boston Childrens Hosp, Dept Anesthesia, Boston, MA USA. [Miller, David T.] Boston Childrens Hosp, Dept Genet, Boston, MA USA. [Silvera, V. Michelle] Boston Childrens Hosp, Dept Radiol, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. [Gordon, Leslie B.] Hasbro Childrens Hosp, Dept Pediat, Providence, RI USA. Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Giobbie-Hurder, Anita; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Ullrich, NJ (reprint author), Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. EM nicole.ullrich@childrens.harvard.edu OI Kieran, Mark/0000-0003-2184-7692 FU Progeria Research Foundation [PRFCLIN2007-01]; Dana-Farber Cancer Institute Stop & Shop Pediatric Brain Tumor Program; C.J. Buckley Fund; Kyle Johnson Fund; National Center for Research Resources, NIH [MO1-RR02172, UL1 RR025758-01] FX This project was funded by The Progeria Research Foundation (PRFCLIN2007-01), the Dana-Farber Cancer Institute Stop & Shop Pediatric Brain Tumor Program, the C.J. Buckley Fund, the Kyle Johnson Fund, by a National Center for Research Resources, NIH grant to the Children's Hospital Boston General Clinical Research Center (MO1-RR02172), and a grant from the National Center for Research Resources, NIH, to the Harvard Catalyst Clinical & Translational Science Center (Harvard Catalyst) (UL1 RR025758-01). NR 10 TC 8 Z9 9 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 30 PY 2013 VL 81 IS 5 BP 427 EP 430 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 304JB UT WOS:000330741800010 PM 23897869 ER PT J AU Frisoni, GB Bocchetta, M Chetelat, G Rabinovici, GD de Leon, MJ Kaye, J Reiman, EM Scheltens, P Barkhof, F Black, SE Brooks, DJ Carrillo, MC Fox, NC Herholz, K Nordberg, A Jack, CR Jagust, WJ Johnson, KA Rowe, CC Sperling, RA Thies, W Wahlund, LO Weiner, MW Pasqualetti, P DeCarli, C AF Frisoni, Giovanni B. Bocchetta, Martina Chetelat, Gael Rabinovici, Gil D. de Leon, Mony J. Kaye, Jeffrey Reiman, Eric M. Scheltens, Philip Barkhof, Frederik Black, Sandra E. Brooks, David J. Carrillo, Maria C. Fox, Nick C. Herholz, Karl Nordberg, Agneta Jack, Clifford R., Jr. Jagust, William J. Johnson, Keith A. Rowe, Christopher C. Sperling, Reisa A. Thies, William Wahlund, Lars-Olof Weiner, Michael W. Pasqualetti, Patrizio DeCarli, Charles CA ISTAART TI Imaging markers for Alzheimer disease Which vs how SO NEUROLOGY LA English DT Review ID MILD COGNITIVE IMPAIRMENT; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; ASSOCIATION WORKGROUPS; FDG-PET; DIFFERENTIAL-DIAGNOSIS; REVISED CRITERIA; DEMENTIA; RECOMMENDATIONS; BIOMARKERS AB Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, F-18-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR1 and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within F-18-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials. C1 [Frisoni, Giovanni B.; Bocchetta, Martina] IRCCS, LENITEM Lab Epidemiol Neuroimaging & Telemed, Brescia, Italy. [Chetelat, Gael] INSERM, U1077, Caen, France. [Chetelat, Gael] Univ Caen Basse Normandie, UMR S1077, Caen, France. [Chetelat, Gael] Ecole Prat Hautes Etud, UMR S1077, Caen, France. [Chetelat, Gael] CHU Caen, U1077, F-14000 Caen, France. [Rabinovici, Gil D.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. [Weiner, Michael W.; DeCarli, Charles] Univ Calif San Francisco, San Francisco, CA 94143 USA. [de Leon, Mony J.] NYU, Sch Med, Ctr Brain Hlth, New York, NY USA. [Kaye, Jeffrey] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Kaye, Jeffrey] Portland VA Med Ctr, Phoenix, AZ USA. [Reiman, Eric M.] Banner Alzheimers Inst, Phoenix, AZ USA. [Scheltens, Philip] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Scheltens, Philip] Vrije Univ Amsterdam, Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands. [Barkhof, Frederik] Vrije Univ Amsterdam, Med Ctr, Dept Radiol, Amsterdam, Netherlands. [Barkhof, Frederik] Vrije Univ Amsterdam, Med Ctr, Dept Nucl Med, Amsterdam, Netherlands. [Black, Sandra E.] Univ Toronto, Sunnybrook Res Inst, Dept Med Neurol, Toronto, ON, Canada. [Brooks, David J.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Div Brain Sci, London, England. [Brooks, David J.] Aarhus Univ, DK-8000 Aarhus C, Denmark. [Carrillo, Maria C.; Thies, William] Alzheimers Assoc, Med & Sci Relat, Chicago, IL USA. [Fox, Nick C.] UCL, Inst Neurol, London, England. [Herholz, Karl] Univ Manchester, Inst Brain Behav & Mental Hlth, Wolfson Mol Imaging Ctr, Manchester M13 9PL, Lancs, England. [Nordberg, Agneta] Karolinska Inst, Karolinska Univ Hosp Huddinge, Stockholm, Sweden. [Nordberg, Agneta] Karolinska Inst, Alzheimer Neurobiol Ctr, Stockholm, Sweden. [Jack, Clifford R., Jr.] Mayo Clin & Mayo Fdn, Dept Diagnost Radiol, Rochester, MN USA. [Jagust, William J.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Jagust, William J.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Johnson, Keith A.; Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. [Rowe, Christopher C.] Austin Hlth, Ctr PET, Dept Nucl Med, Melbourne, Vic, Australia. [Wahlund, Lars-Olof] Karolinska Inst, Div Clin Geriatr, NVS Dept, Stockholm, Sweden. [Weiner, Michael W.] San Francisco VA Med Ctr, Rome, Italy. [Pasqualetti, Patrizio] Fatebenefratelli Hosp, SeSMIT Serv Med Stat & Informat Technol, AFaR Fatebenefratelli Assoc Res, Rome, Italy. [Pasqualetti, Patrizio] IRCCS San Raffaele Pisana, Unit Clin & Mol Epidemiol, Rome, Italy. RP Frisoni, GB (reprint author), IRCCS, LENITEM Lab Epidemiol Neuroimaging & Telemed, Brescia, Italy. EM gfrisoni@fatebenefratelli.it RI Bocchetta, Martina/B-6331-2013; Fox, Nick/B-1319-2009; Jack, Clifford/F-2508-2010; Frisoni, Giovanni B/K-1360-2016; Chetelat, Gael/G-2316-2015; OI Bocchetta, Martina/0000-0003-1814-5024; Fox, Nick/0000-0002-6660-657X; Jack, Clifford/0000-0001-7916-622X; Frisoni, Giovanni B/0000-0002-6419-1753; Pasqualetti, Patrizio/0000-0001-5560-1979; Black, Sandra/0000-0001-7093-8289; Kaye, Jeffrey/0000-0002-9971-3478; Brooks, David/0000-0003-2602-2518 FU Alzheimer's Association [IIRG-10-174022] FX This study was partially funded by the Alzheimer's Association grant IIRG-10-174022, "A Harmonized Protocol for Hippocampal Volumetry: An EADC-ADNI Effort." NR 46 TC 68 Z9 69 U1 3 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 30 PY 2013 VL 81 IS 5 BP 487 EP 500 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA 304JB UT WOS:000330741800019 PM 23897875 ER PT J AU Samuel, R Daheron, L Liao, S Vardam, T Kamoun, WS Batista, A Buecker, C Schafer, R Han, XX Au, P Scadden, DT Duda, DG Fukumura, D Jain, RK AF Samuel, Rekha Daheron, Laurence Liao, Shan Vardam, Trupti Kamoun, Walid S. Batista, Ana Buecker, Christa Schaefer, Richard Han, Xiaoxing Au, Patrick Scadden, David T. Duda, Dan G. Fukumura, Dai Jain, Rakesh K. TI Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diabetes; vascular endothelial cells; reprogramming ID ENDOTHELIAL-CELLS; MYOCARDIAL-INFARCTION; REGENERATIVE MEDICINE; VASCULAR-PERMEABILITY; PERIPHERAL-BLOOD; IN-VIVO; EXPRESSION; DISEASE; DIFFERENTIATION; ANGIOGENESIS AB Efficient generation of competent vasculogenic cells is a critical challenge of human induced pluripotent stem (hiPS) cell-based regenerative medicine. Biologically relevant systems to assess functionality of the engineered vessels in vivo are equally important for such development. Here, we report a unique approach for the derivation of endothelial precursor cells from hiPS cells using a triple combination of selection markers-CD34, neuropilin 1, and human kinase insert domain-containing receptor-and an efficient 2D culture system for hiPS cell-derived endothelial precursor cell expansion. With these methods, we successfully generated endothelial cells (ECs) from hiPS cells obtained from healthy donors and formed stable functional blood vessels in vivo, lasting for 280 d in mice. In addition, we developed an approach to generate mesenchymal precursor cells (MPCs) from hiPS cells in parallel. Moreover, we successfully generated functional blood vessels in vivo using these ECs and MPCs derived from the same hiPS cell line. These data provide proof of the principle that autologous hiPS cell-derived vascular precursors can be used for in vivo applications, once safety and immunological issues of hiPS-based cellular therapy have been resolved. Additionally, the durability of hiPS-derived blood vessels in vivo demonstrates a potential translation of this approach in long-term vascularization for tissue engineering and treatment of vascular diseases. Of note, we have also successfully generated ECs and MPCs from type 1 diabetic patient-derived hiPS cell lines and use them to generate blood vessels in vivo, which is an important milestone toward clinical translation of this approach. C1 [Samuel, Rekha; Liao, Shan; Vardam, Trupti; Kamoun, Walid S.; Batista, Ana; Han, Xiaoxing; Au, Patrick; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Daheron, Laurence; Buecker, Christa; Schaefer, Richard] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Richard B Simches Res Ctr, Boston, MA 02114 USA. RP Fukumura, D (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. EM dai@steele.mgh.harvard.edu; jain@steele.mgh.harvard.edu OI Schafer, Richard/0000-0003-1530-7980; Buecker, Christa/0000-0003-3055-2642 FU Department of Biotechnology, Ministry of Science and Technology, Government of India; Tosteson Postdoctoral Fellowship; Charles A. King Trust Fellowship [K99HL111343-01A1]; Harvard Stem Cell Institute; National Institutes of Health [P01-CA080124]; Federal Share/National Cancer Institute Proton Beam Program Income Grants [R01-CA115767, R01-CA085140, R01-CA126642, R01CA159258, R01-CA096915]; American Cancer Society [120733-RSG-11-073-01-TBG] FX We thank Sylvie Roberge, Peigen Huang, Christina Koppel, Phyllis McNally, and Julia Kahn for outstanding technical assistance and Drs. Vikash Pal Singh Chauhan, Ravi Mylvaganam, and Matija Snuderl for help with the experiments. We also thank Dr. Douglas Melton for his generous gift of T1D-iPS cell lines and helpful scientific input on our manuscript. This work was supported by a fellowship from the Department of Biotechnology, Ministry of Science and Technology, Government of India (to R. Samuel); a Tosteson Postdoctoral Fellowship, Charles A. King Trust Fellowship, and Grant K99HL111343-01A1 (to S. L.); funds from the Harvard Stem Cell Institute; National Institutes of Health Grant P01-CA080124; Federal Share/National Cancer Institute Proton Beam Program Income Grants R01-CA115767, R01-CA085140, and R01-CA126642 (to R. K. J.), R01CA159258 (to D. G. D.), and R01-CA096915 (to D. F.); and American Cancer Society Grant 120733-RSG-11-073-01-TBG (to D.G.D.). NR 45 TC 48 Z9 53 U1 4 U2 37 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 JUL 30 PY 2013 VL 110 IS 31 BP 12774 EP 12779 DI 10.1073/pnas.1310675110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 191VH UT WOS:000322441500064 PM 23861493 ER PT J AU Donaldson, GC Mullerova, H Locantore, N Hurst, JR Calverley, PMA Vestbo, J Anzueto, A Wedzicha, JA AF Donaldson, Gavin C. Muellerova, Hanna Locantore, Nicholas Hurst, John R. Calverley, Peter M. A. Vestbo, Jorgen Anzueto, Antonio Wedzicha, Jadwiga A. TI Factors associated with change in exacerbation frequency in COPD SO RESPIRATORY RESEARCH LA English DT Article DE COPD; Exacerbations; Exacerbation frequency; Exacerbation phenotype ID OBSTRUCTIVE PULMONARY-DISEASE; LUNG-FUNCTION DECLINE; QUALITY-OF-LIFE; ECLIPSE COHORT; INFLAMMATORY MARKERS; TIME; POPULATION; SEVERITY; SYMPTOMS; DISTANCE AB Background: Patients with chronic obstructive pulmonary disease (COPD) can be categorized as having frequent (FE) or infrequent (IE) exacerbations depending on whether they respectively experience two or more, or one or zero exacerbations per year. Although most patients do not change category from year to year, some will, and the factors associated with this behaviour have not been examined. Methods: 1832 patients completing two year follow-up in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study were examined at baseline and then yearly. Exacerbations were defined by health care utilisation. Patient characteristics compared between those patients who did or did not change exacerbation category from year 1 to year 2. Findings: Between years 1 and 2, 221 patients (17%) changed from IE to FE and 210 patients (39%) from FE to IE. More severe disease was associated with changing from IE to FE and less severe disease from FE to IE. Over the preceding year, small falls in FEV1 and 6-minute walking distance were associated with changing from IE to FE, and small falls in platelet count associated with changing from FE to IE. Conclusion: No parameter clearly predicts an imminent change in exacerbation frequency category. C1 [Donaldson, Gavin C.; Wedzicha, Jadwiga A.] UCL Med Sch, Ctr Resp Med, London NW3 2PF, England. [Muellerova, Hanna] GlaxoSmithKline R&D, Uxbridge UB11 1BT, Middx, England. [Locantore, Nicholas] GlaxoSmithKline, Res Triangle Pk, NC USA. [Hurst, John R.] UCL, Ctr Inflammat & Tissue Repair, London, England. [Calverley, Peter M. A.] Aintree Univ Hosp NHS Fdn Trust, Sch Ageing & Chron Dis, Liverpool L9 7AL, Merseyside, England. [Vestbo, Jorgen] Odense Univ Hosp, Dept Resp Med, DK-5000 Odense, Denmark. [Vestbo, Jorgen] Univ Southern Denmark, Odense, Denmark. [Vestbo, Jorgen] Univ Manchester, Resp Res Grp, Sch Translat Med, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr, Pulm Sect, San Antonio, TX USA. [Anzueto, Antonio] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Donaldson, GC (reprint author), UCL Med Sch, Ctr Resp Med, Royal Free Campus,Rowland Hill St Hampstead, London NW3 2PF, England. EM g.donaldson@ucl.ac.uk OI Vestbo, Jorgen/0000-0001-6355-6362; Mullerova, Hana/0000-0002-0949-0101 FU GlaxoSmithKline FX This work was funded by GlaxoSmithKline. The authors acknowledge the principle investigators, steering and scientific committee of the ECLIPSE study. The authors would also like to thank the patients participating in the ECLIPSE study. NR 39 TC 21 Z9 21 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X J9 RESP RES JI Respir. Res. PD JUL 30 PY 2013 VL 14 AR 79 DI 10.1186/1465-9921-14-79 PG 9 WC Respiratory System SC Respiratory System GA 193ZX UT WOS:000322601100001 PM 23899210 ER PT J AU Pinto, DS Pride, YB AF Pinto, Duane S. Pride, Yuri B. TI Paved With Good Intentions and Marred by Half-Truths SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE cause of death; coronary intervention; mortality; public reporting; risk avoidance ID PERCUTANEOUS CORONARY INTERVENTION; OUTCOMES C1 [Pinto, Duane S.; Pride, Yuri B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Sch Med,Dept Med, Boston, MA 02215 USA. RP Pinto, DS (reprint author), Beth Israel Deaconess Med Ctr, 185 Pilgrim Rd,W Baker 4, Boston, MA 02215 USA. EM dpinto@bidmc.harvard.edu NR 7 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 30 PY 2013 VL 62 IS 5 BP 416 EP 417 DI 10.1016/j.jacc.2013.04.026 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 186SL UT WOS:000322064900004 PM 23665366 ER PT J AU Hanlon, CA Hartwell, KJ Canterberry, M Li, XB Owens, M LeMatty, T Prisciandaro, JJ Borckardt, J Brady, KT George, MS AF Hanlon, Colleen A. Hartwell, Karen J. Canterberry, Melanie Li, Xingbao Owens, Max LeMatty, Todd Prisciandaro, James J. Borckardt, Jeffrey Brady, Kathleen T. George, Mark S. TI Reduction of cue-induced craving through realtime neurofeedback in nicotine users: The role of region of interest selection and multiple visits SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Addiction; Prefrontal cortex; Cingulate ID SELF-CONTROL; SMOKING; ADDICTION; ACTIVATION; CESSATION; SMOKERS; LOCUS AB This multi-visit, real-time functional magnetic resonance imaging feedback study demonstrates that treatment-seeking smokers can effectively modulate their behavioral and brain responses to smoking cues. They are more effective at decreasing activity in functionally defined regions involved in "craving" (e.g. ventral anterior cingulate cortex (vACC)) rather than increasing activity in regions involved in "resisting" (e.g. dorsal medial prefrontal cortex (dmPFC)). (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Hanlon, Colleen A.; Hartwell, Karen J.; Canterberry, Melanie; Li, Xingbao; Owens, Max; LeMatty, Todd; Prisciandaro, James J.; Borckardt, Jeffrey; Brady, Kathleen T.; George, Mark S.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Brady, Kathleen T.; George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. RP Hanlon, CA (reprint author), Med Univ S Carolina, Dept Psychiat, Ctr Biomed Imaging, 67 President St, Charleston, SC 29425 USA. EM hanlon@musc.edu FU National Institutes of Health [K01DA027756, GA30523K, UL1 RR029882]; [R33DA026085] FX Funding was provided by R33DA026085 (Brady) with additional support from K01DA027756 (Hanlon), GA30523K and UL1 RR029882 (CSTA) from the National Institutes of Health. The authors received no compensation from other external organizations related to this manuscript. NR 16 TC 24 Z9 24 U1 1 U2 22 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUL 30 PY 2013 VL 213 IS 1 BP 79 EP 81 DI 10.1016/j.pscychresns.2013.03.003 PG 3 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 169DF UT WOS:000320756700011 PM 23683344 ER PT J AU Dai, J Brooks, Y Lefort, K Getsios, S Dotto, GP AF Dai, Jun Brooks, Yang Lefort, Karine Getsios, Spiro Dotto, G. Paolo TI The Retinoid-Related Orphan Receptor ROR alpha Promotes Keratinocyte Differentiation via FOXN1 SO PLOS ONE LA English DT Article ID LIGAND-BINDING DOMAIN; TERMINAL DIFFERENTIATION; NUCLEAR RECEPTOR; CHOLESTEROL SULFATE; HUMAN EPIDERMIS; STEM-CELLS; SKIN; NOTCH; GENE; EXPRESSION AB ROR alpha is a retinoid-related orphan nuclear receptor that regulates inflammation, lipid metabolism, and cellular differentiation of several non-epithelial tissues. In spite of its high expression in skin epithelium, its functions in this tissue remain unclear. Using gain- and loss-of-function approaches to alter ROR alpha gene expression in human keratinocytes (HKCs), we have found that this transcription factor functions as a regulator of epidermal differentiation. Among the 4 ROR alpha isoforms, ROR alpha 4 is prominently expressed by keratinocytes in a manner that increases with differentiation. In contrast, ROR alpha levels are significantly lower in skin squamous cell carcinoma tumors (SCCs) and cell lines. Increasing the levels of ROR alpha 4 in HKCs enhanced the expression of structural proteins associated with early and late differentiation, as well as genes involved in lipid barrier formation. Gene silencing of ROR alpha impaired the ability of keratinocytes to differentiate in an in vivo epidermal cyst model. The pro-differentiation function of ROR alpha is mediated at least in part by FOXN1, a well-known pro-differentiation transcription factor that we establish as a novel direct target of ROR alpha in keratinocytes. Our results point to ROR alpha as a novel node in the keratinocyte differentiation network and further suggest that the identification of ROR alpha ligands may prove useful for treating skin disorders that are associated with abnormal keratinocyte differentiation, including cancer. C1 [Dai, Jun; Brooks, Yang; Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Lefort, Karine] Univ Lausanne Hosp, Dept Dermatol, Epalinges, Switzerland. [Getsios, Spiro] Northwestern Univ, Dept Dermatol, Feinberg Sch Med, Chicago, IL 60611 USA. [Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. RP Dotto, GP (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. EM Paolo.Dotto@unil.ch RI Dai, Jun/J-9718-2015 FU National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS) [K01 AR062132, R01 AR039190, AR054856]; Swiss National Science Foundation [3100A0-122281/1, CRSI33-130576/1] FX This work was supported by grants from National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS) (K01 AR062132 to J.D. and R01 AR039190 and AR054856 to G. P. D.) and by the Swiss National Science Foundation (Grant 3100A0-122281/1; CRSI33-130576/1) to G. P. D. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 6 Z9 7 U1 0 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 JUL 29 PY 2013 VL 8 IS 7 AR e70392 DI 10.1371/journal.pone.0070392 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204MP UT WOS:000323369700181 PM 23922987 ER PT J AU Kaczmarek, E Bakker, JP Clarke, DN Csizmadia, E Kocher, O Veves, A Tecilazich, F O'Donnell, CP Ferran, C Malhotra, A AF Kaczmarek, Elzbieta Bakker, Jessie P. Clarke, Douglas N. Csizmadia, Eva Kocher, Olivier Veves, Aristidis Tecilazich, Francesco O'Donnell, Christopher P. Ferran, Christiane Malhotra, Atul TI Molecular Biomarkers of Vascular Dysfunction in Obstructive Sleep Apnea SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; NITRIC-OXIDE SYNTHASE; FACTOR-KAPPA-B; CELLULAR ADHESION MOLECULES; HYPOXIA-INDUCIBLE FACTOR-1; INTERMITTENT HYPOXIA; OXIDATIVE STRESS; GENE-EXPRESSION; IN-VIVO; DEPENDENT MECHANISM AB Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro) vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1 alpha?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO(2)]<75%) compared to mildly hypoxemic OSA patients (SaO(2) 75%-90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1 alpha expression in HMVEC, while increased A20, VCAM-1 and HIF-1 alpha expression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients. C1 [Kaczmarek, Elzbieta; Clarke, Douglas N.; Csizmadia, Eva; Ferran, Christiane] Harvard Univ, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Div Vasc & Endovasc Surg,Dept Surg,Med Sch, Boston, MA 02215 USA. [Bakker, Jessie P.; Malhotra, Atul] Harvard Univ, Brigham & Womens Hosp, Div Sleep Med, Sch Med, Boston, MA 02115 USA. [Kocher, Olivier] Harvard Univ, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Dept Pathol,Med Sch, Boston, MA 02215 USA. [Veves, Aristidis; Tecilazich, Francesco] Harvard Univ, Beth Israel Deaconess Med Ctr, Microcirculat Lab, Sch Med, Boston, MA 02215 USA. [Veves, Aristidis; Tecilazich, Francesco] Harvard Univ, Beth Israel Deaconess Med Ctr, Joslin Beth Israel Deaconess Foot Ctr, Dept Surg,Med Sch, Boston, MA 02215 USA. [O'Donnell, Christopher P.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Malhotra, Atul] Univ Calif San Diego, Div Pulm & Crit Care Med, La Jolla, CA 92093 USA. RP Kaczmarek, E (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Div Vasc & Endovasc Surg,Dept Surg,Med Sch, Boston, MA 02215 USA. EM ekaczmar@bidmc.harvard.edu FU National Institutes of Health (NIH) [HL106227, HL077785, HL080130, HL090897, HL093218, HL095491, HL110350, HL085188]; AHA [0840159N]; Harvard Catalyst [RR025758] FX This study was supported by grants from National Institutes of Health (NIH) (EK - HL106227; CPO - HL077785; CF - HL080130; AM - HL090897, HL093218, HL095491, HL110350, HL085188), AHA (AM - 0840159N), and Harvard Catalyst (AM - RR025758). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 21 Z9 21 U1 0 U2 10 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 JUL 29 PY 2013 VL 8 IS 7 AR e70559 DI 10.1371/journal.pone.0070559 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204MP UT WOS:000323369700194 PM 23923005 ER PT J AU Zhao, ZM Webb, BT Jia, PL Bigdeli, TB Maher, BS van den Oord, E Bergen, SE Amdur, RL O'Neill, FA Walsh, D Thiselton, DL Chen, XN Pato, CN Riley, BP Kendler, KS Fanous, AH AF Zhao, Zhongming Webb, Bradley T. Jia, Peilin Bigdeli, T. Bernard Maher, Brion S. van den Oord, Edwin Bergen, Sarah E. Amdur, Richard L. O'Neill, Francis A. Walsh, Dermot Thiselton, Dawn L. Chen, Xiangning Pato, Carlos N. Riley, Brien P. Kendler, Kenneth S. Fanous, Ayman H. CA Int Schizophrenia Consortium TI Association Study of 167 Candidate Genes for Schizophrenia Selected by a Multi-Domain Evidence-Based Prioritization Algorithm and Neurodevelopmental Hypothesis SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; CONVERGENT FUNCTIONAL GENOMICS; COMMON VARIANTS; BETA-CATENIN; NRG1 GENE; LINKAGE; METAANALYSIS; EXPRESSION; IMPUTATION; FAMILIES AB Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n = 3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein-protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene Ontology terms related to neurodevelopment. Subsequently, genotypes of 3725 SNPs in 167 genes from a custom Illumina iSelect array were used to evaluate the top ranked vs. hypothesis selected genes. Seventy-three genes were both highly ranked and involved in neurodevelopment (category 1) while 42 and 52 genes were exclusive to neurodevelopment (category 2) or highly ranked (category 3), respectively. The most significant associations were observed in genes PRKG1, PRKCE, and CNTN4 but no individual SNPs were significant after correction for multiple testing. Comparison of the approaches showed an excess of significant tests using the hypothesis-driven neurodevelopment category. Random selection of similar sized genes from two independent genome-wide association studies (GWAS) of schizophrenia showed the excess was unlikely by chance. In a further meta-analysis of three GWAS datasets, four candidate SNPs reached nominal significance. Although gene ranking using integrated sources of prior information did not enrich for significant results in the current experiment, gene selection using an a priori hypothesis (neurodevelopment) was superior to random selection. As such, further development of gene ranking strategies using more carefully selected sources of information is warranted. C1 [Zhao, Zhongming; Jia, Peilin] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA. [Zhao, Zhongming] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. [Webb, Bradley T.; Bigdeli, T. Bernard; van den Oord, Edwin; Thiselton, Dawn L.; Chen, Xiangning; Riley, Brien P.; Kendler, Kenneth S.; Fanous, Ayman H.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. [Webb, Bradley T.; van den Oord, Edwin] Virginia Commonwealth Univ, Ctr Biomarker Res & Personalized Med, Richmond, VA USA. [Maher, Brion S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Bergen, Sarah E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Bergen, Sarah E.] MIT, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. [Bergen, Sarah E.] Harvard, Cambridge, MA USA. [Amdur, Richard L.; Fanous, Ayman H.] Washington VA Med Ctr, Washington, DC USA. [O'Neill, Francis A.] Queens Univ, Dept Psychiat, Belfast, Antrim, North Ireland. [Walsh, Dermot] Hlth Res Board, Dublin, Ireland. [Chen, Xiangning; Riley, Brien P.; Kendler, Kenneth S.; Fanous, Ayman H.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Chen, Xiangning; Riley, Brien P.; Kendler, Kenneth S.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA. [Fanous, Ayman H.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Pato, Carlos N.; Fanous, Ayman H.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. RP Fanous, AH (reprint author), Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23284 USA. EM ayman.fanous@va.gov RI Webb, Bradley/B-1459-2009; OI Webb, Bradley/0000-0002-0576-5366; Bergen, Sarah/0000-0002-5888-0034; O'Neill, Francis Anthony/0000-0002-7531-7657 FU National Institute of Mental Health [N01 MH900001, MH074027]; Eli Lilly and Company; Department of Veterans Affairs Merit Review Program [1I01CX000278]; NARSAD Maltz Investigator Award; NARSAD Young Investigator Award FX Two dataset(s) used in the analyses described in this manuscript were obtained from the database of Genotype and Phenotype (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number [GAIN: phs000021.v2.p1, nonGAIN: phs00167.v1.p1]. For the GAIN dataset, the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. The CATIE dataset was approved to use in this analysis through the authors' application. This work was supported by Department of Veterans Affairs Merit Review Program (1I01CX000278, to AHF), 2009 NARSAD Maltz Investigator Award (to ZZ) and 2010 NARSAD Young Investigator Award (to PJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 3 Z9 3 U1 1 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 JUL 29 PY 2013 VL 8 IS 7 AR e67776 DI 10.1371/journal.pone.0067776 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204MP UT WOS:000323369700002 PM 23922650 ER PT J AU Sung, YJ Sheppard, CJR Barbastathis, G Ando, M Gupta, R AF Sung, Yongjin Sheppard, Colin J. R. Barbastathis, George Ando, Masami Gupta, Rajiv TI Full-wave approach for x-ray phase imaging SO OPTICS EXPRESS LA English DT Article ID DARK-FIELD; CONTRAST MICROTOMOGRAPHY; RYTOV APPROXIMATION; ARTICULAR-CARTILAGE; TOMOGRAPHY; DIFFRACTION; SCATTERING; RESOLUTION; ANALYZER AB We present a rigorous forward model for phase imaging of a 3-D object illuminated by a cone-shaped x-ray beam. Our model is based on a full-wave approach valid under the first Rytov approximation, and thus can be used with large and thick objects, e. g., luggage and human patients. We unify light-matter interaction and free-space propagation into an integrated wave optics framework. Therefore, our model can accurately calculate x-ray phase images formed with sources of arbitrary shape, and it can be effectively incorporated into x-ray phase tomography as a forward model. Within the best of our knowledge, this is the first non-paraxial, full-wave model for X-ray phase imaging. (C) 2013 Optical Society of America C1 [Sung, Yongjin; Barbastathis, George] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Sung, Yongjin; Gupta, Rajiv] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sung, Yongjin; Gupta, Rajiv] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Sheppard, Colin J. R.] Ist Italiano Tecnol, I-16163 Genoa, Italy. [Ando, Masami] Tokyo Univ Sci, Res Inst Sci & Technol, Noda, Chiba 2788510, Japan. RP Sung, YJ (reprint author), MIT, Dept Mech Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM yongjin.sung@gmail.com FU Department of Homeland Security's Science and Technology Directorate [HSHQDC-11-C-0083]; National Research Foundation of Singapore through the Singapore-MIT Alliance for Research and Technology Centre; DARPA AXiS program [N66001-11-4204, 1300217190] FX This work was supported by the Department of Homeland Security's Science and Technology Directorate through contract HSHQDC-11-C-0083, the National Research Foundation of Singapore through the Singapore-MIT Alliance for Research and Technology Centre, and the DARPA AXiS program (Grant No. N66001-11-4204, P.R. No. 1300217190). The experiment was performed under the approval of the PF User Association (PF-UA) at KEK under No. 2008S2-002, 2011G-672 for use of the Photon Factory. The authors thank Dr. Synho Do and Dr. Omid Khalilzadeh for helpful discussion. NR 37 TC 5 Z9 5 U1 1 U2 14 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUL 29 PY 2013 VL 21 IS 15 BP 17547 EP 17557 DI 10.1364/OE.21.017547 PG 11 WC Optics SC Optics GA 190UJ UT WOS:000322366300015 PM 23938626 ER PT J AU Mansour, MR Sanda, T Lawton, LN Li, XY Kreslavsky, T Novina, CD Brand, M Gutierrez, A Kelliher, MA Jamieson, CHM von Boehmer, H Young, RA Look, AT AF Mansour, Marc R. Sanda, Takaomi Lawton, Lee N. Li, Xiaoyu Kreslavsky, Taras Novina, Carl D. Brand, Marjorie Gutierrez, Alejandro Kelliher, Michelle A. Jamieson, Catriona H. M. von Boehmer, Harald Young, Richard A. Look, A. Thomas TI The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; GENE-EXPRESSION; TRANSCRIPTIONAL CONTROL; HUMAN GRANULOPOIESIS; UBIQUITIN LIGASE; HUMAN CANCERS; DIFFERENTIATION; SCL; MICRORNA-223; ONCOPROTEIN AB The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor. C1 [Mansour, Marc R.; Sanda, Takaomi; Gutierrez, Alejandro; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02216 USA. [Li, Xiaoyu; Kreslavsky, Taras; Novina, Carl D.; von Boehmer, Harald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02216 USA. [Mansour, Marc R.] UCL, Univ Coll London Canc Inst, Dept Haematol, London WC1E 6BT, England. [Sanda, Takaomi] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117599, Singapore. [Lawton, Lee N.; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Novina, Carl D.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Novina, Carl D.] MIT, Cambridge, MA 02142 USA. [Brand, Marjorie] Ottawa Hosp Res Inst, Sprott Ctr Stem Cell Res, Dept Regenerat Med, Ottawa, ON K1Y 4E9, Canada. [Brand, Marjorie] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5, Canada. [Gutierrez, Alejandro; Look, A. Thomas] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Kelliher, Michelle A.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. [Jamieson, Catriona H. M.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Jamieson, Catriona H. M.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02142 USA. RP Look, AT (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02216 USA. EM thomas_look@dfci.harvard.edu RI Young, Richard/F-6495-2012; OI Young, Richard/0000-0001-8855-8647; Gutierrez, Alejandro/0000-0002-0249-9007 FU Kay Kendall Leukaemia Fund of the UK; Team Path To the Cure grant; National Cancer Institute [5P01CA109901, 5P01CA68484, 1K99CA157951]; National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; William Lawrence and Blanche Hughes Foundation; Children's Leukemia Research Association; Japan Society for the Promotion of Science; NIH [1K08CA133103] FX This research was supported by the Kay Kendall Leukaemia Fund of the UK (M. R. Mansour), Team Path To the Cure grant (M. R. Mansour and A. T. Look), grants from the National Cancer Institute (5P01CA109901, 5P01CA68484, and 1K99CA157951), and by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. T. Sanda is supported by grants from the William Lawrence and Blanche Hughes Foundation, the Children's Leukemia Research Association and the Japan Society for the Promotion of Science. A. Gutierrez is supported by NIH grant 1K08CA133103 and is a Scholar of the American Society of Hematology-Amos Faculty Development Program. NR 52 TC 41 Z9 43 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 29 PY 2013 VL 210 IS 8 BP 1545 EP 1557 DI 10.1084/jem.20122516 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 190WG UT WOS:000322372800005 PM 23857984 ER PT J AU Jones, V Katiyar, SK AF Jones, Virginia Katiyar, Santosh K. TI Emerging phytochemicals for prevention of melanoma invasion SO CANCER LETTERS LA English DT Review DE Cyclooxygenase-2; Melanoma; Phytochemicals; Prostaglandins; beta-Catenin ID E-CADHERIN EXPRESSION; EPITHELIAL-MESENCHYMAL TRANSITION; HUMAN BREAST-CANCER; NF-KAPPA-B; BETA-CATENIN; MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; CELL-LINES; GREEN TEA; PANCREATIC-CARCINOMA AB Cutaneous malignant melanoma is the leading cause of death from skin diseases due to its propensity to metastasize. Once diagnosed with metastatic melanoma, most patients will die of their disease within 2 years. As suppression of metastases requires long-term interventions, potential anti-metastatic agents must not only be efficacious but also have low toxicity. Many phytochemicals used in traditional medicine have low toxicity and recent studies suggest that some are promising candidates for the prevention or treatment of metastatic melanoma. Here, we review the recent literature regarding phytochemicals that have shown inhibitory effects on melanoma cell migration or invasion. (c) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Jones, Virginia; Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Skin Dis Res Ctr, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Nutr Obes Res Ctr, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 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 [1I01BX001410]; National Institutes of Health/NCI [CA166883] FX The work reported from Dr. Katiyar's laboratory was supported by Veterans Administration Merit Review Award (1I01BX001410) and National Institutes of Health/NCI (CA166883). The content of this article does not necessarily reflect the views or policies of the funding sources. We thank Dr. Fiona Hunter for her assistance in editing the manuscript. NR 77 TC 9 Z9 9 U1 2 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUL 28 PY 2013 VL 335 IS 2 BP 251 EP 258 DI 10.1016/j.canlet.2013.02.056 PG 8 WC Oncology SC Oncology GA 168CE UT WOS:000320682500001 PM 23474498 ER PT J AU Briant, JA Kotton, CN AF Briant, Judith A. Kotton, Camille N. TI Two "Lost Boys of Sudan" Undergo Liver Transplantation: Infectious Disease Issues SO TRANSPLANTATION LA English DT Letter ID PRESUMPTIVE TREATMENT; SCHISTOSOMIASIS C1 [Briant, Judith A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kotton, Camille N.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Briant, JA (reprint author), 15 Parkman St,Wang 625, Boston, MA 02114 USA. EM jbriant@partners.org NR 7 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 27 PY 2013 VL 96 IS 2 BP E7 EP E9 DI 10.1097/TP.0b013e318297ae0e PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 299EO UT WOS:000330378600004 PM 23857005 ER PT J AU Kang, SA Pacold, ME Cervantes, CL Lim, D Lou, HJ Ottina, K Gray, NS Turk, BE Yaffe, MB Sabatini, DM AF Kang, Seong A. Pacold, Michael E. Cervantes, Christopher L. Lim, Daniel Lou, Hua Jane Ottina, Kathleen Gray, Nathanael S. Turk, Benjamin E. Yaffe, Michael B. Sabatini, David M. TI mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin SO SCIENCE LA English DT Article ID GENETICALLY HETEROGENEOUS MICE; MESSENGER-RNA TRANSLATION; EXTENDS LIFE-SPAN; MAMMALIAN TARGET; PROTEIN-KINASE; S6 KINASE; FKBP12-RAPAMYCIN COMPLEX; INHIBITION; AUTOPHAGY; PATHWAY AB The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin, as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals. C1 [Kang, Seong A.; Pacold, Michael E.; Cervantes, Christopher L.; Ottina, Kathleen; Sabatini, David M.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Kang, Seong A.; Pacold, Michael E.; Cervantes, Christopher L.; Ottina, Kathleen; Yaffe, Michael B.; Sabatini, David M.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Pacold, Michael E.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Pacold, Michael E.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Lim, Daniel; Yaffe, Michael B.; Sabatini, David M.] MIT, David H Koch Ctr Integrat Canc Res, Cambridge, MA 02139 USA. [Lou, Hua Jane; Turk, Benjamin E.] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. [Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Yaffe, Michael B.] Harvard Univ, Sch Med, Beth Israel Deaconess Hosp, Dept Surg, Boston, MA 02215 USA. RP Sabatini, DM (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM sabatini@wi.mit.edu FU NIH [CA103866, AI047389, ES015339, GM59281, CA112967]; Department of Defense [W81XWH-07-0448]; W.M. Keck Foundation; LAM (lymphangioleiomyomatosis) Foundation; American Cancer Society; LAM Foundation; Damon Runyon Cancer Research Foundation; Department of Defense Breast Cancer Research Program FX We thank members of the Sabatini laboratory for helpful discussions, especially S. Wang, D. Kim, C. Thoreen, T. Wang, and J. Cantor and E. Spooner for the mass spectrometric analysis of samples. We also thank M. Pende for the S6K1/2 null cells and R. Shaw and C. Thompson for the ULK1/2 null cells. This work was supported by grants from the NIH (CA103866 and AI047389 to D. M. S.; ES015339, GM59281, and CA112967 to M.B.Y.) and Department of Defense (W81XWH-07-0448 to D. M. S.); awards from the W.M. Keck Foundation and the LAM (lymphangioleiomyomatosis) Foundation to D. M. S.; fellowships from the American Cancer Society and the LAM Foundation to S. A. K. and the Damon Runyon Cancer Research Foundation and the Department of Defense Breast Cancer Research Program to M. E. P. D. M. S. is an investigator of the Howard Hughes Medical Institute. Torin1, the inhibitor used here, is part of a Whitehead-Dana-Farber Cancer Institute patent application on which S. A. K., N.S.G., and D. M. S. are inventors. Shared reagents are subject to a materials transfer agreement. NR 49 TC 115 Z9 118 U1 6 U2 31 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 JUL 26 PY 2013 VL 341 IS 6144 BP 364 EP + AR 1236566 DI 10.1126/science.1236566 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 189HX UT WOS:000322259200040 PM 23888043 ER PT J AU Galaleldeen, A Taylor, AB Chen, D Schuermann, JP Holloway, SP Hou, SP Gong, SQ Zhong, GM Hart, PJ AF Galaleldeen, Ahmad Taylor, Alexander B. Chen, Ding Schuermann, Jonathan P. Holloway, Stephen P. Hou, Shuping Gong, Siqi Zhong, Guangming Hart, P. John TI Structure of the Chlamydia trachomatis Immunodominant Antigen Pgp3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Bacterial Pathogenesis; Chlamydia; Immunology; Tumor Necrosis Factor (TNF); X-ray Crystallography; Beta-Helix; Beta-Propeller; Helical Coiled-coil; Pgp3; Sexually Transmitted Disease ID SEGMENTED COILED-COIL; TUMOR-NECROSIS-FACTOR; C-TERMINAL DOMAIN; CRYSTAL-STRUCTURE; BACTERIOPHAGE-T4 FIBRITIN; BACILLUS-ANTHRACIS; TRANSCRIPTIONAL REGULATOR; VIRULENCE FACTOR; PROTEIN; PLASMID AB Chlamydia trachomatis infection is the most common sexually transmitted bacterial disease. Left untreated, it can lead to ectopic pregnancy, pelvic inflammatory disease, and infertility. Here we present the structure of the secreted C. trachomatis protein Pgp3, an immunodominant antigen and putative virulence factor. The approximate to 84-kDa Pgp3 homotrimer, encoded on a cryptic plasmid, consists of globular N- and C-terminal assemblies connected by a triple-helical coiled-coil. The C-terminal domains possess folds similar to members of the TNF family of cytokines. The closest Pgp3 C-terminal domain structural homologs include a lectin from Burkholderia cenocepacia, the C1q component of complement, and a portion of the Bacillus anthracis spore surface protein BclA, all of which play roles in bioadhesion. The N-terminal domain consists of a concatenation of structural motifs typically found in trimeric viral proteins. The central parallel triple-helical coiled-coil contains an unusual alternating pattern of apolar and polar residue pairs that generate a rare right-handed superhelical twist. The unique architecture of Pgp3 provides the basis for understanding its role in chlamydial pathogenesis and serves as the platform for its optimization as a potential vaccine antigen candidate. C1 [Galaleldeen, Ahmad; Taylor, Alexander B.; Holloway, Stephen P.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Chen, Ding; Hou, Shuping; Gong, Siqi; Zhong, Guangming] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Galaleldeen, Ahmad] St Marys Univ, Dept Biol Sci, San Antonio, TX 78228 USA. [Schuermann, Jonathan P.] Cornell Univ, Dept Chem & Chem Biol, Northeastern Collaborat Access Team, Ithaca, NY 14853 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. RP Zhong, GM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol, San Antonio, TX 78229 USA. EM zhongg@uthscsa.edu; pjhart@biochem.uthscsa.edu FU National Institutes of Health [AI47997, AI64537]; Robert A. Welch Foundation [AQ-1399]; National Center for Research Resources at the National Institute of Health [RR-15301]; U.S. Department of Energy, Office of Basic Energy Sciences [W-31-109-ENG-38]; Cancer Therapy & Research Center Cancer Center [NCI P30CA054174]; United States Department of Defense to the UTSA/UTHSCSA Center for Excellence in Genomics Research [W911NF-11-1-0136] FX This work was supported, in whole or in part, by National Institutes of Health Grants AI47997 and AI64537 (to G.Z.). This work was also supported by Robert A. Welch Foundation Grant AQ-1399 (to P.J.H.). This work is partially the result of research conducted at the Northeastern Collaborative Access Team beamlines of the Advanced Photon Source, supported by Award RR-15301 from the National Center for Research Resources at the National Institute of Health. Use of the Advanced Photon Source is supported by the U.S. Department of Energy, Office of Basic Energy Sciences under Contract W-31-109-ENG-38. This work was also supported in part by Cancer Therapy & Research Center Cancer Center Support Grant NCI P30CA054174 and Contract Number W911NF-11-1-0136 from the United States Department of Defense to the UTSA/UTHSCSA Center for Excellence in Genomics Research. NR 76 TC 6 Z9 8 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 26 PY 2013 VL 288 IS 30 BP 22068 EP 22079 DI 10.1074/jbc.M113.475012 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 277TJ UT WOS:000328841900052 PM 23703617 ER PT J AU Fernandez, TF Samal, AB Bedwell, GJ Chen, YB Saad, JS AF Fernandez, Timothy F. Samal, Alexandra B. Bedwell, Gregory J. Chen, Yabing Saad, Jamil S. TI Structural and Biophysical Characterization of the Interactions between the Death Domain of Fas Receptor and Calmodulin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Apoptosis; Calmodulin; Fas; NMR; Surface Plasmon Resonance (SPR); Cholangiocarcinoma ID SIZE-DISTRIBUTION ANALYSIS; HIV-1 MATRIX PROTEIN; CHOLANGIOCARCINOMA CELLS; ANALYTICAL ULTRACENTRIFUGATION; TARGET RECOGNITION; BINDING DOMAIN; PEPTIDE INTERACTION; MEDIATED APOPTOSIS; INHIBITORY PROTEIN; NMR-SPECTROSCOPY AB The extrinsic apoptotic pathway is initiated by cell surface death receptors such as Fas. Engagement of Fas by Fas ligand triggers a conformational change that allows Fas to interact with adaptor protein Fas-associated death domain (FADD) via the death domain, which recruits downstream signaling proteins to form the death-inducing signaling complex (DISC). Previous studies have shown that calmodulin (CaM) is recruited into the DISC in cholangiocarcinoma cells, suggesting a novel role of CaM in Fas-mediated signaling. CaM antagonists induce apoptosis through a Fas-related mechanism in cholangiocarcinoma and other cancer cell lines possibly by inhibiting Fas-CaM interactions. The structural determinants of Fas-CaM interaction and the underlying molecular mechanisms of inhibition, however, are unknown. Here we employed NMR and biophysical techniques to elucidate these mechanisms. Our data show that CaM binds to the death domain of Fas (FasDD) with an apparent dissociation constant (K-d) of approximate to 2 m and 2:1 CaM:FasDD stoichiometry. The interactions between FasDD and CaM are endothermic and entropically driven, suggesting that hydrophobic contacts are critical for binding. We also show that both the N- and C-terminal lobes of CaM are important for binding. NMR and surface plasmon resonance data show that three CaM antagonists (N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide, tamoxifen, and trifluoperazine) greatly inhibit Fas-CaM interactions by blocking the Fas-binding site on CaM. Our findings provide the first structural evidence for Fas-CaM interactions and mechanism of inhibition and provide new insight into the molecular basis for a novel role of CaM in regulating Fas-mediated apoptosis. C1 [Fernandez, Timothy F.; Samal, Alexandra B.; Bedwell, Gregory J.; Saad, Jamil S.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Chen, Yabing] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Chen, Yabing] Birmingham Vet Affairs Med Ctr, Res Dept, Birmingham, AL 35294 USA. RP Saad, JS (reprint author), 845 19th St S, Birmingham, AL 35294 USA. EM saad@uab.edu FU NCI, National Institutes of Health (NIH) [P30CA13148]; NIH [1S10RR026478] FX We thank members of our laboratories and Dr. Jay McDonald (University of Alabama at Birmingham) for helpful discussions. We thank Diego Esposito and Paul Driscoll (Medical Research Council National Institute for Medical Research, United Kingdom) for providing NMR signal assignments of FasDD. We thank the University of Alabama Comprehensive Cancer Center X-ray core facility, funded by NCI, National Institutes of Health (NIH) Grant P30CA13148, which houses the Auto-ITC200, acquired through NIH Grant 1S10RR026478. NR 68 TC 11 Z9 11 U1 0 U2 7 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 JUL 26 PY 2013 VL 288 IS 30 AR 21898 DI 10.1074/jbc.M113.471821 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 277TJ UT WOS:000328841900038 PM 23760276 ER PT J AU Izamis, ML Tolboom, H Uygun, B Berthiaume, F Yarmush, ML Uygun, K AF Izamis, Maria-Louisa Tolboom, Herman Uygun, Basak Berthiaume, Francois Yarmush, Martin L. Uygun, Korkut TI Resuscitation of Ischemic Donor Livers with Normothermic Machine Perfusion: A Metabolic Flux Analysis of Treatment in Rats SO PLOS ONE LA English DT Article ID ACTIVATED PROTEIN-KINASE; CYTOCHROME-C-OXIDASE; FATTY-ACID OXIDATION; NITRIC-OXIDE; REPERFUSION INJURY; CULTURED-HEPATOCYTES; MITOCHONDRIAL RESPIRATION; EXTRACORPOREAL PERFUSION; COLD-STORAGE; TRANSPLANTATION AB Normothermic machine perfusion has previously been demonstrated to restore damaged warm ischemic livers to transplantable condition in animal models. However, the mechanisms of recovery are unclear, preventing rational optimization of perfusion systems and slowing clinical translation of machine perfusion. In this study, organ recovery time and major perfusate shortcomings were evaluated using a comprehensive metabolic analysis of organ function in perfusion prior to successful transplantation. Two groups, Fresh livers and livers subjected to 1 hr of warm ischemia (WI) received perfusion for a total preservation time of 6 hrs, followed by successful transplantation. 24 metabolic fluxes were directly measured and 38 stoichiometrically-related fluxes were estimated via a mass balance model of the major pathways of energy metabolism. This analysis revealed stable metabolism in Fresh livers throughout perfusion while identifying two distinct metabolic states in WI livers, separated at t = 2 hrs, coinciding with recovery of oxygen uptake rates to Fresh liver values. This finding strongly suggests successful organ resuscitation within 2 hrs of perfusion. Overall perfused livers regulated metabolism of perfusate substrates according to their metabolic needs, despite supraphysiological levels of some metabolites. This study establishes the first integrative metabolic basis for the dynamics of recovery during perfusion treatment of marginal livers. Our initial findings support enhanced oxygen delivery for both timely recovery and long-term sustenance. These results are expected to lead the optimization of the treatment protocols and perfusion media from a metabolic perspective, facilitating translation to clinical use. C1 [Izamis, Maria-Louisa; Uygun, Basak; Yarmush, Martin L.; Uygun, Korkut] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Izamis, Maria-Louisa; Uygun, Basak; Yarmush, Martin L.; Uygun, Korkut] Shriners Hosp Children, Boston, MA USA. [Tolboom, Herman] Univ Zurich Hosp, Div Cardiac & Vasc Surg, CH-8091 Zurich, Switzerland. [Berthiaume, Francois; Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. RP Uygun, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. EM uygun.korkut@mgh.harvard.edu RI Uygun, Basak/I-1792-2012 OI Uygun, Basak/0000-0002-2600-7900 FU National Institutes of Health [R01DK096075, R01EB008678, R00DK080942, K99DK088962]; Shriners Hospitals for Children FX This work was supported by grants from the National Institutes of Health (R01DK096075, R01EB008678, R00DK080942, K99DK088962), and the Shriners Hospitals for Children. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 11 Z9 13 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 JUL 26 PY 2013 VL 8 IS 7 AR e69758 DI 10.1371/journal.pone.0069758 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 197GU UT WOS:000322838900078 PM 23922793 ER PT J AU Saeidi, N Meoli, L Nestoridi, E Gupta, NK Kvas, S Kucharczyk, J Bonab, AA Fischman, AJ Yarmush, ML Stylopoulos, N AF Saeidi, Nima Meoli, Luca Nestoridi, Eirini Gupta, Nitin K. Kvas, Stephanie Kucharczyk, John Bonab, Ali A. Fischman, Alan J. Yarmush, Martin L. Stylopoulos, Nicholas TI Reprogramming of Intestinal Glucose Metabolism and Glycemic Control in Rats After Gastric Bypass SO SCIENCE LA English DT Article ID BARIATRIC SURGERY; INSULIN SENSITIVITY; CELL-PROLIFERATION; MEDICAL THERAPY; TRANSPORT; MODEL; MICE AB The resolution of type 2 diabetes after Roux-en-Y gastric bypass (RYGB) attests to the important role of the gastrointestinal tract in glucose homeostasis. Previous studies in RYGB-treated rats have shown that the Roux limb displays hyperplasia and hypertrophy. Here, we report that the Roux limb of RYGB-treated rats exhibits reprogramming of intestinal glucose metabolism to meet its increased bioenergetic demands; glucose transporter-1 is up-regulated, basolateral glucose uptake is enhanced, aerobic glycolysis is augmented, and glucose is directed toward metabolic pathways that support tissue growth. We show that reprogramming of intestinal glucose metabolism is triggered by the exposure of the Roux limb to undigested nutrients. We demonstrate by positron emission tomography-computed tomography scanning and biodistribution analysis using 2-deoxy-2-[18F]fluoro-D-glucose that reprogramming of intestinal glucose metabolism renders the intestine a major tissue for glucose disposal, contributing to the improvement in glycemic control after RYGB. C1 [Saeidi, Nima; Meoli, Luca; Nestoridi, Eirini; Gupta, Nitin K.; Kvas, Stephanie; Kucharczyk, John; Stylopoulos, Nicholas] Harvard Univ, Sch Med, Ctr Basic & Translat Obes Res, Div Endocrinol,Boston Childrens Hosp, Boston, MA 02115 USA. [Saeidi, Nima; Bonab, Ali A.; Fischman, Alan J.; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA 02114 USA. [Saeidi, Nima; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. RP Stylopoulos, N (reprint author), Harvard Univ, Sch Med, Ctr Basic & Translat Obes Res, Div Endocrinol,Boston Childrens Hosp, Boston, MA 02115 USA. EM Nicholas.Stylopoulos@childrens.harvard.edu RI Gupta, Nitin/A-1076-2016 OI Gupta, Nitin/0000-0002-4471-2363 FU Department of Medicine; Clinical and Translational Executive Committee at Boston Children's Hospital; National Institutes of Health (NIH) [T32DK007191, F32DK095558]; NIH [DK089503] FX We thank N. Li for help with tissue sectioning, G. Gorski for help with electron microscopy, M. Markle and M. Luitje for help with biodistribution analysis, and A. Moses for help with lipid analysis. This research was supported by funds from the Department of Medicine and the Clinical and Translational Executive Committee at Boston Children's Hospital (N. Stylopoulos) and grants T32DK007191 (N. K. G.) and F32DK095558 (N. Saeidi) from the National Institutes of Health (NIH). We used the core services of the Lipidomics Lab at the Nutrition Obesity Research Center of the University of Michigan (Ann Arbor, MI), which is supported by grant DK089503 from NIH. NR 31 TC 112 Z9 116 U1 1 U2 54 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 JUL 26 PY 2013 VL 341 IS 6144 BP 406 EP 410 DI 10.1126/science.1235103 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 189HX UT WOS:000322259200052 PM 23888041 ER PT J AU Edwards, AL Gavathiotis, E LaBelle, JL Braun, CR Opoku-Nsiah, KA Bird, GH Walensky, LD AF Edwards, Amanda L. Gavathiotis, Evripidis LaBelle, James L. Braun, Craig R. Opoku-Nsiah, Kwadwo A. Bird, Gregory H. Walensky, Loren D. TI Multimodal Interaction with BCL-2 Family Proteins Underlies the Proapoptotic Activity of PUMA BH3 SO CHEMISTRY & BIOLOGY LA English DT Article ID STABILIZED ALPHA-HELICES; BH3-ONLY PROTEINS; INDUCED APOPTOSIS; CELL-DEATH; BAX ACTIVATION; MITOCHONDRIAL APOPTOSIS; CONFORMATIONAL-CHANGE; NEURONAL APOPTOSIS; PROMOTE APOPTOSIS; IN-VIVO AB PUMA is a proapoptotic BCL-2 family member that drives the apoptotic response to a diversity of cellular insults. Deciphering the spectrum of PUMA interactions that confer its context-dependent proapoptotic properties remains a high priority goal. Here, we report the synthesis of PUMA SAHBs, structurally stabilized PUMA BH3 helices that, in addition to broadly targeting antiapoptotic proteins, directly bind to proapoptotic BAX. NMR, photocrosslinking, and biochemical analyses revealed that PUMA SAHBs engage an alpha 1/alpha 6 trigger site on BAX to initiate its functional activation. We further demonstrated that a cell-permeable PUMA SAHB analog induces apoptosis in neuroblastoma cells and, like expressed PUMA protein, engages BCL-2, MCL-1, and BAX. Thus, we find that PUMA BH3 is a dual antiapoptotic inhibitor and proapoptotic direct activator, and its mimetics may serve as effective pharmacologic triggers of apoptosis in resistant human cancers. C1 [Edwards, Amanda L.; Gavathiotis, Evripidis; LaBelle, James L.; Braun, Craig R.; Opoku-Nsiah, Kwadwo A.; Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Linde Program Canc Chem Biol, Dept Pediat Oncol, Boston, MA 02215 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Linde Program Canc Chem Biol, Dept Pediat Oncol, Boston, MA 02215 USA. EM loren_walensky@dfci.harvard.edu FU National Institutes of Health [5R01CA050239, 5R01GM090299]; Stand Up to Cancer Innovative Research Grant; National Science Foundation Graduate Research Fellowship FX We thank E. Smith for editorial and graphics assistance, R. George and T. Look for neuroblastoma cell lines, and D. Andrews for guidance on the liposomal assay system. This work was supported by grants from the National Institutes of Health (5R01CA050239 and 5R01GM090299), a Stand Up to Cancer Innovative Research Grant (to L.D.W.), and a National Science Foundation Graduate Research Fellowship (to A.L.E.). L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics. NR 66 TC 29 Z9 30 U1 0 U2 11 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 JUL 25 PY 2013 VL 20 IS 7 BP 888 EP 902 DI 10.1016/j.chembiol.2013.06.007 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 195FL UT WOS:000322687600006 PM 23890007 ER PT J AU Ballen, KK Gluckman, E Broxmeyer, HE AF Ballen, Karen K. Gluckman, Eliane Broxmeyer, Hal E. TI Umbilical cord blood transplantation: the first 25 years and beyond SO BLOOD LA English DT Review ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; MYELOABLATIVE CONDITIONING REGIMEN; MULTIPOTENTIAL PROGENITOR CELLS; VERSUS-HOST-DISEASE; ANTI-HLA ANTIBODIES; HEMATOPOIETIC STEM; UNRELATED DONOR; ACUTE-LEUKEMIA; FANCONI-ANEMIA AB Umbilical cord blood is an alternative hematopoietic stem cell source for patients with hematologic diseases who can be cured by allogeneic hematopoietic cell transplantation. Initially, umbilical cord blood transplantation was limited to children, given the low cell dose infused. Both related and unrelated cord blood transplants have been performed with high rates of success for a variety of hematologic disorders and metabolic storage diseases in the pediatric setting. The results for adult umbilical cord blood transplantation have improved, with greater emphasis on cord blood units of sufficient cell dose and human leukocyte antigen match and with the use of double umbilical cord blood units and improved supportive care techniques. Cord blood expansion trials have recently shown improvement in time to engraftment. Umbilical cord blood is being compared with other graft sources in both retrospective and prospective trials. The growth of the field over the last 25 years and the plans for future exploration are discussed. C1 [Ballen, Karen K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Gluckman, Eliane] Univ Paris Diderot, Eurocord Hosp St Louis, APHP, Paris, France. [Broxmeyer, Hal E.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Ballen, KK (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Suite 118, Boston, MA 02114 USA. EM kballen@partners.org FU NHLBI NIH HHS [R01 HL067384, R01 HL112669] NR 97 TC 163 Z9 168 U1 5 U2 29 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 25 PY 2013 VL 122 IS 4 BP 491 EP 498 DI 10.1182/blood-2013-02-453175 PG 8 WC Hematology SC Hematology GA 196RD UT WOS:000322792300009 PM 23673863 ER PT J AU Salzer, WL Asselin, B Supko, JG Devidas, M Kaiser, NA Plourde, P Winick, NJ Reaman, GH Raetz, E Carroll, WL Hunger, SP AF Salzer, Wanda L. Asselin, Barbara Supko, Jeffrey G. Devidas, Meenakshi Kaiser, Nicole A. Plourde, Paul Winick, Naomi J. Reaman, Gregory H. Raetz, Elizabeth Carroll, William L. Hunger, Stephen P. TI Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children's Oncology Group SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ESCHERICHIA-COLI-ASPARAGINASE; ACUTE LYMPHOCYTIC-LEUKEMIA; CANCER-STUDY-GROUP; CEREBROSPINAL-FLUID; E. COLI; INTENSIVE ASPARAGINASE; PEG-ASPARAGINASE; SINGLE-AGENT; PHARMACOKINETICS AB AALL07P2 evaluated whether substitution of Erwinia asparaginase 25 000 IU/m(2) for 6 doses given intramuscularly Monday/Wednesday/Friday (M/W/F) to children and young adults with acute lymphoblastic leukemia and clinical allergy to pegaspargase would provide a 48-hour nadir serum asparaginase activity (NSAA) >= 0.10 IU/mL. AALL07P2 enrolled 55 eligible/evaluable patients. NSAA >= 0.1 IU/mL was achieved in 38 of 41 patients (92.7%) with acceptable samples 48 hours and in 38 of 43 patients (88.4%) 72 hours after dosing during course 1. Among samples obtained during all courses, 95.8% (252 of 263) of 48-hour samples and 84.5% (125 of 148) of 72-hour samples had NSAA >= 0.10-IU/mL. Pharmacokinetic parameters were estimated by fitting the serum asparaginase activity-time course for all 6 doses given during course 1 to a 1-compartment open model with first order absorption. Erwinia asparaginase administered with this schedule achieved therapeutic NSAA at both 48 and 72 hours and was well tolerated with no reports of hemorrhage, thrombosis, or death, and few cases of grade 2 to 3 allergic reaction (n = 6), grade 1 to 3 hyperglycemia (n = 6), or grade 1 pancreatitis (n = 1). Following allergy to pegaspargase, Erwinia asparaginase 25 000 IU/m(2) x 6 intramuscularly M/W/F can be substituted for a single dose of pegaspargase. C1 [Salzer, Wanda L.] US Army Med Res & Mat Command, Ft Detrick, MD 21702 USA. [Asselin, Barbara] Univ Rochester, Sch Med, Dept Pediat, Golisano Childrens Hosp,Med Ctr, Rochester, NY 14642 USA. [Supko, Jeffrey G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Devidas, Meenakshi] Univ Florida, Dept Biostat, Coll Med, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA. [Kaiser, Nicole A.; Hunger, Stephen P.] Childrens Hosp Colorado, Aurora, CO USA. [Plourde, Paul] EUSA Pharma, Langhorne, PA USA. [Winick, Naomi J.] Univ Texas SW Med Ctr Dallas, Div Pediat Hematol Oncol, Dallas, TX 75390 USA. [Reaman, Gregory H.] Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. [Raetz, Elizabeth] NYU, Langone Med Ctr, New York, NY USA. [Carroll, William L.] NYU, Inst Canc, New York, NY USA. [Hunger, Stephen P.] Univ Colorado, Dept Pediat, Sch Med, Aurora, CO USA. [Hunger, Stephen P.] Childrens Hosp Colorado, Aurora, CO USA. RP Salzer, WL (reprint author), US Army Med Res & Mat Command, Combat Casualty Care Res Program, 504 Scott St, Ft Detrick, MD 21702 USA. EM wanda.l.salzer.mil@mail.mil FU National Institutes of Health [CA13539, CA98543] FX This work was supported by grants CA13539 and CA98543 from the National Institutes of Health and a research agreement with Jazz Pharma, Inc (Langhorne, PA), formerly EUSA Pharma, Inc. S. P. H. is the Ergen Family Chair in Pediatric Cancer. NR 50 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 25 PY 2013 VL 122 IS 4 BP 507 EP 514 DI 10.1182/blood-2013-01-480822 PG 8 WC Hematology SC Hematology GA 196RD UT WOS:000322792300011 PM 23741010 ER PT J AU Huik, K Avi, R Carrillo, A Harper, N Pauskar, M Sadam, M Karki, T Krispin, T Kongo, UK Jermilova, T Ruutel, K Talu, A Abel-Ollo, K Uuskula, A Ahuja, SK He, WJ Lutsar, I AF Huik, Kristi Avi, Radko Carrillo, Andrew Harper, Nathan Pauskar, Merit Sadam, Maarja Karki, Tonis Krispin, Tonu Kongo, Ulvi-Kaire Jermilova, Tatiana Rueuetel, Kristi Talu, Ave Abel-Ollo, Katri Uuskuela, Anneli Ahuja, Sunil K. He, Weijing Lutsar, Irja TI CCR5 Haplotypes Influence HCV Serostatus in Caucasian Intravenous Drug Users SO PLOS ONE LA English DT Article ID CHRONIC HEPATITIS-C; HUMAN-IMMUNODEFICIENCY-VIRUS; DISEASE PROGRESSION; HIV-1 INFECTION; INJECT DRUGS; CHEMOKINE; EXPRESSION; CCR5-DELTA-32; ASSOCIATION; FREQUENCY AB Background: Up to 90% HIV-1 positive intravenous drug users (IDUs) are co-infected with HCV. Although best recognized for its function as a major co-receptor for cell entry of HIV, CC chemokine receptor 5 (CCR5) has also been implicated in the pathogenesis of HCV infection. Here, we investigated whether CCR5 haplotypes influence HIV-1 and HCV seropositivity among 373 Caucasian IDUs from Estonia. Methods: Of these IDUs, 56% and 44% were HIV and HCV seropositive, respectively, and 47% were coinfected. 500 blood donors seronegative for HIV and HCV were also evaluated. CCR5 haplotypes (HHA to HHG*2) were derived after genotyping nine CCR2-CCR5 polymorphisms. The association between CCR5 haplotypes with HIV and/or HCV seropositivity was determined using logistic regression analysis. Co-variates included in the models were length of intravenous drug use, HBV serostatus and copy number of CCL3L1, the gene encoding the most potent HIV-suppressive chemokine and ligand for CCR5. Results: Compared to IDUs seronegative for both HCV and HIV (HCV2/HIV-), IDUs who were HCV+/HIV- and HCV+/HIV+ were 92% and 82%, respectively, less likely to possess the CCR5-HHG*1 haplotype, after controlling for co-variates (P-adjusted = 1.89x10(-4) and 0.003, respectively). This association was mostly due to subjects bearing the CCR5 HHE and HHG*1 haplotype pairs. Approximately 25% and < 10% of HCV-/HIV- IDUs and HCV2/HIV- blood donors, respectively, possessed the HHE/HHG*1 genotype. Conclusions: Our findings suggest that HHG*1-bearing CCR5 genotypes influence HCV seropositivity in a group of Caucasian IDUs. C1 [Huik, Kristi; Avi, Radko; Pauskar, Merit; Sadam, Maarja; Karki, Tonis; Krispin, Tonu; Lutsar, Irja] Univ Tartu, Fac Med, Dept Microbiol, EE-50090 Tartu, Estonia. [Carrillo, Andrew; Harper, Nathan; Ahuja, Sunil K.; He, Weijing] South Texas Vet Hlth Care Syst, Vet Adm Res Ctr AIDS & HIV 1 Infect, San Antonio, TX USA. [Carrillo, Andrew; Harper, Nathan; Ahuja, Sunil K.; He, Weijing] South Texas Vet Hlth Care Syst, Ctr Personalized Med, San Antonio, TX USA. [Carrillo, Andrew; Harper, Nathan; Ahuja, Sunil K.; He, Weijing] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Kongo, Ulvi-Kaire] North Estonia Med Ctr Fdn, Immunoheamatol Reference Lab, Tallinn, Estonia. [Jermilova, Tatiana] Blood Ctr Kohtla Jarve, Kohtla Jarve, Estonia. [Rueuetel, Kristi; Talu, Ave; Abel-Ollo, Katri] Natl Inst Hlth Dev, Tallinn, Estonia. [Uuskuela, Anneli] Univ Tartu, Fac Med, Dept Publ Hlth, EE-50090 Tartu, Estonia. RP He, WJ (reprint author), South Texas Vet Hlth Care Syst, Vet Adm Res Ctr AIDS & HIV 1 Infect, San Antonio, TX USA. EM hew@uthscsa.edu; Irja.Lutsar@ut.ee RI lutsar, irja/H-3177-2015; Uuskula, Anneli/H-3303-2015 FU Veterans Affairs (VA) Center for AIDS and HIV Infection; VA Center for Personalized Medicine of the South Texas Veterans Health Care System; National Institutes of Health (NIH) [R37AI046326]; Doris Duke Distinguished Clinical Scientist Award; VA MERIT award; Elizabeth Glaser Pediatric AIDS Foundation; Max and Minnie Tomerlin Voelcker Fund; European Union through the European Regional Development Fund; Estonian Science Foundation [8004, 8415, 8856]; Basic Financing and the Target Financing of Estonian Ministry of Education and Research [SF0180004s12]; European Commission funded project Expanding Network for Comprehensive; Coordinated Action on HIV/AIDS prevention among IDUs and Bridging Population [2005305]; Global Fund; National HIV/AIDS Strategy; US Civilian Research Development Foundation [ESX0-2722-TA06]; US National Institutes of Health, National Institute on Drug Abuse [R01DA03574]; Archimedes Foundation and Norwegian Financial Mechanism/ EEA [EE0016] FX The work at San Antonio was supported by the Veterans Affairs (VA) Center for AIDS and HIV Infection and VA Center for Personalized Medicine of the South Texas Veterans Health Care System, a National Institutes of Health (NIH) MERIT grant (R37AI046326), and the Doris Duke Distinguished Clinical Scientist Award to S.K.A. S.K.A. is also supported by a VA MERIT award, the Elizabeth Glaser Pediatric AIDS Foundation, the Burroughs Welcome Clinical Scientist Award in Translational Research and the Senior Scholar Award from the Max and Minnie Tomerlin Voelcker Fund. The work at Estonia was supported by European Union through the European Regional Development Fund; Estonian Science Foundation (grants 8004, 8415 and 8856); Basic Financing and the Target Financing of Estonian Ministry of Education and Research (SF0180004s12); European Commission funded project Expanding Network for Comprehensive and Coordinated Action on HIV/AIDS prevention among IDUs and Bridging Population Nr. 2005305 (ENCAP); Global Fund to Fight HIV, Tuberculosis and Malaria Program "Scaling up the response to HIV in Estonia'' for 2003-2007; National HIV/AIDS Strategy for 2006-2015; US Civilian Research Development Foundation (grant ESX0-2722-TA06); US National Institutes of Health, National Institute on Drug Abuse (grant R01DA03574); the Archimedes Foundation and Norwegian Financial Mechanism/EEA(grant EE0016). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 1 Z9 1 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 JUL 25 PY 2013 VL 8 IS 7 AR e70561 DI 10.1371/journal.pone.0070561 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 191SQ UT WOS:000322433300109 PM 23936229 ER PT J AU Schulze, MSED Anders, AK Sethi, DK Call, MJ AF Schulze, Monika-Sarah E. D. Anders, Anne-Kathrin Sethi, Dhruv K. Call, Melissa J. TI Disruption of Hydrogen Bonds between Major Histocompatibility Complex Class II and the Peptide N-Terminus Is Not Sufficient to Form a Human Leukocyte Antigen-DM Receptive State of Major Histocompatibility Complex Class II SO PLOS ONE LA English DT Article ID HLA-DR MOLECULES; HIGH-AFFINITY BINDING; CRYSTAL-STRUCTURE; PROTEIN HLA-DR1; BOUND PEPTIDES; MHC; CHAIN; DISSOCIATION; EXCHANGE; SUSCEPTIBILITY AB Peptide presentation by MHC class II is of critical importance to the function of CD4+ T cells. HLA-DM resides in the endosomal pathway and edits the peptide repertoire of newly synthesized MHC class II molecules before they are exported to the cell surface. HLA-DM ensures MHC class II molecules bind high affinity peptides by targeting unstable MHC class II: peptide complexes for peptide exchange. Research over the past decade has implicated the peptide N-terminus in modulating the ability of HLA-DM to target a given MHC class II: peptide combination. In particular, attention has been focused on both the hydrogen bonds between MHC class II and peptide, and the occupancy of the P1 anchor pocket. We sought to solve the crystal structure of a HLA-DR1 molecule containing a truncated hemagglutinin peptide missing three N-terminal residues compared to the full-length sequence (residues 306-318) to determine the nature of the MHC class II: peptide species that binds HLA-DM. Here we present structural evidence that HLA-DR1 that is loaded with a peptide truncated to the P1 anchor residue such that it cannot make select hydrogen bonds with the peptide N-terminus, adopts the same conformation as molecules loaded with full-length peptide. HLA-DR1: peptide combinations that were unable to engage up to four key hydrogen bonds were also unable to bind HLA-DM, while those truncated to the P2 residue bound well. These results indicate that the conformational changes in MHC class II molecules that are recognized by HLA-DM occur after disengagement of the P1 anchor residue. C1 [Schulze, Monika-Sarah E. D.; Anders, Anne-Kathrin; Sethi, Dhruv K.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Anders, Anne-Kathrin] Harvard Univ, Sch Med, Program Immunol, Boston, MA USA. [Call, Melissa J.] Univ Melbourne, Struct Biol Div, Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. RP Call, MJ (reprint author), Univ Melbourne, Struct Biol Div, Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. EM call@wehi.edu.au FU Australian Research Council Future Fellowship [FT120100145]; National Multiple Sclerosis Society; National Institutes of Health [5R01NS044914]; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; U.S. DOE [DE-AC02-06CH11357] FX MJC is supported by an Australian Research Council Future Fellowship (FT120100145) and DKS is supported by a Postdoctoral Fellowship from The National Multiple Sclerosis Society. This work was supported by the National Institutes of Health (5R01NS044914). Diffraction data were collected at the Advanced Photon Source using beamline 23-ID-D of the General Medicine and Cancer Institutes Collaborative Access Team, which is supported by grants from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104). Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. We thank the Dana-Farber Molecular Biology Core Facility for Mass Spectrometry measurements. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 5 Z9 6 U1 0 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 JUL 25 PY 2013 VL 8 IS 7 AR e69228 DI 10.1371/journal.pone.0069228 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 191SQ UT WOS:000322433300028 PM 23976922 ER PT J AU Kalantar-Zadeh, K Uppot, RN Lewandrowski, KB AF Kalantar-Zadeh, Kamyar Uppot, Raul N. Lewandrowski, Kent B. TI Case 23-2013: A 54-Year-Old Woman with Abdominal Pain, Vomiting, and Confusion SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LACTIC-ACIDOSIS; RENAL-FAILURE; PANCREATITIS; INTOXICATION; DIALYSIS C1 [Kalantar-Zadeh, Kamyar] Univ Calif Irvine, Dept Med, Orange, CA 92717 USA. [Uppot, Raul N.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lewandrowski, Kent B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Uppot, Raul N.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA USA. [Lewandrowski, Kent B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. RP Kalantar-Zadeh, K (reprint author), Univ Calif Irvine, Dept Med, Orange, CA 92717 USA. NR 19 TC 14 Z9 14 U1 0 U2 5 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 JUL 25 PY 2013 VL 369 IS 4 BP 374 EP 382 DI 10.1056/NEJMcpc1208154 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 188VJ UT WOS:000322223900013 PM 23841704 ER PT J AU Ackerman, M Alter, G AF Ackerman, Margaret Alter, Galit TI Mapping the Journey to an HIV Vaccine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID BROAD C1 [Ackerman, Margaret] Dartmouth Coll, Sch Engn, Hanover, NH 03755 USA. [Alter, Galit] MIT, Ragon Inst, Massachusetts Gen Hosp, Cambridge, MA 02139 USA. [Alter, Galit] Harvard Univ, Cambridge, MA 02138 USA. RP Ackerman, M (reprint author), Dartmouth Coll, Sch Engn, Hanover, NH 03755 USA. NR 5 TC 9 Z9 9 U1 0 U2 8 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 JUL 25 PY 2013 VL 369 IS 4 BP 389 EP 391 DI 10.1056/NEJMcibr1304437 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 188VJ UT WOS:000322223900016 PM 23883384 ER PT J AU McEvoy, J Baillie, RA Zhu, HJ Buckley, P Keshavan, MS Nasrallah, HA Dougherty, GG Yao, JK Kaddurah-Daouk, R AF McEvoy, Joseph Baillie, Rebecca A. Zhu, Hongjie Buckley, Peter Keshavan, Matcheri S. Nasrallah, Henry A. Dougherty, George G. Yao, Jeffrey K. Kaddurah-Daouk, Rima TI Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics SO PLOS ONE LA English DT Article ID FATTY-ACIDS; SEROTONIN AB There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naive patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease. C1 [McEvoy, Joseph; Zhu, Hongjie; Kaddurah-Daouk, Rima] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27708 USA. [Baillie, Rebecca A.] Rosa & Co LLC, San Carlos, CA USA. [Buckley, Peter] Med Coll Georgia, Augusta, GA 30912 USA. [Keshavan, Matcheri S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Keshavan, Matcheri S.] Harvard Univ, Sch Med, Boston, MA USA. [Nasrallah, Henry A.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Dougherty, George G.; Yao, Jeffrey K.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. RP Kaddurah-Daouk, R (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27708 USA. EM kaddu001@mc.duke.edu FU National Institute of Mental Health (NIMH) [1R01MH084941-01A2]; Department of Veterans Affairs Senior Research Career Scientist Award FX Funding for this study was provided by National Institute of Mental Health (NIMH) Grant # 1R01MH084941-01A2 (RKD) and the Department of Veterans Affairs Senior Research Career Scientist Award (JKY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 24 Z9 25 U1 1 U2 23 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 JUL 24 PY 2013 VL 8 IS 7 AR e68717 DI 10.1371/journal.pone.0068717 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188BY UT WOS:000322167900022 PM 23894336 ER PT J AU Haslinger, R Ba, D Galuske, R Williams, Z Pipa, G AF Haslinger, Robert Ba, Demba Galuske, Ralf Williams, Ziv Pipa, Gordon TI Missing mass approximations for the partition function of stimulus driven lsing models SO FRONTIERS IN COMPUTATIONAL NEUROSCIENCE LA English DT Article DE lsing model; stimulus coding; population codes; partition function; multiple unit recordings; network function ID NEURAL SPIKING ACTIVITY; NEURONAL POPULATION; ENSEMBLE; PATTERNS; HISTORY; CODES AB lsing models are routinely used to quantify the second order, functional structure of neural populations. With some recent exceptions, they generally do not include the influence of time varying stimulus drive. Yet if the dynamics of network function are to be understood, time varying stimuli must be taken into account. Inclusion of stimulus drive carries a heavy computational burden because the partition function becomes stimulus dependent and must be separately calculated for all unique stimuli observed. This potentially increases computation time by the length of the data set. Here we present an extremely fast, yet simply implemented, method for approximating the stimulus dependent partition function in minutes or seconds. Noting that the most probable spike patterns (which are few) occur in the training data, we sum partition function terms corresponding to those patterns explicitly. We then approximate the sum over the remaining patterns (which are improbable, but many) by casting it in terms of the stimulus modulated missing mass (total stimulus dependent probability of all patterns not observed in the training data). We use a product of conditioned logistic regression models to approximate the stimulus modulated missing mass. This method has complexity of roughly O(LNNpat) where is L the data length, N the number of neurons and N-pat the number of unique patterns in the data, contrasting with the O(L2(N)) complexity of alternate methods. Using multiple unit recordings from rat hippocampus, macaque DLPFC and cat Area 18 we demonstrate our method requires orders of magnitude less computation time than Monte Carlo methods and can approximate the stimulus driven partition function more accurately than either Monte Carlo methods or deterministic approximations. This advance allows stimuli to be easily included in lsing models making them suitable for studying population based stimulus encoding. C1 [Haslinger, Robert] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Haslinger, Robert; Ba, Demba] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Galuske, Ralf] Tech Univ Darmstadt, Dept Biol, Darmstadt, Germany. [Williams, Ziv] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Pipa, Gordon] Univ Osnabruck, Inst Cognit Sci, Dept Neuroinformat, Osnabruck, Germany. RP Haslinger, R (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM rob.haslinger@gmail.com RI Pipa, Gordon/M-1813-2014 OI Pipa, Gordon/0000-0002-3416-2652 FU NIH [K25 N5052422-02, 5R01-HD059852]; PECASE; Whitehall Foundation FX The authors would like to thank Emery Brown for helpful conversations regarding the research presented in this paper and also the use of his rat hippocampal data. This work was supported by NIH grant K25 N5052422-02 (Robert Haslinger), the Max Planck-Gesellschaft (Ralf Galuske), and NIH grant 5R01-HD059852, PECASE and the Whitehall Foundation (Ziv Williams). NR 71 TC 1 Z9 1 U1 0 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5188 J9 FRONT COMPUT NEUROSC JI Front. Comput. Neurosci. PD JUL 24 PY 2013 VL 7 AR UNSP 96 DI 10.3389/fncom.2013.00096 PG 21 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 192TW UT WOS:000322509300001 PM 23898262 ER PT J AU Zhang, XL Poschel, B Faul, C Upreti, C Stanton, PK Mundel, P AF Zhang, Xiao-lei Poeschel, Beatrice Faul, Christian Upreti, Chirag Stanton, Patric K. Mundel, Peter TI Essential Role for Synaptopodin in Dendritic Spine Plasticity of the Developing Hippocampus SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; SCHAFFER COLLATERAL-CA1 SYNAPSES; ACTIN-ASSOCIATED PROTEIN; SYNAPTIC PLASTICITY; PRESYNAPTIC RELEASE; KIDNEY PODOCYTES; AMPA RECEPTORS; NITRIC-OXIDE; VESICLE POOL; LATE-PHASE AB Dendritic spines are a major substrate of brain plasticity. Although many studies have focused on Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated regulation of spine dynamics and synaptic function in adult brain, much less is know about protein kinase A (PKA)-dependent regulation of spine shape dynamics during postnatal brain development. Synaptopodin is a dendritic spine associated modulator of actin dynamics and a substrate of PKA. Here we show that NMDA and cAMP-induced dendritic spine expansion is impaired in hippocampal slices from 15- and 21-d-old synaptopodin-deficient mice. We further show that synaptopodin is required for full expression of PKA-dependent hippocampal long-term potentiation in 15- and 21-d-old, but not adult, mice. PKA-induced cAMP response element-binding phosphorylation is normal in the hippocampus of synaptopodin-deficient mice, suggesting that synaptopodin functions independently of cAMP response element-binding. Our results identify synaptopodin as a substrate of PKA in hippocampal neurons and point to an essential role for synaptopodin in activity-dependent regulation of dendritic spine dynamics and synaptic plasticity in postnatal brain development. C1 [Zhang, Xiao-lei; Poeschel, Beatrice; Upreti, Chirag; Stanton, Patric K.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. [Upreti, Chirag; Stanton, Patric K.] New York Med Coll, Dept Neurol, Valhalla, NY 10595 USA. [Poeschel, Beatrice] Univ Med Ctr Hamburg Eppendorf, Ctr Mol Neurobiol, D-20251 Hamburg, Germany. [Faul, Christian] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Mundel, Peter] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Mundel, Peter] Massachusetts Gen Hosp, Dept Med, Boston, MA 02129 USA. RP Mundel, P (reprint author), Massachusetts Gen Hosp, Div Nephrol, 149 13th St, Charlestown, MA 02129 USA. EM patric_stanton@nymc.edu; mundel.peter@mgh.harvard.edu FU US National Institutes of Health [DA18886, DK57683, NS044421] FX This work was supported by US National Institutes of Health Grants DA18886, DK57683 (to P. M.), and NS044421 (to P.S.). We thank Anna Greka, Boston, MA, for helpful discussions. NR 36 TC 19 Z9 19 U1 0 U2 2 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 JUL 24 PY 2013 VL 33 IS 30 BP 12510 EP 12518 DI 10.1523/JNEUROSCI.2983-12.2013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 188CF UT WOS:000322168600033 PM 23884954 ER PT J AU Ferraro, PM Taylor, EN Eisner, BH Gambaro, G Rimm, EB Mukamal, KJ Curhan, GC AF Ferraro, Pietro Manuel Taylor, Eric N. Eisner, Brian H. Gambaro, Giovanni Rimm, Eric B. Mukamal, Kenneth J. Curhan, Gary C. TI History of Kidney Stones and the Risk of Coronary Heart Disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; DIETARY CALCIUM; BLOOD-PRESSURE; UNITED-STATES; NEPHROLITHIASIS; POPULATION; HYPERTENSION AB IMPORTANCE Kidney stone disease is common and may be associated with an increased risk of coronary heart disease (CHD). Previous studies of the association between kidney stones and CHD have often not controlled for important risk factors, and the results have been inconsistent. OBJECTIVE To examine the association between a history of kidney stones and the risk of CHD in 3 large prospective cohorts. DESIGN, SETTING, AND PARTICIPANTS A prospective study of 45 748 men and 196 357 women in the United States without a history of CHD at baseline who were participants in the Health Professionals Follow-up Study (HPFS) (45 748 men aged 40-75 years; follow-up from 1986 to 2010), Nurses' Health Study I (NHS I) (90 235 women aged 30-55 years; follow-up from 1992 to 2010), and Nurses' Health Study II (NHS II) (106 122 women aged 25-42 years; follow-up from 1991 to 2009). The diagnoses of kidney stones and CHD were updated biennially during follow-up. MAIN OUTCOMES AND MEASURES Coronary heart disease was defined as fatal or nonfatal myocardial infarction (MI) or coronary revascularization. The outcome was identified by biennial questionnaires and confirmed through review of medical records. RESULTS Of a total of 242 105 participants, 19 678 reported a history of kidney stones. After up to 24 years of follow-up in men and 18 years in women, 16 838 incident cases of CHD occurred. After adjusting for potential confounders, among women, those with a reported history of kidney stones had an increased risk of CHD than those without a history of kidney stones in NHS I (incidence rate [IR], 754 vs 514 per 100 000 person-years; multivariable hazard ratio [HR], 1.18 [95% CI, 1.08-1.28]) and NHS II (IR, 144 vs 55 per 100 000 person-years; multivariable HR, 1.48 [95% CI, 1.23-1.78]). There was no significant association in men (IR, 1355 vs 1022 per 100 000 person-years; multivariable HR, 1.06 [95% CI, 0.99-1.13]). Similar results were found when analyzing the individual end points (fatal and nonfatal MI and revascularization). CONCLUSIONS AND RELEVANCE Among the 2 cohorts of women, a history of kidney stones was associated with a modest but statistically significantly increased risk of CHD; there was no significant association in a separate cohort of men. Further research is needed to determine whether the association is sex-specific. C1 [Ferraro, Pietro Manuel; Gambaro, Giovanni] Columbus Gemelli Hosp, Dept Internal Med & Med Specialties, Div Nephrol, Renal Program, Rome, Italy. [Ferraro, Pietro Manuel; Taylor, Eric N.; Rimm, Eric B.; Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Eisner, Brian H.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. RP Ferraro, PM (reprint author), Univ Cattolica Sacro Cuore, Dept Internal Med & Med Specialties, Via G Moscati 31, I-00168 Rome, Italy. EM manuel.ferraro@channing.harvard.edu RI Ferraro, Pietro Manuel/H-1517-2012 OI Ferraro, Pietro Manuel/0000-0002-1379-022X FU National Institutes of Health [DK91417, DK70756, CA087969, CA50385, CA055075, HL034594, HL35464] FX This work was supported by grants DK91417, DK70756, CA087969, CA50385, CA055075, HL034594, and HL35464 from the National Institutes of Health. NR 42 TC 40 Z9 40 U1 1 U2 9 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 JUL 24 PY 2013 VL 310 IS 4 BP 408 EP 415 DI 10.1001/jama.2013.8780 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 187LV UT WOS:000322121500018 PM 23917291 ER PT J AU Simon, NM AF Simon, Naomi M. TI Treating Complicated Grief SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID COGNITIVE-BEHAVIORAL THERAPY; BEREAVEMENT-RELATED DEPRESSION; RANDOMIZED CONTROLLED-TRIAL; DUAL PROCESS MODEL; QUALITY-OF-LIFE; PROLONGED GRIEF; TRAUMATIC GRIEF; DIAGNOSTIC-CRITERIA; POSTTRAUMATIC STRESS; OLDER-ADULTS AB IMPORTANCE The death of a loved one is one of life's greatest, universal stressors to which most bereaved individuals successfully adapt without clinical intervention. For a minority of bereaved individuals, grief is complicated by superimposed problems and healing does not occur. The resulting syndrome of complicated grief causes substantial distress and functional impairment even years after a loss, yet knowing when and how to intervene can be a challenge. OBJECTIVE To discuss the differential diagnosis, risk factors for and management of complicated grief based on available evidence and clinical observations. EVIDENCE REVIEW MEDLINE was searched from January 1990 to October 2012. Additional citations were procured from references of select research and review articles. Available treatment studies targeting complicated grief were included. RESULTS A strong research literature led to inclusion of complicated grief in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (termed persistent complex bereavement disorder as a subtype of other specified trauma and stressor-related disorders), although it is a condition for which more research is formally recommended, and there is still ongoing discussion about the optimal name and diagnostic criteria for the disorder. Reliable screening instruments are available, and the estimated prevalence rate is 7% of bereaved people. Randomized controlled data support the efficacy of a targeted psychotherapy including elements that foster resolution of complicating problems and facilitate the natural healing process. Preliminary studies suggest antidepressant medications may be helpful. CONCLUSION AND RELEVANCE Individuals with complicated grief have greater risk of adverse health outcomes, should be diagnosed and assessed for suicide risk and comorbid conditions such as depression and posttraumatic stress disorder, and should be considered for treatment. C1 [Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. [Simon, Naomi M.] Massachusetts Gen Hosp, Dept Psychiat, Complicated Grief Program, Boston, MA 02114 USA. [Simon, Naomi M.] Red Sox Fdn MGH Home Base Program, Boston, MA USA. RP Simon, NM (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM nsimon@partners.org FU National Institute for Mental Health [5R01MH085308] FX Clinical Crossroads receives no external support. Dr Simon's work was supported in part by grant 5R01MH085308 from the National Institute for Mental Health. NR 66 TC 25 Z9 25 U1 5 U2 57 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 JUL 24 PY 2013 VL 310 IS 4 BP 416 EP 423 DI 10.1001/jama.2013.8614 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 187LV UT WOS:000322121500019 PM 23917292 ER PT J AU Vemuri, P Mormino, EC AF Vemuri, Prashanthi Mormino, Elizabeth C. TI Cognitively stimulating activities to keep dementia at bay SO NEUROLOGY LA English DT Editorial Material ID DISEASE BIOMARKERS; ALZHEIMERS-DISEASE; RESERVE; RISK C1 [Vemuri, Prashanthi] Mayo Clin, Dept Radiol, Rochester, MN 55902 USA. [Mormino, Elizabeth C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. RP Vemuri, P (reprint author), Mayo Clin, Dept Radiol, Rochester, MN 55902 USA. EM vemuri.prashanthi@mayo.edu NR 10 TC 4 Z9 5 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 23 PY 2013 VL 81 IS 4 BP 308 EP 309 DI 10.1212/WNL.0b013e31829c5f05 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 304JX UT WOS:000330744000004 PM 23825176 ER PT J AU Bohl, C Bowder, D Thompson, J Abrahamyan, L Gonzalez-Ramirez, S Mao, YD Sodroski, J Wood, C Xiang, SH AF Bohl, Christopher Bowder, Dane Thompson, Jesse Abrahamyan, Levon Gonzalez-Ramirez, Sandra Mao, Youdong Sodroski, Joseph Wood, Charles Xiang, Shi-hua TI A Twin-Cysteine Motif in the V2 Region of gp120 Is Associated with SIV Envelope Trimer Stabilization SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODY PG9; HIV-1 GP120; MONOCLONAL-ANTIBODIES; VARIABLE LOOPS; V1/V2 DOMAIN; AIDS; INFECTION; PATHOGENESIS; GLYCOPROTEIN AB The V1 and V2 variable regions of the primate immunodeficiency viruses contribute to the trimer association domain of the gp120 exterior envelope glycoprotein. A pair of V2 cysteine residues at 183 and 191 ("twin cysteines") is present in several simian immunodeficiency viruses, human immunodeficiency virus type 2 (HIV-2) and some SIVcpz lineages, but not in HIV-1. To examine the role of this potentially disulfide-bonded twin-cysteine motif, the cysteine residues in the SIVmac239 envelope glycoproteins were individually and pairwise substituted by alanine residues. All of the twin-cysteine mutants exhibited decreases in gp120 association with the Env trimer, membrane-fusing activity, and ability to support virus entry. Thus, the twin-cysteine motif plays a role in Env trimer stabilization in SIV and may do so in HIV-2 and some SIVcpz as well. This implies that HIV-1 lost the twin-cysteines, and may have relatively unstable Env trimers compared to SIV and HIV-2. C1 [Bohl, Christopher; Bowder, Dane; Thompson, Jesse; Abrahamyan, Levon; Gonzalez-Ramirez, Sandra; Wood, Charles; Xiang, Shi-hua] Univ Nebraska, Nebraska Ctr Virol, Lincoln, NE USA. [Thompson, Jesse; Xiang, Shi-hua] Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE USA. [Bohl, Christopher; Bowder, Dane; Abrahamyan, Levon; Gonzalez-Ramirez, Sandra; Wood, Charles; Xiang, Shi-hua] Univ Nebraska, Sch Biol Sci, Lincoln, NE USA. [Mao, Youdong; Sodroski, Joseph] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Mao, Youdong; Sodroski, Joseph] Harvard Univ, Sch Med, Div Aids, Dept Microbiol & Immunol, Boston, MA USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Sodroski, Joseph] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. RP Xiang, SH (reprint author), Univ Nebraska, Nebraska Ctr Virol, Lincoln, NE USA. EM sxiang2@unl.edu RI Abrahamyan, Levon/E-1982-2013 OI Abrahamyan, Levon/0000-0002-0849-0134 FU Bill and Melinda Gates Foundation; National Institutes of Health (NIH) [AI24755, AI67854]; National Institutes of Health (NIH) (Center for AIDS Research) [AI060354]; International AIDS Vaccine Initiative; Public Health Service grants NIGMS COBRE [P30 GM103509, D43 TW001492, T32 AI060547] FX This work was supported by grants from the Bill and Melinda Gates Foundation, and the National Institutes of Health (NIH) (AI24755, AI67854 and Center for AIDS Research Award AI060354), the International AIDS Vaccine Initiative and the late William F. McCarty-Cooper, and the Public Health Service grants NIGMS COBRE grant P30 GM103509, D43 TW001492 and T32 AI060547; DB is an NIH Ruth L. Kirschstein Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 7 Z9 7 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 23 PY 2013 VL 8 IS 7 AR e69406 DI 10.1371/journal.pone.0069406 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 228SX UT WOS:000325211000114 PM 23936006 ER PT J AU Chanda, P Huang, HL Arking, DE Bader, JS AF Chanda, Pritam Huang, Hailiang Arking, Dan E. Bader, Joel S. TI Fast Association Tests for Genes with FAST SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; TRAITS; LOCI AB Gene-based tests of association can increase the power of a genome-wide association study by aggregating multiple independent effects across a gene or locus into a single stronger signal. Recent gene-based tests have distinct approaches to selecting which variants to aggregate within a locus, modeling the effects of linkage disequilibrium, representing fractional allele counts from imputation, and managing permutation tests for p-values. Implementing these tests in a single, efficient framework has great practical value. Fast ASsociation Tests (FAST) addresses this need by implementing leading gene-based association tests together with conventional SNP-based univariate tests and providing a consolidated, easily interpreted report. Fast scales readily to genome-wide SNP data with millions of SNPs and tens of thousands of individuals, provides implementations that are orders of magnitude faster than original literature reports, and provides a unified framework for performing several gene based association tests concurrently and efficiently on the same data. Availability: https://bitbucket.org/baderlab/fast/downloads/FAST.tar.gz, with documentation at https://bitbucket.org/baderlab/fast/wiki/Home C1 [Chanda, Pritam; Bader, Joel S.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. [Chanda, Pritam; Bader, Joel S.] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD USA. [Chanda, Pritam; Bader, Joel S.] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD USA. [Huang, Hailiang] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Huang, Hailiang] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Bader, JS (reprint author), Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. EM joel.bader@jhu.edu OI Huang, Hailiang/0000-0003-1461-5762 FU Robert J. Kleberg Jr. and Helen C. Kleberg Foundation; NSF [DMS-1228248]; Simons Foundation [SFARI 137603] FX JSB and PC acknowledge funding from the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation. JSB and DEA acknowledge funding from the NSF (DMS-1228248). DEA, JSB, PC and HH acknowledge funding from the Simons Foundation (SFARI 137603 to DEA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 6 Z9 6 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 23 PY 2013 VL 8 IS 7 AR e68585 DI 10.1371/journal.pone.0068585 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 228SX UT WOS:000325211000031 PM 23935874 ER PT J AU Kucherlapati, MH Esfahani, S Habibollahi, P Wang, JN Still, ER Bronson, RT Mahmood, U Kucherlapati, RS AF Kucherlapati, Melanie H. Esfahani, Shadi Habibollahi, Peiman Wang, Junning Still, Eric R. Bronson, Roderick T. Mahmood, Umar Kucherlapati, Raju S. TI Genotype Directed Therapy in Murine Mismatch Repair Deficient Tumors SO PLOS ONE LA English DT Article ID DUAL PI3K/MTOR INHIBITOR; RENAL-CELL CARCINOMA; SERINE METABOLISM; CANCER METABOLISM; NVP-BEZ235; PATHWAY; PI3K; IDENTIFICATION; COMBINATION; ACTIVATION AB The PI3K/AKT/mTOR pathway has frequently been found activated in human tumors. We show that in addition to Wnt signaling dysfunction, the PI3K/AKT/mTOR pathway is often upregulated in mouse Msh2(-/-) initiated intestinal tumors. NVP-BEZ235 is a dual PI3K/mTOR inhibitor toxic to many cancer cell lines and currently involved in clinical trials. We have treated two mouse models involving Msh2 that develop small intestinal and/or colonic tumors with NVP-BEZ235, and a subset of animals with NVP-BEZ235 and MEK inhibitor ADZ4266. The disease phenotype has been followed with pathology, F-18 FDG PET imaging, and endoscopy. Intestinal adenocarcinomas are significantly decreased in multiplicity by both drug regimens. The majority of tumors treated with combined therapy regress significantly, while a small number of highly progressed tumors persist. We have examined PTEN, AKT, MEK 1&2, MAPK, S6K, mTOR, PDPK1, and Cyclin D1 and find variable alterations that include downregulation of PTEN, upregulation of AKT and changes in its phosphorylated forms, upregulation of pMEK 1&2, p42p44MAPK, pS6K, and Cyclin D1. Apoptosis has been found intact in some tumors and not in others. Our data indicate that NVP-BEZ235 alone and in combination with ADZ4266 are effective in treating a proportion of colorectal cancers, but that highly progressed resistant tumors grow in the presence of the drugs. Pathways upregulated in some resistant tumors also include PDPK1, suggesting that metabolic inhibitors may also be useful in treating these tumors. C1 [Kucherlapati, Melanie H.; Wang, Junning; Still, Eric R.; Kucherlapati, Raju S.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Kucherlapati, Melanie H.; Wang, Junning; Still, Eric R.; Kucherlapati, Raju S.] Brigham & Womens Hosp Boston, Dept Med, Div Genet, Boston, MA USA. [Esfahani, Shadi; Habibollahi, Peiman; Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Rodent Histopathol Core, Boston, MA USA. [Bronson, Roderick T.] Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. [Bronson, Roderick T.] Tufts Univ, Sch Vet Med, Dept Pathol, Boston, MA 02111 USA. RP Kucherlapati, RS (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. EM mkucherlapati@partners.org FU National Cancer Institute (NCI) [5U01CA084301-13] FX The work in this study was supported by a grant from the National Cancer Institute (NCI) to Raju S. Kucherlapati and Umar Mahmood, entitled: Mouse Models for Human Cancer, 5U01CA084301-13. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 4 Z9 4 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 JUL 23 PY 2013 VL 8 IS 7 AR e68817 DI 10.1371/journal.pone.0068817 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 228SX UT WOS:000325211000039 PM 23935891 ER PT J AU Gibson, CM Chakrabarti, AK Mega, J Bode, C Bassand, JP Verheugt, FWA Bhatt, DL Goto, S Cohen, M Mohanavelu, S Burton, P Stone, G Braunwald, E AF Gibson, C. Michael Chakrabarti, Anjan K. Mega, Jessica Bode, Christophe Bassand, Jean-Pierre Verheugt, Freek W. A. Bhatt, Deepak L. Goto, Shinya Cohen, Marc Mohanavelu, Satishkumar Burton, Paul Stone, Gregg Braunwald, Eugene CA ATLAS-ACS 2 TIMI 51 Investigators TI Reduction of Stent Thrombosis in Patients With Acute Coronary Syndromes Treated With Rivaroxaban in ATLAS-ACS 2 TIMI 51 SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute coronary syndrome(s); factor Xa inhibitor; rivaroxaban; stent thrombosis ID ANTIPLATELET THERAPY; TRIAL AB Objectives The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial. Background Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis. Methods The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. Results Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014). Conclusions Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965) (C) 2013 by the American College of Cardiology Foundation C1 [Gibson, C. Michael; Chakrabarti, Anjan K.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Cardiovasc Div, Boston, MA USA. [Gibson, C. Michael; Mega, Jessica; Bhatt, Deepak L.; Mohanavelu, Satishkumar; Braunwald, Eugene] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Cardiovasc Div,TIMI Study Grp, Boston, MA USA. [Bode, Christophe] Univ Freiburg, Dept Cardiol & Angiol, D-79106 Freiburg, Germany. [Bassand, Jean-Pierre] Univ Hosp Jean Minjoz, Besancon, France. [Verheugt, Freek W. A.] OnzeLieveVrouweGasthuis, Amsterdam, Netherlands. [Bhatt, Deepak L.] VA Healthcare Syst, Boston, MA USA. [Goto, Shinya] Tokai Univ, Sch Med, Dept Med Cardiol, Isehara, Kanagawa 25911, Japan. [Cohen, Marc] Newark Beth Israel Med Ctr, Div Cardiol, Newark, NJ USA. [Burton, Paul] Janssen Res & Dev, Titusville, NJ USA. [Stone, Gregg] Columbia Univ, New York, NY 10027 USA. RP Gibson, CM (reprint author), Beth Israel Deaconess Med Ctr, 185 Pilgrim Rd,Farr 319, Boston, MA 02215 USA. EM mgibson@perfuse.org RI Verheugt, F.W.A./H-8105-2014 NR 10 TC 34 Z9 35 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 23 PY 2013 VL 62 IS 4 BP 286 EP 290 DI 10.1016/j.jacc.2013.03.041 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 186SD UT WOS:000322064100005 PM 23602776 ER PT J AU Mao, YD Wang, LP Gu, C Herschhorn, A Desormeaux, A Finzi, A Xiang, SH Sodroski, JG AF Mao, Youdong Wang, Liping Gu, Christopher Herschhorn, Alon Desormeaux, Anik Finzi, Andres Xiang, Shi-Hua Sodroski, Joseph G. TI Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE vaccine immunogen; retrovirus; spike; cryo-EM; membrane protein ID VIRUS TYPE-1 GP120; CONFORMATIONAL-CHANGES; NEUTRALIZING ANTIBODY; ATOMIC-STRUCTURE; STRUCTURAL BASIS; RATIONAL DESIGN; AIDS PATIENTS; INNER DOMAIN; CD4 BINDING; HTLV-III AB The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer, a membrane-fusing machine, mediates virus entry into host cells and is the sole virus-specific target for neutralizing antibodies. Binding the receptors, CD4 and CCR5/CXCR4, triggers Env conformational changes from the metastable unliganded state to the fusion-active state. We used cryo-electron microscopy to obtain a 6-angstrom structure of the membrane-bound, heavily glycosylated HIV-1 Env trimer in its uncleaved and unliganded state. The spatial organization of secondary structure elements reveals that the unliganded conformations of both glycoprotein (gp)120 and gp41 subunits differ from those induced by receptor binding. The gp120 trimer association domains, which contribute to interprotomer contacts in the unliganded Env trimer, undergo rearrangement upon CD4 binding. In the unliganded Env, intersubunit interactions maintain the gp41 ecto-domain helical bundles in a "spring-loaded" conformation distinct from the extended helical coils of the fusion-active state. Quaternary structure regulates the virus-neutralizing potency of antibodies targeting the conserved CD4-binding site on gp120. The Env trimer architecture provides mechanistic insights into the metastability of the unliganded state, receptor-induced conformational changes, and quaternary structure-based strategies for immune evasion. C1 [Mao, Youdong; Wang, Liping; Gu, Christopher; Herschhorn, Alon; Sodroski, Joseph G.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Mao, Youdong; Wang, Liping; Gu, Christopher; Herschhorn, Alon; Sodroski, Joseph G.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Desormeaux, Anik; Finzi, Andres] Univ Montreal, Ctr Rech, Ctr Hosp Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. [Xiang, Shi-Hua] Univ Nebraska, Nebraska Ctr Virol, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA. [Sodroski, Joseph G.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. [Sodroski, Joseph G.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Mao, YD (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM youdong_mao@dfci.harvard.edu; joseph_sodroski@dfci.harvard.edu FU National Science Foundation (NSF) under NSF Award [ECS-0335765]; National Institutes of Health [AI93256, AI67854, AI24755]; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard; International AIDS Vaccine Initiative; Mathilde Krim Fellowship in Basic Science from the American Foundation for AIDS Research; Canada Foundation for Innovation Program Leader [29866]; Canadian Institutes of Health Research operating [257792]; Fonds de Recherche en Sante du Quebec Chercheur Boursier Junior 1 fellowship [24639] FX We thank P. Kwong, J. Robinson, P. Poignard, S. Zolla-Pazner, H. Katinger, M. Posner, and L. Cavacini for kindly providing antibodies; D. R. Burton for helpful discussion and encouragement; A. Leschziner for help in cryo-specimen preparation; D. Bell and E. Hodges for coordination in data collection; J. Faltskog, S. Doktor, and B. Battle for laboratory coordination; J. Jackson and B. Richter for assistance in building and maintaining the high-performance computing system; and Y. McLaughlin and E. Carpelan for assistance in manuscript preparation. The experiments and data processing were performed in part at the Center for Nanoscale Systems at Harvard University, a member of National Nanotechnology Infrastructure Network, which is supported by the National Science Foundation (NSF) under NSF Award ECS-0335765. This work was funded by National Institutes of Health Grants AI93256, AI67854, and AI24755, by an Innovation Award and a Fellowship Award from the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, by the International AIDS Vaccine Initiative, and by gifts from Mr. and Mrs. Daniel J. Sullivan, Jr. and the late William F. McCarty-Cooper. A.H. is the recipient of a Mathilde Krim Fellowship in Basic Science from the American Foundation for AIDS Research. A.F. is the recipient of a Canada Foundation for Innovation Program Leader (#29866), a Canadian Institutes of Health Research operating (#257792) and an Fonds de Recherche en Sante du Quebec Chercheur Boursier Junior 1 fellowship (#24639). NR 52 TC 52 Z9 52 U1 4 U2 53 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 JUL 23 PY 2013 VL 110 IS 30 BP 12438 EP 12443 DI 10.1073/pnas.1307382110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187JA UT WOS:000322112300067 PM 23757493 ER PT J AU Ye, L Wu, J Cohen, P Kazak, L Khandekar, MJ Jedrychowski, MP Zeng, X Gygi, SP Spiegelman, BM AF Ye, Li Wu, Jun Cohen, Paul Kazak, Lawrence Khandekar, Melin J. Jedrychowski, Mark P. Zeng, Xing Gygi, Steven P. Spiegelman, Bruce M. TI Fat cells directly sense temperature to activate thermogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Ucp1; cold sensing ID BROWN ADIPOSE-TISSUE; DIET-INDUCED THERMOGENESIS; HEAT-EVOKED ACTIVATION; CAPSAICIN-RECEPTOR; ADULT HUMANS; ION-CHANNEL; TRP CHANNEL; WHITE FAT; ADIPOCYTES; OBESITY AB Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes. Cold is known to act indirectly through the sympathetic nervous systems and beta-adrenergic signaling, but here we report that cool temperature (27-33 degrees C) can directly activate a thermogenic gene program in adipocytes in a cell-autonomous manner. White and beige fat cells respond to cool temperatures, but classic brown fat cells do not. Importantly, this activation in isolated cells is independent of the canonical cAMP/Protein Kinase A/cAMP response element-binding protein pathway downstream of the beta-adrenergic receptors. These findings provide an unusual insight into the role of adipose tissues in thermoregulation, as well as an alternative way to target nonshivering thermogenesis for treatment of obesity and metabolic diseases. C1 [Ye, Li; Wu, Jun; Cohen, Paul; Kazak, Lawrence; Khandekar, Melin J.; Zeng, Xing; Spiegelman, Bruce M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ye, Li; Wu, Jun; Cohen, Paul; Kazak, Lawrence; Khandekar, Melin J.; Jedrychowski, Mark P.; Zeng, Xing; Gygi, Steven P.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM Bruce_Spiegelman@dfci.harvard.edu FU National Institutes of Health Interdisciplinary Training Grant [DK071507]; National Institutes of Health Grant [DK094824, DK31403, DK080261] FX We thank Dr. Brad Lowell for providing the beta-less mice, Dr. Wolfgang Liedtke for providing Trpv4-/- mice, and Dr. Jeffery Gimble for providing human adipose cells. We also thank Dr. Sandra Kleiner, Dr. Rana Gupta, Dr. Jorge Ruas, Dr. Patrick Seale, Dr. Jennifer Estall, Dr. Shingo Kajimura, and Dr. Rajan Sah for discussion. Support was provided by National Institutes of Health Interdisciplinary Training Grant DK071507 (to L.Y.) and National Institutes of Health Grant DK094824 (to J.W.) DK31403, and DK080261 (to B.M.S.). NR 37 TC 73 Z9 73 U1 13 U2 60 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 JUL 23 PY 2013 VL 110 IS 30 BP 12480 EP 12485 DI 10.1073/pnas.1310261110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187JA UT WOS:000322112300074 PM 23818608 ER PT J AU Podrid, PJ AF Podrid, Philip J. TI ECG Response: July 23, 2013 SO CIRCULATION LA English DT Editorial Material C1 [Podrid, Philip J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Podrid, Philip J.] Harvard Univ, Sch Med, Boston, MA USA. [Podrid, Philip J.] VA Boston Healthcare Syst, Boston, MA USA. RP Podrid, PJ (reprint author), West Roxbury VA Hosp, Cardiol Sect, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM ppodrid@circulationjournal.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 23 PY 2013 VL 128 IS 4 BP 414 EP 414 DI 10.1161/CIRCULATIONAHA.113.004371 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 187MP UT WOS:000322123500025 PM 23877064 ER PT J AU Jackevicius, CA Tu, JV Ko, DT de Leon, N Krumholz, HM AF Jackevicius, Cynthia A. Tu, Jack V. Ko, Dennis T. de Leon, Noelle Krumholz, Harlan M. TI Use of Niacin in the United States and Canada SO JAMA INTERNAL MEDICINE LA English DT Letter ID THERAPY; DISEASE C1 [Jackevicius, Cynthia A.; de Leon, Noelle] Western Univ Hlth Sci, Coll Pharm, Dept Pharm Practice & Adm, Pomona, CA USA. [Jackevicius, Cynthia A.; Tu, Jack V.; Ko, Dennis T.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Jackevicius, Cynthia A.; Tu, Jack V.; Ko, Dennis T.] Univ Toronto, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Jackevicius, Cynthia A.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Jackevicius, Cynthia A.] Univ Hlth Network, Toronto, ON, Canada. [Tu, Jack V.; Ko, Dennis T.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Schulich Heart Ctr, Div Cardiol, Toronto, ON, Canada. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Sect Cardiovascr Med Epidemiol & Publ Hlth & Hlth, New Haven, CT 06510 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Robert Wood Johnson Clin Scholars Program, New Haven, CT USA. [Krumholz, Harlan M.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. RP Jackevicius, CA (reprint author), Western Univ Hlth Sci, Coll Pharm, 309 E 2nd St, Pomona, CA 91766 USA. EM cjackevicius@westernu.edu OI Ko, Dennis/0000-0001-6840-8051 FU Canadian Institutes of Health Research; NHLBI NIH HHS [U01-HL105270-03] NR 9 TC 11 Z9 11 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL 22 PY 2013 VL 173 IS 14 BP 1379 EP 1383 DI 10.1001/jamainternmed.2013.6489 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 214TX UT WOS:000324160100027 PM 23753308 ER PT J AU Yaffe, K Falvey, CM Hamilton, N Harris, TB Simonsick, EM Strotmeyer, ES Shorr, RI Metti, A Schwartz, AV AF Yaffe, Kristine Falvey, Cherie M. Hamilton, Nathan Harris, Tamara B. Simonsick, Eleanor M. Strotmeyer, Elsa S. Shorr, Ronald I. Metti, Andrea Schwartz, Ann V. CA Hlth ABC Study TI Association Between Hypoglycemia and Dementia in a Biracial Cohort of Older Adults With Diabetes Mellitus SO JAMA INTERNAL MEDICINE LA English DT Article ID COGNITIVE FUNCTION; ALZHEIMERS-DISEASE; RISK; DYSFUNCTION; IMPAIRMENT; VETERANS; TRIAL AB IMPORTANCE Hypoglycemia commonly occurs in patients with diabetes mellitus (DM) and may negatively influence cognitive performance. Cognitive impairment in turn can compromise DM management and lead to hypoglycemia. OBJECTIVE To prospectively evaluate the association between hypoglycemia and dementia in a biracial cohort of older adults with DM. DESIGN AND SETTING Prospective population-based study. PARTICIPANTS We studied 783 older adults with DM (mean age, 74.0 years; 47.0% of black race/ethnicity; and 47.6% female) who were participating in the prospective population-based Health, Aging, and Body Composition Study beginning in 1997 and who had baseline Modified Mini-Mental State Examination scores of 80 or higher. MAIN OUTCOME MEASURES Dementia diagnosis was determined during the follow-up period from hospital records indicating an admission associated with dementia or the use of prescribed dementia medications. Hypoglycemic events were determined during the follow-up period by hospital records. RESULTS During the 12-year follow-up period, 61 participants (7.8%) had a reported hypoglycemic event, and 148 (18.9%) developed dementia. Those who experienced a hypoglycemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycemic event (34.4% vs 17.6%, P < .001; multivariate-adjusted hazard ratio, 2.1; 95% CI, 1.0-4.4). Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycemic event compared with participants who did not develop dementia (14.2% vs 6.3%, P < .001; multivariate-adjusted hazard ratio, 3.1; 95% CI, 1.5-6.6). Further adjustment for stroke, hypertension, myocardial infarction, and cognitive change scores produced similar results. CONCLUSION AND RELEVANCE Among older adults with DM, there seems to be a bidirectional association between hypoglycemia and dementia. C1 [Yaffe, Kristine; Falvey, Cherie M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine; Schwartz, Ann V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. [Yaffe, Kristine; Falvey, Cherie M.; Hamilton, Nathan] San Francisco VA Med Ctr, San Francisco, CA USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Strotmeyer, Elsa S.; Metti, Andrea] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Shorr, Ronald I.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, 4150 Clement St,POB 181, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu RI Strotmeyer, Elsa/F-3015-2014; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Strotmeyer, Elsa/0000-0002-4093-6036 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, K24AG031155]; National Institute of Nursing Research [R01-AG028050, R01-NR012459]; Intramural Research Program of the National Institutes of Health; American Health Assistance Foundation [A201-0029] FX This study was supported by grants N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 from the National Institute on Aging and by grants R01-AG028050 and R01-NR012459 from the National Institute of Nursing Research. This research was supported in part by the Intramural Research Program of the National Institutes of Health, by the National Institute on Aging, and by grant A201-0029 from the American Health Assistance Foundation. Dr Yaffe is supported in part by grant K24AG031155 from the National Institute on Aging. NR 33 TC 76 Z9 79 U1 5 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL 22 PY 2013 VL 173 IS 14 BP 1300 EP + DI 10.1001/jamainternmed.2013.6176 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 214TX UT WOS:000324160100007 PM 23753199 ER PT J AU McCrum, ML Joynt, KE Orav, EJ Gawande, AA Jha, AK AF McCrum, Marta L. Joynt, Karen E. Orav, E. John Gawande, Atul A. Jha, Ashish K. TI Mortality for Publicly Reported Conditions and Overall Hospital Mortality Rates SO JAMA INTERNAL MEDICINE LA English DT Article ID QUALITY; CARE; SURGERY; VOLUME AB IMPORTANCE Federal efforts about public reporting and quality improvement programs for hospitals have focused primarily on a small number of medical conditions. Whether performance on these conditions accurately predicts the quality of broader hospital care is unknown. OBJECTIVE To determine whether mortality rates for publicly reported medical conditions are correlated with hospitals' overall performance. METHODS Using national Medicare data, we compared hospital performance at 2322 US acute care hospitals on 30-day risk-adjusted mortality, aggregated across the 3 publicly reported conditions (acute myocardial infarction, congestive heart failure, and pneumonia), with performance on a composite risk-adjusted mortality rate across 9 other common medical conditions, a composite mortality rate across 10 surgical conditions, and both composites combined. We also examined the relationship between alternative surrogates of quality (hospital size and teaching status) and performance on these composite outcomes. RESULTS Our sample included 6 670 859 hospitalizations for Medicare fee-for-service beneficiaries from 2008 through 2009. Hospitals in the top quartile of performance on publicly reported conditions had a 3.6% lower absolute risk-adjusted mortality rate on the combined medical-surgical composite than those in the bottom quartile (9.4% vs 13.0%; P < .001). These top performers on publicly reported conditions had 5 times greater odds of being in the top quartile on the overall combined composite risk-adjusted mortality rate (odds ratio [OR], 5.3; 95% CI, 4.3-6.5). Mortality rates for the index condition were predictive of medical (OR, 8.4; 95% CI, 6.8-10.3) and surgical (2.7; 2.2-3.3) performance when these groups were considered separately. In comparison, large size (OR, 1.9; 95% CI, 1.5-2.4) and teaching status (2.4; 1.8-3.2) showed weaker relationships with overall hospital mortality rates. CONCLUSIONS AND RELEVANCE Hospital performance on publicly reported conditions can potentially be used as a signal of overall hospital mortality rates. C1 [McCrum, Marta L.; Joynt, Karen E.; Gawande, Atul A.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Orav, E. John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [McCrum, Marta L.; Gawande, Atul A.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA USA. [Orav, E. John; Jha, Ashish K.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Joynt, Karen E.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Gawande, Atul A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gawande, Atul A.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Joynt, Karen E.; Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. RP Jha, AK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM ajha@hsph.harvard.edu OI Gawande, Atul/0000-0002-1824-9176 FU Center for Surgery and Public Health at Brigham and Women's Hospital; National Heart, Lung, and Blood Institute [1K23HL109177-01]; Brigham and Women's Hospital, Division of Cardiovascular Medicine; Harvard School of Public Health FX This study was supported by the Cabot Fellowship from the Center for Surgery and Public Health at Brigham and Women's Hospital (Dr McCrum); grant 1K23HL109177-01 from the National Heart, Lung, and Blood Institute (Dr Joynt); and the Lerner Research Award from Brigham and Women's Hospital, Division of Cardiovascular Medicine (Dr Joynt). Additional support was provided from internal department funds from the Harvard School of Public Health. NR 13 TC 12 Z9 12 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL 22 PY 2013 VL 173 IS 14 BP 1351 EP 1357 DI 10.1001/jamainternmed.2013.7049 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 214TX UT WOS:000324160100017 PM 23797306 ER PT J AU Chen, CM Wonsey, DR Lemieux, ME Kung, AL AF Chen, Changmin Wonsey, Diane R. Lemieux, Madeleine E. Kung, Andrew L. TI Differential Disruption of EWS-FLI1 Binding by DNA-Binding Agents SO PLOS ONE LA English DT Article ID MAGNETIC-RESONANCE INVESTIGATIONS; ACTINOMYCIN-D; EWINGS-SARCOMA; AQUEOUS-SOLUTION; ONCOGENIC TRANSCRIPTION; COMPLEX-FORMATION; GROWTH-FACTOR; GENE; FUSION; TUMOR AB Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an aberrant gene expression program responsible for the development of Ewing sarcoma. We used a homogenous proximity assay to screen for compounds that disrupt the binding of EWS-FLI1 to its cognate DNA targets. A number of DNA-binding chemotherapeutic agents were found to non-specifically disrupt protein binding to DNA. In contrast, actinomycin D was found to preferentially disrupt EWS-FLI1 binding by comparison to p53 binding to their respective cognate DNA targets in vitro. In cell-based assays, low concentrations of actinomycin D preferentially blocked EWS-FLI1 binding to chromatin, and disrupted EWS-FLI1-mediated gene expression. Higher concentrations of actinomycin D globally repressed transcription. These results demonstrate that actinomycin D preferentially disrupts EWS-FLI1 binding to DNA at selected concentrations. Although the window between this preferential effect and global suppression is too narrow to exploit in a therapeutic manner, these results suggest that base-preferences may be exploited to find DNA-binding compounds that preferentially disrupt subclasses of transcription factors. C1 [Chen, Changmin; Wonsey, Diane R.; Lemieux, Madeleine E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Chen, Changmin; Wonsey, Diane R.; Lemieux, Madeleine E.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Kung, Andrew L.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10027 USA. RP Kung, AL (reprint author), Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10027 USA. EM akung@columbia.edu OI Lemieux, Madeleine/0000-0001-6355-8691; Kung, Andrew/0000-0002-9091-488X FU St. Baldrick's Foundation FX Funding provided by St. Baldrick's Foundation (Kung). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 4 Z9 5 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 JUL 22 PY 2013 VL 8 IS 7 AR e69714 DI 10.1371/journal.pone.0069714 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187PW UT WOS:000322132100077 PM 23894528 ER PT J AU Pfitzner, E Wachauf, C Kilchherr, F Pelz, B Shih, WM Rief, M Dietz, H AF Pfitzner, Emanuel Wachauf, Christian Kilchherr, Fabian Pelz, Benjamin Shih, William M. Rief, Matthias Dietz, Hendrik TI Rigid DNA Beams for High-Resolution Single-Molecule Mechanics SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE biophysics; DNA nanotechnology; DNA structures; force spectroscopy; single-molecule experiments ID OPTICAL TWEEZERS; NANOSCALE SHAPES; NUCLEIC-ACID; FOLDING DNA; PROTEIN; TRAJECTORIES; LANDSCAPES; ELASTICITY; RIBOSWITCH; ORIGAMI C1 [Pfitzner, Emanuel; Wachauf, Christian; Kilchherr, Fabian; Dietz, Hendrik] Tech Univ Munich, Dept Phys, Walter Schottky Inst, D-85748 Garching, Germany. [Pelz, Benjamin; Rief, Matthias] Tech Univ Munich, Dept Phys, Lehrstuhl Biophys, D-85748 Garching, Germany. [Shih, William M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Dietz, H (reprint author), Tech Univ Munich, Dept Phys, Walter Schottky Inst, Coulombwall 4A, D-85748 Garching, Germany. EM dietz@tum.de FU European Research Council [256270]; Deutsche Forschungsgemeinschaft (DFG) through the programs Collaborative Research Center [SFB 863]; Center for Integrated Protein Science Munich; Nanosystems Initiative Munich; CompInt of Elitenetzwerk Bayern FX E.P., C.W., F.K. performed experiments; H.D. and M.R. designed research; E.P., C.W., F.K., H.D., M.R. analyzed data; B.P. built the experimental setup; W.S. provided custom reagents; E.P., C.W., H.D. prepared figures, H.D. wrote the paper; M.R. and W.S. edited the paper. This work was supported by a European Research Council Starting Grant to H.D. (GA no 256270), the Deutsche Forschungsgemeinschaft (DFG) through the programs Collaborative Research Center SFB 863, Center for Integrated Protein Science Munich, and Nanosystems Initiative Munich. F.K. was supported by a stipend from CompInt of Elitenetzwerk Bayern. We thank Florian Praetorius and Johannes Stigler for technical support, and Michael Woodside, Felix Ritort, Ciro Cecconi, Zev Bryant, Thorsten Hugel, and Achillefs Kapanidis for discussions. NR 39 TC 29 Z9 29 U1 5 U2 69 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1433-7851 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD JUL 22 PY 2013 VL 52 IS 30 BP 7766 EP 7771 DI 10.1002/anie.201302727 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 184NE UT WOS:000321896800031 PM 23794413 ER PT J AU Atkins, BD Yoshida, S Saito, K Wu, CF Lew, DJ Pellman, D AF Atkins, Benjamin D. Yoshida, Satoshi Saito, Koji Wu, Chi-Fang Lew, Daniel J. Pellman, David TI Inhibition of Cdc42 during mitotic exit is required for cytokinesis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID GTPASE-ACTIVATING PROTEIN; CELL POLARITY DETERMINANTS; BUDDING YEAST CYTOKINESIS; SACCHAROMYCES-CEREVISIAE; ACTOMYOSIN-RING; BUD EMERGENCE; SEPTIN RING; LOCAL ACTIVATION; CLEAVAGE FURROW; MYOSIN-II AB The role of Cdc42 and its regulation during cytokinesis is not well understood. Using biochemical and imaging approaches in budding yeast, we demonstrate that Cdc42 activation peaks during the G(1)/S transition and during anaphase but drops during mitotic exit and cytokinesis. Cdc5/Polo kinase is an important upstream cell cycle regulator that suppresses Cdc42 activity. Failure to down-regulate Cdc42 during mitotic exit impairs the normal localization of key cytokinesis regulators-Iqg1 and Inn1-at the division site, and results in an abnormal septum. The effects of Cdc42 hyperactivation are largely mediated by the Cdc42 effector p21-activated kinase Ste20. Inhibition of Cdc42 and related Rho guanosine triphosphatases may be a general feature of cytokinesis in eukaryotes. C1 [Atkins, Benjamin D.; Yoshida, Satoshi; Pellman, David] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Atkins, Benjamin D.; Yoshida, Satoshi; Pellman, David] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Yoshida, Satoshi] Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. [Yoshida, Satoshi] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02454 USA. [Pellman, David] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Saito, Koji; Wu, Chi-Fang; Lew, Daniel J.] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. RP Pellman, D (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM david_pellman@dfci.harvard.edu FU National Institutes of Health [RO1 GM061345, R01 GM62300] FX This work was supported by National Institutes of Health grants RO1 GM061345 and R01 GM62300. NR 65 TC 19 Z9 19 U1 0 U2 8 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 22 PY 2013 VL 202 IS 2 BP 231 EP 240 DI 10.1083/jcb.201301090 PG 10 WC Cell Biology SC Cell Biology GA 186RR UT WOS:000322062300008 PM 23878274 ER PT J AU Janssen, AM Rampersad, SM Lucka, F Lanfer, B Lew, S Aydin, U Wolters, CH Stegeman, DF Oostendorp, TF AF Janssen, A. M. Rampersad, S. M. Lucka, F. Lanfer, B. Lew, S. Aydin, Ue Wolters, C. H. Stegeman, D. F. Oostendorp, T. F. TI The influence of sulcus width on simulated electric fields induced by transcranial magnetic stimulation SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID BRAIN-TISSUE; IMPEDANCE METHOD; ELEMENT-METHOD; MODEL; GEOMETRY; TMS; COMPUTATION; MECHANISMS; ANISOTROPY; ACCURACY AB Volume conduction models can help in acquiring knowledge about the distribution of the electric field induced by transcranial magnetic stimulation. One aspect of a detailed model is an accurate description of the cortical surface geometry. Since its estimation is difficult, it is important to know how accurate the geometry has to be represented. Previous studies only looked at the differences caused by neglecting the complete boundary between cerebrospinal fluid (CSF) and grey matter (Thielscher et al 2011 NeuroImage 54 234-43, Bijsterbosch et al 2012 Med. Biol. Eng. Comput. 50 671-81), or by resizing the whole brain (Wagner et al 2008 Exp. Brain Res. 186 539-50). However, due to the high conductive properties of the CSF, it can be expected that alterations in sulcus width can already have a significant effect on the distribution of the electric field. To answer this question, the sulcus width of a highly realistic head model, based on T1-, T2- and diffusion-weighted magnetic resonance images, was altered systematically. This study shows that alterations in the sulcus width do not cause large differences in the majority of the electric field values. However, considerable overestimation of sulcus width produces an overestimation of the calculated field strength, also at locations distant from the target location. C1 [Janssen, A. M.; Rampersad, S. M.; Stegeman, D. F.; Oostendorp, T. F.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, NL-6525 CG Nijmegen, Netherlands. [Lucka, F.] Univ Munster, Inst Computat & Appl Math, D-48149 Munster, Germany. [Lucka, F.; Lanfer, B.; Aydin, Ue; Wolters, C. H.] Univ Munster, Inst Biomagnetism & Biosignalanal, D-48149 Munster, Germany. [Lanfer, B.] BESA GmbH, D-82166 Grafelfing, Germany. [Lew, S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Stegeman, D. F.] Vrije Univ Amsterdam, Fac Human Movement Sci, Res Inst MOVE, NL-1081 BT Amsterdam, Netherlands. RP Janssen, AM (reprint author), Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Reinier Postlaan 4, NL-6525 CG Nijmegen, Netherlands. EM A.Janssen@neuro.umcn.nl RI Wolters, Carsten/R-4234-2016 OI Wolters, Carsten/0000-0001-6233-424X FU German Research Foundation [DFG WO1425/2-1]; BESA GmbH, Grafelfing, Germany; German National Academic Foundation ('Studienstiftung des deutschen Volkes'); NIH [R01EB0009048] FX This study was performed in the context of the BrainGain Smart Mix program of the Dutch government. It was further supported by funding awarded to CHW from the German Research Foundation (DFG WO1425/2-1) for UA and from BESA GmbH, Grafelfing, Germany, for BL. FL was funded by the German National Academic Foundation ('Studienstiftung des deutschen Volkes'). SL was funded by NIH (NIH grant R01EB0009048). The study was made possible in part by software from the NIH/NIGMS Center for Integrative Biomedical Computing, 2P41 RR0112553-12. NR 28 TC 7 Z9 7 U1 3 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 21 PY 2013 VL 58 IS 14 BP 4881 EP 4896 DI 10.1088/0031-9155/58/14/4881 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 175PR UT WOS:000321243600013 PM 23787706 ER PT J AU Kiaii, S Clear, AJ Ramsay, AG Davies, D Sangaralingam, A Lee, A Calaminici, M Neuberg, DS Gribben, JG AF Kiaii, Shahryar Clear, Andrew J. Ramsay, Alan G. Davies, Derek Sangaralingam, Ajanthah Lee, Abigail Calaminici, Maria Neuberg, Donna S. Gribben, John G. TI Follicular Lymphoma Cells Induce Changes in T-Cell Gene Expression and Function: Potential Impact on Survival and Risk of Transformation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MELANIN-CONCENTRATING HORMONE; CHRONIC LYMPHOCYTIC-LEUKEMIA; TUMOR-ASSOCIATED MACROPHAGES; NF-KAPPA-B; IMMUNE CELLS; MICROENVIRONMENT; RECEPTOR; CANCER; ETV1 AB Purpose Previous studies have demonstrated the prognostic importance of the immune microenvironment in follicular lymphoma (FL). To investigate the molecular mechanisms during which tumor-infiltrating T cells (TILs) are altered in the FL microenvironment, we studied highly purified CD4 and CD8 TILs from lymph node biopsies at diagnosis in treatment-naive patients with FL compared with reactive tonsils and the peripheral blood of healthy donors. Patients and Methods Gene expression profiling of highly purified CD4 and CD8 TILs was performed on the Affymetrix platform. Diagnostic tissue microarrays from an independent patient set (n = 172) were used to verify protein expression and analyze any impact of TIL-expressed genes on outcome. Time-lapse imaging was used to assess T-cell motility. Results The most upregulated genes in both CD4 and CD8 TILs were PMCH, ETV1, and TNFRSF9. PMCH is not expressed in peripheral blood T cells, but expression is highly induced on culture with FL. Both CD4 and CD8 TILs from patients with FL have significantly impaired motility compared with those of healthy TILs from reactive tonsils and this can be induced on healthy T cells by FL cells. During multivariate analysis, a model incorporating the number and location of T cells expressing PMCH, NAMPT, and ETV1 showed prognostic significance for overall survival and for time to transformation. Conclusion We showed altered gene expression in TILs in FL and demonstrated that altering the immune microenvironment in FL affects overall survival and time to transformation in this disease. (C) 2013 by American Society of Clinical Oncology C1 [Kiaii, Shahryar; Clear, Andrew J.; Ramsay, Alan G.; Sangaralingam, Ajanthah; Lee, Abigail; Gribben, John G.] Barts Canc Inst, London, England. [Sangaralingam, Ajanthah] Univ London, London Sch Med, London, England. [Davies, Derek] Canc Res UK, London Res Inst, FACS Lab, London, England. [Lee, Abigail; Calaminici, Maria] Barts Hlth NHS Trust, London, England. [Neuberg, Donna S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gribben, JG (reprint author), Queen Mary Univ London, Barts & London Sch Med, Ctr Haematooncol, Barts Canc Ins, Charterhouse Sq, London EC1M 6BQ, England. EM j.gribben@qmul.ac.uk RI Ramsay, Alan/A-8374-2015 OI Ramsay, Alan/0000-0002-0452-0420 FU Cancer Research UK [C1574/A6806]; National Cancer Institute [P01 CA81538] FX Supported by Grant No. C1574/A6806 from Cancer Research UK (J.G.G.) and Grant No. P01 CA81538 from the National Cancer Institute. NR 38 TC 29 Z9 29 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2013 VL 31 IS 21 BP 2654 EP + DI 10.1200/JCO.2012.44.2137 PG 9 WC Oncology SC Oncology GA 301NJ UT WOS:000330538700012 PM 23775959 ER PT J AU Koreth, J Pidala, J Perez, WS Deeg, HJ Garcia-Manero, G Malcovati, L Cazzola, M Park, S Itzykson, R Ades, L Fenaux, P Jadersten, M Hellstrom-Lindberg, E Gale, RP Beach, CL Lee, SJ Horowitz, MM Greenberg, PL Tallman, MS DiPersio, JF Bunjes, D Weisdorf, DJ Cutler, C AF Koreth, John Pidala, Joseph Perez, Waleska S. Deeg, H. Joachim Garcia-Manero, Guillermo Malcovati, Luca Cazzola, Mario Park, Sophie Itzykson, Raphael Ades, Lionel Fenaux, Pierre Jadersten, Martin Hellstrom-Lindberg, Eva Gale, Robert Peter Beach, C. L. Lee, Stephanie J. Horowitz, Mary M. Greenberg, Peter L. Tallman, Martin S. DiPersio, John F. Bunjes, Donald Weisdorf, Daniel J. Cutler, Corey TI Role of Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem-Cell Transplantation in Older Patients With De Novo Myelodysplastic Syndromes: An International Collaborative Decision Analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; PROGNOSTIC SCORING SYSTEM; HLA-IDENTICAL SIBLINGS; ACUTE MYELOID-LEUKEMIA; MYELOPROLIFERATIVE DISORDERS; PREDICTING SURVIVAL; HODGKINS-DISEASE; LIFE EXPECTANCY; PHASE-III AB Purpose Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are more common in patients aged >= 60 years and are incurable with conventional therapies. Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem-cell transplantation is potentially curative but has additional mortality risk. We evaluated RIC transplantation versus nontransplantation therapies in older patients with MDS stratified by International Prognostic Scoring System (IPSS) risk. Patients and Methods A Markov decision model with quality-of-life utility estimates for different MDS and transplantation states was assessed. Outcomes were life expectancy (LE) and quality-adjusted life expectancy (QALE). A total of 514 patients with de novo MDS aged 60 to 70 years were evaluated. Chronic myelomonocytic leukemia, isolated 5q-syndrome, unclassifiable, and therapy-related MDS were excluded. Transplantation using T-cell depletion or HLA-mismatched or umbilical cord donors was also excluded. RIC transplantation (n = 132) stratified by IPSS risk was compared with best supportive care for patients with nonanemic low/intermediate-1 IPSS (n = 123), hematopoietic growth factors for patients with anemic low/intermediate-1 IPSS (n = 94), and hypomethylating agents for patients with intermediate-2/high IPSS (n = 165). Results For patients with low/intermediate-1 IPSS MDS, RIC transplantation LE was 38 months versus 77 months with nontransplantation approaches. QALE and sensitivity analysis did not favor RIC transplantation across plausible utility estimates. For intermediate-2/high IPSS MDS, RIC transplantation LE was 36 months versus 28 months for nontransplantation therapies. QALE and sensitivity analysis favored RIC transplantation across plausible utility estimates. Conclusion For patients with de novo MDS aged 60 to 70 years, favored treatments vary with IPSS risk. For low/intermediate-1 IPSS, nontransplantation approaches are preferred. For intermediate-2/high IPSS, RIC transplantation offers overall and quality-adjusted survival benefit. (C) 2013 by American Society of Clinical Oncology C1 [Koreth, John; Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02215 USA. [Pidala, Joseph] H Lee Moffitt Canc & Res Inst, Tampa, FL USA. [Perez, Waleska S.; Horowitz, Mary M.] Ctr Int Blood & Marrow Transplant Res, Ctr Stat, Milwaukee, WI USA. [Deeg, H. Joachim; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Garcia-Manero, Guillermo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Malcovati, Luca; Cazzola, Mario] Univ Pavia, Sch Med, I-27100 Pavia, Italy. [Park, Sophie] Univ Paris 05, F-75270 Paris 06, France. [Itzykson, Raphael; Ades, Lionel; Fenaux, Pierre] Univ Paris 13, Paris, France. [Jadersten, Martin; Hellstrom-Lindberg, Eva] Karolinska Inst, Stockholm, Sweden. [Gale, Robert Peter; Beach, C. L.] Celgene, Summit, NJ USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, London, England. [Greenberg, Peter L.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [DiPersio, John F.] Washington Univ, Sch Med, St Louis, MO USA. [Bunjes, Donald] Univ Hosp Ulm, Ulm, Germany. [Weisdorf, Daniel J.] Univ Minnesota, Minneapolis, MN USA. RP Koreth, J (reprint author), Dana Farber Canc Inst, D1B05,450 Brookline Ave, Boston, MA 02215 USA. EM jkoreth@partners.org FU Stem Cell Cyclists of the Pan Mass Challenge FX J.K. is a Leukemia and Lymphoma Society Scholar in Clinical Research. C. C. is supported by the Stem Cell Cyclists of the Pan Mass Challenge. NR 56 TC 84 Z9 86 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2013 VL 31 IS 21 BP 2662 EP + DI 10.1200/JCO.2012.46.8652 PG 10 WC Oncology SC Oncology GA 301NJ UT WOS:000330538700013 PM 23797000 ER PT J AU Moy, B Bradbury, AR Helft, PR Egleston, BL Sheikh-Salah, M Peppercorn, J AF Moy, Beverly Bradbury, Angela R. Helft, Paul R. Egleston, Brian L. Sheikh-Salah, Moktar Peppercorn, Jeffrey TI Correlation Between Financial Relationships With Commercial Interests and Research Prominence at an Oncology Meeting SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CONFLICTS-OF-INTEREST; CLINICAL-TRIALS; CANCER-RESEARCH; INDUSTRY; POLICIES; PUBLICATION; ASSOCIATION; FREQUENCY AB Purpose Little is known about the effects of financial relationships between biomedical researchers and industry (financial conflicts of interest [FCOIs]) on research prominence. We examined the prevalence of FCOIs in oncology and associations between FCOIs and research prominence among abstracts presented at American Society of Clinical Oncology (ASCO) annual meetings. Methods We analyzed 20,718 abstracts presented at ASCO meetings in 2006 and 2008 to 2011. Measures included the following: financial relationships, peer review score (PRS), and meeting placement prominence (descending order of prominence: plenary session, clinical science symposium, oral presentation, poster discussion, general posters, and publish only). Results Of 20,718 abstracts, 36% reported at least one author with an FCOI. The proportion of abstracts with any FCOI increased from 33% in 2006 to 38% in 2011 (P < .001). Abstracts with FCOIs had significantly higher meeting prominence compared with publish only and general poster abstracts. The odds ratios compared with general posters were 7.3 for plenary session, 2.2 for clinical science symposium, 1.9 for oral presentation, and 1.7 for poster discussion (P < .001). Abstracts with FCOIs had significantly better PRSs compared with those without FCOIs. For all abstracts, PRS was 2.76 (95% CI, 2.75 to 2.77) with FCOIs compared with 3.01 (95% CI, 3.001 to 3.02) without FCOIs (P < 001). Omitting publish-only abstracts, PRS was 2.62 (95% CI, 2.61 to 2.63) with FCOIs compared with 2.73 without FCOIs (95% CI, 2.71 to 2.73). Conclusion Abstracts with FCOIs had more prominent meeting placement and better PRSs. FCOIs were reported more frequently by year, suggesting an increasing influence of industry on cancer research, greater disclosure, or both. (C) 2013 by American Society of Clinical Oncology C1 [Moy, Beverly] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Bradbury, Angela R.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Egleston, Brian L.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Helft, Paul R.] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Sheikh-Salah, Moktar] Amer Soc Clin Oncol, Alexandria, VA USA. [Peppercorn, Jeffrey] Duke Univ, Med Ctr, Durham, NC USA. RP Moy, B (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 9A, Boston, MA 02114 USA. EM bmoy@partners.org FU Novartis FX Research Funding: Jeffrey Peppercorn, Novartis NR 29 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2013 VL 31 IS 21 BP 2678 EP + DI 10.1200/JCO.2012.46.6375 PG 8 WC Oncology SC Oncology GA 301NJ UT WOS:000330538700015 PM 23775973 ER PT J AU Partridge, AH Gelber, S Piccart-Gebhart, MJ Focant, F Scullion, M Holmes, E Winer, EP Gelber, RD AF Partridge, Ann H. Gelber, Shari Piccart-Gebhart, Martine J. Focant, Florine Scullion, Matthew Holmes, Eileen Winer, Eric P. Gelber, Richard D. TI Effect of Age on Breast Cancer Outcomes in Women With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From a Herceptin Adjuvant Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID YOUNG-WOMEN; PATHOLOGICAL FEATURES; LESS-THAN-35 YEARS; SURVIVAL-DATA; DIAGNOSIS; CHEMOTHERAPY; DISEASE; TRASTUZUMAB; EXPRESSION; PROGNOSIS AB Purpose Previous research has suggested that young age at diagnosis is an independent risk factor for breast cancer recurrence and death. No prior studies have adequately controlled for human epidermal growth factor receptor 2 (HER2) status or anti-HER2 treatment. We sought to evaluate whether age was a prognostic or predictive factor in the HERA trial. Patients and Methods We used 2-year median follow-up data and dichotomized age at 40 years to evaluate its prognostic effect on outcomes for women assigned to trastuzumab for 1 year or observation. Results Of the 1,703 women randomly assigned to 1 year of trastuzumab and 1,698 to observation, 722 (21%) were age <= 40 years at study entry. In separate Cox models, controlling for relevant prognostic and predictive factors, disease-free (DFS) and overall survival (OS) hazard ratios (HRs) were consistent for women age <= 40 versus > 40 years, regardless of treatment assignment (observation group: DFS HR age <= 40 v > 40 years, 1.18; 95% CI, 0.90 to 1.54; OS HR age <= 40 v > 40 years, 1.01; 95% CI, 0.60 to 1.69; trastuzumab group: DFS HR age <= 40 v > 40 years, 1.11; 95% CI, 0.81 to 1.51; OS HR age <= 40 v > 40 years, 1.18; 95% CI, 0.66 to 2.09). Interaction between age group and treatment effect was not statistically significant (DFS P = .89; OS P = .55). Conclusion In a retrospective analysis of a large randomized controlled trial of women with early-stage HER2-positive breast cancer, age was not strongly associated with risk of early recurrence or prediction of benefit from trastuzumab therapy. Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes. (C) 2013 by American Society of Clinical Oncology C1 [Partridge, Ann H.; Gelber, Shari; Winer, Eric P.; Gelber, Richard D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Piccart-Gebhart, Martine J.; Focant, Florine] Univ Libre Brussels, Inst Jules Bordet, Brussels, Belgium. [Scullion, Matthew] Roche Prod Ltd, Welwyn Garden City AL7 3AY, Herts, England. [Holmes, Eileen] Frontier Sci Scotland, Kincraig, Scotland. RP Partridge, AH (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM ahpartridge@partners.org FU Roche; Genentech FX Research Funding: Shari Gelber, Roche; Eileen Holmes, Roche; Eric P. Winer, Genentech; Richard D. Gelber, Roche NR 33 TC 36 Z9 37 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2013 VL 31 IS 21 BP 2692 EP 2698 DI 10.1200/JCO.2012.44.1956 PG 7 WC Oncology SC Oncology GA 301NJ UT WOS:000330538700017 PM 23752109 ER PT J AU Ryoo, JJ Ordin, DL Antonio, ALM Oishi, SM Gould, MK Asch, SM Malin, JL AF Ryoo, Joan J. Ordin, Diana L. Antonio, Anna Liza M. Oishi, Sabine M. Gould, Michael K. Asch, Steven M. Malin, Jennifer L. TI Patient Preference and Contraindications in Measuring Quality of Care: What Do Administrative Data Miss? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; CORONARY-ARTERY-DISEASE; RACIAL-DIFFERENCES; PERFORMANCE-MEASURES; INITIAL TREATMENT; MEDICARE PATIENTS; PRIVATE-SECTOR; VETERANS; SURVIVAL; CHEMOTHERAPY AB Purpose Prior studies report that half of patients with lung cancer do not receive guideline-concordant care. With data from a national Veterans Health Administration (VHA) study on quality of care, we sought to determine what proportion of patients refused or had a contraindication to recommended lung cancer therapy. Patients and Methods Through medical record abstraction, we evaluated adherence to six quality indicators addressing lung cancer-directed therapy for patients diagnosed within the VHA during 2007 and calculated the proportion of patients receiving, refusing, or having contraindications to recommended treatment. Results Mean age of the predominantly male population was 67.7 years (standard deviation, 9.4 years), and 15% were black. Adherence to quality indicators ranged from 81% for adjuvant chemotherapy to 98% for curative resection; however, many patients met quality indicator criteria without actually receiving recommended therapy by having a refusal (0% to 14%) or contraindication (1% to 30%) documented. Less than 1% of patients refused palliative chemotherapy. Black patients were more likely to refuse or bear a contraindication to surgery even when controlling for comorbidity; race was not associated with refusals or contraindications to other treatments. Conclusion Refusals and contraindications are common and may account for previously demonstrated low rates of recommended lung cancer therapy performance at the VHA. Racial disparities in treatment may be explained, in part, by such factors. These results sound a cautionary note for quality measurement that depends on data that do not reflect patient preference or contraindications in conditions where such considerations are important. (C) 2013 by American Society of Clinical Oncology C1 [Ryoo, Joan J.; Ordin, Diana L.; Antonio, Anna Liza M.; Malin, Jennifer L.] Vet Adm Greater Los Angeles Healthcare Syst, West Los Angeles, CA USA. [Ryoo, Joan J.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Ryoo, Joan J.] Kaiser Permanente Los Angeles Med Ctr, Los Angeles, CA 90027 USA. [Antonio, Anna Liza M.] Univ Calif Los Angeles, Los Angeles, CA USA. [Oishi, Sabine M.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Gould, Michael K.] Kaiser Permanente So Calif, Pasadena, CA 91101 USA. [Asch, Steven M.] Vet Adm Palo Alto Healthcare Syst, Palo Alto, CA USA. [Asch, Steven M.] Stanford Sch Med, Palo Alto, CA USA. [Ordin, Diana L.] Vet Hlth Adm, Washington, DC USA. [Malin, Jennifer L.] WellPoint, Indianapolis, IN USA. RP Ryoo, JJ (reprint author), Kaiser Permanente Los Angeles Med Ctr, Dept Radiat Oncol, 4950 Sunset Blvd,Second Floor, Los Angeles, CA 90027 USA. EM joan.j.ryoo@kp.org FU Robert Wood Johnson Clinical Scholars Program; University of California, Los Angeles Career Development Program in Cancer Prevention and Control Research National Cancer Institute R25 Grant FX Supported in part by the Robert Wood Johnson Clinical Scholars Program (J.J.R.) and the University of California, Los Angeles Career Development Program in Cancer Prevention and Control Research National Cancer Institute R25 Grant (J.J.R.). NR 58 TC 17 Z9 17 U1 2 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2013 VL 31 IS 21 BP 2716 EP + DI 10.1200/JCO.2012.45.7473 PG 9 WC Oncology SC Oncology GA 301NJ UT WOS:000330538700020 PM 23752110 ER PT J AU Chen, AB Cronin, A Weeks, JC Chrischilles, EA Malin, J Hayman, JA Schrag, D AF Chen, Aileen B. Cronin, Angel Weeks, Jane C. Chrischilles, Elizabeth A. Malin, Jennifer Hayman, James A. Schrag, Deborah TI Expectations About the Effectiveness of Radiation Therapy Among Patients With Incurable Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CARE OUTCOMES RESEARCH; INTERNATIONAL CONSENSUS WORKSHOP; PALLIATIVE RADIOTHERAPY; SURVEILLANCE CONSORTIUM; MULTIPLE IMPUTATION; SYMPTOM CONTROL; PROGNOSIS; PERCEPTIONS; PREDICTIONS; METASTASES AB Purpose Although radiation therapy (RT) can palliate symptoms and may prolong life, it is not curative for patients with metastatic lung cancer. We investigated patient expectations about the goals of RT for incurable lung cancers. Patients and Methods The Cancer Care Outcomes Research and Surveillance Consortium enrolled a population-and health system-based cohort of patients diagnosed with lung cancer from 2003 to 2005. We identified patients with stage wet IIIB or IV lung cancer who received RT and answered questions on their expectations about RT. We assessed patient expectations about the goals of RT and identified factors associated with inaccurate beliefs about cure. Results In all, 384 patients completed surveys on their expectations about RT. Seventy-eight percent of patients believed that RT was very or somewhat likely to help them live longer, and 67% believed that RT was very or somewhat likely to help them with problems related to their cancer. However, 64% did not understand that RT was not at all likely to cure them. Older patients and nonwhites were more likely to have inaccurate beliefs, and patients whose surveys were completed by surrogates were less likely to have inaccurate beliefs. Ninety-two percent of patients with inaccurate beliefs about cure from RT also had inaccurate beliefs about chemotherapy. Conclusion Although patients receiving RT for incurable lung cancer believe it will help them, most do not understand that it is not at all likely to cure their disease. This indicates a need to improve communication regarding the goals and limitations of palliative RT. (C) 2013 by American Society of Clinical Oncology C1 [Chen, Aileen B.; Cronin, Angel; Weeks, Jane C.; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02215 USA. [Chen, Aileen B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chrischilles, Elizabeth A.] Univ Iowa, Iowa City, IA USA. [Malin, Jennifer] Univ Calif Los Angeles, Los Angeles, CA USA. [Hayman, James A.] Univ Michigan Hlth Syst, Ann Arbor, MI USA. RP Chen, AB (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,D1111, Boston, MA 02215 USA. EM achen@lroc.harvard.edu OI Chen, Aileen/0000-0002-5385-3360 FU Mentored Research Scholar Grants from the American Cancer Society [MRSG-10-170-01-PCSM]; National Cancer Institute [U01 CA093332]; Harvard Medical School/Northern California Cancer Center [U01 CA093324]; RAND/University of California, Los Angeles [U01 CA093348]; University of Alabama at Birmingham [U01 CA093329]; University of Iowa [U01 CA093339]; University of North Carolina [U01 CA093326]; Statistical Coordinating Center [U01 CA093344]; Department of Veterans Affairs [CRS 02-164] FX Supported by Mentored Research Scholar Grants No. MRSG-10-170-01-PCSM (A. B. C.) from the American Cancer Society; No. U01 CA093332 from the National Cancer Institute to the Dana-Farber Cancer Institute/Cancer Research Network; No. U01 CA093324 from Harvard Medical School/Northern California Cancer Center; No. U01 CA093348 from RAND/University of California, Los Angeles; No. U01 CA093329 from the University of Alabama at Birmingham; No. U01 CA093339 from the University of Iowa; No. U01 CA093326 from the University of North Carolina; and No. U01 CA093344 from the Statistical Coordinating Center and by Department of Veterans Affairs Grant No. CRS 02-164 to the Durham VA Medical Center. NR 29 TC 29 Z9 29 U1 1 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2013 VL 31 IS 21 BP 2730 EP 2735 DI 10.1200/JCO.2012.48.5748 PG 6 WC Oncology SC Oncology GA 301NJ UT WOS:000330538700022 PM 23775958 ER PT J AU Rae, JM Regan, M Leyland-Jones, B Hayes, DF Dowsett, M AF Rae, James M. Regan, Meredith Leyland-Jones, Brian Hayes, Daniel F. Dowsett, Mitch TI CYP2D6 Genotype Should Not Be Used for Deciding About Tamoxifen Therapy in Postmenopausal Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID WOMEN; RECURRENCE; OUTCOMES; TUMORS; 22Q13 C1 [Rae, James M.; Hayes, Daniel F.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Rae, James M.; Hayes, Daniel F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Regan, Meredith] Dana Farber Canc Inst, Boston, MA 02115 USA. [Regan, Meredith] Harvard Univ, Sch Med, Boston, MA USA. [Leyland-Jones, Brian] Sanford Hlth & Res, Sioux Falls, SD USA. [Dowsett, Mitch] Marsden Hosp, London, England. [Dowsett, Mitch] Breakthrough Breast Canc Res Ctr, London, England. RP Rae, JM (reprint author), Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. NR 15 TC 5 Z9 5 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2013 VL 31 IS 21 BP 2753 EP 2755 DI 10.1200/JCO.2013.49.4278 PG 4 WC Oncology SC Oncology GA 301NJ UT WOS:000330538700030 PM 23775974 ER PT J AU Chen, AB Schrag, D AF Chen, Aileen B. Schrag, Deborah TI Radiation Therapy for Metastatic Non-Small-Cell Lung Cancer: When to Bring in Palliative Care? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID PAINFUL BONE METASTASES; FRACTION RADIOTHERAPY; SINGLE; PROGNOSIS C1 [Chen, Aileen B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chen, Aileen B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chen, Aileen B.; Schrag, Deborah] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. RP Chen, AB (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [U01 CA093339, U01 CA093329, U01 CA093344, U01 CA093326, U01 CA093348, U01 CA093332, U01 CA093324] NR 12 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2013 VL 31 IS 21 BP 2759 EP 2760 DI 10.1200/JCO.2013.50.2088 PG 3 WC Oncology SC Oncology GA 301NJ UT WOS:000330538700036 PM 24040666 ER PT J AU Kotloff, KL Nataro, JP Blackwelder, WC Nasrin, D Farag, TH Panchalingam, S Wu, Y Sow, SO Sur, D Breiman, RF Faruque, ASG Zaidi, AKM Saha, D Alonso, PL Tamboura, B Sanogo, D Onwuchekwa, U Manna, B Ramamurthy, T Kanungo, S Ochieng, JB Omore, R Oundo, JO Hossain, A Das, SK Ahmed, S Qureshi, S Quadri, F Adegbola, RA Antonio, M Hossain, MJ Akinsola, A Mandomando, I Nhampossa, T Acacio, S Biswas, K O'Reilly, CE Mintz, ED Berkeley, LY Muhsen, K Sommerfelt, H Robins-Browne, RM Levine, MM AF Kotloff, Karen L. Nataro, James P. Blackwelder, William C. Nasrin, Dilruba Farag, Tamer H. Panchalingam, Sandra Wu, Yukun Sow, Samba O. Sur, Dipika Breiman, Robert F. Faruque, Abu S. G. Zaidi, Anita K. M. Saha, Debasish Alonso, Pedro L. Tamboura, Boubou Sanogo, Doh Onwuchekwa, Uma Manna, Byomkesh Ramamurthy, Thandavarayan Kanungo, Suman Ochieng, John B. Omore, Richard Oundo, Joseph O. Hossain, Anowar Das, Sumon K. Ahmed, Shahnawaz Qureshi, Shahida Quadri, Farheen Adegbola, Richard A. Antonio, Martin Hossain, M. Jahangir Akinsola, Adebayo Mandomando, Inacio Nhampossa, Tacilta Acacio, Sozinho Biswas, Kousick O'Reilly, Ciara E. Mintz, Eric D. Berkeley, Lynette Y. Muhsen, Khitam Sommerfelt, Halvor Robins-Browne, Roy M. Levine, Myron M. TI Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study SO LANCET LA English DT Article ID ENTEROPATHOGENIC ESCHERICHIA-COLI; SUB-SAHARAN AFRICA; ROTAVIRUS VACCINATION; CHILDHOOD MORTALITY; ATTRIBUTABLE RISK; EPIDEMIOLOGY; CASE/CONTROL; CRYPTOSPORIDIOSIS; PERFORMANCE; POPULATION AB Background Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia. Methods The GEMS is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0-59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measure ments, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth. Findings We enrolled 9439 children with moderate-to-severe diarrhoea and 13 129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8.5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8.5, 95% CI 5.8-12.5, p<0.0001); most deaths (167 [87.9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1.9; 0.99-3.5) and typical enteropathogenic E coli (HR 2.6; 1.6-4.1) in infants aged 0-11 months, and Cryptosporidium (HR 2.3; 1.3-4.3) in toddlers aged 12-23 months. Interpretation Interventions targeting five pathogens (rotavirus, Shigella, ST-ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes. C1 [Kotloff, Karen L.; Nataro, James P.; Blackwelder, William C.; Nasrin, Dilruba; Farag, Tamer H.; Panchalingam, Sandra; Wu, Yukun; Berkeley, Lynette Y.; Muhsen, Khitam; Levine, Myron M.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Kotloff, Karen L.; Nataro, James P.; Levine, Myron M.] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. [Kotloff, Karen L.; Nataro, James P.; Blackwelder, William C.; Nasrin, Dilruba; Farag, Tamer H.; Panchalingam, Sandra; Wu, Yukun; Muhsen, Khitam; Levine, Myron M.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Nataro, James P.] Univ Virginia, Sch Med, Dept Pediat, Charlottesville, VA 22908 USA. [Sow, Samba O.; Tamboura, Boubou; Sanogo, Doh; Onwuchekwa, Uma] Ctr Dev Vaccins, Bamako, Mali. [Sur, Dipika; Manna, Byomkesh; Ramamurthy, Thandavarayan; Kanungo, Suman] Natl Inst Cholera & Enter Dis, Kolkata, India. [Breiman, Robert F.] US Ctr Dis Control & Prevent, Kenya Off, Global Dis Detect Div, Nairobi, Kenya. [Faruque, Abu S. G.; Hossain, Anowar; Das, Sumon K.; Ahmed, Shahnawaz] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Zaidi, Anita K. M.; Qureshi, Shahida; Quadri, Farheen] Aga Khan Univ, Dept Paediat & Child Hlth, Karachi, Pakistan. [Saha, Debasish; Adegbola, Richard A.; Antonio, Martin; Hossain, M. Jahangir; Akinsola, Adebayo] Med Res Council UK Unit, Fajara, Gambia. [Alonso, Pedro L.; Mandomando, Inacio; Nhampossa, Tacilta; Acacio, Sozinho] Ctr Invest Saude Manhica, Maputo, Mozambique. [Alonso, Pedro L.] Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, Barcelona, Spain. [Ochieng, John B.; Omore, Richard; Oundo, Joseph O.] Ctr Dis Control & Prevent KEMRI CDC, Kenya Med Res Inst, Kisumu, Kenya. [Adegbola, Richard A.] GlaxoSmithKline Biol, Global Med Affairs, Wavre, Belgium. [Akinsola, Adebayo] Daffodils Pediat & Family Med, Tucker, GA USA. [Mandomando, Inacio; Nhampossa, Tacilta; Acacio, Sozinho] Minist Saude, Inst Nacl Saude, Maputo, Mozambique. [Biswas, Kousick] US Dept Vet Affairs, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [O'Reilly, Ciara E.; Mintz, Eric D.] US Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. [Berkeley, Lynette Y.] Ctr Drug Evaluat & Res, Off Antimicrobial Prod, Div Antiinfect Prod, Silver Spring, MD USA. [Sommerfelt, Halvor] Univ Bergen, Ctr Int Hlth, Bergen, Norway. [Sommerfelt, Halvor] Norwegian Inst Publ Hlth, Div Infect Dis Control, Oslo, Norway. [Robins-Browne, Roy M.] Univ Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. RP Kotloff, KL (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. EM kkotloff@medicine.umaryland.edu OI Robins-Browne, Roy/0000-0001-9179-7884 FU Bill & Melinda Gates Foundation FX The Bill & Melinda Gates Foundation. NR 36 TC 604 Z9 616 U1 15 U2 135 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 20 PY 2013 VL 382 IS 9888 BP 209 EP 222 DI 10.1016/S0140-6736(13)60844-2 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 193FL UT WOS:000322543700031 PM 23680352 ER PT J AU Doros, G Pencina, M Rybin, D Meisner, A Fava, M AF Doros, Gheorghe Pencina, Michael Rybin, Denis Meisner, Allison Fava, Maurizio TI A repeated measures model for analysis of continuous outcomes in sequential parallel comparison design studies SO STATISTICS IN MEDICINE LA English DT Article DE SPCD; repeated measures; placebo effect ID PSYCHIATRIC CLINICAL-TRIALS; PLACEBO-RESPONSE AB Previous authors have proposed the sequential parallel comparison design (SPCD) to address the issue of high placebo response rate in clinical trials. The original use of SPCD focused on binary outcomes, but recent use has since been extended to continuous outcomes that arise more naturally in many fields, including psychiatry. Analytic methods proposed to date for analysis of SPCD trial continuous data included methods based on seemingly unrelated regression and ordinary least squares. Here, we propose a repeated measures linear model that uses all outcome data collected in the trial and accounts for data that are missing at random. An appropriate contrast formulated after the model has been fit can be used to test the primary hypothesis of no difference in treatment effects between study arms. Our extensive simulations show that when compared with the other methods, our approach preserves the type I error even for small sample sizes and offers adequate power and the smallest mean squared error under a wide variety of assumptions. We recommend consideration of our approach for analysis of data coming from SPCD trials. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Doros, Gheorghe; Pencina, Michael; Rybin, Denis; Meisner, Allison] Boston Univ, Dept Biostat, Boston, MA 02118 USA. [Doros, Gheorghe; Pencina, Michael] HCRI, Boston, MA 02215 USA. [Doros, Gheorghe] VA Boston Healthcare Syst, Massachusetts Epidemiol Res & Informat Ctr MAVERI, Boston, MA USA. [Fava, Maurizio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Doros, G (reprint author), Boston Univ, Dept Biostat, 801 Massachusetts Ave, Boston, MA 02118 USA. EM doros@bu.edu OI Rybin, Denis/0000-0002-3657-4829 NR 17 TC 9 Z9 9 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUL 20 PY 2013 VL 32 IS 16 BP 2767 EP 2789 DI 10.1002/sim.5728 PG 23 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 164HW UT WOS:000320400900005 PM 23355369 ER PT J AU Mendivil, CO Robles-Osorio, L Horton, ES Hamdy, O Caballero, AE AF Mendivil, Carlos O. Robles-Osorio, Ludivina Horton, Edward S. Hamdy, Osama Caballero, Augusto Enrique TI Young Hispanics at risk of type 2 diabetes display endothelial activation, subclinical inflammation and alterations of coagulation and fibrinolysis SO DIABETOLOGY & METABOLIC SYNDROME LA English DT Article DE Diabetes; Cardiovacular disease; Endothelial; ICAM-1; Hispanics; Prevention ID INTERCELLULAR-ADHESION MOLECULE-1; CORONARY-HEART-DISEASE; INSULIN-RESISTANCE; ADIPOSE-TISSUE; BODY-FAT; ATHEROSCLEROSIS; DYSFUNCTION; MARKERS; PROTEIN; WOMEN AB Background: Hispanics have a high rate of diabetes that exposes them to an increased risk of cardiovascular disease. We hypothesized that many of the pathophysiological mechanisms that cause atherosclerotic disease may be present in young Hispanics who do not have clinical diabetes but are at increased risk of developing it. Methods: We studied 36 young Hispanic adults without diabetes (ages 18-40). Seventeen participants were at increased risk of developing type 2 diabetes given by overweight and a family history of diabetes on one or both parents (at risk group). Nineteen participants with normal body-mass index and no parental history of diabetes constituted the control group. We measured and compared plasma markers of endothelial dysfunction, disturbed coagulation and fibrinolysis, subclinical inflammation and adipose tissue dysfunction in the at risk and control groups. Results: Participants at risk of diabetes were more insulin-resistant according to different indicators, and had significantly higher levels of soluble intercellular adhesion molecule-1 (sICAM-1), tissue plasminogen activator (tPA), inhibitor of plasminogen activator-1 (PAi-1), high sensitivity C-reactive protein and free fatty acids, signaling the presence of multiple proatherogenic alterations despite the absence of overt diabetes. Levels of the prothrombotic molecule PAi-1 were most elevated in participants who were not only at risk of diabetes by the study definition, but also abdominally obese. Conclusions: Young adult Hispanics at risk of type 2 diabetes but without overt disease already bear considerably high levels of markers reflecting processes that lead to the development of atherosclerotic cardiovascular disease. C1 [Mendivil, Carlos O.] Univ Los Andes, Sch Med, Bogota, Colombia. [Robles-Osorio, Ludivina; Horton, Edward S.; Hamdy, Osama; Caballero, Augusto Enrique] Harvard Univ, Sch Med, Clin Res Ctr, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Caballero, AE (reprint author), Harvard Univ, Sch Med, Clin Res Ctr, Joslin Diabet Ctr, Boston, MA 02115 USA. EM enrique.caballero@joslin.harvard.edu NR 35 TC 3 Z9 4 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-5996 J9 DIABETOL METAB SYNDR JI Diabetol. Metab. Syndr. PD JUL 19 PY 2013 VL 5 AR 37 DI 10.1186/1758-5996-5-37 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196AH UT WOS:000322744800001 PM 23870459 ER PT J AU Ruan, GX Kazlauskas, A AF Ruan, Guo-Xiang Kazlauskas, Andrius TI Lactate Engages Receptor Tyrosine Kinases Axl, Tie2, and Vascular Endothelial Growth Factor Receptor 2 to Activate Phosphoinositide 3-Kinase/Akt and Promote Angiogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE; DEPENDENT ACTIVATION; TUMOR ANGIOGENESIS; PROLONGS SURVIVAL; CELLS; VEGF; EXPRESSION; HYPOXIA; AKT; METABOLISM AB Although a high level of lactate is quintessential to both tumors and wound healing, the manner by which lactate impacts endothelial cells to promote angiogenesis and thereby create or restore vascular perfusion to growing tissues has not been fully elucidated. Here we report that lactate activated the PI3K/Akt pathway in primary human endothelial cells. Furthermore, activating this signaling pathway was required for lactate-stimulated organization of endothelial cells into tubes and for sprouting of vessels from mouse aortic explants. Lactate engaged the PI3K/Akt pathway via ligand-mediated activation of the three receptor tyrosine kinases Axl, Tie2, and VEGF receptor 2. Neutralizing the ligands for these receptor tyrosine kinases, pharmacologically inhibiting their kinase activity or suppressing their expression largely eliminated the ability of cells and explants to respond to lactate. Elucidating the mechanism by which lactate communicates with endothelial cells presents a previously unappreciated opportunity to improve our understanding of the angiogenic program and to govern it. C1 [Ruan, Guo-Xiang; Kazlauskas, Andrius] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. RP Kazlauskas, A (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM andrius_kazlauskas@meei.harvard.edu FU National Institutes of Health [EY018344]; Juvenile Diabetes Research Foundation Advanced Postdoctoral Fellowship [102011367] FX This work was supported, in whole or in part, by National Institutes of Health Grant EY018344 (to A. K.). This work was also supported by Juvenile Diabetes Research Foundation Advanced Postdoctoral Fellowship 102011367 (to G. X. R.). NR 51 TC 35 Z9 36 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 19 PY 2013 VL 288 IS 29 BP 21161 EP 21172 DI 10.1074/jbc.M113.474619 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 186AU UT WOS:000322014400036 PM 23754286 ER PT J AU Yang, XH Meyer, K Friedl, A AF Yang, Xinhai Meyer, Kristy Friedl, Andreas TI STAT5 and Prolactin Participate in a Positive Autocrine Feedback Loop That Promotes Angiogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; N-TERMINAL FRAGMENTS; ANTIANGIOGENIC FACTOR; RECEPTOR ANTAGONISTS; MOLECULAR-MECHANISMS; GENE-TRANSCRIPTION; CELL PROLIFERATION; PITUITARY-TUMORS; RETINOIC ACID; FACTOR VEGF AB We have shown previously that the murine prolactin/growth hormone family member proliferin plays a pivotal role in angiogenesis induced by the FGF2/STAT5 signaling cascade. To delineate the signaling pathway downstream of STAT5 in the human system, where proliferin does not exist, we expressed constitutively active (CA) or dominant-negative (DN) mutant STAT5A in hCMEC/D3 human brain endothelial cells. We found that conditioned medium from CA-STAT5A- but not from DN-STAT5A-overexpressing endothelial cells (EC) is sufficient to induce EC migration and tube formation but not proliferation, indicating that STAT5A regulates the secretion of autocrine proangiogenic factors. We identified prolactin (PRL) as a candidate autocrine factor. CA-STAT5A expression stimulates PRL production at the RNA and protein level, and STAT5A binds to the PRL promoter region, suggesting direct transcriptional regulation. Medium conditioned by CA-STAT5A-over-expressing EC induces phosphorylation of the PRL receptor and activates MAPK. Knockdown of PRL expression by shRNA or blocking of PRL activity with neutralizing antibodies removed the CA-STAT5A-dependent proangiogenic activity from the conditioned medium of EC. The addition of recombinant PRL restores this activity. STAT5A-induced PRL in the conditioned medium can activate STAT5, STAT1, and to a lesser extent STAT3 in hCMEC/D3 cells, suggesting the existence of a positive feedback loop between STAT5 and PRL that promotes angiogenesis. Furthermore, we find that VEGF, a potent proangiogenic factor, is induced by activation of STAT5A, and VEGF induction depends on PRL expression. These observations demonstrate a STAT5/PRL/VEGF signaling cascade in human brain EC and implicate PRL and VEGF as autocrine regulators of EC migration, invasion, and tube formation. C1 [Yang, Xinhai; Meyer, Kristy; Friedl, Andreas] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53705 USA. [Friedl, Andreas] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Dept Vet Affairs Med Ctr, Madison, WI 53705 USA. [Friedl, Andreas] UW Carbone Canc Ctr, Madison, WI 53792 USA. RP Friedl, A (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, 6051 WIMR,MC-2275,1111 Highland Ave, Madison, WI 53705 USA. EM afriedl@wisc.edu FU UW Department of Pathology and Laboratory Medicine; UW Carbone Cancer Center [P30 CA014520] FX We thank Dr. Charles Clevenger, Northwestern University, for immunohistochemical labeling of the glioma samples and Dr. Babette Weksler, Weill Cornell Medical College, for kindly providing hCMEC/D3 cells. Korise Rasmusson helped with manuscript preparation. We thank the University of Wisconsin Translational Research Initiatives in Pathology laboratory, in part supported by the UW Department of Pathology and Laboratory Medicine and UW Carbone Cancer Center Grant P30 CA014520 for use of its facilities and services. NR 63 TC 15 Z9 15 U1 0 U2 20 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 JUL 19 PY 2013 VL 288 IS 29 BP 21184 EP 21196 DI 10.1074/jbc.M113.481119 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 186AU UT WOS:000322014400038 PM 23729680 ER PT J AU Kembabazi, A Bajunirwe, F Hunt, PW Martin, JN Muzoora, C Haberer, JE Bangsberg, DR Siedner, MJ AF Kembabazi, Annet Bajunirwe, Francis Hunt, Peter W. Martin, Jeffrey N. Muzoora, Conrad Haberer, Jessica E. Bangsberg, David R. Siedner, Mark J. TI Disinhibition in Risky Sexual Behavior in Men, but Not Women, during Four Years of Antiretroviral Therapy in Rural, Southwestern Uganda SO PLOS ONE LA English DT Article ID HIV-INFECTED PATIENTS; SOUTH-AFRICA; PROSPECTIVE COHORT; HOMOSEXUAL-MEN; PREVENTION; TRANSMISSION; SEROCONVERSION; INTERVENTIONS; METAANALYSIS; ESTIMATOR AB Background: In resource-rich areas, risky sexual behavior (RSB) largely diminishes after initiation of anti-retroviral therapy, with notable exceptions among some populations who perceive a protected benefit from anti-retroviral therapy (ART). Yet, there is limited data about long-term trends in risky sexual behavior among HIV-infected people in sub-Saharan Africa after initiation of anti-retroviral therapy. Methods: We administered questionnaires every three months to collect sexual behavior data among patients taking ART in southwestern Uganda over four years of follow-up time. We defined RSB as having unprotected sex with an HIV-negative or unknown status partner, or unprotected sex with a casual partner. We fit logistic regression models to estimate changes in RSB by time on ART, with and without adjustment for calendar year and CD4 count. Results: 506 participants were enrolled between 2005 and 2011 and contributed a median of 13 visits and 3.5 years of observation time. The majority were female (70%) and median age was 34 years (interquartile range 29-39). There was a decrease in the proportion of men reporting RSB from the pre-ART visit to the first post-ART visit (16.2 to 4.3%, p < 0.01) but not women (14.1 to 13.3%, p = 0.80). With each year of ART, women reported decreasing RSB (OR 0.85 per year, 95% CI 0.74-0.98, p = 0.03). In contrast, men had increasing odds of reporting RSB with each year of ART to near pre-treatment rates (OR 1.41, 95% CI 1.14-1.74, p = 0.001), which was partially confounded by changes in calendar time and CD4 count (AOR = 1.24, 95% CI 0.92-1.67, p = 0.16). Conclusions: Men in southwestern Uganda reported increasing RSB over four years on ART, to levels approaching pretreatment rates. Strategies to promote long-term safe sex practices targeted to HIV-infected men on ART might have a significant impact on preventing HIV transmission in this setting. C1 [Kembabazi, Annet; Muzoora, Conrad] Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. [Bajunirwe, Francis] Mbarara Univ Sci & Technol, Dept Community Hlth, Mbarara, Uganda. [Hunt, Peter W.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Haberer, Jessica E.; Bangsberg, David R.; Siedner, Mark J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Haberer, Jessica E.; Bangsberg, David R.; Siedner, Mark J.] Harvard Univ, Sch Med, Boston, MA USA. [Bangsberg, David R.] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Cambridge, MA USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Kembabazi, A (reprint author), Mbarara Univ Sci & Technol, Dept Med, Mbarara, Uganda. EM akembabazi2005@yahoo.com FU U.S. National Institutes of Health (NIH) [R01 MH54907, P30 AI27763]; NIH [K23 MH087228, K24 MH87227, T32 AI007433]; Harvard Institute for Global Health; Mark and Lisa Schwartz Family Foundation; Sullivan Family Foundation; Bacca Foundation FX The Uganda AIDS Rural Treatment Outcomes Study is funded by U.S. National Institutes of Health (NIH) R01 MH54907 and P30 AI27763. The authors also acknowledge the following additional sources of salary support: NIH K23 MH087228 (Haberer); NIH K24 MH87227 (Bangsberg); the Harvard Institute for Global Health and NIH T32 AI007433 (Siedner). Additional study funding was provided by the Mark and Lisa Schwartz Family Foundation, the Sullivan Family Foundation, and the Bacca Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 9 Z9 9 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 JUL 19 PY 2013 VL 8 IS 7 AR e69634 DI 10.1371/journal.pone.0069634 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 191CY UT WOS:000322391400063 PM 23894514 ER PT J AU Wojczynski, MK Li, MY Bielak, LF Kerr, KF Reiner, AP Wong, ND Yanek, LR Qu, LM White, CC Lange, LA Ferguson, JF He, J Young, T Mosley, TH Smith, JA Kral, BG Guo, XQ Wong, Q Ganesh, SK Heckbert, SR Griswold, ME O'Leary, DH Budoff, M Carr, JJ Taylor, HA Bluemke, DA Demissie, S Hwang, SJ Paltoo, DN Polak, JF Psaty, BM Becker, DM Province, MA Post, WS O'Donnell, CJ Wilson, JG Harris, TB Kavousi, M Cupples, LA Rotter, JI Fornage, M Becker, LC Peyser, PA Borecki, IB Reilly, MP AF Wojczynski, Mary K. Li, Mingyao Bielak, Lawrence F. Kerr, Kathleen F. Reiner, Alex P. Wong, Nathan D. Yanek, Lisa R. Qu, Liming White, Charles C. Lange, Leslie A. Ferguson, Jane F. He, Jing Young, Taylor Mosley, Thomas H. Smith, Jennifer A. Kral, Brian G. Guo, Xiuqing Wong, Quenna Ganesh, Santhi K. Heckbert, Susan R. Griswold, Michael E. O'Leary, Daniel H. Budoff, Matthew Carr, J. Jeffrey Taylor, Herman A., Jr. Bluemke, David A. Demissie, Serkalem Hwang, Shih-Jen Paltoo, Dina N. Polak, Joseph F. Psaty, Bruce M. Becker, Diane M. Province, Michael A. Post, Wendy S. O'Donnell, Christopher J. Wilson, James G. Harris, Tamara B. Kavousi, Maryam Cupples, L. Adrienne Rotter, Jerome I. Fornage, Myriam Becker, Lewis C. Peyser, Patricia A. Borecki, Ingrid B. Reilly, Muredach P. TI Genetics of coronary artery calcification among African Americans, a meta-analysis SO BMC MEDICAL GENETICS LA English DT Article DE Atherosclerosis; Coronary artery calcium; Genetics; Meta-analysis; African-American ID GENOME-WIDE ASSOCIATION; BEAM COMPUTED-TOMOGRAPHY; SINGLE NUCLEOTIDE POLYMORPHISMS; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS MESA; ETHNIC-DIFFERENCES; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ASYMPTOMATIC ADULTS; QUANTITATIVE-TRAIT AB Background: Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. Methods: We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with similar to 2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. Results: Heritability of CAC was lower in AA (similar to 30%) than previously reported for EA (similar to 50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region. Conclusions: While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations. C1 [Wojczynski, Mary K.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. [Li, Mingyao; Qu, Liming] Univ Penn, Philadelphia, PA 19104 USA. [Bielak, Lawrence F.; Smith, Jennifer A.; Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Kerr, Kathleen F.; Wong, Quenna] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Reiner, Alex P.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Wong, Nathan D.] Univ Calif Irvine, Heart Dis Prevent Program, Irvine, CA USA. [Yanek, Lisa R.; Kral, Brian G.; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [White, Charles C.; Demissie, Serkalem] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Ferguson, Jane F.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Ferguson, Jane F.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Young, Taylor] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Guo, Xiuqing; Rotter, Jerome I.] Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst Harbor, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Griswold, Michael E.] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [O'Leary, Daniel H.; Polak, Joseph F.] Tufts Univ, Sch Med, Dept Radiol, Boston, MA 02111 USA. [Budoff, Matthew] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. [Taylor, Herman A., Jr.] Jackson State Univ, Tougaloo Coll, Jackson, MS USA. [Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Hwang, Shih-Jen; O'Donnell, Christopher J.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hwang, Shih-Jen] Ctr Populat Studies, Framingham, MA USA. [Paltoo, Dina N.] NHLBI, Adv Technol & Surg Branch, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Post, Wendy S.] Johns Hopkins Sch Med & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Post, Wendy S.] Johns Hopkins Sch Med & Publ Hlth, Dept Med, Baltimore, MD USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Bethesda, MD 20892 USA. [Wilson, James G.] Univ Mississippi, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Kavousi, Maryam] Netherlands Genom Initiat Sponsored Netherlands C, Rotterdam, Netherlands. [Kavousi, Maryam] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fornage, Myriam] Univ Texas Houston, Houston Inst Mol Med, Houston, TX USA. RP Wojczynski, MK (reprint author), Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA. EM mwojczynski@wustl.edu; iborecki@wustl.edu; Muredach@mail.med.upenn.edu RI Ferguson, Jane/C-7154-2011; Carr, John/A-1938-2012; Kerr, Kathleen/A-2893-2013; OI Ferguson, Jane/0000-0001-6896-1025; Carr, John/0000-0002-4398-8237; Cupples, L. Adrienne/0000-0003-0273-7965; Bluemke, David/0000-0002-8323-8086; Smith, Jennifer/0000-0002-3575-5468 FU NIH from NHLBI [R01-HL-087700, R01-HL-088215]; NIH from NIDDK [R01-DK-8925601, R01-DK-075681]; National Heart, Lung, and Blood Institute; University of Alabama at Birmingham [N01-HC-48047, N01-HC-95095]; University of Minnesota [N01-HC-48048, N01-HC-95163]; Northwestern University [N01-HC-48049, N01-HC-95164]; Kaiser Foundation Research Institute [N01-HC-48050]; Tufts-New England Medical Center [N01-HC-45204]; Wake Forest University [N01-HC-45205, N01-HC-95165]; Harbor-UCLA Research and Education Institute [N01-HC-05187, N01-HC-95169]; University of California, Irvine [N01-HC-45134, N01-HC-95100]; Jackson Heart Study (JHS): Jackson State University [N01-HC-95170]; University of Mississippi [N01-HC-95171]; Tougaloo College [N01-HC-95172]; Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington [N01-HC-95159]; Regents of the University of California [N01-HC-95160]; Columbia University [N01-HC-95161]; Johns Hopkins University [N01-HC-95162, N01-HC-95168]; University of Vermont [N01-HC-95166]; New England Medical Center [N01-HC-95167]; Cedars-Sinai Medical Center [R01-HL-071205]; University of Virginia [R01-HL-071205]; National Heart, Lung, and Blood Institute [N01-HC-48047, N01-HC-95095, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45204, N01-HC-45205, N01-HC-05187, N01-HC-45134]; NHLBI's Candidate-gene Association REsource (CARe) Study; National Heart, Lung, and Blood Institute (NHLBI); United States Environmental Protection Agency (EPA); NHLBI [N02-HL-6-4278]; National Heart, Lung, and Blood Institute (NHLBI) through the STAMPEED [R01 HL087698-01]; NIH/National Institute of Nursing Research [NR008153-01]; NIH/National Center for Research Resources [M01-RR000052]; National Institutes of Health from National Heart, Lung, Blood Institute [HL085571, HL087660, HL100245]; AXA Research Fund; [R01-HL084099]; [U01-HG004729]; [R01HL071051]; [R01HL071205]; [R01HL071250]; [R01HL071251]; [R01HL071252]; [R01HL071258]; [R01HL071259]; [RD83169701]; [HL58625-01A1]; [HL59684]; [HL071025-01A1]; [R01-DK071224]; [R01-DK-090505]; [U01-HL108636]; [K24-HL107643]; [R01-HL113147] FX The National Heart, Lung, and Blood Institute's Family Heart Study (FamHS) was supported by NIH grants R01-HL-087700 and R01-HL-088215 (Michael A. Province, PI) from NHLBI; and R01-DK-8925601 and R01-DK-075681 (Ingrid B. Borecki, PI) from NIDDK.; The authors from the CARe Consortium wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. The following studies have contributed parent study data, ancillary study data, and DNA samples through the Broad Institute (N01-HC-65226).; Coronary Artery Risk in Young Adults (CARDIA): University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California, Irvine (N01-HC-45134, N01-HC-95100); Jackson Heart Study (JHS): Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172); Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), University of Virginia (subcontract to R01-HL-071205).; The Coronary Artery Risk Development in Young Adults (CARDIA) study is funded by contracts N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, and N01-HC-45204 from the National Heart, Lung, and Blood Institute to the CARDIA investigators. GWAS genotyping and quality control for the CARDIA African-Americans was supported by the NHLBI's Candidate-gene Association REsource (CARe) Study. Statistical analysis of CARDIA data was supported by grants R01-HL084099 and U01-HG004729 to MF. This manuscript has been reviewed by CARDIA for scientific content and consistency of data interpretation with previous CARDIA publications.; The MESA Family/Air Studies were conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) and the United States Environmental Protection Agency (EPA) in collaboration with MESA Family and MESA Air investigators, respectively. Support for MESA Family is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, and R01HL071259. Support for MESA Air is provided by grant RD83169701. Funding for genotyping was provided by NHLBI Contract N02-HL-6-4278. Genotyping was performed at the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) and at Affymetrix (Santa Clara, California, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0.; The GeneSTAR Study was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the STAMPEED (R01 HL087698-01) consortium as well as grants HL58625-01A1, HL59684, and HL071025-01A1, and a grant from the NIH/National Institute of Nursing Research (NR008153-01).; Additional support was provided by a grant from the NIH/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center.; The Genetic Epidemiology Network of Arteriopathy (GENOA) is supported by the National Institutes of Health, grant numbers HL085571, HL087660, and HL100245 from National Heart, Lung, Blood Institute. We thank Eric Boerwinkle, PhD from the Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, Texas, USA and Julie Cunningham, PhD from the Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA for their help with genotyping.; MPR is supported by R01-DK071224, R01-DK-090505, U01-HL108636, K24-HL107643 and R01-HL113147.; MK is supported by the AXA Research Fund. NR 46 TC 18 Z9 18 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUL 19 PY 2013 VL 14 AR 75 DI 10.1186/1471-2350-14-75 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 193ED UT WOS:000322539700001 PM 23870195 ER PT J AU Santagata, S Mendillo, ML Tang, YC Subramanian, A Perley, CC Roche, SP Wong, B Narayan, R Kwon, H Koeva, M Amon, A Golub, TR Porco, JA Whitesell, L Lindquist, S AF Santagata, Sandro Mendillo, Marc L. Tang, Yun-chi Subramanian, Aravind Perley, Casey C. Roche, Stephane P. Wong, Bang Narayan, Rajiv Kwon, Hyoungtae Koeva, Martina Amon, Angelika Golub, Todd R. Porco, John A., Jr. Whitesell, Luke Lindquist, Susan TI Tight Coordination of Protein Translation and HSF1 Activation Supports the Anabolic Malignant State SO SCIENCE LA English DT Article ID HEAT-SHOCK FACTOR-1; TRANSCRIPTION FACTOR HSF1; EUKARYOTIC TRANSLATION; AMINO-ACID; IN-VITRO; CANCER; EXPRESSION; STRESS; SILVESTROL; INHIBITORS AB The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism. Targeting this link with translation initiation inhibitors such as rocaglates deprived cancer cells of their energy and chaperone armamentarium and selectively impaired the proliferation of both malignant and premalignant cells with early-stage oncogenic lesions. C1 [Santagata, Sandro] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [Santagata, Sandro] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Santagata, Sandro] Dana Farber Canc Inst, Boston, MA 02215 USA. [Santagata, Sandro; Mendillo, Marc L.; Perley, Casey C.; Kwon, Hyoungtae; Koeva, Martina; Whitesell, Luke; Lindquist, Susan] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Mendillo, Marc L.; Tang, Yun-chi; Perley, Casey C.; Kwon, Hyoungtae; Koeva, Martina; Amon, Angelika; Lindquist, Susan] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02142 USA. [Tang, Yun-chi; Amon, Angelika] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Tang, Yun-chi; Amon, Angelika] MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA. [Subramanian, Aravind; Wong, Bang; Narayan, Rajiv; Golub, Todd R.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Roche, Stephane P.; Porco, John A., Jr.] Boston Univ, Dept Chem, Ctr Chem Methodol & Lib Dev CMLD BU, Boston, MA 02215 USA. RP Whitesell, L (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM whitesell@wi.mit.edu; lindquist_admin@wi.mit.edu FU Johnson & Johnson's Corporate Office of Science and Technology; Marble Fund; NIH [R01 CA175744-01, K08NS064168]; NIH Common Fund's LINCS program [5U54HG006093]; American Cancer Society New England Division-SpinOdyssey [PF-09-253-01-DMC]; Brain Science Foundation; American Brain Tumor Association; Beez Foundation; V Foundation; Jared Branfman Sunflowers for Life Fund; [R03 MH086465-01]; [R03 DA027713-01]; [R01 GM073855] FX We thank T. Volkert, J. Love, S. Gupta, and the WIBR-Genome Technology Core for sequencing support; S. Malstrom (Koch Institute for Integrative Cancer Research) for assistance with in vivo imaging; G. Bell, P. Thiru, and A. Lancaster for assistance with informatics analysis; the Connectivity Map team at the Broad Institute for generation of the LINCS data set and query tools; Joe Negri and the MLPCN team at the Broad Institute for chemical screening; and M. Duquette for assistance with animal experiments. We also thank C. Rodrigo (Boston University) for compound synthesis. We thank the Lindquist laboratory for helpful discussions and suggestions. The work was supported by the Johnson & Johnson's Corporate Office of Science and Technology focused funding program (L. W.), the Marble Fund (S. L.), and NIH R01 CA175744-01 (L. W.). The MLPCN screen was supported by R03 MH086465-01 and R03 DA027713-01 to L. W. This work was supported by the NIH Common Fund's LINCS program (5U54HG006093, "Large scale gene expression analysis of cellular states") to T. R. G. J. A. P. Jr. is supported by R01 GM073855. S. L. is an Investigator of the Howard Hughes Medical Institute. M. L. M. was supported by American Cancer Society New England Division-SpinOdyssey (PF-09-253-01-DMC). S. S. is supported by NIH (K08NS064168), the Brain Science Foundation, the American Brain Tumor Association, the Beez Foundation, the V Foundation, and the Jared Branfman Sunflowers for Life Fund. The expression profiling and ChIP-Seq data are deposited in GEO (GSE45853). The MLPCN chemical screening data are deposited in Pubchem (AID: 2118). NR 44 TC 81 Z9 82 U1 1 U2 24 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 JUL 19 PY 2013 VL 341 IS 6143 BP 250 EP + AR 1238303 DI 10.1126/science.1238303 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185HV UT WOS:000321959300034 PM 23869022 ER PT J AU Farkas, MH Grant, GR White, JA Sousa, ME Consugar, MB Pierce, EA AF Farkas, Michael H. Grant, Gregory R. White, Joseph A. Sousa, Maria E. Consugar, Mark B. Pierce, Eric A. TI Transcriptome analyses of the human retina identify unprecedented transcript diversity and 3.5 Mb of novel transcribed sequence via significant alternative splicing and novel genes SO BMC GENOMICS LA English DT Article DE RNA-Seq; Transcriptome; Inherited retinal degeneration; Retina; Novel genes; Alternative splicing ID LEBERS CONGENITAL AMAUROSIS; BARDET-BIEDL SYNDROME; LONG NONCODING RNAS; GENOME ANNOTATION; MAMMALIAN TRANSCRIPTOMES; PIGMENT-EPITHELIUM; KABUKI SYNDROME; DISEASE GENES; HUMAN TISSUES; EXPRESSION AB Background: The retina is a complex tissue comprised of multiple cell types that is affected by a diverse set of diseases that are important causes of vision loss. Characterizing the transcripts, both annotated and novel, that are expressed in a given tissue has become vital for understanding the mechanisms underlying the pathology of disease. Results: We sequenced RNA prepared from three normal human retinas and characterized the retinal transcriptome at an unprecedented level due to the increased depth of sampling provided by the RNA-seq approach. We used a non-redundant reference transcriptome from all of the empirically-determined human reference tracks to identify annotated and novel sequences expressed in the retina. We detected 79,915 novel alternative splicing events, including 29,887 novel exons, 21,757 3 ' and 5 ' alternate splice sites, and 28,271 exon skipping events. We also identified 116 potential novel genes. These data represent a significant addition to the annotated human transcriptome. For example, the novel exons detected increase the number of identified exons by 3%. Using a high-throughput RNA capture approach to validate 14,696 of these novel transcriptome features we found that 99% of the putative novel events can be reproducibly detected. Further, 15-36% of the novel splicing events maintain an open reading frame, suggesting they produce novel protein products. Conclusions: To our knowledge, this is the first application of RNA capture to perform large-scale validation of novel transcriptome features. In total, these analyses provide extensive detail about a previously uncharacterized level of transcript diversity in the human retina. C1 [Farkas, Michael H.; White, Joseph A.; Sousa, Maria E.; Consugar, Mark B.; Pierce, Eric A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst,Dept Ophthalmol, Boston, MA 02114 USA. [Farkas, Michael H.; White, Joseph A.; Sousa, Maria E.; Consugar, Mark B.; Pierce, Eric A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Berman Gund Lab Study Retinal Deg, Boston, MA USA. [Grant, Gregory R.] Univ Penn, Penn Ctr Bioinformat, Philadelphia, PA 19104 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 [RO1-EY020902, RO1-EY012910, F32-EY020747]; Foundation Fighting Blindness USA; Penn Genome Frontiers Institute FX We thank the Penn Genome Frontiers Institute at the University of Pennsylvania for sequencing the retinal transcriptome samples. This work was supported by grants from the National Institutes of Health RO1-EY020902 (EAP), RO1-EY012910 (E. A. P.), F32-EY020747 (M. H. F.); the Foundation Fighting Blindness USA; the Penn Genome Frontiers Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations or the National Institutes of Health. NR 92 TC 45 Z9 45 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 18 PY 2013 VL 14 AR 486 DI 10.1186/1471-2164-14-486 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 274RW UT WOS:000328624900001 PM 23865674 ER PT J AU Smith, BW Rozelle, SS Leung, A Ubellacker, J Parks, A Nah, SK French, D Gadue, P Monti, S Chui, DHK Steinberg, MH Frelinger, AL Michelson, AD Theberge, R McComb, ME Costello, CE Kotton, DN Mostoslavsky, G Sherr, DH Murphy, GJ AF Smith, Brenden W. Rozelle, Sarah S. Leung, Amy Ubellacker, Jessalyn Parks, Ashley Nah, Shirley K. French, Deborah Gadue, Paul Monti, Stefano Chui, David H. K. Steinberg, Martin H. Frelinger, Andrew L. Michelson, Alan D. Theberge, Roger McComb, Mark E. Costello, Catherine E. Kotton, Darrell N. Mostoslavsky, Gustavo Sherr, David H. Murphy, George J. TI The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation SO BLOOD LA English DT Article ID PLURIPOTENT STEM-CELLS; BREAST-CANCER CELLS; REGULATORY T-CELLS; GENE-EXPRESSION; AHR REPRESSOR; GENERATION; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; ACTIVATION; PLATELETS; RESPONSES AB The evolutionarily conserved aryl hydrocarbon receptor (AhR) has been studied for its role in environmental chemical-induced toxicity. However, recent studies have demonstrated that the AhR may regulate the hematopoietic and immune systems during development in a cell-specific manner. These results, together with the absence of an in vitro model system enabling production of large numbers of primary human hematopoietic progenitor cells (HPs) capable of differentiating into megakaryocyte- and erythroid-lineage cells, motivated us to determine if AhR modulation could facilitate both progenitor cell expansion and megakaryocyte and erythroid cell differentiation. Using a novel, pluripotent stem cell-based, chemically-defined, serum and feeder cell-free culture system, we show that the AhR is expressed in HPs and that, remarkably, AhR activation drives an unprecedented expansion of HPs, megakaryocyte-lineage cells, and erythroid-lineage cells. Further AhR modulation within rapidly expanding progenitor cell populations directs cell fate, with chronic AhR agonism permissive to erythroid differentiation and acute antagonism favoring megakaryocyte specification. These results highlight the development of a new Good Manufacturing Practice-compliant platform for generating virtually unlimited numbers of human HPs with which to scrutinize red blood cell and platelet development, including the assessment of the role of the AhR critical cell fate decisions during hematopoiesis. C1 [Smith, Brenden W.; Rozelle, Sarah S.; Leung, Amy; Nah, Shirley K.; Chui, David H. K.; Steinberg, Martin H.; Murphy, George J.] Boston Univ, Dept Med, Sch Med, Sect Hematol & Oncol, Boston, MA 02118 USA. [Smith, Brenden W.; Rozelle, Sarah S.; Leung, Amy; Nah, Shirley K.; Kotton, Darrell N.; Mostoslavsky, Gustavo; Murphy, George J.] Boston Univ, Ctr Regenerat Med, Boston, MA 02118 USA. [Smith, Brenden W.; Rozelle, Sarah S.; Leung, Amy; Nah, Shirley K.; Kotton, Darrell N.; Mostoslavsky, Gustavo; Murphy, George J.] Boston Med Ctr, Boston, MA USA. [Ubellacker, Jessalyn; Parks, Ashley; Sherr, David H.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02118 USA. [French, Deborah; Gadue, Paul] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA. [Monti, Stefano] Boston Univ, Sect Computat Biomed, Sch Med, Dept Med, Boston, MA 02118 USA. [Frelinger, Andrew L.; Michelson, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Boston Childrens Hosp, Ctr Platelet Res Studies,Div Hematol Oncol, Boston, MA 02115 USA. [Theberge, Roger; McComb, Mark E.; Costello, Catherine E.] Boston Univ, Ctr Biomed Mass Spectrometry, Sch Med, Boston, MA 02118 USA. RP Murphy, GJ (reprint author), Boston Univ, Ctr Regenerat Med, Sch Med, 650 Albany St,Suite 444, Boston, MA 02118 USA. EM gjmurphy@bu.edu OI Costello, Catherine/0000-0003-1594-5122; Steinberg, Martin/0000-0001-8800-8020; Monti, Stefano/0000-0002-9376-0660; McComb, Mark/0000-0002-4249-485X; Sherr, David/0000-0003-3353-0553; Murphy, George/0000-0003-3464-793X; Kotton, Darrell/0000-0002-9604-8476 FU National Institutes of Health (NIH) [U01 HL107443-01]; American Society of Hematology Scholar Award; Affinity Research Collaborative award from the Evans Center for Interdisciplinary Research at Boston University; NIH [5T32HL007501-30, P01-ES11624, P42ES007381]; Art beCAUSE Breast Cancer Foundation; NIH Mass Spectrometer Resource [P41 GM104603]; NIH National Heart, Lung, and Blood Institute Proteomics contract [HHSN268201000031C]; Shared Instrument grant: MALDI-TOF/TOF [S10 OD010724] FX This work was supported by National Institutes of Health (NIH) U01 HL107443-01, an American Society of Hematology Scholar Award, and an Affinity Research Collaborative award from the Evans Center for Interdisciplinary Research at Boston University (G.J.M.); an NIH training grant 5T32HL007501-30 (S. S. R.); NIH P01-ES11624, P42ES007381, and the Art beCAUSE Breast Cancer Foundation (J.U., A. P., and D. H. S.); and by NIH Mass Spectrometer Resource (P41 GM104603), an NIH National Heart, Lung, and Blood Institute Proteomics contract (HHSN268201000031C), and a Shared Instrument grant: MALDI-TOF/TOF (matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight) Mass Spectrometer (S10 OD010724) (C. E. C., M. E. M., and R.T.). NR 49 TC 32 Z9 34 U1 4 U2 16 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 18 PY 2013 VL 122 IS 3 BP 376 EP 385 DI 10.1182/blood-2012-11-466722 PG 10 WC Hematology SC Hematology GA 196QM UT WOS:000322790500014 PM 23723449 ER PT J AU Frakt, AB Trafton, J Wallace, A Neuman, M Pizer, S AF Frakt, Austin B. Trafton, Jodie Wallace, Amy Neuman, Matthew Pizer, Steven TI Directed funding to address under-provision of treatment for substance use disorders: a quantitative study SO IMPLEMENTATION SCIENCE LA English DT Article DE Substance use disorder; Veterans; Veterans Health Administration; Funding ID HEALTH-CARE UTILIZATION; ABUSE TREATMENT; ALCOHOLISM-TREATMENT; MENTAL-HEALTH; BLOCK GRANTS; DRUG-ABUSE; COSTS; STATE; INTERVENTIONS; BENEFIT AB Background: Substance use disorders (SUDs) are a substantial problem in the United States (U. S.), affecting far more people than receive treatment. This is true broadly and within the U. S. military veteran population, which is our focus. To increase funding for treatment, the Veterans Health Administration (VA) has implemented several initiatives over the past decade to direct funds toward SUD treatment, supplementing the unrestricted funds VA medical centers receive. We study the 'flypaper effect' or the extent to which these directed funds have actually increased SUD treatment spending. Methods: The study sample included all VA facilities and used observational data spanning years 2002 to 2010. Data were analyzed with a fixed effects, ordinary least squares specification with monetized workload as the dependent variable and funding dedicated to SUD specialty clinics the key dependent variable, controlling for unrestricted funding. Results: We observed different effects of dedicated SUD specialty clinic funding over the period 2002 to 2008 versus 2009 to 2010. In the earlier period, there is no evidence of a significant portion of the dedicated funding sticking to its target. In the later period, a substantial proportion-38% in 2009 and 61% in 2010-of funding dedicated to SUD specialty clinics did translate into increased medical center spending for SUD treatment. In comparison, only five cents of every dollar of unrestricted funding is spent on SUD treatment. Conclusions: Relative to unrestricted funding, dedicated funding for SUD treatment was much more effective in increasing workload, but only in years 2009 and 2010. The differences in those years relative to prior ones may be due to the observed management focus on SUD and SUD-related treatment in the later years. If true, this suggests that in a centrally directed healthcare organization such as the VA, funding dedicated to a service is a necessary, but not sufficient condition for increasing resources expended for that service. C1 [Frakt, Austin B.; Pizer, Steven] Boston Univ, VA Boston Healthcare Syst, Boston, MA 02215 USA. [Frakt, Austin B.; Pizer, Steven] Boston Univ, Sch Med, Boston, MA 02215 USA. [Trafton, Jodie; Neuman, Matthew] VA Palo Alto Healthcare Syst, Program Evaluat & Resource Ctr, Menlo Pk, CA USA. [Wallace, Amy] Vet Adm North Texas Hlth Care Syst, Dept Psychiat, Bonham, TX USA. RP Frakt, AB (reprint author), Boston Univ, VA Boston Healthcare Syst, Boston, MA 02215 USA. EM frakt@bu.edu FU VA Program Evaluation and Resource Center as part of an evaluation of VA SUD funding initiatives FX This work was funded by the VA Program Evaluation and Resource Center as part of an evaluation of VA SUD funding initiatives and was deemed to be non-generalizable program evaluation and thus non-research. The views expressed 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. NR 38 TC 4 Z9 4 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD JUL 18 PY 2013 VL 8 AR 79 DI 10.1186/1748-5908-8-79 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 189GO UT WOS:000322255600001 PM 23866119 ER PT J AU Baggett, TP Tobey, ML Rigotti, NA AF Baggett, Travis P. Tobey, Matthew L. Rigotti, Nancy A. TI Tobacco Use among Homeless People - Addressing the Neglected Addiction SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SMOKING C1 [Baggett, Travis P.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Tobey, Matthew L.] Massachusetts Gen Hosp, Global Primary Care Program, Boston, MA 02114 USA. [Baggett, Travis P.; Rigotti, Nancy A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Baggett, Travis P.] Boston Hlth Care Homeless Program, Boston, MA USA. RP Baggett, TP (reprint author), Massachusetts Gen Hosp, Div Gen Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. NR 5 TC 20 Z9 20 U1 1 U2 10 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 JUL 18 PY 2013 VL 369 IS 3 BP 201 EP 204 DI 10.1056/NEJMp1301935 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 185DQ UT WOS:000321945800002 PM 23863048 ER PT J AU Woo, SB Stone, JH Kraft, S AF Woo, Sook-Bin Stone, John H. Kraft, Stefan TI Case 22-2013: A 51-Year-Old Woman with Epistaxis and Oral Mucosal Ulcers SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ERYTHEMA MULTIFORME; WEGENERS-GRANULOMATOSIS; PEMPHIGUS-VULGARIS; LONG-TERM; RITUXIMAB; MANIFESTATIONS; CRITERIA; DISEASE; PATHOGENESIS; DIAGNOSIS C1 [Woo, Sook-Bin] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Woo, Sook-Bin] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Stone, John H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kraft, Stefan] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Woo, Sook-Bin] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Stone, John H.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kraft, Stefan] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Woo, SB (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. FU Genentech and Roche FX Dr. Stone reports receiving consulting fees from Genentech and Roche, grant support through his institution from Genentech and Roche, and travel support through his institution from Genentech, Biogen Idec, and Genzyme. No other potential conflict of interest relevant to this article was reported. NR 26 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 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 18 PY 2013 VL 369 IS 3 BP 265 EP 274 DI 10.1056/NEJMcpc1209275 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 185DQ UT WOS:000321945800013 PM 23863054 ER PT J AU Song, SJ Poliseno, L Song, MS Ala, U Webster, K Ng, C Beringer, G Brikbak, NJ Yuan, X Cantley, LC Richardson, AL Pandolfi, PP AF Song, Su Jung Poliseno, Laura Song, Min Sup Ala, Ugo Webster, Kaitlyn Ng, Christopher Beringer, Gary Brikbak, Nicolai J. Yuan, Xin Cantley, Lewis C. Richardson, Andrea L. Pandolfi, Pier Paolo TI MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family-Dependent Chromatin Remodeling SO CELL LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; MESENCHYMAL TRANSITION; 5-HYDROXYMETHYLCYTOSINE CONTENT; EPITHELIAL PHENOTYPE; DOWN-REGULATION; MIR-200 FAMILY; MESSENGER-RNA; HUMAN GENES; TGF-BETA; CELLS AB Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis in mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes aggressive metastatic disease in MMTV-miR-22 TG mice, as well as compound MMTV-neu or -PyVT-miR-22 TG mice. We demonstrate that miR-22 exerts its metastatic potential by silencing antimetastatic miR-200 through direct targeting of the TET (Ten eleven translocation) family of methylcytosine dioxygenases, thereby inhibiting demethylation of the mir-200 promoter. Finally, we show that miR-22 overexpression correlates with poor clinical outcomes and silencing of the TET-miR-200 axis in patients. Taken together, our findings implicate miR-22 as a crucial epigenetic modifier and promoter of EMT and breast cancer stemness toward metastasis. C1 [Song, Su Jung; Poliseno, Laura; Song, Min Sup; Ala, Ugo; Webster, Kaitlyn; Ng, Christopher; Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Genet Program,Div Genet,Dept Med & Pathol, Boston, MA 02115 USA. [Ng, Christopher; Cantley, Lewis C.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Signal Transduct,Dept Med, Boston, MA 02115 USA. [Yuan, Xin] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Hematol Oncol Div,Dept Med, Boston, MA 02115 USA. [Beringer, Gary; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Brikbak, Nicolai J.; Richardson, Andrea L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Pandolfi, PP (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Genet Program,Div Genet,Dept Med & Pathol, Boston, MA 02115 USA. EM ppandolf@bidmc.harvard.edu RI Cantley, Lewis/D-1800-2014; Poliseno, Laura/B-5711-2012; Ala, Ugo/K-2029-2016 OI Cantley, Lewis/0000-0002-1298-7653; Poliseno, Laura/0000-0001-6557-955X; Ala, Ugo/0000-0001-5408-6397 FU NIH [CA 082328-14] FX We are grateful to all members of the Pandolfi lab and in particular to Keisuke Ito and Leonardo Salmena for advice and discussion. We thank Thomas Garvey for critical editing of the manuscript as well as Yvonne Tay, Luo Man-Lee, April Greene-Colozzi, and Soon Jung Kim for experimental and technical support. This work was supported by NIH grant CA 082328-14 awarded to P.P.P. NR 60 TC 161 Z9 163 U1 9 U2 74 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 18 PY 2013 VL 154 IS 2 BP 311 EP 324 DI 10.1016/j.cell.2013.06.026 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 185FF UT WOS:000321950700009 PM 23830207 ER PT J AU Manoach, DS Agam, Y AF Manoach, Dara S. Agam, Yigal TI Neural markers of errors as endophenotypes in neuropsychiatric disorders SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Review DE error-related negativity; anterior cingulate; error processing; response monitoring; imaging genetics ID ANTERIOR CINGULATE CORTEX; OBSESSIVE-COMPULSIVE DISORDER; AUTISM SPECTRUM DISORDERS; EVENT-RELATED FMRI; MEDIAL FRONTAL-CORTEX; DOPAMINE D2 RECEPTOR; HIGH-FUNCTIONING AUTISM; CATECHOL-O-METHYLTRANSFERASE; MATTER DIFFUSION ANISOTROPY; DEFAULT MODE NETWORK AB Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive-compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromally-unaffected family members, and evidence of genetic mediation. Understanding the mechanisms of error processing deficits in neuropsychiatric disorders may provide novel neural and behavioral targets for treatment and sensitive surrogate markers of treatment response. Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments. Given the dearth of effective interventions for cognitive deficits in neuropsychiatric disorders, this represents a potentially promising approach. C1 [Manoach, Dara S.; Agam, Yigal] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Manoach, Dara S.; Agam, Yigal] Harvard Univ, Sch Med, Boston, MA USA. [Manoach, Dara S.; Agam, Yigal] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Manoach, DS (reprint author), Massachusetts Gen Hosp, 149 13th St,Room 1-111, Charlestown, MA 02129 USA. EM dara@nmr.mgh.harvard.edu FU National Institute for Mental Health [R01 MH67720, F32 MH088081] FX The authors are grateful to Jordan Smoller and Daniel Z. Press for consultation. Support: National Institute for Mental Health: R01 MH67720 (Dara S. Manoach); F32 MH088081 (Yigal Agam). NR 258 TC 24 Z9 25 U1 6 U2 33 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD JUL 18 PY 2013 VL 7 AR 350 DI 10.3389/fnhum.2013.00350 PG 19 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 185CM UT WOS:000321942800001 PM 23882201 ER PT J AU Ebert, DH Gabel, HW Robinson, ND Kastan, NR Hu, LS Cohen, S Navarro, AJ Lyst, MJ Ekiert, R Bird, AP Greenberg, ME AF Ebert, Daniel H. Gabel, Harrison W. Robinson, Nathaniel D. Kastan, Nathaniel R. Hu, Linda S. Cohen, Sonia Navarro, Adrija J. Lyst, Matthew J. Ekiert, Robert Bird, Adrian P. Greenberg, Michael E. TI Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR SO NATURE LA English DT Article ID METHYL-CPG; BDNF TRANSCRIPTION; RETT-SYNDROME; BINDING; REPRESSION; CHROMATIN; ASSOCIATION; INHIBITION; MUTATIONS; DISORDER AB Rett syndrome (RTT) is an X-linked human neurodevelopmental disorder with features of autism and severe neurological dysfunction in females. RTT is caused by mutations in methyl-CpG-binding protein 2 (MeCP2), a nuclear protein that, in neurons, regulates transcription, is expressed at high levels similar to that of histones, and binds to methylated cytosines broadly across the genome(1-5). By phosphotryptic mapping, we identify three sites (S86, S274 and T308) of activity-dependent MeCP2 phosphorylation. Phosphorylation of these sites is differentially induced by neuronal activity, brain-derived neurotrophic factor, or agents that elevate the intracellular level of 3',5'-cyclic AMP (cAMP), indicating that MeCP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. Here we show that the phosphorylation of T308 blocks the interaction of the repressor domain of MeCP2 with the nuclear receptor co-repressor (NCoR) complex and suppresses the ability of MeCP2 to repress transcription. In knock-in mice bearing the common human RTT missense mutation R306C, neuronal activity fails to induce MeCP2 T308 phosphorylation, suggesting that the loss of T308 phosphorylation might contribute to RTT. Consistent with this possibility, the mutation of MeCP2 T308A in mice leads to a decrease in the induction of a subset of activity-regulated genes and to RTT-like symptoms. These findings indicate that the activity-dependent phosphorylation of MeCP2 at T308 regulates the interaction of MeCP2 with the NCoR complex, and that RTT in humans may be due, in part, to the loss of activity-dependent MeCP2 T308 phosphorylation and a disruption of the phosphorylation-regulated interaction of MeCP2 with the NCoR complex. C1 [Ebert, Daniel H.; Gabel, Harrison W.; Robinson, Nathaniel D.; Kastan, Nathaniel R.; Hu, Linda S.; Cohen, Sonia; Navarro, Adrija J.; Greenberg, Michael E.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Ebert, Daniel H.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lyst, Matthew J.; Ekiert, Robert; Bird, Adrian P.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. RP Greenberg, ME (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. EM michael_greenberg@hms.harvard.edu OI Ekiert, Robert/0000-0002-8879-0646; Lyst, Matthew/0000-0001-9018-4138 FU NIH [RO1NS048276, K08MH90306, P30-HD 18655]; Rett Syndrome Research Trust; Dupont-Warren Fellowship in the Department of Psychiatry at Harvard Medical School; Nancy Lurie Marks Fellowship in Autism at Harvard Medical School; Damon Runyon Cancer Research Foundation [DRG-2048-10] FX This work was supported by NIH grant RO1NS048276 and the Rett Syndrome Research Trust to M. E. G. D. H. E was supported by NIH grant K08MH90306, the Dupont-Warren Fellowship in the Department of Psychiatry at Harvard Medical School, and the Nancy Lurie Marks Fellowship in Autism at Harvard Medical School. H. W. G. was supported by Damon Runyon Cancer Research Foundation Grant DRG-2048-10. The Mouse Gene Manipulation Facility of the Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (IDDRC), funded by NIH grant P30-HD 18655, assisted in generation of the knock-in mice. We thank members of the Greenberg laboratory, particularly C. Mandel-Brehm and E. Griffith, and also G. Mandel and R. S. Greenberg for helpful discussions. NR 26 TC 74 Z9 78 U1 2 U2 49 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 18 PY 2013 VL 499 IS 7458 BP 341 EP U116 DI 10.1038/nature12348 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 184RJ UT WOS:000321910700037 PM 23770587 ER PT J AU Linger, RMA Cohen, RA Cummings, CT Sather, S Migdall-Wilson, J Middleton, DHG Lu, X Baron, AE Franklin, WA Merrick, DT Jedlicka, P DeRyckere, D Heasley, LE Graham, DK AF Linger, R. M. A. Cohen, R. A. Cummings, C. T. Sather, S. Migdall-Wilson, J. Middleton, D. H. G. Lu, X. Baron, A. E. Franklin, W. A. Merrick, D. T. Jedlicka, P. DeRyckere, D. Heasley, L. E. Graham, D. K. TI Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer SO ONCOGENE LA English DT Article DE targeted therapy; receptor tyrosine kinase; MerTK; signal transduction; xenograft; chemosensitivity ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ELEMENT-BINDING PROTEIN; NF-KAPPA-B; GENE-EXPRESSION; BREAST-CANCER; TUMOR-GROWTH; THERAPEUTIC TARGETS; PROLONGS SURVIVAL; DISEASE-ACTIVITY; DRUG-RESISTANCE AB Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl. C1 [Linger, R. M. A.; Cohen, R. A.; Cummings, C. T.; Sather, S.; Migdall-Wilson, J.; DeRyckere, D.; Graham, D. K.] Univ Colorado, Dept Pediat, Sect Hematol Oncol & Bone Marrow Transplantat, Aurora, CO 80045 USA. [Middleton, D. H. G.] Univ Colorado, Program Canc Biol, Aurora, CO 80045 USA. [Lu, X.; Baron, A. E.] Univ Colorado, Dept Biostat & Informat, Aurora, CO 80045 USA. [Franklin, W. A.; Merrick, D. T.; Jedlicka, P.] Univ Colorado, Dept Pathol, Aurora, CO 80045 USA. [Merrick, D. T.] Denver VA Med Ctr, Dept Pathol, Denver, CO USA. [Heasley, L. E.] Denver VA Med Ctr, Dept Craniofacial Biol, Denver, CO USA. RP Graham, DK (reprint author), Univ Colorado, Dept Pediat, Sect Hematol Oncol & Bone Marrow Transplantat, Anschutz Med Campus,Mail Stop 8302,12800 East 19t, Aurora, CO 80045 USA. EM doug.graham@ucdenver.edu FU Uniting Against Lung Cancer: Elliot's Legacy (RMAL); Lung Cancer Research Foundation (RMAL); American Cancer Society [RSG-08-291-01-LIB]; National Institutes of Health [RO1CA137078]; University of Colorado Cancer Center SPORE in Lung Cancer [NIH 5P50CA058187]; Damon Runyon Cancer Research Foundation [CI-39-07] FX This work was supported in part by grants from Uniting Against Lung Cancer: Elliot's Legacy (RMAL), the Lung Cancer Research Foundation (RMAL), the American Cancer Society (RSG-08-291-01-LIB, DKG) and the National Institutes of Health (RO1CA137078, DKG). RMA Linger received a Career Development Award from the University of Colorado Cancer Center SPORE in Lung Cancer (NIH 5P50CA058187). DK Graham is the Damon Runyon-Novartis Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI-39-07). The authors wish to thank Karen Helm, Christine Childs and Lester Acosta in the University of Colorado Cancer Center Flow Cytometry Core for their expert technical assistance, Randall Wong in the University of Colorado Denver Diabetes and Endocrinology Research Center Molecular Biology Core Facility (NIH P30 DK57516) for cell line authentication services, Patricia Lenhart for help optimizing Mer and Axl immunohistochemistry of human tissues, and Storey Wilson and Andrea Abeyta for technical assistance with the Aperio imaging system used to digitize stained tumor microarray slides. NR 65 TC 45 Z9 45 U1 3 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 18 PY 2013 VL 32 IS 29 BP 3420 EP 3431 DI 10.1038/onc.2012.355 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 186AZ UT WOS:000322014900003 PM 22890323 ER PT J AU Kloverpris, HN Stryhn, A Harndahl, M Carlson, JM Leslie, AJ Chen, F Riddell, L Mulenga, J Walker, BD Ndung'u, T Buus, S Goulder, P AF Kloverpris, Henrik N. Stryhn, Anette Harndahl, Mikkel Carlson, Jonathan M. Leslie, Alasdair J. Chen, Fabian Riddell, Lynn Mulenga, Joseph Walker, Bruce D. Ndung'u, Thumbi Buus, Soren Goulder, Philip TI HLA-AM*68:02-restricted Gag-specific cytotoxic T lymphocyte responses can drive selection pressure on HIV but are subdominant and ineffective SO AIDS LA English DT Article DE CD8(+) T cells; HIV-1; HLA-peptide binding ID HLA CLASS-I; IMMUNODEFICIENCY-VIRUS TYPE-1; IMMUNE CONTROL; ESCAPE PATHWAYS; INFECTED-CELLS; CTL EPITOPES; VIRAL LOAD; TRANSMISSION; ASSOCIATIONS; IMMUNOGENICITY AB Background:Human leukocyte allele (HLA) class I polymorphism has the greatest impact of human genetic variation on viral load set point. A substantial part of this effect is due to the action of HLA-B and HLA-C alleles. With few exceptions the role of HLA-A molecules in immune control of HIV is unclear.Methods:We here study HLA-A68:02, one of the most highly prevalent HLA-A alleles in C-clade infected sub-Saharan African populations, and one that plays a prominent role in the HIV-specific CD8(+) T-cell responses made against the virus.Results:We define eight epitopes restricted by this allele and propose the peptide binding motif for HLA-A68:02. Although one of these epitopes almost exactly overlaps an HLA-B57-restricted epitope in Gag linked with immune control of HIV, this HLA-A68:02-restricted Gag-TA10 response imposed only weak selection pressure on the virus and was not associated with significantly lower viral setpoint. The only HLA-A68:02-restricted responses imposing strong selection pressure on HIV were in the flanking regions of Pol-EA8 and Pol-EA11 and within the Vpr-EV10 epitope (P=8x10(-8)). However, targeting of this latter epitope was associated with significantly higher viral loads (P=0.003), suggesting lack of efficacy.Conclusion:This study is consistent with previous data showing that HLA-A-restricted Gag-specific responses can impose selection pressure on HIV. In the case of HLA-A68:02 the Gag response is subdominant, and apparently has little impact in natural infection. However, these data suggest the potential for high frequency vaccine-induced Gag responses restricted by this allele to have significant antiviral efficacy in vaccine recipients. C1 [Kloverpris, Henrik N.; Goulder, Philip] Univ Oxford, Dept Paediat, Oxford, England. [Kloverpris, Henrik N.; Stryhn, Anette; Harndahl, Mikkel; Buus, Soren] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Copenhagen, Denmark. [Walker, Bruce D.; Ndung'u, Thumbi; Goulder, Philip] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Program, Durban, South Africa. [Walker, Bruce D.] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Chen, Fabian] Royal Berkshire Hosp Reading, Dept Sexual Hlth, Reading, Berks, England. [Riddell, Lynn] Northamptonshire Healthcare Natl Hlth Serv Trust, Northampton Gen Hosp, Dept Genitourinary Med, Northampton, England. [Carlson, Jonathan M.] eSci Grp, Microsoft Res, Los Angeles, CA USA. [Kloverpris, Henrik N.; Leslie, Alasdair J.] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, Nelson R Mandela Sch Med, K RITH, Kwa Zulu, South Africa. [Mulenga, Joseph] Zambia Emory HIV Res Project, Lusaka, Zambia. RP Kloverpris, HN (reprint author), Univ Oxford, Oxford, England. EM henrik.kloverpris@k-rith.org RI Buus, Soren/F-5446-2010 FU Welcome Trust; National Institutes of Health [R01 AI46995]; Danish Agency for Science, Technology and Innovation [12-132295] FX This work was supported by the Welcome Trust (P.G.) and the National Institutes of Health, grant R01 AI46995. H.N.K. holds a grant from the Danish Agency for Science, Technology and Innovation #12-132295. NR 37 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 17 PY 2013 VL 27 IS 11 BP 1717 EP 1723 DI 10.1097/QAD.0b013e32836146cd PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 250HL UT WOS:000326841200004 PM 23525031 ER PT J AU Dowling, NM Gleason, CE Manson, JE Hodis, HN Miller, VM Brinton, EA Neal-Perry, G Santoro, MN Cedars, M Lobo, R Merriam, GR Wharton, W Naftolin, F Taylor, H Harman, SM Asthana, S AF Dowling, N. Maritza Gleason, Carey E. Manson, JoAnn E. Hodis, Howard N. Miller, Virginia M. Brinton, Eliot A. Neal-Perry, Genevieve Santoro, M. Nanette Cedars, Marcelle Lobo, Rogerio Merriam, George R. Wharton, Whitney Naftolin, Frederick Taylor, Hugh Harman, S. Mitchell Asthana, Sanjay TI Characterization of Vascular Disease Risk in Postmenopausal Women and Its Association with Cognitive Performance SO PLOS ONE LA English DT Article ID CORONARY-HEART-DISEASE; ACUTE MYOCARDIAL-INFARCTION; EARLY ESTROGEN PREVENTION; APOLIPOPROTEIN-E GENOTYPE; NON-HISPANIC WHITES; BODY-MASS INDEX; CARDIOVASCULAR RISK; ALZHEIMERS-DISEASE; SOCIOECONOMIC-STATUS; DENSITY-LIPOPROTEIN AB Objectives: While global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterogeneity in CV risk factor profiles and its association with demographic, genetic, and cognitive variables. Methods: A latent profile analysis was applied to data from 727 recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Women were cognitively healthy, within three years of their last menstrual period, and free of current or past CV disease. Education level, apolipoprotein E epsilon 4 allele (APOE4), ethnicity, and age were modeled as predictors of latent class membership. The association between class membership, characterizing CV risk profiles, and performance on five cognitive factors was examined. A supervised random forest algorithm with a 10-fold cross-validation estimator was used to test accuracy of CV risk classification. Results: The best-fitting model generated two distinct phenotypic classes of CV risk 62% of women were "low-risk" and 38% "high-risk". Women classified as low-risk outperformed high-risk women on language and mental flexibility tasks (p = 0.008) and a global measure of cognition (p = 0.029). Women with a college degree or above were more likely to be in the low-risk class (OR = 1.595, p = 0.044). Older age and a Hispanic ethnicity increased the probability of being at high-risk (OR = 1.140, p = 0.002; OR = 2.622, p = 0.012; respectively). The prevalence rate of APOE-epsilon 4 was higher in the high-risk class compared with rates in the low-risk class. Conclusion: Among recently menopausal women, significant heterogeneity in CV risk is associated with education level, age, ethnicity, and genetic indicators. The model-based latent classes were also associated with cognitive function. These differences may point to phenotypes for CV disease risk. Evaluating the evolution of phenotypes could in turn clarify preclinical disease, and screening and preventive strategies. ClinicalTrials.gov NCT00154180 C1 [Dowling, N. Maritza] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biostat & Med Informat, Madison, WI 53706 USA. [Dowling, N. Maritza; Gleason, Carey E.; Asthana, Sanjay] Wisconsin Alzheimers Dis Res Ctr, Madison, WI USA. [Gleason, Carey E.; Wharton, Whitney; Asthana, Sanjay] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Gleason, Carey E.; Wharton, Whitney; Asthana, Sanjay] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Hodis, Howard N.] Univ So Calif, Atherosclerosis Res Unit, Los Angeles, CA USA. [Miller, Virginia M.] Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN USA. [Miller, Virginia M.] Mayo Clin, Dept Surg, Rochester, MN USA. [Brinton, Eliot A.] Univ Utah, Dept Cardiovasc Genet, Salt Lake City, UT USA. [Neal-Perry, Genevieve] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, Bronx, NY 10467 USA. [Neal-Perry, Genevieve] Albert Einstein Coll Med, Dominick Purpura Dept Neurosci, Bronx, NY 10467 USA. [Santoro, M. Nanette] Univ Colorado, Sch Med, Dept Obstet & Gynecol, Aurora, CO USA. [Cedars, Marcelle] Univ Calif San Francisco, Dept Obstet & Gynecol, San Francisco, CA 94143 USA. [Lobo, Rogerio] Columbia Univ Coll Phys & Surg, Dept Obstet & Gynecol, New York, NY 10032 USA. [Merriam, George R.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Merriam, George R.] Univ Washington, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Naftolin, Frederick] NYU, Dept Obstet & Gynecol, New York, NY 10016 USA. [Taylor, Hugh] Yale Univ, Sch Med, Dept Obstet & Gynecol, New Haven, CT 06510 USA. [Harman, S. Mitchell] Kronos Longev Res Inst, Phoenix, AZ USA. [Harman, S. Mitchell] Phoenix VA Med Ctr, Phoenix, AZ USA. RP Dowling, NM (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Biostat & Med Informat, Madison, WI 53706 USA. EM nmdowlin@biostat.wisc.edu FU National Institutes of Health (NIH) [R01 AG029624, P50AG033514, R01AG031790]; Aurora Foundation; NIH [HL90639]; Mayo [CTSA1 UL1 RR024150]; Einstein College of Medicine CTSA [UL1 RR025750, KL2 RR025749, TL1 RR025748]; Mayo Foundation; United States Department of Veterans Affairs Puget Sound Health Care System; Brigham and Women's Hospital/Harvard Medical School CTSA; CTSA [UL1 RR024139]; UCSF CTSA from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH [UL1 RR024131]; NIH Roadmap for Medical Research FX The KEEPS-cog project was supported by grants from the National Institutes of Health (NIH) R01 AG029624, P50AG033514, and R01AG031790. The parent KEEPS trial is funded by grants from the Aurora Foundation to the Kronos Longevity Research Institute, NIH HL90639 to VMM, Mayo CTSA1 UL1 RR024150, the Einstein College of Medicine CTSA UL1 RR025750, KL2 RR025749 and TL1 RR025748, the Mayo Foundation, the United States Department of Veterans Affairs Puget Sound Health Care System, Brigham and Women's Hospital/Harvard Medical School CTSA, CTSA UL1 RR024139 and UCSF CTSA UL1 RR024131 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH and NIH Roadmap for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 4 Z9 4 U1 0 U2 6 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 JUL 17 PY 2013 VL 8 IS 7 AR UNSP e68741 DI 10.1371/journal.pone.0068741 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185WH UT WOS:000322000600022 PM 23874743 ER PT J AU Zhu, HJ Bogdanov, MB Boyle, SH Matson, W Sharma, S Matson, S Churchill, E Fiehn, O Rush, JA Krishnan, RR Pickering, E Delnomdedieu, M Kaddurah-Daouk, R AF Zhu, Hongjie Bogdanov, Mikhail B. Boyle, Stephen H. Matson, Wayne Sharma, Swati Matson, Samantha Churchill, Erik Fiehn, Oliver Rush, John A. Krishnan, Ranga R. Pickering, Eve Delnomdedieu, Marielle Kaddurah-Daouk, Rima CA Pharmacometabolomics Res Network TI Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder - Possible Role for Methoxyindole Pathway SO PLOS ONE LA English DT Article ID SEROTONIN REUPTAKE INHIBITORS; VENTRAL TEGMENTAL AREA; PREFRONTAL CORTEX; EXTRACELLULAR LEVELS; METABOLOMIC ANALYSIS; GABA CONCENTRATIONS; PARKINSONS-DISEASE; CIRCADIAN-RHYTHMS; GOLDEN-HAMSTER; PINEAL-GLAND AB Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD(17)). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, chi(2) (1) = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL. C1 [Zhu, Hongjie; Boyle, Stephen H.; Churchill, Erik; Krishnan, Ranga R.; Kaddurah-Daouk, Rima] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [Bogdanov, Mikhail B.] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY USA. [Matson, Wayne; Sharma, Swati; Matson, Samantha] Bedford VA Med Ctr, Dept Syst Biochem, Bedford, MA USA. [Matson, Samantha] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fiehn, Oliver] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Rush, John A.; Krishnan, Ranga R.] Duke NUS Grad Med Sch, Singapore, Singapore. [Pickering, Eve] Pfizer Global R&D, Clin Res Stat, Groton, CT USA. [Delnomdedieu, Marielle] Pfizer Global R&D, Neurosci Clin Res, Groton, CT USA. RP Kaddurah-Daouk, R (reprint author), Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. OI Rush, Augustus/0000-0003-2004-2382 FU Pfizer Corporation; National Institute of General Medical Sciences [GM078233] FX This work was done with funding from Pfizer Corporation and from National Institute of General Medical Sciences grant GM078233, "The Metabolomics Research Network for Drug Response Phenotype." The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 21 Z9 22 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 JUL 17 PY 2013 VL 8 IS 7 AR e68283 DI 10.1371/journal.pone.0068283 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185WH UT WOS:000322000600007 PM 23874572 ER PT J AU Singh, JA Lewallen, DG AF Singh, Jasvinder A. Lewallen, David G. TI Operative diagnosis for revision total hip arthroplasty is associated with patient-reported outcomes (PROs) SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE Total hip replacement; Arthroplasty; Joint replacement; Patient-reported outcomes; Diagnosis ID TOTAL KNEE ARTHROPLASTY; UNITED-STATES; PREDICTORS; PAIN; RESPONSIVENESS; QUESTIONNAIRE; COMORBIDITY; REPLACEMENT; FRACTURES; MORBIDITY AB Background: Little is known about the impact of the reason for revision total hip arthroplasty (THA) on the outcomes following revision THA. In this study, our objective was to assess the association of operative diagnosis with patient-reported outcomes (PROs) after revision THA. Methods: We used prospectively collected data from the Mayo Clinic Total Joint Registry that collects pre- and post-operative pain and function outcomes using a validated Hip questionnaire, on all revision THAs from 1993-2005. We used logistic regression to assess the odds of moderate-severe index hip pain and moderate-severe limitation in activities of daily living (ADLs) 2- and 5-years after revision THA. We calculated odds ratios (OR) and 95% confidence intervals (CIs). Results: For the 2- and 5-year cohorts, the operative diagnosis was loosening/wear/osteolysis in 73% and 75%; dislocation/bone or prosthesis fracture/instability or non-union in 17% and 15%; and failed prior arthroplasty with components removed/infection in 11% and 11%, respectively. In multivariable-adjusted analyses that included preoperative ADL limitations, compared to patients with loosening/wear/osteolysis, patients with dislocation/fracture/instability/non-union had OR of 2.2 (95% CI, 1.3-3.5; p = 0.002) for overall moderate-severe ADL limitation and those with failed prior arthroplasty/infection had OR of 1.6 (95% CI, 1.0-2.8; p = 0.06). At 5-years, ORs were lower and differences were no longer significant. Moderate-severe pain did not differ significantly by diagnosis, at 2- or 5-years in multivariable adjusted analyses, with one exception, i.e. failed prior arthroplasty/infection had a trend towards significance with odds ratio of 1.9 (95% CI, 0.9-3.8; p = 0.07). Conclusions: Operative diagnosis is independently associated with ADL limitations, but not pain, at 2-years after revision THA. Patients should be informed of the risk of poorer short-term outcomes based on their diagnosis. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Ctr Surg Med Acute care Res & Transit C SMART, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Singh, Jasvinder A.; Lewallen, David G.] Mayo Clin, Coll Med, Dept Orthopaed Surg, Rochester, MN USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. EM Jasvinder.md@gmail.com OI singh, jasvinder/0000-0003-3485-0006 FU Mayo Clinic Orthopedic Surgery research funds; Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs); National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS); National Institute of Aging (NIA); National Cancer Institute (NCI) FX This material is the result of work supported Mayo Clinic Orthopedic Surgery research funds and the resources and use of facilities at the Birmingham VA Medical Center, Alabama, USA. J.A.S. is also supported by grants from the Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs), National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institute of Aging (NIA) and National Cancer Institute (NCI). NR 31 TC 3 Z9 3 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD JUL 17 PY 2013 VL 14 AR 210 DI 10.1186/1471-2474-14-210 PG 7 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 188KY UT WOS:000322193100001 PM 23866848 ER PT J AU Niziolek, CA Guenther, FH AF Niziolek, Caroline A. Guenther, Frank H. TI Vowel Category Boundaries Enhance Cortical and Behavioral Responses to Speech Feedback Alterations SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SURFACE-BASED ANALYSIS; NEURAL-NETWORK MODEL; AUDITORY-FEEDBACK; FMRI; PITCH; COMPENSATION; TIME; DISCRIMINATION; MANIPULATIONS; ACQUISITION AB Auditory feedback is instrumental in the online control of speech, allowing speakers to compare their self-produced speech signal with a desired auditory target and correct for errors. However, there is little account of the representation of "target" and "error": does error depend purely on acoustic distance from a target, or is error enhanced by phoneme category changes? Here, we show an effect of vowel boundaries on compensatory responses to a real-time auditory perturbation. While human subjects spoke monosyllabic words, event-triggered functional magnetic resonance imaging was used to characterize neural responses to unexpected changes in auditory feedback. Capitalizing on speakers' natural variability, we contrasted the responses to feedback perturbations applied to two classes of utterances: (1) those that fell nearer to the category boundary, for which perturbations were designed to change the phonemic identity of the heard speech; and (2) those that fell farther from the boundary, for which perturbations resulted in only sub-phonemic auditory differences. Subjects' behavioral compensation was more than three times greater when feedback shifts were applied nearer to a category boundary. Furthermore, a near-boundary shift resulted in stronger cortical responses, most notably in right posterior superior temporal gyrus, than an identical shift that occurred far from the boundary. Across participants, a correlation was found between the amount of compensation to the perturbation and the amount of activity in a network of superior temporal and inferior frontal brain regions. Together, these results demonstrate that auditory feedback control of speech is sensitive to linguistic categories learned through auditory experience. C1 [Niziolek, Caroline A.] Univ Calif San Francisco, Dept Otolaryngol, San Francisco, CA 94143 USA. [Guenther, Frank H.] Boston Univ, Dept Speech Language & Hearing Sci, Boston, MA 02215 USA. [Guenther, Frank H.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Guenther, Frank H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Neuroimaging, Charlestown, MA 02139 USA. [Guenther, Frank H.] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. RP Niziolek, CA (reprint author), 513 Parnassus Ave,Box 0628, San Francisco, CA 94143 USA. EM carrien@mit.edu OI Niziolek, Caroline/0000-0002-6085-1371 FU National Institutes of Health [R01 DC002852, F32 DC011249] FX This research was supported in part by National Institutes of Health Grants R01 DC002852 (F. H. G.) and F32 DC011249 (C.A.N.). We thank Kevin Reilly for providing formant analysis code. NR 49 TC 14 Z9 14 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 17 PY 2013 VL 33 IS 29 BP 12090 EP 12098 DI 10.1523/JNEUROSCI.1008-13.2013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 184MG UT WOS:000321893500033 PM 23864694 ER PT J AU Clair, C Rigotti, NA Meigs, JB AF Clair, Carole Rigotti, Nancy A. Meigs, James B. TI Smoking Cessation, Weight Change, and Risk of Cardiovascular Disease Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Clair, Carole] Univ Lausanne, Dept Ambulatory Care & Community Med, Lausanne, Switzerland. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Clair, C (reprint author), Policlin Med Univ, 44 Rue Bugnon, CH-1011 Lausanne Vaud, Switzerland. EM carole.willi@gmail.com RI Clair, Carole/D-9786-2014 OI Clair, Carole/0000-0001-5281-0943 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 17 PY 2013 VL 310 IS 3 BP 323 EP 323 DI 10.1001/jama.2013.7945 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 183RU UT WOS:000321835700025 PM 23860997 ER PT J AU Heinrichs, S Conover, LF Bueso-Ramos, CE Kilpivaara, O Stevenson, K Neuberg, D Loh, ML Wu, WS Rodig, SJ Garcia-Manero, G Kantarjian, HM Look, AT AF Heinrichs, Stefan Conover, Lillian F. Bueso-Ramos, Carlos E. Kilpivaara, Outi Stevenson, Kristen Neuberg, Donna Loh, Mignon L. Wu, Wen-Shu Rodig, Scott J. Garcia-Manero, Guillermo Kantarjian, Hagop M. Look, A. Thomas TI MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy SO ELIFE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; ARRAY ANALYSIS; B-MYB; IDENTIFICATION; EXPRESSION; TRANSCRIPTION; CANCER; 5Q-SYNDROME; REDUCTION; PHENOTYPE AB A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20-30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these 'sub-haploinsufficient' cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies. C1 [Heinrichs, Stefan] Univ Hosp Essen, Inst Transfus Med, Essen, Germany. [Heinrichs, Stefan; Conover, Lillian F.; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Bueso-Ramos, Carlos E.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Kilpivaara, Outi] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Stevenson, Kristen; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Loh, Mignon L.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Wu, Wen-Shu] Childrens Hosp, Oakland Res Inst, Ctr Cell Therapies, Oakland, CA 94609 USA. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Garcia-Manero, Guillermo; Kantarjian, Hagop M.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. RP Heinrichs, S (reprint author), Univ Hosp Essen, Inst Transfus Med, Essen, Germany. EM stefan.heinrichs@uk-essen.de RI Wu, Wen-Shu/I-1258-2014 OI Wu, Wen-Shu/0000-0002-0225-2522 FU National Institutes of Health [NIH P01 CA-108631] FX National Institutes of Health NIH P01 CA-108631 Stefan Heinrichs, Lillian F Conover, Carlos E Bueso-Ramos, Outi Kilpivaara, Kristen Stevenson, Donna Neuberg, Mignon L Loh, Guillermo Garcia-Manero, Hagop M Kantarjian NR 31 TC 6 Z9 6 U1 0 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JUL 16 PY 2013 VL 2 AR e00825 DI 10.7554/eLife.00825 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 274QM UT WOS:000328621200005 PM 23878725 ER PT J AU Usta, OB Kim, Y Ozer, S Bruinsma, BG Lee, J Demir, E Berendsen, TA Puts, CF Izamis, ML Uygun, K Uygun, BE Yarmush, ML AF Usta, O. Berk Kim, Yeonhee Ozer, Sinan Bruinsma, Bote G. Lee, Jungwoo Demir, Esin Berendsen, Tim A. Puts, Catheleyne F. Izamis, Maria-Louisa Uygun, Korkut Uygun, Basak E. Yarmush, Martin L. TI Supercooling as a Viable Non-Freezing Cell Preservation Method of Rat Hepatocytes SO PLOS ONE LA English DT Article ID UNIVERSITY-OF-WISCONSIN; SUBZERO NONFREEZING STORAGE; UREA CYCLE ENZYMES; LIVER PRESERVATION; HYPOTHERMIC PRESERVATION; SANDWICH CONFIGURATION; ANTIFREEZE PROTEIN; COLLAGEN SANDWICH; GENE-EXPRESSION; COLD-STORAGE AB Supercooling preservation holds the potential to drastically extend the preservation time of organs, tissues and engineered tissue products, and fragile cell types that do not lend themselves well to cryopreservation or vitrification. Here, we investigate the effects of supercooling preservation (SCP at -4 degrees C) on primary rat hepatocytes stored in cryovials and compare its success (high viability and good functional characteristics) to that of static cold storage (CS at +4 degrees C) and cryopreservation. We consider two prominent preservation solutions a) Hypothermosol (HTS-FRS) and b) University of Wisconsin solution (UW) and a range of preservation temperatures (-4 to -10 degrees C). We find that there exists an optimum temperature (-4 degrees C) for SCP of rat hepatocytes which yields the highest viability; at this temperature HTS-FRS significantly outperforms UW solution in terms of viability and functional characteristics (secretions and enzymatic activity in suspension and plate culture). With the HTS-FRS solution we show that the cells can be stored for up to a week with high viability (similar to 56%); moreover we also show that the preservation can be performed in large batches (50 million cells) with equal or better viability and no loss of functionality as compared to smaller batches (1.5 million cells) performed in cryovials. C1 [Usta, O. Berk] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02115 USA. Shriners Hosp Children, Boston, MA USA. RP Usta, OB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02115 USA. EM berkusta@gmail.com RI USTA, O. Berk/A-5818-2008; Uygun, Basak/I-1792-2012; OI USTA, O. Berk/0000-0001-9328-568X; Uygun, Basak/0000-0002-2600-7900; Bruinsma, Bote/0000-0003-1537-4948 FU NIH [R01DK096075, R01EB008678, R00DK080942, K99DK088962]; Shriners Fellowship [84202] FX NIH #R01DK096075, NIH #R01EB008678, NIH #R00DK080942, NIH #K99DK088962, Shriners Fellowship #84202. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 5 Z9 6 U1 1 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 JUL 16 PY 2013 VL 8 IS 7 AR e69334 DI 10.1371/journal.pone.0069334 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 186SF UT WOS:000322064300098 PM 23874947 ER PT J AU Gellad, WF Donohue, JM Zhao, XH Mor, MK Thorpe, CT Smith, J Good, CB Fine, MJ Morden, NE AF Gellad, Walid F. Donohue, Julie M. Zhao, Xinhua Mor, Maria K. Thorpe, Carolyn T. Smith, Jeremy Good, Chester B. Fine, Michael J. Morden, Nancy E. TI Brand-Name Prescription Drug Use Among Veterans Affairs and Medicare Part D Patients With Diabetes A National Cohort Comparison SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HEALTH-CARE-SYSTEM; QUALITY-OF-CARE; GEOGRAPHIC-VARIATION; OLDER-ADULTS; COST; PRICES; IMPLEMENTATION; HYPERTENSION; MEDICATIONS; PHYSICIANS AB Background: Medicare Part D and the U.S. Department of Veterans Affairs (VA) use different approaches to manage prescription drug benefits, with implications for spending. Medicare relies on private plans with distinct formularies, whereas the VA administers its own benefit using a national formulary. Objective: To compare overall and regional rates of brand-name drug use among older adults with diabetes in Medicare and the VA. Design: Retrospective cohort. Setting: Medicare and the VA, 2008. Patients: 1 061 095 Medicare Part D beneficiaries and 510 485 veterans aged 65 years or older with diabetes. Measurements: Percentage of patients taking oral hypoglycemics, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) who filled brand-name drug prescriptions and percentage of patients taking long-acting insulins who filled analogue prescriptions. Sociodemographic-and health status-adjusted hospital referral region (HRR) brand-name drug use was compared, and changes in spending were calculated if use of brand-name drugs in 1 system mirrored the other. Results: Brand-name drug use in Medicare was 2 to 3 times that in the VA: 35.3% versus 12.7% for oral hypoglycemics, 50.7% versus 18.2% for statins, 42.5% versus 20.8% for ACE inhibitors or ARBs, and 75.1% versus 27.0% for insulin analogues. Adjusted HRR-level brand-name statin use ranged (from the 5th to 95th percentiles) from 41.0% to 58.3% in Medicare and 6.2% to 38.2% in the VA. For each drug group, the 95th-percentile HRR in the VA had lower brand-name drug use than the 5th-percentile HRR in Medicare. Medicare spending in this population would have been $1.4 billion less if brand-name drug use matched that of the VA. Limitation: This analysis cannot fully describe the factors underlying differences in brand-name drug use. Conclusion: Medicare beneficiaries with diabetes use 2 to 3 times more brand-name drugs than a comparable group within the VA, at substantial excess cost. C1 Univ Pittsburgh, RAND Corp, Vet Affairs Pittsburgh Healthcare Syst, Grad Sch Publ Hlth,Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. [Smith, Jeremy; Morden, Nancy E.] Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH 03766 USA. US Dept Vet Affairs, Pharm Benefits Management Serv, Hines, IL USA. Geisel Sch Med Dartmouth, Hanover, NH USA. RP Gellad, WF (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM walid.gellad@va.gov FU U.S. Department of Veterans Affairs; National Institutes of Health; Robert Wood Johnson Foundation FX Primary Funding Source: U.S. Department of Veterans Affairs, National Institutes of Health, and Robert Wood Johnson Foundation. NR 49 TC 17 Z9 17 U1 4 U2 15 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 16 PY 2013 VL 159 IS 2 BP 105 EP W39 DI 10.7326/0003-4819-159-2-201307160-00664 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 187IX UT WOS:000322112000016 PM 23752663 ER PT J AU Conn, A AF Conn, Alasdair TI Marathon Day at Massachusetts General SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Conn, A (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Founders 114, Boston, MA 02114 USA. EM aconn@partners.org NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 16 PY 2013 VL 159 IS 2 BP 143 EP 144 DI 10.7326/0003-4819-159-2-201307160-00648 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 187IX UT WOS:000322112000021 PM 23698555 ER PT J AU Luc, S Orkin, SH AF Luc, Sidinh Orkin, Stuart H. TI Delineating the mixed lineage leukemia gene expression network in hematopoietic stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID DROSOPHILA-TRITHORAX; MLL TRANSLOCATIONS; SELF-RENEWAL; TISSUES; UNIQUE C1 [Orkin, Stuart H.] Harvard Univ, Sch Med, Div Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst,Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Div Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU Howard Hughes Medical Institute NR 16 TC 0 Z9 0 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 16 PY 2013 VL 110 IS 29 BP 11670 EP 11671 DI 10.1073/pnas.1310349110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187AB UT WOS:000322086100017 PM 23824294 ER PT J AU Butler, TC Kardar, M Chakraborty, AK AF Butler, Thomas Charles Kardar, Mehran Chakraborty, Arup K. TI Quorum sensing allows T cells to discriminate between self and nonself SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE statistical mechanics; T-cell-mediated autoimmunity; self tolerance ID RANDOM-ENERGY MODEL; REPERTOIRE DIVERSITY; NEGATIVE SELECTION; RESPONSE MAGNITUDE; CENTRAL TOLERANCE; THYMIC SELECTION; DENDRITIC CELLS; IMMUNE-RESPONSE; AFFINITY; RECRUITMENT AB T cells orchestrate pathogen-specific adaptive immune responses by identifying peptides derived from pathogenic proteins that are displayed on the surface of infected cells. Host cells also display peptide fragments from the host's own proteins. Incorrectly identifying peptides derived from the body's own proteome as pathogenic can result in autoimmune disease. To minimize autoreactivity, immature T cells that respond to self-peptides are deleted in the thymus by a process called negative selection. However, negative selection is imperfect, and autoreactive T cells exist in healthy individuals. To understand how autoimmunity is yet avoided, without loss of responsiveness to pathogens, we have developed a model of T-cell training and response. Our model shows that T cells reliably respond to infection and avoid autoimmunity because collective decisions made by the T-cell population, rather than the responses of individual T cells, determine biological outcomes. The theory is qualitatively consistent with experimental data and yields a criterion for thymic selection to be adequate for suppressing autoimmunity. C1 [Butler, Thomas Charles; Kardar, Mehran] MIT, Dept Phys, Cambridge, MA 02139 USA. [Butler, Thomas Charles] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Dept Chem Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Dept Biol Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] Harvard Univ, Cambridge, MA 02138 USA. RP Kardar, M (reprint author), MIT, Dept Phys, Cambridge, MA 02139 USA. EM kardar@mit.edu; arupc@mit.edu FU National Institutes of Health; National Science Foundation [12-06323] FX This work was partially supported by a National Institutes of Health Pioneer Award (to A.K.C.) and National Science Foundation Grant 12-06323 (to M.K.). NR 42 TC 15 Z9 15 U1 0 U2 24 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 JUL 16 PY 2013 VL 110 IS 29 BP 11833 EP 11838 DI 10.1073/pnas.1222467110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187AB UT WOS:000322086100047 PM 23818603 ER PT J AU Lee, JH Yi, LN Li, JX Schweitzer, K Borgmann, M Naumann, M Wu, H AF Lee, Jung-Hoon Yi, Lina Li, Jixi Schweitzer, Katrin Borgmann, Marc Naumann, Michael Wu, Hao TI Crystal structure and versatile functional roles of the COP9 signalosome subunit 1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GENE-EXPRESSION; 26S PROTEASOME; PCI DOMAIN; REGULATORY PARTICLE; FISSION YEAST; KAPPA-B; COMPLEX; ARABIDOPSIS; PROTEIN; COP9/SIGNALOSOME AB The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) plays key roles in many biological processes, such as repression of photomorphogenesis in plants and protein subcellular localization, DNA-damage response, and NF-kappa B activation in mammals. It is an evolutionarily conserved eight-protein complex with subunits CSN1 to CSN8 named following the descending order of molecular weights. Here, we report the crystal structure of the largest CSN subunit, CSN1 from Arabidopsis thaliana (atCSN1), which belongs to the Proteasome, COP9 signalosome, Initiation factor 3 (PCI) domain containing CSN subunit family, at 2.7 angstrom resolution. In contrast to previous predictions and distinct from the PCI-containing 26S proteasome regulatory particle subunit Rpn6 structure, the atCSN1 structure reveals an overall globular fold, with four domains consisting of helical repeat-I, linker helix, helical repeat-II, and the C-terminal PCI domain. Our small-angle X-ray scattering envelope of the CSN1-CSN7 complex agrees with the EM structure of the CSN alone (apo-CSN) and suggests that the PCI end of each molecule may mediate the interaction. Fitting of the CSN1 structure into the CSN-Skp1-Cul1-Fbox (SCF) EM structure shows that the PCI domain of CSN1 situates at the hub of the CSN for interaction with several other subunits whereas the linker helix and helical repeat-II of CSN1 contacts SCF using a conserved surface patch. Furthermore, we show that, in human, the C-terminal tail of CSN1, a segment not included in our crystal structure, interacts with I kappa B alpha in the NF-kappa B pathway. Therefore, the CSN complex uses multiple mechanisms to hinder NF-kappa B activation, a principle likely to hold true for its regulation of many other targets and pathways. C1 [Lee, Jung-Hoon; Yi, Lina; Li, Jixi; Wu, Hao] Weill Cornell Med Coll, Dept Biochem, New York, NY 10065 USA. [Yi, Lina; Li, Jixi; Wu, Hao] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02114 USA. [Yi, Lina; Li, Jixi; Wu, Hao] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02114 USA. [Schweitzer, Katrin; Borgmann, Marc; Naumann, Michael] Univ Magdeburg, Inst Expt Internal Med, D-39120 Magdeburg, Germany. RP Wu, H (reprint author), Weill Cornell Med Coll, Dept Biochem, New York, NY 10065 USA. EM hao.wu@childrens.harvard.edu RI Naumann, Michael/B-5285-2011 OI Naumann, Michael/0000-0002-8060-2313 NR 50 TC 4 Z9 7 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 16 PY 2013 VL 110 IS 29 BP 11845 EP 11850 DI 10.1073/pnas.1302418110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187AB UT WOS:000322086100049 PM 23818606 ER PT J AU Cheema, TA Wakimoto, H Fecci, PE Ning, JF Kuroda, T Jeyaretna, DS Martuza, RL Rabkin, SD AF Cheema, Tooba A. Wakimoto, Hiroaki Fecci, Peter E. Ning, Jianfang Kuroda, Toshihiko Jeyaretna, Deva S. Martuza, Robert L. Rabkin, Samuel D. TI Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antiangiogenesis; immunotherapy; virotherapy ID HERPES-SIMPLEX-VIRUS; REGULATORY T-CELLS; MALIGNANT GLIOMA; TUMORS; EXPRESSION; VECTORS; IL-12; INTERLEUKIN-12; LINES; VIROTHERAPY AB Glioblastoma (World Health Organization grade IV) is an aggressive adult brain tumor that is inevitably fatal despite surgery, radiation, and chemotherapy. Treatment failures are attributed to combinations of cellular heterogeneity, including a subpopulation of often-resistant cancer stem cells, aberrant vasculature, and noteworthy immune suppression. Current preclinical models and treatment strategies do not incorporate or address all these features satisfactorily. Herein, we describe a murine glioblastoma stem cell (GSC) model that recapitulates tumor heterogeneity, invasiveness, vascularity, and immunosuppressive microenvironment in syngeneic immunocompetent mice and should prove useful for a range of therapeutic studies. Using this model, we tested a genetically engineered oncolytic herpes simplex virus that is armed with an immunomodulatory cytokine, interleukin 12 (G47 Delta-mIL12). G47 Delta-mIL12 infects and replicates similarly to its unarmed oncolytic herpes simplex virus counterpart in mouse 005 GSCs in vitro, whereas in vivo, it significantly enhances survival in syngeneic mice bearing intracerebral 005 tumors. Mechanistically, G47 Delta-mIL12 targets not only GSCs but also increases IFN-gamma release, inhibits angiogenesis, and reduces the number of regulatory T cells in the tumor. The increased efficacy is dependent upon T cells, but not natural killer cells. Taken together, our findings demonstrate that G47 Delta-mIL12 provides a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system, with resultant therapeutic benefit in a stringent glioblastoma model. C1 [Rabkin, Samuel D.] Massachusetts Gen Hosp, Brain Tumor Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurosurg, Mol Neurosurg Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Rabkin, SD (reprint author), Massachusetts Gen Hosp, Brain Tumor Res Ctr, Boston, MA 02114 USA. EM rabkin@helix.mgh.harvard.edu OI Kuroda, Toshihiko/0000-0001-6660-8930 FU National Institutes of Health [R01NS032677, R01CA160762, R25NS065743]; Joelle Syverson American Brain Tumor Association Research Fellowship; Rendina Family Foundation FX We thank Drs. Inder Verma and Yasushi Soda for the 005 GSC cells; David Dombowski for sorting of GFP-positive cells; Kat Folz-Donahue and Laura Prickett-Rice from the Harvard Stem Cell Institute Flow Cytometry Core facility for assistance with flow cytometry analysis; John Chen and Derrick Jeon at the Massachusetts General Hospital Center for Systems Biology for assistance with the bioluminescence imaging; and members of the Molecular Neurosurgery Laboratory, especially Cecile Zaupa, Anoop Patel, Melissa Humphreys, and Howie Latimer for technical assistance and support. These studies were supported in part by National Institutes of Health Grants R01NS032677 (to R.L.M.), R01CA160762 (to S.D.R.), and R25NS065743 (to P.E.F.); a Joelle Syverson American Brain Tumor Association Research Fellowship (to T.A.C.); and the Rendina Family Foundation. NR 50 TC 35 Z9 36 U1 1 U2 28 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 JUL 16 PY 2013 VL 110 IS 29 BP 12006 EP 12011 DI 10.1073/pnas.1307935110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187AB UT WOS:000322086100076 PM 23754388 ER PT J AU Lee, JK Shin, JH Hwang, SG Gwag, BJ Mckee, AC Lee, J Kowall, NW Ryu, H Lim, DS Choi, EJ AF Lee, Jae Keun Shin, Jin Hee Hwang, Sang Gil Gwag, Byoung Joo McKee, Ann C. Lee, Junghee Kowall, Neil W. Ryu, Hoon Lim, Dae-Sik Choi, Eui-Ju TI MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neurotoxicity; ROS ID AMYOTROPHIC-LATERAL-SCLEROSIS; INCREASED OXIDATIVE DAMAGE; MOTOR-NEURON DEATH; PROTEIN-KINASE; AUTOPHAGY; ACTIVATION; APOPTOSIS; CELLS; STE20; MICE AB Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Dominant mutations in the gene for superoxide dismutase 1 (SOD1) give rise to familial ALS by an unknown mechanism. Here we show that genetic deficiency of mammalian sterile 20-like kinase 1 (MST1) delays disease onset and extends survival in mice expressing the ALS-associated G93A mutant of human SOD1. SOD1(G93A) induces dissociation of MST1 from a redox protein thioredoxin-1 and promotes MST1 activation in spinal cord neurons in a reactive oxygen species-dependent manner. Moreover, MST1 was found to mediate SOD1(G93A)-induced activation of p38 mitogen-activated protein kinase and caspases as well as impairment of autophagy in spinal cord motoneurons of SOD1(G93A) mice. Our findings implicate MST1 as a key determinant of neurodegeneration in ALS. C1 [Lee, Jae Keun; Shin, Jin Hee; Choi, Eui-Ju] Korea Univ, Sch Life Sci & Biotechnol, Lab Cell Death & Human Dis, Seoul 136701, South Korea. [Shin, Jin Hee; Gwag, Byoung Joo] GNT Pharma, Suwon 446906, South Korea. [McKee, Ann C.; Lee, Junghee; Kowall, Neil W.; Ryu, Hoon] Boston Univ, Sch Med, Dept Neurol & Pathol, Boston, MA 02130 USA. [McKee, Ann C.; Lee, Junghee; Kowall, Neil W.; Ryu, Hoon] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Lim, Dae-Sik] Korea Adv Inst Sci & Technol, Biomed Res Ctr, Dept Biol Sci, Taejon 305701, South Korea. [Choi, Eui-Ju] Korea Univ, Coll Pharm, Yeongi 339700, Chungnam, South Korea. RP Choi, EJ (reprint author), Korea Univ, Sch Life Sci & Biotechnol, Lab Cell Death & Human Dis, Seoul 136701, South Korea. EM ejchoi@korea.ac.kr RI Kowall, Neil/G-6364-2012; Lim, Dae-Sik/C-1599-2011 OI Kowall, Neil/0000-0002-6624-0213; Lim, Dae-Sik/0000-0003-2356-7555 FU National Research Foundation [2006-0093855, 2011-0030141, 2009-0081488]; Ministry of Science, ICT & Future Planning of Korea; Korea University; Veterans Affairs Merit Award; [351-2009-1-E00030] FX We thank S. Kang (Korea University) for providing Flag-SOD1 and Flag-SOD1(G93A) cDNAs. This work was supported by Grant 351-2009-1-E00030 (to J.K.L) and by National Research Foundation Grants 2006-0093855, and 2011-0030141, and 2009-0081488 funded by the Ministry of Science, ICT & Future Planning of Korea (to E.-J.C.). J.K.L was supported by a Korea University grant. J.L. and N.W.K. were supported by Veterans Affairs Merit Award. NR 31 TC 12 Z9 13 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 JUL 16 PY 2013 VL 110 IS 29 BP 12066 EP 12071 DI 10.1073/pnas.1300894110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 187AB UT WOS:000322086100086 PM 23818595 ER PT J AU Podrid, PJ AF Podrid, Philip J. TI ECG Challenge: July 16, 2013 SO CIRCULATION LA English DT Editorial Material C1 [Podrid, Philip J.] Harvard Univ, Sch Med, Boston Univ, Sch Med, Boston, MA USA. [Podrid, Philip J.] VA Boston Healthcare Syst, Boston, MA USA. RP Podrid, PJ (reprint author), West Roxbury VA Hosp, Cardiol Sect, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM ppodrid@circulationjournal.org NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 16 PY 2013 VL 128 IS 3 BP 278 EP 278 DI 10.1161/CIRCULATIONAHA.113.004369 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 184NJ UT WOS:000321897400023 ER PT J AU van Erven, B Gubbels, CS van Golde, RJ Dunselman, GA Derhaag, JG de Wert, G Geraedts, JP Bosch, AM Treacy, EP Welt, CK Berry, GT Rubio-Gozalbo, ME AF van Erven, Britt Gubbels, Cynthia S. van Golde, Ron J. Dunselman, Gerard A. Derhaag, Josien G. de Wert, Guido Geraedts, Joep P. Bosch, Annet M. Treacy, Eileen P. Welt, Corrine K. Berry, Gerard T. Rubio-Gozalbo, M. Estela TI Fertility preservation in female classic galactosemia patients SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Review DE Classic galactosemia; GALT deficiency; Primary ovarian insufficiency; POI; Fertility preservation; Cryopreservation ID OVARIAN TISSUE CRYOPRESERVATION; HYPERGONADOTROPIC HYPOGONADISM; PRENATAL EXPOSURE; CANCER-PATIENTS; GERM-CELLS; FAILURE; OOCYTE; INSUFFICIENCY; DYSFUNCTION; PREGNANCY AB Almost every female classic galactosemia patient develops primary ovarian insufficiency (POI) as a diet-independent complication of the disease. This is a major concern for patients and their parents, and physicians are often asked about possible options to preserve fertility. Unfortunately, there are no recommendations on fertility preservation in this group. The unique pathophysiology of classic galactosemia with a severely reduced follicle pool at an early age requires an adjusted approach. In this article recommendations for physicians based on current knowledge concerning galactosemia and fertility preservation are made. Fertility preservation is only likely to be successful in very young prepubertal patients. In this group, cryopreservation of ovarian tissue is currently the only available technique. However, this technique is not ready for clinical application, it is considered experimental and reduces the ovarian reserve. Fertility preservation at an early age also raises ethical questions that should be taken into account. In addition, spontaneous conception despite POI is well described in classic galactosemia. The uncertainty surrounding fertility preservation and the significant chance of spontaneous pregnancy warrant counseling towards conservative application of these techniques. We propose that fertility preservation should only be offered with appropriate institutional research ethics approval to classic galactosemia girls at a young prepubertal age. C1 [van Erven, Britt; Rubio-Gozalbo, M. Estela] Maastricht Univ, Med Ctr, Dept Pediat, Maastricht, Netherlands. [van Erven, Britt; Rubio-Gozalbo, M. Estela] Maastricht Univ, Med Ctr, Dept Genet Metab Dis Lab, Maastricht, Netherlands. [van Erven, Britt; van Golde, Ron J.; Dunselman, Gerard A.; Derhaag, Josien G.; de Wert, Guido; Geraedts, Joep P.; Rubio-Gozalbo, M. Estela] Maastricht Univ, GROW, Res Sch Oncol & Dev Biol, Maastricht, Netherlands. [Gubbels, Cynthia S.; Geraedts, Joep P.] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [van Golde, Ron J.; Dunselman, Gerard A.; Derhaag, Josien G.] Maastricht Univ, Med Ctr, Dept Obstet & Gynecol, Maastricht, Netherlands. [de Wert, Guido] Maastricht Univ, Dept Hlth Eth & Soc, Maastricht, Netherlands. [Bosch, Annet M.] Univ Amsterdam, Acad Med Ctr, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands. [Treacy, Eileen P.] Childrens Univ Hosp, Trinity Coll, Natl Ctr Inherited Metab Disorders, Dublin, Ireland. [Welt, Corrine K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Reprod Endocrine Unit, Boston, MA USA. [Berry, Gerard T.] Harvard Univ, Sch Med, Boston Childrens Hosp, Manton Ctr Orphan Dis Res,Div Genet, Boston, MA USA. RP Rubio-Gozalbo, ME (reprint author), Maastricht Univ, Med Ctr, Dept Pediat, Maastricht, Netherlands. EM estela.rubio@mumc.nl RI rubio, estela/H-1833-2011; OI Berry, Gerard/0000-0001-5299-3313; Welt, Corrine/0000-0002-8219-5504 FU Dutch Revalidatie Fonds FX This study was financially supported by a grant from the Dutch Revalidatie Fonds to CG and ER. NR 68 TC 4 Z9 4 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD JUL 16 PY 2013 VL 8 AR 107 DI 10.1186/1750-1172-8-107 PG 8 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 186HO UT WOS:000322033100001 PM 23866841 ER PT J AU Lebl, DR Bono, CM Velmahos, G Metkar, U Nguyen, J Harris, MB AF Lebl, Darren R. Bono, Christopher M. Velmahos, George Metkar, Umesh Nguyen, Joseph Harris, Mitchel B. TI Vertebral Artery Injury Associated With Blunt Cervical Spine Trauma A Multivariate Regression Analysis SO SPINE LA English DT Article DE cervical trauma; vertebral artery; vascular injury; computed tomographic angiography ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; DELAYED CORTICAL BLINDNESS; NONINVASIVE SCREENING-TEST; CEREBROVASCULAR INJURIES; VASCULAR INJURY; FRACTURE; DIAGNOSIS; OCCLUSION; OUTCOMES; TIME AB Study Design. Retrospective analysis of prospective registry data. Objective. To determine the patient characteristics, risk factors, and fracture patterns associated with vertebral artery injury (VAI) in patients with blunt cervical spine injury. Summary of Background Data. VAI associated with cervical spine trauma has the potential for catastrophical clinical sequelae. The patterns of cervical spine injury and patient characteristics associated with VAI remain to be determined. Methods. A retrospective review of prospectively collected data from the American College of Surgeons trauma registries at 3 level-1 trauma centers identified all patients with a cervical spine injury on multidetector computed tomographic scan during a 3-year period (January 1, 2007, to January 1, 2010). Fracture pattern and patient characteristics were recorded. Logistic multivariate regression analysis of independent predictors for VAI and subgroup analysis of neurological events related to VAI was performed. Results. Twenty-one percent of 1204 patients with cervical injuries (n = 253) underwent screening for VAI by multidetector computed tomography angiogram. VAI was diagnosed in 17% (42 of 253), unilateral in 15% (38 of 253), and bilateral in 1.6% (4 of 253) and was associated with a lower Glasgow coma scale (P < 0.001), a higher injury severity score (P < 0.01), and a higher mortality (P < 0.001). VAI was associated with ankylosing spondylitis/diffuse idiopathic skeletal hyperosteosis (crude odds ratio [OR] = 8.04; 95% confidence interval [CI], 1.30-49.68; P = 0.034), and occipitocervical dissociation (P < 0.001) by univariate analysis and fracture displacement into the transverse foramen 1 mm or more (adjusted OR = 3.29; 95% CI, 1.15-9.41; P = 0.026), and basilar skull fracture (adjusted OR = 4.25; 95% CI, 1.25-14.47; P = 0.021), by multivariate regression model. Subgroup analyses of neurological events secondary to VAI occurred in 14% (6 of 42) and the stroke-related mortality rate was 4.8% (2 of 42). Neurological events were associated with male sex (P = 0.024), facet subluxation/ dislocation (crude OR = 9.00; 95% CI, 1.51-53.74; P = 0.004) and the diagnosis of ankylosing spondylitis/diffuse idiopathic skeletal hyperosteosis (OR = 40.67; 95% CI, 5.27-313.96; P < 0.001). Conclusion. VAI associated with blunt cervical spine injury is a marker for more severely injured patients. High-risk patients with basilar skull fractures, occipitocervical dissociation, fracture displacement into the transverse foramen more than 1 mm, ankylosing spondylitis/diffuse idiopathic skeletal hyperosteosis, and facet subluxation/dislocation deserve focused consideration for VAI screening. C1 [Lebl, Darren R.] Hosp Special Surg, Spine Care Inst, New York, NY 10021 USA. [Bono, Christopher M.; Harris, Mitchel B.] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Velmahos, George] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Metkar, Umesh] Beth Israel Deaconess Med Ctr, Dept Orthopaed Surg, Boston, MA 02215 USA. [Nguyen, Joseph] Hosp Special Surg, New York, NY 10021 USA. RP Lebl, DR (reprint author), Hosp Special Surg, Spine Care Inst, 523 East 72nd St, New York, NY 10021 USA. EM drlebl@stanfordalumni.org NR 44 TC 5 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD JUL 15 PY 2013 VL 38 IS 16 BP 1352 EP 1361 DI 10.1097/BRS.0b013e318294bacb PG 10 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 298YS UT WOS:000330361500012 PM 23574813 ER PT J AU Khera, N Storer, B Sandmaier, BM Chapko, MK Lee, SJ AF Khera, Nandita Storer, Barry Sandmaier, Brenda M. Chapko, Michael K. Lee, Stephanie J. TI Costs of Second Allogeneic Hematopoietic Cell Transplantation SO TRANSPLANTATION LA English DT Article DE Hematopoietic cell transplantation; Economics; Costs; Cost effectiveness; Pharmacoeconomics ID BONE-MARROW-TRANSPLANTATION; MULTIPLE-MYELOMA; ACUTE-LEUKEMIA; GRAFT FAILURE; RELAPSE; CHEMOTHERAPY; LYMPHOMA; SURVIVAL; BLOOD; SCT AB Background. A second allogeneic transplantation after a prior allogeneic (allo-allo) or autologous (auto-allo) hematopoietic cell transplantation (HCT) is usually performed for graft failure, disease recurrence, secondary malignancy, and, as planned, auto-allo transplantation for some diseases. Methods. We sought to describe the costs of second allogeneic HCT and evaluate their relationship with patient characteristics and posttransplantation complications. Clinical information and medical costs for the first 100 days after transplantation of 245 patients (allo-allo, 55; auto-allo, 190) who underwent a second HCT between 2004 and 2010 were collected. Results. Median costs of the second allogeneic HCT were U.S. $151,000 (range, U.S. $62,000-405,000) for the allo-allo group and U.S. $109,000 (range, U.S. $26,000-490,000) for the auto-allo group. Median length of hospital stay was 23 days (range, 0-76) for the allo-allo group and 9 days (range, 0-96) for the auto-allo group. Only the year of transplantation and posttransplantation complications were significantly associated with costs in both groups when both pre- and posttransplantation variables were considered. The overall costs of the second HCT were higher than the first in the allo-allo group. For the auto-allo group, there was no difference between the costs whether preformed as a planned tandem or as salvage for relapse. Conclusions. Our results suggest that second allogeneic HCT is costly, particularly if it follows a prior allogeneic transplantation, and is driven by the costs of complications. C1 [Khera, Nandita] Mayo Clin Arizona, Div Hematol Oncol, Phoenix, AZ USA. [Storer, Barry; Sandmaier, Brenda M.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Chapko, Michael K.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. RP Khera, N (reprint author), 5777 East Mayo Blvd,C-211, Phoenix, AZ 85054 USA. EM khera.nandita@mayo.edu FU National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000423]; National Institutes of Health [CA 78902, HL36444, CA18029] FX The study was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000423 and grants CA 78902, HL36444, and CA18029 from the National Institutes of Health. NR 25 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2013 VL 96 IS 1 BP 108 EP 115 DI 10.1097/TP.0b013e318294caf1 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 299EJ UT WOS:000330378000018 PM 23694949 ER PT J AU Nimptsch, K Bernstein, AM Giovannucci, E Fuchs, CS Willett, WC Wu, KN AF Nimptsch, Katharina Bernstein, Adam M. Giovannucci, Edward Fuchs, Charles S. Willett, Walter C. Wu, Kana TI Dietary Intakes of Red Meat, Poultry, and Fish During High School and Risk of Colorectal Adenomas in Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adenomatous polyps; adolescent; fish; food intake; meat; poultry ID CANCER-RISK; BREAST-CANCER; COLON-CANCER; PREMENOPAUSAL WOMEN; ADOLESCENT DIET; CONSUMPTION; COHORT; CHILDHOOD; MEN; ASSOCIATION AB Adolescent diet may be etiologically relevant for colorectal carcinogenesis. We examined the association between meat and fish intakes during adolescence and the risk of colorectal adenomas later in life among 19,771 women participating in the Nurses' Health Study II. Subjects had completed a validated food frequency questionnaire in 1998 (when aged 34-51 years) about their diets during high school and subsequently underwent at least 1 lower-bowel endoscopy during the study period (1998-2007). During this period, 1,494 subjects were diagnosed with colorectal adenomas. Intake of red meat during adolescence was not associated with colorectal adenoma risk when comparing those in the highest versus lowest category of intake (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.81, 1.35). Similarly, intake of fish during adolescence was not associated with colorectal adenoma risk (OR = 0.96, 95% CI: 0.78, 1.17). Intake of poultry during adolescence was associated with a lower risk of total colorectal (OR = 0.80, 95% CI: 0.64, 0.99), distal (OR = 0.71, 95% CI: 0.51, 0.99), rectal (OR = 0.51, 95% CI: 0.29, 0.90), and advanced (OR = 0.60, 95% CI: 0.38, 0.93) adenomas. Replacement of 1 serving per day of red meat with 1 serving per day of poultry or fish was associated with 41% and 35% decreased risks for rectal adenomas and advanced adenomas, respectively. Our findings do not suggest an association between red meat intake during adolescence and colorectal adenomas later in life, but higher poultry intake during this time was associated with a lower risk of colorectal adenomas. C1 [Nimptsch, Katharina; Bernstein, Adam M.; Giovannucci, Edward; Willett, Walter C.; Wu, Kana] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Nimptsch, Katharina] Max Delbruck Ctr Mol Med, Mol Epidemiol Res Grp, Berlin, Germany. [Giovannucci, Edward; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward; Fuchs, Charles S.; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Giovannucci, Edward; Fuchs, Charles S.; Willett, Walter C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bernstein, Adam M.] Cleveland Clin, Wellness Inst, Lyndhurst, OH USA. RP Nimptsch, K (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM knimptsc@hsph.harvard.edu OI Nimptsch, Katharina/0000-0001-7877-205X FU American Institute for Cancer Research; National Cancer Institute [R01 CA50385]; Entertainment Industry Foundation's National Colorectal Cancer Research Alliance FX The authors acknowledge funding from the American Institute for Cancer Research (investigator-initiated grant to K. W.), the National Cancer Institute (grant R01 CA50385 to W. C. W.), and the Entertainment Industry Foundation's National Colorectal Cancer Research Alliance. NR 47 TC 5 Z9 6 U1 0 U2 19 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2013 VL 178 IS 2 BP 172 EP 183 DI 10.1093/aje/kwt099 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 186DD UT WOS:000322021300002 PM 23785116 ER PT J AU Rosner, B Glynn, RJ Tamimi, RM Chen, WY Colditz, GA Willett, WC Hankinson, SE AF Rosner, Bernard Glynn, Robert J. Tamimi, Rulla M. Chen, Wendy Y. Colditz, Graham A. Willett, Walter C. Hankinson, Susan E. TI Breast Cancer Risk Prediction with Heterogeneous Risk Profiles According to Breast Cancer Tumor Markers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast cancer; competing risks; proportional hazards model ID PROGESTERONE-RECEPTOR STATUS; COMPETING RISKS; NURSES HEALTH; ESTROGEN; SUBTYPES; DISEASE AB Relationships between some risk factors and breast cancer incidence are known to vary by tumor subtype. However, breast tumors can be classified according to a number of markers, which may be correlated, making it difficult to identify heterogeneity of risk factors with specific tumor markers when using standard competing-risk survival analysis. In this paper, we propose a constrained competing-risk survival model that allows for assessment of heterogeneity of risk factor associations according to specific tumor markers while controlling for other markers. These methods are applied to Nurses' Health Study data from 1980-2006, during which 3,398 incident invasive breast cancers occurred over 1.4 million person-years of follow-up. Results suggested that when estrogen receptor (ER) and progesterone receptor (PR) status are mutually considered, some risk factors thought to be characteristic of "estrogen-positive tumors," such as high body mass index during postmenopause and increased height, are actually significantly associated with PR-positive tumors but not ER-positive tumors, while other risk factors thought to be characteristic of "estrogen-negative tumors," such as late age at first birth, are actually significantly associated with PR-negative rather than ER-negative breast cancer. This approach provides a strategy for evaluating heterogeneity of risk factor associations by tumor marker levels while controlling for additional tumor markers. C1 [Rosner, Bernard; Glynn, Robert J.; Tamimi, Rulla M.; Chen, Wendy Y.; Willett, Walter C.; Hankinson, Susan E.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Rosner, Bernard; Glynn, Robert J.; Tamimi, Rulla M.; Chen, Wendy Y.; Willett, Walter C.; Hankinson, Susan E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Colditz, Graham A.] Washington Univ, Alvin J Siteman Canc Ctr, St Louis, MO USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Rosner, Bernard; Glynn, Robert J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Glynn, Robert J.] Harvard Univ, Sch Med, Div Prevent Med, Boston, MA USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Hankinson, Susan E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Rosner, B (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM stbar@channing.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU National Cancer Institute [PO1 CA87969]; American Cancer Society Clinical Research Professorship FX This work was supported by the National Cancer Institute (grant PO1 CA87969). G.A.C. was also supported by an American Cancer Society Clinical Research Professorship. NR 13 TC 26 Z9 26 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2013 VL 178 IS 2 BP 296 EP 308 DI 10.1093/aje/kws457 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 186DD UT WOS:000322021300016 PM 23645624 ER PT J AU Vaturi, M Vaduganathan, M Bental, T Solodky, A Kornowski, R Lev, EI AF Vaturi, Mordehay Vaduganathan, Muthiah Bental, Tamir Solodky, Alejandro Kornowski, Ran Lev, Eli I. TI Relation of Aspirin Response to Age in Patients With Stable Coronary Artery Disease SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LOW-DOSE ASPIRIN; HEART-ASSOCIATION COUNCIL; HEALTH-CARE PROFESSIONALS; CARDIOVASCULAR-DISEASE; PLATELET REACTIVITY; THROMBOXANE BIOSYNTHESIS; MYOCARDIAL-INFARCTION; ANTIPLATELET THERAPY; SCIENTIFIC STATEMENT; GERIATRIC-CARDIOLOGY AB Recent studies have suggested that clopidogrel response may vary significantly with age. Limited data are available exploring the age dependency of ex vivo aspirin response in young and old patients with stable coronary artery disease. Patients with stable coronary artery disease (n = 583) who had been treated with aspirin 75 to 325 mg/day for >= 1 week were recruited from a general cardiology practice. The study cohort was divided into 2 groups: patients aged <75 years (n = 438) and patients aged >= 75 years (n = 145). Aspirin response was determined using the Verify Now Aspirin Test, and resistance was defined as >= 500 or 550 aspirin reaction units (ARU). The independent predictive value of age on Verify Now score (as a continuous function) was determined using multivariate linear regression, adjusted for gender, body mass index, and diabetes mellitus. Younger and older patients had similar baseline clinical profiles, including relative doses of aspirin therapy. The mean Verify Now Aspirin Test score was significantly higher in patients aged >= 75 years: 450 +/- 54 versus 434 +/- 53 ARU (p = 0.0007). After accounting for the primary covariates, age remained a predictor of Verify Now score (p = 0.007). Aspirin resistance on the basis of the 500-ARU cutoff was higher in older patients (19% vs 11%, p = 0.009), but there was no difference when the 550-ARU cutoff was used (7% vs 5%, p = 0.40). In conclusion, aspirin response differs significantly by age in patients with stable CAD. (C) 2013 Elsevier Inc. All rights reserved. C1 [Vaturi, Mordehay; Bental, Tamir; Solodky, Alejandro; Kornowski, Ran; Lev, Eli I.] Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. [Vaturi, Mordehay; Bental, Tamir; Solodky, Alejandro; Kornowski, Ran; Lev, Eli I.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Vaduganathan, Muthiah] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. RP Lev, EI (reprint author), Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. EM elil@clalit.org.il NR 27 TC 7 Z9 8 U1 1 U2 6 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 JUL 15 PY 2013 VL 112 IS 2 BP 212 EP 216 DI 10.1016/j.amjcard.2013.03.022 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188PR UT WOS:000322206500012 PM 23566542 ER PT J AU Kandala, J Upadhyay, GA Pokushalov, E Wu, S Drachman, DE Singh, JP AF Kandala, Jagdesh Upadhyay, Gaurav A. Pokushalov, Evgeny Wu, Sean Drachman, Douglas E. Singh, Jagmeet P. TI Meta-Analysis of Stem Cell Therapy in Chronic Ischemic Cardiomyopathy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID MARROW MONONUCLEAR-CELLS; LEFT-VENTRICULAR FUNCTION; CHRONIC HEART-FAILURE; MYOCARDIAL-INFARCTION; PROGENITOR CELLS; TRANSPLANTATION; DELIVERY; TRIAL; NEOVASCULARIZATION; INJECTION AB Studies investigating bone marrow stem cell therapy (BMSCT) in patients with chronic ischemic cardiomyopathy have yielded mixed results. A meta-analysis of randomized controlled trials of BMSCT in patients with chronic ischemic cardiomyopathy was undertaken to assess its efficacy and the best route of administration. The MEDLINE, Embase, Cumulative Index to Nursing & Allied Health Literature, and Cochrane Library databases were searched through April 2012 for randomized controlled trials that investigated the impact of BMSCT and its route of administration on left ventricular (LV) function in patients with chronic ischemic cardiomyopathy and systolic dysfunction. Of the 226 reports identified, 10 randomized controlled trials including 519 patients (average LV ejection fraction [LVEF] at baseline 32 +/- 7%) were included in the analysis. On the basis of a random-effects model, BMSCT improved the LVEF at 6 months by 4.48% (95% confidence interval [CI] 2.43% to 6.53%, p = 0.0001). A greater improvement in the LVEF was seen with intramyocardial injection compared with intracoronary infusion (5.13% [95% CI 3.17% to 7.10%], p <0.00001, vs 2.32% [95% CI -2.06% to 6.70%], p = 0.30). Overall, there were reductions in LV end-systolic volume of -20.64 ml (95% CI -33.21 to -8.07, p = 0.001) and LV end-diastolic volume of -16.71 ml (95% CI -31.36 to -2.06, p = 0.03). In conclusion, stem cell therapy may improve LVEF and favorably remodel the heart in patients with chronic ischemic cardiomyopathy. On the basis of current limited data, intramyocardial injection may be superior to intracoronary infusion in patients with LV systolic dysfunction. (C) 2013 Elsevier Inc. All rights reserved. C1 [Kandala, Jagdesh; Upadhyay, Gaurav A.; Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA 02115 USA. [Wu, Sean] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Drachman, Douglas E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Pokushalov, Evgeny] State Res Inst Circulat Pathol, Novosibirsk, Russia. RP Singh, JP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA 02115 USA. EM jsingh@partners.org RI Pokushalov, Evgeny/L-7993-2014 OI Pokushalov, Evgeny/0000-0002-2560-5167 NR 27 TC 36 Z9 36 U1 1 U2 14 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 JUL 15 PY 2013 VL 112 IS 2 BP 217 EP 225 DI 10.1016/j.amjcard.2013.03.021 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188PR UT WOS:000322206500013 PM 23623290 ER PT J AU Bethel, MA Chacra, AR Deedwania, P Fulcher, GR Holman, RR Jenssen, T Kahn, SE Levitt, NS McMurray, JJV Califf, RM Raptis, SA Thomas, L Sun, JL Haffner, SM AF Bethel, M. Angelyn Chacra, Antonio R. Deedwania, Prakash Fulcher, Gregory R. Holman, Rury R. Jenssen, Trond Kahn, Steven E. Levitt, Naomi S. McMurray, John J. V. Califf, Robert M. Raptis, Sotirios A. Thomas, Laine Sun, Jie-Lena Haffner, Steven M. TI A Novel Risk Classification Paradigm for Patients With Impaired Glucose Tolerance and High Cardiovascular Risk SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; DIABETES-MELLITUS; FASTING GLUCOSE; LIVER FIBROSIS; TASK-FORCE; HEART; TRIAL; NATEGLINIDE; PREVENTION AB We used baseline data from the NAVIGATOR trial to (1) identify risk factors for diabetes progression in those with impaired glucose tolerance and high cardiovascular risk, (2) create models predicting 5-year incident diabetes, and (3) provide risk classification tools to guide clinical interventions. Multivariate Cox proportional hazards models estimated 5-year incident diabetes risk and simplified models examined the relative importance of measures of glycemia in assessing diabetes risk. The C-statistic was used to compare models; reclassification analyses compare the models' ability to identify risk groups defined by potential therapies (routine or intensive lifestyle advice or pharmacologic therapy). Diabetes developed in 3,254 (35%) participants over 5 years median follow-up. The full prediction model included fasting and 2-hour glucose and hemoglobin A1c (HbA1c) values but demonstrated only moderate discrimination for diabetes (C = 0.70). Simplified models with only fasting glucose (C = 0.67) or oral glucose tolerance test values (C = 0.68) had higher C statistics than models with HbA1c alone (C = 0.63). The models were unlikely to inappropriately reclassify participants to risk groups that might receive pharmacologic therapy. Our results confirm that in a population with dysglycemia and high cardiovascular risk, traditional risk factors are appropriate predictors and glucose values are better predictors than HbA1c, but discrimination is moderate at best, illustrating the challenges of predicting diabetes in a high-risk population. In conclusion, our novel risk classification paradigm based on potential treatment could be used to guide clinical practice based on cost and availability of screening tests. (C) 2013 Elsevier Inc. All rights reserved. C1 [Bethel, M. Angelyn; Holman, Rury R.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Diabet Trials Unit, Oxford, England. [Bethel, M. Angelyn] Duke Univ, Med Ctr, Dept Med, Div Metab Endocrinol & Nutr, Durham, NC 27710 USA. [Chacra, Antonio R.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Deedwania, Prakash] Univ Calif San Francisco Program Fresno, Fresno, CA USA. [Deedwania, Prakash] Vet Adm Cent Calif Hlth Care Syst, Fresno, CA USA. [Fulcher, Gregory R.] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Jenssen, Trond] Univ Tromso, Oslo Univ Hosp, Rigshosp, Inst Clin Med, Oslo, Norway. [Kahn, Steven E.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Levitt, Naomi S.] Univ Cape Town, Dept Med, Groote Schuur Hosp, Endocrine Unit, ZA-7925 Cape Town, South Africa. [McMurray, John J. V.] Univ Glasgow, Glasgow Cardiovasc Res Ctr, British Heart Fdn, Glasgow, Lanark, Scotland. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC USA. [Raptis, Sotirios A.] Attikon Univ Hosp, Hellen Natl Diabet Ctr, Dept Internal Med Endocrinol & Diabetol 2, Athens, Greece. [Thomas, Laine] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Thomas, Laine; Sun, Jie-Lena] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. RP Bethel, MA (reprint author), Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Diabet Trials Unit, Oxford, England. EM angelyn.bethel@dtu.ox.ac.uk OI Kahn, Steven/0000-0001-7307-9002; mcmurray, john/0000-0002-6317-3975 FU Novartis Pharmaceuticals FX The NAVIGATOR trial was funded by Novartis Pharmaceuticals. NR 21 TC 2 Z9 2 U1 0 U2 1 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 JUL 15 PY 2013 VL 112 IS 2 BP 231 EP 237 DI 10.1016/j.amjcard.2013.03.019 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188PR UT WOS:000322206500015 PM 23608615 ER PT J AU Villiger, M Zhang, EZ Nadkarni, SK Oh, WY Vakoc, BJ Bouma, BE AF Villiger, Martin Zhang, Ellen Ziyi Nadkarni, Seemantini K. Oh, Wang-Yuhl Vakoc, Benjamin J. Bouma, Brett E. TI Spectral binning for mitigation of polarization mode dispersion artifacts in catheter-based optical frequency domain imaging SO OPTICS EXPRESS LA English DT Article ID COHERENCE TOMOGRAPHY; IN-VIVO; MAINTAINING FIBER; BIREFRINGENCE; ORIENTATION; COLLAGEN; PMD AB Polarization mode dispersion (PMD) has been recognized as a significant barrier to sensitive and reproducible birefringence measurements with fiber-based, polarization-sensitive optical coherence tomography systems. Here, we present a signal processing strategy that reconstructs the local retardation robustly in the presence of system PMD. The algorithm uses a spectral binning approach to limit the detrimental impact of system PMD and benefits from the final averaging of the PMD-corrected retardation vectors of the spectral bins. The algorithm was validated with numerical simulations and experimental measurements of a rubber phantom. When applied to the imaging of human cadaveric coronary arteries, the algorithm was found to yield a substantial improvement in the reconstructed birefringence maps. (C) 2013 Optical Society of America C1 [Villiger, Martin; Zhang, Ellen Ziyi; Nadkarni, Seemantini K.; Vakoc, Benjamin J.; Bouma, Brett E.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Villiger, Martin; Zhang, Ellen Ziyi; Nadkarni, Seemantini K.; Vakoc, Benjamin J.; Bouma, Brett E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Oh, Wang-Yuhl] Korea Adv Inst Sci & Technol, Dept Mech Engn, Taejon 305701, South Korea. [Vakoc, Benjamin J.; Bouma, Brett E.] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA 02142 USA. RP Villiger, M (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. EM mvilliger@partners.org FU National Institutes of Health [P41 EB015903, R01 CA163528]; NRF of Korea [2012-0005633]; Terumo Corporation; Swiss National Science Foundation FX Research reported in this publication was supported in part by the National Institutes of Health, grants P41 EB015903 and R01 CA163528, by the NRF of Korea, grant 2012-0005633, and by Terumo Corporation. M.V. was supported by a fellowship from the Swiss National Science Foundation. NR 31 TC 23 Z9 23 U1 2 U2 13 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUL 15 PY 2013 VL 21 IS 14 BP 16353 EP 16369 DI 10.1364/OE.21.016353 PG 17 WC Optics SC Optics GA 183MK UT WOS:000321819400015 PM 23938487 ER PT J AU Jubran, A AF Jubran, Amal TI Has the Twitching Hour Arrived for the Ventilated Patient? SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID MECHANICAL VENTILATION; RANDOMIZED-TRIAL; PRESSURE; DURATION; FAILURE; SUPPORT; HUMANS; MUSCLE C1 [Jubran, Amal] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Div Pulm & Crit Care Med, Hines, IL 60141 USA. [Jubran, Amal] Loyola Univ Chicago, Stritch Sch Med, Maywood, IL USA. RP Jubran, A (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Div Pulm & Crit Care Med, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. NR 12 TC 2 Z9 2 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2013 VL 188 IS 2 BP 126 EP 128 DI 10.1164/rccm.201305-0890ED PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 183LV UT WOS:000321817400004 PM 23855688 ER PT J AU Esteban, A Frutos-Vivar, F Muriel, A Ferguson, ND Penuelas, O Abraira, V Raymondos, K Rios, F Nin, N Apezteguia, C Violi, DA Thille, AW Brochard, L Gonzalez, M Villagomez, AJ Hurtado, J Davies, AR Du, B Maggiore, SM Pelosi, P Soto, L Tomicic, V D'Empaire, G Matamis, D Abroug, F Moreno, RP Soares, MA Arabi, Y Sandi, F Jibaja, M Amin, P Koh, Y Kuiper, MA Bulow, HH Zeggwagh, AA Anzueto, A AF Esteban, Andres Frutos-Vivar, Fernando Muriel, Alfonso Ferguson, Niall D. Penuelas, Oscar Abraira, Victor Raymondos, Konstantinos Rios, Fernando Nin, Nicolas Apezteguia, Carlos Violi, Damian A. Thille, Arnaud W. Brochard, Laurent Gonzalez, Marco Villagomez, Asisclo J. Hurtado, Javier Davies, Andrew R. Du, Bin Maggiore, Salvatore M. Pelosi, Paolo Soto, Luis Tomicic, Vinko D'Empaire, Gabriel Matamis, Dimitrios Abroug, Fekri Moreno, Rui P. Soares, Marco Antonio Arabi, Yaseen Sandi, Freddy Jibaja, Manuel Amin, Pravin Koh, Younsuck Kuiper, Michael A. Bulow, Hans-Henrik Zeggwagh, Amine Ali Anzueto, Antonio TI Evolution of Mortality over Time in Patients Receiving Mechanical Ventilation SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE mechanical ventilation; mortality; epidemiology; cohort study ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE LUNG INJURY; RANDOMIZED CONTROLLED-TRIAL; END-EXPIRATORY PRESSURE; LOWER TIDAL VOLUMES; CRITICALLY-ILL PATIENTS; PROTECTIVE-VENTILATION; STRATEGY; METAANALYSIS; SEDATION AB Rationale: Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear. Objectives: To estimate whether mortality in mechanically ventilated patients has changed over time. Methods: Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models. Measurements and Main Results: We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P, 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an increase in applied positive end-expiratory pressure (mean 4.2 cm H2O [SD = 3.8] in 1998 to 7.0 cm of H2O [SD = 3.0] in 2010). Crude mortality in the intensive care unit decreased in 2010 compared with 1998 (28 versus 31%; odds ratio, 0.87; 95% confidence interval, 0.80-0.94), despite a similar complication rate. Hospital mortality decreased similarly. After adjusting for baseline and management variables, this difference remained significant (odds ratio, 0.78; 95% confidence interval, 0.67-0.92). Conclusions: Patient characteristics and ventilation practices have changed over time, and outcomes of mechanically ventilated patients have improved. Clinical trials registered with www.clinicaltrials.gov (NCT01093482). C1 [Esteban, Andres; Frutos-Vivar, Fernando; Penuelas, Oscar; Nin, Nicolas] Hosp Univ Getafe, Madrid 28905, Spain. [Muriel, Alfonso; Abraira, Victor] Hosp Ramon & Cajal, Dept Clin Biostat, Inst Ramon y Cajal Invest Sanitaria, Madrid, Spain. [Ferguson, Niall D.] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON M5S 1A1, Canada. [Ferguson, Niall D.] Univ Toronto, Dept Med, Toronto, ON M5S 1A1, Canada. [Ferguson, Niall D.] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A1, Canada. [Raymondos, Konstantinos] Hannover Med Sch, Hannover, Germany. [Rios, Fernando; Apezteguia, Carlos] Hosp Nacl Alejandro Posadas, Buenos Aires, DF, Argentina. [Violi, Damian A.] Hosp Interzonal Gen Agudos Dr Luis Guemes, Haedo, Argentina. [Thille, Arnaud W.] CHU Henri Mondor, F-94010 Creteil, France. [Brochard, Laurent] Univ Hosp Geneva, Geneva, Switzerland. [Gonzalez, Marco] Clin Medellin, Medellin, Colombia. [Gonzalez, Marco] Univ Pontificia Bolivariana, Medellin, Colombia. [Villagomez, Asisclo J.] Hosp Reg 1 Octubre, Inst Seguridad & Serv Sociales Trabajadores Estad, Mexico City, DF, Mexico. [Hurtado, Javier] Hosp Clin Montevideo, Montevideo, Uruguay. [Davies, Andrew R.] Alfred Hosp, Melbourne, Vic, Australia. [Davies, Andrew R.] Monash Univ, Melbourne, Vic 3004, Australia. [Du, Bin] Beijing Union Med Coll Hosp, Beijing, Peoples R China. [Maggiore, Salvatore M.] Univ Cattolica Sacro Cuore, Policlin Agostino Gemelli, Rome, Italy. [Pelosi, Paolo] Univ Genoa, Dipartimento Sci Chirurg & Diagnost Integrate, Genoa, Italy. [Soto, Luis] Inst Nacl Torax Santiago, Santiago, Chile. [Tomicic, Vinko] Clin Las Lilas Santiago, Santiago, Chile. [D'Empaire, Gabriel] Hosp Clin Caracas, Caracas, Venezuela. [Matamis, Dimitrios] Papageorgiou Hosp, Thessaloniki, Greece. [Abroug, Fekri] Hosp Fattouma Bourguina, Monastir, Tunisia. [Moreno, Rui P.] Ctr Hosp Lisboa Cent, Hosp Sao Jose, Unidade Cuidados Intens Neurocrit, Lisbon, Portugal. [Soares, Marco Antonio] Hosp Univ Sao Jose, Belo Horizonte, MG, Brazil. [Arabi, Yaseen] King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia. [Sandi, Freddy] Hosp Obrero 1, La Paz, Bolivia. [Jibaja, Manuel] Hosp Eugenio Espejo, Quito, Ecuador. [Amin, Pravin] Bombay Hosp Inst Med Sci, Bombay, Maharashtra, India. [Koh, Younsuck] Univ Ulsan, Asan Med Ctr, Seoul, South Korea. [Kuiper, Michael A.] Med Ctr Leeuwarden, Leeuwarden, Netherlands. [Bulow, Hans-Henrik] Reg Zealand Univ Copenhagen, Holbak Hosp, Copenhagen, Denmark. [Zeggwagh, Amine Ali] Hop Ibn Sina, Rabat, Morocco. [Anzueto, Antonio] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Esteban, A (reprint author), Hosp Univ Getafe, Intens Care Unit, Carretera Toledo,Km 12,500, Madrid 28905, Spain. EM aesteban@ucigetafe.com OI Abraira, Victor/0000-0002-4615-8503; Frutos-Vivar, Fernando/0000-0002-4648-9636; MAGGIORE, Salvatore Maurizio/0000-0002-1828-9143; Ferguson, Niall/0000-0002-6213-5264; Muriel, Alfonso /0000-0002-4805-4011 FU Centro de Investigacion Biomedica en red Enfermedades Respiratorias, CIBER en Epidemiologia y Salud Publica; Instituto de Salud Carlos III, Madrid, Spain; Instituto Ramon y Cajal de Investigacion Sanitaria, Madrid, Spain; Canadian Institutes of Health Research (Ottawa, ON, Canada) FX Supported by Centro de Investigacion Biomedica en red Enfermedades Respiratorias, CIBER en Epidemiologia y Salud Publica. Instituto de Salud Carlos III, Madrid, Spain, Instituto Ramon y Cajal de Investigacion Sanitaria, Madrid, Spain, and by a Canadian Institutes of Health Research (Ottawa, ON, Canada) New Investigator Award (N.D.F.). NR 43 TC 122 Z9 129 U1 2 U2 14 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2013 VL 188 IS 2 BP 220 EP 230 DI 10.1164/rccm.201212-2169OC PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 183LV UT WOS:000321817400017 PM 23631814 ER PT J AU Schulz, TJ Tseng, YH AF Schulz, Tim J. Tseng, Yu-Hua TI Brown adipose tissue: development, metabolism and beyond SO BIOCHEMICAL JOURNAL LA English DT Review DE adipocyte; brown adipose tissue; obesity; thermogenesis; white adipose tissue ID BONE MORPHOGENETIC PROTEIN-7; DIET-INDUCED THERMOGENESIS; WHITE FAT; TRANSCRIPTIONAL CONTROL; ENERGY-EXPENDITURE; SKELETAL-MUSCLE; INDUCED OBESITY; ADULT HUMANS; STEM-CELLS; IN-VIVO AB Obesity represents a major risk factor for the development of several of our most common medical conditions, including Type 2 diabetes, dyslipidaemia, non-alcoholic fatty liver, cardiovascular disease and even some cancers. Although increased fat mass is the main feature of obesity, not all fat depots are created equal. Adipocytes found in white adipose tissue contain a single large lipid droplet and play well-known roles in energy storage. By contrast, brown adipose tissue is specialized for thermogenic energy expenditure. Owing to its significant capacity to dissipate energy and regulate triacylglycerol (triglyceride) and glucose metabolism, and its demonstrated presence in adult humans, brown fat could be a potential target for the treatment of obesity and metabolic syndrome. Undoubtedly, fundamental knowledge about the formation of brown fat and regulation of its activity is imperatively needed to make such therapeutics possible. In the present review, we integrate the recent advancements on the regulation of brown fat formation and activity by developmental and hormonal signals in relation to its metabolic function. C1 [Schulz, Tim J.] German Inst Human Nutr, Res Grp Adipocyte Dev, D-14558 Nuthetal, Germany. [Tseng, Yu-Hua] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Tseng, Yu-Hua] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Tseng, YH (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. EM yu-hua.tseng@joslin.harvard.edu RI Schulz, Tim/F-4842-2013 OI Schulz, Tim/0000-0002-8413-3972 FU National Institutes of Health [R01 DK077097]; Joslin Diabetes Center's Diabetes Research Center (from the National Institute of Diabetes and Digestive and Kidney Disease) [P30 DK036836]; American Diabetes Association; Harvard Stem Cell Institute; Mary K. Iacocca Foundation; German Research Foundation [SCHU 2445/1-1, SCHU 2445/2-1]; European Research Council [ERC-StG-311082] FX This work was supported, in part, by the National Institutes of Health [grant number R01 DK077097 (to Y.-H.T.)], the Joslin Diabetes Center's Diabetes Research Center [grant number P30 DK036836 (from the National Institute of Diabetes and Digestive and Kidney Disease)], the American Diabetes Association and the Harvard Stem Cell Institute (to Y.-H.T.). T.J.S. was supported by the Mary K. Iacocca Foundation, the German Research Foundation [grant numbers SCHU 2445/1-1 and SCHU 2445/2-1] and the European Research Council [grant number ERC-StG-311082]. NR 149 TC 33 Z9 33 U1 4 U2 46 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 JUL 15 PY 2013 VL 453 BP 167 EP 178 DI 10.1042/BJ20130457 PN 2 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 183IS UT WOS:000321808800002 PM 23805974 ER PT J AU Fendt, SM Bell, EL Keibler, MA Davidson, SM Wirth, GJ Fiske, B Mayers, JR Schwab, M Bellinger, G Csibi, A Patnaik, A Blouin, MJ Cantley, LC Guarente, L Blenis, J Pollak, MN Olumi, AF Vander Heiden, MG Stephanopoulos, G AF Fendt, Sarah-Maria Bell, Eric L. Keibler, Mark A. Davidson, Shawn M. Wirth, Gregory J. Fiske, Brian Mayers, Jared R. Schwab, Matthias Bellinger, Gary Csibi, Alfredo Patnaik, Akash Blouin, Marie Jose Cantley, Lewis C. Guarente, Leonard Blenis, John Pollak, Michael N. Olumi, Aria F. Vander Heiden, Matthew G. Stephanopoulos, Gregory TI Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism SO CANCER RESEARCH LA English DT Article ID PROLIFERATION; GROWTH; INHIBITION; RISK; FLUX; APOPTOSIS; THERAPY; BIOLOGY; ARREST; EMU AB Metformin inhibits cancer cell proliferation, and epidemiology studies suggest an association with increased survival in patients with cancer taking metformin; however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation, whereas increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer. (C) 2013 AACR. C1 [Fendt, Sarah-Maria; Keibler, Mark A.; Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Bell, Eric L.; Davidson, Shawn M.; Fiske, Brian; Mayers, Jared R.; Guarente, Leonard; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Davidson, Shawn M.; Fiske, Brian; Mayers, Jared R.; Vander Heiden, Matthew G.] MIT, Koch Inst Canc Res, Cambridge, MA 02139 USA. [Wirth, Gregory J.; Olumi, Aria F.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Bellinger, Gary; Cantley, Lewis C.] Beth Israel Deaconess Canc Ctr, Div Signal Transduct, Dept Med, Boston, MA USA. [Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Csibi, Alfredo] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pollak, Michael N.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Schwab, Matthias] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. [Schwab, Matthias] Doctor Margarete Fischer Bosch Inst Clin Pharmaco, Stuttgart, Germany. [Schwab, Matthias] Univ Hosp, Inst Expt & Clin Pharmacol & Toxicol, Dept Clin Pharmacol, Tubingen, Germany. RP Stephanopoulos, G (reprint author), MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mvh@mit.edu; gregstep@mit.edu RI Cantley, Lewis/D-1800-2014; OI Cantley, Lewis/0000-0002-1298-7653; Wirth, Gregory J./0000-0003-0636-3438; Mayers, Jared/0000-0002-8607-1787; Fendt, Sarah-Maria/0000-0001-6018-9296 FU German Research Foundation (DFG) [FE1185]; NIH [5-P50-090381-09, 5-P30-CA14051-39, 1R01DK075850-01, 1R01CA160458-01A1]; Glenn Foundation for Medical Research; LAM Foundation; Burrough's Wellcome Fund; Smith Family; Damon Runyon Cancer Research Foundation FX S.-M. Fendt is supported by the German Research Foundation (DFG), grant FE1185. L. Guarente is supported by the NIH and the Glenn Foundation for Medical Research. A. Csibi is supported by a fellowship from the LAM Foundation. M.G. Vander Heiden acknowledges NIH grant support from 5-P50-090381-09 and 5-P30-CA14051-39 and support from the Burrough's Wellcome Fund, the Smith Family, and the Damon Runyon Cancer Research Foundation. The authors also received grants 1R01DK075850-01 and 1R01CA160458-01A1 from the NIH (G. Stephanopoulos). NR 47 TC 64 Z9 65 U1 5 U2 28 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 JUL 15 PY 2013 VL 73 IS 14 BP 4429 EP 4438 DI 10.1158/0008-5472.CAN-13-0080 PG 10 WC Oncology SC Oncology GA 183NR UT WOS:000321823600025 PM 23687346 ER PT J AU Wang, Q Von, T Bronson, R Ruan, MZ Mu, WX Huang, A Maira, SM Zhao, JJ AF Wang, Qi Thanh Von Bronson, Roderick Ruan, Minzi Mu, Wenxia Huang, Alan Maira, Sauveur-Michel Zhao, Jean J. TI Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome SO GENES & DEVELOPMENT LA English DT Article DE genetic mouse models; PI3K inhibitors; PI3K isoforms; skin; PTEN hamartoma tumor syndrome ID PHOSPHOINOSITIDE 3-KINASE; P110-ALPHA ISOFORM; BREAST-CANCER; EPIDERMAL HOMEOSTASIS; P110-BETA ISOFORMS; COWDEN-SYNDROME; MOUSE MODEL; STEM-CELLS; SUPPRESSOR; SKIN AB PTEN hamartoma tumor syndrome (PHTS) comprises a collection of genetic disorders associated with germline mutations in the tumor suppressor gene PTEN. Therapeutic options and preventative measures for PHTS are limited. Using both genetically engineered mouse models and pharmacological PI3K isoform-selective inhibitors, we found that the roles of PI3K isoforms are spatially distinct in the skin: While p110 alpha is responsible for the sustained survival of suprabasal cells of the epidermis in the absence of PTEN, p110 beta is important for the hyperproliferation of basal cells in PHTS. Furthermore, we identified a differential expression pattern of p110 alpha and p110 beta in basal and suprabasal keratinocytes as well as differential PI3K regulation by upstream signals in the basal and suprabasal compartments of the epidermis, providing a potential molecular mechanism underlying the specific roles of PI3K isoforms in the epidermis. Finally, we demonstrate that combined inhibition of both PI3K isoforms prevents the development of PHTS and also reverses skin hamartomas that have reached advanced stages in mice. Together, these results not only advance our overall understanding of the diverse roles of PI3K isoforms, but also have the potential for meaningful translation via the clinical utilization of PI3K inhibitors for both prevention and therapy in PHTS patients. C1 [Wang, Qi; Thanh Von; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Wang, Qi; Thanh Von; Zhao, Jean J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. [Bronson, Roderick] Harvard Univ, Sch Med, Dana Farber Harvard Canc Ctr Rodent Histopathol C, Boston, MA 02215 USA. [Ruan, Minzi; Mu, Wenxia] VigeneTech Inc, Carlisle, MA 01741 USA. [Huang, Alan] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Maira, Sauveur-Michel] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. RP Zhao, JJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM jean_zhao@dfci.harvard.edu FU NIH [CA134502, CA172461-01]; Stand Up To Cancer [SU2C-AACR-DT0209]; Department of Defense [BC112689] FX We thank T.M. Roberts, L.C. Cantley, P.P. Pandolfi, and D.M. Livingston for scientific discussions, and L.K. Clayton for critical reading. We thank A. Ang, P. Liu, and M. Pusung for technical assistance. K14Cre mice were generously provided by J. Jonkers at the Netherlands Cancer Institute, Netherlands. Floxed Pten mice were generously provided by H. Wu at the University of California at Los Angeles School of Medicine. This work was supported by NIH grants CA134502 (to J.J.Z.) and CA172461-01 (to J.J.Z.), Stand Up To Cancer (SU2C-AACR-DT0209) (to J.J.Z.), and the Department of Defense (BC112689 to J.J.Z.). NR 46 TC 8 Z9 8 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2013 VL 27 IS 14 BP 1568 EP 1580 DI 10.1101/gad.216069.113 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 185ZU UT WOS:000322011500005 PM 23873941 ER PT J AU Sadovski, O Hicks, JW Parkes, J Raymond, R Nobrega, J Houle, S Cipriano, M Fowler, CJ Vasdev, N Wilson, AA AF Sadovski, Oleg Hicks, Justin W. Parkes, Jun Raymond, Roger Nobrega, Jose Houle, Sylvain Cipriano, Mariateresa Fowler, Christopher J. Vasdev, Neil Wilson, Alan A. TI Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE PET; FAAH; Radiosynthesis; Fluorine-18; Rat; Endocannabinoid; Anandamide ID POSITRON-EMISSION-TOMOGRAPHY; CANNABINOID CB1 RECEPTORS; ENDOCANNABINOID SYSTEM; HUMAN BRAIN; FAAH; ANANDAMIDE; INHIBITORS; RAT; PET; EXPRESSION AB Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an F-18-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [F-18]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17-22% (from [F-18]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82 nM after a preincubation of 60 min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [F-18]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [H-18]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [F-18]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved. C1 [Sadovski, Oleg; Hicks, Justin W.; Parkes, Jun; Raymond, Roger; Nobrega, Jose; Houle, Sylvain; Wilson, Alan A.] Ctr Addict & Mental Hlth, Res Imaging Ctr, Toronto, ON M5T 1R8, Canada. [Nobrega, Jose; Houle, Sylvain; Wilson, Alan A.] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada. [Cipriano, Mariateresa; Fowler, Christopher J.] Umea Univ, Dept Pharmacol & Clin Neurosci, SE-90187 Umea, Sweden. [Vasdev, Neil] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Vasdev, Neil] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Vasdev, Neil] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Wilson, AA (reprint author), Ctr Addict & Mental Hlth, Res Imaging Ctr, 250 Coll St, Toronto, ON M5T 1R8, Canada. EM alan.wilson@camhpet.ca RI Wilson, Alan/A-1788-2011; OI Cipriano, Mariateresa/0000-0001-6644-7137 FU NIH [1R21MH094424]; University of Toronto Institute of Medical Science; Swedish Research Council [12158] FX This work was supported by NIH Grant # 1R21MH094424 to A.A.W., a University of Toronto Institute of Medical Science Open Fellowship award to J.W.H., and by a Grant from the Swedish Research Council (Grant no. 12158, medicine) to C.J.F. We would like to thank Armando Garcia, Winston Stableford, Min Wong, and Alvina Ng for their assistance with the radiochemistry and animal dissection experiments. NR 51 TC 12 Z9 12 U1 3 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2013 VL 21 IS 14 BP 4351 EP 4357 DI 10.1016/j.bmc.2013.04.077 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 170GK UT WOS:000320838200042 PM 23712084 ER PT J AU Guenova, E Watanabe, R Teague, JE Desimone, JA Jiang, Y Dowlatshahi, M Schlapbach, C Schaekel, K Rook, AH Tawa, M Fisher, DC Kupper, TS Clark, RA AF Guenova, Emmanuella Watanabe, Rei Teague, Jessica E. Desimone, Jennifer A. Jiang, Ying Dowlatshahi, Mitra Schlapbach, Christoph Schaekel, Knut Rook, Alain H. Tawa, Marianne Fisher, David C. Kupper, Thomas S. Clark, Rachael A. TI T(H)2 Cytokines from Malignant Cells Suppress T(H)1 Responses and Enforce a Global T(H)2 Bias in Leukemic Cutaneous T-cell Lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article ID SEZARY-SYNDROME; MYCOSIS-FUNGOIDES; EORTC CLASSIFICATION; EXPRESS; IMMUNOPATHOGENESIS; PROLIFERATION; SURVIVAL; SUBSETS; PATTERN; BLOOD AB Purpose: In leukemic cutaneous T-cell lymphoma (L-CTCL), malignant T cells accumulate in the blood and give rise to widespread skin inflammation. Patients have intense pruritus, increased immunoglobulin E (IgE), and decreased T-helper (T-H)-1 responses, and most die from infection. Depleting malignant T cells while preserving normal immunity is a clinical challenge. L-CTCL has been variably described as a malignancy of regulatory, T(H)2 and T(H)17 cells. Experimental Design: We analyzed phenotype and cytokine production in malignant and benign L-CTCL T cells, characterized the effects of malignant T cells on healthy T cells, and studied the immunomodulatory effects of treatment modalities in patients with L-CTCL. Results: Twelve out of 12 patients with L-CTCL overproduced T(H)2 cytokines. Remaining benign T cells were also strongly T(H)2 biased, suggesting a global T(H)2 skewing of the T-cell repertoire. Culture of benign T cells away from the malignant clone reduced T(H)2 and enhanced T(H)1 responses, but separate culture had no effect on malignant T cells. Coculture of healthy T cells with L-CTCL T cells reduced IFN gamma production and neutralizing antibodies to interleukin (IL)-4 and IL-13 restored T(H)1 responses. In patients, enhanced T(H)1 responses were observed following a variety of treatment modalities that reduced malignant T-cell burden. Conclusions: A global T(H)2 bias exists in both benign and malignant T cells in L-CTCL and may underlie the infectious susceptibility of patients. T(H)2 cytokines from malignant cells strongly inhibited T(H)1 responses. Our results suggest that therapies that inhibit T(H)2 cytokine activity, by virtue of their ability to improve T(H)1 responses, may have the potential to enhance both anticancer and antipathogen responses. (C) 2013 AACR. C1 [Guenova, Emmanuella; Watanabe, Rei; Teague, Jessica E.; Desimone, Jennifer A.; Dowlatshahi, Mitra; Schlapbach, Christoph; Kupper, Thomas S.; Clark, Rachael A.] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Guenova, Emmanuella; Watanabe, Rei; Teague, Jessica E.; Desimone, Jennifer A.; Dowlatshahi, Mitra; Schlapbach, Christoph; Kupper, Thomas S.; Clark, Rachael A.] Harvard Univ, Sch Med, Boston, MA USA. [Tawa, Marianne; Fisher, David C.; Kupper, Thomas S.; Clark, Rachael A.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Jiang, Ying] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Rook, Alain H.] Hosp Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Schaekel, Knut] Univ Heidelberg Hosp, Dept Dermatol, Heidelberg, Germany. RP Clark, RA (reprint author), Brigham & Womens Hosp, Dept Dermatol, Room 505A,221 Longwood Ave, Boston, MA 02115 USA. EM rclark1@partners.org RI Guenova, Emmanuella/A-4656-2015; Schlapbach, Christoph/D-5832-2013 OI Schlapbach, Christoph/0000-0003-0258-1243 FU Damon Runyon Clinical Investigator Award [R01 AR056720, R03 MH095529]; SPORE in Skin Cancer [P50 CA9368305]; NIH/National Cancer Institute; NIH/National Institute of Allergy and Infectious Diseases [R01 A1025082]; Leukemia & Lymphoma Society; German Research Foundation (DFG); Swiss National Science Foundation; Fondation Rene Touraine; [R01 AI097128]; [R01 CA122569]; [GU1271/2-1] FX This work was supported by a generous charitable contribution from Edward P. Lawrence, Esq., a Damon Runyon Clinical Investigator Award (to R.A. Clark) R01 AR056720 (to R.A. Clark) and R03 MH095529 (to R.A. Clark), the SPORE in Skin Cancer P50 CA9368305 NIH/National Cancer Institute (to T.S. Kupper), R01 A1025082 NIH/National Institute of Allergy and Infectious Diseases (to T. S. Kupper), R01 AI097128 (to T.S. Kupper and R.A. Clark), R01 CA122569 (to A.H. Rook), and by a Special Fellow Award from the Leukemia & Lymphoma Society (to R. Watanabe). Grant support GU1271/2-1 (to E. Guenova) was provided by the German Research Foundation (DFG), and salary support for C. Schlapbach was provided by the Swiss National Science Foundation and the Fondation Rene Touraine. NR 28 TC 31 Z9 32 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 JUL 15 PY 2013 VL 19 IS 14 BP 3755 EP 3763 DI 10.1158/1078-0432.CCR-12-3488 PG 9 WC Oncology SC Oncology GA 183NE UT WOS:000321822000006 PM 23785046 ER PT J AU Zhang, YX van Oosterwijk, JG Sicinska, E Moss, S Remillard, SP Van Wezel, T Uhnemann, CB Hassan, AB Demetri, GD Bovee, JVMG Wagner, AJ AF Zhang, Yi-Xiang van Oosterwijk, Jolieke G. Sicinska, Ewa Moss, Samuel Remillard, Stephen P. Van Wezel, Tom Uhnemann, Claudia B. Hassan, Andrew B. Demetri, George D. Bovee, Judith V. M. G. Wagner, Andrew J. TI Functional Profiling of Receptor Tyrosine Kinases and Downstream Signaling in Human Chondrosarcomas Identifies Pathways for Rational Targeted Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID IN-VITRO; ANTITUMOR-ACTIVITY; TUMOR-GROWTH; CELL-LINE; INHIBITOR; CANCER; TRANSLATION; MUTATIONS; NVP-BEZ235; INSULIN AB Purpose: Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. us were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model. Results: Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas. Conclusions: RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors. C1 [Zhang, Yi-Xiang; Remillard, Stephen P.; Demetri, George D.; Wagner, Andrew J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ludwig Ctr,Dana Farber Harvard, Boston, MA 02215 USA. [Zhang, Yi-Xiang; Remillard, Stephen P.; Demetri, George D.; Wagner, Andrew J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol,Dept Med Oncol, Boston, MA 02215 USA. [Sicinska, Ewa; Moss, Samuel] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Sicinska, Ewa; Moss, Samuel] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02215 USA. [van Oosterwijk, Jolieke G.; Van Wezel, Tom; Bovee, Judith V. M. G.] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Uhnemann, Claudia B.; Hassan, Andrew B.] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England. RP Wagner, AJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Andrew_Wagner@dfci.harvard.edu RI van Wezel, Tom/A-9599-2008 OI Bovee, Judith/0000-0003-1155-0481; van Wezel, Tom/0000-0001-5773-7730 FU Dunkin Donuts Rising Star Award; Fund for Cancer Research supporting the Dana-Farber/Harvard Ludwig Center; Netherlands Organization for Scientific Research [91767-315]; Dutch Cancer Society [UL2010-4873]; EC seventh framework programme [278742] FX Dunkin Donuts Rising Star Award (to A.J. Wagner) and D.K. Ludwig Fund for Cancer Research supporting the Dana-Farber/Harvard Ludwig Center (to G.D. Demetri), the Netherlands Organization for Scientific Research (91767-315; to J.G. van Oosterwijk and J.V.M.G. Bovee) and Dutch Cancer Society (UL2010-4873; to J.G. van Oosterwijk and J.V.M.G. Bovee). Leiden and Oxford are partners in the context of EuroSarc, an EC seventh framework programme under grant agreement no 278742. NR 46 TC 15 Z9 15 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2013 VL 19 IS 14 BP 3796 EP 3807 DI 10.1158/1078-0432.CCR-12-3647 PG 12 WC Oncology SC Oncology GA 183NE UT WOS:000321822000010 PM 23714727 ER PT J AU Nishino, M Giobbie-Hurder, A Gargano, M Suda, M Ramaiya, NH Hodi, FS AF Nishino, Mizuki Giobbie-Hurder, Anita Gargano, Maria Suda, Margaret Ramaiya, Nikhil H. Hodi, F. Stephen TI Developing a Common Language for Tumor Response to Immunotherapy: Immune-Related Response Criteria Using Unidimensional Measurements SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; GUIDELINE VERSION 1.1; SOLID TUMORS; PHASE-II; DOUBLE-BLIND; RECIST; IPILIMUMAB; ANTIBODY; THERAPY; SAFETY AB Purpose: Immune-related response criteria (irRC) was developed to adequately assess tumor response to immunotherapy. The irRC are based on bidimensional measurements, as opposed to unidimensional measurements defined by Response Evaluation Criteria in Solid Tumors, which has been widely used in solid tumors. We aimed to compare response assessment by bidimensional versus unidimensional irRC in patients with advanced melanoma treated with ipilimumab. Experimental Design: Fifty-seven patients with advanced melanoma treated with ipilimumab in a phase II, expanded access trial were studied. Bidimensional tumor measurement records prospectively conducted during the trial were reviewed to generate a second set of measurements using unidimensional, longest diameter measurements. The percent changes of measurements at follow-up, best overall response, and time-to-progression (TTP) were compared between bidimensional and unidimensional irRC. Interobserver variability for bidimensional and unidimensional measurements was assessed in 25 randomly selected patients. Results: The percent changes at follow-up scans were highly concordant between the 2 criteria (Spearman r: 0.953-0.965, first to fourth follow-up). The best immune-related response was highly concordant between the 2 criteria (kappa(w) = 0.881). TTP was similar between the bidimensional and unidimensional assessments (progression-free at 6 months: 70% vs. 81%, respectively). The unidimensional measurements were more reproducible than bidimensional measurements, with the 95% limits of agreement of (-16.1%, 5.8%) versus (-31.3%, 19.7%), respectively. Conclusion: irRC using the unidimensional measurements provided highly concordant response assessment compared with the bidimensional irRC, with less measurement variability. The use of unidimensional irRC is proposed to assess response to immunotherapy in solid tumors, given its simplicity, higher reproducibility, and high concordance with the bidimensional irRC. (C) 2013 AACR. C1 [Nishino, Mizuki; Ramaiya, Nikhil H.] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Gargano, Maria; Suda, Margaret; Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gargano, Maria; Suda, Margaret; Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. [Giobbie-Hurder, Anita] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Nishino, M (reprint author), Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02115 USA. EM Mizuki_Nishino@dfci.harvard.edu FU NCI [1K23CA157631]; Dana-Farber Cancer Institute FX The investigator M. Nishino was supported by 1K23CA157631 (NCI) and Dana-Farber Cancer Institute Fellowship for the Eleanor and Miles Shore 50th Anniversary Fellowship Program. NR 20 TC 59 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 JUL 15 PY 2013 VL 19 IS 14 BP 3936 EP 3943 DI 10.1158/1078-0432.CCR-13-0895 PG 8 WC Oncology SC Oncology GA 183NE UT WOS:000321822000022 PM 23743568 ER PT J AU Ng, K Tabernero, J Hwang, J Bajetta, E Sharma, S Del Prete, SA Arrowsmith, ER Ryan, DP Sedova, M Jin, J Malek, K Fuchs, CS AF Ng, Kimmie Tabernero, Josep Hwang, Jimmy Bajetta, Emilio Sharma, Sunil Del Prete, Salvatore A. Arrowsmith, Edward R. Ryan, David P. Sedova, Michaela Jin, Jin Malek, Kamel Fuchs, Charles S. TI Phase II Study of Everolimus in Patients with Metastatic Colorectal Adenocarcinoma Previously Treated with Bevacizumab-, Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Based Regimens SO CLINICAL CANCER RESEARCH LA English DT Article ID KIRSTEN RAS MUTATIONS; ADVANCED SOLID TUMORS; MAMMALIAN TARGET; NEUROENDOCRINE TUMORS; SIGNALING PATHWAYS; HUMAN CANCER; INHIBITION; KINASE; MTOR; AKT AB Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is seen in 40% to 60% of patients with colorectal cancer. Everolimus, an oral inhibitor of mTOR, showed efficacy in patients with metastatic colorectal cancers in phase I studies. Experimental Design: In sequential phase II studies assessing two dosing schedules, patients with metastatic colorectal cancers refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/wk (n = 99) or 10 mg/d (n = 100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses. Results: Seventy-one patients were included in the per-protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 and 4.9 months and 1.8 and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = 0.008) and lower DCR (P = 0.035) compared with those with wild-type KRAS in exploratory biomarker analyses. Conclusions: Everolimus 70 mg/wk or 10 mg/d was well tolerated but did not confer meaningful efficacy in heavily pretreated patients with metastatic colorectal cancers. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway. (C) 2013 AACR. C1 [Ng, Kimmie; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Ryan, David P.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Tabernero, Josep] Univ Autonoma Barcelona, Dept Med Oncol, Vall dHebron Univ Hosp, E-08193 Barcelona, Spain. [Hwang, Jimmy] Georgetown Univ, Lombardi Canc Ctr, Dept Hematol Oncol, Washington, DC USA. [Bajetta, Emilio] Policlin Monza, Inst Oncol, Dept Med Oncol, Monza, Italy. [Sharma, Sunil] Nevada Canc Inst, Las Vegas, NV USA. [Del Prete, Salvatore A.] Hematol Oncol PC, Stamford, CT USA. [Arrowsmith, Edward R.] Chattanooga Oncol Hematol Associates, Chattanooga, TN USA. [Sedova, Michaela; Malek, Kamel] Novartis Pharma AG, Basel, Switzerland. [Jin, Jin] Novartis Pharmaceut, E Hanover, NJ USA. RP Ng, K (reprint author), Dana Farber Canc Inst, Ctr Gastrointestinal Oncol, Dept Med Oncol, 450 Brookline Ave,Dana 1220, Boston, MA 02215 USA. EM Kimmie_Ng@dfci.harvard.edu FU Novartis Pharmaceuticals Corporation FX This work was supported by Novartis Pharmaceuticals Corporation. NR 29 TC 17 Z9 17 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2013 VL 19 IS 14 BP 3987 EP 3995 DI 10.1158/1078-0432.CCR-13-0027 PG 9 WC Oncology SC Oncology GA 183NE UT WOS:000321822000027 PM 23743569 ER PT J AU Stearns, V Jacobs, LK Fackler, M Tsangaris, TN Rudek, MA Higgins, M Lange, J Cheng, Z Slater, SA Jeter, SC Powers, P Briest, S Chao, C Yoshizawa, C Sugar, E Espinoza-Delgado, I Sukumar, S Gabrielson, E Davidson, NE AF Stearns, Vered Jacobs, Lisa K. Fackler, MaryJo Tsangaris, Theodore N. Rudek, Michelle A. Higgins, Michaela Lange, Julie Cheng, Zandra Slater, Shannon A. Jeter, Stacie C. Powers, Penny Briest, Susanne Chao, Calvin Yoshizawa, Carl Sugar, Elizabeth Espinoza-Delgado, Igor Sukumar, Saraswati Gabrielson, Edward Davidson, Nancy E. TI Biomarker Modulation following Short-Term Vorinostat in Women with Newly Diagnosed Primary Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID SUBEROYLANILIDE HYDROXAMIC ACID; HISTONE DEACETYLASE INHIBITOR; METHYLATION-SPECIFIC PCR; PROMOTER HYPERMETHYLATION; PHASE-II; CELLS; TAMOXIFEN; ASSAY; THERAPY; TARGET AB Purpose: Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not. Experimental Design: Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples. Results: Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed. Conclusions: Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer. (C) 2013 AACR. C1 [Stearns, Vered; Fackler, MaryJo; Rudek, Michelle A.; Higgins, Michaela; Slater, Shannon A.; Jeter, Stacie C.; Powers, Penny; Briest, Susanne; Sugar, Elizabeth; Sukumar, Saraswati; Davidson, Nancy E.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Jacobs, Lisa K.; Tsangaris, Theodore N.; Lange, Julie] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Gabrielson, Edward] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Sugar, Elizabeth] Johns Hopkins Bloomberg, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Sugar, Elizabeth] Johns Hopkins Bloomberg, Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Cheng, Zandra] Anne Arundel Med Ctr, Annapolis, MD USA. [Espinoza-Delgado, Igor] NCI, NIH, Bethesda, MD 20892 USA. [Chao, Calvin; Yoshizawa, Carl] Genom Hlth Inc, Redwood City, CA USA. RP Higgins, M (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM theodore.tsangaris@yale.edu; mjhiggins@partners.org FU CTEP; NIH [U01 CA 70095]; SAIC [P6914, P30CA47904, U01-CA099168]; American Society of Clinical Oncology Advanced Clinical Research Award; Young Investigator Award; Specialized Program of Research Excellence in Breast Cancer [P50 CA88843]; Avon Foundation; Merck FX This work was supported by the CTEP, NIH U01 CA 70095 (to V. Stearns VS and M.A. Rudek) and SAIC (P6914 to V. Stearns), P30CA47904 (to M. Egorin) and U01-CA099168 (to M. Egorin), American Society of Clinical Oncology Advanced Clinical Research Award (to V. Stearns), Young Investigator Award (to M.J. Higgins), Specialized Program of Research Excellence in Breast Cancer (P50 CA88843 to S. Sukumar and N.E. Davidson), and by the Avon Foundation. Vorinostat for the vorinostat and tamoxifen study was supplied by Merck. The Oncotype DX 21-gene assays were conducted by Genomic Health, Inc. NR 23 TC 14 Z9 14 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2013 VL 19 IS 14 BP 4008 EP 4016 DI 10.1158/1078-0432.CCR-13-0033 PG 9 WC Oncology SC Oncology GA 183NE UT WOS:000321822000029 PM 23719261 ER PT J AU Storer, NY White, RM Uong, A Price, E Nielsen, GP Langenau, DM Zon, LI AF Storer, Narie Y. White, Richard M. Uong, Audrey Price, Emily Nielsen, G. Petur Langenau, David M. Zon, Leonard I. TI Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis SO DEVELOPMENT LA English DT Article DE Rhabdomyosarcoma; Zebrafish; Muscle ID CHILDRENS-ONCOLOGY-GROUP; MOUSE SKELETAL-MUSCLE; EMBRYONAL RHABDOMYOSARCOMA; ALVEOLAR RHABDOMYOSARCOMA; TRANSGENIC ZEBRAFISH; GENE-EXPRESSION; M-CADHERIN; RAS GENES; CELLS; MUTATIONS AB Rhabdomyosarcoma is a pediatric malignancy thought to arise from the uncontrolled proliferation of myogenic cells. Here, we have generated models of rhabdomyosarcoma in the zebrafish by inducing oncogenic KRAS(G12D) expression at different stages during muscle development. Several zebrafish promoters were used, including the cdh15 and rag2 promoters, which drive gene expression in early muscle progenitors, and the mylz2 promoter, which is expressed in differentiating myoblasts. The tumors that developed differed in their ability to recapitulate normal myogenesis. cdh15:KRAS(G12D) and rag2:KRAS(G12D) fish developed tumors that displayed an inability to complete muscle differentiation as determined by histological appearance and gene expression analyses. By contrast, mylz2: KRAS(G12D) tumors more closely resembled mature skeletal muscle and were most similar to well-differentiated human rhabdomyosarcoma in terms of gene expression. mylz2:KRAS(G12D) fish showed significantly improved survival compared with cdh15:KRAS(G12D) and rag2:KRAS(G12D) fish. Tumor-propagating activity was enriched in myf5-expressing cell populations within all of the tumor types. Our results demonstrate that oncogenic KRAS(G12D) expression at different stages during muscle development has profound effects on the ability of tumor cells to recapitulate normal myogenesis, altering the tumorigenic capability of these cells. C1 [Storer, Narie Y.; Uong, Audrey; Price, Emily; Zon, Leonard I.] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Storer, Narie Y.; Uong, Audrey; Price, Emily; Zon, Leonard I.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Storer, Narie Y.; Uong, Audrey; Price, Emily; Zon, Leonard I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Storer, Narie Y.; Uong, Audrey; Price, Emily; Zon, Leonard I.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [White, Richard M.; Nielsen, G. Petur] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Langenau, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zon, LI (reprint author), Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU National Institutes of Health [R01CA103846]; National Institute of General Medical Sciences [T32GM007753] FX This work was supported by the National Institutes of Health [R01CA103846 to L.I.Z.] and the National Institute of General Medical Sciences [T32GM007753 to N.Y.S.]. Deposited in PMC for release after 12 months. NR 47 TC 11 Z9 13 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUL 15 PY 2013 VL 140 IS 14 BP 3040 EP 3050 DI 10.1242/dev.087858 PG 11 WC Developmental Biology SC Developmental Biology GA 176AQ UT WOS:000321275700019 PM 23821038 ER PT J AU Youngblood, B Noto, A Porichis, F Akondy, RS Ndhlovu, ZM Austin, JW Bordi, R Procopio, FA Miura, T Allen, TM Sidney, J Sette, A Walker, BD Ahmed, R Boss, JM Sekaly, RP Kaufmann, DE AF Youngblood, Ben Noto, Alessandra Porichis, Filippos Akondy, Rama S. Ndhlovu, Zaza M. Austin, James W. Bordi, Rebeka Procopio, Francesco A. Miura, Toshiyuki Allen, Todd M. Sidney, John Sette, Alessandro Walker, Bruce D. Ahmed, Rafi Boss, Jeremy M. Sekaly, Rafick-Pierre Kaufmann, Daniel E. TI Cutting Edge: Prolonged Exposure to HIV Reinforces a Poised Epigenetic Program for PD-1 Expression in Virus-Specific CD8 T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC VIRAL-INFECTION; ANTIRETROVIRAL THERAPY; EXHAUSTION; MEMORY; LIGANDS; DEMETHYLATION; REPLICATION; PERSISTENCE; COMMITMENT; TISSUE AB Ag-specific CD8 T cells play a critical role in controlling HIV infection but eventually lose antiviral functions in part because of expression and signaling through the inhibitory programmed death-1 (PD-1) receptor. To better understand the impact of prolonged TCR ligation on regulation of PD-1 expression in HIV-specific CD8 T cells, we investigated the capacity of virus-specific CD8 T cells to modify the PD-1 epigenetic program after reduction in viral load. We observed that the transcriptional regulatory region was unmethylated in the PD-1 hi HIV-specific CD8 T cells, whereas it remained methylated in donor-matched naive cells at acute and chronic stages of infection. Surprisingly, the PD-1 promoter remained unmethylated in HIV-specific CD8 T cells from subjects with a viral load controlled by antiviral therapy for >2 y or from elite controllers. Together, these data demonstrate that the epigenetic program at the PD-1 locus becomes fixed after prolonged exposure to HIV virus. C1 [Youngblood, Ben; Akondy, Rama S.; Austin, James W.; Ahmed, Rafi; Boss, Jeremy M.] Emory Univ, Emory Vaccine Ctr, Sch Med, Atlanta, GA 30322 USA. [Youngblood, Ben; Akondy, Rama S.; Austin, James W.; Ahmed, Rafi; Boss, Jeremy M.] Emory Univ, Dept Microbiol & Immunol, Sch Med, Atlanta, GA 30322 USA. [Noto, Alessandra; Bordi, Rebeka; Procopio, Francesco A.; Sekaly, Rafick-Pierre] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34987 USA. [Porichis, Filippos; Ndhlovu, Zaza M.; Allen, Todd M.; Walker, Bruce D.; Kaufmann, Daniel E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. [Ndhlovu, Zaza M.] Univ KwaZulu Natal, Nelson Mandela Sch Med, HIV Pathogenesis Program, Durban, South Africa. [Miura, Toshiyuki] ViiV Healthcare, Tokyo 1518566, Japan. [Miura, Toshiyuki] Nagasaki Univ, Inst Trop Med, Nagasaki 8528521, Japan. [Sidney, John; Sette, Alessandro] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Kaufmann, Daniel E.] Ctr Hosp Univ Montreal, Ctr Rech, Montreal, PQ H2X 1P1, Canada. RP Sekaly, RP (reprint author), Vaccine & Gene Therapy Inst Florida, 9801 SW Discovery Way, Port St Lucie, FL 34987 USA. EM rpsekaly@vgtifl.org; dkaufmann@partners.org RI Allen, Todd/F-5473-2011; OI Akondy, Rama/0000-0003-4737-5240 FU National Institutes of Health [P01 AI080192-04, R37 AI30048-17, R01 HL092565]; American Cancer Society Postdoctoral Fellowship [PF-09-134-01-MPC]; Research Scholar Career Award of the Quebec Health Research Fund (FRQS) FX This work was supported by National Institutes of Health Grants P01 AI080192-04 (to R.A., J.M.B, R.-P.S., and D.E.K.), R37 AI30048-17 (to R.A.), and R01 HL092565 (to D.E.K.), and American Cancer Society Postdoctoral Fellowship PF-09-134-01-MPC (to B.Y.). D.E.K is supported by a Research Scholar Career Award of the Quebec Health Research Fund (FRQS). NR 30 TC 47 Z9 48 U1 0 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2013 VL 191 IS 2 BP 540 EP 544 DI 10.4049/jimmunol.1203161 PG 5 WC Immunology SC Immunology GA 175UW UT WOS:000321260100005 PM 23772031 ER PT J AU Archambault, AS Carrero, JA Barnett, LG McGee, NG Sim, J Wright, JO Raabe, T Chen, PQ Ding, H Allenspach, EJ Dragatsis, I Laufer, TM Wu, GF AF Archambault, Angela S. Carrero, Javier A. Barnett, Lisa G. McGee, Nigel G. Sim, Julia Wright, Jonathan O. Raabe, Tobias Chen, Peiquin Ding, Hua Allenspach, Eric J. Dragatsis, Ioannis Laufer, Terri M. Wu, Gregory F. TI Cutting Edge: Conditional MHC Class II Expression Reveals a Limited Role for B Cell Antigen Presentation in Primary and Secondary CD4 T Cell Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; DENDRITIC CELLS; IN-VIVO; MICE; REQUIREMENT; PROGRESSION; MUTATIONS; IMMUNITY; DISEASE AB The activation, differentiation, and subsequent effector functions of CD4 T cells depend on interactions with a multitude of MHC class II (MHCII)-expressing APCs. To evaluate the individual contribution of various APCs to CD4 T cell function, we have designed a new murine tool for selective in vivo expression of MHCII in subsets of APCs. Conditional expression of MHCII in B cells was achieved using a cre-loxP approach. After i.v. or s.c. priming, partial proliferation and activation of CD4 T cells was observed in mice expressing MHCII only by B cells. Restricting MHCII expression to B cells constrained secondary CD4 T cell responses in vivo, as demonstrated in a CD4 T cell-dependent model of autoimmunity, experimental autoimmune encephalomyelitis. These results highlight the limitations of B cell Ag presentation during initiation and propagation of CD4 T cell function in vivo using a novel system to study individual APCs by the conditional expression of MHCII. C1 [Archambault, Angela S.; McGee, Nigel G.; Wright, Jonathan O.; Wu, Gregory F.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Carrero, Javier A.; Wu, Gregory F.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Barnett, Lisa G.; Allenspach, Eric J.; Laufer, Terri M.] Univ Penn, Dept Med, Sch Med, Philadelphia, PA 19004 USA. [Sim, Julia] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Raabe, Tobias; Chen, Peiquin] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19004 USA. [Ding, Hua] Childrens Hosp Philadelphia, Joseph Stokes Jr Res Inst, Philadelphia, PA 19004 USA. [Dragatsis, Ioannis] Univ Tennessee, Ctr Hlth Sci, Dept Physiol, Memphis, TN 38163 USA. [Laufer, Terri M.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19004 USA. RP Wu, GF (reprint author), Washington Univ, Sch Med, 660 South Euclid Ave,Box 8111, St Louis, MO 63110 USA. EM wug@neuro.wustl.edu OI Allenspach, Eric/0000-0001-7346-5835 FU National Cancer Institute Cancer Center Support Grant [P30 CA91842]; National Institute of Neurological Disorders and Stroke [5K08NS062138]; Barnes-Jewish Foundation FX We thank the Alvin J. Siteman Cancer Center (supported in part by National Cancer Institute Cancer Center Support Grant #P30 CA91842) and the Barnes-Jewish Hospital for the use of the Embryonic Stem Cell Core, which provided all ES cell services.; This work was supported by the National Institute of Neurological Disorders and Stroke (Grant 5K08NS062138) and the Barnes-Jewish Foundation. NR 25 TC 9 Z9 9 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2013 VL 191 IS 2 BP 545 EP 550 DI 10.4049/jimmunol.1201598 PG 6 WC Immunology SC Immunology GA 175UW UT WOS:000321260100006 PM 23772037 ER PT J AU Liu, Z Jiang, Y Li, YH Wang, J Fan, LY Scott, MJ Xiao, GZ Li, S Billiar, TR Wilson, MA Fan, J AF Liu, Zheng Jiang, Yong Li, Yuehua Wang, Juan Fan, Liyan Scott, Melanie J. Xiao, Guozhi Li, Song Billiar, Timothy R. Wilson, Mark A. Fan, Jie TI TLR4 Signaling Augments Monocyte Chemotaxis by Regulating G Protein-Coupled Receptor Kinase 2 Translocation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHEMOKINE RECEPTORS; NEUTROPHIL MIGRATION; CELL RECRUITMENT; EXPRESSION; GRK2; MICE; CHEMOATTRACTANT; DESENSITIZATION; INFLAMMATION; ACTIVATION AB Monocytes are critical effector cells of the innate immune system that protect the host by migrating to inflammatory sites, differentiating to macrophages and dendritic cells, eliciting immune responses, and killing pathogenic microbes. MCP-1, also known as CCL2, plays an important role in monocyte activation and migration. The chemotactic function of MCP-1 is mediated by binding to the CCR2 receptor, a member of the G protein-coupled receptor (GPCR) family. Desensitization of GPCR chemokine receptors is an important regulator of the intensity and duration of chemokine stimulation. GPCR kinases (GRKs) induce GPCR phosphorylation, and this leads to GPCR desensitization. Regulation of subcellular localization of GRKs is considered an important early regulatory mechanism of GRK function and subsequent GPCR desensitization. Chemokines and LPS are both present during Gram-negative bacterial infection, and LPS often synergistically exaggerates leukocyte migration in response to chemokines. In this study, we investigated the role and mechanism of LPS-TLR4 signaling on the regulation of monocyte chemotaxis. We demonstrate that LPS augments MCP-1-induced monocyte migration. We also show that LPS, through p38 MAPK signaling, induces phosphorylation of GRK2 at serine 670, which, in turn, suppresses GRK2 translocation to the membrane, thereby preventing GRK2-initiated internalization and desensitization of CCR2 in response to MCP-1. This results in enhanced monocyte migration. These findings reveal a novel function for TLR4 signaling in promoting innate immune cell migration. The Journal of Immunology, 2013, 191: 857-864. C1 [Liu, Zheng; Jiang, Yong; Wang, Juan] Southern Med Univ, Dept Pathophysiol, Guangzhou 510515, Guangdong, Peoples R China. [Liu, Zheng; Li, Yuehua; Wang, Juan; Scott, Melanie J.; Billiar, Timothy R.; Wilson, Mark A.; Fan, Jie] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. [Fan, Liyan] Univ Pittsburgh, Sch Arts & Sci, Pittsburgh, PA 15213 USA. [Xiao, Guozhi] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Li, Song] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA. [Billiar, Timothy R.; Fan, Jie] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15219 USA. [Wilson, Mark A.; Fan, Jie] Vet Affairs Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA. RP Fan, J (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. EM jiang48231@163.com; jif7@pitt.edu FU National Institutes of Health [R01-HL-079669, R01-GM-50441]; National Institutes of Health Center [P50-GM-53789]; Veterans Affairs Merit Award; National Key Basic Research (973) Program of China [2011CB510200]; National Natural Science Foundation of China [81030055]; Natural Science Foundation of China-Guangdong Joint Fund [U0632004]; Program for Changjiang Scholars and Innovative Research Team in University [IRT0731] FX This work was supported by National Institutes of Health Grant R01-HL-079669 (to J.F. and M. A. W.), National Institutes of Health Center Grant P50-GM-53789 (to T. R. B. and J.F.), National Institutes of Health Grant R01-GM-50441 (to T. R. B.), a Veterans Affairs Merit Award (to J.F.), National Key Basic Research (973) Program of China 2011CB510200 (to Y.J.), National Natural Science Foundation of China 81030055 (to Y.J.), Natural Science Foundation of China-Guangdong Joint Fund U0632004 (to Y.J.), and Program for Changjiang Scholars and Innovative Research Team in University IRT0731 (to Y.J.). NR 45 TC 17 Z9 17 U1 0 U2 12 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2013 VL 191 IS 2 BP 857 EP 864 DI 10.4049/jimmunol.1300790 PG 8 WC Immunology SC Immunology GA 175UW UT WOS:000321260100038 PM 23772028 ER PT J AU Spencer, TJ Biederman, J Faraone, SV Madras, BK Bonab, AA Dougherty, DD Batchelder, H Clarke, A Fischman, AJ AF Spencer, Thomas J. Biederman, Joseph Faraone, Stephen V. Madras, Bertha K. Bonab, Ali A. Dougherty, Darin D. Batchelder, Holly Clarke, Allison Fischman, Alan J. TI Functional Genomics of Attention-Deficit/Hyperactivity Disorder (ADHD) Risk Alleles on Dopamine Transporter Binding in ADHD and Healthy Control Subjects SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ADHD; altropane; dopamine; dopamine transporter; genetics; PET imaging ID DEFICIT HYPERACTIVITY DISORDER; REPORTER GENE-EXPRESSION; CANDIDATE GENE; METHYLPHENIDATE; AVAILABILITY; POLYMORPHISMS; DENSITY; CHILDREN; REGION; ADULTS AB Background: The main aim of this study was to examine the relationship between dopamine transporter (DAT) binding in the striatum in individuals with and without attention-deficit/hyperactivity disorder (ADHD), attending to the 3'-untranslated region of the gene (3'-UTR) and intron8 variable number of tandem repeats (VNTR) polymorphisms of the DAT (SLC6A3) gene. Methods: Subjects consisted of 68 psychotropic (including stimulant)-naive and smoking-naive volunteers between 18 and 55 years of age (ADHD n = 34; control subjects n = 34). Striatal DAT binding was measured with positron emission tomography with 11C altropane. Genotyping of the two DAT (SLC6A3) 3'-UTR and intron8 VNTRs used standard protocols. Results: The gene frequencies of each of the gene polymorphisms assessed did not differ between the ADHD and control groups. The ADHD status (t = 2.99; p < .004) and 3'-UTR of SLC6A3 9 repeat carrier status (t = 2.74; p < .008) were independently and additively associated with increased DAT binding in the caudate. The ADHD status was associated with increased striatal (caudate) DAT binding regardless of 3'-UTR genotype, and 3'-UTR genotype was associated with increased striatal (caudate) DAT binding regardless of ADHD status. In contrast, there were no significant associations between polymorphisms of DAT intron8 or the 3'-UTR-intron8 haplotype with DAT binding. Conclusions: The 3'-UTR but not intron8 VNTR genotypes were associated with increased DAT binding in both ADHD patients and healthy control subjects. Both ADHD status and the 3'-UTR polymorphism status had an additive effect on DAT binding. Our findings suggest that an ADHD risk polymorphism (3'-UTR) of SLC6A3 has functional consequences on central nervous system DAT binding in humans. C1 [Spencer, Thomas J.; Biederman, Joseph; Batchelder, Holly; Clarke, Allison] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Dept Psychiat, Boston, MA 02114 USA. [Spencer, Thomas J.; Biederman, Joseph; Dougherty, Darin D.; Batchelder, Holly; Clarke, Allison] Massachusetts Gen Hosp, Psychiat Serv, Dept Psychiat, Boston, MA 02114 USA. [Bonab, Ali A.] Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. [Spencer, Thomas J.; Bonab, Ali A.; Fischman, Alan J.] Shriners Hosp Children, Boston, MA USA. [Madras, Bertha K.] New England Primate Res Ctr, Div Neurosci, Boston, MA USA. [Spencer, Thomas J.; Biederman, Joseph; Madras, Bertha K.; Bonab, Ali A.; Dougherty, Darin D.; Fischman, Alan J.] Harvard Univ, Sch Med, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. RP Spencer, TJ (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit Yaw 6A, Fruit St, Boston, MA 02114 USA. EM tspencer@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU National Institute of Mental Health [RO1MH064019]; Shire Laboratories; Cephalon; Eli Lilly and Company; Janssen; McNeil Pharmaceutical; Novartis Pharmaceuticals; Department of Defense; GlaxoSmithKline; Janssen Pharmaceutical; Pfizer; National Institute of Mental Health; Massachusetts General Hospital (MGH) Corporate; Elminda; Shire; McNeil; Alza; Abbott; AstraZeneca; Boston University; Bristol Myers Squibb; Celltech; Esai; Fundacion Areces (Spain); Forest; Glaxo; Gliatech; Hastings Center; Medice Pharmaceuticals (Germany); MMC Pediatric; National Alliance for Research on Schizophrenia and Depression; National Institute on Drug Abuse; New River; National Institute of Child Health and Human Development; Noven; Neurosearch; Organon; Otsuka; Pharmacia; Phase V Communications; Physicians Academy; The Prechter Foundation; Quantia Communications; Reed Exhibitions; Spanish Child Psychiatry Association; Stanley Foundation; UCB Pharma; Veritas; Wyeth; Alcobra; National Institutes of Health; Medtronic; Cyberonics FX Research support for this work was provided by National Institute of Mental Health Grant RO1MH064019 (TJS).; In the last 2 years, TJS has received research support from the following sources: Shire Laboratories, Cephalon, Eli Lilly and Company, Janssen, McNeil Pharmaceutical, Novartis Pharmaceuticals, and the Department of Defense.; In previous years, TJS has received research support from, been a speaker for, served on a Speakers' bureau, or has been an Advisor or on an Advisory Board of the following sources: Shire Laboratories, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceutical, McNeil Pharmaceutical, Novartis Pharmaceuticals, Cephalon, Pfizer, and the National Institute of Mental Health.; TJS receives research support from royalties and licensing fees on copyrighted attention-deficit/hyperactivity disorder (ADHD) scales through Massachusetts General Hospital (MGH) Corporate Sponsored Research and Licensing.; JB is currently receiving research support from the following sources: Elminda, Janssen, McNeil, and Shire.; In previous years, JB received research support, consultation fees, or speaker's fees for/from the following additional sources: Abbott, Alza, AstraZeneca, Boston University, Bristol Myers Squibb, Celltech, Cephalon, Eli Lilly and Company, Esai, Fundacion Areces (Spain), Forest, Glaxo, Gliatech, Hastings Center, Janssen, McNeil, Medice Pharmaceuticals (Germany), Merck, MMC Pediatric, National Alliance for Research on Schizophrenia and Depression, National Institute on Drug Abuse, New River, National Institute of Child Health and Human Development, National Institute of Mental Health, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, Phase V Communications, Physicians Academy, The Prechter Foundation, Quantia Communications, Reed Exhibitions, Shire, the Spanish Child Psychiatry Association, The Stanley Foundation, UCB Pharma, Veritas, and Wyeth.; In the past year, SVF received consulting income and research support from Shire, Otsuka, and Alcobra and research support from the National Institutes of Health. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly. SVF receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health; and Oxford University Press: Schizophrenia: The Facts.; DDD has received honoraria from Medtronic and research support from Medtronic, Cyberonics, and Eli Lilly. NR 36 TC 20 Z9 20 U1 3 U2 20 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 JUL 15 PY 2013 VL 74 IS 2 BP 84 EP 89 DI 10.1016/j.biopsych.2012.11.010 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 173VF UT WOS:000321108800004 PM 23273726 ER PT J AU Shenoy, ES Kim, J Rosenberg, ES Cotter, JA Lee, H Walensky, RP Hooper, DC AF Shenoy, Erica S. Kim, JiYeon Rosenberg, Eric S. Cotter, Jessica A. Lee, Hang Walensky, Rochelle P. Hooper, David C. TI Discontinuation of Contact Precautions for Methicillin-Resistant Staphylococcus aureus: A Randomized Controlled Trial Comparing Passive and Active Screening With Culture and Polymerase Chain Reaction SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE MRSA; infection control; contact precautions; isolation; clinical trial ID HEALTH-CARE SETTINGS; XPERT MRSA ASSAY; RISK-FACTORS; HOSPITAL DISCHARGE; INFECTION-CONTROL; CARRIAGE; ACQUISITION; DURATION; COLONIZATION; TRANSMISSION AB Background. There have been no randomized controlled trials comparing active and passive screening for documenting clearance of colonization with methicillin-resistant Staphylococcus aureus (MRSA). We compared the efficacy of active and passive screening using both culture and commercial polymerase chain reaction (PCR) for documentation of MRSA clearance and discontinuation of MRSA contact precautions (CPs). Methods. Inpatients with a history of MRSA infection or colonization enrolled between December 2010 and September 2011 were randomized to either passive (nonintervention arm; n = 202; observation with local standard of care) or active screening (intervention arm; n = 405; study staff screened using culture and commercial PCR). The primary outcome was discontinuation of CPs by trial arm based on 3 negative cultures. In the intervention arm, sensitivity, specificity, and positive and negative predictive values of the first PCR were compared to cultures. Results. CPs were discontinued significantly more often (rate ratio [RR], 4.1; 95% confidence interval [CI], 2.3%-7.1%) in the intervention arm, including in an intent-to-screen analysis (RR, 2.6; 95% CI, 1.5%-4.7%). The first PCR, compared to 3 cultures, detected MRSA with a sensitivity of 93.9% (95% CI, 85.4%-97.6%), a specificity of 92.0% (95% CI, 85.9%-95.6%), a positive predictive value of 86.1% (95% CI, 75.9%-93.1%), and a negative predictive value of 96.6% (95% CI, 91.6%-99.1%). Conclusions. Compared to passive screening using culture methods, active screening resulted in discontinuation of MRSA CPs at a significantly higher frequency. Active screening with a single PCR would significantly increase the completion of the screening process. C1 [Shenoy, Erica S.; Kim, JiYeon; Rosenberg, Eric S.; Walensky, Rochelle P.; Hooper, David C.] Harvard Univ, Sch Med, Boston, MA USA. [Shenoy, Erica S.; Rosenberg, Eric S.; Walensky, Rochelle P.; Hooper, David C.] Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Ctr AIDS Res, Boston, MA 02114 USA. [Kim, JiYeon; Rosenberg, Eric S.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Shenoy, Erica S.; Cotter, Jessica A.; Hooper, David C.] Massachusetts Gen Hosp, Infect Control Unit, Boston, MA 02114 USA. RP Shenoy, ES (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,Bulfinch 340, Boston, MA 02114 USA. EM eshenoy@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU Harvard Catalyst; National Center for Research Resources; National Center for Advanced Translational Sciences; Harvard University; MGH Clinical Innovation Award; National Institutes of Health [T32 A107061]; Harvard Clinical and Translational Science Center, National Institutes of Health [8UL1TR000170-05, 1 UL1 RR025758] FX This work was conducted with support from Harvard Catalyst, National Center for Research Resources and the National Center for Advanced Translational Sciences, and financial contributions from Harvard University and its affiliated academic healthcare centers. This work was supported by MGH 2010-2011 Clinical Innovation Award; National Institutes of Health Training Grant (T32 A107061); and The Harvard Clinical and Translational Science Center, National Institutes of Health (8UL1TR000170-05, 1 UL1 RR025758). Reagents and PCR testing equipment were provided without charge by Cepheid. NR 30 TC 25 Z9 25 U1 1 U2 5 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 JUL 15 PY 2013 VL 57 IS 2 BP 176 EP 184 DI 10.1093/cid/cit206 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 173AY UT WOS:000321051600003 PM 23572482 ER PT J AU D'Ascenzo, F Biondi-Zoccai, G Reed, MJ Gabayan, GZ Suzuki, M Costantino, G Furlan, R Del Rosso, A Sarasin, FP Sun, BC Modena, MG Gaita, F AF D'Ascenzo, Fabrizio Biondi-Zoccai, Giuseppe Reed, Matthew J. Gabayan, Gelareh Z. Suzuki, Masaru Costantino, Giorgio Furlan, Raffaello Del Rosso, Andrea Sarasin, Francois P. Sun, Benjamin C. Modena, Maria Grazia Gaita, Fiorenzo TI Incidence, etiology and predictors of adverse outcomes in 43,315 patients presenting to the Emergency Department with syncope: An international meta-analysis SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Syncope; Meta-analysis; Prognosis; Prognosis; Multivariate predictors; Emergency Department ID RISK STRATIFICATION; SHORT-TERM; CLINICAL PREDICTORS; UNEXPLAINED SYNCOPE; SCORE; MANAGEMENT; ARRHYTHMIAS; GUIDELINES; PROGNOSIS; QUALITY AB Background: Syncope remains challenging for Emergency Department (ED) physicians due to difficulties in assessing the risk of future adverse outcomes. The aim of this meta-analysis is to establish the incidence and etiology of adverse outcomes as well as the predictors, in patients presenting with syncope to the ED. Methods: A systematic electronic literature review was performed looking for eligible studies published between 1990 and 2010. Studies reporting multivariate predictors of adverse outcomes in patients presenting with syncope to the ED were included and pooled, when appropriate, using a random-effect method. Adverse events were defined as 'incidence of death, or of hospitalization and interventional procedures because of arrhythmias, ischemic heart disease or valvular heart disease'. Results: 11 studies were included. Pooled analysis showed 42% (CI 95%; 32-52) of patients were admitted to hospital. Risk of death was 4.4% (CI 95%; 3.1-5.1) and 1.1% (CI 95%; 0.7-1.5) had a cardiovascular etiology. One third of patients were discharged without a diagnosis, while the most frequent diagnosis was 'situational, orthostatic or vasavagal syncope' in 29% (CI 95%; 12-47). 10.4% (CI 95%; 7.8-16) was diagnosed with heart disease, the most frequent type being bradyarrhythmia, 4.8% (CI 95%; 2.2-6.4) and tachyarrhythmia 2.6% (CI 95%; 1.1-3.1). Palpitations preceding syncope, exertional syncope, a history consistent of heart failure or ischemic heart disease, and evidence of bleeding were the most powerful predictors of an adverse outcome. Conclusion: Syncope carries a high risk of death, mainly related to cardiovascular disease. This large study which has established the most powerful predictors of adverse outcomes, may enable care and resources to be better focused at high risk patients. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [D'Ascenzo, Fabrizio; Gaita, Fiorenzo] Univ Turin, Div Cardiol, I-10126 Turin, Italy. [Biondi-Zoccai, Giuseppe; Modena, Maria Grazia] Univ Modena & Reggio Emilia, Div Cardiol, Modena, Italy. [Gabayan, Gelareh Z.; Sun, Benjamin C.] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Med, Los Angeles, CA USA. [Reed, Matthew J.] Dept Emergency Med, Edinburgh, Midlothian, Scotland. [Suzuki, Masaru] Keio Univ, Sch Med, Dept Emergency Med, Tokyo, Japan. [Costantino, Giorgio; Furlan, Raffaello] Univ Milan, L Sacco Hosp, Syncope Unit, Milan, Italy. [Del Rosso, Andrea] Azienda USL 11 Empoli, Dept Cardiol, Empoli, Italy. [Sarasin, Francois P.] Univ Geneva, Hop Cantonal, Sch Med, Div Emergency Med, CH-1211 Geneva, Switzerland. RP D'Ascenzo, F (reprint author), Univ Turin, S Giovanni Battista Molinette Hosp, Div Cardiol, Corso Bramante 88-90, I-10126 Turin, Italy. EM fabrizio.dascenzo@gmail.com RI modena, maria grazia/N-2442-2015; OI modena, maria grazia/0000-0002-4704-4663; Furlan, Raffaello/0000-0001-5209-6786; Reed, Matthew/0000-0003-1308-4824 FU Chief Scientist Office [CAF/06/01] NR 38 TC 20 Z9 20 U1 1 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2013 VL 167 IS 1 BP 57 EP 62 DI 10.1016/j.ijcard.2011.11.083 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 167AR UT WOS:000320603100019 PM 22192287 ER PT J AU Zietman, A AF Zietman, Anthony TI Expanding the Number of Trainess in Radiation Oncology: Has the Pendulum Swung Too Far? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zietman, A (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2013 VL 86 IS 4 BP 597 EP 597 DI 10.1016/j.ijrobp.2013.05.035 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 166WL UT WOS:000320590200005 PM 23773385 ER PT J AU Terezakis, S MacDonald, S Nilsson, K Villar, R Dieckmann, K Chen, M Nechesnyuk, A Ford, E Ermoian, R Winey, B Malet, C Claude, L Tryggestad, E AF Terezakis, S. MacDonald, S. Nilsson, K. Villar, R. Dieckmann, K. Chen, M. Nechesnyuk, A. Ford, E. Ermoian, R. Winey, B. Malet, C. Claude, L. Tryggestad, E. TI Practice Patterns of Photon and Proton Pediatric Image Guided Radiation Treatment: Results From an International Pediatric Research Consortium SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Congress of the Pediatric-Radiation-Oncology-Society CY MAY 08-11, 2013 CL Louisville, KY SP Pediat Radiat Oncol Soc C1 [Terezakis, S.; Ermoian, R.; Tryggestad, E.] Johns Hopkins Sch Med, Baltimore, MD USA. [MacDonald, S.; Winey, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nilsson, K.] Akad Sjukhuset, Uppsala, Sweden. [Villar, R.] Ctr Boldrini, Sao Paulo, Brazil. [Dieckmann, K.] Univ Klin Strahlentherapie & Strahlenbiol, Vienna, Austria. [Chen, M.] GRAACC Support Grp Adolescents & Children Canc, Sao Paulo, Brazil. [Nechesnyuk, A.] Fed Sci Clin Ctr Pediat Hematol Oncol & Immunol, Moscow, Russia. [Ford, E.] Univ Washington, Seattle, WA 98195 USA. [Malet, C.; Claude, L.] Ctr Leon Berard, UNICANC, F-69373 Lyon, France. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2013 VL 86 IS 4 MA OP9 BP 802 EP 803 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 166WL UT WOS:000320590200048 ER PT J AU Brunner, AM Campigotto, F Sadrzadeh, H Drapkin, BJ Chen, YB Neuberg, DS Fathi, AT AF Brunner, Andrew M. Campigotto, Federico Sadrzadeh, Hossein Drapkin, Benjamin J. Chen, Yi-Bin Neuberg, Donna S. Fathi, Amir T. TI Trends in all-cause mortality among patients with chronic myeloid leukemia SO CANCER LA English DT Article DE chronic myeloid leukemia; population survival; tyrosine kinase inhibitor; age groups; bcr-abl ID CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOCYTIC-LEUKEMIA; CML WORKING PARTY; PHILADELPHIA-CHROMOSOME; TYROSINE KINASE; UNITED-STATES; BLAST CRISIS; SURVIVAL; IMATINIB; THERAPY AB BACKGROUND Outcomes for patients with chronic myeloid leukemia (CML) have improved after the advent of tyrosine kinase inhibitors (TKIs), which target the BCR/ABL fusion gene product. Nonetheless, differences in survival persist between age groups. The authors performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database to assess 5-year overall survival (OS) in various patient age groups. METHODS Patients who had a diagnosis of CML were identified using the SEER 19 registries database. Patients who were included had SEER diagnosis codes for CML not otherwise specified (code 9863) and BCR/ABL-positive CML (code 9875) diagnosed between January 2000 and December 2005. Patients were divided into cohorts based on age at diagnosis: ages 15 to 44 years, 45 to 64 years, 65 to 74 years, and 75 to 84 years. OS was estimated using the Kaplan-Meier method, and Cox regression was used to estimate predictors of patient survival. RESULTS In total, 5138 patients with a new CML diagnosis were identified. Five-year OS improved for all patients between the years 2000 and 2005. Compared with patients who were diagnosed in 2000, 5-year survival improved among patients ages 15 to 44 years (hazard ratio [HR] for mortality, 0.424; P<.0001), ages 45 to 64 years (HR, 0.716; P=.0315), and ages 65 to 74 years (HR, 0.692; P=.0126); and patients ages 75 to 84 years had an increased 5-year OS rate from 19.2% in 2000 to 36.4% in 2005 (HR, 0.568; P<.0001). CONCLUSIONS OS at 5 years improved among all patients, including those ages 75 to 84 years, a group with historically poor outcomes. However, older age retained an association with worse survival, suggesting opportunities for further progress. Cancer 2013;119:2620-2629. (c) 2013 American Cancer Society. C1 [Brunner, Andrew M.; Sadrzadeh, Hossein; Drapkin, Benjamin J.; Chen, Yi-Bin; Fathi, Amir T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Campigotto, Federico; Neuberg, Donna S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Brunner, AM (reprint author), Massachusetts Gen Hosp, Hematol Oncol Associates, 100 Blossom St,COX 1, Boston, MA 02114 USA. EM afathi@partners.org NR 35 TC 14 Z9 14 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2013 VL 119 IS 14 BP 2620 EP 2629 DI 10.1002/cncr.28106 PG 10 WC Oncology SC Oncology GA 237JB UT WOS:000325864500016 PM 23625575 ER PT J AU Mandeville, JB Sander, CYM Jenkins, BG Hooker, JM Catana, C Vanduffel, W Alpert, NM Rosen, BR Normandin, MD AF Mandeville, Joseph B. Sander, Christin Y. M. Jenkins, Bruce G. Hooker, Jacob M. Catana, Ciprian Vanduffel, Wim Alpert, Nathaniel M. Rosen, Bruce R. Normandin, Marc D. TI A receptor-based model for dopamine-induced fMRI signal SO NEUROIMAGE LA English DT Article DE fMRI; PET; Dopamine; Model; Striatum; NHP ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; IN-VIVO BINDING; HUMAN-BRAIN; ENDOGENOUS DOPAMINE; PHARMACOLOGICAL MRI; BLOOD-VOLUME; D-2-DOPAMINE RECEPTORS; TEMPORAL RESPONSES; NONHUMAN-PRIMATES AB This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine's effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET C-11-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations. (C) 2013 Elsevier Inc. All rights reserved. C1 [Mandeville, Joseph B.; Jenkins, Bruce G.; Hooker, Jacob M.; Catana, Ciprian; Vanduffel, Wim; Rosen, Bruce R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sander, Christin Y. M.] MIT, Cambridge, MA 02139 USA. [Alpert, Nathaniel M.; Normandin, Marc D.] Massachusetts Gen Hosp, Div Nucl Med, Boston, MA 02114 USA. RP Mandeville, JB (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM jbm@nmr.mgh.harvard.edu RI Normandin, Marc/C-6728-2015; OI Normandin, Marc/0000-0003-1645-523X; Hooker, Jacob/0000-0002-9394-7708 FU NIH [R21NS072148, P41RR14075, P30DA28800, S10RR026666, S10RR017208, S10RR022976, S10RR019933] FX We thank Helen Deng, Steve Carlin, Chris Moseley, Grae Arabasz and Shirley Hsu for their help with animal handling, radioligand synthesis, and MR-PET imaging. This research was supported by NIH grants R21NS072148, P41RR14075, P30DA28800, S10RR026666, S10RR017208, S10RR022976, and S10RR019933. NR 84 TC 14 Z9 14 U1 1 U2 33 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 JUL 15 PY 2013 VL 75 BP 46 EP 57 DI 10.1016/j.neuroimage.2013.02.036 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 134KB UT WOS:000318208000006 PM 23466936 ER PT J AU Douw, L de Groot, M van Dellen, E Aronica, E Heimans, JJ Klein, M Stam, CJ Reijneveld, JC Hillebrand, A AF Douw, L. de Groot, M. van Dellen, E. Aronica, E. Heimans, J. J. Klein, M. Stam, C. J. Reijneveld, J. C. Hillebrand, A. TI Local MEG networks: The missing link between protein expression and epilepsy in glioma patients? SO NEUROIMAGE LA English DT Article DE Functional connectivity; Graph theory; Neuro-oncology ID TEMPORAL-LOBE EPILEPSY; FUNCTIONAL CONNECTIVITY; BRAIN ACTIVITY; P-GLYCOPROTEIN; HUMAN CORTEX; EEG; MAGNETOENCEPHALOGRAPHY; LOCALIZATION; ORGANIZATION; RESISTANCE AB Connectivity and network analysis in neuroscience has been applied to multiple spatial scales, but the links between these different scales have rarely been investigated. In tumor-related epilepsy, altered network topology is related to behavior, but the molecular basis of these observations is unknown. We elucidate the associations between microscopic features of brain tumors, local network topology, and functional patient status. We hypothesize that expression of proteins related to tumor-related epilepsy is directly correlated with network characteristics of the tumor area. Glioma patients underwent magnetoencephalography, and functional network topology of the tumor area was used to predict tissue protein expression patterns of tumor tissue collected during neurosurgery. Protein expression and network topology were interdependent; in particular between-module connectivity was selectively associated with two epilepsy-related proteins. Total number of seizures was related to both the role of the tumor area in the functional network and to protein expression. Importantly, classification of protein expression was predicted by between-module connectivity with up to 100% accuracy. Thus, network topology may serve as an intermediate level between molecular features of tumor tissue and symptomatology in brain tumor patients, and can potentially be used as a non-invasive marker for microscopic tissue characteristics. (C) 2013 Elsevier Inc. All rights reserved. C1 [Douw, L.; de Groot, M.; van Dellen, E.; Heimans, J. J.; Reijneveld, J. C.] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, NL-1081 HV Amsterdam, Netherlands. [Douw, L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02134 USA. [Douw, L.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [de Groot, M.; Aronica, E.] Univ Amsterdam, Acad Med Ctr, Dept Neuro Pathol, NL-1105 AZ Amsterdam, Netherlands. [Aronica, E.] Stichting Epilepie Instellingen Nederland, NL-2103 SW Heemstede, Netherlands. [Klein, M.] Vrije Univ Amsterdam, Med Ctr, Dept Med Psychol, NL-1081 BT Amsterdam, Netherlands. [Hillebrand, A.] Vrije Univ Amsterdam, Med Ctr, Dept Clin Neurophysiol, NL-1081 HZ Amsterdam, Netherlands. [Hillebrand, A.] Vrije Univ Amsterdam, Med Ctr, MEG Ctr, NL-1081 HZ Amsterdam, Netherlands. RP Douw, L (reprint author), MGH, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Room 2301,149 13th St, Charlestown, MA 02129 USA. EM douw@nmr.mgh.harvard.edu RI Klein, Martin/C-4192-2012 OI Klein, Martin/0000-0003-4160-5746 FU UCB Pharma; Dutch Epilepsy Foundation (NEF); Dutch Cancer Society (KWF Kankerbestrijding); Foundation "NutsOhra"; Foundation "STOPhersentumoren.nl"; UCB; Sanofi-Aventis; EU; National Brain Tumor Foundation/Tug McGraw Foundation; Dutch Cancer Society; Royal Society; Japan Society for the Promotion of Science; EPSRC; BBSRC; Dr. Hadwen Trust FX Dr. Douw and Mr. Van Dellen are sponsored by the Dutch Epilepsy Foundation (NEF). Dr. De Groot is sponsored by UCB Pharma. Prof. Stam is an unpaid advisor for Danone, associate editor of Clinical Neurophysiology, and chair of the scientific board of the Dutch Epilepsy Foundation (NEF). Prof. Heimans received research support from the Dutch Epilepsy Foundation (NEF); the Dutch Cancer Society (KWF Kankerbestrijding), Foundation "NutsOhra", and Foundation "STOPhersentumoren.nl", and received unrestricted grants from UCB and Sanofi-Aventis. Dr. Reijneveld received funding from EU Framework Program 7, the Dutch Epilepsy Foundation (NEF), the Dutch Cancer Society (KWF Kankerbestrijding), Foundation "NutsOhra", and Foundation "STOPhersentumoren.nl", and the National Brain Tumor Foundation/Tug McGraw Foundation, and received unrestricted grants from UCB and Sanofi-Aventis. Dr. Aronica is supported by the Dutch Epilepsy Foundation (NEF). Dr. Klein is consultant for Hoffmann-La Roche, received funding from the Dutch Cancer Society, Foundation "NutsOhra", and the National Brain Tumor Foundation/Tug McGraw Foundation. Dr. Hillebrand received funding from The Royal Society, Japan Society for the Promotion of Science, EPSRC, BBSRC, and the Dr. Hadwen Trust. NR 64 TC 10 Z9 10 U1 2 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2013 VL 75 BP 195 EP 203 DI 10.1016/j.neuroimage.2013.02.067 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 134KB UT WOS:000318208000021 PM 23507380 ER PT J AU Levitan, EB Shikany, JM Ahmed, A Snetselaar, LG Martin, LW Curb, JD Lewis, CE AF Levitan, Emily B. Shikany, James M. Ahmed, Ali Snetselaar, Linda G. Martin, Lisa W. Curb, J. David Lewis, Cora E. TI Calcium, magnesium and potassium intake and mortality in women with heart failure: the Women's Health Initiative SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Heart failure; Mortality; Calcium; Magnesium; Potassium ID QUALITY-OF-LIFE; PRIMARY HYPERTENSION; ENDOTHELIAL DYSFUNCTION; SUPPLEMENTATION; MANAGEMENT; ADULTS; RISK; INFLAMMATION; ASSOCIATION; DISEASE AB Although diet is thought to affect the natural history of heart failure (HF), nutrient intake in HF patients has not been well studied. Based on prior research linking high intake of Ca, Mg and K to improved cardiovascular health, we hypothesised that these nutrients would be inversely associated with mortality in people with HF. Of the 161 808 participants in the Women's Health Initiative (WHI), we studied 3340 who experienced a HF hospitalisation. These participants were followed for post-hospitalisation all- cause mortality. Intake was assessed using questionnaires on food and supplement intake. Hazard ratios (HR) and 95% CI were calculated using Cox proportional hazards models adjusted for demographics, physical function, co-morbidities and dietary covariates. Over a median of 4.6 years of follow-up, 1433 (42.9%) of the women died. HR across quartiles of dietary Ca intake were 1.00 (referent), 0.86 (95% CI 0.73, 1.00), 0.88 (95% CI 0.75, 1.04) and 0.92 (95% CI 0.76, 1.11) (P for trend=0.63). Corresponding HR were 1.00 (referent), 0.86 (95% CI 0.71, 1.04), 0.88 (95% CI 0.69, 1.11) and 0.84 (95% CI 0.63, 1.12) (P for trend=0.29), across quartiles of dietary Mg intake, and 1.00 (referent), 1.20 (95% CI 1.01, 1.43), 1.06 (95% CI 0.86, 1.32) and 1.16 (95% CI 0.90, 1.51) (P for trend=0.35), across quartiles of dietary K intake. Results were similar when total (dietary plus supplemental) nutrient intakes were examined. In summary, among WHI participants with incident HF hospitalisation, intakes of Ca, Mg and K were not significantly associated with subsequent mortality. C1 [Levitan, Emily B.; Shikany, James M.; Ahmed, Ali; Lewis, Cora E.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL 35924 USA. [Ahmed, Ali] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. [Snetselaar, Linda G.] Univ Iowa, Iowa City, IA 52246 USA. [Martin, Lisa W.] George Washington Univ, Washington, DC 20052 USA. [Curb, J. David] Univ Hawaii Manoa, Honolulu, HI 96822 USA. RP Levitan, EB (reprint author), Univ Alabama Birmingham, Dept Epidemiol, 1530 3rd Ave South,RPHB 230K, Birmingham, AL 35924 USA. EM elevitan@uab.edu OI Martin, Lisa Warsinger/0000-0003-4352-0914 FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH 22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX All authors were involved in the design of the study. J. M. S., L. G. S., L. W. M., J. D. C. and C. E. L. collected the data. E. B. L. performed the statistical analysis and wrote the paper. All authors revised the paper and are responsible for the final manuscript. The authors declare no conflict of interest. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH 22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32 and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. NR 35 TC 9 Z9 9 U1 1 U2 18 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD JUL 14 PY 2013 VL 110 IS 1 BP 179 EP 185 DI 10.1017/S0007114512004667 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 160MK UT WOS:000320123500020 PM 23199414 ER PT J AU Hayes, SM Hayes, JP Cadden, M Verfaellie, M AF Hayes, Scott M. Hayes, Jasmeet P. Cadden, Margaret Verfaellie, Mieke TI A review of cardiorespiratory fitness-related neuroplasticity in the aging brain SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Review DE exercise; physical fitness; physical activity; fMRI; structural MRI; diffusion tensor imaging; episodic memory; executive functions ID MILD COGNITIVE IMPAIRMENT; WHITE-MATTER INTEGRITY; SEMANTIC MEMORY ACTIVATION; PHYSICAL-ACTIVITY; ALZHEIMERS-DISEASE; AEROBIC FITNESS; OLDER-ADULTS; DEFAULT NETWORK; CARDIOVASCULAR FITNESS; DENTATE GYRUS AB The literature examining the relationship between cardiorespiratory fitness and the brain in older adults has increased rapidly, with 30 of 34 studies published since 2008. Here we review cross-sectional and exercise intervention studies in older adults examining the relationship between cardiorespiratory fitness and brain structure and function, typically assessed using Magnetic Resonance Imaging (MRI). Studies of patients with Alzheimer's disease are discussed when available. The structural MRI studies revealed a consistent positive relationship between cardiorespiratory fitness and brain volume in cortical regions including anterior cingulate, lateral prefrontal, and lateral parietal cortex. Support for a positive relationship between cardiorespiratory fitness and medial temporal lobe volume was less consistent, although evident when a region-of-interest approach was implemented. In fMRI studies, cardiorespiratory fitness in older adults was associated with activation in similar regions as those identified in the structural studies, including anterior cingulate, lateral prefrontal, and lateral parietal cortex, despite heterogeneity among the functional tasks implemented. This comprehensive review highlights the overlap in brain regions showing a positive relationship with cardiorespiratory fitness in both structural and functional imaging modalities. The findings suggest that aerobic exercise and cardiorespiratory fitness contribute to healthy brain aging, although additional studies in Alzheimer's disease are needed. C1 [Hayes, Scott M.; Cadden, Margaret; Verfaellie, Mieke] Boston Univ, Sch Med, VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA 02118 USA. [Hayes, Scott M.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. [Hayes, Scott M.; Hayes, Jasmeet P.; Verfaellie, Mieke] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Hayes, Jasmeet P.] VA Boston Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, Boston, MA 02130 USA. RP Hayes, SM (reprint author), VA Boston Healthcare Syst, Memory Disorders Res Ctr 151A, 150 South Huntington Ave, Boston, MA 02130 USA. EM smhayes@bu.edu OI Verfaellie, Mieke/0000-0001-5535-4584 FU Department of Veterans Affairs Rehabilitation Research & Development Service [e7822w]; Department of Veterans Affairs Clinical Science Research & Development Service; National Institutes of Health, National Institutes of Mental Health [K23 MH084013] FX This work was supported by the Department of Veterans Affairs Rehabilitation Research & Development Service [Career Development Award e7822w awarded to Scott M. Hayes], the Department of Veterans Affairs Clinical Science Research & Development Service [Mieke Verfaellie], and the National Institutes of Health, National Institutes of Mental Health [grant number K23 MH084013 awarded to Jasmeet P. Hayes]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the VA, NIH or NIMH. None of the authors reported a conflict of interest. NR 100 TC 39 Z9 39 U1 5 U2 55 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD JUL 12 PY 2013 VL 5 AR UNSP 31 DI 10.3389/fnagi.2013.00031 PG 16 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 205OO UT WOS:000323454000001 PM 23874299 ER PT J AU Grove, ML Yu, B Cochran, BJ Haritunians, T Bis, JC Taylor, KD Hansen, M Borecki, IB Cupples, LA Fornage, M Gudnason, V Harris, TB Kathiresan, S Kraaij, R Launer, LJ Levy, D Liu, YM Mosley, T Peloso, GM Psaty, BM Rich, SS Rivadeneira, F Siscovick, DS Smith, AV Uitterlinden, A van Duijn, CM Wilson, JG O'Donnell, CJ Rotter, JI Boerwinkle, E AF Grove, Megan L. Yu, Bing Cochran, Barbara J. Haritunians, Talin Bis, Joshua C. Taylor, Kent D. Hansen, Mark Borecki, Ingrid B. Cupples, L. Adrienne Fornage, Myriam Gudnason, Vilmundur Harris, Tamara B. Kathiresan, Sekar Kraaij, Robert Launer, Lenore J. Levy, Daniel Liu, Yongmei Mosley, Thomas Peloso, Gina M. Psaty, Bruce M. Rich, Stephen S. Rivadeneira, Fernando Siscovick, David S. Smith, Albert V. Uitterlinden, Andre van Duijn, Cornelia M. Wilson, James G. O'Donnell, Christopher J. Rotter, Jerome I. Boerwinkle, Eric TI Best Practices and Joint Calling of the HumanExome BeadChip: The CHARGE Consortium SO PLOS ONE LA English DT Article ID STUDY OBJECTIVES; DESIGN; ASSOCIATION; POPULATION; MUTATION; HEART AB Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] < 0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip. C1 [Grove, Megan L.; Yu, Bing; Cochran, Barbara J.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA. [Haritunians, Talin; Taylor, Kent D.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Bis, Joshua C.; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Hansen, Mark] Illumina Inc, San Diego, CA USA. [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Gen, St Louis, MO USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Cupples, L. Adrienne; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Inst Mol Med, Houston, TX 77030 USA. [Gudnason, Vilmundur; Smith, Albert V.] Iceland Heart Assoc, Res Inst, Kopavogur, Iceland. [Gudnason, Vilmundur; Smith, Albert V.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Populat Sci, Bethesda, MD 20892 USA. [Peloso, Gina M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Kathiresan, Sekar] Broad Inst Harvard, Cambridge, MA USA. [Kathiresan, Sekar] MIT, Cambridge, MA 02139 USA. [Kraaij, Robert; Rivadeneira, Fernando] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Liu, Yongmei] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Mosley, Thomas] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Seattle, WA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA. [Rivadeneira, Fernando; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, ErasmusAGE, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre; van Duijn, Cornelia M.] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP Grove, ML (reprint author), Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX 77030 USA. EM Megan.L.Grove@uth.tmc.edu RI Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Cupples, L. Adrienne/0000-0003-0273-7965 FU Building on GWAS for NHLBI-diseases; U.S. CHARGE consortium through the National Institutes of Health (NIH) American Recovery and Reinvestment Act (ARRA) [5RC2HL102419]; NIH [N01-AG-12100]; NIA Intramural Research Program; Icelandic Heart Association; Icelandic Parliament; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011000010C, HHSN2682011000011C, HHSN2682011000012C]; National Heart, Lung, and Blood Institute [HL41993, HL091244, N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, N01-HC-45204, U01 HL56563, U01 HL56564, U01 HL56565]; University of Washington Clinical Nutrition Research Unit [DK-35816]; Medic One Foundation, Seattle, WA; NHLBI [N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085]; NIA [AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Center of Advancing Translational Technologies CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR); Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Illumina, Inc.; Intramural Research Program of the NIH, National Institute on Aging; National Center on Minority Health and Health Disparities; [U01-HG-004729]; [R01-HL-084099]; [N01-HC-25195]; [N01-HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165] FX Support for the centralized work was provided by Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium through the National Institutes of Health (NIH) American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419) (PI: E. Boerwinkle). Funding support of the individual cohorts is detailed below. The Age, Gene/Environment, Susceptibility-Reykjavik (AGES) study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, the Icelandic Heart Association, and the Icelandic Parliament. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN2682011000010C, HHSN2682011000011C, and HHSN2682011000012C). The authors thank the staff and participants of the ARIC study for their important contributions. The research reported in this manuscript on behalf of the Cardiac Arrest Blood Study (CABS) was supported by grants from the National Heart, Lung, and Blood Institute (HL41993 and HL091244); the University of Washington Clinical Nutrition Research Unit (DK-35816); and the Medic One Foundation, Seattle, WA. The authors gratefully acknowledge the Coronary Artery Risk Development in Young Adults (CARDIA) study participants and staff for their valuable contributions. The CARDIA study is funded by contracts N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, and N01-HC-45204 from the National Heart, Lung, and Blood Institute to the CARDIA investigators. Genotyping of the CARDIA participants was supported by grants U01-HG-004729 and R01-HL-084099. This manuscript has been reviewed by CARDIA for scientific content and consistency of data interpretation with previous CARDIA publications. This CHS research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi. DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124, the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center, and Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR). The Rotterdam Study is supported by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The NHLBI's Framingham Heart Study is a joint project of the National Institutes of Health and Boston University School of Medicine and was supported by contract N01-HC-25195 and its contract with Illumina, Inc. for genotyping services.; The Family Heart Study (FamHS) was supported by grants from the National Heart, Lung, & Blood Institute (U01 HL56563, U01 HL56564, U01 HL56565, U01 HL56566, U01 HL56567, U01 HL56568, U01 HL56569, and K01-HL70444). The Health, Aging, and Body Composition (HABC) Study is supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The Jackson Heart Study (JHS) is supported by the National Heart, Lung, and Blood Institute (N01 HC-95170, N01 HC-95171 and N01 HC-95172) and the National Center on Minority Health and Health Disparities. The authors thank the staff, interns and participants in JHS for their long-term commitment and important contributions to the study. MESA is supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159 through N01-HC-95169 and UL1-RR-024156. Funding for MESA Family is provided by grants R01- HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, UL1-RR-025005. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Gina Peloso was supported by Award Number T32HL007208 from the National Heart, Lung, And Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 74 Z9 74 U1 0 U2 6 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 JUL 12 PY 2013 VL 8 IS 7 AR e68095 DI 10.1371/journal.pone.0068095 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182CS UT WOS:000321718700009 PM 23874508 ER PT J AU Jung, M Arya, M Viswanath, K AF Jung, Minsoo Arya, Monisha Viswanath, Kasisomayajula TI Effect of Media Use on HIV/AIDS-Related Knowledge and Condom Use in Sub-Saharan Africa: A Cross-Sectional Study SO PLOS ONE LA English DT Article ID MASS-MEDIA; CAMPAIGNS; COUNTRIES; HEALTH AB It is known that the level of HIV/AIDS-related knowledge and the degree of condom use varies by socioeconomic status (SES). However, there is limited research on the effect of mass media use on HIV/AIDS-related cognitive and behavioral outcomes in low-income countries and how it might influence the association between SES and HIV-related outcomes. We investigated the moderating effect of media use on the relationship between SES and HIV/AIDS-related knowledge and condom use in sub-Saharan Africa in terms of communication inequalities. Cross-sectional data from the Demographic Health Surveys from 13 sub-Saharan countries (2004-10) were pooled. Gender-stratified multivariable poisson regression of 151,209 women and 68,890 men were used to calculate adjusted relative ratios and 95% confidence intervals for the associations between SES, media use, HIV-related outcomes, and condom use. We found significant disparities in mass media use among people from different SES groups as well as among countries. Education and wealth are strongly and positively associated with awareness of HIV/AIDS and knowledge about transmission and prevention of HIV/AIDS and are significantly associated with condom use. These associations are attenuated when the use of various types of mass media is added to the models, with newspapers showing the strongest effect. The findings of this study suggest that media use has the potential to blunt the impact of socioeconomic status though not completely eliminate it. Thus, we need to pay attention to reducing communication inequalities among social groups and countries to moderate the effect of wealth and SES on HIV/AIDS. C1 [Jung, Minsoo; Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Jung, Minsoo] Dongduk Womens Univ, Dept Hlth Sci, Seoul, South Korea. [Arya, Monisha] Baylor Coll Med, Dept Med, Infect Dis Sect, Houston, TX 77030 USA. [Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. RP Jung, M (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. EM minsoo_jung@dfci.harvard.edu OI Jung, Minsoo/0000-0003-3317-6507 FU NIMH NIH HHS [K23 MH094235] NR 29 TC 6 Z9 6 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 JUL 12 PY 2013 VL 8 IS 7 AR e68359 DI 10.1371/journal.pone.0068359 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182CS UT WOS:000321718700019 PM 23874598 ER PT J AU Saini, V Marengi, DA Barry, KJ Fulzele, KS Heiden, E Liu, X Dedic, C Maeda, A Lotinun, S Baron, R Pajevic, PD AF Saini, Vaibhav Marengi, Dean A. Barry, Kevin J. Fulzele, Keertik S. Heiden, Erica Liu, Xiaolong Dedic, Christopher Maeda, Akira Lotinun, Sutada Baron, Roland Pajevic, Paola Divieti TI Parathyroid Hormone (PTH)/PTH-related Peptide Type 1 Receptor (PPR) Signaling in Osteocytes Regulates Anabolic and Catabolic Skeletal Responses to PTH SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INCREASES BONE-FORMATION; LINING CELLS; EXPRESSION; SOST; MASS; SCLEROSTIN; PROTEIN; OSTEOBLASTS; ACTIVATION; PREVENTION AB Parathyroid hormone (PTH) is the only Food and Drug Administration-approved anabolic agent to treat osteoporosis; however, the cellular targets of PTH action in bone remain controversial. PTH modulates bone turnover by binding to the PTH/PTH-related peptide (PTHrP) type 1 receptor (PPR), a G-protein-coupled receptor highly expressed in bone and kidneys. Osteocytes, the most abundant cells in adult bone, also express PPR. However, the physiological relevance of PPR signaling in osteocytes remains to be elucidated. Toward this goal, we generated mice with PPR deletion in osteocytes (Ocy-PPRKO). Skeletal analysis of these mice revealed a significant increase in bone mineral density and trabecular and cortical bone parameters. Osteoblast activities were reduced in these animals, as demonstrated by decreased collagen type I alpha 1 mRNA and receptor activator of NF-kappa B ligand (RANKL) expression. Importantly, when subjected to an anabolic or catabolic PTH regimen, Ocy-PPRKO animals demonstrated blunted skeletal responses. PTH failed to suppress SOST/Sclerostin or induce RANKL expression in Ocy-PPRKO animals compared with controls. In vitro, osteoclastogenesis was significantly impaired in Ocy-PPRKO upon PTH administration, indicating that osteocytes control osteoclast formation through a PPR-mediated mechanism. Taken together, these data indicate that PPR signaling in osteocytes is required for bone remodeling, and receptor signaling in osteocytes is needed for anabolic and catabolic skeletal responses. C1 [Saini, Vaibhav; Marengi, Dean A.; Barry, Kevin J.; Fulzele, Keertik S.; Heiden, Erica; Liu, Xiaolong; Dedic, Christopher; Maeda, Akira; Baron, Roland; Pajevic, Paola Divieti] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02114 USA. [Lotinun, Sutada; Baron, Roland] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Pajevic, PD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Thier 1101, Boston, MA 02114 USA. EM divieti@helix.mgh.harvard.edu FU National Institutes of Health from the NIDDK [DK079161] FX This work was supported, in whole or in part, by National Institutes of Health Grant DK079161 from the NIDDK (to P.D.P.). NR 31 TC 49 Z9 50 U1 0 U2 7 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 JUL 12 PY 2013 VL 288 IS 28 BP 20122 EP 20134 DI 10.1074/jbc.M112.441360 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 182BI UT WOS:000321715100003 PM 23729679 ER PT J AU Takeuchi, K Morizane, Y Kamami-Levy, C Suzuki, J Kayama, M Cai, WY Miller, JW Vavvas, DG AF Takeuchi, Kimio Morizane, Yuki Kamami-Levy, Cynthia Suzuki, Jun Kayama, Maki Cai, Wenyi Miller, Joan W. Vavvas, Demetrios G. TI AMP-dependent Kinase Inhibits Oxidative Stress-induced Caveolin-1 Phosphorylation and Endocytosis by Suppressing the Dissociation between c-Abl and Prdx1 Proteins in Endothelial Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CARBOXAMIDE RIBONUCLEOTIDE AICAR; PAG GENE-PRODUCT; TYROSINE KINASE; GLUCOKINASE TRANSLOCATION; PHYSIOLOGICAL INHIBITOR; SRC KINASE; ACTIVATION; MICE; PERMEABILITY; PATHWAY AB Caveolin-1 is the primary structural component of endothelial caveolae that is essential for transcellular trafficking of albumin and is also a critical scaffolding protein that regulates the activity of signaling molecules in caveolae. Phosphorylation of caveolin-1 plays a fundamental role in the mechanism of oxidant-induced vascular hyper permeability. However, the regulatory mechanism of caveolin-1 phosphorylation remains unclear. Here we identify a previously unexpected role for AMPK in inhibition of caveolin-1 phosphorylation under oxidative stress. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), inhibited oxidative stress-induced phosphorylation of both caveolin-1 and c-Abl, which is the major kinase of caveolin-1, and endocytosis of albumin in human umbilical vein endothelial cell. These effects were abolished by treatment with two specific inhibitors of AICAR, dipyridamole, and 5-iodotubericidin. Consistently, knockdown of the catalytic AMPK alpha subunit by siRNA abolished the inhibitory effect of AICAR on oxidant-induced phosphorylation of both caveolin-1 and c-Abl. Pretreatment with specific c-Abl inhibitor, imatinib mesylate, and knock down of c-Abl significantly decreased the caveolin-1 phosphorylation after H2O2 exposure and abolished the inhibitory effect of AICAR on the caveolin-1 phosphorylation. Interestingly, knockdown of Prdx-1, an antioxidant enzyme associated with c-Abl, increased phosphorylation of both caveolin-1 and c-Abl and abolished the inhibitory effect of AICAR on the caveolin-1 phosphorylation. Furthermore, co-immunoprecipitation experiment showed that AICAR suppressed the oxidant-induced dissociation between c-Abl and Prdx1. Overall, our results suggest that activation of AMPK inhibits oxidative stress-induced caveolin-1 phosphorylation and endocytosis, and this effect is mediated in part by stabilizing the interaction between c-Abl and Prdx-1. C1 [Takeuchi, Kimio; Morizane, Yuki; Kamami-Levy, Cynthia; Suzuki, Jun; Kayama, Maki; Cai, Wenyi; Miller, Joan W.; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Morizane, Yuki] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Ophthalmol, Okayama 7008558, Japan. RP Vavvas, DG (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Demetrios_Vavvas@meei.harvard.edu OI Kamami-Levy, Cynthia/0000-0002-5770-5269; Vavvas, Demetrios/0000-0002-8622-6478 FU National Institutes of Health [EY014104]; Research to Prevent Blindness Foundation; Lions Eye Research Fund; Fight for Sight Grant in Aid; Harvard Ophthalmology Department; Yeatts Family Fund; Bausch and Lomb Japan Vitreoretinal fellowship FX This work was supported, in whole or in part, by National Institutes of Health Grant EY014104 (NEI). This work was also supported by an unrestricted grant to Massachusetts Eye and Ear Infirmary from the Research to Prevent Blindness Foundation (to D. G. V. and J. W. M.), the Lions Eye Research Fund (to D. G. V. and J. W. M.), the Fight for Sight Grant in Aid (to D. G. V.), the Harvard Ophthalmology Department (to D. G. V.), Yeatts Family Fund (to D. G. V. and J. W. M.), and a Bausch and Lomb Japan Vitreoretinal fellowship (to K. T., Y. M., J. S., and M. K.). NR 52 TC 18 Z9 19 U1 0 U2 7 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 JUL 12 PY 2013 VL 288 IS 28 BP 20581 EP 20591 DI 10.1074/jbc.M113.460832 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 182BI UT WOS:000321715100044 PM 23723070 ER PT J AU Pasquale, LR Loomis, SJ Weinreb, RN Kang, JH Yaspan, BL Bailey, JC Gaasterland, D Gaasterland, T Lee, RK Scott, WK Lichter, PR Budenz, DL Liu, YT Realini, T Friedman, DS McCarty, CA Moroi, SE Olson, L Schuman, JS Singh, K Vollrath, D Wollstein, G Zack, DJ Brilliant, M Sit, AJ Christen, WG Fingert, J Kraft, P Zhang, K Allingham, RR Pericak-Vance, MA Richards, JE Hauser, MA Haines, JL Wiggs, JL AF Pasquale, Louis R. Loomis, Stephanie J. Weinreb, Robert N. Kang, Jae H. Yaspan, Brian L. Bailey, Jessica Cooke Gaasterland, Douglas Gaasterland, Terry Lee, Richard K. Scott, William K. Lichter, Paul R. Budenz, Donald L. Liu, Yutao Realini, Tony Friedman, David S. McCarty, Catherine A. Moroi, Sayoko E. Olson, Lana Schuman, Joel S. Singh, Kuldev Vollrath, Douglas Wollstein, Gadi Zack, Donald J. Brilliant, Murray Sit, Arthur J. Christen, William G. Fingert, John Kraft, Peter Zhang, Kang Allingham, R. Rand Pericak-Vance, Margaret A. Richards, Julia E. Hauser, Michael A. Haines, Jonathan L. Wiggs, Janey L. TI Estrogen pathway polymorphisms in relation to primary open angle glaucoma: An analysis accounting for gender from the United States SO MOLECULAR VISION LA English DT Article ID HORMONE REPLACEMENT THERAPY; CENTRAL CORNEAL THICKNESS; INTRAOCULAR-PRESSURE; RECEPTOR-BETA; REPRODUCTIVE FACTORS; MENSTRUAL-CYCLE; COMT VAL158MET; GENE VARIANTS; OPTIC-NERVE; ASSOCIATION AB Purpose: Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender. Methods: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) >= 22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women. Results: Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p <= 0.001) and NPG (permuted gene p=0.01). Conclusions: The estrogen SNP pathway was associated with POAG among women. C1 [Pasquale, Louis R.; Loomis, Stephanie J.; Wiggs, Janey L.] Harvard Univ, Sch Med, Dept Ophthalmol, Mass Eye & Ear Infirm, Boston, MA USA. [Pasquale, Louis R.; Kang, Jae H.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. [Weinreb, Robert N.; Zhang, Kang] Univ Calif San Diego, Dept Ophthalmol, Sd, CA USA. [Weinreb, Robert N.; Zhang, Kang] Univ Calif San Diego, Hamilton Glaucoma Ctr, Sd, CA USA. [Yaspan, Brian L.] Genentech Inc, San Francisco, CA 94080 USA. [Bailey, Jessica Cooke; Olson, Lana; Haines, Jonathan L.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. [Gaasterland, Douglas] Eye Doctors Washington, Chevy Chase, MD USA. [Gaasterland, Terry] Univ Calif San Diego, Scripps Genome Ctr, San Diego, CA 92103 USA. [Lee, Richard K.; Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Lee, Richard K.; Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Hussman Inst Human Gen, Miami, FL 33136 USA. [Lichter, Paul R.; Moroi, Sayoko E.; Richards, Julia E.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Budenz, Donald L.] Univ N Carolina, Dept Ophthalmol, Chapel Hill, NC USA. [Liu, Yutao; Allingham, R. Rand; Hauser, Michael A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Liu, Yutao; Hauser, Michael A.] Duke Univ, Med Ctr, Durham, NC USA. [Realini, Tony] W Virginia Univ, Inst Eye, Dept Ophthalmol, Morgantown, WV 26506 USA. [Friedman, David S.; Zack, Donald J.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD 21205 USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Duluth, MN USA. [Schuman, Joel S.; Wollstein, Gadi] Univ Pittsburgh, Dept Ophthalmol, UPMC Eye Ctr, Pittsburgh, PA 15260 USA. [Singh, Kuldev] Stanford Univ, Dept Ophthalmol, Palo Alto, CA 94304 USA. [Vollrath, Douglas] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. [Brilliant, Murray] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Sit, Arthur J.] Mayo Clin, Dept Ophthalmol, Rochester, MN USA. [Christen, William G.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Fingert, John] Univ Iowa, Coll Med, Dept Ophthalmol, Iowa City, IA USA. [Fingert, John] Univ Iowa, Coll Med, Dept Anat Cell Biol, Iowa City, IA USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Pasquale, LR (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Louis_Pasquale@meei.harvard.edu RI Fingert, John/F-8787-2012; Schuman, Joel/K-7304-2012; OI Fingert, John/0000-0002-0377-0479; Schuman, Joel/0000-0002-8885-3766; Zack, Don/0000-0002-7966-1973; Sit, Arthur/0000-0002-3904-2625 FU Harvard Glaucoma Center of Excellence and Margolis fund (Boston, MA); Prevent Blindness, Inc. (New York, NY); American Health Assistance Foundation (Clarksburg, MD); Glaucoma Foundation (New York, NY); National Institutes of Health [HHSN268200782096C]; National Human Genome Research Institute (Bethesda, MD) [HG004728, HG004424, HG004446]; National Eye Institute [HG005259-01]; National Human Genome Research Institute (Bethesda, MD); National Institutes of Health (Bethesda, MD) [EY015543, EY006827, HL073389, EY13315, EY09611, EY009149, HG004608, EY008208, EY015473, EY012118, EY015682, EY011671, EY09580, EY013178, EY015872, EY010886, EY009847, EY011008, EY144428, EY144448, EY18660] FX Funding/Support: A Horizon Grant to MEEI from Allergan (Irvine, CA) supported the collection of some glaucoma feature data. The Harvard Glaucoma Center of Excellence and Margolis fund (Boston, MA) support LRP and JLW. LRP, JER and JLW are also supported by Research to Prevent Blindness, Inc. (New York, NY). The Arthur Ashley Foundation also supports Dr. Pasquale. The Glaucoma Research Foundation (San Francisco, CA), American Health Assistance Foundation (Clarksburg, MD), and the Glaucoma Foundation (New York, NY) support YL. The following National Institutes of Health grants support the maintenance of the Nurses Health Study and Health Professionals Follow-up, allowing these health professionals to contribute to this analysis: CA87969, CA49449, UM1 CA167552, and HL35464. The following grants from the National Human Genome Research Institute (Bethesda, MD) supported GLAUGEN: HG004728 (LRP), HG004424 (Broad Institute to support genotyping), HG004446 (C. Laurie, U. Washington, to support genotype data cleaning and analysis). Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through grant HG005259-01 (JLW). Additionally CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. The National Eye Institute (Bethesda, MD) through ARRA grants EY015872 (JLW) and EY019126 (MAH) supported the collection and processing of samples for the NEIGHBOR dataset. Funding for the collection of cases and controls was provided by National Institutes of Health (Bethesda, MD) grants: EY015543 (RRA), EY006827 (DG), HL073389 (Hauser, E); EY13315 (MAH); EY09611 (Hankinson, S), and EY015473 (LRP). EY009149 (PRL), HG004608 (CAM), EY008208 (Medeiros, P.), EY015473 (LRP), EY012118 (MAP-V), EY015682 (TR), EY011671 (JER), EY09580 (JER), EY013178 (JSS), EY015872 (JLW), EY010886 (JLW), EY009847 (JLW), EY011008 (Zangwill, L), EY144428 (KZ), EY144448 (KZ), EY18660 (KZ). None of the authors have any commercial interests in the subject of the manuscript or in entities discussed in the manuscript. This work was presented in part at the American Society of Human Genetics Meeting, November 2012, San Francisco, CA and at the ARVO Meeting May 2013, Seattle Washington. NR 56 TC 17 Z9 17 U1 0 U2 3 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 12 PY 2013 VL 19 BP 1471 EP 1481 PG 11 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 183AT UT WOS:000321786700003 PM 23869166 ER PT J AU Laviolette, LA Wilson, J Koller, J Neil, C Hulick, P Rejtar, T Karger, B Teh, BT Iliopoulos, O AF Laviolette, Laura A. Wilson, Jonas Koller, Julia Neil, Christopher Hulick, Peter Rejtar, Tomas Karger, Barry Teh, Bin Tean Iliopoulos, Othon TI Human Folliculin Delays Cell Cycle Progression through Late S and G2/M-Phases: Effect of Phosphorylation and Tumor Associated Mutations SO PLOS ONE LA English DT Article ID BIRT-HOGG-DUBE; HEREDITARY MULTIPLE FIBROFOLLICULOMAS; GENE-PRODUCT; SPONTANEOUS PNEUMOTHORAX; POLYCYSTIC KIDNEYS; SUPPRESSOR FLCN; MTOR ACTIVATION; PROTEIN; NEOPLASIA; TRICHODISCOMAS AB The Birt-Hogg-Dube disease occurs as a result of germline mutations in the human Folliculin gene (FLCN), and is characterized by clinical features including fibrofolliculomas, lung cysts and multifocal renal neoplasia. Clinical and genetic evidence suggest that FLCN acts as a tumor suppressor gene. The human cell line UOK257, derived from the renal cell carcinoma of a patient with a germline mutation in the FLCN gene, harbors a truncated version of the FLCN protein. Reconstitution of the wild type FLCN protein into UOK257 cells delays cell cycle progression, due to a slower progression through the late S and G2/M-phases. Similarly, Flcn(-/-) mouse embryonic fibroblasts progress more rapidly through the cell cycle than wild type controls (Flcn(flox/flox)). The reintroduction of tumor-associated FLCN mutants (FLCN Delta F157, FLCN 1-469 or FLCN K508R) fails to delay cell cycle progression in UOK257 cells. Additionally, FLCN phosphorylation (on Serines 62 and 73) fluctuates throughout the cell cycle and peaks during the G2/M phase in cells treated with nocodazole. In keeping with this observation, the reintroduction of a FLCN phosphomimetic mutant into the UOK257 cell line results in faster progression through the cell cycle compared to those expressing the wild type FLCN protein. These findings suggest that the tumor suppression function of FLCN may be linked to its impact on the cell cycle and that FLCN phosphorylation is important for this activity. Additionally, these observations describe a novel in vitro assay for testing the functional significance of FLCN mutations and/or genetic polymorphisms. C1 Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Ctr Canc, Dept Med, Div Hematol Oncol, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. Van Andel Res Inst, Canc Genet Lab, Grand Rapids, MI USA. [Teh, Bin Tean] Natl Canc Ctr Singapore, NCCS VARI Translat Res Lab, Singapore, Singapore. RP Iliopoulos, O (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA 02129 USA. EM oiliopoulos@partners.org FU National Institutes of Health [RO1 CA-208647, RO1 GM15847]; Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE Development Award FX This work was supported by the National Institutes of Health [RO1 CA-208647 to OI, RO1 GM15847 to BK]; and by a Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE Development Award to OI. For the Barnett Institute researchers [BK] this is manuscript contribution No 1022. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 4 Z9 4 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 JUL 11 PY 2013 VL 8 IS 7 AR e66775 DI 10.1371/journal.pone.0066775 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188UA UT WOS:000322218800003 PM 23874397 ER PT J AU Fathi, AT Le, L Hasserjian, RP Sadrzadeh, H Levis, M Chen, YB AF Fathi, Amir T. Le, Long Hasserjian, Robert P. Sadrzadeh, Hossein Levis, Mark Chen, Yi-Bin TI FLT3 inhibitor-induced neutrophilic dermatosis SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; TYROSINE KINASE INHIBITOR; C/EBP-ALPHA; ADULT PATIENTS; IN-VIVO; MUTATIONS; DIFFERENTIATION; EXPRESSION; CELLS AB The FLT3-ITD mutation is associated with poor outcomes in acute myeloid leukemia. Multiple FMS-like tyrosine kinase 3 (FLT3)-inhibitors have been studied in clinical trials. Recently, potent FLT3 inhibition was shown to induce terminal differentiation of FLT3-mutant myeloblasts. In 3 patients who developed characteristic skin nodules on initiation of FLT3-inhibition, we conducted dermatopathologic evaluation of skin samples, as well as FLT3 and NPM1 mutational analysis and fluorescence in situ hybridization. All 3 patients demonstrated characteristically deep dermal and subcutaneous neutrophilic infiltrates without evidence of myeloblasts. Discovery of FLT3-ITD and NPM1 mutations in 2 of the samples, as well as the presence of FLT3-ITD and deletion of 7q in the other, confirmed the ancestry of the differentiated neutrophils as that of the original FLT3-mutant myeloblasts. FLT3 inhibition can lead to clinically distinct dermatoses, which suggests the effect of FLT3 inhibition on myeloid differentiation and a manifestation of a broader "syndrome" associated with this therapy. C1 [Fathi, Amir T.; Le, Long; Hasserjian, Robert P.; Sadrzadeh, Hossein; Chen, Yi-Bin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Levis, Mark] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Fathi, AT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Zero Emerson Pl,Suite 118, Boston, MA 02114 USA. EM afathi@partners.org FU Bayer/Onyx FX M.L. is on the clinical advisory board for Ambit Biosciences. Y.C. receives grant support from Bayer/Onyx to conduct clinical trials. The remaining authors declare no competing financial interests. NR 27 TC 9 Z9 9 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 11 PY 2013 VL 122 IS 2 BP 239 EP 242 DI 10.1182/blood-2013-01-478172 PG 4 WC Hematology SC Hematology GA 184QY UT WOS:000321909600013 PM 23687091 ER PT J AU Carss, KJ Stevens, E Foley, AR Cirak, S Riemersma, M Torelli, S Hoischen, A Willer, T van Scherpenzeel, M Moore, SA Messina, S Bertini, E Bonnemann, CG Abdenur, JE Grosmann, CM Kesari, A Punetha, J Quinlivan, R Waddell, LB Young, HK Wraige, E Yau, S Brodd, L Feng, L Sewry, C MacArthur, DG North, KN Hoffinan, E Stemple, DL Hurles, ME van Bokhoven, H Campbell, KP Lefeber, DJ Lin, YY Muntoni, F AF Carss, Keren J. Stevens, Elizabeth Foley, A. Reghan Cirak, Sebahattin Riemersma, Moniek Torelli, Silvia Hoischen, Alexander Willer, Tobias van Scherpenzeel, Monique Moore, Steven A. Messina, Sonia Bertini, Enrico Boennemann, Carsten G. Abdenur, Jose E. Grosmann, Carla M. Kesari, Akanchha Punetha, Jaya Quinlivan, Ros Waddell, Leigh B. Young, Helen K. Wraige, Elizabeth Yau, Shu Brodd, Lina Feng, Lucy Sewry, Caroline MacArthur, Daniel G. North, Kathryn N. Hoffinan, Eric Stemple, Derek L. Hurles, Matthew E. van Bokhoven, Hans Campbell, Kevin P. Lefeber, Dirk J. Lin, Yung-Yao Muntoni, Francesco CA UK10K consortium TI Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of alpha-Dystroglycan SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID WALKER-WARBURG-SYNDROME; CELL-WALL INTEGRITY; O-GLYCAN STRUCTURES; DEFECTIVE GLYCOSYLATION; ABNORMAL GLYCOSYLATION; GLYCOPROTEIN COMPLEX; SKELETAL-MUSCLE; GENE; ZEBRAFISH; LAMININ AB Congenital muscular dystrophies with hypoglycosylation of alpha-dystroglycan (alpha-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of alpha-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated alpha-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-l-phosphate. GDP-mannose is required for O-mannosylation of proteins, including alpha-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced alpha-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of alpha-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of alpha-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of alpha-DG. C1 [Carss, Keren J.; Stemple, Derek L.; Hurles, Matthew E.; Lin, Yung-Yao] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Stevens, Elizabeth; Foley, A. Reghan; Cirak, Sebahattin; Torelli, Silvia; Quinlivan, Ros; Feng, Lucy; Sewry, Caroline; Muntoni, Francesco] UCL Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England. [Cirak, Sebahattin; Kesari, Akanchha; Punetha, Jaya; Hoffinan, Eric] Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. [Riemersma, Moniek; Lefeber, Dirk J.] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Neurol, NL-6525 HB Nijmegen, Netherlands. [Riemersma, Moniek; van Scherpenzeel, Monique; Lefeber, Dirk J.] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Lab Med, NL-6525 HB Nijmegen, Netherlands. [Riemersma, Moniek; Hoischen, Alexander] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Human Genet,Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Willer, Tobias; Campbell, Kevin P.] Univ Iowa, Carver Coll Med, Howard Hughes Med Inst, Iowa City, IA 52242 USA. [Willer, Tobias; Campbell, Kevin P.] Univ Iowa, Carver Coll Med, Dept Neurol, Iowa City, IA 52242 USA. [Willer, Tobias; Campbell, Kevin P.] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Willer, Tobias; Campbell, Kevin P.] Univ Iowa, Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. [Moore, Steven A.] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA. [Messina, Sonia] Univ Messina, Azienda Osped Univ Policlin G Martino, Dept Neurosci, I-98125 Messina, Italy. [Bertini, Enrico] Bambino Gesu Childrens Res Hosp, Mol Med Lab, I-00146 Rome, Italy. [Boennemann, Carsten G.] NINDS, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Abdenur, Jose E.] Childrens Hosp Orange Cty, Div Metab Disorders, Orange, CA 92868 USA. [Abdenur, Jose E.] Univ Calif Irvine, Sch Med, Dept Pediat, Irvine, CA 92697 USA. [Grosmann, Carla M.] Univ Calif San Diego, Rady Childrens Hosp, Sch Med, Dept Neurosci, San Diego, CA 92123 USA. [Grosmann, Carla M.] Univ Calif San Diego, Rady Childrens Hosp, Sch Med, Dept Pediat, San Diego, CA 92123 USA. [Punetha, Jaya; Hoffinan, Eric] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20037 USA. [Quinlivan, Ros] Natl Hosp Neurol & Neurosurg, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England. [Waddell, Leigh B.; North, Kathryn N.] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia. [Young, Helen K.] Childrens Hosp Westmead, Dept Neurogenet, Sydney, NSW 2145, Australia. [Young, Helen K.] Univ Sydney, Royal N Shore Hosp, Northern Clin Sch, St Leonards, NSW 2065, Australia. [Wraige, Elizabeth] Guys & St Thomas NHS Fdn Trust, Evelina Childrens Hosp, Dept Paediat Neurol, London SE1 7EH, England. [Yau, Shu; Brodd, Lina] GSTS Pathol, DNA Lab, London SE1 9RT, England. [Sewry, Caroline] Robert Jones & Agnes Hunt Orthopaed Hosp NHS Fdn, Wolfson Ctr Inherited Neuromuscular Dis, Oswestry SY10 7AG, Shrops, England. [MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [MacArthur, Daniel G.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [North, Kathryn N.] Univ Sydney, Sydney Med Sch, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [van Bokhoven, Hans] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands. [van Bokhoven, Hans] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, NL-6500 HB Nijmegen, Netherlands. [Lin, Yung-Yao] Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England. RP Muntoni, F (reprint author), UCL Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England. EM f.muntoni@ucl.ac.uk RI Schmidts, Miriam/A-3777-2012; van Scherpenzeel, Monique/N-7008-2015; North, Kathryn/K-6476-2012; McQuillin, Andrew/C-1623-2008; Scambler, Peter/C-4998-2008; Moayyeri, Alireza/N-3332-2014; Lefeber, Dirk/A-2146-2014; Bolton, Patrick/E-8501-2010; Hoischen, Alexander/D-1282-2013; Bokhoven, J.H.L.M./H-8015-2014 OI Messina, Sonia/0000-0001-7994-3391; Suvisaari, Jaana/0000-0001-7167-0990; Schmidts, Miriam/0000-0002-1714-6749; van Scherpenzeel, Monique/0000-0002-9696-4562; North, Kathryn/0000-0003-0841-8009; McQuillin, Andrew/0000-0003-1567-2240; Scambler, Peter/0000-0002-1487-4628; Ritchie, Graham/0000-0002-6456-9736; Punetha, Jaya/0000-0002-6774-4464; Moayyeri, Alireza/0000-0002-9143-2161; Bolton, Patrick/0000-0002-5270-6262; Hoischen, Alexander/0000-0002-8072-4476; FU Wellcome Trust [WT091310] FX This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available at http://www.uk10k.org/publications_and_posters.html. Funding for UK10K was provided by the Wellcome Trust under award WT091310. We are grateful to the UK10K consortium for making this study possible. Acknowledgments are continued in the Supplemental Data. NR 63 TC 60 Z9 62 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 11 PY 2013 VL 93 IS 1 BP 29 EP 41 DI 10.1016/j.ajhg.2013.05.009 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 183HG UT WOS:000321804500003 PM 23768512 ER PT J AU Chudasama, KK Winnay, J Johansson, S Claudi, T Konig, R Haldorsen, I Johansson, B Woo, JR Aarskog, D Sagen, JV Kahn, CR Molven, A Njolstad, PR AF Chudasama, Kishan Kumar Winnay, Jonathon Johansson, Stefan Claudi, Tor Koenig, Rainer Haldorsen, Ingfrid Johansson, Bente Woo, Ju Rang Aarskog, Dagfinn Sagen, Jorn V. Kahn, C. Ronald Molven, Anders Njolstad, Pal Rasmus TI SHORT Syndrome with Partial Lipodystrophy Due to Impaired Phosphatidylinositol 3 Kinase Signaling SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE; REGULATORY SUBUNIT; ADIPOCYTES; MUTATIONS; P85-ALPHA; PATHWAYS; BINDING AB The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85 alpha, regulatory subunit, encoded by PIK3R1. Using whole-exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85 alpha and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling. C1 [Chudasama, Kishan Kumar; Johansson, Stefan; Johansson, Bente; Aarskog, Dagfinn; Sagen, Jorn V.; Molven, Anders; Njolstad, Pal Rasmus] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, N-5020 Bergen, Norway. [Chudasama, Kishan Kumar; Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Winnay, Jonathon; Woo, Ju Rang; Kahn, C. Ronald; Molven, Anders] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Claudi, Tor] Nordlandssykehuset, Dept Med, N-8092 Bodo, Norway. [Koenig, Rainer] Goethe Univ Frankfurt, Dept Human Genet, G-60325 Frankfurt, Germany. [Haldorsen, Ingfrid; Molven, Anders] Univ Bergen, Dept Clin Med, N-5020 Bergen, Norway. [Sagen, Jorn V.] Univ Bergen, Dept Clin Sci, N-5020 Bergen, Norway. [Sagen, Jorn V.] Haukeland Hosp, Hormone Lab, N-5021 Bergen, Norway. [Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Njolstad, Pal Rasmus] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Njolstad, Pal Rasmus] Broad Inst Harvard & MIT, Med & Populat Genet Program, Cambridge, MA 02142 USA. RP Njolstad, PR (reprint author), Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, N-5020 Bergen, Norway. EM pal.njolstad@uib.no RI Johansson, Stefan/C-4394-2011; OI Johansson, Stefan/0000-0002-2298-7008; Haldorsen, Ingfrid S./0000-0001-9313-7564; Johansson, Bente Berg/0000-0001-8893-1915 FU Research Council of Norway; University of Bergen; K.G. Jebsen Foundation; Helse Vest; Innovest; European Research Council; Nils Normans Foundation; National Institutes of Health [DK55545] FX We thank the families for participation, as well as Stig A. Eide and Louise Grevle for technical assistance, Francisco S. Roque and Inge Jonassen for support with computational analysis, and the University of Bergen Audiovisual Section for help with the photographs. The study was supported by the Research Council of Norway, the University of Bergen, the K.G. Jebsen Foundation, Helse Vest, Innovest, and the European Research Council (to P.R.N.), the Nils Normans Foundation (to S.J.), and National Institutes of Health grant DK55545 (to C.R.K.). NR 26 TC 26 Z9 27 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL 11 PY 2013 VL 93 IS 1 BP 150 EP 157 DI 10.1016/j.ajhg.2013.05.023 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 183HG UT WOS:000321804500015 PM 23810379 ER PT J AU Reece-Hoyes, JS Pons, C Diallo, A Mori, A Shrestha, S Kadreppa, S Nelson, J DiPrima, S Dricot, A Lajoie, BR Ribeiro, PSM Weirauch, MT Hill, DE Hughes, TR Myers, CL Walhout, AJM AF Reece-Hoyes, John S. Pons, Carles Diallo, Alos Mori, Akihiro Shrestha, Shaleen Kadreppa, Sreenath Nelson, Justin DiPrima, Stephanie Dricot, Amelie Lajoie, Bryan R. Ribeiro, Philippe Souza Moraes Weirauch, Matthew T. Hill, David E. Hughes, Timothy R. Myers, Chad L. Walhout, Albertha J. M. TI Extensive Rewiring and Complex Evolutionary Dynamics in a C. elegans Multiparameter Transcription Factor Network SO MOLECULAR CELL LA English DT Article ID GENE REGULATORY NETWORK; DNA INTERACTION NETWORK; ONE-HYBRID ASSAYS; DUPLICATE GENES; PROTEIN-DNA; DOSAGE SENSITIVITY; SYSTEMS-APPROACH; YEAST; FAMILY; RECOGNITION AB Gene duplication results in two identical paralogs that diverge through mutation, leading to loss or gain of interactions with other biomolecules. Here, we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks. Remarkably, we find that even highly similar TFs often have different interaction degrees and partners. In addition, we find that most TF families have a member that is highly connected in multiple networks. Further, different TF families have opposing correlations between network connectivity and phylogenetic age, suggesting that they are subject to different evolutionary pressures. Finally, TFs that have similar partners in one network generally do not in another, indicating a lack of pressure to retain cross-network similarity. Our multiparameter analyses provide unique insights into the evolutionary dynamics that shaped TF networks. C1 [Reece-Hoyes, John S.; Diallo, Alos; Mori, Akihiro; Shrestha, Shaleen; Kadreppa, Sreenath; Lajoie, Bryan R.; Walhout, Albertha J. M.] Univ Massachusetts, Sch Med, Program Mol Med, Program Syst Biol, Worcester, MA 01605 USA. [Pons, Carles; Nelson, Justin; DiPrima, Stephanie; Ribeiro, Philippe Souza Moraes; Myers, Chad L.] Univ Minnesota Twin Cities, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA. [Dricot, Amelie; Hill, David E.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Weirauch, Matthew T.; Hughes, Timothy R.] Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. [Weirauch, Matthew T.] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA. [Weirauch, Matthew T.] Cincinnati Childrens Hosp Med Ctr, CAGE, Cincinnati, OH 45229 USA. RP Myers, CL (reprint author), Univ Minnesota Twin Cities, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA. EM cmyers@cs.umn.edu; marian.walhout@umassmed.edu RI Pons, Carles/B-6841-2016; OI Walhout, Marian/0000-0001-5587-3608 FU National Institutes of Health (NIH) [GM082971, DK06429, HG005084-01A1, HG005853-01]; CIHR [MOP-111007]; CIFAR; National Science Foundation [DBI 0953881] FX We thank members of the Walhout and Myers laboratories, J. Dekker, and N. Springer for discussions and critical reading of the manuscript. This work was supported by National Institutes of Health (NIH) grant GM082971 to A.J.M.W. and D.E.H.; NIH grant DK06429 to A.J.M.W.; CIHR grant MOP-111007 to T.R.H.; fellowships from CIHR and CIFAR to M.T.W.; and C.L.M., C.P., J.N., and P.S.M.R. are partially supported by grants from the NIH (HG005084-01A1, HG005853-01) and the National Science Foundation (DBI 0953881). NR 46 TC 25 Z9 25 U1 2 U2 10 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 JUL 11 PY 2013 VL 51 IS 1 BP 116 EP 127 DI 10.1016/j.molcel.2013.05.018 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 183DL UT WOS:000321794100012 PM 23791784 ER PT J AU Lawrence, MS Stojanov, P Polak, P Kryukov, GV Cibulskis, K Sivachenko, A Carter, SL Stewart, C Mermel, CH Roberts, SA Kiezun, A Hammerman, PS McKenna, A Drier, Y Zou, LH Ramos, AH Pugh, TJ Stransky, N Helman, E Kim, J Sougnez, C Ambrogio, L Nickerson, E Shefler, E Cortes, ML Auclair, D Saksena, G Voet, D Noble, M DiCara, D Lin, P Lichtenstein, L Heiman, DI Fennell, T Imielinski, M Hernandez, B Hodis, E Baca, S Dulak, AM Lohr, J Landau, DA Wu, CJ Melendez-Zajgla, J Hidalgo-Miranda, A Koren, A McCarroll, SA Mora, J Lee, RS Crompton, B Onofrio, R Parkin, M Winckler, W Ardlie, K Gabriel, SB Roberts, CWM Biegel, JA Stegmaier, K Bass, AJ Garraway, LA Meyerson, M Golub, TR Gordenin, DA Sunyaev, S Lander, ES Getz, G AF Lawrence, Michael S. Stojanov, Petar Polak, Paz Kryukov, Gregory V. Cibulskis, Kristian Sivachenko, Andrey Carter, Scott L. Stewart, Chip Mermel, Craig H. Roberts, Steven A. Kiezun, Adam Hammerman, Peter S. McKenna, Aaron Drier, Yotam Zou, Lihua Ramos, Alex H. Pugh, Trevor J. Stransky, Nicolas Helman, Elena Kim, Jaegil Sougnez, Carrie Ambrogio, Lauren Nickerson, Elizabeth Shefler, Erica Cortes, Maria L. Auclair, Daniel Saksena, Gordon Voet, Douglas Noble, Michael DiCara, Daniel Lin, Pei Lichtenstein, Lee Heiman, David I. Fennell, Timothy Imielinski, Marcin Hernandez, Bryan Hodis, Eran Baca, Sylvan Dulak, Austin M. Lohr, Jens Landau, Dan-Avi Wu, Catherine J. Melendez-Zajgla, Jorge Hidalgo-Miranda, Alfredo Koren, Amnon McCarroll, Steven A. Mora, Jaume Lee, Ryan S. Crompton, Brian Onofrio, Robert Parkin, Melissa Winckler, Wendy Ardlie, Kristin Gabriel, Stacey B. Roberts, Charles W. M. Biegel, Jaclyn A. Stegmaier, Kimberly Bass, Adam J. Garraway, Levi A. Meyerson, Matthew Golub, Todd R. Gordenin, Dmitry A. Sunyaev, Shamil Lander, Eric S. Getz, Gad TI Mutational heterogeneity in cancer and the search for new cancer-associated genes SO NATURE LA English DT Article ID COMPREHENSIVE GENOMIC CHARACTERIZATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; SOMATIC MUTATIONS; HUMAN-PAPILLOMAVIRUS; MAMMALIAN GENOMES; DNA; LANDSCAPE; CARCINOMA; PATHWAYS; LYMPHOMA AB Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer(1-9). These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer. C1 [Lawrence, Michael S.; Stojanov, Petar; Polak, Paz; Kryukov, Gregory V.; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Stewart, Chip; Mermel, Craig H.; Kiezun, Adam; Hammerman, Peter S.; McKenna, Aaron; Drier, Yotam; Zou, Lihua; Ramos, Alex H.; Pugh, Trevor J.; Stransky, Nicolas; Helman, Elena; Kim, Jaegil; Sougnez, Carrie; Ambrogio, Lauren; Nickerson, Elizabeth; Shefler, Erica; Cortes, Maria L.; Auclair, Daniel; Saksena, Gordon; Voet, Douglas; Noble, Michael; DiCara, Daniel; Lin, Pei; Lichtenstein, Lee; Heiman, David I.; Fennell, Timothy; Imielinski, Marcin; Hernandez, Bryan; Hodis, Eran; Baca, Sylvan; Dulak, Austin M.; Lohr, Jens; Landau, Dan-Avi; Koren, Amnon; McCarroll, Steven A.; Onofrio, Robert; Parkin, Melissa; Winckler, Wendy; Ardlie, Kristin; Gabriel, Stacey B.; Stegmaier, Kimberly; Bass, Adam J.; Garraway, Levi A.; Meyerson, Matthew; Golub, Todd R.; Sunyaev, Shamil; Lander, Eric S.; Getz, Gad] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. [Stojanov, Petar; Hammerman, Peter S.; Pugh, Trevor J.; Hodis, Eran; Baca, Sylvan; Dulak, Austin M.; Lohr, Jens; Landau, Dan-Avi; Wu, Catherine J.; Lee, Ryan S.; Crompton, Brian; Roberts, Charles W. M.; Stegmaier, Kimberly; Bass, Adam J.; Garraway, Levi A.; Meyerson, Matthew; Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Polak, Paz; Kryukov, Gregory V.; Drier, Yotam; Pugh, Trevor J.; Wu, Catherine J.; Koren, Amnon; McCarroll, Steven A.; Lee, Ryan S.; Roberts, Charles W. M.; Bass, Adam J.; Garraway, Levi A.; Meyerson, Matthew; Golub, Todd R.; Sunyaev, Shamil; Lander, Eric S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Polak, Paz; Kryukov, Gregory V.; Sunyaev, Shamil] Brigham & Womens Hosp, Boston, MA 02115 USA. [Mermel, Craig H.; Drier, Yotam; Imielinski, Marcin; Getz, Gad] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Roberts, Steven A.; Gordenin, Dmitry A.] NIEHS, Lab Mol Genet, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [McKenna, Aaron] Univ Washington, Seattle, WA 98195 USA. [Drier, Yotam; Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Stransky, Nicolas] Blueprint Med, Cambridge, MA 02142 USA. [Helman, Elena; Lander, Eric S.] MIT, Cambridge, MA 02139 USA. [Landau, Dan-Avi] Yale Canc Ctr, Dept Hematol, New Haven, CT 06510 USA. [Melendez-Zajgla, Jorge; Hidalgo-Miranda, Alfredo] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico. [Mora, Jaume] Hosp St Joan de Deu, Dept Pediat Oncol, Barcelona 08950, Spain. [Lee, Ryan S.; Crompton, Brian; Roberts, Charles W. M.; Stegmaier, Kimberly] Boston Childrens Hosp, Boston, MA 02115 USA. [Biegel, Jaclyn A.] Childrens Hosp, Philadelphia, PA 19104 USA. RP Lander, ES (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. EM lander@broadinstitute.org; gadgetz@broadinstitute.org RI Hidalgo-Miranda, Alfredo/B-2123-2010; Kryukov, Gregory/A-9592-2008; Drier, Yotam/K-5208-2012; OI Hidalgo-Miranda, Alfredo/0000-0003-2315-3977; Drier, Yotam/0000-0003-1725-2995; Gordenin, Dmitry/0000-0002-8399-1836 FU Intramural Research Program of the National Institute of Environmental Health Sciences (National Institutes of Health, United States Department of Health and Human Services) [ES065073] FX This work was conducted as part of TCGA, a project of the National Cancer Institute and National Human Genome Research Institute. This work was conducted as part of the Slim Initiative for Genomic Medicine, a joint US-Mexico project founded by the Carlos Slim Health Institute. Support to D. A. G. and S. A. R. was through the Intramural Research Program of the National Institute of Environmental Health Sciences (National Institutes of Health, United States Department of Health and Human Services) project ES065073 (principal investigator M. Resnick). NR 30 TC 1037 Z9 1050 U1 26 U2 207 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 JUL 11 PY 2013 VL 499 IS 7457 BP 214 EP 218 DI 10.1038/nature12213 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179YA UT WOS:000321557600063 PM 23770567 ER PT J AU Sharma, S Quintana, A Findlay, GM Mettlen, M Baust, B Jain, M Nilsson, R Rao, A Hogan, PG AF Sharma, Sonia Quintana, Ariel Findlay, Gregory M. Mettlen, Marcel Baust, Beate Jain, Mohit Nilsson, Roland Rao, Anjana Hogan, Patrick G. TI An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry SO NATURE LA English DT Article ID CHANNEL ACTIVATION; ORAI1; STIM1; CALCIUM; CYTOSKELETON; RELEASE; CRAC; FORCHLORFENURON; ORGANIZATION; DOMAINS AB The STIM1-ORAI1 pathway of store-operated Ca2+ entry is an essential component of cellular Ca2+ signalling(1). STIM1 senses depletion of intracellular Ca2+ stores in response to physiological stimuli, and relocalizes within the endoplasmic reticulum to plasma-membrane-apposed junctions, where it recruits and gates open plasma membrane ORAI1 Ca2+ channels. Here we use a genome-wide RNA interference screen in HeLa cells to identify filamentous septin proteins as crucial regulators of store-operated Ca2+ entry. Septin filaments and phosphatidylinositol-4,5-bisphosphate (also known as PtdIns(4,5)P-2) rearrange locally at endoplasmic reticulum-plasma membrane junctions before and during formation of STIM1-ORAI1 clusters, facilitating STIM1 targeting to these junctions and promoting the stable recruitment of ORAI1. Septin rearrangement at junctions is required for PtdIns(4,5) P2 reorganization and efficient STIM1-ORAI1 communication. Septins are known to demarcate specialized membrane regions such as dendritic spines, the yeast bud and the primary cilium, and to serve as membrane diffusion barriers and/or signalling hubs in cellular processes such as vesicle trafficking, cell polarity and cytokinesis2-4. Our data show that septins also organize the highly localized plasma membrane domains that are important in STIM1-ORAI1 signalling, and indicate that septins may organize membrane microdomains relevant to other signalling processes. C1 [Sharma, Sonia; Quintana, Ariel; Rao, Anjana; Hogan, Patrick G.] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Sharma, Sonia; Quintana, Ariel; Findlay, Gregory M.; Baust, Beate; Rao, Anjana; Hogan, Patrick G.] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA. [Mettlen, Marcel] Scripps Res Inst, La Jolla, CA 92037 USA. [Jain, Mohit] Broad Inst, Cambridge, MA 02142 USA. [Jain, Mohit] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Nilsson, Roland] Karolinska Inst, S-17176 Stockholm, Sweden. RP Rao, A (reprint author), La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. EM arao@liai.org; phogan@liai.org FU National Institutes of Health (NIH) [AI040127, AI084167]; NIH [AI092763, K08 HL107451, R01GM73165]; Canadian Institutes for Health Research; Leukemia & Lymphoma Society; Deutsche Forschungsgemeinschaft [QU298/1-1]; Knut & Alice Wallenberg Foundation FX We thank C. Shamu, S. Rudnicki, S. Johnston and D. Wrobel for screening support; A. Carpenter and M. Bray for CellProfiler optimization; P. Meraner and Y. Zhou for cell lines and constructs; S. Schmid, J. Fitzpatrick and the Waitt Advanced Biophotonics Center at the Salk Institute for access to TIRF microscopes; C. Junker for the RFP-ER construct; S. Field for the PLC delta-PH-eGFP plasmid; and S. Schmid for manuscript review. The work was supported by National Institutes of Health (NIH) R01 grants AI040127 and AI084167(to A. R. and P. G. H.), NIH RC4 grant AI092763 (to A. R. and S. S.); a Fellowship from the Canadian Institutes for Health Research and a Special Fellowship from The Leukemia & Lymphoma Society (to S. S.); postdoctoral fellowship QU298/1-1 from the Deutsche Forschungsgemeinschaft (to A. Q.); NIH grant K08 HL107451 (to M. J.); a postdoctoral scholarship from the Knut & Alice Wallenberg Foundation (to R. N.); NIH R01 grant R01GM73165 (to S. Schmid, which supports M.M.). NR 30 TC 84 Z9 84 U1 1 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 11 PY 2013 VL 499 IS 7457 BP 238 EP + DI 10.1038/nature12229 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 179YA UT WOS:000321557600068 PM 23792561 ER PT J AU Hamid, O Robert, C Daud, A Hodi, FS Hwu, WJ Kefford, R Wolchok, JD Hersey, P Joseph, RW Weber, JS Dronca, R Gangadhar, TC Patnaik, A Zarour, H Joshua, AM Gergich, K Elassaiss-Schaap, J Algazi, A Mateus, C Boasberg, P Tumeh, PC Chmielowski, B Ebbinghaus, SW Li, XN Kang, SP Ribas, A AF Hamid, Omid Robert, Caroline Daud, Adil Hodi, F. Stephen Hwu, Wen-Jen Kefford, Richard Wolchok, Jedd D. Hersey, Peter Joseph, Richard W. Weber, Jeffrey S. Dronca, Roxana Gangadhar, Tara C. Patnaik, Amita Zarour, Hassane Joshua, Anthony M. Gergich, Kevin Elassaiss-Schaap, Jeroen Algazi, Alain Mateus, Christine Boasberg, Peter Tumeh, Paul C. Chmielowski, Bartosz Ebbinghaus, Scot W. Li, Xiaoyun Nicole Kang, S. Peter Ribas, Antoni TI Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID METASTATIC MELANOMA; CANCER; IMMUNOTHERAPY; PHASE; BLOCKADE; ANTIBODY; CRITERIA; THERAPY; PD-1 AB BACKGROUND The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. METHODS We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. RESULTS A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. CONCLUSIONS In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. C1 [Hamid, Omid; Boasberg, Peter] Angeles Clin & Res Inst, Los Angeles, CA USA. [Tumeh, Paul C.; Chmielowski, Bartosz; Ribas, Antoni] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Robert, Caroline; Mateus, Christine] Inst Gustave Roussy, Villejuif, France. [Daud, Adil; Algazi, Alain] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hwu, Wen-Jen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kefford, Richard] Univ Sydney, Westmead Hosp, Sydney, NSW 2006, Australia. [Kefford, Richard] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia. [Hersey, Peter] Melanoma Inst Australia, Kolling Inst, Newcastle, NSW, Australia. [Hersey, Peter] Newcastle Melanoma Unit, Newcastle, NSW, Australia. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Joseph, Richard W.] Mayo Clin, Jacksonville, FL 32224 USA. [Weber, Jeffrey S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Dronca, Roxana] Mayo Clin, Rochester, MN USA. [Gangadhar, Tara C.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Patnaik, Amita] South Texas Accelerated Res Therapeut, San Antonio, TX USA. [Zarour, Hassane] Univ Pittsburgh, Pittsburgh, PA USA. [Joshua, Anthony M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Gergich, Kevin; Elassaiss-Schaap, Jeroen; Ebbinghaus, Scot W.; Li, Xiaoyun Nicole; Kang, S. Peter] Merck Sharp & Dohme Ltd, Whitehouse Stn, NJ USA. RP Ribas, A (reprint author), Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Jonsson Comprehens Canc Ctr, 11-934 Factor Bldg,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM aribas@mednet.ucla.edu RI Li, Xiaoyun/P-8265-2014; Kanemura, Takashi/H-5717-2015; Elassaiss-Schaap , Jeroen/Q-5451-2016; OI Chmielowski, Bartosz/0000-0002-2374-3320 FU Merck Sharp; Dohme FX Supported by Merck Sharp and Dohme. NR 16 TC 1212 Z9 1256 U1 31 U2 168 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 JUL 11 PY 2013 VL 369 IS 2 BP 134 EP 144 DI 10.1056/NEJMoa1305133 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 180BH UT WOS:000321567300009 PM 23724846 ER PT J AU Wing, R Bolin, P Brancati, FL Bray, GA Clark, JM Coday, M Crow, RS Curtis, JM Egan, CM Espeland, MA Evans, M Foreyt, JP Ghazarian, S Gregg, EW Harrison, B Hazuda, HP Hill, JO Horton, ES Hubbard, V Jakicic, JM Jeffery, RW Johnson, KC Kahn, SE Kitabchi, AE Knowler, WC Lewis, CE Maschak-Carey, BJ Montez, MG Murillo, A Nathan, DM Patricio, J Peters, A Pi-Sunyer, X Pownall, H Reboussin, D Regensteiner, JG Rickman, AD Ryan, DH Safford, M Wadden, TA Wagenknecht, LE West, DS Williamson, DF Yanovski, SZ AF Wing, Rena Bolin, Paula Brancati, Frederick L. Bray, George A. Clark, Jeanne M. Coday, Mace Crow, Richard S. Curtis, Jeffrey M. Egan, Caitlin M. Espeland, Mark A. Evans, Mary Foreyt, John P. Ghazarian, Siran Gregg, Edward W. Harrison, Barbara Hazuda, Helen P. Hill, James O. Horton, Edward S. Hubbard, Van S. Jakicic, John M. Jeffery, Robert W. Johnson, Karen C. Kahn, Steven E. Kitabchi, Abbas E. Knowler, William C. Lewis, Cora E. Maschak-Carey, Barbara J. Montez, Maria G. Murillo, Anne Nathan, David M. Patricio, Jennifer Peters, Anne Pi-Sunyer, Xavier Pownall, Henry Reboussin, David Regensteiner, Judith G. Rickman, Amy D. Ryan, Donna H. Safford, Monika Wadden, Thomas A. Wagenknecht, Lynne E. West, Delia S. Williamson, David F. Yanovski, Susan Z. CA Look AHEAD Res Grp TI Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LOOK-AHEAD ACTION; WEIGHT-LOSS; CLINICAL-TRIAL; OBESE ADULTS; PREVENTION; MORTALITY; HEALTH; INDIVIDUALS; MELLITUS; PROGRAM AB Background Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. Methods In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. Results The trial was stopped early on the basis of a futility analysis when the median follow- up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P = 0.51). Conclusions An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. C1 [Wing, Rena; Curtis, Jeffrey M.] Brown Univ, Warren Alpert Med Sch, Weight Control & Diabet Res Ctr, Providence, RI 02903 USA. [Bolin, Paula; Evans, Mary; Harrison, Barbara; Hubbard, Van S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Brancati, Frederick L.; Clark, Jeanne M.] Johns Hopkins Sch Med, Baltimore, MD USA. [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Coday, Mace; Johnson, Karen C.; Kitabchi, Abbas E.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Crow, Richard S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Curtis, Jeffrey M.] NIDDK, NIH, Phoenix, AZ USA. [Egan, Caitlin M.] Miriam Hosp, Providence, RI 02906 USA. [Espeland, Mark A.] Wake Forest Univ, Dept Biostat Sci, Sch Med, Winston Salem, NC 27109 USA. [Foreyt, John P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Ghazarian, Siran; Peters, Anne] Roybal Comprehens Hlth Ctr, Los Angeles, CA USA. [Gregg, Edward W.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hazuda, Helen P.; Montez, Maria G.] Univ Texas Hlth Sci Ctr San Antonio, Dept Clin Epidemiol, San Antonio, TX 78229 USA. [Hill, James O.] Univ Colorado, Hlth Sci Ctr, Ctr Human Nutr, Aurora, CO USA. [Horton, Edward S.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Jakicic, John M.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Jeffery, Robert W.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Kahn, Steven E.; Murillo, Anne] Univ Washington, Dept Med, Seattle, WA USA. [Knowler, William C.] NIDDK, NIH, Southwest Amer Indian Ctr, Phoenix, AZ USA. [Lewis, Cora E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Maschak-Carey, Barbara J.] Univ Penn, Weight & Eating Disorder Program, Philadelphia, PA 19104 USA. [Nathan, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Patricio, Jennifer] St Lukes Roosevelt Hosp, Dept Med, New York, NY 10025 USA. [Pi-Sunyer, Xavier] St Lukes Roosevelt Hosp, Dept Med, New York, NY 10025 USA. [Pownall, Henry] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Reboussin, David] Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Regensteiner, Judith G.] Univ Colorado, Hlth Sci Ctr, Ctr Womens Hlth Res, Aurora, CO USA. [Rickman, Amy D.] Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. [Ryan, Donna H.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Safford, Monika] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Wadden, Thomas A.] Univ Penn, Weight & Eating Disorder Program, Philadelphia, PA 19104 USA. [Wagenknecht, Lynne E.] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [West, Delia S.] Univ Arkansas Med Sci, Coll Publ Hlth, Dept Hlth Behav & Hlth Educ, Little Rock, AR 72205 USA. [Williamson, David F.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Yanovski, Susan Z.] NIDDK, NIH, Bethesda, MD USA. RP Wing, R (reprint author), Brown Univ, Warren Alpert Med Sch, Weight Control & Diabet Res Ctr, 196 Richmond St, Providence, RI 02903 USA. EM rwing@lifespan.org OI Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health (NIH); Department of Health and Human Services agencies; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, DK56992]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Nursing Research; National Center on Minority Health and Health Disparities; NIH Office of Research on Women's Health; Centers for Disease Control and Prevention; Johns Hopkins Medical Institutions Bayview General Clinical Research Center [M01RR02719]; Massachusetts General Hospital Mallinckrodt General Clinical Research Center; Massachusetts Institute of Technology General Clinical Research Center [M01RR01066]; University of Colorado Health Sciences Center General Clinical Research Center [M01RR00051]; Clinical Nutrition Research Unit [P30 DK48520]; University of Tennessee at Memphis General Clinical Research Center [M01RR0021140]; University of Pittsburgh General Clinical Research Center [M01RR000056]; Clinical Translational Research Center; Clinical and Translational Science Award [UL1 RR 024153]; NIH [DK 046204]; VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; Frederic C. Bartter General Clinical Research Center [M01RR01346]; FedEx; Health Management Resources; Johnson Johnson; Nestle HealthCare Nutrition; Hoffmann-La Roche; Abbott Nutrition; Unilever North America FX Supported by the National Institutes of Health (NIH) and other Department of Health and Human Services agencies through cooperative agreements with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK57136, DK57149, DK56990, DK57177, DK57171, DK57151, DK57182, DK57131, DK57002, DK57078, DK57154, DK57178, DK57219, DK57008, DK57135, and DK56992). Additional funding was provided by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung, and Blood Institute; the National Institute of Nursing Research; the National Center on Minority Health and Health Disparities; the NIH Office of Research on Women's Health; and the Centers for Disease Control and Prevention. The Indian Health Service (IHS) provided personnel, medical oversight, and use of facilities. Additional support was provided by the Johns Hopkins Medical Institutions Bayview General Clinical Research Center (M01RR02719); the Massachusetts General Hospital Mallinckrodt General Clinical Research Center and the Massachusetts Institute of Technology General Clinical Research Center (M01RR01066); the University of Colorado Health Sciences Center General Clinical Research Center (M01RR00051) and Clinical Nutrition Research Unit (P30 DK48520); the University of Tennessee at Memphis General Clinical Research Center (M01RR0021140); the University of Pittsburgh General Clinical Research Center(M01RR000056) and Clinical Translational Research Center (funded by a Clinical and Translational Science Award [UL1 RR 024153] and an NIH grant [DK 046204]); the VA Puget Sound Health Care System Medical Research Service, Department of Veterans Affairs; and the Frederic C. Bartter General Clinical Research Center (M01RR01346); and by FedEx, Health Management Resources, Johnson & Johnson, Nestle HealthCare Nutrition, Hoffmann-La Roche, Abbott Nutrition, and Unilever North America. NR 28 TC 578 Z9 589 U1 10 U2 102 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 JUL 11 PY 2013 VL 369 IS 2 BP 145 EP 154 DI 10.1056/NEJMoa1212914 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 180BH UT WOS:000321567300010 ER PT J AU Sullivan, RJ Lawrence, DP Wargo, JA Oh, KS Gonzalez, RG Piris, A AF Sullivan, Ryan J. Lawrence, Donald P. Wargo, Jennifer A. Oh, Kevin S. Gonzalez, R. Gilberto Piris, Adriano TI Case 21-2013: A 68-Year-Old Man with Metastatic Melanoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; BRAIN METASTASES; OPEN-LABEL; ANTITUMOR-ACTIVITY; IMPROVED SURVIVAL; MEK INHIBITION; PHASE-2 TRIAL; T-CELLS; IPILIMUMAB; VEMURAFENIB C1 [Sullivan, Ryan J.; Lawrence, Donald P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Wargo, Jennifer A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Oh, Kevin S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Piris, Adriano] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sullivan, Ryan J.; Lawrence, Donald P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wargo, Jennifer A.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Oh, Kevin S.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Gonzalez, R. Gilberto] Harvard Univ, Sch Med, Dept Neuroradiol, Boston, MA USA. [Piris, Adriano] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Sullivan, RJ (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 39 TC 21 Z9 22 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 11 PY 2013 VL 369 IS 2 BP 173 EP 183 DI 10.1056/NEJMcpc1302332 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 180BH UT WOS:000321567300014 PM 23841733 ER PT J AU Eypper, EH Johnson, PV Purro, EI Hohmann, EL AF Eypper, Elizabeth H. Johnson, Paul V. Purro, Eva I. Hohmann, Elizabeth L. TI Transcutaneous immunization of healthy volunteers with an attenuated Listeria monocytogenes vaccine strain and cholera toxin adjuvant SO VACCINE LA English DT Article DE Listeria monocytogenes; Transcutaneous; Vaccination; ELISpot; attenuated vector; Clinical trial ID SAFETY; IMMUNITY; CELLS AB Background: Attenuated Listeria monocytogenes vaccine strains have been administered intravenously (Le et al. [1], Maciag et al. [21) and orally (Angelakopoulos et al. [3], Johnson et al. [4]) to humans. Here, one was given transcutaneously with cholera toxin adjuvant. Methods: Eight healthy volunteers were studied (5 active, 3 placebo). Safety was assessed by physical exam and labs. Systemic immunological responses were measured by ELISA and IFN-gamma ELISpot. Results: 4/5 active volunteers had cellular responses to listerial antigens. 5/5 active volunteers showed humoral responses to cholera toxin. Conclusions: An attenuated L. monocytogenes vector was safely administered transcutaneously. Topical administration appeared at least as immunogenic as previously studied oral delivery. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved. C1 [Eypper, Elizabeth H.; Johnson, Paul V.; Hohmann, Elizabeth L.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Purro, Eva I.] List Biol Inc, Campbell, CA 95008 USA. RP Hohmann, EL (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. EM ehohmann@partners.org FU National Institute for Allergy and Infectious Diseases at the National Institutes of Health [R01AI51206] FX EIP is a full-time employee of List Biologicals. EHE, PVJ, ELH have no conflicts of interest. Funding: This work was supported in part by National Institute for Allergy and Infectious Diseases at the National Institutes of Health [R01AI51206] to ELH. The funder had no role in the design or execution of the study nor in the preparation or submission of the article. NR 12 TC 6 Z9 7 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 11 PY 2013 VL 31 IS 32 BP 3257 EP 3261 DI 10.1016/j.vaccine.2013.05.028 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 179RE UT WOS:000321538200008 PM 23707162 ER PT J AU Munshi, NC Anderson, KC AF Munshi, Nikhil C. Anderson, Kenneth C. TI Minimal Residual Disease in Multiple Myeloma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; FLOW-CYTOMETRY; BONE-MARROW; AUTOLOGOUS TRANSPLANTATION; LENALIDOMIDE; MAINTENANCE; REMISSION; THERAPY C1 [Munshi, Nikhil C.] Harvard Univ, Sch Med, Dana Farber Canc Inst,VA Boston Healthcare Syst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. RP Munshi, NC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst,VA Boston Healthcare Syst, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St, Boston, MA 02115 USA. FU BLRD VA [I01 BX001584]; NCI NIH HHS [P50 CA100707, P01 CA078378, P01 CA155258]; PHS HHS [P01-155258, P01-78378, P50-100007, R01-124929, R01-50947] NR 27 TC 17 Z9 18 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2013 VL 31 IS 20 BP 2523 EP 2526 DI 10.1200/JCO.2013.49.2124 PG 4 WC Oncology SC Oncology GA 301NA UT WOS:000330537800012 PM 23733782 ER PT J AU Mack, JW Chen, K Boscoe, FP Gesten, FC Roohan, PJ Weeks, JC Schymura, MJ Schrag, D AF Mack, Jennifer W. Chen, Kun Boscoe, Francis P. Gesten, Foster C. Roohan, Patrick J. Weeks, Jane C. Schymura, Maria J. Schrag, Deborah TI Underuse of Hospice Care by Medicaid-Insured Patients With Stage IV Lung Cancer in New York and California SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; MENTAL-HEALTH; END; OUTCOMES; DEATH; CARCINOMA; PLACE AB Purpose Medicare patients with advanced cancer have low rates of hospice use. We sought to evaluate hospice use among patients in Medicaid, which insures younger and indigent patients, relative to those in Medicare. Patients and Methods Using linked patient-level data from California (CA) and New York (NY) state cancer registries, state Medicaid programs, NY Medicare, and CA Surveillance, Epidemiology, and End Results-Medicare data, we identified 4,797 CA Medicaid patients and 4,001 NY Medicaid patients ages 21 to 64 years, as well as 27,416 CA Medicare patients and 16,496 NY Medicare patients ages >= 65 years who were diagnosed with stage IV lung cancer between 2002 and 2006. We evaluated hospice use, timing of enrollment, and location of death (inpatient hospice; long-term care facility or skilled nursing facility; acute care facility; home with hospice; or home without hospice). We used multiple logistic regressions to evaluate clinical and sociodemographic factors associated with hospice use. Results Although 53% (CA) and 44% (NY) of Medicare patients ages >= 65 years used hospice, fewer than one third of Medicaid-insured patients ages 21 to 64 years enrolled in hospice after a diagnosis of stage IV lung cancer (CA, 32%; NY, 24%). A minority of Medicaid patient deaths (CA, 19%; NY, 14%) occurred at home with hospice. Most Medicaid patient deaths were either in acute-care facilities (CA, 28%; NY, 36%) or at home without hospice (CA, 39%; NY, 41%). Patient race/ethnicity was not associated with hospice use among Medicaid patients. Conclusion Given low rates of hospice use among Medicaid enrollees and considerable evidence of suffering at the end of life, opportunities to improve palliative care delivery should be prioritized. (C) 2013 by American Society of Clinical Oncology C1 [Mack, Jennifer W.; Chen, Kun; Weeks, Jane C.; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02215 USA. [Mack, Jennifer W.] Childrens Hosp, Boston, MA 02115 USA. [Boscoe, Francis P.; Schymura, Maria J.] New York State Dept Hlth, State Canc Registry, Albany, NY 12237 USA. [Gesten, Foster C.; Roohan, Patrick J.] New York State Dept Hlth, Off Qual & Patient Safety, Albany, NY USA. RP Mack, JW (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Jennifer_mack@dfci.harvard.edu FU National Cancer Institute [R01CA131847, RC2CA148185-01]; American Cancer Society Mentored Research Scholar Grant from the American Cancer Society; Association of Schools of Public Health/Centers for Disease Control and Prevention Cooperative Agreement [S3888] FX Supported by Grants No. R01CA131847 (D. S.; Medicaid patients) and RC2CA148185-01 (J.C.W.) from the National Cancer Institute, an American Cancer Society Mentored Research Scholar Grant (J.W.M.) from the American Cancer Society, and the Association of Schools of Public Health/Centers for Disease Control and Prevention Cooperative Agreement No. S3888 (Augmenting New York Cancer Registry Data to Assess Breast and Colorectal Cancer Care; M.J.S.). NR 24 TC 21 Z9 21 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2013 VL 31 IS 20 BP 2569 EP + DI 10.1200/JCO.2012.45.9271 PG 12 WC Oncology SC Oncology GA 301NA UT WOS:000330537800026 PM 23733768 ER PT J AU Judson, TJ Bennett, AV Rogak, LJ Sit, L Barz, A Kris, MG Hudis, CA Scher, HI Sabattini, P Schrag, D Basch, E AF Judson, Timothy J. Bennett, Antonia V. Rogak, Lauren J. Sit, Laura Barz, Allison Kris, Mark G. Hudis, Clifford A. Scher, Howard I. Sabattini, Paul Schrag, Deborah Basch, Ethan TI Feasibility of Long-Term Patient Self-Reporting of Toxicities From Home via the Internet During Routine Chemotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NATIONAL-CANCER-INSTITUTE; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; MANAGEMENT-SYSTEM ASYMS(C); OUTCOMES ASSESSMENT; CLINICAL-TRIALS; COMMUNICATION; CARE; MYELOFIBROSIS; RUXOLITINIB AB Purpose Patient-reported outcomes are increasingly used in routine outpatient cancer care to guide clinical decisions and enhance communication. Prior evidence suggests good patient compliance with reporting at scheduled clinic visits, but there is limited evidence about compliance with long-term longitudinal reporting between visits. Patients and Methods Patients receiving chemotherapy for lung, gynecologic, genitourinary, or breast cancer at a tertiary cancer center, with access to a home computer and prior e-mail experience, were asked to self-report seven symptomatic toxicities via the Web between visits. E-mail reminders were sent to participants weekly; patient-reported high-grade toxicities triggered e-mail alerts to nurses; printed reports were provided to oncologists at visits. A priori threshold criteria were set to determine if this data collection approach merited further development based on monthly (>= 75% participants reporting at least once per month on average) and weekly compliance rates (60% at least once per week). Results Between September 2006 and November 2010, 286 patients were enrolled (64% were women; 88% were white; median age, 58 years). Mean follow-up was 34 weeks (range, 2 to 214). On average, monthly compliance was 83%, and weekly compliance was 62%, without attrition until the month before death. Greater compliance was associated with older age and higher education but not with performance status. Compliance was greatest during the initial 12 weeks. Symptomatic illness and technical problems were rarely barriers to compliance. Conclusion Monthly compliance with home Web reporting was high, but weekly compliance was lower, warranting strategies to enhance compliance in routine care settings. (C) 2013 by American Society of Clinical Oncology C1 [Judson, Timothy J.; Basch, Ethan] Weill Cornell Med Coll, New York, NY USA. [Bennett, Antonia V.; Rogak, Lauren J.; Sit, Laura; Barz, Allison; Kris, Mark G.; Hudis, Clifford A.; Scher, Howard I.; Sabattini, Paul; Basch, Ethan] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Basch, Ethan] Univ N Carolina, Chapel Hill, NC USA. RP Basch, E (reprint author), Univ N Carolina, Canc Outcomes Res Program, 170 Manning Dr CB 7305,Phys Off Bldg,Suite 3185, Chapel Hill, NC 27599 USA. EM ebasch@med.unc.edu OI Kris, Mark/0000-0002-7317-5341 FU National Cancer Institute [5K07CA124851] FX Supported by National Cancer Institute Grant No. 5K07CA124851. NR 38 TC 29 Z9 29 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2013 VL 31 IS 20 BP 2580 EP + DI 10.1200/JCO.2012.47.6804 PG 7 WC Oncology SC Oncology GA 301NA UT WOS:000330537800027 PM 23733753 ER PT J AU McCleary, NJ Meyerhardt, JA Green, E Yothers, G de Gramont, A Van Cutsem, E O'Connell, M Twelves, CJ Saltz, LB Haller, DG Sargent, DJ AF McCleary, Nadine J. Meyerhardt, Jeffrey A. Green, Erin Yothers, Greg de Gramont, Aimery Van Cutsem, Eric O'Connell, Michael Twelves, Christopher J. Saltz, Leonard B. Haller, Daniel G. Sargent, Daniel J. TI Impact of Age on the Efficacy of Newer Adjuvant Therapies in Patients With Stage II/III Colon Cancer: Findings From the ACCENT Database SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol ID COMPREHENSIVE GERIATRIC ASSESSMENT; COLORECTAL-CANCER; INDEPENDENTLY CONTRIBUTE; ELDERLY-PATIENTS; PLUS LEUCOVORIN; POOLED ANALYSIS; III CARCINOMA; OLDER-ADULTS; FLUOROURACIL; CHEMOTHERAPY AB Purpose Prior studies have suggested that patients with stage II/III colon cancer receive similar benefit from intravenous (IV) fluoropyrimidine adjuvant therapy regardless of age. Combination regimens and oral fluorouracil (FU) therapy are now standard. We examined the impact of age on colon cancer recurrence and mortality after adjuvant therapy with these newer options. Patients and Methods We analyzed 11,953 patients age <70 and 2,575 age >70 years from seven adjuvant therapy trials comparing IV FU with oral fluoropyrimidines (capecitabine, uracil, or tegafur) or combinations of fluoropyrimidines with oxaliplatin or irinotecan in stage II/III colon cancer. End points were disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Results In three studies comparing oxaliplatin-based chemotherapy with IV FU, statistically significant interactions were not observed between treatment arm and age (P interaction = .09 for DFS, .05 for OS, and .36 for TTR), although the stratified point estimates suggested limited benefit from the addition of oxaliplatin in elderly patients (DFS hazard ratio [HR], 0.94; 95% CI, 0.78 to 1.13; OS HR, 1.04; 95% CI, 0.85 to 1.27). No significant interactions by age were detected with oral fluoropyrimidine therapy compared with IV FU; noninferiority was supported in both age populations. Conclusion Patients age >= 70 years seemed to experience reduced benefit from adding oxaliplatin to fluoropyrimidines in the adjuvant setting, although statistically, there was not a significant effect modification by age, whereas oral fluoropyrimidines retained their efficacy. (C) 2013 by American Society of Clinical Oncology C1 [McCleary, Nadine J.; Meyerhardt, Jeffrey A.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Green, Erin; O'Connell, Michael; Sargent, Daniel J.] Mayo Clin, Rochester, MN USA. [Yothers, Greg] Univ Pittsburgh, Pittsburgh, PA USA. [Haller, Daniel G.] Univ Penn, Philadelphia, PA 19104 USA. [de Gramont, Aimery] Hop St Antoine, F-75571 Paris, France. [Van Cutsem, Eric] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Twelves, Christopher J.] Univ Leeds, Leeds, W Yorkshire, England. [Twelves, Christopher J.] St Jamess Inst Oncol, Leeds, W Yorkshire, England. [Saltz, Leonard B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP McCleary, NJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM nj_mccleary@dfci.harvard.edu OI Sargent, Daniel/0000-0002-2684-4741; Yothers, Greg/0000-0002-7965-7333; Saltz, Leonard/0000-0001-8353-4670 FU NCI NIH HHS [CA25224, P50 CA127003, R01 CA169141, U10 CA025224] NR 31 TC 52 Z9 53 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2013 VL 31 IS 20 BP 2600 EP + DI 10.1200/JCO.2013.49.6638 PG 8 WC Oncology SC Oncology GA 301NA UT WOS:000330537800030 PM 23733765 ER PT J AU Johnstone, DB Ikizler, O Zhang, JD Holzman, LB AF Johnstone, Duncan B. Ikizler, Omer Zhang, Jidong Holzman, Lawrence B. TI Background Strain and the Differential Susceptibility of Podocyte-Specific Deletion of Myh9 on Murine Models of Experimental Glomerulosclerosis and HIV Nephropathy SO PLOS ONE LA English DT Article ID DECAY-ACCELERATING FACTOR; NEPHROTOXIC NEPHRITIS; AFRICAN-AMERICANS; KIDNEY-DISEASE; MYH9-RELATED DISEASE; EUROPEAN-AMERICANS; BASEMENT-MEMBRANE; LUPUS NEPHRITIS; II-A; MICE AB We previously reported that podocyte-specific deletion of Myh9 (conventional myosin heavy chain 2A) in C57BL/6 mice does not cause spontaneous kidney disease but instead results in a predisposition to glomerulosclerosis in response to a second model of glomerular injury. In contrast, other investigators reported that podocyte-specific deletion of Myh9 (Pod Delta Myh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9(flox) alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in Pod Delta Myh9 mice vs control littermates (urine MAC ratio all p > 0.05). We also tested C57BL/6 Pod Delta Myh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p < 0.05 or less). In contrast, we found that Pod Delta Myh9 mice were not predisposed to injury in response to other injury models including puromycin nephropathy and sheep nephrotoxic serum. While the mechanism of injury in these models is not fully understood, we conclude that Pod Delta Myh9 results in a variable susceptibility to glomerulosclerosis in response to different models of glomerular injury. In addition, based on the lack of a spontaneous phenotype of glomerulosclerosis in both C57BL/6 and FVB/N mice, we propose that Myh9 is not absolutely required in adult podocytes. C1 [Johnstone, Duncan B.] Temple Univ, Sch Med, Div Nephrol, Philadelphia, PA 19122 USA. [Ikizler, Omer; Zhang, Jidong; Holzman, Lawrence B.] Univ Penn, Sch Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Holzman, Lawrence B.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Johnstone, DB (reprint author), Temple Univ, Sch Med, Div Nephrol, Philadelphia, PA 19122 USA. EM duncan.johnstone@tuhs.temple.edu FU VA merit award; [K08DK082616] FX Sources of funding for this study were K08DK082616 (to DBJ) and VA merit award (to LBH). These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 11 Z9 11 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2013 VL 8 IS 7 AR e67839 DI 10.1371/journal.pone.0067839 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182SU UT WOS:000321765300014 PM 23874454 ER PT J AU Sahani, DV Jiang, T Hayano, K Duda, DG Catalano, OA Ancukiewicz, M Jain, RK Zhu, AX AF Sahani, Dushyant V. Jiang, Tao Hayano, Koichi Duda, Dan G. Catalano, Onofrio A. Ancukiewicz, Marek Jain, Rakesh K. Zhu, Andrew X. TI Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article DE Hepatocellular carcinoma; Antiangiogenic treatment; Image biomarker; Dynamic contrast-enhanced MRI; Diffusion-weighted imaging; Circulating biomarker ID ENDOTHELIAL GROWTH-FACTOR; CONTRAST-ENHANCED MRI; PHASE-II; PHARMACOKINETIC MODELS; COMPUTED-TOMOGRAPHY; SYSTEMIC THERAPY; FACTOR RECEPTOR; PORTAL-VEIN; DCE-MRI; CANCER AB Background: To investigate the hypothesis that MRI derived diffusion-weighted imaging (DWI) and perfusion (MRP) parameters are sensitive image biomarkers for monitoring early antiangiogenic effects and predicting progression free survival (PFS) in advanced hepatocellular carcinoma (HCC). Methods: In this phase II clinical trial, 23 of 34 patients were included in the imaging and circulating biomarker study. DWI and MRP were performed at the baseline and at 2-weeks after initiation of sunitinib. The imaging protocol included an axial DWI sequence using b values of 50, 400 and 800 sec/mm(2), and MRP using a series of coronal 3D-VIBE following 20 ml of Gd-DTPA at 2 ml/sec. These parameters were compared with clinical outcome and PFS at 6-months. Correlation between changes in MRI parameters and plasma biomarkers was also evaluated. Results: After 2-week of sunitinib, substantial Ktrans changes in HCC were observed from median baseline value 2.15 min(-1) to 0.94 min(-1) (P = 0.0001) with increases in median apparent diffusion coefficient (ADC) from 0.88 x 10(-3) mm(2)/s to 0.98 x 10(-3) mm(2)/s (P = 0.0001). Tumor size remained unchanged by RECIST and mRECIST (both P > 0.05). Patients who showed larger drop in Ktrans and Kep at 2 weeks correlated with favorable clinical outcome, and higher baseline Ktrans and larger drop in EVF correlated with longer PFS (all P < 0.05). There was a significant association between a decrease in sVEGFR2 and the drop in Ktrans and Kep (P = 0.044, P = 0.030), and a significant and borderline association between decrease in TNF-alpha and the drop in Ktrans and Kep, respectively (P = 0.051, P = 0.035). Conclusion: In HCC, MRP may be a more sensitive biomarker in predicting early response and PFS following sunitinib than RECIST and mRECIST. C1 [Sahani, Dushyant V.; Jiang, Tao; Hayano, Koichi; Catalano, Onofrio A.] Harvard Univ, Sch Med, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Sahani, Dushyant V.; Jiang, Tao; Hayano, Koichi; Catalano, Onofrio A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jiang, Tao] Second Mil Med Univ, ChangZheng Hosp, Dept Radiol, Shanghai 200003, Peoples R China. [Duda, Dan G.; Ancukiewicz, Marek; Jain, Rakesh K.] Massachusetts Gen Hosp, Steele Lab, Boston, MA 02114 USA. [Catalano, Onofrio A.] IRCCS, Dept Radiol, SDN Fdn, I-80143 Naples, Italy. [Zhu, Andrew X.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Harvard Univ, Sch Med, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org FU National Natural Science Foundation of China [81101044]; NIH [P01-CA080124] FX Tao Jiang, M. D. received research support from the National Natural Science Foundation of China (No. 81101044). The research of Drs. Jain and Duda is in part supported through NIH grant P01-CA080124. NR 43 TC 23 Z9 26 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD JUL 10 PY 2013 VL 6 AR 51 DI 10.1186/1756-8722-6-51 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 188LX UT WOS:000322195600001 PM 23842041 ER PT J AU Harvey, HB Cohen, IG AF Harvey, H. Benjamin Cohen, I. Glenn TI The Looming Threat of Liability for Accountable Care Organizations and What to Do About It SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Harvey, H. Benjamin] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Cohen, I. Glenn] Harvard Univ, Sch Law, Cambridge, MA 02138 USA. RP Cohen, IG (reprint author), Harvard Univ, Sch Law, 1525 Massachusetts Ave,Griswold Hall,Room 503, Cambridge, MA 02138 USA. EM igcohen@law.harvard.edu NR 7 TC 5 Z9 5 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 10 PY 2013 VL 310 IS 2 BP 141 EP 142 DI 10.1001/jama.2013.7339 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 179HU UT WOS:000321511500008 PM 23775236 ER PT J AU Madison, K Schmidt, H Volpp, KG AF Madison, Kristin Schmidt, Harald Volpp, Kevin G. TI Smoking, Obesity, Health Insurance, and Health Incentives in the Affordable Care Act SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Madison, Kristin] Northeastern Univ, Sch Law, Boston, MA 02115 USA. [Madison, Kristin] Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Schmidt, Harald] Univ Penn, Dept Med Eth & Hlth Policy, Perelman Sch Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Volpp, Kevin G.] Univ Penn, Perelman Sch Med, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. RP Madison, K (reprint author), Northeastern Univ, Sch Law, 400 Huntington Ave, Boston, MA 02115 USA. EM k.madison@neu.edu NR 6 TC 17 Z9 17 U1 0 U2 15 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 JUL 10 PY 2013 VL 310 IS 2 BP 143 EP 144 DI 10.1001/jama.2013.7617 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 179HU UT WOS:000321511500009 PM 23765171 ER PT J AU Matlock, DD Groeneveld, PW Sidney, S Shetterly, S Goodrich, G Glenn, K Xu, S Yang, L Farmer, SA Reynolds, K Cassidy-Bushrow, AE Lieu, T Boudreau, DM Greenlee, RT Tom, J Vupputuri, S Adams, KF Smith, DH Gunter, MJ Go, AS Magid, DJ AF Matlock, Daniel D. Groeneveld, Peter W. Sidney, Steve Shetterly, Susan Goodrich, Glenn Glenn, Karen Xu, Stan Yang, Lin Farmer, Steven A. Reynolds, Kristi Cassidy-Bushrow, Andrea E. Lieu, Tracy Boudreau, Denise M. Greenlee, Robert T. Tom, Jeffrey Vupputuri, Suma Adams, Kenneth F. Smith, David H. Gunter, Margaret J. Go, Alan S. Magid, David J. TI Geographic Variation in Cardiovascular Procedure Use Among Medicare Fee-for-Service vs Medicare Advantage Beneficiaries SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LIFE TREATMENT INTENSITY; REGIONAL-VARIATION; UNITED-STATES; RESOURCE USE; HEALTH-CARE; QUALITY; PERCEPTIONS; OUTCOMES; POLICY; RISK AB IMPORTANCE Little is known about how different financial incentives between Medicare Advantage and Medicare fee-for-service (FFS) reimbursement structures influence use of cardiovascular procedures. OBJECTIVE To compare regional cardiovascular procedure rates between Medicare Advantage and Medicare FFS beneficiaries. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of Medicare beneficiaries older than 65 years between 2003-2007 comparing rates of coronary angiography, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) surgery across 32 hospital referral regions in 12 states. MAIN OUTCOMES AND MEASURES Rates of coronary angiography, PCI, and CABG surgery. RESULTS We evaluated a total of 878 339 Medicare Advantage patients and 5 013 650 Medicare FFS patients. Compared with Medicare FFS patients, Medicare Advantage patients had lower age-, sex-, race-, and income-adjusted procedure rates per 1000 person-years for angiography (16.5 [95% CI, 14.8-18.2] vs 25.9 [95% CI, 24.0-27.9]; P < .001) and PCI (6.8 [95% CI, 6.0-7.6] vs 9.8 [95% CI, 9.0-10.6]; P < .001) but similar rates for CABG surgery (3.1 [95% CI, 2.8-3.5] vs 3.4 [95% CI, 3.1-3.7]; P = .33). There were no significant differences between Medicare Advantage and Medicare FFS patients in the rates per 1000 person-years of urgent angiography (3.9 [95% CI, 3.6-4.2] vs 4.3 [95% CI, 4.0-4.6]; P = .24) or PCI (2.4 [95% CI, 2.2-2.7] vs 2.7 [95% CI, 2.5-2.9]; P = .16). Procedure rates varied widely across hospital referral regions among Medicare Advantage and Medicare FFS patients. For angiography, the rates per 1000 person-years ranged from 9.8 to 40.6 for Medicare Advantage beneficiaries and from 15.7 to 44.3 for Medicare FFS beneficiaries. For PCI, the rates ranged from 3.5 to 16.8 for Medicare Advantage and from 4.7 to 16.1 for Medicare FFS. The rates for CABG surgery ranged from 1.5 to 6.1 for Medicare Advantage and from 2.5 to 6.0 for Medicare FFS. Across regions, we found no statistically significant correlation between Medicare Advantage and Medicare FFS beneficiary utilization for angiography (Spearman r = 0.19, P = .29) and modest correlations for PCI (Spearman r = 0.33, P = .06) and CABG surgery (Spearman r = 0.35, P = .05). Among Medicare Advantage beneficiaries, adjustment for additional cardiac risk factors had little influence on procedure rates. CONCLUSIONS AND RELEVANCE Although Medicare beneficiaries enrolled in capitated Medicare Advantage programs had lower angiography and PCI procedure rates than those enrolled in Medicare FFS, the degree of geographic variation in procedure rates was substantial among Medicare Advantage beneficiaries and was similar in magnitude to that observed among Medicare FFS beneficiaries. C1 [Matlock, Daniel D.] Univ Colorado, Sch Med, Aurora, CO USA. [Matlock, Daniel D.; Shetterly, Susan; Xu, Stan; Magid, David J.] Colorado Cardiovasc Outcomes Res Grp, Denver, CO USA. [Matlock, Daniel D.; Shetterly, Susan; Goodrich, Glenn; Glenn, Karen; Xu, Stan; Magid, David J.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Groeneveld, Peter W.; Yang, Lin] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Groeneveld, Peter W.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Sidney, Steve; Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Farmer, Steven A.] Northwestern Univ, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Farmer, Steven A.] Northwestern Univ, Kellogg Sch Management, Chicago, IL 60611 USA. [Reynolds, Kristi] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA 91101 USA. [Cassidy-Bushrow, Andrea E.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Lieu, Tracy] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Lieu, Tracy] Harvard Univ, Sch Med, Boston, MA USA. [Boudreau, Denise M.] Grp Hlth Res Inst, Seattle, WA USA. [Greenlee, Robert T.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Tom, Jeffrey] Kaiser Permanente Ctr Hlth Res, Honolulu, HI USA. [Vupputuri, Suma] Kaiser Permanente Ctr Hlth Res Southeast, Atlanta, GA USA. [Adams, Kenneth F.] HealthPartners Res Fdn, Minneapolis, MN USA. [Smith, David H.] Kaiser Permanente Northwest Ctr Hlth Res, Portland, OR USA. [Gunter, Margaret J.] Lovelace Clin Fdn, Albuquerque, NM USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Go, Alan S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. RP Matlock, DD (reprint author), Univ Colorado Denver, Sch Med, Div Gen Internal Med, Acad Off 1, 12631 E 17th Ave,Campus Box B-180, Aurora, CO 80045 USA. EM daniel.matlock@ucdenver.edu OI Cassidy-Bushrow, Andrea/0000-0001-8272-4448 FU National Institute on Aging [1K23AG040696]; National Heart, Lung, and Blood Institute; Cardiovascular Research Network [U19 HL91179-01, 1RC2HL101666-01, 1R01HL086919]; Agency for Healthcare Research and Quality [1R01HS018403] FX Dr Matlock was supported by a career development award from the National Institute on Aging (1K23AG040696). The study was supported by the National Heart, Lung, and Blood Institute and the Cardiovascular Research Network (U19 HL91179-01, 1RC2HL101666-01, and 1R01HL086919). Medicare data for the project were obtained under Agency for Healthcare Research and Quality grant 1R01HS018403. NR 30 TC 23 Z9 23 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 10 PY 2013 VL 310 IS 2 BP 155 EP 162 DI 10.1001/jama.2013.7837 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 179HU UT WOS:000321511500014 PM 23839749 ER PT J AU Heilig, EA Gutti, U Tai, T Shen, J Kelleher, RJ AF Heilig, Elizabeth A. Gutti, Usha Tai, Tara Shen, Jie Kelleher, Raymond J., III TI Trans-Dominant Negative Effects of Pathogenic PSEN1 Mutations on gamma-Secretase Activity and A beta Production SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; PRESENILIN-1 PROTECTS; ASPARTYL PROTEASE; TRANSGENIC MICE; NEURONAL LOSS; NICASTRIN; COMPLEX; MUTANT; EXPRESSION AB Mutations in the PSEN1 gene encoding Presenilin-1 (PS1) are the predominant cause of familial Alzheimer's disease (FAD), but the underlying mechanisms remain unresolved. To reconcile the dominant action of pathogenic PSEN1 mutations with evidence that they confer a loss of mutant protein function, we tested the hypothesis that PSEN1 mutations interfere with gamma-secretase activity in a dominant-negative manner. Here, we show that pathogenic PSEN1 mutations act in cis to impair mutant PS1 function and act in trans to inhibit wild-type PS1 function. Coexpression of mutant and wild-type PS1 at equal gene dosage in presenilin-deficient mouse embryo fibroblasts resulted in trans-dominant-negative inhibition of wild-type PS1 activity, suppressing gamma-secretase-dependent cleavage of APP and Notch. Surprisingly, mutant PS1 could stimulate production of A beta 42 by wild-type PS1 while decreasing its production of A beta 40. Mutant and wild-type PS1 efficiently coimmunoprecipitated, suggesting that mutant PS1 interferes with wild-type PS1 activity via physical interaction. These results support the conclusion that mutant PS1 causes wild-type PS1 to adopt an altered conformation with impaired catalytic activity and substrate specificity. Our findings reveal a novel mechanism of action for pathogenic PSEN1 mutations and suggest that dominant-negative inhibition of presenilin activity plays an important role in FAD pathogenesis. C1 [Heilig, Elizabeth A.; Gutti, Usha; Tai, Tara; Kelleher, Raymond J., III] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Heilig, Elizabeth A.; Gutti, Usha; Tai, Tara; Kelleher, Raymond J., III] Harvard Univ, Sch Med, MGH Simches Res Ctr, Boston, MA 02114 USA. [Shen, Jie] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Shen, Jie] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Shen, Jie; Kelleher, Raymond J., III] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Shen, Jie; Kelleher, Raymond J., III] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Kelleher, RJ (reprint author), MGH Simches Res Ctr, CPZN 6234,185 Cambridge St, Boston, MA 02114 USA. EM kelleher@helix.mgh.harvard.edu OI Gutti, Usha/0000-0003-0927-0923 FU National Institute of Neurological Disorders and Stroke [R01NS041783, R01NS075346]; Alzheimer's Association; National Institutes of Health [T32 AG000222-18]; Pew Scholar award; John Merck Scholar award FX This work was supported by the National Institute of Neurological Disorders and Stroke Grant R01NS041783 to J.S., National Institute of Neurological Disorders and Stroke Grant R01NS075346 to R.J.K., and the Alzheimer's Association (to J.S. and R.J.K.). E. A. H. was supported by National Institutes of Health Training Grant T32 AG000222-18. R.J.K. was supported by Pew Scholar and John Merck Scholar awards. We thank Dr. Alison Goate for the APP C99 construct, Dr. Raphael Kopan for the Notch Delta E construct, and members of the J.S. and R.J.K. laboratories for helpful discussions. NR 39 TC 20 Z9 20 U1 1 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 10 PY 2013 VL 33 IS 28 BP 11606 EP 11617 DI 10.1523/JNEUROSCI.0954-13.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 180TX UT WOS:000321622600025 PM 23843529 ER PT J AU Hanlon, CA Canterberry, M Taylor, JJ DeVries, W Li, XB Brown, TR George, MS AF Hanlon, Colleen A. Canterberry, Melanie Taylor, Joseph J. DeVries, William Li, Xingbao Brown, Truman R. George, Mark S. TI Probing the Frontostriatal Loops Involved in Executive and Limbic Processing via Interleaved TMS and Functional MRI at Two Prefrontal Locations: A Pilot Study SO PLOS ONE LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; RHESUS-MONKEY; MOTOR CORTEX; BOLD-FMRI; MEMORY FORMATION; WORKING-MEMORY; BASAL GANGLIA; REWARD SYSTEM; ACTIVATION; ORGANIZATION AB Background: The prefrontal cortex (PFC) is an anatomically and functionally heterogeneous area which influences cognitive and limbic processing through connectivity to subcortical targets. As proposed by Alexander et al. (1986) the lateral and medial aspects of the PFC project to distinct areas of the striatum in parallel but functionally distinct circuits. The purpose of this preliminary study was to determine if we could differentially and consistently activate these lateral and medial cortical-subcortical circuits involved in executive and limbic processing though interleaved transcranial magnetic stimulation (TMS) in the MR environment. Methods: Seventeen healthy individuals received interleaved TMS-BOLD imaging with the coil positioned over the dorsolateral (EEG: F3) and ventromedial PFC (EEG: FP1). BOLD signal change was calculated in the areas directly stimulated by the coil and in subcortical regions with afferent and efferent connectivity to the TMS target areas. Additionally, five individuals were tested on two occasions to determine test-retest reliability. Results: Region of interest analysis revealed that TMS at both prefrontal sites led to significant BOLD signal increases in the cortex under the coil, in the striatum, and the thalamus, but not in the visual cortex (negative control region). There was a significantly larger BOLD signal change in the caudate following medial PFC TMS, relative to lateral TMS. The hippocampus in contrast was significantly more activated by lateral TMS. Post-hoc voxel-based analysis revealed that within the caudate the location of peak activity was in the ventral caudate following medial TMS and the dorsal caudate following lateral TMS. Test-retest reliability data revealed consistent BOLD responses to TMS within each individual but a large variation between individuals. Conclusion: These data demonstrate that, through an optimized TMS/BOLD sequence over two unique prefrontal targets, it is possible to selectively interrogate the patency of these established cortical-subcortical networks in healthy individuals, and potentially patient populations. C1 [Hanlon, Colleen A.; Canterberry, Melanie; Taylor, Joseph J.; DeVries, William; Li, Xingbao; George, Mark S.] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Hanlon, Colleen A.; Brown, Truman R.; George, Mark S.] Med Univ S Carolina, Ctr Biomed Imaging, Charleston, SC 29425 USA. [Brown, Truman R.] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. [George, Mark S.] Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Hanlon, CA (reprint author), Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. EM hanlon@musc.edu FU National Institutes of Health [K01DA027756, 1F30DA033748-01, T32DA007288] FX This work was supported by the National Institutes of Health (grant numbers, K01DA027756 (CAH), 1F30DA033748-01 (JJT), T32DA007288). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 10 Z9 10 U1 2 U2 16 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 JUL 9 PY 2013 VL 8 IS 7 AR e67917 DI 10.1371/journal.pone.0067917 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JD UT WOS:000321736900036 PM 23874466 ER PT J AU Hwang, WY Fu, YF Reyon, D Maeder, ML Kaini, P Sander, JD Joung, JK Peterson, RT Yeh, JRJ AF Hwang, Woong Y. Fu, Yanfang Reyon, Deepak Maeder, Morgan L. Kaini, Prakriti Sander, Jeffry D. Joung, J. Keith Peterson, Randall T. Yeh, Jing-Ruey Joanna TI Heritable and Precise Zebrafish Genome Editing Using a CRISPR-Cas System SO PLOS ONE LA English DT Article ID ZINC-FINGER NUCLEASES; TARGETED GENE DISRUPTION; TALENS; ENDONUCLEASE; MUTAGENESIS; BACTERIA; ARCHAEA; CELLS AB We have previously reported a simple and customizable CRISPR (clustered regularly interspaced short palindromic repeats) RNA-guided Cas9 nuclease (RGN) system that can be used to efficiently and robustly introduce somatic indel mutations in endogenous zebrafish genes. Here we demonstrate that RGN-induced mutations are heritable, with efficiencies of germline transmission reaching as high as 100%. In addition, we extend the power of the RGN system by showing that these nucleases can be used with single-stranded oligodeoxynucleotides (ssODNs) to create precise intended sequence modifications, including single nucleotide substitutions. Finally, we describe and validate simple strategies that improve the targeting range of RGNs from 1 in every 128 basepairs (bps) of random DNA sequence to 1 in every 8 bps. Together, these advances expand the utility of the CRISPR-Cas system in the zebrafish beyond somatic indel formation to heritable and precise genome modifications. C1 [Hwang, Woong Y.; Kaini, Prakriti; Peterson, Randall T.; Yeh, Jing-Ruey Joanna] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Hwang, Woong Y.; Kaini, Prakriti; Peterson, Randall T.; Yeh, Jing-Ruey Joanna] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Fu, Yanfang; Reyon, Deepak; Maeder, Morgan L.; Sander, Jeffry D.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Mol Pathol Unit, Charlestown, MA USA. [Fu, Yanfang; Reyon, Deepak; Maeder, Morgan L.; Sander, Jeffry D.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA. [Fu, Yanfang; Reyon, Deepak; Sander, Jeffry D.; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Peterson, Randall T.] Broad Inst, Cambridge, MA USA. RP Peterson, RT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM peterson@cvrc.mgh.harvard.edu; jyeh1@partners.org FU National Institutes of Health [R01 GM088040]; NIH Director's Pioneer Award [DP1 OD006862, K01 AG031300, R01 CA140188]; Defense Advanced Research Projects Agency (DARPA) [W911NF-11-2-0056]; Jim and Ann Orr MGH Research Scholar award; Charles and Ann Sanders MGH Research Scholar award; MGH Claflin Distinguished Scholar Award FX This work was supported by National Institutes of Health [R01 GM088040 to JKJ and RTP, NIH Director's Pioneer Award DP1 OD006862 to JKJ, K01 AG031300 to JRJY, R01 CA140188 to JRJY]; Defense Advanced Research Projects Agency (DARPA) [W911NF-11-2-0056 to JKJ]; the Jim and Ann Orr MGH Research Scholar award (JKJ); the Charles and Ann Sanders MGH Research Scholar award (RTP); and the MGH Claflin Distinguished Scholar Award (JRJY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 126 Z9 131 U1 9 U2 95 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 JUL 9 PY 2013 VL 8 IS 7 AR e68708 DI 10.1371/journal.pone.0068708 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182JD UT WOS:000321736900106 PM 23874735 ER PT J AU Bekelman, DB Plomondon, ME Sullivan, MD Nelson, K Hattler, B McBryde, C Lehmann, KG Potfay, J Heidenreich, P Rumsfeld, JS AF Bekelman, David B. Plomondon, Mary E. Sullivan, Mark D. Nelson, Karin Hattler, Brack McBryde, Connor Lehmann, Kenneth G. Potfay, Jonathan Heidenreich, Paul Rumsfeld, John S. TI Patient-centered disease management (PCDM) for heart failure: study protocol for a randomised controlled trial SO BMC CARDIOVASCULAR DISORDERS LA English DT Article DE Heart failure; Clinical trial; Patient reported outcomes; Quality of life; Health status ID HEALTH-STATUS; RESOURCE UTILIZATION; CARE MANAGEMENT; HOSPITALIZATION; DEPRESSION; POPULATION; OUTCOMES; TRENDS; DEATH; RISK AB Background: Chronic heart failure (HF) disease management programs have reported inconsistent results and have not included comorbid depression management or specifically focused on improving patient-reported outcomes. The Patient Centered Disease Management (PCDM) trial was designed to test the effectiveness of collaborative care disease management in improving health status (symptoms, functioning, and quality of life) in patients with HF who reported poor HF-specific health status. Methods/design: Patients with a HF diagnosis at four VA Medical Centers were identified through population-based sampling. Patients with a Kansas City Cardiomyopathy Questionnaire (KCCQ, a measure of HF-specific health status) score of < 60 (heavy symptom burden and impaired quality of life) were invited to enroll in the PCDM trial. Enrolled patients were randomized to receive usual care or the PCDM intervention, which included: (1) collaborative care management by VA clinicians including a nurse, cardiologist, internist, and psychiatrist, who worked with patients and their primary care providers to provide guideline-concordant care management, (2) home telemonitoring and guided patient self-management support, and (3) screening and treatment for comorbid depression. The primary study outcome is change in overall KCCQ score. Secondary outcomes include depression, medication adherence, guideline-based care, hospitalizations, and mortality. Discussion: The PCDM trial builds on previous studies of HF disease management by prioritizing patient health status, implementing a collaborative care model of health care delivery, and addressing depression, a key barrier to optimal disease management. The study has been designed as an 'effectiveness trial' to support broader implementation in the healthcare system if it is successful. C1 [Bekelman, David B.; McBryde, Connor] Eastern Colorado Hlth Care Syst, Dept Vet Affairs, Denver, CO 80220 USA. [Bekelman, David B.; Hattler, Brack; McBryde, Connor; Rumsfeld, John S.] Univ Colorado, Sch Med, Dept Med, Aurora, CO USA. [Plomondon, Mary E.; Hattler, Brack; Rumsfeld, John S.] Eastern Colorado Hlth Care Syst Cardiol 111B, Dept Vet Affairs, Denver, CO 80220 USA. [Sullivan, Mark D.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Nelson, Karin; Lehmann, Kenneth G.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Nelson, Karin; McBryde, Connor] Northwest HSR&D Ctr Excellence, Seattle, WA USA. [Nelson, Karin] Univ Washington, Dept Med, Seattle, WA USA. [Potfay, Jonathan] Richmond VA Med Ctr, Richmond, VA 23249 USA. [Heidenreich, Paul] VA Palo Alto Hlth Care Syst Cardiol 111C, Palo Alto, CA 94304 USA. RP Bekelman, DB (reprint author), Eastern Colorado Hlth Care Syst, Dept Vet Affairs, Res 151,1055 Clermont St, Denver, CO 80220 USA. EM david.bekelman@va.gov OI Heidenreich, Paul/0000-0001-7730-8490 FU Department of Veterans Affairs HSRD [IIR 06-068]; Department of Veterans Affairs [HSRD CDA 08-022] FX The PCDM trial is funded by the Department of Veterans Affairs HSR&D grant IIR 06-068. Dr. Bekelman is funded by the Department of Veterans Affairs (HSR&D CDA 08-022). After approval of funding, the funding organizations did not participate in the study design or manuscript preparation. We thank our nurse coordinators, Darcy Donaldson, Laura Gaskin, Julie LaGuire, Susan Walker, and Barbara Watson for the care they provided. The views in this article are those of the authors and do not necessarily reflect the views of the Department of Veterans Affairs. NR 27 TC 4 Z9 4 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2261 J9 BMC CARDIOVASC DISOR JI BMC Cardiovasc. Disord. PD JUL 9 PY 2013 VL 13 AR 49 DI 10.1186/1471-2261-13-49 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 186IU UT WOS:000322037600001 PM 23837415 ER PT J AU Bowman, SK Simon, MD Deaton, AM Tolstorukov, M Borowsky, ML Kingston, RE AF Bowman, Sarah K. Simon, Matthew D. Deaton, Aimee M. Tolstorukov, Michael Borowsky, Mark L. Kingston, Robert E. TI Multiplexed Illumina sequencing libraries from picogram quantities of DNA SO BMC GENOMICS LA English DT Article DE Illumina; ChIP-seq; Multiplex; Barcoding; Library preparation ID CHIP-SEQ; GENOME; AMPLIFICATION AB Background: High throughput sequencing is frequently used to discover the location of regulatory interactions on chromatin. However, techniques that enrich DNA where regulatory activity takes place, such as chromatin immunoprecipitation (ChIP), often yield less DNA than optimal for sequencing library preparation. Existing protocols for picogram-scale libraries require concomitant fragmentation of DNA, pre-amplification, or long overnight steps. Results: We report a simple and fast library construction method that produces libraries from sub-nanogram quantities of DNA. This protocol yields conventional libraries with barcodes suitable for multiplexed sample analysis on the Illumina platform. We demonstrate the utility of this method by constructing a ChIP-seq library from 100 pg of ChIP DNA that demonstrates equivalent genomic coverage of target regions to a library produced from a larger scale experiment. Conclusions: Application of this method allows whole genome studies from samples where material or yields are limiting. C1 [Bowman, Sarah K.; Simon, Matthew D.; Deaton, Aimee M.; Borowsky, Mark L.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Bowman, Sarah K.; Simon, Matthew D.; Deaton, Aimee M.; Borowsky, Mark L.; Kingston, Robert E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Tolstorukov, Michael] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Tolstorukov, Michael] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. RP Bowman, SK (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM bowman@molbio.mgh.harvard.edu FU Damon Runyon Cancer Research Foundation [DRG-1995-08]; Helen Hay Whitney Foundation FX The authors would like to acknowledge Welcome Bender for supplying the Drosophila strains used in the ChIP, Kaleena Shirley for assistance with oligo design, and the MGH NextGen Sequencing Core as well as Kingston lab members for helpful discussions. SKB was a Damon Runyon Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-1995-08) and MDS was supported by a Helen Hay Whitney Foundation Postdoctoral Fellowship. NR 16 TC 28 Z9 30 U1 5 U2 36 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 9 PY 2013 VL 14 AR 466 DI 10.1186/1471-2164-14-466 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 182XN UT WOS:000321778200001 PM 23837789 ER PT J AU Maisel, A Mueller, C Neath, SX Christenson, RH Morgenthaler, NG McCord, J Nowak, RM Vilke, G Daniels, LB Hollander, JE Apple, FS Cannon, C Nagurney, JT Schreiber, D deFilippi, C Hogan, C Diercks, DB Stein, JC Headden, G Limkakeng, AT Anand, I Wu, AHB Papassotiriou, J Hartmann, O Ebmeyer, S Clopton, P Jaffe, AS Peacock, WF AF Maisel, Alan Mueller, Christian Neath, Sean-Xavier Christenson, Robert H. Morgenthaler, Nils G. McCord, James Nowak, Richard M. Vilke, Gary Daniels, Lori B. Hollander, Judd E. Apple, Fred S. Cannon, Chad Nagurney, John T. Schreiber, Donald deFilippi, Christopher Hogan, Christopher Diercks, Deborah B. Stein, John C. Headden, Gary Limkakeng, Alexander T., Jr. Anand, Inder Wu, Alan H. B. Papassotiriou, Jana Hartmann, Oliver Ebmeyer, Stefan Clopton, Paul Jaffe, Allan S. Peacock, W. Frank TI Copeptin Helps in the Early Detection of Patients With Acute Myocardial Infarction Primary Results of the CHOPIN Trial (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE copeptin; emergency department; myocardial infarction; quality improvement; troponin ID TERMINAL PROVASOPRESSIN COPEPTIN; HIGH-SENSITIVITY TROPONIN; CHRONIC HEART-FAILURE; EMERGENCY-DEPARTMENT; PROGNOSTIC MARKER; CARDIAC TROPONIN; RAPID RULE; VASOPRESSIN; PEPTIDE; RISK AB Objectives The goal of this study was to demonstrate that copeptin levels <14 pmol/L allow ruling out acute myocardial infarction (AMI) when used in combination with cardiac troponin I (cTnI) <99th percentile and a nondiagnostic electrocardiogram at the time of presentation to the emergency department (ED). Background Copeptin is secreted from the pituitary early in the course of AMI. Methods This was a 16-site study in 1,967 patients with chest pain presenting to an ED within 6 hours of pain onset. Baseline demographic characteristics and clinical data were collected prospectively. Copeptin levels and a contemporary sensitive cTnI (99th percentile 40 ng/l; 10% coefficient of variation 0.03 mu g/l) were measured in a core laboratory. Patients were followed up for 180 days. The primary outcome was diagnosis of AMI. Final diagnoses were adjudicated by 2 independent cardiologists blinded to copeptin results. Results AMI was the final diagnosis in 156 patients (7.9%). A negative copeptin and cTnI at baseline ruled out AMI for 58% of patients, with a negative predictive value of 99.2% (95% confidence interval: 98.5 to 99.6). AMIs not detected by the initial cTnI alone were picked up with copeptin >14 pmol/l in 23 (72%) of 32 patients. Non-ST-segment elevation myocardial infarctions undetected by cTnI at 0 h were detected with copeptin >14 pmol/l in 10 (53%) of 19 patients. Projected average time-to-decision could be reduced by 43% (from 3.0 h to 1.8 h) by the early rule out of 58% of patients. Both abnormal copeptin and cTnI were predictors of death at 180 days (p < 0.0001 for both; c index 0.784 and 0.800, respectively). Both were independent of age and each other and provided additional predictive value (all p < 0.0001). Conclusions Adding copeptin to cTnI allowed safe rule out of AMI with a negative predictive value >99% in patients presenting with suspected acute coronary syndromes. This combination has the potential to rule out AMI in 58% of patients without serial blood draws. (Investigation of the Biomarker Copeptin in Patients With Acute Myocardial Infarction [NCT00952744]) (C) 2013 by the American College of Cardiology Foundation C1 [Maisel, Alan; Clopton, Paul] VA San Diego Healthcare Syst, San Diego, CA USA. [Maisel, Alan; Neath, Sean-Xavier; Vilke, Gary; Daniels, Lori B.] Univ Calif San Diego, San Diego, CA 92103 USA. [Mueller, Christian] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Christenson, Robert H.; deFilippi, Christopher] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Morgenthaler, Nils G.] Campus Virchow Klinikum, Charite, Berlin, Germany. [McCord, James; Nowak, Richard M.] Henry Ford Hlth Syst, Detroit, MI USA. [Hollander, Judd E.] Univ Penn, Philadelphia, PA 19104 USA. [Apple, Fred S.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Cannon, Chad] Univ Kansas Hosp, Kansas City, KS USA. [Nagurney, John T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schreiber, Donald] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Hogan, Christopher] Virginia Commonwealth Univ, Richmond, VA USA. [Diercks, Deborah B.] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Stein, John C.; Wu, Alan H. B.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Headden, Gary] Med Univ S Carolina, Charleston, SC 29425 USA. [Limkakeng, Alexander T., Jr.] Duke Univ, Med Ctr, Durham, NC USA. [Anand, Inder] VA Minneapolis, Minneapolis, MN USA. [Papassotiriou, Jana; Hartmann, Oliver; Ebmeyer, Stefan] Thermo Fisher Sci BRAHMS GmbH, Thermo Sci Biomarkers, Hennigsdorf, Germany. [Jaffe, Allan S.] Mayo Clin, Rochester, MN USA. [Peacock, W. Frank] Baylor Coll Med, Houston, TX 77030 USA. RP Maisel, A (reprint author), San Diego VA Healthcare, Cardiol, 3350 La Jolla Village Dr, San Diego, CA 92161 USA. EM amaisel@ucsd.edu OI Limkakeng, Alexander T./0000-0002-9822-5595; Hollander, Judd/0000-0002-1318-2785 FU Thermo Fisher Scientific FX The investigators thank BRAHMS AG (now part of Thermo Fisher Scientific) for its generous and unrestricted support of this trial. We are grateful for the work done by CLINDEVOR TriMed, Inc., for the organization, management, and monitoring of this multinational trial. NR 25 TC 61 Z9 68 U1 0 U2 16 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 JUL 9 PY 2013 VL 62 IS 2 BP 150 EP 160 DI 10.1016/j.jacc.2013.04.011 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 176WY UT WOS:000321338600012 PM 23643595 ER PT J AU Lee, KY Yamamoto, Y Boucher, J Winnay, JN Gesta, S Cobb, J Bluher, M Kahn, CR AF Lee, Kevin Y. Yamamoto, Yuji Boucher, Jeremie Winnay, Jonathon N. Gesta, Stephane Cobb, John Blueher, Matthias Kahn, C. Ronald TI Shox2 is a molecular determinant of depot-specific adipocyte function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE developmental genes; adipose depots; lipid metabolism ID BETA(3)-ADRENERGIC RECEPTOR GENE; BODY-FAT DISTRIBUTION; MOUSE ADIPOSE-TISSUE; SHORT-STATURE; DIABETES-MELLITUS; TURNER-SYNDROME; OBESITY; ALPHA; RISK; TRANSPLANTATION AB Visceral and s.c. fat exhibit different intrinsic properties, including rates of lipolysis, and are associated with differential risk for the development of type 2 diabetes. These effects are in part related to cell autonomous differences in gene expression. In the present study, we show that expression of Shox2 (Short stature homeobox 2) is higher in s.c. than visceral fat in both rodents and humans and that levels are further increased in humans with visceral obesity. Fat-specific disruption of Shox2 in male mice results in protection from high fat diet-induced obesity, with a preferential loss of s.c. fat. The reduced adipocyte size is secondary to a twofold increase in the expression of beta 3 adrenergic receptor (Adrb3) at both the mRNA and protein level and a parallel increase in lipolytic rate. These effects are mimicked by knockdown of Shox2 in C3H10T1/2 cells. Conversely, overexpression of Shox2 leads to a repression of Adrb3 expression and decrease lipolytic rate. Shox2 does not affect differentiation but directly interacts with CCAAT/enhancer binding protein alpha and attenuates its transcriptional activity of the Adrb3 promoter. Thus, Shox2 can regulate the expression of Adrb3 and control the rate of lipolysis and, in this way, exerts control of the phenotypic differences between visceral and s.c. adipocytes. C1 [Lee, Kevin Y.; Yamamoto, Yuji; Boucher, Jeremie; Winnay, Jonathon N.; Gesta, Stephane; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Cobb, John] Univ Calgary, Dept Biol Sci, Calgary, AB T2N 1N4, Canada. [Blueher, Matthias] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU Joslin Training Grant [T32DK007260]; National Institutes of Health [DK 60837, DK 82655]; American Diabetes Association mentor-based award; Mary K. Iacocca Professorship FX We thank Dr. Denis Duboule (University of Geneva) for the Shox2 floxed mice and Dr. Sheila Collins (Sanford-Burnham Medical Research Institute) for the Adrb3-luciferase constructs. We are grateful to A. Clermont, M. Poillucci [Diabetes Research Center (DRC) Physiology Core], and H. Li (DRC Specialized Assay Core). This work was supported by Joslin Training Grant T32DK007260, National Institutes of Health Grants DK 60837 and DK 82655, an American Diabetes Association mentor-based award, and the Mary K. Iacocca Professorship (to C.R.K.). NR 29 TC 17 Z9 18 U1 0 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 9 PY 2013 VL 110 IS 28 BP 11409 EP 11414 DI 10.1073/pnas.1310331110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 183OT UT WOS:000321827000054 PM 23798383 ER PT J AU Stanley, SA Kawate, T Iwase, N Shimizu, M Clatworthy, AE Kazyanskaya, E Sacchettini, JC Ioerger, TR Siddiqi, NA Minami, S Aquadro, JA Grant, SS Rubin, EJ Hung, DT AF Stanley, Sarah A. Kawate, Tomohiko Iwase, Noriaki Shimizu, Motohisa Clatworthy, Anne E. Kazyanskaya, Edward Sacchettini, James C. Ioerger, Thomas R. Siddiqi, Noman A. Minami, Shoko Aquadro, John A. Grant, Sarah Schmidt Rubin, Eric J. Hung, Deborah T. TI Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INHA; ACTIVATION; INSIGHTS; GROWTH; DRUGS; IDENTIFICATION; ZEBRAFISH; COUMARINS; INFECTION; DISCOVERY AB Infection with the bacterial pathogen Mycobacterium tuberculosis imposes an enormous burden on global public health. New antibiotics are urgently needed to combat the global tuberculosis pandemic; however, the development of new small molecules is hindered by a lack of validated drug targets. Here, we describe the identification of a 4,6-diaryl-5,7-dimethyl coumarin series that kills M. tuberculosis by inhibiting fatty acid degradation protein D32 (FadD32), an enzyme that is required for biosynthesis of cell-wall mycolic acids. These substituted coumarin inhibitors directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32. They effectively block bacterial replication both in vitro and in animal models of tuberculosis, validating FadD32 as a target for antibiotic development that works in the same pathway as the established antibiotic isoniazid. Targeting new steps in well-validated biosynthetic pathways in antitubercular therapy is a powerful strategy that removes much of the usual uncertainty surrounding new targets and in vivo clinical efficacy, while circumventing existing resistance to established targets. C1 [Stanley, Sarah A.; Kawate, Tomohiko; Iwase, Noriaki; Shimizu, Motohisa; Clatworthy, Anne E.; Kazyanskaya, Edward; Sacchettini, James C.; Aquadro, John A.; Grant, Sarah Schmidt; Hung, Deborah T.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Stanley, Sarah A.; Kawate, Tomohiko; Iwase, Noriaki; Shimizu, Motohisa; Clatworthy, Anne E.; Kazyanskaya, Edward; Aquadro, John A.; Grant, Sarah Schmidt; Hung, Deborah T.] MIT, Cambridge, MA 02142 USA. [Stanley, Sarah A.; Kawate, Tomohiko; Iwase, Noriaki; Shimizu, Motohisa; Clatworthy, Anne E.; Kazyanskaya, Edward; Aquadro, John A.; Grant, Sarah Schmidt; Hung, Deborah T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Stanley, Sarah A.; Kawate, Tomohiko; Iwase, Noriaki; Shimizu, Motohisa; Clatworthy, Anne E.; Grant, Sarah Schmidt; Hung, Deborah T.] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Sacchettini, James C.] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. [Sacchettini, James C.] Texas A&M Univ, Dept Comp Sci, College Stn, TX 77843 USA. [Siddiqi, Noman A.; Minami, Shoko; Rubin, Eric J.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Hung, DT (reprint author), Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. EM hung@molbio.mgh.harvard.edu OI Rubin, Eric/0000-0001-5120-962X FU Bill and Melinda Gates Foundation; Novartis; Helen Hay Whitney Foundation FX We thank L. Verplank, N. Tolliday, and J. Bittker for HTS data management and advice on assay development; J. Gomez, S. Grant, and A. Stern for helpful discussion; M. Ericsson for electron microscopy; A. Slotsky for the gift of clinical isolates of M. tuberculosis; D. Savage for assistance with protein purification; New England Regional Center of Excellence Microbiology and Animal Resources Core (AI057159) for initial toxicity testing; S. Johnston for compound physicochemical property measurements; C. Mosher for measurement of exact mass of compounds; and S.L. Zheng (Harvard University) for assistance with X-ray data collection and structure determination. S.A.S. gratefully acknowledges Novartis and the Helen Hay Whitney Foundation for funding. This work was supported through funding from the Bill and Melinda Gates Foundation (to D.T.H., E.J.R., and J.C.S.). NR 42 TC 27 Z9 27 U1 2 U2 18 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 JUL 9 PY 2013 VL 110 IS 28 BP 11565 EP 11570 DI 10.1073/pnas.1302114110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 183OT UT WOS:000321827000080 PM 23798446 ER PT J AU Bai, HJ Chen, T Ming, J Sun, H Cao, P Fusco, DN Chung, RT Chorev, M Jin, Q Aktas, BH AF Bai, Huijun Chen, Ting Ming, Jie Sun, Hong Cao, Peng Fusco, Dahlene N. Chung, Raymond T. Chorev, Michael Jin, Qi Aktas, Bertal H. TI Dual Activators of Protein Kinase R (PKR) and Protein Kinase R-Like Kinase (PERK) Identify Common and Divergent Catalytic Targets SO CHEMBIOCHEM LA English DT Article DE chemical genetics; eIF2; endoplasmic reticulum stress; kinases; NF-B ID NF-KAPPA-B; ENDOPLASMIC-RETICULUM KINASE; TRANSLATION INITIATION; CELL-PROLIFERATION; TUMOR SUPPRESSION; IN-VITRO; STRESS; INHIBITION; PHOSPHORYLATION; EIF2-ALPHA AB Chemical genetics has evolved into a powerful tool for studying gene function in normal and pathobiology. PKR and PERK, two eukaryotic translation initiation factor 2 alpha (eIF2) kinases, play critical roles in the maintenance of cellular hemostasis, metabolic stability, and anti-viral defenses. Both kinases interact with and phosphorylate additional substrates including tumor suppressor p53 and nuclear protein 90. Loss of function of both kinases has been studied by reverse genetics and with recently identified inhibitors. In contrast, no activating probes for studying the catalytic activity of these kinases are available. We identified 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dihydroxy-4H-chromen-4-one (DHBDC) as a specific dual activator of PKR and PERK by screening a chemical library of 20000 small molecules in a dual luciferase surrogate eIF2 phosphorylation assay. We present here extensive biological characterization and a preliminary structure-activity relationship of DHBDC, which phosphorylates eIF2 by activating PKR and PERK but no other eIF2 kinases. These agents also activate downstream effectors of eIF2 phosphorylation by inducing CEBP homologue protein, suppressing cyclin D1 expression, and inhibiting cancer cell proliferation, all in a manner dependent on PKR and PERK. Consistent with the role of eIF2 phosphorylation in viral infection, DHBDC inhibits the proliferation of human hepatitis C virus. Finally, DHBDC induces the phosphorylation of IB and activates the NF-B pathway. Surprisingly, activation of the NF-B pathway is dependent on PERK but independent of PKR activity. These data indicate that DHBDC is an invaluable probe for elucidating the role of PKR and PERK in normal and pathobiology. C1 [Bai, Huijun; Jin, Qi] Chinese Acad Med Sci, Inst Pathogen Biol, Beijing 100176, Peoples R China. [Bai, Huijun; Jin, Qi] Peking Union Med Coll, Beijing 100176, Peoples R China. [Bai, Huijun; Chen, Ting; Chorev, Michael; Aktas, Bertal H.] Brigham & Womens Hosp, Dept Med, Hematol Lab Translat Res, Boston, MA 02115 USA. [Bai, Huijun; Chen, Ting; Ming, Jie; Sun, Hong; Cao, Peng; Chorev, Michael; Aktas, Bertal H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sun, Hong] Hebei United Univ, Basic Med Coll, Tangshan 063000, Hebei, Peoples R China. [Fusco, Dahlene N.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Aktas, BH (reprint author), Brigham & Womens Hosp, Dept Med, Hematol Lab Translat Res, 75 Francis St, Boston, MA 02115 USA. EM huseyin_aktas@hms.harvard.edu FU NIH [R21AG032546, 1RO1A152312] FX This work was supported by NIH grants R21AG032546 and 1RO1A152312 to B. H. A. We thank Jose A. Halperin (Brigham and Women's Hospital/Harvard Medical School) for critical comments on the manuscript; and Caroline Shamu, Jennifer Smith, Steward Rudnicki, Sean M. Johnston, Doug Flood, Jennifer Nale and David Wrobel from ICCB-Longwood for technical assistance and advice. NR 49 TC 6 Z9 6 U1 1 U2 9 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1439-4227 EI 1439-7633 J9 CHEMBIOCHEM JI ChemBioChem PD JUL 8 PY 2013 VL 14 IS 10 BP 1255 EP 1262 DI 10.1002/cbic.201300177 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 237DX UT WOS:000325849600017 PM 23784735 ER PT J AU Smith, AK Lo, B Sudore, R AF Smith, Alexander K. Lo, Bernard Sudore, Rebecca TI When Previously Expressed Wishes Conflict With Best Interests SO JAMA INTERNAL MEDICINE LA English DT Article ID SURROGATE DECISION-MAKING; ADVANCE DIRECTIVES; LIFE; END; RECOMMENDATIONS; PREFERENCES; AUTONOMY; WANT AB Rising use of advance directives has made surrogate decision making both easier and harder. In many cases, these directives help guide decision making for patients who have lost decision-making capacity. In some cases, however, directives may conflict with what physicians or surrogates view as what is in the patient's best interest. These conflicts can place substantial emotional and moral burdens on physicians and surrogates, and there is little practical guidance for how to address them. We propose a 5-question framework for untangling the conflict between advance directives and best interests of a patient with a surrogate decision maker: (1) Is the clinical situation an emergency? (2) In view of the patient's values and goals, how likely is it that the benefits of the intervention will outweigh the burdens? (3) How well does the advance directive fit the situation at hand? (4) How much leeway did the patient provide the surrogate for overriding the advance directive? (5) How well does the surrogate represent the patient's best interests? We use 2 clinical cases with contrasting outcomes to demonstrate how this framework can help resolve common dilemmas. C1 [Smith, Alexander K.; Sudore, Rebecca] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94941 USA. [Lo, Bernard] Univ Calif San Francisco, Div Gen Internal Med, Dept Med, San Francisco, CA 94941 USA. [Smith, Alexander K.; Sudore, Rebecca] San Francisco VA Med Ctr, San Francisco, CA USA. [Lo, Bernard] Greenwall Fdn, New York, NY USA. RP Smith, AK (reprint author), Univ Calif San Francisco, 4150 Clement St 181G, San Francisco, CA 94941 USA. EM aksmith@ucsf.edu FU Greenwall Faculty Scholars in Bioethics award from Greenwall Foundation FX Dr Smith was supported by a Greenwall Faculty Scholars in Bioethics award from the Greenwall Foundation. NR 24 TC 9 Z9 9 U1 2 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL 8 PY 2013 VL 173 IS 13 BP 1241 EP 1245 DI 10.1001/jamainternmed.2013.6053 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 207LU UT WOS:000323602100018 PM 23712743 ER PT J AU Linos, E Wehner, MR Frosch, DL Walter, L Chren, MM AF Linos, Eleni Wehner, Mackenzie R. Frosch, Dominick L. Walter, Louise Chren, Mary Margaret TI Patient-Reported Problems After Office Procedures SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Linos, Eleni; Wehner, Mackenzie R.; Chren, Mary Margaret] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Frosch, Dominick L.] Gordon & Betty Moore Fdn, Patient Care Program, San Francisco, CA USA. [Walter, Louise] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA USA. [Walter, Louise] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Linos, E (reprint author), Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St,N421,Box 0808, San Francisco, CA 94143 USA. EM linose@derm.ucsf.edu RI Linos, Eleni/C-4392-2014; OI Linos, Eleni/0000-0002-5856-6301; , Eleni/0000-0003-2538-0700 FU NIA NIH HHS [K24 AG041180]; NIAMS NIH HHS [K24 AR052667] NR 4 TC 5 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL 8 PY 2013 VL 173 IS 13 BP 1249 EP 1250 DI 10.1001/jamainternmed.2013.1040 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 207LU UT WOS:000323602100020 PM 23689235 ER PT J AU Baggett, TP AF Baggett, Travis P. TI Overdose Fatality and Surveillance as a Method for Understanding Mortality Trends in Homeless Populations Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Baggett, Travis P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Baggett, Travis P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Baggett, Travis P.] Boston Hlth Care Homeless Program, Boston, MA USA. RP Baggett, TP (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM tbaggett@partners.org FU NIDA NIH HHS [K23DA034008] NR 4 TC 0 Z9 0 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL 8 PY 2013 VL 173 IS 13 BP 1265 EP 1266 DI 10.1001/jamainternmed.2013.7766 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 207LU UT WOS:000323602100030 PM 23836272 ER PT J AU Bojarski, EF Strauss, AC Fagin, AP Plantinga, TS Hoischen, A Veltman, J Allsop, SA Granadillo, VJA William, A Netea, MG Dimitrakoff, J AF Bojarski, Emeric F. Strauss, Adam C. Fagin, Adam P. Plantinga, Theo S. Hoischen, Alexander Veltman, Joris Allsop, Stephen A. Granadillo, Victor J. Anciano William, Arsani Netea, Mihai G. Dimitrakoff, Jordan TI Novel PI3K gamma Mutation in a 44-Year-Old Man with Chronic Infections and Chronic Pelvic Pain SO PLOS ONE LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE-GAMMA; CELL DEVELOPMENT; INFLAMMATION; PROSTATITIS; GAMMA; PI3K; TRANSFORMATION; PROLIFERATION; P110-GAMMA; ACTIVATION AB A 44-year-old man is presented here with 14 years of chronic purulent sinusitis, a chronic fungal rash of the scrotum, and chronic pelvic pain. Treatment with antifungal therapy resulted in symptom improvement, however he was unable to establish an effective long-term treatment regimen, resulting in debilitating symptoms. He had undergone extensive work-up without identifying a clear underlying etiology, although Candida species were cultured from the prostatic fluid. 100 genes involved in the cellular immune response were sequenced and a missense mutation was identified in the Ras-binding domain of PI3K gamma. PI3K gamma is a crucial signaling element in leukotaxis and other leukocyte functions. We hypothesize that his mutation led to his chronic infections and pelvic pain. C1 [Bojarski, Emeric F.; Strauss, Adam C.; Allsop, Stephen A.; Granadillo, Victor J. Anciano; William, Arsani; Dimitrakoff, Jordan] Harvard Univ, Sch Med, Boston, MA 02138 USA. [Dimitrakoff, Jordan] Harvard Univ, Sch Med, Dept Surg Urol, Boston, MA USA. [Dimitrakoff, Jordan] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Dimitrakoff, Jordan] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Fagin, Adam P.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Plantinga, Theo S.; Netea, Mihai G.] Radboud Univ Nijmegen, Nijmegen Med Ctr, Dept Med, NL-6525 ED Nijmegen, Netherlands. [Plantinga, Theo S.; Netea, Mihai G.] Radboud Univ Nijmegen, Nijmegen Med Ctr, Nijmegen Inst Infect Inflammat & Immun, NL-6525 ED Nijmegen, Netherlands. [Hoischen, Alexander; Veltman, Joris] Radboud Univ Nijmegen, Nijmegen Med Ctr, Dept Genet, NL-6525 ED Nijmegen, Netherlands. RP Dimitrakoff, J (reprint author), Harvard Univ, Sch Med, Boston, MA 02138 USA. EM jordan.dimitrakoff@gmail.com RI Plantinga, Theo/A-6895-2015; Veltman, Joris/F-5128-2010; Hoischen, Alexander/D-1282-2013; Netea, Mihai/N-5155-2014 OI Veltman, Joris/0000-0002-3218-8250; Hoischen, Alexander/0000-0002-8072-4476; FU Netherlands Organization for Scientific Research FX This work was supported by a Vici Grant of the Netherlands Organization for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2013 VL 8 IS 7 AR e68118 DI 10.1371/journal.pone.0068118 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 181TS UT WOS:000321692000016 PM 23861857 ER PT J AU Miller, PG Al-Shahrour, F Hartwell, KA Chu, LP Jaras, M Puram, RV Puissant, A Callahan, KP Ashton, J McConkey, ME Poveromo, LP Cowley, GS Kharas, MG Labelle, M Shterental, S Fujisaki, J Silberstein, L Alexe, G Al-Hajj, MA Shelton, CA Armstrong, SA Root, DE Scadden, DT Hynes, RO Mukherjee, S Stegmaier, K Jordan, CT Ebert, BL AF Miller, Peter G. Al-Shahrour, Fatima Hartwell, Kimberly A. Chu, Lisa P. Jaeras, Marcus Puram, Rishi V. Puissant, Alexandre Callahan, Kevin P. Ashton, John McConkey, Marie E. Poveromo, Luke P. Cowley, Glenn S. Kharas, Michael G. Labelle, Myriam Shterental, Sebastian Fujisaki, Joji Silberstein, Lev Alexe, Gabriela Al-Hajj, Muhammad A. Shelton, Christopher A. Armstrong, Scott A. Root, David E. Scadden, David T. Hynes, Richard O. Mukherjee, Siddhartha Stegmaier, Kimberly Jordan, Craig T. Ebert, Benjamin L. TI In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling SO CANCER CELL LA English DT Article ID HEMATOPOIETIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; GLANZMANN THROMBASTHENIA; EXPRESSION PROFILES; KINASE INHIBITOR; SYK; AML; MICE; PROGRESSION; PROGENITOR AB We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that lntegrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML. C1 [Miller, Peter G.; Al-Shahrour, Fatima; Chu, Lisa P.; Jaeras, Marcus; Puram, Rishi V.; McConkey, Marie E.; Poveromo, Luke P.; Shterental, Sebastian; Ebert, Benjamin L.] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Miller, Peter G.] Harvard Univ, Sch Med, Program Immunol, Boston, MA 02115 USA. [Puissant, Alexandre; Alexe, Gabriela; Stegmaier, Kimberly] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Puissant, Alexandre; Alexe, Gabriela; Stegmaier, Kimberly] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Al-Shahrour, Fatima; Hartwell, Kimberly A.; Cowley, Glenn S.; Root, David E.; Stegmaier, Kimberly; Ebert, Benjamin L.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Al-Shahrour, Fatima; Hartwell, Kimberly A.; Cowley, Glenn S.; Root, David E.; Stegmaier, Kimberly; Ebert, Benjamin L.] MIT, Cambridge, MA 02142 USA. [Callahan, Kevin P.; Ashton, John; Jordan, Craig T.] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. [Kharas, Michael G.] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA. [Kharas, Michael G.] Mem Sloan Kettering Canc Ctr, Ctr Cellular Engn, New York, NY 10065 USA. [Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Mem Hosp Res Labs, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Labelle, Myriam; Hynes, Richard O.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Labelle, Myriam; Hynes, Richard O.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Fujisaki, Joji; Silberstein, Lev; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Fujisaki, Joji; Silberstein, Lev; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Fujisaki, Joji] Massachusetts Gen Hosp, Ctr Syst Biol, Adv Microscopy Program, Boston, MA 02114 USA. [Fujisaki, Joji] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Silberstein, Lev; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Al-Hajj, Muhammad A.; Shelton, Christopher A.] GlaxoSmithKline R&D, Oncol Unit, Collegeville, PA 19426 USA. [Hynes, Richard O.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Mukherjee, Siddhartha] Columbia Univ, Sch Med, Dept Med, New York, NY 10032 USA. [Mukherjee, Siddhartha] Columbia Univ, Sch Med, Irving Canc Res Ctr, New York, NY 10032 USA. RP Ebert, BL (reprint author), Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. EM bebert@partners.org RI PUISSANT, ALEXANDRE/O-9575-2016; OI PUISSANT, ALEXANDRE/0000-0002-3997-9282; Jaras, Marcus/0000-0003-4080-7055 FU GlaxoSmithKline; Harvard Stem Cell Institute; NIH [P01 CA108631, RC1 CA145229, R01 CA140292, CA148180]; Leukemia and Lymphoma Society; Medical Scientist Training Program from the National Institute of General Medical Sciences [T32GM007753] FX The authors thank D. Gary Gilliland, Charles Lin, and Jon Aster for helpful scientific discussions. This work was supported by a collaboration between GlaxoSmithKline and the Harvard Stem Cell Institute and by grants from the NIH (P01 CA108631, RC1 CA145229, R01 CA140292, and CA148180) to B.L.E., K.S., and D.T.S. A.P. and B.L.E. were supported by grants from the Leukemia and Lymphoma Society. P.G.M. was funded by Medical Scientist Training Program grant T32GM007753 from the National Institute of General Medical Sciences. C.A.S. and M.A.A.-H. are employees of GlaxoSmithKline. NR 59 TC 50 Z9 53 U1 0 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUL 8 PY 2013 VL 24 IS 1 BP 45 EP 58 DI 10.1016/j.ccr.2013.05.004 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 180OH UT WOS:000321604000009 PM 23770013 ER PT J AU Gothesen, O Slover, J Havelin, L Askildsen, JE Malchau, H Furnes, O AF Gothesen, Oystein Slover, James Havelin, Leif Askildsen, Jan Erik Malchau, Henrik Furnes, Ove TI An economic model to evaluate cost-effectiveness of computer assisted knee replacement surgery in Norway SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article DE Artrhroplasty; Computer navigation; Cost-effectiveness; Health economy; Register; Markov ID NORWEGIAN ARTHROPLASTY REGISTER; FOLLOW-UP; TOTAL HIP; NAVIGATION; ALIGNMENT; METAANALYSIS; SURVIVAL; OUTCOMES; TIME AB Background: The use of Computer Assisted Surgery (CAS) for knee replacements is intended to improve the alignment of knee prostheses in order to reduce the number of revision operations. Is the cost effectiveness of computer assisted surgery influenced by patient volume and age? Methods: By employing a Markov model, we analysed the cost effectiveness of computer assisted surgery versus conventional arthroplasty with respect to implant survival and operation volume in two theoretical Norwegian age cohorts. We obtained mortality and hospital cost data over a 20-year period from Norwegian registers. We presumed that the cost of an intervention would need to be below NOK 500,000 per QALY (Quality Adjusted Life Year) gained, to be considered cost effective. Results: The added cost of computer assisted surgery, provided this has no impact on implant survival, is NOK 1037 and NOK 1414 respectively for 60 and 75-year-olds per quality-adjusted life year at a volume of 25 prostheses per year, and NOK 128 and NOK 175 respectively at a volume of 250 prostheses per year. Sensitivity analyses showed that the 10-year implant survival in cohort 1 needs to rise from 89.8% to 90.6% at 25 prostheses per year, and from 89.8 to 89.9% at 250 prostheses per year for computer assisted surgery to be considered cost effective. In cohort 2, the required improvement is a rise from 95.1% to 95.4% at 25 prostheses per year, and from 95.10% to 95.14% at 250 prostheses per year. Conclusions: The cost of using computer navigation for total knee replacements may be acceptable for 60-year-old as well as 75-year-old patients if the technique increases the implant survival rate just marginally, and the department has a high operation volume. A low volume department might not achieve cost-effectiveness unless computer navigation has a more significant impact on implant survival, thus may defer the investments until such data are available. C1 [Gothesen, Oystein] Haugesund Hosp, Dept Orthopaed Surg, N-5528 Haugesund, Norway. [Slover, James] NYU, Hosp Joint Dis, Dept Orthopaed Surg, New York, NY 10003 USA. [Havelin, Leif; Furnes, Ove] Haukeland Hosp, Dept Orthoped Surg, N-5053 Bergen, Norway. [Havelin, Leif; Furnes, Ove] Univ Bergen, Dept Surg Sci, N-5021 Bergen, Norway. [Askildsen, Jan Erik] Univ Bergen, Uni Res, Stein Rokkan Ctr Social Studies, N-5021 Bergen, Norway. [Malchau, Henrik] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Gothesen, O (reprint author), Haugesund Hosp, Dept Orthopaed Surg, Karmsundsgate 120, N-5528 Haugesund, Norway. EM oystein.gothesen@helse-fonna.no OI Malchau, Henrik/0000-0002-4291-2441 FU Council of Norway FX Conflicts of interest declared: The project's main sponsor is the Research Council of Norway and Oystein Gothesen has had a PhD grant. NR 34 TC 4 Z9 5 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD JUL 6 PY 2013 VL 14 AR 202 DI 10.1186/1471-2474-14-202 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 189NP UT WOS:000322274200001 PM 23829478 ER PT J AU Tsai, JN Uihlein, AV Lee, H Kumbhani, R Siwila-Sackman, E McKay, EA Burnett-Bowie, SAM Neer, RM Leder, BZ AF Tsai, Joy N. Uihlein, Alexander V. Lee, Hang Kumbhani, Ruchit Siwila-Sackman, Erica McKay, Elizabeth A. Burnett-Bowie, Sherri-Ann M. Neer, Robert M. Leder, Benjamin Z. TI Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial SO LANCET LA English DT Article AB Background Osteoporosis medications increase bone-mineral density (BMD) and lower but do not eliminate fracture risk. The combining of anabolic agents with bisphosphonates has not improved efficacy. We compared combined teriparatide and denosumab with both agents alone. Methods From September, 2009, to January, 2011, we enrolled postmenopausal women with osteoporosis into this randomised, controlled trial. Patients were assigned in a 1: 1: 1 ratio to receive 20 mu g teriparatide daily, 60 mg denosumab every 6 months, or both. BMD was measured at 0, 3, 6, and 12 months. Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00926380. Findings 94 (94%) of 100 eligible women completed at least one study visit after baseline. At 12 months, posterior-anterior lumbar spine BMD increased more in the combination group (9.1%, [SD 3.9]) than in the teriparatide (6.2% [4.6], p=0.0139) or denosumab (5.5% [3.3], p=0.0005) groups. Femoral-neck BMD also increased more in the combination group (4.2% [3.0]) than in the teriparatide (0.8% [4.1], p=0.0007) and denosumab (2.1% [3.8], p=0.0238) groups, as did total-hip BMD (combination, 4.9% [2.9]; teriparatide, 0.7% [2.7], p<0.0001; denosumab 2.5% [2.6], p=0.0011). Interpretation Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture. C1 [Tsai, Joy N.; Uihlein, Alexander V.; Kumbhani, Ruchit; Siwila-Sackman, Erica; McKay, Elizabeth A.; Burnett-Bowie, Sherri-Ann M.; Neer, Robert M.; Leder, Benjamin Z.] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Leder, BZ (reprint author), Massachusetts Gen Hosp, Dept Med, Endocrine Unit, 50 Blossom St,Thier 1051, Boston, MA 02114 USA. EM bzleder@partners.org OI Burnett-Bowie, Sherri-Ann/0000-0002-0064-096X FU Amgen; Eli Lilly; National Center for Research Resources FX Amgen, Eli Lilly, National Center for Research Resources. NR 0 TC 105 Z9 110 U1 5 U2 33 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUL 6 PY 2013 VL 382 IS 9886 BP 50 EP 56 DI 10.1016/S0140-6736(13)60856-9 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 177AD UT WOS:000321347000028 PM 23683600 ER PT J AU Chiara, DC Jayakar, SS Zhou, XJ Zhang, X Savechenkov, PY Bruzik, KS Miller, KW Cohen, JB AF Chiara, David C. Jayakar, Selwyn S. Zhou, Xiaojuan Zhang, Xi Savechenkov, Pavel Y. Bruzik, Karol S. Miller, Keith W. Cohen, Jonathan B. TI Specificity of Intersubunit General Anesthetic-binding Sites in the Transmembrane Domain of the Human alpha 1 beta 3 gamma 2 gamma-Aminobutyric Acid Type A (GABA(A)) Receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTOR; GATED ION CHANNELS; AMINO-ACID; SUBUNIT INTERFACES; BETA-3 SUBUNIT; ETOMIDATE; PROPOFOL; IDENTIFICATION; POTENCIES; AGONIST AB GABA type A receptors (GABA(A)R), the brain's major inhibitory neurotransmitter receptors, are the targets for many general anesthetics, including volatile anesthetics, etomidate, propofol, and barbiturates. Howsuch structurally diverse agents can act similarly as positive allosteric modulators of GABA(A) Rs remains unclear. Previously, photoreactive etomidate analogs identified two equivalent anesthetic-binding sites in the transmembrane domain at the beta(+)-alpha(-) subunit interfaces, which also contain the GABA-binding sites in the extracellular domain. Here, we used R-[H-3]5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (R-mTFD-MPAB), a potent stereospecific barbiturate anesthetic, to photolabel expressed human alpha 1 beta 3 gamma 2 GABA(A)Rs. Protein microsequencing revealed that R-[3H]mTFD-MPAB did not photolabel the etomidate sites at the alpha(+) -beta(-) subunit interfaces. Instead, it photolabeled sites at the alpha(+) -beta(-) and gamma(+) -beta(-) subunit interfaces in the transmembrane domain. On the (similar to)-side, alpha 1M3 was labeled at Ala-291 and Tyr294 and gamma 2M3 at Ser-301, and on the (-)-side, beta 3M1 was labeled at Met-227. These residues, like those in the etomidate site, are located at subunit interfaces near the synaptic side of the transmembrane domain. The selectivity of R-etomidate for the beta(+) -alpha(-) interface relative to the alpha(+) -beta(-)/gamma(+)-beta(-) interfaces was > 100-fold, whereas that of R-mTFD-MPAB for its sites was > 50-fold. Each ligand could enhance photoincorporation of the other, demonstrating allosteric interactions between the sites. The structural heterogeneity of barbiturate, etomidate, and propofol derivatives is accommodated by varying selectivities for these two classes of sites. Wehypothesize that binding at any of these homologous intersubunit sites is sufficient for anesthetic action and that this explains to some degree the puzzling structural heterogeneity of anesthetics. C1 [Chiara, David C.; Jayakar, Selwyn S.; Cohen, Jonathan B.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Miller, Keith W.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Zhou, Xiaojuan; Zhang, Xi; Miller, Keith W.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Savechenkov, Pavel Y.; Bruzik, Karol S.] Univ Illinois, Deparment Med Chem & Pharmacognosy, Chicago, IL 60612 USA. RP Cohen, JB (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. EM jonathan_cohen@hms.harvard.edu FU National Institutes of Health, USPHS [GM-58448] FX This work was supported, in whole or in part, by National Institutes of Health Grant GM-58448 from USPHS. NR 55 TC 53 Z9 53 U1 0 U2 19 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 JUL 5 PY 2013 VL 288 IS 27 BP 19343 EP 19357 DI 10.1074/jbc.M113.479725 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 179JG UT WOS:000321515800005 PM 23677991 ER PT J AU Lin, JY Zhang, MF Schatton, T Wilson, BJ Alloo, A Ma, J Qureshi, AA Frank, NY Han, JL Frank, MH AF Lin, Jennifer Y. Zhang, Mingfeng Schatton, Tobias Wilson, Brian J. Alloo, Allireza Ma, Jie Qureshi, Abrar A. Frank, Natasha Y. Han, Jiali Frank, Markus H. TI Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE ABCB5; Single nucleotide polymorphism; Genotype; Melanoma; Cancer; Cancer stem cells; Pigmentation; Case-controlled study; Humans ID HUMAN-MALIGNANT MELANOMA; INITIATING CELLS; P-GLYCOPROTEIN; STEM-CELLS; IN-VIVO; CANCER; CHEMORESISTANCE; TRANSPORTERS; GENOME; NEVI AB ABCB5 is a multidrug resistance (MDR) member of the ATP-binding cassette (ABC) superfamily of active transporters and represents a marker for chemoresistant malignant melanoma-initiating cells. ABCB5 expression is closely linked to tumorigenicity and progression of diverse human malignancies, including melanoma, and is functionally required for tumor growth. Here, we genotyped 585 melanoma cases and 605 age-matched controls for 44 ABCB5 tagging single nucleotide polymorphisms (SNPs) to span a region covering 108.2 kb of the gene on the 7p21.1 locus. We identified three SNPs that were associated with decreased melanoma risk in additive models: rs10231520 (OR: 0.83, 95% CI: 0.70-0.98), rs17817117 (OR: 0.82, 95% CI: 0.68-0.98), and rs2301641 (OR: 0.83, 95% CI: 0.69-0.98). Additionally, the rs2301641 SNP was associated with non-red compared to red hair color (OR: 0.38, 95% CI: 0.14-1.03) in controls. Twelve human melanoma cell lines were genotyped for the rs2301641 SNP, which encodes a non-synonymous ABCB5 amino acid change (K115E). Functional studies revealed that the E form associated with lower melanoma risk correlated significantly with decreased ABCB5 transport capacity (P < 0.01) and increased melanin production (P < 0.05). Our results identify novel associations of the ABCB5 K115E polymorphism with human pigmentation phenotype and melanoma risk and point to potential functional roles of ABCB5 in melanomagenesis. Moreover, they provide a first example that functional variation in a prospective cancer stem cell marker can be associated with disease risk for the corresponding malignancy. (C) 2013 Elsevier Inc. All rights reserved. C1 [Lin, Jennifer Y.; Zhang, Mingfeng; Schatton, Tobias; Wilson, Brian J.; Alloo, Allireza; Ma, Jie; Qureshi, Abrar A.; Han, Jiali; Frank, Markus H.] Harvard Univ, Sch Med, Dept Dermatol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Wilson, Brian J.; Alloo, Allireza; Ma, Jie; Frank, Markus H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Transplant Res Program, Boston, MA USA. [Frank, Natasha Y.] VA Boston Healthcare Syst, Dept Med, Boston, MA USA. [Frank, Natasha Y.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Han, Jiali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. RP Frank, MH (reprint author), Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM jiali.han@channing.harvard.edu; markus.frank@chil-drens.harvard.edu RI Frank, Markus/O-1625-2014 OI Frank, Markus/0000-0002-1312-0488 FU NIH/NCI [R01CA113796, R01CA138231, R01CA158467, P50CA093683, R01CA122838, PO1CA87969, PO1CA055075, RO1CA49449]; U.S. Department of Veterans Affairs (BLR&D VA Merit Award) [10688354] FX This work was supported by funds from the NIH/NCI (Grants R01CA113796, R01CA138231, R01CA158467 and P50CA093683 to M.H.F; R01CA122838, PO1CA87969, PO1CA055075 and RO1CA49449 to J.H), and the U.S. Department of Veterans Affairs (BLR&D VA Merit Award 10688354 to N.Y.F). NR 25 TC 6 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 5 PY 2013 VL 436 IS 3 BP 536 EP 542 DI 10.1016/j.bbrc.2013.06.006 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 185UN UT WOS:000321995900032 PM 23770371 ER PT J AU Greenwald, DR Li, HL Luger, SM Go, RS King, D Patel, T Gascoyne, RD Kolesar, J Kahl, BS Horning, S AF Greenwald, Daniel R. Li, Hailun Luger, Selina M. Go, Ronald S. King, David Patel, Taral Gascoyne, Randy D. Kolesar, Jill Kahl, Brad S. Horning, Sandra TI A phase II study of sorafenib (BAY 43-9006) in recurrent diffuse large B cell lymphoma: an eastern cooperative oncology group study (E1404) SO JOURNAL OF HEMATOLOGY & ONCOLOGY LA English DT Article DE NHL; Diffuse large B cell lymphoma; MAP kinase signaling; Sorafenib ID NON-HODGKINS-LYMPHOMA; ENDOTHELIAL GROWTH-FACTOR; SIGNALING PATHWAY; CLINICAL-TRIALS; KINASE; RAS; MALIGNANCIES; INHIBITION; EXPRESSION; RESISTANCE AB Patients with diffuse large B cell lymphoma (DLBCL) who are not candidates for or recur after autologous stem cell transplant have a poor overall prognosis. We conducted a phase II study of sorafenib (formerly BAY 43-9006) in the treatment of relapsed DLBCL. Fourteen patients were enrolled and assessed for response. Median number of cycles administered was 3 (range, 1-12). Common grade 3 toxicities included fatigue (29%), rash/desquamation (21%) and diarrhea (14%). One complete response (CR) was observed (the 14th patient enrolled). Response rate was 7% (90% CI, 0.4 - 30%). Duration of response was 6 months. Median progression-free survival (PFS) was 2 months (90% CI, 1 - 5 months). Median overall survival (OS) was 9 months (90% CI, 5 - 16 months). Although sorafenib has demonstrated activity in solid malignancies it demonstrated low single agent activity in treatment of DLBCL. C1 [Greenwald, Daniel R.; Horning, Sandra] Stanford Univ, Stanford, CA 94305 USA. [Li, Hailun] Dana Farber Canc Inst, Boston, MA 02115 USA. [Luger, Selina M.] Univ Penn, Philadelphia, PA 19104 USA. [Go, Ronald S.] Gundersen Lutheran Hlth Syst, La Crosse, WI USA. [King, David] Hlth One Mercy Hosp, Coon Rapids, MN USA. [Patel, Taral] Columbus CCOP, Columbus, OH USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Kolesar, Jill; Kahl, Brad S.] Univ Wisconsin, Madison, WI USA. [Horning, Sandra] Roche Genentech, San Francisco, CA USA. [Greenwald, Daniel R.] Canc Ctr Santa Barbara, Santa Barbara, CA 93105 USA. RP Greenwald, DR (reprint author), Stanford Univ, Stanford, CA 94305 USA. EM dgreenwald@ccsb.org FU National Cancer Institute, DHHS [CA-23318]; Public Health Service [CA21115, CA23318, CA66636, CA15488, CA21076]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX This investigation was supported by Grant CA-23318, awarded by the National Cancer Institute, DHHS.; This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, M. D., Chair) and supported in part by Public Health Service Grants CA21115, CA23318, CA66636, CA15488, CA21076 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. NR 27 TC 7 Z9 7 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-8722 J9 J HEMATOL ONCOL JI J. Hematol. Oncol. PD JUL 5 PY 2013 VL 6 AR 46 DI 10.1186/1756-8722-6-46 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 185II UT WOS:000321960600001 PM 23829878 ER PT J AU Bhayana, B AF Bhayana, Bruesh TI Wilcox Molecular Torsion Balance with Rigid Side Arm and Separable Atropisomers for Investigating CH-pi Interactions SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ORTHOGONAL DIPOLAR INTERACTIONS; FACE AROMATIC INTERACTIONS; RECOGNITION AB A new variant of the Wilcox molecular torsion balance featuring a naphthyl-alkyl side arm was synthesized The energy barrier for axial isomerization in the new balance was sufficiently high to allow for separation of the two rotamers and to observe their isomerization kinetics. The CH-pi interaction energies in derivatives of the new and the original ester balance were in close agreement, suggesting that the motion in ester linkage is not an important factor in folding in the ester balance. C1 Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Bhayana, B (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. EM bbhayana@partners.org NR 19 TC 7 Z9 7 U1 2 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD JUL 5 PY 2013 VL 78 IS 13 BP 6758 EP 6762 DI 10.1021/jo400782e PG 5 WC Chemistry, Organic SC Chemistry GA 180PA UT WOS:000321605900038 PM 23755968 ER PT J AU Katsel, P Tan, WL Fam, P Purohit, DP Haroutunian, V AF Katsel, Pavel Tan, Weilun Fam, Peter Purohit, Dushyant P. Haroutunian, Vahram TI Cycle Checkpoint Abnormalities during Dementia: A Plausible Association with the Loss of Protection against Oxidative Stress in Alzheimer's Disease SO PLOS ONE LA English DT Article ID MULTIPLE BRAIN-REGIONS; NEURONAL CELL-DEATH; GENE-EXPRESSION; ATAXIA-TELANGIECTASIA; TAU PHOSPHORYLATION; ELDERLY-PATIENTS; DNA-REPLICATION; RATING-SCALE; G2/M PHASE; SCHIZOPHRENIA AB Background: Increasing evidence suggests an association between neuronal cell cycle (CCL) events and the processes that underlie neurodegeneration in Alzheimer's disease (AD). Elevated levels of oxidative stress markers and mitochondrial dysfunction are also among early events in AD. Recent studies have reported the role of CCL checkpoint proteins and tumor suppressors, such as ATM and p53 in the control of glycolysis and oxidative metabolism in cancer, but their involvement in AD remains uncertain. Methods and Findings: In this postmortem study, we measured gene expression levels of eight CCL checkpoint proteins in the superior temporal cortex (STC) of persons with varying severities of AD dementia and compare them to those of cognitively normal controls. To assess whether the CCL changes associated with cognitive impairment in AD are specific to dementia, gene expression of the same proteins was also measured in STC of persons with schizophrenia (SZ), which is also characterized by mitochondrial dysfunction. The expression of CCL-checkpoint and DNA damage response genes: MDM4, ATM and ATR was strongly upregulated and associated with progression of dementia (cognitive dementia rating, CDR), appearing as early as questionable or mild dementia (CDRs 0.5-1). In addition to gene expression changes, the downstream target of ATM-p53 signaling - TIGAR, a p53-inducible protein, the activation of which can regulate energy metabolism and protect against oxidative stress was progressively decreased as severity of dementia evolved, but it was unaffected in subjects with SZ. In contrast to AD, different CCL checkpoint proteins, which include p53, CHEK1 and BRCA1 were significantly downregulated in SZ. Conclusions: These results support the activation of an ATM signaling and DNA damage response network during the progression of AD dementia, while the progressive decrease in the levels of TIGAR suggests loss of protection initiated by ATM-p53 signaling against intensifying oxidative stress in AD. C1 [Katsel, Pavel; Tan, Weilun; Haroutunian, Vahram] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Fam, Peter; Haroutunian, Vahram] James J Peters VA Med Ctr, Dept Psychiat, Bronx, NY USA. [Haroutunian, Vahram] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Purohit, Dushyant P.] Mt Sinai Sch Med, Dept Pathol, New York, NY USA. RP Katsel, P (reprint author), Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. EM pavel.katsel@mssm.edu FU National Institutes of Health [P01-AG02219, P50-AG05138, MH066392, MH064673]; Veteran Administration MIRECC, Leir Foundation FX This work was supported by National Institutes of Health (P01-AG02219, P50-AG05138, MH066392 and by MH064673 to VH), Veteran Administration MIRECC, Leir Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 85 TC 16 Z9 16 U1 1 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 JUL 5 PY 2013 VL 8 IS 7 AR e68361 DI 10.1371/journal.pone.0068361 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 178DW UT WOS:000321425300059 PM 23861893 ER PT J AU Pulli, B Ali, M Forghani, R Schob, S Hsieh, KLC Wojtkiewicz, G Linnoila, JJ Chen, JW AF Pulli, Benjamin Ali, Muhammad Forghani, Reza Schob, Stefan Hsieh, Kevin L. C. Wojtkiewicz, Gregory Linnoila, Jenny J. Chen, John W. TI Measuring Myeloperoxidase Activity in Biological Samples SO PLOS ONE LA English DT Article ID IN-VIVO; HYDROGEN-PEROXIDE; INHIBITION; ASSAY; MICE; 3-CHLOROTYROSINE; ATHEROSCLEROSIS; POLYMORPHISM; BIOMARKER; OXIDANTS AB Background: Enzymatic activity measurements of the highly oxidative enzyme myeloperoxidase (MPO), which is implicated in many diseases, are widely used in the literature, but often suffer from nonspecificity and lack of uniformity. Thus, validation and standardization are needed to establish a robust method that is highly specific, sensitive, and reproducible for assaying MPO activity in biological samples. Principal findings: We found conflicting results between in vivo molecular MR imaging of MPO, which measures extracellular activity, and commonly used in vitro MPO activity assays. Thus, we established and validated a protocol to obtain extra- and intracellular MPO from murine organs. To validate the MPO activity assays, three different classes of MPO activity assays were used in spike and recovery experiments. However, these assay methods yielded inconsistent results, likely because of interfering substances and other peroxidases present in tissue extracts. To circumvent this, we first captured MPO with an antibody. The MPO activity of the resultant samples was assessed by ADHP and validated against samples from MPO-knockout mice in murine disease models of multiple sclerosis, steatohepatitis, and myocardial infarction. We found the measurements performed using this protocol to be highly specific and reproducible, and when performed using ADHP, to be highly sensitive over a broad range. In addition, we found that intracellular MPO activity correlated well with tissue neutrophil content, and can be used as a marker to assess neutrophil infiltration in the tissue. Conclusion: We validated a highly specific and sensitive assay protocol that should be used as the standard method for all MPO activity assays in biological samples. We also established a method to obtain extra- and intracellular MPO from murine organs. Extracellular MPO activity gives an estimate of the oxidative stress in inflammatory diseases, while intracellular MPO activity correlates well with tissue neutrophil content. A detailed step-by-step protocol is provided. C1 [Pulli, Benjamin; Ali, Muhammad; Schob, Stefan; Hsieh, Kevin L. C.; Wojtkiewicz, Gregory; Linnoila, Jenny J.; Chen, John W.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Pulli, Benjamin; Ali, Muhammad; Schob, Stefan; Hsieh, Kevin L. C.; Wojtkiewicz, Gregory; Linnoila, Jenny J.; Chen, John W.] Harvard Univ, Sch Med, Boston, MA USA. [Pulli, Benjamin; Chen, John W.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Forghani, Reza] McGill Univ, Jewish Gen Hosp, Dept Radiol, Montreal, PQ H3T 1E2, Canada. [Forghani, Reza] McGill Univ, Montreal, PQ, Canada. [Hsieh, Kevin L. C.] Far Eastern Mem Hosp, Dept Med Imaging, Taipei, Taiwan. RP Chen, JW (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM jwchen@mgh.harvard.edu FU NIH [R01-NS070835, R01-NS072167]; Ernst Schering Foundation in Berlin, Germany; National Natural Science Foundation, Beijing, China FX This study was supported in part by the NIH (R01-NS070835 and R01-NS072167 to JWC). Additional funds have come from a fellowship from the Ernst Schering Foundation in Berlin, Germany, and a grant from the National Natural Science Foundation, Beijing, China, awarded to BP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 48 Z9 49 U1 1 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 JUL 5 PY 2013 VL 8 IS 7 AR e67976 DI 10.1371/journal.pone.0067976 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 178DW UT WOS:000321425300033 PM 23861842 ER PT J AU Fogg, M Murphy, JR Lorch, J Posner, M Wang, F AF Fogg, Mark Murphy, John R. Lorch, Jochen Posner, Marshall Wang, Fred TI Therapeutic targeting of regulatory T cells enhances tumor-specific CD8+T cell responses in Epstein-Barr virus associated nasopharyngeal carcinoma SO VIROLOGY LA English DT Article DE Epstein-Barr virus; Nasopharyngeal carcinoma; CD8+T cells; T regulatory cells; Ontak ID ADOPTIVE IMMUNOTHERAPY; IMMUNE-RESPONSE; IN-VITRO; LYMPHOCYTES; ANTIGEN; INFECTION; DEPLETION; LESSONS; DISEASE; VIVO AB Epstein-Barr virus (EBV) is associated with multiple malignancies including nasopharyngeal carcinoma (NPC). In nasopharynx cancer, CD8+ T cells specific for EBV Nuclear Antigen-1 (EBNA-1) and Latent Membrane Protein 2 (LMP2) are important components of anti-tumor immunity since both are consistently expressed in NPC. We have previously shown that EBNA-1-specific CD8+ T cell responses were suppressed in NPC patients compared to healthy controls. We now find that CD8+ T cell responses specific for LMP2 are also abnormal in NPC patients, and both EBNA-1- and LMP2-specific responses are suppressed by regulatory T cells (Treg). EBNA-1 and LMP2-specific CD8+ T cell responses, as well as immune control of EBV-infected cells in vitro, could be restored by the depletion of Tregs and by use of a clinically approved drug targeting Tregs. Thus, in vivo modulation of Tregs may be an effective means of enhancing these anti-tumor immune responses in NPC patients. (C) 2013 Elsevier Inc. All rights reserved. C1 [Fogg, Mark; Wang, Fred] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wang, Fred] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Murphy, John R.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Murphy, John R.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Lorch, Jochen; Posner, Marshall] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Wang, F (reprint author), 181 Longwood Ave,MCP8, Boston, MA 02115 USA. EM fwang@research.bwh.harvard.edu FU Dana Farber Cancer Institute Friends of Head and Neck Cancer Research; National Institutes of Health [CA68051, CA132279] FX This work was supported by Grants from the Dana Farber Cancer Institute Friends of Head and Neck Cancer Research and the National Institutes of Health (CA68051, CA132279). NR 27 TC 10 Z9 10 U1 0 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL 5 PY 2013 VL 441 IS 2 BP 107 EP 113 DI 10.1016/j.virol.2013.03.016 PG 7 WC Virology SC Virology GA 155XD UT WOS:000319782800002 PM 23601786 ER PT J AU Kochupurakkal, BS Iglehart, JD AF Kochupurakkal, Bose S. Iglehart, J. Dirk TI Nourseothricin N-Acetyl Transferase: A Positive Selection Marker for Mammalian Cells SO PLOS ONE LA English DT Article ID TRANSFORMATION AB Development of Nourseothricin N-acetyl transferase (NAT) as a selection marker for mammalian cells is described. Mammalian cells are acutely susceptible to Nourseothricin, similar to the widely used drug Puromycin, and NAT allows for quick and robust selection of transfected/transduced cells in the presence of Nourseothricin. NAT is compatible with other selection markers puromycin, hygromycin, neomycin, blasticidin, and is a valuable addition to the repertoire of mammalian selection markers. C1 [Kochupurakkal, Bose S.; Iglehart, J. Dirk] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Iglehart, J. Dirk] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Iglehart, JD (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM JIGLEHART@partners.org FU Teri Brodeur Fellowship; Hale Fellowship; Women's Cancer Program at Dana-Farber Cancer Institute; National Cancer Institute Specialized Program in Research Excellence in Breast Cancer at Dana-Farber/Harvard Cancer Center [CA89393] FX KSB is a recipient of the Teri Brodeur Fellowship and the Hale Fellowship. The work was supported by the Women's Cancer Program at Dana-Farber Cancer Institute and National Cancer Institute Specialized Program in Research Excellence in Breast Cancer at Dana-Farber/Harvard Cancer Center (CA89393). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 10 TC 2 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 4 PY 2013 VL 8 IS 7 AR e68509 DI 10.1371/journal.pone.0068509 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204FO UT WOS:000323350700090 PM 23861913 ER PT J AU Becker, AE Kleinman, A AF Becker, Anne E. Kleinman, Arthur TI GLOBAL HEALTH Mental Health and the Global Agenda SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID MIDDLE-INCOME COUNTRIES; NONCOMMUNICABLE DISEASE CRISIS; RANDOMIZED CONTROLLED-TRIAL; SYSTEMATIC ANALYSIS; PRIORITY ACTIONS; SCALE-UP; PSYCHIATRY; DISORDERS; DEPRESSION; SERVICES AB WHEN THE WORLD HEALTH ORGANIZATION (WHO) EUROPEAN MINISterial Conference on Mental Health endorsed the statement "No health without mental health" in 2005,(1) it spoke to the intrinsic - and indispensable - role of mental health care in health care writ large. Yet mental health has long been treated in ways that reflect the opposite of that sentiment. This historical divide - in practice and in policy - between physical health and mental health has in turn perpetuated large gaps in resources across economic, social, and scientific domains. The upshot is a global tragedy: a legacy of the neglect and marginalization of mental health.(2) The scale of the global impact of mental illness is substantial, with mental illness constituting an estimated 7.4% of the world's measurable burden of disease.(3) The lack of access to mental health services of good quality is profound in populations with limited resources, for whom numerous social hazards exacerbate vulnerability to poor health. The human toll of mental disorders is further compounded by collateral adverse effects on health and social well-being, including exposure to stigma and human rights abuses, forestallment of educational and social opportunities, and entry into a pernicious cycle of social disenfranchisement and poverty.(4,5) Advances in efforts to alleviate the human and social costs of mental disorders have been both too slow and too few. C1 [Becker, Anne E.; Kleinman, Arthur] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Becker, Anne E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kleinman, Arthur] Harvard Univ, Dept Anthropol, Cambridge, MA 02138 USA. RP Kleinman, A (reprint author), Harvard Univ, Dept Anthropol, William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. EM kleinman@wjh.harvard.edu FU John Wiley and Sons FX Dr. Becker reports receiving payments for editorial work from John Wiley and Sons, for editorial work, travel, and meeting participation from the Academy for Eating Disorders, and for travel and meeting participation from MA Healthcare, the Succeed Foundation, the American Psychiatric Association, and the National Eating Disorders Association. No other potential conflict of interest relevant to this article was reported. NR 57 TC 57 Z9 60 U1 7 U2 32 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 JUL 4 PY 2013 VL 369 IS 1 BP 66 EP 73 DI 10.1056/NEJMra1110827 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 175WE UT WOS:000321263500011 PM 23822778 ER PT J AU Devkota, S Turnbaugh, PJ AF Devkota, Suzanne Turnbaugh, Peter J. TI CANCER An acidic link SO NATURE LA English DT Editorial Material ID GUT MICROBIOME; OBESITY; DIETARY; MICE C1 [Devkota, Suzanne] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Turnbaugh, Peter J.] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. RP Devkota, S (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. EM pturnbaugh@fas.harvard.edu NR 11 TC 3 Z9 3 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 4 PY 2013 VL 499 IS 7456 BP 37 EP 38 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176ED UT WOS:000321285600026 PM 23803768 ER PT J AU Creighton, CJ Morgan, M Gunaratne, PH Wheeler, DA Gibbs, RA Robertson, AG Chu, A Beroukhim, R Cibulskis, K Signoretti, S Vandin, F Wu, HT Raphael, BJ Verhaak, RGW Tamboli, P Torres-Garcia, W Akbani, R Weinstein, JN Reuter, V Hsieh, JJ Brannon, AR Hakimi, AA Jacobsen, A Ciriello, G Reva, B Ricketts, CJ Linehan, WM Stuart, JM Rathmell, WK Shen, H Laird, PW Muzny, D Davis, C Morgan, M Xi, L Chang, K Kakkar, N Trevino, LR Benton, S Reid, JG Morton, D Doddapaneni, H Han, Y Lewis, L Dinh, H Kovar, C Zhu, YM Santibanez, J Wang, M Hale, W Kalra, D Creighton, CJ Wheeler, DA Gibbs, RA Getz, G Cibulskis, K Lawrence, MS Sougnez, C Carter, SL Sivachenko, A Lichtenstein, L Stewart, C Voet, D Fisher, S Gabriel, SB Lander, E Beroukhim, R Schumacher, SE Tabak, B Saksena, G Onofrio, RC Carter, SL Cherniack, AD Gentry, J Ardlie, K Sougnez, C Getz, G Gabriel, SB Meyerson, M Robertson, AG Chu, AD Chun, HJE Mungall, AJ Sipahimalani, P Stoll, D Ally, A Balasundaram, M Butterfield, YSN Carlsen, R Carter, C Chuah, E Coope, RJN Dhalla, N Gorski, S Guin, R Hirst, C Hirst, M Holt, RA Lebovitz, C Lee, D Li, HYI Mayo, M Moore, RA Pleasance, E Plettner, P Schein, JE Shafiei, A Slobodan, JR Tam, A Thiessen, N Varhol, RJ Wye, N Zhao, YJ Birol, I Jones, SJM Marra, MA Auman, JT Tan, DH Jones, CD Hoadley, KA Mieczkowski, PA Mose, LE Jefferys, SR Topal, M Liquori, C Turman, YJ Shi, Y Waring, S Buda, E Walsh, J Wu, JY Bodenheimer, T Hoyle, AP Simons, JV Soloway, M Balu, S Parker, JS Hayes, DN Perou, CM Kucherlapati, R Park, P Shen, H Triche, T Weisenberger, DJ Lai, PH Bootwalla, MS Maglinte, DT Mahurkar, S Berman, BP Van den Berg, DJ Cope, L Baylin, SB Laird, PW Creighton, CJ Wheeler, DA Getz, G Noble, MS DiCara, D Zhang, HL Cho, J Heiman, DI Gehlenborg, N Voet, D Mallard, W Lin, P Frazer, S Stojanov, P Liu, YC Zhou, LH Kim, J Lawrence, MS Chin, L Vandin, F Wu, HT Raphael, BJ Benz, C Yau, C Reynolds, SM Shmulevich, I Verhaak, RGW Torres-Garcia, W Vegesna, R Kim, H Zhang, W Cogdell, D Jonasch, E Ding, ZY Lu, YL Akbani, R Zhang, NX Unruh, AK Casasent, TD Wakefield, C Tsavachidou, D Chin, L Mills, GB Weinstein, JN Jacobsen, A Brannon, AR Ciriello, G Schultz, N Hakimi, AA Reva, B Antipin, Y Gao, JJ Cerami, E Gross, B Aksoy, BA Sinha, R Weinhold, N Sumer, SO Taylor, BS Shen, RL Ostrovnaya, I Hsieh, JJ Berger, MF Ladanyi, M Sander, C Fei, SS Stout, A Spellman, PT Rubin, DL Liu, TT Stuart, JM Ng, S Paull, EO Carlin, D Goldstein, T Waltman, P Ellrott, K Zhu, J Haussler, D Gunaratne, PH Xiao, WM Shelton, C Gardner, J Penny, R Sherman, M Mallery, D Morris, S Paulauskis, J Burnett, K Shelton, T Signoretti, S Kaelin, WG Choueiri, T Atkins, MB Penny, R Burnett, K Mallery, D Curley, E Tickoo, S Reuter, V Rathmell, WK Thorne, L Boice, L Huang, M Fisher, JC Linehan, WM Vocke, CD Peterson, J Worrell, R Merino, MJ Schmidt, LS Tamboli, P Czerniak, BA Aldape, KD Wood, CG Boyd, J Weaver, J Iacocca, MV Petrelli, N Witkin, G Brown, J Czerwinski, C Huelsenbeck-Dill, L Rabeno, B Myers, J Morrison, C Bergsten, J Eckman, J Harr, J Smith, C Tucker, K Zach, LA Bshara, W Gaudioso, C Morrison, C Dhir, R Maranchie, J Nelson, J Parwani, A Potapova, O Fedosenko, K Cheville, JC Thompson, RH Signoretti, S Kaelin, WG Atkins, MB Tickoo, S Reuter, V Linehan, WM Vocke, CD Peterson, J Merino, MJ Schmidt, LS Tamboli, P Mosquera, JM Rubin, MA Blute, ML Rathmell, WK Pihl, T Jensen, M Sfeir, R Kahn, A Chu, A Kothiyal, P Snyder, E Pontius, J Ayala, B Backus, M Walton, J Baboud, J Berton, D Nicholls, M Srinivasan, D Raman, R Girshik, S Kigonya, P Alonso, S Sanbhadti, R Barletta, S Pot, D Sheth, M Demchok, JA Davidsen, T Wang, ZN Yang, LM Tarnuzzer, RW Zhang, JS Eley, G Ferguson, ML Shaw, KRM Guyer, MS Ozenberger, BA Sofia, HJ AF Creighton, Chad J. Morgan, Margaret Gunaratne, Preethi H. Wheeler, David A. Gibbs, Richard A. Robertson, A. Gordon Chu, Andy Beroukhim, Rameen Cibulskis, Kristian Signoretti, Sabina Vandin, Fabio Wu, Hsin-Ta Raphael, Benjamin J. Verhaak, Roel G. W. Tamboli, Pheroze Torres-Garcia, Wandaliz Akbani, Rehan Weinstein, John N. Reuter, Victor Hsieh, James J. Brannon, A. Rose Hakimi, A. Ari Jacobsen, Anders Ciriello, Giovanni Reva, Boris Ricketts, Christopher J. Linehan, W. Marston Stuart, Joshua M. Rathmell, W. Kimryn Shen, Hui Laird, Peter W. Muzny, Donna Davis, Caleb Morgan, Margaret Xi, Liu Chang, Kyle Kakkar, Nipun Trevino, Lisa R. Benton, Susan Reid, Jeffrey G. Morton, Donna Doddapaneni, Harsha Han, Yi Lewis, Lora Dinh, Huyen Kovar, Christie Zhu, Yiming Santibanez, Jireh Wang, Min Hale, Walker Kalra, Divya Creighton, Chad J. Wheeler, David A. Gibbs, Richard A. Getz, Gad Cibulskis, Kristian Lawrence, Michael S. Sougnez, Carrie Carter, Scott L. Sivachenko, Andrey Lichtenstein, Lee Stewart, Chip Voet, Doug Fisher, Sheila Gabriel, Stacey B. Lander, Eric Beroukhim, Rameen Schumacher, Steve E. Tabak, Barbara Saksena, Gordon Onofrio, Robert C. Carter, Scott L. Cherniack, Andrew D. Gentry, Jeff Ardlie, Kristin Sougnez, Carrie Getz, Gad Gabriel, Stacey B. Meyerson, Matthew Robertson, A. Gordon Chu, Andy Chun, Hye-Jung E. Mungall, Andrew J. Sipahimalani, Payal Stoll, Dominik Ally, Adrian Balasundaram, Miruna Butterfield, Yaron S. N. Carlsen, Rebecca Carter, Candace Chuah, Eric Coope, Robin J. N. Dhalla, Noreen Gorski, Sharon Guin, Ranabir Hirst, Carrie Hirst, Martin Holt, Robert A. Lebovitz, Chandra Lee, Darlene Li, Haiyan I. Mayo, Michael Moore, Richard A. Pleasance, Erin Plettner, Patrick Schein, Jacqueline E. Shafiei, Arash Slobodan, Jared R. Tam, Angela Thiessen, Nina Varhol, Richard J. Wye, Natasja Zhao, Yongjun Birol, Inanc Jones, Steven J. M. Marra, Marco A. Auman, J. Todd Tan, Donghui Jones, Corbin D. Hoadley, Katherine A. Mieczkowski, Piotr A. Mose, Lisle E. Jefferys, Stuart R. Topal, MichaelD. Liquori, Christina Turman, Yidi J. Shi, Yan Waring, Scot Buda, Elizabeth Walsh, Jesse Wu, Junyuan Bodenheimer, Tom Hoyle, Alan P. Simons, Janae V. Soloway, MathewG. Balu, Saianand Parker, Joel S. Hayes, D. Neil Perou, Charles M. Kucherlapati, Raju Park, Peter Shen, Hui Triche, Timothy, Jr. Weisenberger, Daniel J. Lai, Phillip H. Bootwalla, Moiz S. Maglinte, Dennis T. Mahurkar, Swapna Berman, Benjamin P. Van den Berg, David J. Cope, Leslie Baylin, Stephen B. Laird, Peter W. Creighton, Chad J. Wheeler, David A. Getz, Gad Noble, Michael S. DiCara, Daniel Zhang, Hailei Cho, Juok Heiman, David I. Gehlenborg, Nils Voet, Doug Mallard, William Lin, Pei Frazer, Scott Stojanov, Petar Liu, Yingchun Zhou, Lihua Kim, Jaegil Lawrence, Michael S. Chin, Lynda Vandin, Fabio Wu, Hsin-Ta Raphael, Benjamin J. Benz, Christopher Yau, Christina Reynolds, Sheila M. Shmulevich, Ilya Verhaak, Roel G. W. Torres-Garcia, Wandaliz Vegesna, Rahul Kim, Hoon Zhang, Wei Cogdell, David Jonasch, Eric Ding, Zhiyong Lu, Yiling Akbani, Rehan Zhang, Nianxiang Unruh, Anna K. Casasent, Tod D. Wakefield, Chris Tsavachidou, Dimitra Chin, Lynda Mills, Gordon B. Weinstein, John N. Jacobsen, Anders Brannon, A. Rose Ciriello, Giovanni Schultz, Nikolaus Hakimi, A. Ari Reva, Boris Antipin, Yevgeniy Gao, Jianjiong Cerami, Ethan Gross, Benjamin Aksoy, B. Arman Sinha, Rileen Weinhold, Nils Sumer, S. Onur Taylor, Barry S. Shen, Ronglai Ostrovnaya, Irina Hsieh, James J. Berger, Michael F. Ladanyi, Marc Sander, Chris Fei, Suzanne S. Stout, Andrew Spellman, Paul T. Rubin, Daniel L. Liu, Tiffany T. Stuart, Joshua M. Sam Ng Paull, Evan O. Carlin, Daniel Goldstein, Theodore Waltman, Peter Ellrott, Kyle Zhu, Jing Haussler, David Gunaratne, Preethi H. Xiao, Weimin Shelton, Candace Gardner, Johanna Penny, Robert Sherman, Mark Mallery, David Morris, Scott Paulauskis, Joseph Burnett, Ken Shelton, Troy Signoretti, Sabina Kaelin, William G. Choueiri, Toni Atkins, Michael B. Penny, Robert Burnett, Ken Mallery, David Curley, Erin Tickoo, Satish Reuter, Victor Rathmell, W. Kimryn Thorne, Leigh Boice, Lori Huang, Mei Fisher, Jennifer C. Linehan, W. Marston Vocke, Cathy D. Peterson, James Worrell, Robert Merino, Maria J. Schmidt, Laura S. Tamboli, Pheroze Czerniak, Bogdan A. Aldape, Kenneth D. Wood, Christopher G. Boyd, Jeff Weaver, JoEllen Iacocca, Mary V. Petrelli, Nicholas Witkin, Gary Brown, Jennifer Czerwinski, Christine Huelsenbeck-Dill, Lori Rabeno, Brenda Myers, Jerome Morrison, Carl Bergsten, Julie Eckman, John Harr, Jodi Smith, Christine Tucker, Kelinda Zach, Leigh Anne Bshara, Wiam Gaudioso, Carmelo Morrison, Carl Dhir, Rajiv Maranchie, Jodi Nelson, Joel Parwani, Anil Potapova, Olga Fedosenko, Konstantin Cheville, John C. Thompson, R. Houston Signoretti, Sabina Kaelin, William G. Atkins, Michael B. Tickoo, Satish Reuter, Victor Linehan, W. Marston Vocke, Cathy D. Peterson, James Merino, Maria J. Schmidt, Laura S. Tamboli, Pheroze Mosquera, Juan M. Rubin, Mark A. Blute, Michael L. Rathmell, W. Kimryn Pihl, Todd Jensen, Mark Sfeir, Robert Kahn, Ari Chu, Anna Kothiyal, Prachi Snyder, Eric Pontius, Joan Ayala, Brenda Backus, Mark Walton, Jessica Baboud, Julien Berton, Dominique Nicholls, Matthew Srinivasan, Deepak Raman, Rohini Girshik, Stanley Kigonya, Peter Alonso, Shelley Sanbhadti, Rashmi Barletta, Sean Pot, David Sheth, Margi Demchok, John A. Davidsen, Tanja Wang, Zhining Yang, Liming Tarnuzzer, Roy W. Zhang, Jiashan Eley, Greg Ferguson, Martin L. Shaw, Kenna R. Mills Guyer, Mark S. Ozenberger, Bradley A. Sofia, Heidi J. CA Canc Genome Atlas Res Network Anal Working Grp TI Comprehensivemolecular characterization of clear cell renal cell carcinoma SO NATURE LA English DT Article ID KIDNEY CANCER; TUMOR-SUPPRESSOR; DNA METHYLATION; GENETIC-BASIS; TARGETS; PROTEIN; TRIAL; ARM AB Genetic changes underlying clear cell renal cell carcinoma(ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3) K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment. C1 [Creighton, Chad J.; Morgan, Margaret; Gunaratne, Preethi H.; Wheeler, David A.; Gibbs, Richard A.; Muzny, Donna; Davis, Caleb; Xi, Liu; Chang, Kyle; Kakkar, Nipun; Trevino, Lisa R.; Benton, Susan; Reid, Jeffrey G.; Morton, Donna; Doddapaneni, Harsha; Han, Yi; Lewis, Lora; Dinh, Huyen; Kovar, Christie; Zhu, Yiming; Santibanez, Jireh; Wang, Min; Hale, Walker; Kalra, Divya] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Xiao, Weimin] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. [Robertson, A. Gordon; Chu, Andy; Chun, Hye-Jung E.; Mungall, Andrew J.; Sipahimalani, Payal; Stoll, Dominik; Ally, Adrian; Balasundaram, Miruna; Butterfield, Yaron S. N.; Carlsen, Rebecca; Carter, Candace; Chuah, Eric; Coope, Robin J. N.; Dhalla, Noreen; Gorski, Sharon; Guin, Ranabir; Hirst, Carrie; Hirst, Martin; Holt, Robert A.; Lebovitz, Chandra; Lee, Darlene; Li, Haiyan I.; Mayo, Michael; Moore, Richard A.; Pleasance, Erin; Plettner, Patrick; Schein, Jacqueline E.; Shafiei, Arash; Slobodan, Jared R.; Tam, Angela; Thiessen, Nina; Varhol, Richard J.; Wye, Natasja; Zhao, Yongjun; Birol, Inanc; Jones, Steven J. M.; Marra, Marco A.] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z, Canada. [Beroukhim, Rameen; Beroukhim, Rameen; Carter, Scott L.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02215 USA. [Beroukhim, Rameen; Cibulskis, Kristian; Getz, Gad; Lawrence, Michael S.; Sougnez, Carrie; Carter, Scott L.; Sivachenko, Andrey; Lichtenstein, Lee; Stewart, Chip; Voet, Doug; Fisher, Sheila; Gabriel, Stacey B.; Lander, Eric; Beroukhim, Rameen; Schumacher, Steve E.; Tabak, Barbara; Saksena, Gordon; Onofrio, Robert C.; Cherniack, Andrew D.; Gentry, Jeff; Ardlie, Kristin; Meyerson, Matthew; Noble, Michael S.; DiCara, Daniel; Zhang, Hailei; Cho, Juok; Heiman, David I.; Gehlenborg, Nils; Mallard, William; Lin, Pei; Frazer, Scott; Stojanov, Petar; Liu, Yingchun; Zhou, Lihua; Kim, Jaegil; Chin, Lynda] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Beroukhim, Rameen; Carter, Scott L.; Sivachenko, Andrey; Lichtenstein, Lee; Stewart, Chip; Fisher, Sheila; Lander, Eric; Beroukhim, Rameen; Schumacher, Steve E.; Tabak, Barbara; Saksena, Gordon; Onofrio, Robert C.; Cherniack, Andrew D.; Gentry, Jeff; Ardlie, Kristin; Meyerson, Matthew; Noble, Michael S.; DiCara, Daniel; Zhang, Hailei; Cho, Juok; Heiman, David I.; Gehlenborg, Nils; Mallard, William; Lin, Pei; Frazer, Scott; Stojanov, Petar; Liu, Yingchun; Zhou, Lihua; Kim, Jaegil] Harvard Univ, Cambridge, MA 02142 USA. [Signoretti, Sabina; Meyerson, Matthew] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02215 USA. [Vandin, Fabio; Wu, Hsin-Ta; Raphael, Benjamin J.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Verhaak, Roel G. W.; Torres-Garcia, Wandaliz; Akbani, Rehan; Weinstein, John N.; Vegesna, Rahul; Kim, Hoon; Jonasch, Eric; Ding, Zhiyong; Zhang, Nianxiang; Unruh, Anna K.; Casasent, Tod D.; Wakefield, Chris] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Tamboli, Pheroze; Zhang, Wei; Cogdell, David; Czerniak, Bogdan A.; Aldape, Kenneth D.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Reuter, Victor; Brannon, A. Rose; Berger, Michael F.; Tickoo, Satish] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Hsieh, James J.; Hakimi, A. Ari; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Jacobsen, Anders; Ciriello, Giovanni; Reva, Boris; Schultz, Nikolaus; Antipin, Yevgeniy; Gao, Jianjiong; Cerami, Ethan; Gross, Benjamin; Aksoy, B. Arman; Sinha, Rileen; Weinhold, Nils; Sumer, S. Onur; Taylor, Barry S.; Shen, Ronglai; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Ricketts, Christopher J.; Linehan, W. Marston; Vocke, Cathy D.; Peterson, James; Worrell, Robert; Merino, Maria J.; Schmidt, Laura S.] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Stuart, Joshua M.; Sam Ng; Paull, Evan O.; Carlin, Daniel; Goldstein, Theodore; Waltman, Peter; Ellrott, Kyle; Zhu, Jing; Haussler, David] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Sam Ng; Paull, Evan O.; Carlin, Daniel; Goldstein, Theodore; Waltman, Peter; Ellrott, Kyle; Zhu, Jing; Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Rathmell, W. Kimryn; Hoadley, Katherine A.; Liquori, Christina; Turman, Yidi J.; Shi, Yan; Waring, Scot; Buda, Elizabeth; Walsh, Jesse; Wu, Junyuan; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, MathewG.; Balu, Saianand; Parker, Joel S.; Hayes, D. Neil; Perou, Charles M.; Thorne, Leigh; Boice, Lori; Huang, Mei; Fisher, Jennifer C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Shen, Hui; Laird, Peter W.; Triche, Timothy, Jr.; Weisenberger, Daniel J.; Lai, Phillip H.; Bootwalla, Moiz S.; Maglinte, Dennis T.; Mahurkar, Swapna; Berman, Benjamin P.; Van den Berg, David J.] Univ So Calif, USC Epigenome Ctr, Los Angeles, CA 90033 USA. [Auman, J. Todd] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Tan, Donghui] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Jones, Corbin D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Mose, Lisle E.; Topal, MichaelD.; Perou, Charles M.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Hoadley, Katherine A.; Mieczkowski, Piotr A.; Jefferys, Stuart R.; Topal, MichaelD.; Perou, Charles M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Hayes, D. Neil] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC 27599 USA. [Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. [Kucherlapati, Raju; Park, Peter] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Park, Peter; Gehlenborg, Nils] Harvard Univ, Ctr Biomed Informat, Sch Med, Boston, MA 02115 USA. [Park, Peter] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Cope, Leslie; Baylin, Stephen B.] Johns Hopkins Univ, Canc Biol Div, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Reynolds, Sheila M.; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Lu, Yiling; Tsavachidou, Dimitra; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77054 USA. [Ostrovnaya, Irina] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Fei, Suzanne S.; Stout, Andrew; Spellman, Paul T.] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portand, OR 97239 USA. [Rubin, Daniel L.; Liu, Tiffany T.] Stanford Univ, Dept Radiol, Med Ctr, Stanford, CA 94305 USA. [Haussler, David] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Shelton, Candace; Gardner, Johanna; Penny, Robert; Sherman, Mark; Mallery, David; Morris, Scott; Paulauskis, Joseph; Burnett, Ken; Shelton, Troy; Curley, Erin] Int Genom Consortium, Phoenix, AZ 85004 USA. [Atkins, Michael B.] Georgetown Univ, Georgetown Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. SAIC Frederick Inc, Basic Sci Program, Frederick Natl Lab, Frederick, MD 21702 USA. [Wood, Christopher G.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Boyd, Jeff; Weaver, JoEllen] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA. [Iacocca, Mary V.; Petrelli, Nicholas; Witkin, Gary; Brown, Jennifer; Czerwinski, Christine; Huelsenbeck-Dill, Lori; Rabeno, Brenda] Christiana Care, Helen F Graham Canc Ctr, Newark, DC 19713 USA. [Myers, Jerome; Morrison, Carl; Bergsten, Julie; Eckman, John; Harr, Jodi; Smith, Christine; Tucker, Kelinda; Zach, Leigh Anne] Penrose St Francis Hlth Serv, Colorado Springs, CO 80907 USA. [Bshara, Wiam; Gaudioso, Carmelo; Morrison, Carl] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA. [Dhir, Rajiv; Maranchie, Jodi; Nelson, Joel; Parwani, Anil] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. [Potapova, Olga] Cureline Inc, San Francisco, CA 94080 USA. [Fedosenko, Konstantin] St Petersburg City Clin Oncol Dispensary, St Petersburg 198255, Russia. [Mosquera, Juan M.; Rubin, Mark A.] Weill Cornell Coll Med, Dept Pathol & Lab Med, New York, NY 10065 USA. [Blute, Michael L.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Pihl, Todd; Jensen, Mark; Sfeir, Robert; Kahn, Ari; Chu, Anna; Kothiyal, Prachi; Snyder, Eric; Pontius, Joan; Ayala, Brenda; Backus, Mark; Walton, Jessica; Baboud, Julien; Berton, Dominique; Nicholls, Matthew; Srinivasan, Deepak; Raman, Rohini; Girshik, Stanley; Kigonya, Peter; Alonso, Shelley; Sanbhadti, Rashmi; Barletta, Sean; Pot, David] SRA Int, Fairfax, VA 22033 USA. [Sheth, Margi; Demchok, John A.; Davidsen, Tanja; Wang, Zhining; Yang, Liming; Tarnuzzer, Roy W.; Zhang, Jiashan; Shaw, Kenna R. Mills] NCI, Canc Genome Atlas Program Off, Ctr Canc Genom, Bethesda, MD 20892 USA. [Eley, Greg] TCGA Consultant Scimentis LLC, Atlanta, GA 30666 USA. [Ferguson, Martin L.] MLF Consulting, Arlington, MA 02474 USA. [Guyer, Mark S.; Ozenberger, Bradley A.; Sofia, Heidi J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Beroukhim, Rameen; Meyerson, Matthew; Stojanov, Petar; Kaelin, William G.; Choueiri, Toni] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Benz, Christopher; Yau, Christina] Buck Inst Res Aging, Novato, CA 94945 USA. [Beroukhim, Rameen; Schumacher, Steve E.; Tabak, Barbara] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cheville, John C.; Thompson, R. Houston] Mayo Clin, Rochester, MN 55905 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Gibbs, RA (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. EM agibbs@bcm.edu; linehanm@mail.nih.gov RI Birol, Inanc/G-5440-2011; Jacobsen, Anders/K-1081-2013; Schumacher, Steven/E-9821-2013; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; Reva, Boris/B-6436-2014; Berman, Benjamin/D-5942-2014; Gorski, Sharon/E-9375-2012; Holt, Robert/C-3303-2009; Kalra, Divya/N-5453-2014; Laird, Peter/G-8683-2012; Schein, Jacquie/G-3674-2015; Gao, Jianjiong/B-5673-2016; Hirst, Martin/B-7684-2016 OI Gehlenborg, Nils/0000-0003-0327-8297; Birol, Inanc/0000-0003-0950-7839; Schultz, Nikolaus/0000-0002-0131-4904; parwani, anil/0000-0002-7616-1666; Triche, Tim/0000-0001-5665-946X; Maranchie, Jodi/0000-0002-8534-9468; Rubin, Mark/0000-0002-8321-9950; Pot, David/0000-0002-1480-9826; Sinha, Rileen/0000-0001-5497-5055; Casasent, Anna/0000-0002-7857-179X; Perou, Charles/0000-0001-9827-2247; Jacobsen, Anders/0000-0001-6847-4980; Schumacher, Steven/0000-0002-6819-5647; Reva, Boris/0000-0002-8805-389X; Gorski, Sharon/0000-0002-3821-8289; Gao, Jianjiong/0000-0002-5739-1781; NR 33 TC 167 Z9 172 U1 9 U2 116 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 4 PY 2013 VL 499 IS 7456 BP 43 EP + DI 10.1038/nature12222 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176ED UT WOS:000321285600029 ER PT J AU Kim, KH Roberts, CWM AF Kim, Kimberly H. Roberts, Charles W. M. TI CHD7 in Charge of Neurogenesis SO CELL STEM CELL LA English DT Editorial Material ID MUTATIONS AB In this issue of Cell Stem Cell, Feng et al. (2013) report that the gene mutated in human CHARGE syndrome, ATP-dependent chromatin remodeling factor CHD7, contributes to the control of neurogenesis. The authors also report that exercise ameliorates these defects and suggest it as an intervention worthy of study in CHARGE syndrome. C1 [Kim, Kimberly H.; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Kim, Kimberly H.; Roberts, Charles W. M.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Kim, Kimberly H.; Roberts, Charles W. M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Roberts, CWM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM charles_roberts@dfci.harvard.edu NR 9 TC 3 Z9 4 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2013 VL 13 IS 1 BP 1 EP 2 DI 10.1016/j.stem.2013.06.010 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VJ UT WOS:000329570100001 PM 23827700 ER PT J AU Choudhury, S Almendro, V Merino, VF Wu, ZH Maruyama, R Su, Y Martins, FC Fackler, MJ Bessarabova, M Kowalczyk, A Conway, T Beresford-Smith, B Macintyre, G Cheng, YK Lopez-Bujanda, Z Kaspi, A Hu, R Robens, J Nikolskaya, T Haakensen, VD Schnitt, SJ Argani, P Ethington, G Panos, L Grant, M Clark, J Herlihy, W Lin, SJ Chew, G Thompson, EW Greene-Colozzi, A Richardson, AL Rosson, GD Pike, M Garber, JE Nikolsky, Y Blum, JL Au, A Hwang, ES Tamimi, RM Michor, F Haviv, I Liu, XS Sukumar, S Polyak, K AF Choudhury, Sibgat Almendro, Vanessa Merino, Vanessa F. Wu, Zhenhua Maruyama, Reo Su, Ying Martins, Filipe C. Fackler, Mary Jo Bessarabova, Marina Kowalczyk, Adam Conway, Thomas Beresford-Smith, Bryan Macintyre, Geoff Cheng, Yu-Kang Lopez-Bujanda, Zoila Kaspi, Antony Hu, Rong Robens, Judith Nikolskaya, Tatiana Haakensen, Vilde D. Schnitt, Stuart J. Argani, Pedram Ethington, Gabrielle Panos, Laura Grant, Michael Clark, Jason Herlihy, William Lin, S. Joyce Chew, Grace Thompson, Erik W. Greene-Colozzi, April Richardson, Andrea L. Rosson, Gedge D. Pike, Malcolm Garber, Judy E. Nikolsky, Yuri Blum, Joanne L. Au, Alfred Hwang, E. Shelley Tamimi, Rulla M. Michor, Franziska Haviv, Izhak Liu, X. Shirley Sukumar, Saraswati Polyak, Kornelia TI Molecular Profiling of Human Mammary Gland Links Breast Cancer Risk to a p27(+) Cell Population with Progenitor Characteristics SO CELL STEM CELL LA English DT Article ID HORMONE-INDUCED PROTECTION; GENE-EXPRESSION; STEM-CELLS; MUTATION CARRIERS; GENOMIC SIGNATURE; PREGNANCY; P27(KIP1); INHIBITOR; GROWTH; TUMORIGENESIS AB Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44(+) progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44(+)p27(+) cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27(+) cells and their proliferation. Our results suggest that pathways controlling p27(+) mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention. C1 [Choudhury, Sibgat; Almendro, Vanessa; Maruyama, Reo; Su, Ying; Martins, Filipe C.; Garber, Judy E.; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Wu, Zhenhua; Cheng, Yu-Kang; Michor, Franziska; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Greene-Colozzi, April; Richardson, Andrea L.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Garber, Judy E.] Dana Farber Canc Inst, Ctr Clin Canc Genet, Boston, MA 02215 USA. [Choudhury, Sibgat; Almendro, Vanessa; Maruyama, Reo; Su, Ying; Hu, Rong; Garber, Judy E.; Tamimi, Rulla M.; Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Richardson, Andrea L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Choudhury, Sibgat; Almendro, Vanessa; Maruyama, Reo; Su, Ying; Garber, Judy E.; Polyak, Kornelia] Harvard Univ, Dept Med, Boston, MA 02115 USA. [Robens, Judith; Schnitt, Stuart J.; Richardson, Andrea L.] Harvard Univ, Dept Pathol, Boston, MA 02115 USA. [Wu, Zhenhua; Cheng, Yu-Kang; Tamimi, Rulla M.; Michor, Franziska; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Almendro, Vanessa] Hosp Clin Barcelona, Dept Med, Inst Invest Biomed August Pi & Sunyer, E-08036 Barcelona, Spain. [Merino, Vanessa F.; Fackler, Mary Jo; Lopez-Bujanda, Zoila; Sukumar, Saraswati] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA. [Argani, Pedram] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA. [Rosson, Gedge D.] Johns Hopkins Univ, Sch Med, Dept Plast Surg, Baltimore, MD 21231 USA. [Martins, Filipe C.] Coimbra Univ Hosp, Dept Obstet & Gynaecol, P-3000354 Coimbra, Portugal. [Martins, Filipe C.] Programa Gulbenkian Formacao Med Avancada, P-1067001 Lisbon, Portugal. [Bessarabova, Marina; Nikolskaya, Tatiana; Nikolsky, Yuri] Thomson Reuters Healthcare & Sci, Encinitas, CA 92024 USA. [Kowalczyk, Adam; Conway, Thomas; Beresford-Smith, Bryan; Macintyre, Geoff; Haviv, Izhak] Univ Melbourne, NICTA Victoria Res Lab, Parkville, Vic 3010, Australia. [Kowalczyk, Adam] Univ Melbourne, Dept Elect & Elect Engn, Parkville, Vic 3010, Australia. [Kowalczyk, Adam; Conway, Thomas; Beresford-Smith, Bryan; Macintyre, Geoff] Univ Melbourne, Dept Comp Sci & Software Engn, Parkville, Vic 3010, Australia. [Lin, S. Joyce; Haviv, Izhak] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia. [Chew, Grace; Thompson, Erik W.] Univ Melbourne, Dept Surg, Parkville, Vic 3010, Australia. [Thompson, Erik W.] Univ Melbourne, Dept Biochem, Parkville, Vic 3010, Australia. [Kaspi, Antony; Haviv, Izhak] Baker IDI Heart & Diabet Inst, Prahran, Vic 3004, Australia. [Robens, Judith; Schnitt, Stuart J.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Haakensen, Vilde D.] Univ Oslo, Oslo Univ Hosp, Dept Genet, Inst Canc Res, N-0424 Oslo, Norway. [Haakensen, Vilde D.] Univ Oslo, Oslo Univ Hosp, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0424 Oslo, Norway. [Ethington, Gabrielle; Panos, Laura; Grant, Michael; Clark, Jason; Herlihy, William; Blum, Joanne L.] Baylor Charles A Sammons Canc Ctr, Dallas, TX 75246 USA. [Thompson, Erik W.] St Vincents Inst, Fitzroy, Vic 3065, Australia. [Pike, Malcolm] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Au, Alfred; Hwang, E. Shelley] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Haviv, Izhak] Peter MacCallum Canc Ctr, East Melbourne, Vic 3002, Australia. [Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Sukumar, S (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA. EM saras@jhmi.edu; kornelia_polyak@dfci.harvard.edu RI Nikolskaya, Tatiana/M-5008-2013; Thompson, Erik/A-1425-2009; OI Thompson, Erik/0000-0002-9723-4924; Haakensen, Vilde D/0000-0003-0864-3628; Rosson, Gedge/0000-0003-1817-9443 FU Avon Foundation; National Cancer Institute [P50 CA89383, P01 CA080111, CA116235-04S1, CA087969]; Susan G. Komen Foundation; Terri Brodeur Foundation; US Army Congressionally Directed Research [W81XWH-07-1-0294]; Victorian Breast Cancer Research Consortium; St. Vincent's Hospital Research Endowment Fund; Victorian Government's OIS Program; Programme for Advanced Medical Education; Fundacao Calouste Gulbenkian; Cellex Foundation FX We thank Lisa Cameron in the DFCI Confocal and Light Microscopy Core Facility, members of Dr. Massimo Loda's lab for technical assistance, members of our laboratories and Drs. Elgene Lim and David Livingston for their critical reading of this manuscript, Jonathan Yingling (Eli Lilly) for providing the LY2109761 TGF-beta receptor kinase inhibitor, Drs. Sally Knox, Jeffrey Lamont, and Dao Tuoc (Baylor University Medical Center-Baylor Sammons Cancer Center), Erin Bowlby (University of California San Francisco, San Francisco), and Drs. Eli Golomg and Pikarski (Hadassah Medical Centre) for their help with collecting tissue samples from patients with BRCA1/BRCA2 germline mutation. Samples from the Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center were used in this study. We thank contributors, including Indiana University who collected samples used in this study, as well as donors and their families, whose help and participation made this work possible. This work was supported by the Avon Foundation (to K. P. and S. S.), the National Cancer Institute P50 CA89383 and P01 CA080111 (to S.J.S., K. P., and A. L. R.), CA116235-04S1 (to K. P.), and CA087969 (to R. M. T.), the Susan G. Komen Foundation (to R. M., Y.S., I. H., J.E.G., and K. P.), the Terri Brodeur Foundation (to S. C.), US Army Congressionally Directed Research W81XWH-07-1-0294 (to K. P.), the Victorian Breast Cancer Research Consortium (to S.J.L., G. C., and E. W. T.), the St. Vincent's Hospital Research Endowment Fund and the Victorian Government's OIS Program (to E. W. T.), the Programme for Advanced Medical Education funded by Fundacao Calouste Gulbenkian (to F. M.), and the Cellex Foundation (to V.A.). NR 58 TC 35 Z9 35 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2013 VL 13 IS 1 BP 117 EP 130 DI 10.1016/j.stem.2013.05.004 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VJ UT WOS:000329570100017 PM 23770079 ER PT J AU Zorick, T Mandelkern, MA AF Zorick, Todd Mandelkern, Mark A. TI Multifractal Detrended Fluctuation Analysis of Human EEG: Preliminary Investigation and Comparison with the Wavelet Transform Modulus Maxima Technique SO PLOS ONE LA English DT Article ID NEURONAL AVALANCHES; HUMAN BRAIN; FUNCTIONAL-STATE; SLEEP-APNEA; SIGNALS; OSCILLATIONS; DYNAMICS; CORTEX; SERIES AB Recently, many lines of investigation in neuroscience and statistical physics have converged to raise the hypothesis that the underlying pattern of neuronal activation which results in electroencephalography (EEG) signals is nonlinear, with self-affine dynamics, while scalp-recorded EEG signals themselves are nonstationary. Therefore, traditional methods of EEG analysis may miss many properties inherent in such signals. Similarly, fractal analysis of EEG signals has shown scaling behaviors that may not be consistent with pure monofractal processes. In this study, we hypothesized that scalp-recorded human EEG signals may be better modeled as an underlying multifractal process. We utilized the Physionet online database, a publicly available database of human EEG signals as a standardized reference database for this study. Herein, we report the use of multifractal detrended fluctuation analysis on human EEG signals derived from waking and different sleep stages, and show evidence that supports the use of multifractal methods. Next, we compare multifractal detrended fluctuation analysis to a previously published multifractal technique, wavelet transform modulus maxima, using EEG signals from waking and sleep, and demonstrate that multifractal detrended fluctuation analysis has lower indices of variability. Finally, we report a preliminary investigation into the use of multifractal detrended fluctuation analysis as a pattern classification technique on human EEG signals from waking and different sleep stages, and demonstrate its potential utility for automatic classification of different states of consciousness. Therefore, multifractal detrended fluctuation analysis may be a useful pattern classification technique to distinguish among different states of brain function. C1 [Zorick, Todd] Greater Los Angeles Vet Adm Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. [Mandelkern, Mark A.] Greater Los Angeles Vet Adm Healthcare Syst, Dept Imaging, Los Angeles, CA USA. [Zorick, Todd] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. RP Zorick, T (reprint author), Greater Los Angeles Vet Adm Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. EM tzorick@mednet.ucla.edu NR 50 TC 14 Z9 14 U1 2 U2 14 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 JUL 3 PY 2013 VL 8 IS 7 AR e68360 DI 10.1371/journal.pone.0068360 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 182HT UT WOS:000321733000141 PM 23844189 ER PT J AU Bove, R Musallam, A Healy, BC Houtchens, M Glanz, BI Khoury, S Guttmann, CR De Jager, PL Chitnis, T AF Bove, Riley Musallam, Alexander Healy, Brian C. Houtchens, Maria Glanz, Bonnie I. Khoury, Samia Guttmann, Charles R. De Jager, Philip L. Chitnis, Tanuja TI No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50 SO BMC NEUROLOGY LA English DT Article DE Demyelinating disease; Multiple sclerosis; Natural history studies; MRI; Disease progression; Menopause; Gender ID HORMONE REPLACEMENT THERAPY; QUALITY-OF-LIFE; NATURAL MENOPAUSE; DISABILITY; WOMEN; ONSET; ESTROGEN AB Background: The disease course in multiple sclerosis (MS) is influenced by many factors, including age, sex, and sex hormones. Little is known about sex-specific changes in disease course around age 50, which may represent a key biological transition period for reproductive aging. Methods: Male and female subjects with no prior chemotherapy exposure were selected from a prospective MS cohort to form groups representing the years before (38-46 years, N=351) and after (54-62 years, N=200) age 50. Primary analysis assessed for interaction between effects of sex and age on clinical (Expanded Disability Status Scale, EDSS; relapse rate) and radiologic (T2 lesion volume, T2LV; brain parenchymal fraction, BPF) outcomes. Secondarily, we explored patient-reported outcomes (PROs). Results: As expected, there were age-and sex-related changes with male and older cohorts showing worse disease severity (EDSS), brain atrophy (BPF), and more progressive course. There was no interaction between age and sex on cross-sectional adjusted clinical (EDSS, relapse rate) or radiologic (BPF, T2LV) measures, or on 2-year trajectories of decline. There was a significant interaction between age and sex for a physical functioning PRO (SF-36): the older female cohort reported lower physical functioning than men (p=0.002). There were no differences in depression (Center for Epidemiological Study - Depression, CES-D) or fatigue (Modified Fatigue Impact Scale, MFIS) scores. Conclusions: There was no interaction between age and sex suggestive of an effect of reproductive aging on clinical or radiologic progression. Prospective analyses across the menopausal transition are needed. C1 [Bove, Riley; Musallam, Alexander; Healy, Brian C.; Houtchens, Maria; Glanz, Bonnie I.; Khoury, Samia; Guttmann, Charles R.; De Jager, Philip L.; Chitnis, Tanuja] Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Dept Neurol, Brookline, MA 02445 USA. [Bove, Riley; Healy, Brian C.; Houtchens, Maria; Khoury, Samia; Guttmann, Charles R.; De Jager, Philip L.; Chitnis, Tanuja] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [De Jager, Philip L.] Harvard Univ, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. RP Chitnis, T (reprint author), Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Dept Neurol, Brookline, MA 02445 USA. EM tchitnis@rics.bwh.harvard.edu OI khoury, samia/0000-0003-3198-6063 FU National Multiple Sclerosis Society [TC-RG-4256A4/2/]; NIH T32 [RB-5T32AI074549] FX Supported by the National Multiple Sclerosis Society (TC-RG-4256A4/2/) and the NIH T32 (RB-5T32AI074549). NR 35 TC 9 Z9 9 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD JUL 3 PY 2013 VL 13 AR 73 DI 10.1186/1471-2377-13-73 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 180BZ UT WOS:000321569200001 PM 23822612 ER PT J AU Sandoval, KE Farr, SA Banks, WA Crider, AM Morlef, JE Witt, KA AF Sandoval, Karin E. Farr, Susan A. Banks, William A. Crider, Albert M. Morlef, John E. Witt, Ken A. TI Somatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble A beta(42) oligomers via a metalloproteinase-dependent mechanism SO BRAIN RESEARCH LA English DT Article DE Phosphoramidon; NNC 26-9100; Somatostatin receptor subtype-4; Amyloid-beta oligomer ID AMYLOID-BETA PEPTIDE; INTRANEURONAL A-BETA-42 ACCUMULATION; ENDOTHELIN-CONVERTING ENZYME; ALZHEIMERS-DISEASE; SAMP8 MICE; A-BETA; SYNAPTIC PLASTICITY; WILD-TYPE; DEGRADING ENZYMES; TRANSGENIC MODEL AB Soluble amyloid-beta peptide (A beta) oligomers have been hypothesized to be primary mediators of Alzheimer's disease progression. In this regard, reduction of soluble A beta-oligomers levels within the brain may provide a viable means in which to treat the disease. Somatostatin receptor subtype-4 (SSTR4) agonists have been proposed to reduce A beta levels in the brain via enhancement of enzymatic degradation. Herein we evaluated the effect of selective SSTR4 agonist NNC 26-9100 on the changes in learning and soluble A beta(42) oligomer brain content with and without co-administration of the M13-metalloproteinase family enzyme-inhibitor phosphoramidon, using the senescence-accelerated mouse prone-8 (SAMP8) model. NNC 26-9100 treatment (0.2 mu g i.c.v. in 2 mu L) improved learning, which was blocked by phosphoramidon (1 and 10 mM, respectively). NNC 26-9100 decreased total soluble A beta(42), an effect which was blocked by phosphoramidon (10 mM). Extracellular, intracellular, and membrane fractions were then isolated from cortical tissue and assessed for soluble oligomer alterations. NNC 26-9100 decreased the A beta(42) trimeric (12 kDa) form within the extracellular and intracellular fractions, and produced a band-split effect of the A beta(42) hexameric (25 kDa) form within the extracellular fraction. These effects were also blocked by phosphoramdon (1 and 10 mM, respectively). Subsequent evaluation of NNC 26-9100 in APPswe Tg2576 transgenic mice showed a similar learning improvement and corresponding reduction in soluble A beta(42) oligomers within extracellular, intracellular, and membrane fractions. These data support the hypothesis that NNC 26-9100 reduces soluble A beta(42) oligomers and enhances learning through a phosphoramidon-sensitive metalloproteinase-dependent mechanism. (c) 2013 Elsevier B.V. All rights reserved. C1 [Sandoval, Karin E.; Crider, Albert M.; Witt, Ken A.] So Illinois Univ, Sch Pharm, Edwardsville, IL 62026 USA. [Farr, Susan A.] Vet Affairs Med Ctr St Louis, Res & Dev, St Louis, MO USA. [Farr, Susan A.; Morlef, John E.] St Louis Univ, Sch Med, Dept Internal Med, St Louis, MO 63103 USA. [Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Banks, William A.] Univ Washington, Sch Med, Dept Internal Med, Div Gerontol & Geriatr Med, Seattle, WA USA. [Morlef, John E.] St Louis Univ, Sch Med, Dept Internal Med, Div Endocrinol, St Louis, MO 63103 USA. RP Witt, KA (reprint author), So Illinois Univ, Sch Pharm, 200 Univ Pk Dr, Edwardsville, IL 62026 USA. EM kwitt@siue.edu FU VA Merit Review; National Institutes of Health National Institute on Aging [R21AG029318] FX This work was supported by VA Merit Review, and the National Institutes of Health National Institute on Aging (Grant: R21AG029318). A use-patent has been obtained for NNC 26-9100 by Southern Illinois University Edwardsville. No other disclosures. NR 53 TC 4 Z9 6 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 3 PY 2013 VL 1520 BP 145 EP 156 DI 10.1016/j.brainres.2013.05.006 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 178XO UT WOS:000321480900014 PM 23669069 ER PT J AU Vijayan, S Ching, SN Purdon, PL Brown, EN Kopell, NJ AF Vijayan, Sujith Ching, ShiNung Purdon, Patrick L. Brown, Emery N. Kopell, Nancy J. TI Thalamocortical Mechanisms for the Anteriorization of Alpha Rhythms during Propofol-Induced Unconsciousness SO JOURNAL OF NEUROSCIENCE LA English DT Article ID I-H CONTRIBUTES; GENERAL-ANESTHESIA; SYNCHRONIZED OSCILLATIONS; COHERENCE ANALYSIS; NEURONS; MODEL; EEG; CONSCIOUSNESS; SUPPRESSION; INHIBITION AB As humans are induced into a state of general anesthesia via propofol, the normal alpha rhythm (8-13 Hz) in the occipital cortex disappears and a frontal alpha rhythm emerges. This spatial shift in alpha activity is called anteriorization. We present a thalamocortical model that suggests mechanisms underlying anteriorization. Our model captures the neural dynamics of anteriorization when we adjust it to reflect two key actions of propofol: its potentiation of GABA and its reduction of the hyperpolarization-activated current I-h. The reduction in Ih abolishes the occipital alpha by silencing a specialized subset of thalamocortical cells, thought to generate occipital alpha at depolarized membrane potentials (>-60 mV). The increase in GABA inhibition imposes an alpha timescale on both the cortical and thalamic portions of the frontal component that are reinforced by reciprocal thalamocortical feedback. Anteriorization can thus be understood as a differential effect of anesthetic drugs on thalamic nuclei with disparate spatial projections, i.e.: (1) they disrupt the normal, depolarized alpha in posterior-projecting thalamic nuclei while (2) they engage a new, hyperpolarized alpha in frontothalamic nuclei. Our model generalizes to other anesthetics that include GABA as a target, since the molecular targets of many such anesthetics alter the model dynamics in a manner similar to that of propofol. C1 [Vijayan, Sujith; Ching, ShiNung; Kopell, Nancy J.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Ching, ShiNung; Purdon, Patrick L.; Brown, Emery N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ching, ShiNung; Purdon, Patrick L.; Brown, Emery N.] MIT, Cambridge, MA 02139 USA. [Ching, ShiNung; Purdon, Patrick L.; Brown, Emery N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Purdon, Patrick L.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Vijayan, S (reprint author), Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. EM svijayan9@gmail.com FU National Science Foundation (NSF) [DMS-1042134, DMS-1225647]; Burroughs Wellcome Fund; National Institutes of Health (NIH) [National Institutes of Health (NIH)]; NIH K-Award [K25-NS057580]; NIH Director's Pioneer Award [DP1-OD003646]; NIH Director's Transformative Research Award [R01 GM104948] FX S.V. acknowledges support from National Science Foundation (NSF) Grant DMS-1042134. S. C. acknowledges support from the Burroughs Wellcome Fund. P. L. P. acknowledges support from National Institutes of Health (NIH) New Innovator Award DP2-OD006454 and NIH K-Award K25-NS057580. E.N.B. acknowledges support from NIH Director's Pioneer Award DP1-OD003646 and NIH Director's Transformative Research Award R01 GM104948. N.J.K. acknowledges support from NSF grants DMS-1042134 and DMS-1225647. NR 38 TC 31 Z9 31 U1 0 U2 13 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 JUL 3 PY 2013 VL 33 IS 27 BP 11070 EP 11075 DI 10.1523/JNEUROSCI.5670-12.2013 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 175UC UT WOS:000321258000014 PM 23825412 ER PT J AU Bhattacharyya, R Barren, C Kovacs, DM AF Bhattacharyya, Raja Barren, Cory Kovacs, Dora M. TI Palmitoylation of Amyloid Precursor Protein Regulates Amyloidogenic Processing in Lipid Rafts SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ALZHEIMERS-DISEASE; GAMMA-SECRETASE; BETA-SECRETASE; ENDOPLASMIC-RETICULUM; TRANSGENIC MICE; MOUSE MODEL; RAT-LIVER; CHOLESTEROL; ACYLTRANSFERASE; LOCALIZATION AB Brains of patients affected by Alzheimer's disease (AD) contain large deposits of aggregated amyloid beta-protein (A beta). Only a small fraction of the amyloid precursor protein (APP) gives rise to A beta. Here, we report that similar to 10% of APP undergoes a post-translational lipid modification called palmitoylation. We identified the palmitoylation sites in APP at Cys(186) and Cys(187). Surprisingly, point mutations introduced into these cysteines caused nearly complete ER retention of APP. Thus, either APP palmitoylation or disulfide bridges involving these Cys residues appear to be required for ER exit of APP. In later compartments, palmitoylated APP(palAPP) was specifically enriched in lipid rafts. In vitro BACE1 cleavage assays using cell or mouse brain lipid rafts showed that APP palmitoylation enhanced BACE1-mediated processing of APP. Interestingly, we detected an age-dependent increase in endogenous mouse brain palAPP levels. Overexpression of selected DHHC palmitoyl acyltransferases increased palmitoylation of APP and doubled A beta production, while two palmitoylation inhibitors reduced palAPP levels and APP processing. We have found previously that acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibition led to impaired APP processing. Here we demonstrate that pharmacological inhibition or genetic inactivation of ACAT decrease lipid raft palAPP levels by up to 76%, likely resulting in impaired APP processing. Together, our results indicate that APP palmitoylation enhances amyloidogenic processing by targeting APP to lipid rafts and enhancing its BACE1-mediated cleavage. Thus, inhibition of palAPP formation by ACAT or specific palmitoylation inhibitors would appear to be a valid strategy for prevention and/or treatment of AD. C1 [Bhattacharyya, Raja; Barren, Cory; Kovacs, Dora M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Genet & Aging Res Unit,Dept Neurol, MassGen Inst Neurodegenerat Dis,Neurol Dis Lab, Charlestown, MA 02129 USA. RP Kovacs, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Genet & Aging Res Unit,Dept Neurol, MassGen Inst Neurodegenerat Dis,Neurol Dis Lab, Charlestown, MA 02129 USA. EM dora_kovacs@hms.harvard.edu FU Cure Alzheimer's Fund grants; NIH-NINDS [R01NS45860] FX This wok was supported by Cure Alzheimer's Fund grants and NIH-NINDS Grant R01NS45860 (D. M. K). We thank Dr. Vivek Gautam (Massachusetts General Hospital, Charlestown, MA) for his generous help in preparing primary neurons; Dr. Masaki Fukata (National Institute for Physiological Sciences, Okazaki, Japan) for providing us with the DHHC expression plasmids; Dr. Kiyohito Mizutani (Kobe University Graduate School of Medicine, Kobe, Japan; previously at Massachusetts General Hospital, Charlestown, MA) for generating APP(Delta 343)-expressing cells; Dr. Jordan Tang (Oklahoma Medical Research Foundation, Oklahoma City, OK) for dr9; Lit-Fui Lau (GlaxoSmithKline, Shanghai, China; previously at Pfizer, Groton, CT) for CI-1011; and Dr. Doo Yeon Kim (Massachusetts General Hospital, Charlestown, MA) for helpful advice and discussions. NR 78 TC 35 Z9 36 U1 0 U2 16 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 JUL 3 PY 2013 VL 33 IS 27 BP 11169 EP 11183 DI 10.1523/JNEUROSCI.4704-12.2013 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 175UC UT WOS:000321258000022 PM 23825420 ER PT J AU Drummond, IA AF Drummond, Iain A. TI The cilium in lights: new views of an ancient organelle SO BMC BIOLOGY LA English DT Editorial Material ID LEFT-RIGHT ASYMMETRY; INTRAFLAGELLAR; MOUSE; MICE; PROTEIN; CALCIUM; FLUID; FLOW AB Nearly all cells have cilia, microtubule based projections from the apical cell surface, and nearly all cells use them in essential and unique ways. How mammalian cilia function in vivo as mechanosensors, signal transducers, or in fluid propulsion has been difficult to study due to lack of tools for live imaging of cilia. A new transgenic mouse that enables tissue-specific GFP labeling of cilia creates new opportunities for using live imaging to understand cilium function and to better characterize the many genetic models of ciliopathies. C1 Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. RP Drummond, IA (reprint author), Massachusetts Gen Hosp, Div Nephrol, 149 13th St,Rm 149-8000, Charlestown, MA 02129 USA. EM idrummond@partners.org FU NIH [DK053093, DK071041] FX IAD is supported by NIH grants DK053093 and DK071041. NR 16 TC 0 Z9 0 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD JUL 3 PY 2013 VL 11 AR 74 DI 10.1186/1741-7007-11-74 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 175XG UT WOS:000321266300001 PM 23822867 ER PT J AU Karlsson, EK Harris, JB Tabrizi, S Rahman, A Shlyakhter, I Patterson, N O'Dushlaine, C Schaffner, SF Gupta, S Chowdhury, F Sheikh, A Shin, OS Ellis, C Becker, CE Stuart, LM Calderwood, SB Ryan, ET Qadri, F Sabeti, PC LaRocque, RC AF Karlsson, Elinor K. Harris, Jason B. Tabrizi, Shervin Rahman, Atiqur Shlyakhter, Ilya Patterson, Nick O'Dushlaine, Colm Schaffner, Stephen F. Gupta, Sameer Chowdhury, Fahima Sheikh, Alaullah Shin, Ok Sarah Ellis, Crystal Becker, Christine E. Stuart, Lynda M. Calderwood, Stephen B. Ryan, Edward T. Qadri, Firdausi Sabeti, Pardis C. LaRocque, Regina C. TI Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NF-KAPPA-B; WHOLE-GENOME ASSOCIATION; VIBRIO-CHOLERAE; GASTROINTESTINAL EPITHELIA; INFLAMMASOME ACTIVATION; UNRELATED INDIVIDUALS; EXPRESSION PROFILES; ENRICHMENT ANALYSIS; ULCERATIVE-COLITIS; POSITIVE SELECTION AB As an ancient disease with high fatality, cholera has likely exerted strong selective pressure on affected human populations. We performed a genome-wide study of natural selection in a population from the Ganges River Delta, the historic geographic epicenter of cholera. We identified 305 candidate selected regions using the composite of multiple signals (CMS) method. The regions were enriched for potassium channel genes involved in cyclic adenosine monophosphate-mediated chloride secretion and for components of the innate immune system involved in nuclear factor kappa B (NF-kappa B) signaling. We demonstrate that a number of these strongly selected genes are associated with cholera susceptibility in two separate cohorts. We further identify repeated examples of selection and association in an NF-kappa B/inflammasome-dependent pathway that is activated in vitro by Vibrio cholerae. Our findings shed light on the genetic basis of cholera resistance in a population from the Ganges River Delta and present a promising approach for identifying genetic factors influencing susceptibility to infectious diseases. C1 [Karlsson, Elinor K.; Tabrizi, Shervin; Shlyakhter, Ilya; Sabeti, Pardis C.] Harvard Univ, Dept Organism & Evolutionary Biol, Ctr Syst Biol, Cambridge, MA 02138 USA. [Karlsson, Elinor K.; Tabrizi, Shervin; Shlyakhter, Ilya; Patterson, Nick; O'Dushlaine, Colm; Schaffner, Stephen F.; Stuart, Lynda M.; Sabeti, Pardis C.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Harris, Jason B.; Rahman, Atiqur; Shin, Ok Sarah; Ellis, Crystal; Calderwood, Stephen B.; Ryan, Edward T.; LaRocque, Regina C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02114 USA. [Rahman, Atiqur; Chowdhury, Fahima; Sheikh, Alaullah; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Schaffner, Stephen F.; Ryan, Edward T.; Sabeti, Pardis C.] Harvard Univ, Dept Immunol & Infect Dis, Sch Publ Hlth, Boston, MA 02115 USA. [Gupta, Sameer] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Becker, Christine E.; Stuart, Lynda M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Becker, Christine E.; Stuart, Lynda M.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Becker, Christine E.; Stuart, Lynda M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Calderwood, Stephen B.; Ryan, Edward T.; LaRocque, Regina C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Karlsson, EK (reprint author), Harvard Univ, Dept Organism & Evolutionary Biol, Ctr Syst Biol, Cambridge, MA 02138 USA. EM elinor@broadinstitute.org; psabeti@oeb.harvard.edu; rclarocque@partners.org RI Schaffner, Stephen/D-1189-2011; OI Karlsson, Elinor/0000-0002-4343-3776 FU Howard Hughes Medical Institute; Massachusetts General Hospital; NIH [K01TW007409, AI058935, RO1 AI079198, 1DP2OD006514-01]; FIC-NIH [D43 TW005572]; American Cancer Society Postdoctoral Fellowship; Packard Foundation Fellowship in Science and Engineering FX Supported by a Physician-Scientist Early Career Award from the Howard Hughes Medical Institute (R.C.L.), a Claflin Distinguished Scholar Award from the Massachusetts General Hospital (R.C.L.), an International Research Scientist Development Award from the NIH K01TW007409 (J.B.H.), NIH grant AI058935 (S.B.C., E.T.R., and F.Q.), NIH RO1 AI079198 (C.E.B. and L.M.S.), a FIC-NIH training grant D43 TW005572 (A.S.), an American Cancer Society Postdoctoral Fellowship (E.K.K.), the Packard Foundation Fellowship in Science and Engineering (P.C.S. and E.K.K.), and NIH Innovator award 1DP2OD006514-01 (P.C.S. and E.K.K.). NR 88 TC 16 Z9 16 U1 1 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 JUL 3 PY 2013 VL 5 IS 192 AR 192ra86 DI 10.1126/scitranslmed.3006338 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 175TY UT WOS:000321257600006 PM 23825302 ER PT J AU Bigler, ED Deibert, E Filley, CM AF Bigler, Erin D. Deibert, Ellen Filley, Christopher M. TI When is a concussion no longer a concussion? SO NEUROLOGY LA English DT Editorial Material ID TRAUMATIC BRAIN-INJURY; SPORT C1 [Bigler, Erin D.] Brigham Young Univ, Dept Psychol & Neurosci, Provo, UT 84602 USA. [Bigler, Erin D.] Univ Utah, Sch Med, Dept Psychiat, Salt Lake City, UT 84112 USA. [Deibert, Ellen] Univ Massachusetts, Dept Neurol, Amherst, MA 01003 USA. [Filley, Christopher M.] Univ Colorado, Sch Med, Dept Neurol & Psychiat, Denver, CO USA. [Filley, Christopher M.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Bigler, ED (reprint author), Brigham Young Univ, Dept Psychol & Neurosci, Provo, UT 84602 USA. EM erin_bigler@byu.edu NR 10 TC 2 Z9 2 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 2 PY 2013 VL 81 IS 1 BP 14 EP 15 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 304JC UT WOS:000330741900006 PM 23709592 ER PT J AU Clark, SW Taylor, J Wang, DL Abramson, JS Batchelor, TT AF Clark, Stephen W. Taylor, Jennie Wang, Daphne L. Abramson, Jeremy S. Batchelor, Tracy T. TI PLASMABLASTIC LYMPHOMA AFTER STANDARD-DOSE TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA SO NEUROLOGY LA English DT Editorial Material C1 [Clark, Stephen W.] Vanderbilt Univ, Nashville, TN 37235 USA. [Taylor, Jennie; Wang, Daphne L.; Abramson, Jeremy S.; Batchelor, Tracy T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Clark, SW (reprint author), Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. EM Stephen.w.clark@vanderbilt.edu NR 7 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 2 PY 2013 VL 81 IS 1 BP 93 EP 94 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 304JC UT WOS:000330741900018 PM 23685934 ER PT J AU Dalamaga, M Chou, SH Shields, K Papageorgiou, P Polyzos, SA Mantzoros, CS AF Dalamaga, Maria Chou, Sharon H. Shields, Kelsey Papageorgiou, Panagiotis Polyzos, Stergios A. Mantzoros, Christos S. TI Leptin at the Intersection of Neuroendocrinology and Metabolism: Current Evidence and Therapeutic Perspectives SO CELL METABOLISM LA English DT Review ID RECOMBINANT HUMAN LEPTIN; EMERGING CLINICAL-APPLICATIONS; MELANIN-CONCENTRATING HORMONE; ACTIVE ANTIRETROVIRAL THERAPY; INCREASES BONE-FORMATION; DEFICIENT OB/OB MICE; BETA-CELL FUNCTION; WEIGHT-LOSS; INSULIN-RESISTANCE; HYPOTHALAMIC AMENORRHEA AB Since its discovery as an adipocyte-secreted hormone, leptin has been found to impact food intake, energy homeostasis, and metabolism through its effects on the central nervous system and peripheral organs. Recent research indicates that leptin may also be involved in cognition, immune function, and bone metabolism. These findings place leptin at the intersection of neuroendocrinology and metabolism, and possibly immune function, and render it an appealing therapeutic target for several niche areas of unmet clinical need. Current evidence regarding classic and emerging roles of leptin as well as the pros and cons of its potential clinical use are summarized herein. C1 [Dalamaga, Maria] Univ Athens, Sch Med, Attikon Gen Univ Hosp, Dept Clin Biochem, Athens 12462, Greece. [Chou, Sharon H.; Shields, Kelsey; Papageorgiou, Panagiotis; Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02215 USA. [Polyzos, Stergios A.] Aristotle Univ Thessaloniki, Med Clin 2, Ippokrat Hosp, Thessaloniki 54642, Greece. RP Mantzoros, CS (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. EM cmantzor@bidmc.harvard.edu OI Polyzos, Stergios/0000-0001-9232-4042; Dalamaga, Maria/0000-0002-7008-388X FU National Institute of Diabetes and Digestive and Kidney Diseases [58785, 79929, 81913, AG032030]; VA Merit award [10684957]; Beth Israel Deaconess Medical Center FX The Mantzoros laboratory is supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants 58785, 79929, 81913, and AG032030 and a VA Merit award (grant 10684957). The Mantzoros Laboratory is also supported by a discretionary grant from Beth Israel Deaconess Medical Center. All authors contributed to writing the manuscript. All authors read and approved the final manuscript. NR 98 TC 41 Z9 43 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUL 2 PY 2013 VL 18 IS 1 BP 29 EP 42 DI 10.1016/j.cmet.2013.05.010 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242UE UT WOS:000326267100007 PM 23770129 ER PT J AU Roberts, LD Gerszten, RE AF Roberts, Lee D. Gerszten, Robert E. TI Toward New Biomarkers of Cardiometabolic Diseases SO CELL METABOLISM LA English DT Review ID NUCLEAR-MAGNETIC-RESONANCE; SPINNING H-1-NMR SPECTROSCOPY; CORONARY-HEART-DISEASE; MASS-SPECTROMETRY; ELECTROSPRAY-IONIZATION; CARDIOVASCULAR EVENTS; METABOLIC PROFILES; LIPID MIXTURES; URINE; RISK AB Cardiometabolic diseases can be present long before becoming clinically apparent. Accurate predictors of disease are of particular importance since the delay or prevention of morbidity is possible via pharmacological and behavioral interventions. Metabolomics is increasingly applied to biomarker discovery. Understanding how metabolites relate with established cardiometabolic risk factors is critical in evaluating their potential value as clinical biomarkers. Large epidemiological cohort studies can assess whether metabolite biomarkers improve upon existing disease markers. Furthermore, experimental work in model systems and integration with other functional genomic approaches will facilitate the discovery of causal links between select biomarkers and disease pathogenesis. C1 [Roberts, Lee D.; Gerszten, Robert E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA. [Roberts, Lee D.; Gerszten, Robert E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02115 USA. RP Gerszten, RE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA. EM rgerszten@partners.org OI Roberts, Lee/0000-0002-1455-5248 FU NIH [R01-DK-HL081572, R01 HL098280, NIH-1U01HL107440]; Leducq Foundation Transatlantic Network Grant; American Heart Association; Leducq Foundation Career Development Award FX We would like to acknowledge our research support from the NIH (R01-DK-HL081572, R01 HL098280, and NIH-1U01HL107440), a Leducq Foundation Transatlantic Network Grant, and the American Heart Association. L. D. R. is supported by a Leducq Foundation Career Development Award. NR 44 TC 26 Z9 26 U1 2 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUL 2 PY 2013 VL 18 IS 1 BP 43 EP 50 DI 10.1016/j.cmet.2013.05.009 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242UE UT WOS:000326267100008 PM 23770128 ER PT J AU Shi, XM Zhou, FG Li, XJ Chang, B Li, DP Wang, Y Tong, QC Xu, Y Fukuda, M Zhao, JJ Li, DF Burrin, DG Chan, L Guan, XF AF Shi, Xuemei Zhou, Fuguo Li, Xiaojie Chang, Benny Li, Depei Wang, Yi Tong, Qingchun Xu, Yong Fukuda, Makoto Zhao, Jean J. Li, Defa Burrin, Douglas G. Chan, Lawrence Guan, Xinfu TI Central GLP-2 Enhances Hepatic Insulin Sensitivity via Activating PI3K Signaling in POMC Neurons SO CELL METABOLISM LA English DT Article ID GLUCAGON-LIKE PEPTIDE-2; HYPOTHALAMIC PROOPIOMELANOCORTIN NEURONS; GLUCOSE-HOMEOSTASIS; ENERGY HOMEOSTASIS; FOOD-INTAKE; LEPTIN ACTION; GUT HORMONES; BLOOD-FLOW; RECEPTOR; OBESITY AB Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We show that mice lacking GLP-2 receptor (GLP-2R) in POMC neurons display glucose intolerance and hepatic insulin resistance. GLP-2R activation in POMC neurons is required for GLP-2 to enhance insulin-mediated suppression of hepatic glucose production (HGP) and gluconeogenesis. GLP-2 directly modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners. GLP-2 initiates GLP-2R-p85 alpha interaction and facilitates PI3K-Akt-dependent FoxO1 nuclear exclusion in POMC neurons. Central GLP-2 suppresses basal HGP and enhances insulin sensitivity, which are abolished in POMC-p110 alpha KO mice. Thus, CNS GLP-2 plays a key physiological role in the control of HGP through activating PI3K-dependent modulation of membrane excitability and nuclear transcription of POMC neurons in the brain. C1 [Shi, Xuemei; Zhou, Fuguo; Li, Xiaojie; Wang, Yi; Xu, Yong; Fukuda, Makoto; Burrin, Douglas G.; Guan, Xinfu] Baylor Coll Med, Dept Pediat, USDA ARS, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Chang, Benny; Chan, Lawrence; Guan, Xinfu] Baylor Coll Med, Dept Med, Div Diabet Endocrinol & Metab, Houston, TX 77030 USA. [Li, Depei] Univ Texas MD Anderson Canc Ctr, Dept Crit Care, Houston, TX 77030 USA. [Tong, Qingchun] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Zhao, Jean J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Li, Defa] China Agr Univ, State Key Lab Anim Nutr, Beijing 100083, Peoples R China. RP Guan, XF (reprint author), Baylor Coll Med, Dept Pediat, USDA ARS, Childrens Nutr Res Ctr, Houston, TX 77030 USA. EM xguan@bcm.edu RI Fukuda, Makoto/I-7915-2014; OI Fukuda, Makoto/0000-0003-0112-9925; Tong, Qingchun/0000-0002-4561-2540 FU USDA CRIS [6250-51000-055]; NIH [DK075489, DK084125, P30DK079638]; National Natural Science Foundation of China [30728016] FX The authors thank Zhuo Yang, Maria Truong, Shixiang Wen, An Hong Nguyen, Jian Qi, Wei Wang, Guangchen Zhang, Shaji Chacko, Daniel Donaldson, Jerome Stubblefield, Fang Zou, Liangru Zhu, Qiang Tong, Darryl Hadsell, Marta Fiorotto, Juan Marini, and Dennis Bier at Baylor College of Medicine for scientific and technical support. We also thank Yuanzhong Xu at the University of Texas Health Science Center at Houston for technical support. This work is supported by the USDA CRIS 6250-51000-055, NIH grants DK075489 and DK084125, and the National Natural Science Foundation of China Grant 30728016 (X. G.) and by NIH P30DK079638 (L. C.). X. S. and X. G. contributed to the study concept and design, acquisition of data, statistical analysis, interpretation of data, and drafting the manuscript. In addition, X. G. obtained funding, supervised the study, and finalized the manuscript. X. L. and B. C. contributed to the design and generation of the Glp2r floxed mice. F.Z., Y.W., Q. T., and Depei Li assisted with cell culture, in situ hybridization, and electrophysiological recording. Y.X., M. F., J.J.Z., Defa Li, D. G. B., and L. C. provided technical support and critically reviewed the manuscript. NR 38 TC 25 Z9 26 U1 1 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUL 2 PY 2013 VL 18 IS 1 BP 86 EP 98 DI 10.1016/j.cmet.2013.06.014 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242UE UT WOS:000326267100012 PM 23823479 ER PT J AU Rhee, EP Ho, JE Chen, MH Shen, DX Cheng, S Larson, MG Ghorbani, A Shi, X Helenius, IT O'Donnell, CJ Souza, AL Deik, A Pierce, KA Bullock, K Walford, GA Vasan, RS Florez, JC Clish, C Yeh, JRJ Wang, TJ Gerszten, RE AF Rhee, Eugene P. Ho, Jennifer E. Chen, Ming-Huei Shen, Dongxiao Cheng, Susan Larson, Martin G. Ghorbani, Anahita Shi, Xu Helenius, Iiro T. O'Donnell, Christopher J. Souza, Amanda L. Deik, Amy Pierce, Kerry A. Bullock, Kevin Walford, Geoffrey A. Vasan, Ramachandran S. Florez, Jose C. Clish, Clary Yeh, J. -R. Joanna Wang, Thomas J. Gerszten, Robert E. TI A Genome-wide Association Study of the Human Metabolome in a Community-Based Cohort SO CELL METABOLISM LA English DT Article ID LECITHIN-CHOLESTEROL ACYLTRANSFERASE; CORONARY-ARTERY-DISEASE; CHRONIC KIDNEY-DISEASE; C-REACTIVE PROTEIN; SUSCEPTIBILITY LOCI; GENETIC-VARIATION; CARDIOVASCULAR-DISEASE; BILIRUBIN LEVELS; RISK; GLUCOSE AB Because metabolites are hypothesized to play key roles as markers and effectors of cardiometabolic diseases, recent studies have sought to annotate the genetic determinants of circulating metabolite levels. We report a genome-wide association study (GWAS) of 217 plasma metabolites, including >100 not measured in prior GWAS, in 2076 participants of the Framingham Heart Study (FHS). For the majority of analytes, we find that estimated heritability explains >20% of interindividual variation, and that variation attributable to heritable factors is greater than that attributable to clinical factors. Further, we identify 31 genetic loci associated with plasma metabolites, including 23 that have not previously been reported. Importantly, we include GWAS results for all surveyed metabolites and demonstrate how this information highlights a role for AGXT2 in cholesterol ester and triacylglycerol metabolism. Thus, our study outlines the relative contributions of inherited and clinical factors on the plasma metabolome and provides a resource for metabolism research. C1 [Rhee, Eugene P.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Shen, Dongxiao; Shi, Xu; Helenius, Iiro T.; Yeh, J. -R. Joanna; Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ghorbani, Anahita; O'Donnell, Christopher J.; Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Walford, Geoffrey A.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Rhee, Eugene P.; Souza, Amanda L.; Deik, Amy; Pierce, Kerry A.; Bullock, Kevin; Clish, Clary; Gerszten, Robert E.] Broad Inst, Metabolite Profiling Platform, Cambridge, MA 02142 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Ho, Jennifer E.] Boston Univ, Sch Med, Dept Med, Cardiovasc Med Sect, Boston, MA 02118 USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ho, Jennifer E.; Chen, Ming-Huei; Cheng, Susan; Larson, Martin G.; O'Donnell, Christopher J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Ho, Jennifer E.; Chen, Ming-Huei; Cheng, Susan; Larson, Martin G.; O'Donnell, Christopher J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Framingham, MA 01702 USA. [Chen, Ming-Huei] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Cheng, Susan] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Wang, Thomas J.] Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA. [Wang, Thomas J.] Vanderbilt Univ, Med Ctr, Vanderbilt Heart & Vasc Inst, Nashville, TN 37232 USA. RP Wang, TJ (reprint author), Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA. EM thomas.j.wang@vanderbilt.edu; rgerszten@partners.org OI Larson, Martin/0000-0002-9631-1254; Helenius, Iiro Taneli/0000-0002-0887-7830; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970 FU NIH [N01-HC-25195, R01-DK-HL-081572, R01-HL-098280, R-01-HL-093328, U01-HL-107440, K23-HL-116780, K08-DK-090142]; Leducq Foundation; American Heart Association [12IRG9130006, 0940109N]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center FX This work was supported by NIH contracts N01-HC-25195, R01-DK-HL-081572 (R. E. G. and T.J.W.), R01-HL-098280 (R. E. G.), R-01-HL-093328 (R. S. V.), U01-HL-107440 (R. E. G.), K23-HL-116780 (J.E.H.), K08-DK-090142 (E. P. R.), the Leducq Foundation (to R. E. G.), and the American Heart Association 12IRG9130006 (J.-R.J.Y. and I. T. H.) and 0940109N (R. E. G.). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 73 TC 53 Z9 56 U1 0 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUL 2 PY 2013 VL 18 IS 1 BP 130 EP 143 DI 10.1016/j.cmet.2013.06.013 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242UE UT WOS:000326267100016 PM 23823483 ER PT J AU Sander, CY Hooker, JM Catana, C Normandin, MD Alpert, NM Knudsen, GM Vanduffel, W Rosen, BR Mandeville, JB AF Sander, Christin Y. Hooker, Jacob M. Catana, Ciprian Normandin, Marc D. Alpert, Nathaniel M. Knudsen, Gitte M. Vanduffel, Wim Rosen, Bruce R. Mandeville, Joseph B. TI Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dynamic binding potential; displacement; monkey; NHP ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO BINDING; NEURAL ACTIVITY; HUMAN-BRAIN; HEMIPARKINSONIAN MONKEYS; BLOOD-VOLUME; BOLD SIGNAL; FMRI SIGNAL; PET; DEPLETION AB This study employed simultaneous neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to demonstrate the relationship between changes in receptor occupancy measured by PET and changes in brain activity inferred by fMRI. By administering the D2/D3 dopamine receptor antagonist [C-11] raclopride at varying specific activities to anesthetized nonhuman primates, we mapped associations between changes in receptor occupancy and hemodynamics [cerebral blood volume (CBV)] in the domains of space, time, and dose. Mass doses of raclopride above tracer levels caused increases in CBV and reductions in binding potential that were localized to the dopamine-rich striatum. Moreover, similar temporal profiles were observed for specific binding estimates and changes in CBV. Injection of graded raclopride mass doses revealed a monotonic coupling between neurovascular responses and receptor occupancies. The distinct CBV magnitudes between putamen and caudate at matched occupancies approximately matched literature differences in basal dopamine levels, suggesting that the relative fMRI measurements reflect basal D2/D3 dopamine receptor occupancy. These results can provide a basis for models that relate dopaminergic occupancies to hemodynamic changes in the basal ganglia. Overall, these data demonstrate the utility of simultaneous PET/fMRI for investigations of neurovascular coupling that correlate neurochemistry with hemodynamic changes in vivo for any receptor system with an available PET tracer. C1 [Sander, Christin Y.; Hooker, Jacob M.; Catana, Ciprian; Vanduffel, Wim; Rosen, Bruce R.; Mandeville, Joseph B.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sander, Christin Y.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Normandin, Marc D.; Alpert, Nathaniel M.] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Knudsen, Gitte M.] Univ Copenhagen, Rigshosp, Neurobiol Res Unit, DK-2100 Copenhagen, Denmark. [Knudsen, Gitte M.] Univ Copenhagen, Rigshosp, Cimbi, DK-2100 Copenhagen, Denmark. [Vanduffel, Wim] Katholieke Univ Leuven, Sch Med, Lab Neuro & Psychophysiol, B-3000 Louvain, Belgium. [Rosen, Bruce R.] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Sander, CY (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM csander@mit.edu RI Normandin, Marc/C-6728-2015; Knudsen, Gitte/C-1368-2013; OI Normandin, Marc/0000-0003-1645-523X; Knudsen, Gitte/0000-0003-1508-6866; Hooker, Jacob/0000-0002-9394-7708 FU National Institutes of Health [R90DA023427, P41RR14075, P30DA28800, S10RR026666, S10RR017208, S10RR022976, S10RR019933] FX We thank Helen Deng, Steve Carlin, Chris Moseley, Grae Arabasz, and Shirley Hsu for their help with animal preparation and monitoring, [11C]RAC synthesis, and PET/MR scanning. National Institutes of Health Grants R90DA023427, P41RR14075, P30DA28800, S10RR026666, S10RR017208, S10RR022976, and S10RR019933 supported this research. NR 53 TC 33 Z9 34 U1 2 U2 12 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 JUL 2 PY 2013 VL 110 IS 27 BP 11169 EP 11174 DI 10.1073/pnas.1220512110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185OF UT WOS:000321978000069 PM 23723346 ER PT J AU Maruvka, YE Shnerb, NM Kessler, DA Ricklefs, RE AF Maruvka, Yosef E. Shnerb, Nadav M. Kessler, David A. Ricklefs, Robert E. TI Model for macroevolutionary dynamics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diversification rate; genera origination; species-within-genus statistics; Linnean taxonomy ID MOLECULAR PHYLOGENIES; STOCHASTIC-MODELS; DEPENDENT DIVERSIFICATION; EVOLUTIONARY RADIATIONS; SPECIES RICHNESS; EXTINCTION RATES; NEUTRAL THEORY; LIFE; ABUNDANCE; SIZE AB The highly skewed distribution of species among genera, although challenging to macroevolutionists, provides an opportunity to understand the dynamics of diversification, including species formation, extinction, and morphological evolution. Early models were based on either the work by Yule [Yule GU (1925) Philos Trans R Soc Lond B Biol Sci 213:21-87], which neglects extinction, or a simple birth-death (speciation-extinction) process. Here, we extend the more recent development of a generic, neutral speciation-extinction (of species)-origination (of genera; SEO) model for macroevolutionary dynamics of taxon diversification. Simulations show that deviations from the homogeneity assumptions in the model can be detected in species-per-genus distributions. The SEO model fits observed species-per-genus distributions well for class-to-kingdom-sized taxonomic groups. The model's predictions for the appearance times (the time of the first existing species) of the taxonomic groups also approximately match estimates based on molecular inference and fossil records. Unlike estimates based on analyses of phylogenetic reconstruction, fitted extinction rates for large clades are close to speciation rates, consistent with high rates of species turnover and the relatively slow change in diversity observed in the fossil record. Finally, the SEO model generally supports the consistency of generic boundaries based on morphological differences between species and provides a comparator for rates of lineage splitting and morphological evolution. C1 [Maruvka, Yosef E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Maruvka, Yosef E.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Maruvka, Yosef E.; Shnerb, Nadav M.; Kessler, David A.] Bar Ilan Univ, Dept Phys, IL-52900 Ramat Gan, Israel. [Ricklefs, Robert E.] Univ Missouri, Dept Biol, St Louis, MO 63121 USA. RP Shnerb, NM (reprint author), Bar Ilan Univ, Dept Phys, IL-52900 Ramat Gan, Israel. EM shnerbn@mail.biu.ac.il; ricklefs@umsl.edu RI Kessler, David/B-1391-2008 OI Kessler, David/0000-0002-5279-1655 NR 55 TC 12 Z9 12 U1 1 U2 37 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 JUL 2 PY 2013 VL 110 IS 27 BP E2460 EP E2469 DI 10.1073/pnas.1220014110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185OF UT WOS:000321978000007 PM 23781101 ER PT J AU Wei, F Zhong, S Ma, ZY Kong, H Medvec, A Ahmed, R Freeman, GJ Krogsgaard, M Riley, JL AF Wei, Fang Zhong, Shi Ma, Zhengyu Kong, Hong Medvec, Andrew Ahmed, Rafi Freeman, Gordon J. Krogsgaard, Michelle Riley, James L. TI Strength of PD-1 signaling differentially affects T-cell effector functions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE TCR signaling; peptide counting; HIV-1 specific T cell response ID CHRONIC VIRAL-INFECTION; PROGRAMMED DEATH-1; UP-REGULATION; IMMUNOLOGICAL SYNAPSE; MELANOMA PATIENTS; IN-VITRO; BLOCKADE; EXPRESSION; RECEPTOR; ANTIGEN AB High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca2+ flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-gamma production, and very low levels of PD-1 expression could inhibit TNF-alpha and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade. C1 [Wei, Fang; Kong, Hong; Medvec, Andrew; Riley, James L.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Wei, Fang; Kong, Hong; Medvec, Andrew; Riley, James L.] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Zhong, Shi; Krogsgaard, Michelle] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Zhong, Shi; Krogsgaard, Michelle] NYU, Sch Med, Inst Canc, New York, NY 10016 USA. [Ma, Zhengyu] Nemours AI duPont Hosp Children, Dept Res, Wilmington, DE 19803 USA. [Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM rahmed@emory.edu; rileyj@exchange.upenn.edu OI Riley, James/0000-0002-1057-576X FU National Institutes of Health [P01 P01AI080192, U01CA137070] FX We thank the Center for AIDS Research Immunology Core for providing the purified immune cells used in this study; John Wherry and Mike Dustin for helpful suggestions; and Caitlin Baiduc and Julie Jadlowsky for proofreading. This work was supported by the National Institutes of Health Grants P01 P01AI080192 (to J.L.R, M.K., G.J.F., and R.A.) and U01CA137070 (to M.K.). NR 60 TC 60 Z9 62 U1 1 U2 14 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 JUL 2 PY 2013 VL 110 IS 27 BP E2480 EP E2489 DI 10.1073/pnas.1305394110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 185OF UT WOS:000321978000009 PM 23610399 ER PT J AU Goldfine, AB Fonseca, V Jablonski, KA Chen, YDI Tipton, L Staten, MA Shoelson, SE AF Goldfine, Allison B. Fonseca, Vivian Jablonski, Kathleen A. Chen, Yii-Der Ida Tipton, Laura Staten, Myrlene A. Shoelson, Steven E. CA Targeting Inflammation Using Salsa TI Salicylate (Salsalate) in Patients With Type 2 Diabetes A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; HEAT-SHOCK RESPONSE; BLOOD-CELL COUNT; SODIUM-SALICYLATE; INSULIN-RESISTANCE; NONACETYLATED SALICYLATE; ALPHA PHOSPHORYLATION; ASPIRIN; INHIBITION AB Background: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM). Objective: To assess 1-year efficacy and safety of salsalate in T2DM. Design: Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (ClinicalTrials.gov: NCT00799643) Setting: 3 private practices and 18 academic centers in the United States. Patients: Persons aged 18 to 75 years with fasting glucose levels of 12.5 mmol/L or less (<= 225 mg/dL) and hemoglobin A(1c) (HbA(1c)) levels of 7.0% to 9.5% who were treated for diabetes. Intervention: 286 participants were randomly assigned (between January 2009 and July 2011) to 48 weeks of placebo (n = 140) or salsalate, 3.5 g/d (n = 146), in addition to current therapies, and 283 participants were analyzed (placebo, n = 137; salsalate, n = 146). Measurements: Change in hemoglobin A(1c) level (primary outcome) and safety and efficacy measures. Results: The mean HbA(1c) level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, -0.53% to -0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged. Limitation: Trial duration and number of patients studied were insufficient to determine long-term risk-benefit of salsalate in T2DM. Conclusion: Salsalate improves glycemia in patients with T2DM and decreases inflammatory mediators. Continued evaluation of mixed cardiorenal signals is warranted. C1 [Shoelson, Steven E.] Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. Tulane Univ, New Orleans, LA 70118 USA. George Washington Univ, Rockville, MD USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Natl Inst Diabet & Digest & Kidney Dis, Washington, DC USA. RP Shoelson, SE (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM steven.shoelson@joslin.harvard.edu FU National Institutes of Health [U01 DK74556, P50 HL83813, P30 DK03836]; National Institutes of Health (General Clinical Research Center); National Institutes of Health (Clinical and Translational Science Award); Tullis-Tulane Chair; Helen and Morton Adler Chair FX Grant Support: By National Institutes of Health (U01 DK74556, P50 HL83813, P30 DK03836, and General Clinical Research Center and Clinical and Translational Science Award at several sites) and the Tullis-Tulane (Dr. Fonseca) and Helen and Morton Adler (Dr. Shoelson) Chairs. Caraco Pharmaceutical Laboratories (Detroit, Michigan) supplied the salsalate and placebo, LifeScan (Milpitas, California) supplied the home glucose-monitoring kits, and Mercodia (Uppsala, Sweden) supplied the insulin assay kits. NR 53 TC 80 Z9 84 U1 0 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 2 PY 2013 VL 159 IS 1 BP 1 EP + DI 10.7326/0003-4819-159-1-201307020-00003 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 179JJ UT WOS:000321516200001 PM 23817699 ER PT J AU Smith, MEB Totten, A Hickam, DH Fu, RW Wasson, N Rahman, B Motu'apuaka, M Saha, S AF Smith, M. E. Beth Totten, Annette Hickam, David H. Fu, Rongwei Ngoc Wasson Rahman, Basmah Motu'apuaka, Makalapua Saha, Somnath TI Pressure Ulcer Treatment Strategies A Systematic Comparative Effectiveness Review SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; SPINAL-CORD-INJURY; III DECUBITUS ULCERS; GROWTH FACTOR-BB; AIR-FLUIDIZED THERAPY; LEVEL LASER THERAPY; CLINICAL-TRIAL; ELDERLY-PATIENTS; STAGE-II; HYDROCOLLOID DRESSINGS AB Background: Pressure ulcers affect as many as 3 million Americans and are major sources of morbidity, mortality, and health care costs. Purpose: To summarize evidence comparing the effectiveness and safety of treatment strategies for adults with pressure ulcers. Data Sources: MEDLINE, EMBASE, CINAHL, Evidence-Based Medicine Reviews, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database for English-or foreign-language studies; reference lists; gray literature; and individual product packets from manufacturers (January 1985 to October 2012). Study Selection: Randomized trials and comparative observational studies of treatments for pressure ulcers in adults and noncomparative intervention series (n > 50) for surgical interventions and evaluation of harms. Data Extraction: Data were extracted and evaluated for accuracy of the extraction, quality of included studies, and strength of evidence. Data Synthesis: 174 studies met inclusion criteria and 92 evaluated complete wound healing. In comparison with standard care, placebo, or sham interventions, moderate-strength evidence showed that air-fluidized beds (5 studies [n = 908]; high consistency), protein-containing nutritional supplements (12 studies [n = 562]; high consistency), radiant heat dressings (4 studies [n = 160]; moderate consistency), and electrical stimulation (9 studies [n = 397]; moderate consistency) improved healing of pressure ulcers. Low-strength evidence showed that alternating-pressure surfaces, hydrocolloid dressings, platelet-derived growth factor, and light therapy improved healing of pressure ulcers. The evidence about harms was limited. Limitation: Applicability of results is limited by study quality, heterogeneity in methods and outcomes, and inadequate duration to assess complete wound healing. Conclusion: Moderate-strength evidence shows that healing of pressure ulcers in adults is improved with the use of air-fluidized beds, protein supplementation, radiant heat dressings, and electrical stimulation. C1 Oregon Hlth & Sci Univ, Oregon Evidence Based Practice Ctr, Portland, OR 97239 USA. Portland VA Med Ctr, Portland, OR USA. RP Smith, MEB (reprint author), Oregon Hlth & Sci Univ, 3181 Southwest Sam Jackson Pk Rd, Portland, OR 97239 USA. EM smithbet@ohsu.edu FU AHRQ [290-2007-10057-I]; U.S. Department of Veterans Affairs; Agency for Healthcare Research and Quality FX Grant Support: By AHRQ (contract 290-2007-10057-I, Task Order 8). Dr. Saha is supported by the U.S. Department of Veterans Affairs.; Primary Funding Source: Agency for Healthcare Research and Quality. NR 167 TC 28 Z9 31 U1 1 U2 32 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 2 PY 2013 VL 159 IS 1 BP 39 EP + DI 10.7326/0003-4819-159-1-201307020-00007 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 179JJ UT WOS:000321516200005 PM 23817703 ER PT J AU Branda, JA Rosenberg, ES AF Branda, John A. Rosenberg, Eric S. TI Borrelia miyamotoi: A Lesson in Disease Discovery SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID LYME-DISEASE; VECTOR; TICK; SPIROCHETE C1 [Branda, John A.; Rosenberg, Eric S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rosenberg, ES (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Gray J-504,55 Fruit St, Boston, MA 02114 USA. NR 11 TC 10 Z9 10 U1 1 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 2 PY 2013 VL 159 IS 1 BP 61 EP + DI 10.7326/0003-4819-159-1-201307020-00009 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 179JJ UT WOS:000321516200007 PM 23817704 ER PT J AU Das, M Volberding, P AF Das, Moupali Volberding, Paul TI Bringing the End in Sight: Consensus Regarding HIV Screening Strategies SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID ANTIRETROVIRAL THERAPY; RECOMMENDATIONS; INFECTION C1 [Das, Moupali; Volberding, Paul] Univ Calif San Francisco, San Francisco, CA 94105 USA. [Volberding, Paul] San Francisco VA Med Ctr, San Francisco, CA USA. RP Volberding, P (reprint author), Univ Calif San Francisco, AIDS Res Inst, 50 Beale St,Suite 1300, San Francisco, CA 94105 USA. EM paul.volberding@ucsf.edu NR 10 TC 3 Z9 3 U1 1 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 2 PY 2013 VL 159 IS 1 BP 63 EP + DI 10.7326/0003-4819-159-1-201307020-00643 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 179JJ UT WOS:000321516200008 PM 23698261 ER PT J AU Kimball, AB Gu, YH Okun, M AF Kimball, Alexa B. Gu, Yihua Okun, Martin TI Treatment of Moderate to Severe Hidradenitis Suppurativa RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Kimball, Alexa B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kimball, Alexa B.] Harvard Univ, Sch Med, Boston, MA USA. [Gu, Yihua; Okun, Martin] AbbVie, N Chicago, IL USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 2 Z9 2 U1 0 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 2 PY 2013 VL 159 IS 1 BP 72 EP 73 DI 10.7326/0003-4819-159-1-201307020-00016 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 179JJ UT WOS:000321516200011 PM 23817710 ER PT J AU Delgado, FF Cermak, N Hecht, VC Son, S Li, YZ Knudsen, SM Olcum, S Higgins, JM Chen, JZ Grover, WH Manalis, SR AF Delgado, Francisco Feijo Cermak, Nathan Hecht, Vivian C. Son, Sungmin Li, Yingzhong Knudsen, Scott M. Olcum, Selim Higgins, John M. Chen, Jianzhu Grover, William H. Manalis, Scott R. TI Intracellular Water Exchange for Measuring the Dry Mass, Water Mass and Changes in Chemical Composition of Living Cells SO PLOS ONE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; HUMAN ERYTHROCYTES; ESCHERICHIA-COLI; RIBONUCLEIC-ACID; BUOYANT DENSITY; SINGLE CELLS; GROWTH-RATE; PROTEIN; YEAST; VOLUME AB We present a method for direct non-optical quantification of dry mass, dry density and water mass of single living cells in suspension. Dry mass and dry density are obtained simultaneously by measuring a cell's buoyant mass sequentially in an H2O-based fluid and a D2O-based fluid. Rapid exchange of intracellular H2O for D2O renders the cell's water content neutrally buoyant in both measurements, and thus the paired measurements yield the mass and density of the cell's dry material alone. Utilizing this same property of rapid water exchange, we also demonstrate the quantification of intracellular water mass. In a population of E. coli, we paired these measurements to estimate the percent dry weight by mass and volume. We then focused on cellular dry density - the average density of all cellular biomolecules, weighted by their relative abundances. Given that densities vary across biomolecule types (RNA, DNA, protein), we investigated whether we could detect changes in biomolecular composition in bacteria, fungi, and mammalian cells. In E. coli, and S. cerevisiae, dry density increases from stationary to exponential phase, consistent with previously known increases in the RNA/protein ratio from up-regulated ribosome production. For mammalian cells, changes in growth conditions cause substantial shifts in dry density, suggesting concurrent changes in the protein, nucleic acid and lipid content of the cell. C1 [Delgado, Francisco Feijo; Hecht, Vivian C.; Knudsen, Scott M.; Olcum, Selim; Grover, William H.; Manalis, Scott R.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Cermak, Nathan; Manalis, Scott R.] MIT, Computat & Syst Biol Initiat, Cambridge, MA 02139 USA. [Son, Sungmin; Manalis, Scott R.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Li, Yingzhong; Chen, Jianzhu; Grover, William H.; Manalis, Scott R.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Higgins, John M.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Higgins, John M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Higgins, John M.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Chen, Jianzhu] MIT, Dept Biol, Cambridge, MA USA. RP Manalis, SR (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM scottm@media.mit.edu RI Olcum, Selim/I-8523-2012; OI Olcum, Selim/0000-0002-6417-1007; Grover, William/0000-0001-6854-8951 FU Physical Sciences Oncology Center at the Massachusetts Institute of Technology from the United States National Cancer Institute [U54CA143874]; United States National Institutes of Health [P50GM68762, R01CA170592]; Institute for Collaborative Biotechnologies from the United States Army Research Office [W911NF-09-D-0001]; Fundacao para a Ciencia e a Tecnologia, Portugal [SFRH/BD/47736/2008] FX Physical Sciences Oncology Center at the Massachusetts Institute of Technology (U54CA143874) from the United States National Cancer Institute. Center for Cell Decision Process Grant (P50GM68762) and contract R01CA170592, both from the United States National Institutes of Health. Institute for Collaborative Biotechnologies through contract number W911NF-09-D-0001 from the United States Army Research Office. F. F. D. acknowledges support from Fundacao para a Ciencia e a Tecnologia, Portugal, through a graduate fellowship (SFRH/BD/47736/2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 27 Z9 27 U1 0 U2 41 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 JUL 2 PY 2013 VL 8 IS 7 AR e67590 DI 10.1371/journal.pone.0067590 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176XV UT WOS:000321341000062 ER PT J AU Ferguson, BD Liu, R Rolle, CE Tan, YHC Krasnoperov, V Kanteti, R Tretiakova, MS Cervantes, GM Hasina, R Hseu, RD Iafrate, AJ Karrison, T Ferguson, MK Husain, AN Faoro, L Vokes, EE Gill, PS Salgia, R AF Ferguson, Benjamin D. Liu, Ren Rolle, Cleo E. Tan, Yi-Hung Carol Krasnoperov, Valery Kanteti, Rajani Tretiakova, Maria S. Cervantes, Gustavo M. Hasina, Rifat Hseu, Robyn D. Iafrate, A. John Karrison, Theodore Ferguson, Mark K. Husain, Aliya N. Faoro, Leonardo Vokes, Everett E. Gill, Parkash S. Salgia, Ravi TI The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target SO PLOS ONE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; TOPOISOMERASE-I ACTIVITY; BIOLOGICAL SIGNIFICANCE; TUMOR ADVANCEMENT; EXPRESSION; SURVIVAL; EPHRINB2; INHIBITORS; COMPLEX; HEAD AB Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted. C1 [Ferguson, Benjamin D.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Ferguson, Benjamin D.; Rolle, Cleo E.; Tan, Yi-Hung Carol; Kanteti, Rajani; Cervantes, Gustavo M.; Hasina, Rifat; Hseu, Robyn D.; Faoro, Leonardo; Vokes, Everett E.; Salgia, Ravi] Univ Chicago, Dept Med, Sect Hematol Oncol, Chicago, IL 60637 USA. [Tretiakova, Maria S.; Husain, Aliya N.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Ferguson, Mark K.] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [Karrison, Theodore] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ferguson, Mark K.; Salgia, Ravi] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Liu, Ren; Gill, Parkash S.] Univ So Calif, Dept Med, Div Med Oncol, Los Angeles, CA USA. [Krasnoperov, Valery; Gill, Parkash S.] Vasgene Therapeut Inc, Los Angeles, CA USA. [Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Salgia, R (reprint author), Univ Chicago, Dept Med, Sect Hematol Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM rsalgia@medicine.bsd.uchicago.edu RI Ferguson, Benjamin/O-3214-2013 OI Ferguson, Benjamin/0000-0001-8358-3368 FU NIH/NICHD [T32HD009007]; ASCO Translational Award; NIH/NCI [R01 CA 129501 05]; Janice Lamb McArdle Cancer Research Foundation FX This research has been supported in part by NIH/NICHD T32HD009007, "Graduate Training in Growth and Development" (BDF), ASCO Translational Award (EEV), NIH/NCI R01 CA 129501 05 (RS), and Janice Lamb McArdle Cancer Research Foundation (RS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 15 Z9 15 U1 1 U2 10 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 JUL 2 PY 2013 VL 8 IS 7 AR e67668 DI 10.1371/journal.pone.0067668 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176XV UT WOS:000321341000071 PM 23844053 ER PT J AU Herskovits, AZ Locascio, JJ Peskind, ER Li, G Hyman, BT AF Herskovits, Adrianna Z. Locascio, Joseph J. Peskind, Elaine R. Li, Ge Hyman, Bradley T. TI A Luminex Assay Detects Amyloid beta Oligomers in Alzheimer's Disease Cerebrospinal Fluid SO PLOS ONE LA English DT Article ID 2 ANALYTICAL PLATFORMS; A-BETA; NATIONAL INSTITUTE; PRECURSOR PROTEIN; NEUROPATHOLOGIC ASSESSMENT; ASSOCIATION GUIDELINES; CLINICAL-DIAGNOSIS; TOTAL TAU; DEMENTIA; BIOMARKERS AB Amyloid beta (a beta) protein assembles into larger protein aggregates during the pathogenesis of Alzheimer's disease (AD) and there is increasing evidence that soluble a beta oligomers are a critical pathologic species. Diagnostic evaluations rely on the measurement of increased tau and decreased a beta 42 in the cerebrospinal fluid (CSF) from AD patients and evidence for oligomeric a beta in patient CSF is conflicting. In this study, we have adapted a monoclonal single antibody sandwich ELISA assay to a Luminex platform and found that this assay can detect oligomerized a beta 42 and sAPP alpha fragments. We evaluated oligomeric a beta reactivity in 20 patients with AD relative to 19 age matched controls and compared these values with a commercially available Alzbio3 kit that detects tau, phosphorylated tau and a beta 42 on the same diagnostic platform. We found that CSF samples of patients with AD had elevated a beta oligomers compared to control subjects (p < 0.05) and the ratio of a beta oligomers to a beta 42 was also significantly elevated (p < 0.0001). Further research to develop high sensitivity analytical platforms and rigorous methods of developing stable assay standards will be needed before the analysis of oligomeric a beta becomes a routine diagnostic assay for the evaluation of late onset AD patients. C1 [Herskovits, Adrianna Z.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Locascio, Joseph J.] Massachusetts Gen Hosp, Alzheimers Dis Res Ctr, Memory Disorders Unit, Boston, MA 02114 USA. [Locascio, Joseph J.] Massachusetts Gen Hosp, Alzheimers Dis Res Ctr, Movement Disorders Unit, Boston, MA 02114 USA. [Peskind, Elaine R.; Li, Ge] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Peskind, Elaine R.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res & Educ Clin Ctr, Seattle, WA USA. [Herskovits, Adrianna Z.; Hyman, Bradley T.] Massachusetts Gen Hosp, Mass Gen Inst Neurodegenerat Dis, Dept Neurol, Charlestown, MA USA. RP Herskovits, AZ (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM azherskovits@partners.org FU NIH [P50AG05134, 2T32HL007627-26]; NIH/NIA [P50 AG005136] FX This study was supported by NIH P50AG05134 (B.T.H.) and 2T32HL007627-26 (A.Z.H.) and NIH/NIA P50 AG005136 (E.P. and G.L.). BTH is a consultant for Takeda Pharmaceutical Company. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 21 Z9 21 U1 0 U2 18 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 JUL 2 PY 2013 VL 8 IS 7 AR e67898 DI 10.1371/journal.pone.0067898 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176XV UT WOS:000321341000115 PM 23844122 ER PT J AU Watanabe, T Hiasa, Y Tokumoto, Y Hirooka, M Abe, M Ikeda, Y Matsuura, B Chung, RT Onji, M AF Watanabe, Takao Hiasa, Yoichi Tokumoto, Yoshio Hirooka, Masashi Abe, Masanori Ikeda, Yoshio Matsuura, Bunzo Chung, Raymond T. Onji, Morikazu TI Protein Kinase R Modulates c-Fos and c-Jun Signaling to Promote Proliferation of Hepatocellular Carcinoma with Hepatitis C Virus Infection SO PLOS ONE LA English DT Article ID TUMOR-SUPPRESSOR FUNCTION; INITIATION-FACTOR EIF-2; MALIGNANT-TRANSFORMATION; RNA REPLICATION; GENE-EXPRESSION; CELL-LINE; PKR; CANCER; LIVER; INTERLEUKIN-8 AB Double-stranded RNA-activated protein kinase R (PKR) is known to be upregulated by hepatitis C virus (HCV) and overexpressed in hepatocellular carcinoma (HCC). However, the precise roles of PKR in HCC with HCV infection remain unclear. Two HCV replicating cell lines (JFH-1 and H77s), generated by transfection of Huh7.5.1 cells, were used for experiments reported here. PKR expression was modulated with siRNA and a PKR expression plasmid, and cancer-related genes were assessed by real-time PCR and Western blotting; cell lines were further analyzed using a proliferation assay. Modulation of genes by PKR was also assessed in 34 human HCC specimens. Parallel changes in c-Fos and c-Jun gene expression with PKR were observed. Levels of phosphorylated c-Fos and c-Jun were upregulated by an increase of PKR, and were related to levels of phosphorylated JNK1 and Erk1/2. DNA binding activities of c-Fos and c-Jun also correlated with PKR expression, and cell proliferation was dependent on PKR-modulated c-Fos and c-Jun expression. Coordinate expression of c-Jun and PKR was confirmed in human HCC specimens with HCV infection. PKR upregulated c-Fos and c-Jun activities through activation of Erk1/2 and JNK1, respectively. These modulations resulted in HCC cell proliferation with HCV infection. These findings suggest that PKR-related proliferation pathways could be an attractive therapeutic target. C1 [Watanabe, Takao; Hiasa, Yoichi; Tokumoto, Yoshio; Hirooka, Masashi; Abe, Masanori; Ikeda, Yoshio; Matsuura, Bunzo; Onji, Morikazu] Ehime Univ, Grad Sch Med, Dept Gastroenterol & Metabol, Toon, Ehime, Japan. [Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chung, Raymond T.] Harvard Univ, Sch Med, Boston, MA USA. RP Hiasa, Y (reprint author), Ehime Univ, Grad Sch Med, Dept Gastroenterol & Metabol, Toon, Ehime, Japan. EM hiasa@m.ehime-u.ac.jp FU Japan Society for the Promotion of Science, KAKENHI [24590980]; Program for Enhancing Systematic Education in Graduate School from the Ministry of Education, Culture, Sports, Science and Technology, Japan; Japanese Ministry of Health, Labor and Welfare, Japan FX This work was supported in part by the following: a Grant-in-Aid for Scientific Research, Japan Society for the Promotion of Science, KAKENHI 24590980 (to Y.H.); the Program for Enhancing Systematic Education in Graduate School from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to T.W.); and by a Grant-in-Aid for Scientific Research and Development from the Japanese Ministry of Health, Labor and Welfare, Japan (to Y.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 9 Z9 10 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 JUL 2 PY 2013 VL 8 IS 7 AR e67750 DI 10.1371/journal.pone.0067750 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 176XV UT WOS:000321341000091 PM 23844083 ER PT J AU McLaughlin, HM Kelly, MA Hawley, PP Darras, BT Funke, B Picker, J AF McLaughlin, Heather M. Kelly, Melissa A. Hawley, Pamela P. Darras, Basil T. Funke, Birgit Picker, Jonathan TI Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy SO BMC MEDICAL GENETICS LA English DT Article DE Desminopathy; Myopathy; Dilated cardiomyopathy; Clinical genetics; Genetic testing ID MICE LACKING DESMIN; SKELETAL MYOPATHY; GENE; MUTATIONS; EXPRESSION AB Background: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only similar to 50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established. Case presentation: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent. Conclusions: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies. C1 [McLaughlin, Heather M.; Funke, Birgit] Mol Med Lab, Cambridge, MA 02139 USA. [McLaughlin, Heather M.; Kelly, Melissa A.; Funke, Birgit] Partners Ctr Personalized Genet Med, Mol Med Lab, Cambridge, MA USA. [Hawley, Pamela P.; Picker, Jonathan] Boston Childrens Hosp Boston, Dept Pediat, Div Genet & Metab, Div Genet, Boston, MA USA. [Darras, Basil T.] Childrens Hosp Boston, Div Clin Neurol, Boston, MA USA. [Darras, Basil T.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Funke, Birgit] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Picker, Jonathan] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Funke, B (reprint author), Mol Med Lab, 65 Landsdowne St, Cambridge, MA 02139 USA. EM bfunke@partners.org; Jonathan.Picker@childrens.harvard.edu NR 15 TC 5 Z9 5 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUL 2 PY 2013 VL 14 AR 68 DI 10.1186/1471-2350-14-68 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 182UO UT WOS:000321770400001 PM 23815709 ER PT J AU Miura, LN Boxer, RS AF Miura, Lisa N. Boxer, Rebecca S. TI Women in Medicine and the Ticking Clock SO ANNALS OF FAMILY MEDICINE LA English DT Editorial Material DE delayed childbearing; pregnancy complications; maternal age; infertility AB Our careers began with the long, arduous, and intensely focused commitments of premed, medical school, residency, and fellowship. We planned our lives rationally and enacted our plans with care. Now we have long-desired and satisfying careers. We discovered something, however, that the culture of medical training and our plans had failed to anticipate: We did not allow time for the unexpected. C1 [Miura, Lisa N.] Oregon Hlth & Sci Univ, Portland, OR USA. [Boxer, Rebecca S.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Miura, LN (reprint author), P3MED, Portland VA Med Ctr, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM miural@ohsu.edu NR 2 TC 1 Z9 1 U1 1 U2 4 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 EI 1544-1717 J9 ANN FAM MED JI Ann. Fam. Med. PD JUL-AUG PY 2013 VL 11 IS 4 BP 381 EP 382 DI 10.1370/afm.1515 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AI3XH UT WOS:000336798500012 PM 23835825 ER PT J AU Seton, M AF Seton, Margaret TI Paget disease of bone: Diagnosis and drug therapy SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Review ID SEQUESTOSOME-1 GENE; OSTEITIS DEFORMANS; ZOLEDRONIC ACID; SINGLE INFUSION; NEW-ZEALAND; MANAGEMENT; MUTATIONS; BISPHOSPHONATES; EPIDEMIOLOGY; RISEDRONATE AB Paget disease of bone is a focal disorder of aging bone that may be asymptomatic or may present with pain, bowing deformity, fracture, or a nonspecific rheumatic complaint. It is the second most common disease of bone in the elderly after osteoporosis, and the loss of structural integrity in affected bone conveys a risk of fracture. It may occur sporadically or in geographic or familial clusters. This article discusses the prevalence, pathology, workup, and treatment of Paget disease of bone. C1 [Seton, Margaret] Massachusetts Gen Hosp, Dept Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Seton, Margaret] Harvard Univ, Sch Med, Boston, MA USA. RP Seton, M (reprint author), Massachusetts Gen Hosp, Dept Rheumatol Allergy & Immunol, Arthrit Unit, Bulfinch 165,55 Fruit St, Boston, MA 02114 USA. EM mseton@partners.org NR 72 TC 7 Z9 7 U1 0 U2 1 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 EI 1939-2869 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD JUL PY 2013 VL 80 IS 7 BP 452 EP 462 DI 10.3949/ccjm.80a.12142 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AI2YU UT WOS:000336725900010 PM 23821690 ER PT J AU Rigg, KK Murphy, JW AF Rigg, Khary K. Murphy, John W. TI Understanding the Etiology of Prescription Opioid Abuse: Implications for Prevention and Treatment SO QUALITATIVE HEALTH RESEARCH LA English DT Article DE addiction / substance use; illness and disease, prevention; interviews, semistructured; mental health and illness; psychosocial issues; social constructionism; sociology ID METHADONE-MAINTENANCE TREATMENT; LIFE-COURSE PERSPECTIVE; INJECTION-DRUG USERS; ILLICIT USE; PHARMACEUTICAL OPIOIDS; DEPENDENCE; INITIATION; DIVERSION; PAIN; PERSISTENCE AB Although studies on the initiation of substance abuse abound, the body of literature on prescription opioid abuse (POA) etiology is small. Little is known about why and how the onset of POA occurs, especially among high-risk populations. In this study we aimed to fill this important knowledge gap by exploring the POA initiation experiences of 90 prescription opioid abusers currently in treatment and their narrative accounts of the circumstances surrounding their POA onset. This research was conducted within a storyline framework, which operates on the premise that the path to drug abuse represents a biography or a process rather than a static condition. Audiotapes of in-depth interviews were transcribed, coded, and thematically analyzed. Analyses revealed the presence of four trajectories leading to POA. This study adds to the limited research on POA etiology by not only illuminating the psychosocial factors that contribute to POA onset, but also by situating initiation experiences within broader life processes. The study findings provide crucial insights to policymakers and interventionists in identifying who is at risk for POA, and more important, when and how to intervene most efficaciously. C1 [Rigg, Khary K.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Murphy, John W.] Univ Miami, Coral Gables, FL 33124 USA. RP Rigg, KK (reprint author), Philadelphia VA Med Ctr CHERP, 3900 Woodland Ave,Bldg 4100,Suite 202, Philadelphia, PA 19104 USA. EM kharyrigg@gmail.com FU NIDA NIH HHS [R01DA021330, R01 DA021330] NR 46 TC 10 Z9 10 U1 4 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-7323 EI 1552-7557 J9 QUAL HEALTH RES JI Qual. Health Res. PD JUL PY 2013 VL 23 IS 7 BP 963 EP 975 DI 10.1177/1049732313488837 PG 13 WC Information Science & Library Science; Social Sciences, Interdisciplinary; Social Sciences, Biomedical SC Information Science & Library Science; Social Sciences - Other Topics; Biomedical Social Sciences GA AH6RJ UT WOS:000336258100009 PM 23656723 ER PT J AU van Diepen, S Hellkamp, AS Patel, MR Becker, RC Breithardt, G Hacke, W Halperin, JL Hankey, GJ Nessel, CC Singer, DE Berkowitz, SD Califf, RM Fox, KAA Mahaffey, KW AF van Diepen, Sean Hellkamp, Anne S. Patel, Manesh R. Becker, Richard C. Breithardt, Guenter Hacke, Werner Halperin, Jonathan L. Hankey, Graeme J. Nessel, Christopher C. Singer, Daniel E. Berkowitz, Scott D. Califf, Robert M. Fox, Keith A. A. Mahaffey, Kenneth W. TI Efficacy and Safety of Rivaroxaban in Patients With Heart Failure and Nonvalvular Atrial Fibrillation Insights From ROCKET AF SO CIRCULATION-HEART FAILURE LA English DT Article DE anticoagulants; arrhythmias; cardiac; heart failure ID RHYTHM MANAGEMENT AFFIRM; FACTOR-XA INHIBITOR; STABLE INR CONTROL; EJECTION FRACTION; ANTICOAGULATION THERAPY; VENOUS THROMBOEMBOLISM; ORAL ANTICOAGULANT; NATIONAL REGISTRY; PREDICTING STROKE; BLEEDING RISK AB Background In Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolic events and significantly reduced intracranial bleeding in patients with nonvalvular atrial fibrillation. We explore the safety and efficacy of rivaroxaban in patients with heart failure (HF). Methods and Results A total of 9033 (63.7%) patients had HF. The primary efficacy analysis was rates of stroke or systemic embolism (per 100 patient-years) by intention to treat. The safety outcomes were major or nonmajor clinically relevant bleeding and hemorrhagic stroke during treatment. Patients with HF were younger (72 versus 74 years), more likely to have persistent atrial fibrillation (83.0% versus 77.6%), and had higher mean CHADS(2) scores (3.7 versus 3.1). The efficacy of rivaroxaban compared with warfarin was similar in patients with HF (1.90 versus 2.09) and without HF (2.10 versus 2.54; P-interaction=0.62). The risk of major or nonmajor clinically relevant bleeding with rivaroxaban was similar to warfarin in patients with HF (14.22 versus 14.02) and without HF (16.12 versus 15.35; P-interaction=0.99). A reduction in hemorrhagic stroke was observed with rivaroxaban in patients with HF as in the overall trial (adjusted hazard ratio, 0.38; 95% confidence interval, 0.19-0.76; P-interaction=0.067). Among patients with HF, the efficacy of rivaroxaban was similar, irrespective of ejection fraction <40 or 40% (P-interaction=0.38), New York Heart Association class I-II versus III-IV (P-interaction=0.68), HF preserved or reduced ejection fraction (P-interaction=0.35), or CHADS(2) score 2 versus 3 (P-interaction=0.48). Conclusions Treatment-related outcomes were similar in patients with and without HF and across HF subgroups. These findings support the use of rivaroxaban as an alternative to warfarin in patients with atrial fibrillation and HF. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767. C1 [van Diepen, Sean] Univ Alberta, Div Crit Care, Edmonton, AB, Canada. [van Diepen, Sean] Univ Alberta, Div Cardiol, Edmonton, AB, Canada. [Hellkamp, Anne S.; Patel, Manesh R.; Becker, Richard C.; Mahaffey, Kenneth W.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Breithardt, Guenter] Hosp Univ Munster, Dept Cardiol & Angiol, Munster, Germany. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Halperin, Jonathan L.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Hankey, Graeme J.] Royal Perth Hosp, Perth, WA 6001, Australia. [Nessel, Christopher C.] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Montville, NJ USA. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. RP van Diepen, S (reprint author), Univ Alberta Hosp, Cardiol WMC 2C2, 8440-112 St, Edmonton, AB T6G 2B7, Canada. EM sv9@ualberta.ca RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ; Bayer HealthCare AG, Leverkusen, Germany FX This work was sponsored by Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, and Bayer HealthCare AG, Leverkusen, Germany. NR 41 TC 31 Z9 32 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2013 VL 6 IS 4 BP 740 EP 747 DI 10.1161/CIRCHEARTFAILURE.113.000212 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AG1EL UT WOS:000335157800023 PM 23723250 ER PT J AU Januzzi, JL AF Januzzi, James L. TI Letter by Januzzi Regarding Article, "Galectin-3 and Cardiac Function in Survivors of Acute Myocardial Infarction" SO CIRCULATION-HEART FAILURE LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2013 VL 6 IS 4 BP E57 EP E57 DI 10.1161/CIRCHEARTFAILURE.113.000375 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AG1EL UT WOS:000335157800005 PM 23861511 ER PT J AU Schalock, PC Thyssen, JP AF Schalock, Peter C. Thyssen, Jacob P. TI Patch Testers' Opinions Regarding Diagnostic Criteria for Metal Hypersensitivity Reactions to Metallic Implants SO DERMATITIS LA English DT Article AB Background Metal hypersensitivity reactions to implanted devices remain a challenging and controversial topic. Diagnostic criteria and methods are not well delineated. Objective Diagnostic criteria for hypersensitivity reactions after metallic device implantation are evaluated in this study by a multinational group of patch testers using Thyssen's previously published criteria. Methods A total of 119 dermatologists at the 2012 European Contact Dermatitis Society and 2013 American Contact Dermatitis Society meetings answered a survey regarding their opinions on topics relating to metal hypersensitivity. Conclusions Four major and 5 minor diagnostic criteria emerged. Approximately 80% of respondents found the following criteria useful (major criteria): chronic dermatitis beginning weeks to months after metallic implantation, eruption overlying the metal implant, positive patch test to a metal component of the implant, and complete clearing after removal of the potentially allergenic implant. Minor criteria (<61% of respondents) were as follows: systemic allergic dermatitis reaction, therapy-resistant dermatitis, morphology consistent with dermatitis, histology consistent with allergic contact dermatitis, and a positive in vitro test to metals (eg, lymphocyte transformation test). In the challenging situation such as a symptomatic or failing orthopedic device, applying these 4 major criteria and the 5 supportive minor criteria may be useful for guiding decision making. C1 [Schalock, Peter C.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Thyssen, Jacob P.] Univ Copenhagen, Natl Allergy Res Ctr, Dept Dermatoallergol, Gentofte Hosp, DK-1168 Copenhagen, Denmark. RP Schalock, PC (reprint author), Massachusetts Gen Hosp, Dept Dermatol, BAR622,55 Fruit St, Boston, MA 02114 USA. EM schalock.prof@gmail.com OI Schalock, Peter/0000-0001-8953-4639 NR 8 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1710-3568 EI 2162-5220 J9 DERMATITIS JI Dermatitis PD JUL-AUG PY 2013 VL 24 IS 4 BP 183 EP 185 DI 10.1097/DER.0b013e31829cb113 PG 3 WC Dermatology SC Dermatology GA AG2QI UT WOS:000335260800007 PM 23857019 ER PT J AU John, S Andersson, KL Kotton, CN Hertl, M Markmann, JF Cosimi, AB Chung, RT AF John, Savio Andersson, Karin L. Kotton, Camille N. Hertl, Martin Markmann, James F. Cosimi, A. Benedict Chung, Raymond T. TI Prophylaxis of hepatitis B infection in solid organ transplant recipients SO THERAPEUTIC ADVANCES IN GASTROENTEROLOGY LA English DT Review DE HBV prophylaxis; HBV recurrence; HBV reinfection; solid organ transplant ID ORTHOTOPIC LIVER-TRANSPLANTATION; KIDNEY ALLOGRAFT RECIPIENTS; IMMUNE GLOBULIN PROPHYLAXIS; ANTIBODY-POSITIVE DONORS; VIRUS RECURRENCE; SURFACE-ANTIGEN; PASSIVE-IMMUNIZATION; LAMIVUDINE THERAPY; RENAL-TRANSPLANTATION; ADEFOVIR DIPIVOXIL AB Rates of transmission of hepatitis B virus (HBV) infection from organ donors with HBV markers to recipients along with reactivation of HBV during immunosuppression following transplantation have fallen significantly with the advent of hepatitis B immune globulin (HBIg) and effective antiviral therapy. Although the availability of potent antiviral agents and HBIg has highly impacted the survival rate of HBV-infected patients after transplantation, the high cost associated with this practice represents a major financial burden. The availability of potent antivirals with high genetic barrier to resistance and minimal side effects have made it possible to recommend an HBIg-free prophylactic regimen in selected patients with low viral burden prior to transplant. Significant developments over the last two decades in the understanding and treatment of HBV infection necessitate a re-appraisal of the guidelines for prophylaxis of HBV infection in solid organ transplant recipients. C1 [John, Savio] SUNY Upstate Med Univ, Div Gastroenterol & Hepatol, Syracuse, NY 13210 USA. [John, Savio] SUNY Upstate Med Univ, Div Gastroenterol & Hepatol, Syracuse, NY 13210 USA. [John, Savio; Andersson, Karin L.; Chung, Raymond T.] Massachusetts Gen Hosp, Hepatol Div, Boston, MA 02114 USA. [Kotton, Camille N.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Hertl, Martin; Markmann, James F.; Cosimi, A. Benedict] Massachusetts Gen Hosp, Div Transplant Surg, Boston, MA 02114 USA. RP John, S (reprint author), SUNY Upstate Med Univ, Div Gastroenterol & Hepatol, 750 E Adams St, Syracuse, NY 13210 USA. EM johns@upstate.edu FU Gilead; Roche/Genentech FX R.C. has received research grants from Gilead and Roche/Genentech. NR 66 TC 5 Z9 6 U1 0 U2 2 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 JUL PY 2013 VL 6 IS 4 BP 309 EP 319 DI 10.1177/1756283X13487942 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AG9OE UT WOS:000335748200005 PM 23814610 ER PT J AU Flaumenhaft, R Khodier, C Galinski, CN Nag, P Passam, FH Scalise, A Van Hessem, L Gunnink, S Dandapani, S Munoz, B Kennedy, DR AF Flaumenhaft, R. Khodier, C. Galinski, C. N. Nag, P. Passam, F. H. Scalise, A. Van Hessem, L. Gunnink, S. Dandapani, S. Munoz, B. Kennedy, D. R. TI Identification of novel antagonists of protein disulfide isomerase for inhibition of thrombus formation SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Flaumenhaft, R.; Passam, F. H.; Van Hessem, L.; Gunnink, S.] Harvard Univ, Sch Med, BIDMC, Boston, MA USA. [Khodier, C.; Nag, P.; Dandapani, S.; Munoz, B.] Broad Inst, Cambridge, MA USA. [Galinski, C. N.; Scalise, A.; Kennedy, D. R.] Western New England Coll Pharm, Springfield, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 10 EP 11 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601024 ER PT J AU Penaloza, A Kabrhel, C Verschuren, F Vielle, B Kline, J Le Gal, G Thys, F Roy, PM AF Penaloza, A. Kabrhel, C. Verschuren, F. Vielle, B. Kline, J. Le Gal, G. Thys, F. Roy, P-M TI D-dimer relevance score SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Penaloza, A.; Verschuren, F.; Thys, F.] Clin Univ St Luc, B-1200 Brussels, Belgium. [Kabrhel, C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vielle, B.; Roy, P-M] Univ Angers, CHU Angers, Angers, France. [Kline, J.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Le Gal, G.] Ottawa Hlth Res Inst, Ottawa, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 131 EP 131 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601295 ER PT J AU Kabrhel, C Okechukwu, I Hariharan, P Takayesu, JK Temin, E MacMahon, P Haddad, F Chang, Y AF Kabrhel, C. Okechukwu, I Hariharan, P. Takayesu, J. K. Temin, E. MacMahon, P. Haddad, F. Chang, Y. TI Factors associated with clinical deterioration shortly after an Emergency Department Diagnosis of Pulmonary Embolism SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Kabrhel, C.; Okechukwu, I; Takayesu, J. K.; Temin, E.; Chang, Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Hariharan, P.] Boston Univ, Boston, MA 02215 USA. [MacMahon, P.] Mater Misericordiae Univ Hosp, Dublin, Ireland. [Haddad, F.] Inova Fairfax Hosp, Falls Church, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 242 EP 243 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601550 ER PT J AU Liu, Y Richter, C Maeder, ML Vo, A Huarng, M Swaroop, A Joung, K Shavit, JA AF Liu, Y. Richter, C. Maeder, M. L. Vo, A. Huarng, M. Swaroop, A. Joung, K. Shavit, J. A. TI Identification of dominant thrombosis modifier loci using a sensitized ENU mutagenesis screen SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Liu, Y.; Richter, C.; Vo, A.; Huarng, M.; Swaroop, A.; Shavit, J. A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Maeder, M. L.; Joung, K.] Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 286 EP 286 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833601650 ER PT J AU Mollah, S Grabell, J Rand, ML Clarke, D Christopherson, P Mauer, A Montgomery, R Zimmerman, T Coller, B James, PD AF Mollah, S. Grabell, J. Rand, M. L. Clarke, D. Christopherson, P. Mauer, A. Montgomery, R. Zimmerman, T. Coller, B. James, P. D. TI The merging project: a machine learning approach to merge and analyze data from four different bleeding questionnaires SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Mollah, S.; Coller, B.] Rockefeller Univ, New York, NY 10021 USA. [Grabell, J.; James, P. D.] Queens Univ, Kingston, ON, Canada. [Rand, M. L.; Clarke, D.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Christopherson, P.; Montgomery, R.; Zimmerman, T.] Blood Res Inst, Milwaukee, WI USA. [Christopherson, P.; Montgomery, R.; Zimmerman, T.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Mauer, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 360 EP 360 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833602143 ER PT J AU Kabrhel, C Jaff, M Channick, R Baker, JN Jama, A Manthripragada, GK Hawkins, B O'Dea, J Weinberg, I Rosenfield, K AF Kabrhel, C. Jaff, M. Channick, R. Baker, J. N. Jama, A. Manthripragada, G. K. Hawkins, B. O'Dea, J. Weinberg, I Rosenfield, K. TI A multidisciplinary pulmonary embolism response team (PERT). Initial clinical experience at Massachusetts general hospital SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Kabrhel, C.; Jaff, M.; Channick, R.; Baker, J. N.; Jama, A.; Manthripragada, G. K.; Hawkins, B.; O'Dea, J.; Weinberg, I; Rosenfield, K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 386 EP 387 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833602205 ER PT J AU Frelinger, AL Chang, H Dix, EJ Yanachkova, M Li, Y Barnard, R Wright, E Michelson, AD Yanachkov, IB AF Frelinger, A. L., III Chang, H. Dix, E. J. Yanachkova, M. Li, Y. Barnard, R. Wright, E. Michelson, A. D. Yanachkov, I. B. TI Antiplatelet activity, P2Y1 and P2Y12 inhibition, and metabolism in plasma of diastereomers of the Ap4A analog diadenosine-5 ',5 '''-P1,P4-dithio-P2,P3-chloromethylenetetraphosphate SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Frelinger, A. L., III; Barnard, R.; Michelson, A. D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp, Boston, MA 02115 USA. [Chang, H.] Chang Gung Univ, Chang Gung Mem Hosp, Taipei, Taiwan. [Dix, E. J.; Yanachkova, M.; Wright, E.; Yanachkov, I. B.] GLSynthesis Inc, Worcester, MA USA. [Li, Y.] Univ Massachusetts, Sch Med, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 495 EP 496 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833602463 ER PT J AU Gerrits, AJ Barnard, R Fitzpatrick, MG Berny-Lang, MA Michelson, AD Frelinger, AL AF Gerrits, A. J. Barnard, R. Fitzpatrick, M. G. Berny-Lang, M. A. Michelson, A. D. Frelinger, A. L., III TI Use of high-sensitivity flow cytometry for the characterization of a lyophilized platelet-derived hemostatic agent SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Gerrits, A. J.; Barnard, R.; Berny-Lang, M. A.; Michelson, A. D.; Frelinger, A. L., III] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp, Boston, MA 02115 USA. [Fitzpatrick, M. G.] Cellphire Inc, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 511 EP 511 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833602502 ER PT J AU Berny-Lang, MA Darling, CE AL Frelinger, AA Barnard, M Gerrits, AJ Michelson, AD AF Berny-Lang, M. A. Darling, C. E. AL Frelinger, A. A. Barnard, M. Gerrits, A. J. Michelson, A. D. TI Does the immature platelet function (IPF) in chest pain patients presenting to the emergency department aid in the diagnosis of acute coronory syndrome? SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Berny-Lang, M. A.; AL Frelinger, A. A.; Barnard, M.; Gerrits, A. J.; Michelson, A. D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp, Boston, MA 02115 USA. [Darling, C. E.] Univ Massachusetts, Sch Med, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 731 EP 731 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833603416 ER PT J AU Reny, JL Brun, C Frelinger, AL Daali, Y Zufferey, A Michelson, A Combescure, C Fontana, P Reny, JL AF Reny, J-L Brun, C. Frelinger, A. L. Daali, Y. Zufferey, A. Michelson, A. Combescure, C. Fontana, P. Reny, J-L TI Aspirin response: how to explain striking differences in serum TxB2 levels across clinical studies and what use for serum TxB2? SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Reny, J-L; Brun, C.; Zufferey, A.; Fontana, P.; Reny, J-L] Univ Hosp Geneva, Thonex, Switzerland. [Reny, J-L; Brun, C.; Zufferey, A.; Fontana, P.; Reny, J-L] Geneva Platelet Grp, Thonex, Switzerland. [Frelinger, A. L.; Michelson, A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Childrens Hosp Boston, Boston, MA 02115 USA. [Daali, Y.; Combescure, C.] Univ Hosp Geneva, Geneva, Switzerland. RI Fontana, Pierre/M-3702-2014 OI Fontana, Pierre/0000-0003-1546-0774 NR 2 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 761 EP 761 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833603488 ER PT J AU Beam, D Kabrhel, C Kline, JA AF Beam, D. Kabrhel, C. Kline, J. A. TI The effect of empiric systemic anticoagulation prior to imaging for pulmonary embolism on mortality SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Meeting Abstract C1 [Beam, D.; Kline, J. A.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Kabrhel, C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 EI 1538-7836 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD JUL PY 2013 VL 11 SU 2 SI SI BP 1090 EP 1090 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AB5MV UT WOS:000331833604580 ER PT J AU Chen, WW Balaj, L Liau, LM Samuels, ML Kotsopoulos, SK Maguire, CA LoGuidice, L Soto, H Garrett, M Zhu, LD Sivaraman, S Chen, C Wong, ET Carter, BS Hochberg, FH Breakefield, XO Skog, J AF Chen, Walter W. Balaj, Leonora Liau, Linda M. Samuels, Michael L. Kotsopoulos, Steve K. Maguire, Casey A. LoGuidice, Lori Soto, Horacio Garrett, Matthew Zhu, Lin Dan Sivaraman, Sarada Chen, Clark Wong, Eric T. Carter, Bob S. Hochberg, Fred H. Breakefield, Xandra O. Skog, Johan TI BEAMing and Droplet Digital PCR Analysis of Mutant IDH1 mRNA in Glioma Patient Serum and Cerebrospinal Fluid Extracellular Vesicles SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE BEAMing PCR; biomarkers; cancer; extracellular vesicles; droplet digital PCR ID INTEGRATED GENOMIC ANALYSIS; COLORECTAL-CANCER; GLIOBLASTOMA-MULTIFORME; CLINICAL-SAMPLES; TUMOR DNA; MUTATIONS; MICROVESICLES; BIOMARKERS; SEQUENCES; BREAST AB Development of biofluid-based molecular diagnostic tests for cancer is an important step towards tumor characterization and real-time monitoring in a minimally invasive fashion. Extracellular vesicles (EVs) are released from tumor cells into body fluids and can provide a powerful platform for tumor biomarkers because they carry tumor proteins and nucleic acids. Detecting rare point mutations in the background of wild-type sequences in biofluids such as blood and cerebrospinal fluid (CSF) remains a major challenge. Techniques such as BEAMing (beads, emulsion, amplification, magnetics) PCR and droplet digital PCR (ddPCR) are substantially more sensitive than many other assays for mutant sequence detection. Here, we describe a novel approach that combines biofluid EV RNA and BEAMing RT-PCR (EV-BEAMing), as well droplet digital PCR to interrogate mutations from glioma tumors. EVs from CSF of patients with glioma were shown to contain mutant IDH1 transcripts, and we were able to reliably detect and quantify mutant and wild-type IDH1 RNA transcripts in CSF of patients with gliomas. EV-BEAMing and EV-ddPCR represent a valuable new strategy for cancer diagnostics, which can be applied to a variety of biofluids and neoplasms. C1 [Chen, Walter W.; Balaj, Leonora; Maguire, Casey A.; Zhu, Lin Dan; Sivaraman, Sarada; Hochberg, Fred H.; Breakefield, Xandra O.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Chen, Walter W.; Balaj, Leonora; Maguire, Casey A.; Zhu, Lin Dan; Sivaraman, Sarada; Hochberg, Fred H.; Breakefield, Xandra O.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. [Chen, Walter W.; Maguire, Casey A.; Zhu, Lin Dan; Sivaraman, Sarada; Hochberg, Fred H.; Breakefield, Xandra O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Chen, Walter W.] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [Balaj, Leonora] Amsterdam Canc Ctr, Neurooncol Res Grp, Amsterdam, Netherlands. [Liau, Linda M.; Soto, Horacio; Garrett, Matthew] Univ Calif Los Angeles, David Geffen Sch Med, Med Ctr, Dept Neurosurg, Los Angeles, CA 90095 USA. [Samuels, Michael L.; Kotsopoulos, Steve K.] RainDance Technol, Lexington, MA USA. [LoGuidice, Lori; Skog, Johan] Exosome Diagnost Inc, New York, NY USA. [Chen, Clark; Wong, Eric T.] Beth Israel Deaconess Med Ctr, Brain Tumor Ctr, Boston, MA 02215 USA. [Chen, Clark; Wong, Eric T.] Beth Israel Deaconess Med Ctr, Neurooncol Unit, Boston, MA 02215 USA. [Chen, Clark; Carter, Bob S.] Univ Calif San Diego, Dept Neurosurg, San Diego, CA 92103 USA. RP Breakefield, XO (reprint author), Massachusetts Gen Hosp East, Mol Neurogenet Unit, 13th St,Bldg 149, Charlestown, MA 02129 USA. EM breakefield@hms.harvard.edu FU NIH/NCI [CA069246, CA141226, CA156009, CA141150]; Brain Tumor Funders' Collaborative; American Brain Tumor Association (ABTA); Harvard Catalyst; A Reason To Ride research fund; Hyugens Scholarship NL; Richard Floor Biorepository; Accelerate Brain Cancer Cure (ABC2) FX This work was supported by NIH/NCI grants CA069246 (F. H., X.O.B., B. C.); CA141226 (X.O.B.); CA156009 (X.O.B.); and CA141150 (X.O.B.); Brain Tumor Funders' Collaborative (B. C., X.O.B.); American Brain Tumor Association (ABTA; J.S.); Harvard Catalyst (B. C.); A Reason To Ride research fund (E. T. W.); Hyugens Scholarship NL (L. B.), the Richard Floor Biorepository and the Accelerate Brain Cancer Cure (ABC2). All processing of samples by Exosome Diagnostics Inc and RainDance Technologies was carried out on de-identified samples. We thank Suzanne McDavitt for skilled editorial assistance. We thank N Agrawal for his advice and for providing us with BEAMing reagents and A Mandinova for providing access to the TissueLyser. We thank Karen Messer for help with statistical analysis. We also thank Winston Patrick Kuo and Fatemeh Momen-Heravi for help with TEM and Mikkel Noerholm for help with probe design. J.S. is an inventor on the microvesicle technology used in this study which has been licensed to Exosome Diagnostics, Inc. He holds equity in, and is an employee of that company. Breakefield and Carter are on the Scientific Advisory Board of the company for which they receive cash compensation. M. L. S. and S. K. K. are employees of RainDance Technologies Inc. The other authors declared no conflict of interest. NR 34 TC 57 Z9 60 U1 4 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD JUL PY 2013 VL 2 AR e109 DI 10.1038/mtna.2013.28 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AC4CA UT WOS:000332467000008 PM 23881452 ER PT J AU Hamlett-Berry, K Christofferson, DE Martinello, RA AF Hamlett-Berry, Kim Christofferson, Dana E. Martinello, Richard A. TI SMOKING AND TOBACCO USE WITHIN THE DEPARTMENT OF VETERANS AFFAIRS SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 [Hamlett-Berry, Kim; Christofferson, Dana E.; Martinello, Richard A.] US Dept Vet Affairs, Vet Hlth Adm, Washington, DC 20460 USA. RP Hamlett-Berry, K (reprint author), Dept Vet Affairs, 810 Vermont Ave 10P3B, Washington, DC 20460 USA. EM kim.hamlett@va.gov NR 6 TC 3 Z9 3 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2013 VL 103 IS 7 BP E3 EP E3 DI 10.2105/AJPH.2013.301375 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3FP UT WOS:000330978600003 PM 23678898 ER PT J AU Lameijer, MA Tang, J Nahrendorf, M Beelen, RHJ Mulder, WJM AF Lameijer, Marnix A. Tang, Jun Nahrendorf, Matthias Beelen, Robert H. J. Mulder, Willem J. M. TI Monocytes and macrophages as nanomedicinal targets for improved diagnosis and treatment of disease SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE anti-inflammatory; diagnosis; macrophage; monocyte; nanomedicine; nanoparticles; treatment ID TUMOR-ASSOCIATED MACROPHAGES; RHEUMATOID-ARTHRITIS; INFLAMMATORY ATHEROSCLEROSIS; ANTIINFLAMMATORY TREATMENT; THERAPEUTIC APPLICATIONS; ALVEOLAR MACROPHAGES; DRUG-DELIVERY; CELL-DEATH; NANOPARTICLES; SUBSETS AB The important role of monocytes and macrophages in diseases like cancer and atherosclerosis has started to get uncovered in the last decade. In addition, subsets of these cell types are believed to participate in the initiation and aggravation of several diseases including cancer and cardiovascular disease. For this reason, monocytes and macrophages have recently been identified as interesting targets for both diagnosis and treatment of the aforementioned pathologies. Compared with free therapeutic or imaging agents, nanoparticle formulations provide several advantages that improve the pharmacokinetics and bioavailability of these agents. In addition, the possibility of surface functionalization creates numerous ways to optimize nanoparticle delivery. Recent advances in nanomedicine have led to the development of multifunctional nanoparticles that allow simultaneous diagnosis and treatment of monocytes and macrophages with high specificity. Relying on the inherent ability of monocytes and macrophages to easily take up foreign particles, the use of nanoparticles provides a precious opportunity for the management of several inflammatory diseases. C1 [Lameijer, Marnix A.; Beelen, Robert H. J.] Vrije Univ Amsterdam, Med Ctr, Dept Cell Biol & Immunol, NL-1081 BT Amsterdam, Netherlands. [Tang, Jun; Mulder, Willem J. M.] Icahn Sch Med Mt Sinai, Dept Radiol, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Tang, Jun] Icahn Sch Med, Grad Sch Biomed Sci, New York, NY 10029 USA. [Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Nahrendorf, Matthias] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mulder, Willem J. M.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. RP Mulder, WJM (reprint author), Icahn Sch Med Mt Sinai, Dept Radiol, Translat & Mol Imaging Inst, One Gustave L Levy Pl, New York, NY 10029 USA. EM willem.mulder@mssm.edu OI Tang, Jun/0000-0002-8285-5111 FU National Heart, Lung, and Blood Institute, NIH [HHSN268201000045C]; NIH [R01CA155432]; American Heart Association [13PRE14350020] FX This work was financially supported by the National Heart, Lung, and Blood Institute, NIH, as a Program of Excellence in Nanotechnology (PEN) Award, Contract #HHSN268201000045C, the NIH grant R01CA155432 (WJM Mulder) and the American Heart Association Award #13PRE14350020-Founders (J Tang) The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 115 TC 17 Z9 17 U1 5 U2 26 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 EI 1744-8352 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUL PY 2013 VL 13 IS 6 BP 567 EP 580 DI 10.1586/14737159.2013.819216 PG 14 WC Pathology SC Pathology GA AA7OD UT WOS:000331285900013 PM 23895127 ER PT J AU Cusin, C Iovieno, N Iosifescu, DV Nierenberg, AA Fava, M Rush, AJ Perlis, RH AF Cusin, Cristina Iovieno, Nadia Iosifescu, Dan V. Nierenberg, Andrew A. Fava, Maurizio Rush, A. John Perlis, Roy H. TI A Randomized, Double-Blind, Placebo-Controlled Trial of Pramipexole Augmentation in Treatment-Resistant Major Depressive Disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID SEROTONIN REUPTAKE INHIBITORS; ANTIDEPRESSANT TREATMENT; INADEQUATE-RESPONSE; DOPAMINE; D-3; MULTICENTER; COMBINATION; FLUOXETINE; RELEASE AB Background: Multiple treatments for patients with major depressive disorder (MDD) have demonstrated efficacy, but up to one-third of individuals with MDD do not achieve symptomatic remission despite various interventions. Existing augmentation or combination strategies can have substantial safety concerns that may limit their application. Method: This study investigated the antidepressant efficacy of a flexible dose of the dopamine agonist pramipexole as an adjunct to standard antidepressant treatment in an 8-week, randomized, double-blind, placebo-controlled trial conducted in a tertiary-level depression center. We randomized 60 outpatients (aged 18 to 75 years) with treatment-resistant nonpsychotic MDD (diagnosed according to DSM-IV) to either pramipexole (n = 30) or placebo (n = 30). Treatment resistance was defined as continued depression (Montgomery-Asberg Depression Rating Scale [MADRS] score = 18) despite treatment with at least 1 prior antidepressant in the current depressive episode. Patients were recruited between September 2005 and April 2008. The primary outcome measure was the MADRS score. Results: The analyses that used a mixed-effects linear regression model indicated a modest but statistically significant benefit for pramipexole (P = .038). The last-observation-carried-forward analyses indicated that 40% and 33% of patients randomized to augmentation with pramipexole achieved response (chi(2) = 1.2, P = .27) and remission (chi(2) = 0.74, P = .61), respectively, compared to 27% and 23% with placebo; however, those differences were not statistically significant. Augmentation with pramipexole was well-tolerated, with no serious adverse effects identified. Conclusion: For patients who have failed to respond to standard antidepressant therapies, pramipexole is a safe and potentially efficacious augmentation strategy. (C) Copyright 2013 Physicians Postgraduate Press, Inc. C1 [Cusin, Cristina; Iovieno, Nadia; Nierenberg, Andrew A.; Fava, Maurizio; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA 02114 USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Iosifescu, Dan V.] Mt Sinai Sch Med, Dept Psychiat, Mood & Anxiety Disorders Program, New York, NY USA. [Rush, A. John] Singapore Clin Res Inst, Singapore, Singapore. [Rush, A. John] Duke NUS Grad Med Sch, Singapore, Singapore. RP Cusin, C (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, One Bowdoin Sq,Ste 630, Boston, MA 02114 USA. EM ccusin@partners.org FU NIMH [K23-MH67060]; Dupont-Warren Fellowship from Harvard Medical School FX This study was sponsored by NIMH award K23-MH67060. Dr Cusin's salary was partially supported by a Dupont-Warren Fellowship from Harvard Medical School. NR 33 TC 24 Z9 24 U1 2 U2 4 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2013 VL 74 IS 7 BP E636 EP E641 DI 10.4088/JCP.12m08093 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AA5DO UT WOS:000331116400002 PM 23945458 ER PT J AU Kilbourne, AM Goodrich, DE Lai, ZS Post, EP Schumacher, K Nord, KM Bramlet, M Chermack, S Bialy, D Bauer, MS AF Kilbourne, Amy M. Goodrich, David E. Lai, Zongshan Post, Edward P. Schumacher, Karen Nord, Kristina M. Bramlet, Margretta Chermack, Stephen Bialy, David Bauer, Mark S. TI Randomized Controlled Trial to Assess Reduction of Cardiovascular Disease Risk in Patients With Bipolar Disorder: The Self-Management Addressing Heart Risk Trial (SMAHRT) SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID SERIOUS MENTAL-ILLNESS; COLLABORATIVE CARE; INTERVENTION; DEPRESSION; RATIONALE; MORTALITY; SETTINGS; PROGRAM; BURDEN; ACCESS AB Objectives: Persons with bipolar disorder experience a disproportionate burden of medical conditions, notably cardiovascular disease (CVD), leading to impaired functioning and premature mortality. We hypothesized that the Life Goals Collaborative Care (LGCC) intervention, compared to enhanced usual care, would reduce CVD risk factors and improve physical and mental health outcomes in US Department of Veterans Affairs patients with bipolar disorder. Method: Patients with an ICD-9 diagnosis of bipolar disorder and = 1 CVD risk factor (N = 118) enrolled in the Self-Management Addressing Heart Risk Trial, conducted April 2008-May 2010, were randomized to LGCC (n = 58) or enhanced usual care (n = 60). Life Goals Collaborative Care included 4 weekly self-management sessions followed by tailored contacts combining health behavior change strategies, medical care management, registry tracking, and provider guideline support. Enhanced usual care included quarterly wellness newsletters sent during a 12-month period in addition to standard treatment. Primary outcome measures included systolic and diastolic blood pressure, nonfasting total cholesterol, and physical health-related quality of life. Results: Of the 180 eligible patients identified for study participation, 134 were enrolled (74%) and 118 completed outcomes assessments (mean age = 53 years, 17% female, 5% African American). Mixed effects analyses comparing changes in 24-month outcomes among patients in LGCC (n = 57) versus enhanced usual care (n = 59) groups revealed that patients receiving LGCC had reduced systolic (beta = -3.1, P = .04) and diastolic blood pressure (beta = -2.1, P = .04) as well as reduced manic symptoms (beta = -23.9, P = .01). Life Goals Collaborative Care had no significant impact on other primary outcomes (total cholesterol and physical health-related quality of life). Conclusions: Life Goals Collaborative Care, compared to enhanced usual care, may lead to reduced CVD risk factors, notably through decreased blood pressure, as well as reduced manic symptoms, in patients with bipolar disorder. (C) Copyright 2013 Physicians Postgraduate Press, Inc. C1 [Kilbourne, Amy M.; Goodrich, David E.; Lai, Zongshan; Post, Edward P.; Schumacher, Karen; Nord, Kristina M.; Bramlet, Margretta; Chermack, Stephen; Bialy, David] US Dept Vet Affairs, VA Ann Arbor Ctr Clin Management Res, Ann Arbor, MI USA. [Kilbourne, Amy M.; Goodrich, David E.; Lai, Zongshan; Nord, Kristina M.; Chermack, Stephen] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI USA. [Post, Edward P.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Bauer, Mark S.] VA Boston Ctr Org Leadership & Management Res COL, Boston, MA USA. [Bauer, Mark S.] Harvard Univ, Sch Med, Boston, MA USA. RP Kilbourne, AM (reprint author), VA Ann Arbor Ctr Clin Management Res, North Campus Res Complex,2800 Plymouth Rd,Bldg 14, Ann Arbor, MI 48109 USA. EM amykilbo@umich.edu OI Post, Edward/0000-0002-5782-8736; Goodrich, David/0000-0003-3232-2189 FU Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development [CSRD S06]; VA Health Services Research and Development Center for Organization, Leadership, and Management Research (COLMR); National Institute of Mental Health [R34MH74509] FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Clinical Sciences Research and Development (CSRD S06), the VA Health Services Research and Development Center for Organization, Leadership, and Management Research (COLMR), and the National Institute of Mental Health (R34MH74509). NR 40 TC 22 Z9 22 U1 0 U2 5 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2013 VL 74 IS 7 BP E655 EP E662 DI 10.4088/JCP.12m08082 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AA5DO UT WOS:000331116400004 PM 23945460 ER PT J AU Perry, DJ AF Perry, Donna J. TI Peace Through a Healing Transformation of Human Dignity Possibilities and Dilemmas in Global Health and Peace SO ADVANCES IN NURSING SCIENCE LA English DT Article DE genuine encounter; healing; human dignity; human rights; Israeli-Palestinian conflict; Lonergan; peace; transcendent pluralism ID DIPLOMACY; CONFLICT; ISRAELI; NEED AB Collective violence leads to grievous harm for affected populations, impacting both combatants and noncombatants. In recent years there has been an increased focus on the relationship between peace and health, with the World Health Organization calling for health professionals to engage in efforts to promote peace. While the notion of "health as a bridge for peace" is promising, there are many ambiguities in this emerging field, creating moral and practical dilemmas. In this manuscript I will discuss some of the challenges within the paradigm of health and peace using an exemplar of my research within the Israeli-Palestinian conflict. C1 [Perry, Donna J.] Univ Massachusetts Worcester, Grad Sch Nursing, North Worcester, MA 01655 USA. [Perry, Donna J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Perry, Donna J.] Boston Coll, Chestnut Hill, MA 02167 USA. RP Perry, DJ (reprint author), Univ Massachusetts Worcester, Grad Sch Nursing, 55 Lake Ave, North Worcester, MA 01655 USA. EM DonnaJ.Perry@umassmed.edu NR 49 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0161-9268 EI 1550-5014 J9 ADV NURS SCI JI Adv. Nurs. Sci. PD JUL-SEP PY 2013 VL 36 IS 3 BP 171 EP 185 DI 10.1097/ANS.0b013e31829edd0a PG 15 WC Nursing SC Nursing GA 299XN UT WOS:000330429100003 PM 23907300 ER PT J AU Kurzawa, P Kattapuram, S Hornicek, FJ Antonescu, CR Rosenberg, AE Nielsen, GP AF Kurzawa, Pawel Kattapuram, Susan Hornicek, Francis J. Antonescu, Cristina R. Rosenberg, Andrew E. Nielsen, G. Petur TI Primary Myoepithelioma of Bone A Report of 8 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE primary bone tumors; benign mixed tumor; malignant mixed tumor; myoepithelioma ID GLAND PLEOMORPHIC ADENOMA; SALIVARY-GLAND; SOFT-TISSUE; MIXED TUMOR; CHONDROID SYRINGOMA; FUSION GENE; EWSR1 GENE; GLYCOSAMINOGLYCANS; REARRANGEMENT; INVOLVEMENT AB The clinical and pathologic features of 8 primary myoepitheliomas of bone were analyzed. There were 5 female and 3 male patients who ranged in age from 16 to 49 (mean, 33.5) years. Three tumors arose in the ilium, 2 in the tibia, and 1 each in the maxilla, sacrum, and L1 vertebral body. Microscopically, the tumors had a solid, lobulated, reticular, or storiform growth pattern and were predominantly composed of spindle-shaped cells arranged in intersecting fascicles with eosinophilic cytoplasm. The round to polygonal epithelioid cells were arranged randomly or formed small clusters and contained variable amounts of eosinophilic or clear cytoplasm. Immunohistochemically, all the tumors were positive for vimentin and S100 protein, and 7 were positive for epithelial membrane antigen. No tumors were positive for keratin (AE1.3/CAM5.2). Smooth muscle actin was positive in 3 tumors and negative in 4, whereas desmin was negative in all 7 tumors tested. Nuclear staining for p63 was negative in 3 tested tumors. Staining for GFAP and CD34 was performed on 4 and 5 tumors, respectively, and all showed no expression. Fluorescence in situ hybridization for EWSR1 rearrangement was performed in 7 tumors. Five tumors (71%) showed the presence of EWSR1 gene rearrangement, and 2 were negative. Cytogenetic studies conducted on 1 tumor showed 46, XY, t(1;22)(q21;q12) associated with EWSR1-PBX1 fusion. Surgical procedures included curettage in 3 patients, resection in 3 patients, and 2 patients only had an open biopsy. Follow-up information was available for 4 patients; all remain free of disease with no recurrence. Although experience with primary myoepithelioma of bone is limited, histologically, banal tumors appear to behave in a benign manner, and conservative surgery appears to be sufficient treatment. Immunohistochemical and molecular analyses are helpful in their accurate identification. C1 [Kurzawa, Pawel] Greater Poland Canc Ctr, Dept Pathol, Poznan, Poland. [Kattapuram, Susan] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hornicek, Francis J.] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. [Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Antonescu, Cristina R.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Rosenberg, Andrew E.] Univ Miami Hosp, Dept Pathol, Miami, FL USA. RP Nielsen, GP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM gnielsen@partners.org NR 35 TC 17 Z9 17 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JUL PY 2013 VL 37 IS 7 BP 960 EP 968 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 299EC UT WOS:000330377200003 PM 23681076 ER PT J AU Gupta, NK Masia, R AF Gupta, Nitin K. Masia, Ricard TI Cord Colitis Syndrome A Cause of Granulomatous Inflammation in the Upper and Lower Gastrointestinal Tract SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE cord colitis syndrome; graft-versus-host disease; granulomatous gastritis; granulomatous colitis; umbilical cord blood transplant ID VERSUS-HOST-DISEASE; STEM-CELL TRANSPLANTATION; BONE-MARROW; BLOOD TRANSPLANTATION; UNRELATED DONORS; BOWEL-DISEASE; HEMATOLOGIC MALIGNANCIES; PERIPHERAL-BLOOD; CROHNS-DISEASE; ACUTE-LEUKEMIA AB Cord colitis syndrome (CCS) is a recently described diarrheal illness of uncertain pathogenesis that affects recipients of umbilical cord blood transplant and is associated with negative cultures. CCS exhibits a peculiar histopathologic appearance, as it commonly manifests as granulomatous inflammation involving the upper and lower gastrointestinal tract, with features of chronicity in the colon. Importantly, the treatment for CCS differs from that for acute graft-versus-host disease, which is commonly in the clinical differential diagnosis: CCS responds to antibiotic treatment, whereas acute graft-versus-host disease responds to immunosuppression. We describe here the case of a 36-year-old woman with a history of acute myeloid leukemia who developed refractory diarrhea after cord blood transplant. Endoscopic biopsies of the stomach and colon revealed granulomatous inflammation, consisting of scattered ill-defined aggregates of epithelioid histiocytes, with associated mild neutrophilic inflammation and mildly increased epithelial cell apoptosis. In the colon, the granulomatous inflammation was associated with surface epithelial injury (including surface erosions) and contained occasional multinucleated epithelioid giant cells. Paneth cell metaplasia was present in the distal colon, but crypt architecture was preserved, and there was no basal lymphoplasmacytosis. Special stains and immunohistochemical stains for infectious organisms were negative. A diagnosis of CCS was made, and the patient promptly responded to treatment with ciprofloxacin and metronidazole. We present this case to raise awareness among pathologists of this newly described entity, in order to facilitate its timely diagnosis and treatment. C1 [Gupta, Nitin K.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Masia, Ricard] Massachusetts Gen Hosp, Dept Pathol & Lab Med, Boston, MA 02114 USA. RP Masia, R (reprint author), Massachusetts Gen Hosp, Dept Pathol & Lab Med, 55 Fruit St,Warren 219, Boston, MA 02114 USA. EM rmasia@partners.org RI Gupta, Nitin/A-1076-2016 OI Gupta, Nitin/0000-0002-4471-2363 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [T32DK007191]; National Cancer Institute of the National Institutes of Health [T32CA09216] FX N.K.G. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number T32DK007191. R. M. is supported by the National Cancer Institute of the National Institutes of Health under Award Number T32CA09216. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 32 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JUL PY 2013 VL 37 IS 7 BP 1109 EP 1113 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA 299EC UT WOS:000330377200022 PM 23715165 ER PT J AU Chun, YS Verma, K Sinha, I Rosen, H Hergrueter, C Wong, J Pribaz, JJ AF Chun, Yoon S. Verma, Kapil Sinha, Indranil Rosen, Heather Hergrueter, Charles Wong, Julia Pribaz, Julian J. TI Impact of Prior Ipsilateral Chest Wall Radiation on Pedicled TRAM Flap Breast Reconstruction SO ANNALS OF PLASTIC SURGERY LA English DT Article DE breast reconstruction; TRAM flap; radiation; complications ID PREVIOUSLY IRRADIATED PATIENTS; CANCER-PATIENTS; POSTOPERATIVE RADIOTHERAPY; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; THERAPY; IMPLANTS; WOMEN AB Background: This study compares complication rates between transverse rectus abdominis myocutaneous (TRAM) flaps based on previously irradiated versus nonirradiated superior pedicles to assess the impact of prior ipsilateral chest wall radiation on pedicled TRAM flap breast reconstruction. Methods: A retrospective study of 302 consecutive TRAM flap reconstructions was performed; 76 TRAM flaps based on a previously irradiated superior epigastric pedicle were compared to 226 TRAM flaps based on a nonirradiated pedicle in medical comorbidities, oncologic data, and complications. Results: Patients having undergone previous chest wall irradiation had a higher cancer stage, but demographic data were otherwise similar within the groups. Previous chest wall irradiation did not result in increased rate of flap loss, infection, and fat necrosis. However, there was a trend toward higher revision rate in the previously irradiated TRAM group. Conclusions: Previous radiation to the superior epigastric pedicle is not associated with a significant increase in flap complications and should be considered a viable modality for pedicled TRAM flap breast reconstruction. C1 [Chun, Yoon S.; Sinha, Indranil; Hergrueter, Charles; Pribaz, Julian J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Plast Surg,Dept Surg, Boston, MA 02115 USA. [Verma, Kapil] Harvard Univ, Sch Med, Boston, MA USA. [Sinha, Indranil] Harvard Univ, Sch Med, Harvard Plast Surg Residency Program, Boston, MA USA. [Rosen, Heather] Brigham & Womens Hosp, Dept Surg, Div Plast Surg, Boston, MA 02115 USA. [Wong, Julia] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Chun, YS (reprint author), Faulkner Hosp, Brigham & Womens Hosp, Dept Surg, Div Plast Surg, 1153 Ctr St,Suite 21, Boston, MA 02130 USA. EM ychun@partners.org NR 20 TC 3 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-7043 EI 1536-3708 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD JUL PY 2013 VL 71 IS 1 BP 16 EP 19 DI 10.1097/SAP.0b013e318248b643 PG 4 WC Surgery SC Surgery GA 300EC UT WOS:000330446200006 PM 23123615 ER PT J AU Lawson, EH Hall, BL Louie, R Ettner, SL Zingmond, DS Han, L Rapp, M Ko, CY AF Lawson, Elise H. Hall, Bruce Lee Louie, Rachel Ettner, Susan L. Zingmond, David S. Han, Lein Rapp, Michael Ko, Clifford Y. TI Association Between Occurrence of a Postoperative Complication and Readmission Implications for Quality Improvement and Cost Savings SO ANNALS OF SURGERY LA English DT Article DE complications; cost savings; postoperative; quality improvement; readmission ID PROFILING HOSPITAL PERFORMANCE; COLORECTAL SURGERY; HEART-FAILURE; RISK-FACTORS; CLAIMS DATA; CANCER; RATES; DISCHARGE; REGISTRY; PROGRAM AB Objective: To estimate the effect of preventing postoperative complications on readmission rates and costs. Background: Policymakers are targeting readmission for quality improvement and cost savings. Little is known regarding mutable factors associated with postoperative readmissions. Methods: Patient records (2005-2008) from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) were linked to Medicare inpatient claims. Risk factors, procedure, and 30-day postoperative complications were determined from ACS-NSQIP. The 30-day postoperative readmission and costs were determined from Medicare. Occurrence of a postoperative complication included surgical site infections and cardiac, pulmonary, neurologic, and renal complications. Multivariate regression models predicted the effect of reducing complication rates on risk-adjusted readmission rates and costs by procedure. Results: The 30-day postoperative readmission rate was 12.8%. Complication rates for readmitted and nonreadmitted patients were 53% and 16% (P < 0.001). Patients with a postoperative complication had higher predicted probability of readmission and cost of readmission than patients without a complication. For the 20 procedures accounting for the greatest number of readmissions, reducing ACS-NSQIP complication rates by a relative 5% could result in prevention of 2092 readmissions per year and a savings to Medicare of $31.0 million per year. Preventing all ACS-NSQIP complications for these procedures could result in prevention of 41,846 readmissions per year and a savings of $620.3 million per year. Conclusions: This study provides substantial evidence that efforts to reduce postoperative readmissions should begin by focusing on postoperative complications that can be reliably and validly measured. Such an approach will not eliminate all postoperative readmissions but will likely have a major effect on readmission rates. C1 [Lawson, Elise H.; Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Louie, Rachel; Ettner, Susan L.; Zingmond, David S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Lawson, Elise H.; Hall, Bruce Lee; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Lawson, Elise H.; Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Hall, Bruce Lee] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Hall, Bruce Lee] Barnes Jewish Hosp, St Louis, MO 63110 USA. [Hall, Bruce Lee] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce Lee] Washington Univ, Olin Business Sch, St Louis, MO USA. [Hall, Bruce Lee] John Cochran Vet Affairs Med Ctr, Dept Surg, St Louis, MO USA. [Han, Lein; Rapp, Michael] Ctr Medicare Serv, Baltimore, MD USA. [Han, Lein; Rapp, Michael] Ctr Medicaid Serv, Baltimore, MD USA. [Rapp, Michael] George Washington Univ, Sch Med & Hlth Sci, Dept Emergency Med, Washington, DC 20052 USA. RP Lawson, EH (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 10833 Le Conte Ave,72-215 CHS, Los Angeles, CA 90095 USA. EM elawson@mednet.ucla.edu FU VA Health Services Research and Development program [RWJ 65-020]; American College of Surgeons through the Robert Wood Johnson Foundation Clinical Scholars Program; CMS FX E.H.L.'s time was supported by the VA Health Services Research and Development program (RWJ 65-020) and the American College of Surgeons through the Robert Wood Johnson Foundation Clinical Scholars Program. This study was partially funded by a contract from the CMS. For the remaining authors, none were declared. The views expressed in this article represent the authors' views and do not necessarily represent official policy or opinions of the Department of Health and Human Services, the CMS. The authors declare no conflicts of interest. NR 27 TC 91 Z9 91 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD JUL PY 2013 VL 258 IS 1 BP 10 EP 18 DI 10.1097/SLA.0b013e31828e3ac3 PG 9 WC Surgery SC Surgery GA 300JO UT WOS:000330460400011 PM 23579579 ER PT J AU Bunegin, L Tolstykh, GP Gelineau, JF Cosimi, AB Anderson, LM AF Bunegin, Leonid Tolstykh, Gleb P. Gelineau, Jerry F. Cosimi, A. Benedict Anderson, Lisa M. TI Oxygen Consumption During Oxygenated Hypothermic Perfusion as a Measure of Donor Organ Viability SO ASAIO JOURNAL LA English DT Article DE donor kidney; transplantation; organ preservation; hypothermic machine perfusion; oxygen consumption ID GLUTATHIONE-S-TRANSFERASE; MACHINE PERFUSION; COLD-STORAGE; PULSATILE PERFUSION; RENAL-ALLOGRAFTS; GRAFT FUNCTION; KIDNEYS; PRESERVATION; TRANSPLANTATION; OUTCOMES AB Hypothermic machine perfusion (HMP) for the preservation of kidneys, recovered from extended criteria organ donors (ECDs), presents the opportunity for assessing ex vivo parameters that may have value in predicting postimplantation organ viability. Organ perfusion and vascular resistance are the parameters most frequently cited as the basis for the decision to use or discard a donor kidney. The limitation of these measures is emphasized by the observation that a significant percentage of ECD kidneys with poor perfusion parameters can provide life-sustaining function after transplantation. It has been suggested that whole organ oxygen consumption (OC) during oxygenated HMP may better reflect the proportion of viable tissue in the organ and more reliably predict posttransplant organ function. Our study correlates renal OC and renal vascular resistance (RVR) during oxygenated HMP with postpreservation glomerular filtration rates (GFRs) in rodent kidneys after 24 hours of oxygenated HMP. Kidneys from adult rodents were preserved for 24 hours using oxygenated HMP and static cold storage (SCS). During oxygenated HMP preservation, organ OC, renal organ flow rates, and RVR were serially measured. After the preservation period, organs were mounted onto a Langendorff device for warming to normal body temperature and measurement of GFR. Oxygen consumption and RVR during HMP were correlated with postpreservation GFR. Oxygen consumption during oxygenated HMP was significantly correlated (r(2) = 0.871; p < 0.05) with postpreservation GFR, suggesting that higher OC predicts better postpreservation GFR. In contrast, RVR was poorly correlated with postpreservation GFR (r(2) = 0.258; p = 0.199). Glomerular filtration rate in SCS kidneys was 0.002 +/- 0.003 ml/min/g. We demonstrate that measurement of organ OC during oxygenated HMP may have significant value in predicting postpreservation organ function. C1 [Bunegin, Leonid; Tolstykh, Gleb P.; Gelineau, Jerry F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Anesthesiol, San Antonio, TX 78229 USA. [Cosimi, A. Benedict] Harvard Univ, Sch Med, Dept Surg, Transplantat Unit,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Anderson, Lisa M.] Paragonix Technol Inc, Cambridge, MA USA. RP Bunegin, L (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Anesthesiol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM bunegin@uthscsa.edu NR 31 TC 4 Z9 4 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1058-2916 EI 1538-943X J9 ASAIO J JI Asaio J. PD JUL-AUG PY 2013 VL 59 IS 4 BP 427 EP 432 DI 10.1097/MAT.0b013e318292e865 PG 6 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 301JT UT WOS:000330529300013 PM 23820283 ER PT J AU Harshman, LC Choueiri, TK AF Harshman, Lauren C. Choueiri, Toni K. TI Targeting the Hepatocyte Growth Factor/c-Met Signaling Pathway in Renal Cell Carcinoma SO CANCER JOURNAL LA English DT Review DE c-Met; HGF; hepatocyte growth factor; scatter factor; renal cell carcinoma; clear cell renal cell carcinoma; papillary renal cell carcinoma; cabozantinib; foretinib; tivantinib; rilotumumab ID RECEPTOR TYROSINE KINASE; TUMOR-SUPPRESSOR GENE; PHASE-III TRIAL; TIVANTINIB ARQ 197; C-MET; INTERFERON-ALPHA; PROSTATE-CANCER; SOLID TUMORS; SELECTIVE INHIBITOR; PROGNOSTIC-FACTORS AB The product of a proto-oncogene, the c-Met protein is a transmembrane receptor tyrosine kinase. Its only known ligand, hepatocyte growth factor/scatter factor, regulates cell growth, motility, migration, invasion, proliferation, and angiogenesis. Dysregulation of c-Met and hepatocyte growth factor have been observed in both clear cell and non-clear cell renal cell carcinomas (RCCs), although only papillary RCCs harbor activating mutations in the MET gene. In clear cell RCC, there is evidence of a direct link between loss of von Hippel-Lindau and up-regulation of c-Met. As in other cancers, high expression of c-Met correlates with worse outcomes in RCC. In vitro and in vivo preclinical RCC models demonstrate cancer control with small molecule and antibodies against c-Met. Given these findings, the c-Met pathway is a logical therapeutic target in RCC, and several agents are in clinical testing with early signs of efficacy. C1 [Harshman, Lauren C.; Choueiri, Toni K.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dana Solid Tumor Oncol 1230, Boston, MA 02215 USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dana Solid Tumor Oncol 1230, D1230,450 Brookline Ave, Boston, MA 02215 USA. EM toni_choueiri@dfci.harvard.edu NR 93 TC 20 Z9 21 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD JUL-AUG PY 2013 VL 19 IS 4 BP 316 EP 323 PG 8 WC Oncology SC Oncology GA 300OR UT WOS:000330473800008 PM 23867513 ER PT J AU Cheng, G Alavi, A Del Bello, CV Akers, SR AF Cheng, Gang Alavi, Abass Del Bello, Catherine V. Akers, Scott R. TI Differential Washout of FDG Activity in Two Different Inflammatory Lesions Implications for Delayed Imaging SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE FDG; PET; inflammation; delayed imaging ID DUAL-TIME-POINT; POSITRON-EMISSION-TOMOGRAPHY; SOLITARY PULMONARY NODULES; F-18-FDG PET; BREAST-CANCER; BENIGN; DIAGNOSIS AB We describe the changes of FDG uptake in different inflammatory lesions on multiple time point FDG PET/CT. FDG uptake in granulomatous lesions was more intense and focal, with higher intensity on delayed images. In contrast, FDG uptake in chronic arthritic joint inflammation was diffuse and mild, without significant change over time, while FDG uptake in nonarthritic joints was at near-background level with decreased activity on delayed images. The retention index was significantly higher in patients with granulomatous lesions than that in other groups. Our finding indicates differential FDG uptake and clearance in active granulomas versus chronic inflammation. C1 [Cheng, Gang; Del Bello, Catherine V.; 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 akerssco@me.com NR 21 TC 3 Z9 3 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD JUL PY 2013 VL 38 IS 7 BP 576 EP 579 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 298WG UT WOS:000330354600029 PM 23640221 ER PT J AU Palioura, S Kim, B Dohlman, CH Chodosh, J AF Palioura, Sotiria Kim, Bryan Dohlman, Claes H. Chodosh, James TI The Boston Keratoprosthesis Type I in Mucous Membrane Pemphigoid SO CORNEA LA English DT Article DE Boston keratoprosthesis; mucous membrane pemphigoid; ocular cicatricial pemphigoid; long-term outcomes ID OSTEO-ODONTO-KERATOPROSTHESIS; CORNEAL BLINDNESS; RISK-FACTORS; COMPLICATIONS; EXPERIENCE; OUTCOMES; EYES; ENDOPHTHALMITIS; MULTICENTER; PREVENTION AB Purpose: To evaluate the use of the Boston keratoprosthesis type I implantation in patients with mucous membrane pemphigoid (MMP). Methods: Retrospective review of 8 eyes of 8 patients with severe ocular surface disease and corneal blindness as a result of MMP who underwent Boston keratoprosthesis type I implantation at the Massachusetts Eye and Ear Infirmary from January 1, 2000, through December 31, 2009. The main outcome measures were bestcorrected visual acuity, keratoprosthesis retention, and postoperative complications. Results: The mean age of patients was 71.3 years (range, 55-94 years), and the mean duration of their disease preoperatively was 6.1 years (range, 1.7-11.4 years). Visual acuity after the surgery improved to 20/200 or better in 6 eyes (75%) and to 20/40 or better in 3 eyes (37.5%). Only 1 of 6 eyes (16.7%) was able to maintain visual acuity of 20/200 or better over a mean follow-up period of 3.2 years. Five of the 8 Boston keratoprosthesis type I devices (62.5%) extruded or had to be replaced during a mean follow-up time of 1.7 +/- 1.7 years. Loss of vision to worse than 20/200 during the follow-up period occurred because of keratoprosthesis type I extrusion, end-stage glaucoma, and retinal or choroidal detachment. Conclusions: The clinical outcomes of Boston keratoprosthesis type I implantation in MMP are guarded and, as judged from the literature, less favorable than those with the Boston keratoprosthesis type II for the same disease. C1 [Palioura, Sotiria; Dohlman, Claes H.; Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Kim, Bryan] Univ Illinois, Dept Ophthalmol, Chicago, IL 60680 USA. RP Chodosh, J (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu FU Research to Prevent Blindness, Inc, New York, NY FX Supported in part by an unrestricted grant to the Department of Ophthalmology, Harvard Medical School from the Research to Prevent Blindness, Inc, New York, NY. NR 27 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD JUL PY 2013 VL 32 IS 7 BP 956 EP 961 PG 6 WC Ophthalmology SC Ophthalmology GA 298XA UT WOS:000330356600028 PM 23538625 ER PT J AU Ferrari, G Dastjerdi, MH Okanobo, A Cheng, SF Amparo, F Nallasamy, N Dana, R AF Ferrari, Giulio Dastjerdi, Mohammad H. Okanobo, Andre Cheng, Sheng-Fu Amparo, Francisco Nallasamy, Nambi Dana, Reza TI Topical Ranibizumab as a Treatment of Corneal Neovascularization SO CORNEA LA English DT Article DE corneal neovascularization; VEGF; ranibizumab ID INTRAVITREAL BEVACIZUMAB AVASTIN; ENDOTHELIAL GROWTH-FACTOR; SQUAMOUS-CELL CARCINOMA; SUBCONJUNCTIVAL RANIBIZUMAB; PHOTODYNAMIC THERAPY; MACULAR DEGENERATION; VEGF INHIBITORS; TRANSPLANTATION; CONJUNCTIVA; OCCLUSION AB Purpose: To examine the effect of topical ranibizumab on clinically stable corneal neovascularization (NV). Methods: This was a prospective, open-label, monocentric, uncontrolled noncomparative study. Ten eyes of 9 patients with corneal NV received topical ranibizumab (1%) 4 times a day for 3 weeks with a follow-up period of 16 weeks. The main corneal NV outcome measures were: neovascular area, the area occupied by the corneal neovessels; vessel caliber (VC), the mean diameter of the corneal neovessels; and invasion area (IA), the fraction of the total cornea area covered by the vessels. This study was conducted at the Massachusetts Eye and Ear Infirmary, Boston, MA. Results: Statistically significant decreases in neovascular area (55.3%, P < 0.001), which lasted through 16 weeks, and VC (59%, P < 0.001), which continued to improve up to week 16, were observed after treatment. No significant decrease was observed in IA (12.3%, P = 0.49). There was no statistically significant change in visual acuity or intraocular pressure. No adverse events ascribed to the treatment were noted. Conclusions: Topical application of ranibizumab is effective in reducing the severity of corneal NV in the context of established corneal NV, mostly through decrease in VC rather than IA. C1 [Ferrari, Giulio] GB Bietti Eye Fdn IRCCS, Rome, Italy. [Dastjerdi, Mohammad H.; Okanobo, Andre; Cheng, Sheng-Fu; Amparo, Francisco; Nallasamy, Nambi; Dana, Reza] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Ferrari, G (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM giulio.ferrari@schepens.harvard.edu RI ferrari, giulio/J-9260-2016 OI ferrari, giulio/0000-0001-6474-9908 FU Bietti Eye Foundation, IRCCS, Rome, Italy; Genentech, Inc, South San Francisco, CA; NIH [EY-019098] FX G. Ferrari has received a grant from the Bietti Eye Foundation, IRCCS, Rome, Italy; R. Dana received financial support from Genentech, Inc, South San Francisco, CA and NIH EY-019098. The other authors have no financial or conflicts of interest to disclose. NR 33 TC 10 Z9 12 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD JUL PY 2013 VL 32 IS 7 BP 992 EP 997 PG 6 WC Ophthalmology SC Ophthalmology GA 298XA UT WOS:000330356600034 PM 23407316 ER PT J AU Wang, LQ Shankarappa, SA Tong, R Ciolino, JB Tsui, JH Chiang, HH Kohane, DS AF Wang, Liqiang Shankarappa, Sahadev A. Tong, Rong Ciolino, Joseph B. Tsui, Jonathan H. Chiang, Homer H. Kohane, Daniel S. TI Topical Drug Formulations for Prolonged Corneal Anesthesia SO CORNEA LA English DT Article DE corneal anesthesia; tetrodotoxin; proparacaine; corneal toxicity ID DURATION LOCAL-ANESTHESIA; NERVE BLOCKADE; TETRODOTOXIN; INNERVATION; SAXITOXIN; ENHANCERS; TOXICITY; CHANNELS AB Purpose: Ocular local anesthetics currently used in routine clinical practice for corneal anesthesia are short acting and their ability to delay corneal healing makes them unsuitable for long-term use. In this study, we examined the effect of the site 1 sodium channel blocker tetrodotoxin (TTX) on the duration of corneal anesthesia, applied with either proparacaine (PPC) or the chemical permeation enhancer octyl-trimethyl ammonium bromide (OTAB). The effect of test solutions on corneal healing was also studied. Methods: Solutions of TTX, PPC, and OTAB, singly or in combination, were applied topically to the rat cornea. The blink response, an indirect measure of corneal sensitivity, was recorded using a Cochet-Bonnet esthesiometer, and the duration of corneal anesthesia was calculated. The effect of test compounds on the rate of corneal epithelialization was studied in vivo after corneal debridement. Results: Combination of TTX and PPC resulted in corneal anesthesia that was 8 to 10 times longer in duration than that from either drug administered alone, whereas OTAB did not prolong anesthesia. The rate of corneal healing was moderately delayed after coadministration of TTX and PPC. Conclusions: Coadministration of TTX and PPC significantly prolonged corneal anesthesia, but in view of delayed corneal reepithelialization, caution is suggested in the use of the drug combination. C1 [Wang, Liqiang; Ciolino, Joseph B.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Wang, Liqiang] Chinese Peoples Liberat Army Gen Hosp, Dept Ophthalmol, Beijing, Peoples R China. [Wang, Liqiang; Shankarappa, Sahadev A.; Tong, Rong; Tsui, Jonathan H.; Chiang, Homer H.; Kohane, Daniel S.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Shankarappa, Sahadev A.; Tong, Rong; Ciolino, Joseph B.; Tsui, Jonathan H.; Chiang, Homer H.; Kohane, Daniel S.] Harvard Univ, Sch Med, Lab Biomat & Drug Delivery,Boston Childrens Hosp, Dept Anesthesiol,Div Crit Care Med, Boston, MA USA. RP Kohane, DS (reprint author), Childrens Hosp Boston, Dept Anesthesiol, 300 Longwood Ave, Boston, MA 02115 USA. EM daniel.kohane@childrens.harvard.edu RI Tong, Rong/A-4100-2013; OI Tong, Rong/0000-0002-2034-9272; Shankarappa, Sahadev/0000-0002-7302-6362 FU National Institutes of Health [GM 073626] FX Supported by a grant from the National Institutes of Health (GM 073626). NR 27 TC 3 Z9 3 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD JUL PY 2013 VL 32 IS 7 BP 1040 EP 1045 PG 6 WC Ophthalmology SC Ophthalmology GA 298XA UT WOS:000330356600043 PM 23615270 ER PT J AU Stewart, JM Sommers, MS Brawner, BM AF Stewart, Jennifer M. Sommers, Marilyn S. Brawner, Bridgette M. TI The Black Church, Sexual Health, and Sexuality A Conceptual Framework to Promote Health Through Faith-Based Organizations SO FAMILY & COMMUNITY HEALTH LA English DT Article DE black populations; church; faith-based organizations; implementation science; sexual health ID AFRICAN-AMERICAN CHURCH; SOCIAL SUPPORT; UNITED-STATES; HIV; COMMUNITY; ATTITUDES; MEN; PREVENTION; EDUCATION; BEHAVIOR AB There is a growing body of literature that documents the unique impact of black churches on social and health-related changes in the black community. Sexual health and sexuality, however, have long been sources of contention within the institution. The purpose of this article was to refine existing theoretical models that undergird sexual health research in faith-based organizations. The proposed conceptual model explores social-level factors (racism, homophobia, and heterosexism) and church organizational-level factors (beliefs, social trust, norms, and social support/influence). We make an argument in favor of illuminating the negative social-level barriers and affirming the internal cultural supports. C1 [Stewart, Jennifer M.] Univ Penn, Sch Nursing, Ctr Hlth Equ Res, Philadelphia, PA 19104 USA. [Stewart, Jennifer M.] Univ Penn, Sch Nursing, Ctr Global Womens Hlth, Philadelphia, PA 19104 USA. RP Stewart, JM (reprint author), Univ Penn, Sch Nursing, Ctr Hlth Equ Res, 418 Curie Blvd,233L, Philadelphia, PA 19104 USA. EM stewj@nursing.upenn.edu NR 55 TC 1 Z9 1 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-6379 EI 1550-5057 J9 FAM COMMUNITY HEALTH JI Fam. Community Health PD JUL-SEP PY 2013 VL 36 IS 3 BP 269 EP 279 DI 10.1097/FCH.0b013e318292eb2d PG 11 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA 298ZH UT WOS:000330363200010 PM 23718962 ER PT J AU Hopchik, J AF Hopchik, Jordan TI EXPANDING THE ROLE OF THE ADVANCED PRACTICE REGISTERED NURSE AS AN ENDOSCOPIST SO GASTROENTEROLOGY NURSING LA English DT Letter C1 [Hopchik, Jordan] La Salle Univ, Philadelphia VA Med Ctr, Philadelphia, PA 19141 USA. [Hopchik, Jordan] La Salle Univ, Philadelphia, PA 19141 USA. RP Hopchik, J (reprint author), 15 Stokes Ave, Voorhees, NJ 08043 USA. EM jhopchik@aol.com NR 7 TC 2 Z9 2 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1042-895X EI 1538-9766 J9 GASTROENTEROL NURS JI Gastroenterol. Nurs. PD JUL-AUG PY 2013 VL 36 IS 4 BP 289 EP 290 DI 10.1097/SGA.0b013e3182a14e3f PG 2 WC Gastroenterology & Hepatology; Nursing SC Gastroenterology & Hepatology; Nursing GA 298ZW UT WOS:000330364800008 PM 23899489 ER PT J AU Rauh-Hain, JA Oduyebo, T Diver, EJ Guseh, SH George, S Muto, MG del Carmen, MG AF Rauh-Hain, Jose Alejandro Oduyebo, Titilope Diver, Elisabeth J. Guseh, Stephanie H. George, Suzanne Muto, Micheal G. del Carmen, Marcela G. TI Uterine Leiomyosarcoma An Updated Series SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Uterine leiomyosarcoma; Chemotherapy; Radiotherapy ID GYNECOLOGIC-ONCOLOGY-GROUP; GEMCITABINE PLUS DOCETAXEL; GROUP PHASE-II; PROGNOSTIC-FACTORS; LOCAL-CONTROL; SARCOMAS; UTERUS; THERAPY; RADIOTHERAPY; MANAGEMENT AB Objective: The aim of this study was to analyze and compare the clinicopathologic characteristics, treatment, and survival in patients with uterine leiomyosarcoma (ULMS) during the last 10 years in 3 referral academic centers. Methods: All patients with ULMS who underwent treatment at the participating institutions between January 1, 2000, and December 31, 2010, were identified from the tumor registry database. In each case, the diagnosis was confirmed by a dedicated gynecologic pathologist following postsurgery pathology review. The Kaplan-Meier method was used to generate overall survival (OS) data. Factors predictive of outcome were compared using the log-rank test and Cox regression analysis. Results: Analysis of 167 women with ULMS with adequate follow-up was performed. One hundred twenty-eight patients (77%) were initially managed at the participating institutions, and 39 (23%) were referred after initial management at a different institution. Ninety-two (55%) had stage I disease, 7 (4%) had stage II, 18 (11%) stage III, and 50 (30%) had stage IV disease. The median OS for women with stage I was 75 months, for stage II 66 months, stage III 34 months, and stage IV 20 months (P < 0.001). For patients with early stage (I and II), race, lower grade, smaller tumor size (<11 cm), low number of mitosis (<25/10 high-power field [HPF]), lymphovascular space invasion, and presence of necrosis were identified as variables with prognostic influence on survival in the univariate analysis. A Cox proportional hazards model identified size 11 cm or greater (hazard ratio, 5.9; P < 0.001) and mitotic count of 25/10 HPF or greater (hazard ratio, 2.3; P = 0.05) as independent predictors of OS. For patients with late stage (stage III and IV), race, stage III versus IV, lower grade, smaller tumor size (<11 cm), and low number of mitosis (<25/10HPF) were all associated with significantly improved OS. A Cox proportional hazards model identified mitotic count of 25/10 HPF or greater (P = 0.01) as independent predictor of OS. Conclusions: In early stage, size of the tumor and number of mitosis were associated to survival. In contrast to late stage, only mitotic count was associated to survival. C1 [Rauh-Hain, Jose Alejandro; Oduyebo, Titilope; Diver, Elisabeth J.; Guseh, Stephanie H.; del Carmen, Marcela G.] Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, Boston, MA 02114 USA. [Oduyebo, Titilope; Diver, Elisabeth J.; Guseh, Stephanie H.; Muto, Micheal G.] Brigham & Womens Hosp, Div Gynecol Oncol, Boston, MA 02115 USA. [George, Suzanne] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, 55 Fruit St,Yawkey 9 E, Boston, MA 02114 USA. EM mdelcarmen@partners.org NR 19 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD JUL PY 2013 VL 23 IS 6 BP 1036 EP 1043 DI 10.1097/IGC.0b013e31829590dc PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 299CV UT WOS:000330373600012 PM 23714705 ER PT J AU Naranbhai, V Samsunder, N Sandler, NG Roque, A Karim, QA Ndung'u, T Carr, WH Altfeld, M Douek, DC Karim, SSA AF Naranbhai, Vivek Samsunder, Natasha Sandler, Netanya G. Roque, Annalys Karim, Quarraisha Abdool Ndung'u, Thumbi Carr, William H. Altfeld, Marcus Douek, Daniel C. Karim, Salim S. Abdool CA CAPRISA 004 Trial Team TI Neither Microbial Translocation Nor TLR Responsiveness Are Likely Explanations for Preexisting Immune Activation in Women Who Subsequently Acquired HIV in CAPRISA 004 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; microbial translocation; LPS; sCD14; I-FABP; TLR2; TLR4; TLR7/8; immune activation ID SEX WORKERS; INFECTION; ACQUISITION; RESPONSES; PATHWAYS; TRIAL; GEL AB Innate immune activation was a strong predictor of HIV acquisition in women at risk for HIV in CAPRISA 004. Identifying the cause(s) of activation could enable targeted prevention interventions. In this study, plasma concentrations of lipopolysaccharide, soluble CD14, and intestinal fatty acid-binding protein did not differ between subjects who did or did not subsequently acquire HIV nor were these levels correlated with plasma cytokines or natural killer cell activation. There was no difference between HIV acquirers and non-acquirers in the chemokine and cytokine responses of peripheral blood mononuclear cells stimulated with TLR2, 4, or 7/8 agonists. Further studies are required. C1 [Naranbhai, Vivek; Samsunder, Natasha; Karim, Quarraisha Abdool; Karim, Salim S. Abdool] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Nelson R Mandela Sch Med, Durban, South Africa. [Naranbhai, Vivek; Ndung'u, Thumbi; Carr, William H.; Altfeld, Marcus] Univ KwaZulu Natal, HIV Pathogenesis Program, Nelson R Mandela Sch Med, Durban, South Africa. [Sandler, Netanya G.; Roque, Annalys; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Karim, Quarraisha Abdool; Karim, Salim S. Abdool] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Ndung'u, Thumbi; Carr, William H.; Altfeld, Marcus] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [Ndung'u, Thumbi; Carr, William H.; Altfeld, Marcus] Harvard Univ, Boston, MA 02115 USA. [Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV K RITH, Nelson R Mandela Sch Med, Durban, South Africa. [Carr, William H.] CUNY, Medgar Evers Coll, Brooklyn, NY 11210 USA. RP Karim, SSA (reprint author), Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa CAPRISA, Nelson R Mandela Sch Med, Private Bag X7, ZA-4013 Congella, Kwazulu Natal, South Africa. EM caprisa@ukzn.ac.za RI Abdool Karim, Salim Safurdeen/N-5947-2013; OI Abdool Karim, Salim Safurdeen/0000-0002-4986-2133; Utay, Netanya/0000-0002-6407-8670 FU South African HIV/AIDS Research Platform (SHARP); US National Institutes for Health [FIC K01-TW007793]; LIFELab; Columbia University-South Africa Fogarty AIDS International Training and Research Program (AITRP) [D43 TW000231]; Massachusetts General Hospital Physician Scientist Development Award; Howard Hughes Medical Institute; National Institute of Allergy and Infectious Diseases, National Institutes of Health; United States Agency for International Development (USAID) [FHI360, GPO-A-00-05-00,022-00, 132119]; Technology Innovation Agency (LIFElab) of the South African government's Department of Science Technology; CONRAD, Eastern Virginia Medical School (USAID) [GP00-08-00,005-00, PPA-09-046]; US National Institutes for Health's Comprehensive International Program of Research on AIDS (CIPRA) [AI51794] FX This work was supported by the South African HIV/AIDS Research Platform (SHARP), and US National Institutes for Health FIC K01-TW007793. V. Naranbhai was supported by LIFELab and the Columbia University-South Africa Fogarty AIDS International Training and Research Program (AITRP, grant D43 TW000231). W. H. Carr was supported by a Massachusetts General Hospital Physician Scientist Development Award. T. Ndung'u holds the South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS and is also supported by the Howard Hughes Medical Institute. M. Altfeld is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation. D. C. Douek, N. G. Sandler, and A. Roque were supported by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The parent trial (CAPRISA 004) was supported by the United States Agency for International Development (USAID), FHI360 ([USAID co-operative agreement GPO-A-00-05-00,022-00, contract 132119), and the Technology Innovation Agency (LIFElab) of the South African government's Department of Science & Technology. The current studies are part of the CAPRISA TRAPS (Tenofovir gel Research for AIDS Prevention Science) Program, which is funded by CONRAD, Eastern Virginia Medical School (USAID co-operative grant GP00-08-00,005-00, subproject agreement PPA-09-046). The views expressed by the authors do not necessarily reflect the views of USAID, Gilead Sciences, Eastern Virginia Medical School or CONRAD. We thank the US National Institutes for Health's Comprehensive International Program of Research on AIDS (CIPRA grant AI51794) for the research infrastructure. Clinical trials registration number of parent trial: NCT00441298. NR 18 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2013 VL 63 IS 3 BP 294 EP 298 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FB UT WOS:000330448700015 PM 23481666 ER PT J AU Baeten, JM Haberer, JE Liu, AY Sista, N AF Baeten, Jared M. Haberer, Jessica E. Liu, Albert Y. Sista, Nirupama TI Preexposure Prophylaxis for HIV Prevention: Where Have We Been and Where Are We Going? SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV prevention; preexposure prophylaxis; sexual HIV transmission ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL PROPHYLAXIS; INTERIM GUIDANCE; TRANSMISSION; INFECTION; IMPLEMENTATION; MACAQUES; CHALLENGES; ZIDOVUDINE; TENOFOVIR AB Preexposure prophylaxis (PrEP), in which HIV-uninfected persons with ongoing HIV risk use antiretroviral medications to reduce their risk of acquiring HIV infection, is an efficacious and promising new HIV prevention strategy. The past 2 years have seen significant new advances in knowledge regarding PrEP, including definitive demonstration that PrEP reduces the risk of HIV acquisition, regulatory approval of combination oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as the first PrEP agent with a label indication for sexual HIV prevention, and the development of normative guidance for clinical prescribing of PrEP. In PrEP clinical trials, HIV protection was strongly correlated with PrEP adherence; therefore, understanding and supporting adherence to PrEP are key to maximizing its public health impact. As would be expected for any new HIV prevention approach, questions remain, including how to motivate uptake of and sustain adherence to PrEP for HIV prevention in high-risk populations, how much use is sufficient to achieve HIV protection, and the potential of "next-generation" PrEP agents to improve this effective prevention strategy. At this important transition point-from demonstration of efficacy in clinical trials to thinking about implementation and effectiveness-this review addresses where we have been and where we are going with PrEP for HIV prevention. C1 [Baeten, Jared M.] Univ Washington, Dept Global Hlth, Seattle, WA 98104 USA. [Baeten, Jared M.] Univ Washington, Dept Med, Seattle, WA 98104 USA. [Baeten, Jared M.] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. [Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Haberer, Jessica E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Liu, Albert Y.] Univ Calif San Francisco, San Francisco Dept Publ Hlth, Bridge HIV, San Francisco, CA USA. [Liu, Albert Y.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Sista, Nirupama] FHI360, Global Hlth Populat & Nutr, Durham, NC USA. RP Baeten, JM (reprint author), Univ Washington, Dept Global Hlth, Box 359927,325 Ninth Ave, Seattle, WA 98104 USA. EM jbaeten@uw.edu FU US National Institutes of Health [R01 MH095507, R01 MH098744, R01 MH095628, UM1 AI068619] FX Supported by the US National Institutes of Health (grants R01 MH095507, R01 MH098744, R01 MH095628, and for the HIV Prevention Trials Network: UM1 AI068619). NR 45 TC 56 Z9 57 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2013 VL 63 SU 2 BP S122 EP S129 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300JD UT WOS:000330459300003 PM 23764623 ER PT J AU Singer, AJ Ahrenholz, DH Chang, P Clark, RAF Fey, R Fidler, P Garner, W Greenhalgh, D Honari, S Jones, L Kagan, R Kirby, J Leggett, J Meyer, N Reigart, C Richey, K Rosenberg, L Weber, J Wiggins, B Boyce, ST AF Singer, Adam J. Ahrenholz, David H. Chang, Philip Clark, Richard A. F. Fey, Ryan Fidler, Phil Garner, Warren Greenhalgh, David Honari, Shari Jones, Larry Kagan, Richard Kirby, John Leggett, Jeannie Meyer, Nicholas Reigart, Cynthia Richey, Karen Rosenberg, Lior Weber, Joan Wiggins, Brad Boyce, Steven T. TI Burn Wound Healing Outcomes SO JOURNAL OF BURN CARE & RESEARCH LA English DT Article ID EXCISION; REEPITHELIALIZATION; INFECTIONS; REGISTRY; CARE; SKIN C1 [Singer, Adam J.; Clark, Richard A. F.] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Ahrenholz, David H.] Reg Hosp Burn Ctr, Minneapolis, MN USA. [Chang, Philip] Shriners Hosp Children, Massachusetts Gen Hosp, Boston, MA USA. [Fey, Ryan] Hennepin Cty Med Ctr, Burn Ctr, Minneapolis, MN 55415 USA. [Fidler, Phil] Washington Hosp Ctr, Burn Ctr, Washington, DC USA. [Garner, Warren] Los Angeles Cty & Univ Southern California Burn C, Los Angeles, CA USA. [Greenhalgh, David] Shriners Hosp Children, Burn Ctr, Sacramento, CA USA. [Jones, Larry] Ohio State Univ, Burn Ctr, Wexner Med Ctr, Columbus, OH 43210 USA. [Kagan, Richard] Shriners Hosp Children, Cincinnati, OH USA. [Kagan, Richard] Univ Hosp Burn Ctr, Cincinnati, OH USA. [Kirby, John] Washington Univ, Sch Med, Burn Ctr, St Louis, MO USA. [Leggett, Jeannie] Loyola Univ, Med Ctr, Burn Ctr, Maywood, IL 60153 USA. [Meyer, Nicholas] Columbia St Marys Milwaukee Campus, Burn Ctr, Milwaukee, WI USA. [Reigart, Cynthia] Crozer Chester Med Ctr, Upland, PA USA. [Richey, Karen] Maricopa Cty Gen Hosp, Arizona Burn Ctr, Burn Ctr, Phoenix, AZ USA. [Rosenberg, Lior] Ben Gurion Univ Negev, Soroka Med Ctr, IL-84105 Beer Sheva, Israel. [Weber, Joan] Shriners Hosp Children, Burn Unit, Boston, MA USA. [Wiggins, Brad] Univ Utah Hosp, Burn Ctr, Salt Lake City, UT USA. [Boyce, Steven T.] Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. RP Singer, AJ (reprint author), SUNY Stony Brook, Dept Emergency Med, HSC L4-080,8350 SUNY, Stony Brook, NY 11794 USA. NR 31 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-047X EI 1559-0488 J9 J BURN CARE RES JI J. Burn Care Res. PD JUL-AUG PY 2013 VL 34 IS 4 BP 381 EP 385 PG 5 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA 300LD UT WOS:000330464500018 ER PT J AU Fuzaylov, G Knittel, J Driscoll, DN AF Fuzaylov, Gennadiy Knittel, Justin Driscoll, Daniel N. TI Use of Telemedicine to Improve Burn Care in Ukraine SO JOURNAL OF BURN CARE & RESEARCH LA English DT Article ID FOLLOW-UP; UNITED-STATES; TRAUMA CARE; CONSULTATION; MANAGEMENT; EXPERIENCE; NEED AB Global burn injuries have been described as the "forgotten public health crises" by the World Health Organization. Nearly 11 million people a year suffer burns severe enough to require medical attention; more people are burned each year than are infected with human immunodeficiency virus/acquired immunodeficiency syndrome and tuberculosis combined. Telemedicine has the potential to link experts in specialized fields, such as burn care, to regions of the world that have limited or no access to such specialized care. A multilevel telemedicine program was developed between Massachusetts General Hospital/Shriners Hospital in Boston, Massachusetts, and City Hospital #8 in Lviv, Ukraine. The program should lead to a sustainable improvement in the care of burn victims in Ukraine. The authors helped establish a Learning Center at City Hospital #8 in Lviv, Ukraine, through which they were able to consult from Shriners Hospital in Boston, on a total of 14 acute burn patients in Ukraine. This article discusses two case reports with the use of telemedicine and how it has allowed the authors to provide not only acute care consultation on an international scale, but also to arrange for direct expert examination and international transport to their specialized burn center in the United States. The authors have established a program through doctors from Massachusetts General Hospital/Shriner's Hospital in Boston, which works with a hospital in Ukraine and has provided acute consultation, as well as patient transportation to the United States for treatment and direct assessment. C1 [Fuzaylov, Gennadiy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Knittel, Justin] Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Driscoll, Daniel N.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Fuzaylov, G (reprint author), 55 Fruit St,Gray Jackson 409, Boston, MA USA. NR 28 TC 2 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-047X EI 1559-0488 J9 J BURN CARE RES JI J. Burn Care Res. PD JUL-AUG PY 2013 VL 34 IS 4 BP E232 EP E236 DI 10.1097/BCR.0b013e3182779b40 PG 5 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA 300LD UT WOS:000330464500004 PM 23702854 ER PT J AU Mittal, S El-Serag, HB AF Mittal, Sahil El-Serag, Hashem B. TI Epidemiology of Hepatocellular Carcinoma Consider the Population SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE hepatocellular carcinoma; epidemiology; chronic hepatitis B; chronic hepatitis C; prevention ID HEPATITIS-C VIRUS; FATTY LIVER-DISEASE; TERM-FOLLOW-UP; NONALCOHOLIC STEATOHEPATITIS; RISK-FACTORS; NATURAL-HISTORY; UNITED-STATES; LONG-TERM; CRYPTOGENIC CIRRHOSIS; VIRAL-HEPATITIS AB Hepatocellular carcinoma (HCC) is increasing in incidence and has a very high fatality rate. Cirrhosis due to chronic hepatitis B or hepatitis C is the leading risk factor for HCC. Global epidemiology of HCC is determined by the prevalence of dominant viral hepatitis and the age it is acquired in the underlying population. Upcoming risk factors include obesity, diabetes, and related nonalcoholic fatty liver disease. This review discusses the latest trends of HCC globally and in the United States. It also provides an evidence-based commentary on the risk factors and lists some of the preventive measures to reduce the incidence of HCC. C1 [Mittal, Sahil; El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Sect Gastroenterol & Hepatol, Houston, TX 77030 USA. [Mittal, Sahil; El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP El-Serag, HB (reprint author), Michael E DeBakey VA Med Ctr, 2022 Holcombe Blvd 152, Houston, TX 77030 USA. EM hasheme@bcm.edu FU NCI NIH HHS [R01 CA125487]; NIDDK NIH HHS [K24 DK078154, P30 DK056338] NR 58 TC 175 Z9 179 U1 1 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD JUL PY 2013 VL 47 SU 1 BP S2 EP S6 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 298UJ UT WOS:000330349700002 PM 23632345 ER PT J AU Hughes, KS Schnaper, LA Bellon, JR Cirrincione, CT Berry, DA McCormick, B Muss, HB Smith, BL Hudis, CA Winer, EP Wood, WC AF Hughes, Kevin S. Schnaper, Lauren A. Bellon, Jennifer R. Cirrincione, Constance T. Berry, Donald A. McCormick, Beryl Muss, Hyman B. Smith, Barbara L. Hudis, Clifford A. Winer, Eric P. Wood, William C. TI Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; CONSERVING SURGERY; RADIOTHERAPY; METAANALYSIS; RECURRENCE; THERAPY AB Purpose To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age 70 years with early-stage breast cancer. Patients and Methods Between July 1994 and February 1999, 636 women (age 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) -positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer-specific survival, time to distant metastasis, and overall survival (OS). Results Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer-specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively. Conclusion With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age 70 years with ER-positive early-stage breast cancer. C1 [Hughes, Kevin S.; Smith, Barbara L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bellon, Jennifer R.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schnaper, Lauren A.] Greater Baltimore Med Ctr, Dept Gynecol, Phys Pavill, Baltimore, MD 21204 USA. [Cirrincione, Constance T.] Alliance Canc & Leukemia Grp B Stat, Durham, NC USA. [Cirrincione, Constance T.] Duke Univ, Ctr Data, Durham, NC 27706 USA. [Muss, Hyman B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [McCormick, Beryl; Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Wood, William C.] Emory Univ, Sch Med, Atlanta, GA USA. RP Hughes, KS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, 55 Fruit St,Yawkey 7, Boston, MA 02114 USA. EM kshughes@partners.org OI Hughes, Kevin/0000-0003-4084-6484 FU NCI NIH HHS [P30 CA016672] NR 23 TC 168 Z9 170 U1 2 U2 12 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2013 VL 31 IS 19 BP 2382 EP + DI 10.1200/JCO.2012.45.2615 PG 8 WC Oncology SC Oncology GA 301GK UT WOS:000330520600017 PM 23690420 ER PT J AU Hahn, T McCarthy, PL Hassebroek, A Bredeson, C Gajewski, JL Hale, GA Isola, LM Lazarus, HM Lee, SJ LeMaistre, CF Loberiza, F Maziarz, RT Rizzo, JD Joffe, S Parsons, S Majhail, NS AF Hahn, Theresa McCarthy, Philip L., Jr. Hassebroek, Anna Bredeson, Christopher Gajewski, James L. Hale, Gregory A. Isola, Luis M. Lazarus, Hillard M. Lee, Stephanie J. LeMaistre, Charles F. Loberiza, Fausto Maziarz, Richard T. Rizzo, J. Douglas Joffe, Steven Parsons, Susan Majhail, Navneet S. TI Significant Improvement in Survival After Allogeneic Hematopoietic Cell Transplantation During a Period of Significantly Increased Use, Older Recipient Age, and Use of Unrelated Donors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VERSUS-HOST-DISEASE; MYELODYSPLASTIC SYNDROME; MYELOID-LEUKEMIA; INTENSITY; BLOOD; PROPHYLAXIS; REGISTRY; THERAPY; PROGRAM; MDS AB Purpose Over the past four decades, allogeneic hematopoietic cell transplantation (alloHCT) has evolved as a curative modality for patients with hematologic diseases. This study describes changes in use, technique, and survival in a population-based cohort. Patients and Methods The study included 38,060 patients with hematologic malignancies or disorders who underwent first alloHCT in a US or Canadian center from 1994 to 2005 and were reported to the Center for International Blood and Marrow Transplant Research. Results AlloHCT as treatment for acute lymphoblastic (ALL) and myeloid leukemias (AML), myelodysplastic syndrome (MDS), and Hodgkin and non-Hodgkin lymphomas increased by 45%, from 2,520 to 3,668 patients annually. From 1994 to 2005, use of both peripheral (7% to 6%) and cord blood increased (2% to 10%), whereas use of marrow decreased (90% to 27%). Despite a median age increase from 33 to 40 years and % increase in unrelated donors for alloHCT, overall survival (OS) at day 100 significantly improved for patients with AML in first complete remission after myeloablative sibling alloHCT (85% to 94%; P < .001) and unrelated alloHCT (63% to 86%; P < .001); 1-year OS improved among those undergoing unrelated alloHCT (48% to 63%; P = .003) but not among those undergoing sibling alloHCT. Similar results were seen for ALL and MDS. Day-100 OS after cord blood alloHCT improved significantly from 60% to 78% (P < .001) for AML, ALL, MDS, and chronic myeloid leukemia. Use of reduced-intensity regimens increased, yielding OS rates similar to those of myeloablative regimens. Conclusion Survival for those undergoing alloHCT has significantly improved over time. However, new approaches are needed to further improve 1-year OS. C1 [Hahn, Theresa; McCarthy, Philip L., Jr.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Isola, Luis M.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Hassebroek, Anna] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Majhail, Navneet S.] Natl Marrow Donor Program, Minneapolis, MN 55413 USA. [Bredeson, Christopher] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Gajewski, James L.; Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Cleveland, OH 44106 USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [LeMaistre, Charles F.] Sarah Cannon Res Inst, Nashville, TN USA. [Loberiza, Fausto] Univ Nebraska Med Ctr, Omaha, NE USA. [Rizzo, J. Douglas] Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI USA. [Joffe, Steven] Dana Farber Canc Inst, Boston, MA 02115 USA. [Joffe, Steven] Childrens Hosp, Boston, MA 02115 USA. [Parsons, Susan] Tufts Med Ctr, Boston, MA USA. RP Majhail, NS (reprint author), Natl Marrow Donor Program, 3001 Broadway Ave NE,Suite 100, Minneapolis, MN 55413 USA. EM nmajhail@nmdp.org OI Joffe, Steven/0000-0002-0667-7384 FU National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI) [U24-CA76518]; National Institute of Allergy and Infectious Diseases; NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; Allos; Amgen; Angioblast; Ariad; Be the Match Foundation; BlueCross BlueShield Association; Buchanan Family Foundation; CaridianBCT; Celgene; Celgene, CellGenix; Children's Leukemia Research Association; Fresenius-Biotech North America; Gamida Cell Teva Joint Venture; Genentech; Genzyme; GlaxoSmithKline; HistoGenetics; Kiadis Pharma; Leukemia and Lymphoma Society; Medical College of Wisconsin; Merck; Millennium Pharmaceuticals; Takeda Oncology; Milliman USA; Miltenyi Biotec; National Marrow Donor Program; Optum Healthcare Solutions; Osiris Therapeutics; Otsuka America Pharmaceutical; Remedy MD; sanofi-aventis; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix; StemCyte; Stemsoft Software; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience; THERAKOS; Wellpoint FX The Center for International Blood and Marrow Transplant Research is supported by Public Health Service Grant/Cooperative Agreement No. U24-CA76518 from the National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), and National Institute of Allergy and Infectious Diseases; by Grant/Cooperative Agreement No. 5U01HL069294 from NHLBI and NCI; by Contract No. HHSH234200637015C with the Health Resources and Services Administration; by Grants No. N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and by grants from Allos, Amgen, Angioblast, Ariad, Be the Match Foundation, BlueCross BlueShield Association, Buchanan Family Foundation, CaridianBCT, Celgene, CellGenix, Children's Leukemia Research Association, Fresenius-Biotech North America, Gamida Cell Teva Joint Venture, Genentech, Genzyme, GlaxoSmithKline, HistoGenetics, Kiadis Pharma, Leukemia and Lymphoma Society, Medical College of Wisconsin, Merck, Millennium Pharmaceuticals, Takeda Oncology, Milliman USA, Miltenyi Biotec, National Marrow Donor Program, Optum Healthcare Solutions, Osiris Therapeutics, Otsuka America Pharmaceutical, Remedy MD, sanofi-aventis, Seattle Genetics, Sigma-Tau Pharmaceuticals, Soligenix, StemCyte, Stemsoft Software, Swedish Orphan Biovitrum, Tarix Pharmaceuticals, Teva Neuroscience, THERAKOS, and Wellpoint; and by an anonymous donation to the Medical College of Wisconsin. NR 17 TC 78 Z9 78 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2013 VL 31 IS 19 BP 2437 EP 2449 DI 10.1200/JCO.2012.46.6193 PG 13 WC Oncology SC Oncology GA 301GK UT WOS:000330520600024 PM 23715573 ER PT J AU Schmiegelow, K Levinsen, MF Attarbaschi, A Baruchel, A Devidas, M Escherich, G Gibson, B Heydrich, C Horibe, K Ishida, Y Liang, DC Locatelli, F Michel, G Pieters, R Piette, C Pui, CH Raimondi, S Silverman, L Stanulla, M Stark, B Winick, N Valsecchi, MG AF Schmiegelow, Kjeld Levinsen, Mette Frandsen Attarbaschi, Andishe Baruchel, Andre Devidas, Meenakshi Escherich, Gabriele Gibson, Brenda Heydrich, Christiane Horibe, Keizo Ishida, Yasushi Liang, Der-Cherng Locatelli, Franco Michel, Gerard Pieters, Rob Piette, Caroline Pui, Ching-Hon Raimondi, Susana Silverman, Lewis Stanulla, Martin Stark, Batia Winick, Naomi Valsecchi, Maria Grazia TI Second Malignant Neoplasms After Treatment of Childhood Acute Lymphoblastic Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BFM STUDY-GROUP; CHILDREN; CANCER; RISK; TRIALS; SURVIVORS; EVENT AB Purpose Second malignant neoplasms (SMNs) after diagnosis of childhood acute lymphoblastic leukemia (ALL) are rare events. Patients and Methods We analyzed data on risk factors and outcomes of 642 children with SMNs occurring after treatment for ALL from 18 collaborative study groups between 1980 and 2007. Results Acute myeloid leukemia (AML; n = 186), myelodysplastic syndrome (MDS; n = 69), and nonmeningioma brain tumor (n = 116) were the most common types of SMNs and had the poorest outcome (5-year survival rate, 18.1% 2.9%, 31.1% +/- 6.2%, and 18.3% +/- 3.8%, respectively). Five-year survival estimates for AML were 11.2% +/- 2.9% for 125 patients diagnosed before 2000 and 34.1% +/- 6.3% for 61 patients diagnosed after 2000 (P < .001); 5-year survival estimates for MDS were 17.1% +/- 6.4% (n = 36) and 48.2% +/- 10.6% (n = 33; P = .005). Allogeneic stem-cell transplantation failed to improve outcome of secondary myeloid malignancies after adjusting for waiting time to transplantation. Five-year survival rates were above 90% for patients with meningioma, Hodgkin lymphoma, thyroid carcinoma, basal cell carcinoma, and parotid gland tumor, and 68.5% +/- 6.4% for those with non-Hodgkin lymphoma. Eighty-nine percent of patients with brain tumors had received cranial irradiation. Solid tumors were associated with cyclophosphamide exposure, and myeloid malignancy was associated with topoisomerase II inhibitors and starting doses of methotrexate of at least 25 mg/m(2) per week and mercaptopurine of at least 75 mg/m(2) per day. Myeloid malignancies with monosomy 7/5q- were associated with high hyperdiploid ALL karyotypes, whereas 11q23/MLL-rearranged AML or MDS was associated with ALL harboring translocations of t(9;22), t(4;11), t(1;19), and t(12;21) (P = .03). Conclusion SMNs, except for brain tumors, AML, and MDS, have outcomes similar to their primary counterparts. C1 [Schmiegelow, Kjeld; Levinsen, Mette Frandsen] Rigshosp, DK-2100 Copenhagen, Denmark. [Attarbaschi, Andishe] St Anna Childrens Hosp, A-1090 Vienna, Austria. [Baruchel, Andre; Michel, Gerard] Hop St Louis, Paris, France. [Devidas, Meenakshi] Univ Florida, Gainesville, FL USA. [Escherich, Gabriele] Univ Med Ctr Eppendorf, Hamburg, Germany. [Heydrich, Christiane; Stanulla, Martin] Univ Hosp Schleswig Holstein, Kiel, Germany. [Gibson, Brenda] Royal Hosp Sick Children, Glasgow G3 8SJ, Lanark, Scotland. [Horibe, Keizo] Nagoya Med Ctr, Natl Hosp Org, Nagoya, Aichi, Japan. [Ishida, Yasushi] St Lukes Int Hosp, Tokyo, Japan. [Liang, Der-Cherng] Mackay Mem Hosp, Taipei, Taiwan. [Locatelli, Franco] Bambino Gesu Pediat Hosp, Rome, Italy. [Valsecchi, Maria Grazia] Univ Milano Bicocca, Monza, Italy. [Pieters, Rob] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Rotterdam, Netherlands. [Piette, Caroline] Ctr Hosp Reg Citadelle, Liege, Belgium. [Pui, Ching-Hon; Raimondi, Susana] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Silverman, Lewis] Dana Farber Canc Inst, Boston, MA 02115 USA. [Silverman, Lewis] Childrens Hosp, Boston, MA 02115 USA. [Stark, Batia] Schneider Childrens Med Ctr Israel, Petah Tiqwa, Israel. [Winick, Naomi] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Schmiegelow, K (reprint author), Univ Copenhagen Hosp, Rigshosp, Dept Paediat & Adolescent Med, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. EM kschmiegelow@rh.dk FU Associazione Italiana per la Ricerca sul Cancro [IG 5017]; St Anna Kinderkrebsforschung; Deutsche Krebshilfe; Fordergemeinschaft Kinderkrebszentrum Hamburg; Children's Oncology Group [CA098543, U10 CA98413]; National Cancer Institute [5 P01CA068484]; European Organisation for Research and Treatment of Cancer Charitable Trust; Schroder Foundation; Direction Recherche Clinique-Assistance Publique-Hopitaux de Paris; Centre de Recherche en Oncologie, Hematologie et Pediatrie Association; Israel Cancer Association; Hayim Association for Children with Cancer in Israel; Ministry of Health, Labour and Welfare of Japan; Children's Cancer Association of Japan; Danish Cancer Society [R40-A2154]; Danish Childhood Cancer Foundation; Swedish Childhood Cancer Foundation; National Institutes of Health [CA-21765]; American Lebanese Syrian Associated Charities; Childhood Cancer Foundation Taiwan; Medical Research Council (UK) FX Supported by Grant No. IG 5017 from the Associazione Italiana per la Ricerca sul Cancro (M. G. V.); St Anna Kinderkrebsforschung; Deutsche Krebshilfe; Fordergemeinschaft Kinderkrebszentrum Hamburg; Grants No. CA098543 and U10 CA98413 from the Children's Oncology Group; Grant No. 5 P01CA068484 from the National Cancer Institute; The European Organisation for Research and Treatment of Cancer Charitable Trust and the Schroder Foundation; Direction Recherche Clinique-Assistance Publique-Hopitaux de Paris; Centre de Recherche en Oncologie, Hematologie et Pediatrie Association; Israel Cancer Association; Hayim Association for Children with Cancer in Israel; Ministry of Health, Labour and Welfare of Japan; Children's Cancer Association of Japan; Grant No. R40-A2154 from the Danish Cancer Society; Danish Childhood Cancer Foundation; Swedish Childhood Cancer Foundation; Grant No. CA-21765 from the National Institutes of Health; American Lebanese Syrian Associated Charities; Childhood Cancer Foundation Taiwan; and the Medical Research Council (UK). NR 46 TC 31 Z9 31 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2013 VL 31 IS 19 BP 2469 EP + DI 10.1200/JCO.2012.47.0500 PG 11 WC Oncology SC Oncology GA 301GK UT WOS:000330520600027 PM 23690411 ER PT J AU Demetri, GD Chawla, SP Ray-Coquard, I Le Cesne, A Staddon, AP Milhem, MM Penel, N Riedel, RF Binh, BN Cranmer, LD Reichardt, P Bompas, E Alcindor, T Rushing, D Song, Y Lee, RM Ebbinghaus, S Eid, JE Loewy, JW Haluska, FG Dodion, PF Blay, JY AF Demetri, George D. Chawla, Sant P. Ray-Coquard, Isabelle Le Cesne, Axel Staddon, Arthur P. Milhem, Mohammed M. Penel, Nicolas Riedel, Richard F. Binh Bui-Nguyen Cranmer, Lee D. Reichardt, Peter Bompas, Emmanuelle Alcindor, Thierry Rushing, Daniel Song, Yang Lee, Ruey-min Ebbinghaus, Scot Eid, Joseph E. Loewy, John W. Haluska, Frank G. Dodion, Pierre F. Blay, Jean-Yves TI Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CLINICAL-PRACTICE GUIDELINES; RENAL-CELL CARCINOMA; SOFT-TISSUE SARCOMAS; FOLLOW-UP; ADVANCED MALIGNANCIES; ANTITUMOR-ACTIVITY; I TRIAL; MTOR; DIAGNOSIS; TUMORS AB Purpose Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients and Methods Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. Results A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Conclusion Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas. C1 [Demetri, George D.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Demetri, George D.] Harvard Univ, Sch Med, Boston, MA USA. [Loewy, John W.; Haluska, Frank G.; Dodion, Pierre F.] ARIAD Pharmaceut, Cambridge, MA USA. [Chawla, Sant P.] Int Inst Clin Studies, Santa Monica, CA USA. [Ray-Coquard, Isabelle; Blay, Jean-Yves] Ctr Leon Berard, Ctr Canc, F-69373 Lyon, France. [Le Cesne, Axel] Inst Gustave Roussy, Villejuif, France. [Penel, Nicolas] Ctr Oscar Lambret, F-59020 Lille, France. [Binh Bui-Nguyen] Inst Bergonie, Bordeaux, France. [Bompas, Emmanuelle] Ctr Rene Gauducheau, F-44035 Nantes, France. [Staddon, Arthur P.] Penn Oncol Hematol Associates, Philadelphia, PA USA. [Milhem, Mohammed M.] Univ Iowa, Iowa City, IA USA. [Riedel, Richard F.] Duke Univ, Med Ctr, Durham, NC USA. [Cranmer, Lee D.] Univ Arizona, Tucson, AZ USA. [Reichardt, Peter] HELIOS Klin, Bad Saarow Pieskow, Germany. [Alcindor, Thierry] McGill Univ, Montreal, PQ, Canada. [Rushing, Daniel] Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. [Song, Yang; Lee, Ruey-min; Ebbinghaus, Scot; Eid, Joseph E.] Merck, Whitehouse Stn, NJ USA. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Ludwig Ctr, Dana 1212,450 Brookline Ave, Boston, MA 02215 USA. EM gdemetri@partners.org RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X FU ARIAD Pharmaceuticals; Eisai; Cytrx; Amgen; Hoffmann-La Roche; Merck; Berg; Bayer HealthCare Pharmaceuticals; PharmaMar; GlaxoSmithKline; Infinity; Novartis; Ziopharm; Threshold FX George D. Demetri, Merck, ARIAD Pharmaceuticals; Sant P. Chawla, Eisai, Cytrx, Amgen, Hoffmann-La Roche, Merck, ARIAD Pharmaceuticals, Berg; Arthur P. Staddon, ARIAD Pharmaceuticals; Nicolas Penel, Roche, Bayer HealthCare Pharmaceuticals, PharmaMar; Richard F. Riedel, ARIAD Pharmaceuticals, Merck, GlaxoSmithKline, Infinity, Novartis, Ziopharm, Eisai, Threshold; Lee D. Cranmer, Merck; Jean-Yves Blay, Novartis, Roche, PharmaMar NR 23 TC 78 Z9 84 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2013 VL 31 IS 19 BP 2485 EP + DI 10.1200/JCO.2012.45.5766 PG 12 WC Oncology SC Oncology GA 301GK UT WOS:000330520600029 PM 23715582 ER PT J AU Loren, AW Mangu, PB Beck, LN Brennan, L Magdalinski, AJ Partridge, AH Quinn, G Wallace, WH Oktay, K AF Loren, Alison W. Mangu, Pamela B. Beck, Lindsay Nohr Brennan, Lawrence Magdalinski, Anthony J. Partridge, Ann H. Quinn, Gwendolyn Wallace, W. Hamish Oktay, Kutluk TI Fertility Preservation for Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADICAL VAGINAL TRACHELECTOMY; CRYOPRESERVED OVARIAN TISSUE; CHRONIC MYELOID-LEUKEMIA; IN-VITRO-FERTILIZATION; HODGKIN STUDY-GROUP; BREAST-CANCER; CHILDHOOD-CANCER; SPERM BANKING; YOUNG-WOMEN; PREMENOPAUSAL WOMEN AB Purpose To update guidance for health care providers about fertility preservation for adults and children with cancer. Methods A systematic review of the literature published from March 2006 through January 2013 was completed using MEDLINE and the Cochrane Collaboration Library. An Update Panel reviewed the evidence and updated the recommendation language. Results There were 222 new publications that met inclusion criteria. A majority were observational studies, cohort studies, and case series or reports, with few randomized clinical trials. After review of the new evidence, the Update Panel concluded that no major, substantive revisions to the 2006 American Society of Clinical Oncology recommendations were warranted, but clarifications were added. Recommendations As part of education and informed consent before cancer therapy, health care providers (including medical oncologists, radiation oncologists, gynecologic oncologists, urologists, hematologists, pediatric oncologists, and surgeons) should address the possibility of infertility with patients treated during their reproductive years (or with parents or guardians of children) and be prepared to discuss fertility preservation options and/or to refer all potential patients to appropriate reproductive specialists. Although patients may be focused initially on their cancer diagnosis, the Update Panel encourages providers to advise patients regarding potential threats to fertility as early as possible in the treatment process so as to allow for the widest array of options for fertility preservation. The discussion should be documented. Sperm and embryo cryopreservation as well as oocyte cryopreservation are considered standard practice and are widely available. Other fertility preservation methods should be considered investigational and should be performed by providers with the necessary expertise. C1 [Loren, Alison W.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mangu, Pamela B.] Amer Soc Clin Oncol, Alexandria, VA USA. [Beck, Lindsay Nohr] LIVESTRONG Fdn, Fertile Hope Program, Austin, TX USA. [Oktay, Kutluk] New York Med Coll, Inst Fertil Preservat, Rye, NY USA. [Brennan, Lawrence] Oncol Hematol Care, Crestview Hills, KY USA. [Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Quinn, Gwendolyn] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Wallace, W. Hamish] Royal Hosp Sick Children, Edinburgh EH9 1LF, Midlothian, Scotland. RP Oktay, K (reprint author), New York Med Coll, Inst Fertil Preservat, Rye, NY USA. EM koktay@fertilitypreservation.org OI wallace, william, hamish/0000-0001-8080-5674 FU NICHD NIH HHS [R01 HD053112] NR 102 TC 337 Z9 346 U1 11 U2 48 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2013 VL 31 IS 19 BP 2500 EP + DI 10.1200/JCO.2013.49.2678 PG 12 WC Oncology SC Oncology GA 301GK UT WOS:000330520600031 PM 23715580 ER PT J AU Ginat, DT Ellika, SK Corrigan, J AF Ginat, Daniel Thomas Ellika, Shehanaz K. Corrigan, John TI Multi-Detector-Row Computed Tomography Imaging of Variant Skull Base Foramina SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Review DE skull base; variant foramina; CT ID FOSSA NAVICULARIS MAGNA; ARTERY; CT AB Several inconstant skull base foramina can be observed on multi-detector-row computed tomographic studies. These include the meningo-orbital foramen, foramen of Vesalius, canaliculus innominatus, palatovaginal canal, persistent craniopharyngeal canal, transsphenoidal canal, canalis basilaris medianus, and fossa navicularis. Although many of these foramina are simply incidental findings, there may be associated anomalies and important clinical implications. The multi-detector-row computed tomographic features of variant skull base foramina are depicted and discussed in this article. C1 [Ginat, Daniel Thomas] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ellika, Shehanaz K.] Boston Childrens Hosp, Dept Radiol, Boston, MA USA. [Corrigan, John] Henry Ford Hlth Syst, Dept Radiol, Detroit, MI USA. RP Ginat, DT (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM ginatd01@gmail.com NR 17 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 EI 1532-3145 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD JUL-AUG PY 2013 VL 37 IS 4 BP 481 EP 485 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 298TL UT WOS:000330347300001 PM 23863520 ER PT J AU Fakhry, H Goldenberg, M Sayer, G San Aye, S Bagot, K Pi, S Ghazzaoui, R Vo, N Gowrinathan, S Bolton, M Ishak, WW AF Fakhry, Hala Goldenberg, Matthew Sayer, Gregory San Aye, San Bagot, Kara Pi, Sarah Ghazzaoui, Rassil Vo Ngoctram Gowrinathan, Shanthi Bolton, Michael Ishak, William Waguih TI Health-Related Quality of Life in Childhood Cancer SO JOURNAL OF DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS LA English DT Review DE child or children; pediatric; cancer; quality of life; health-related quality of life; HRQoL ID LONG-TERM COMPLICATIONS; YOUNG-ADULT SURVIVORS; STEM-CELL TRANSPLANT; BRAIN-TUMORS; FOLLOW-UP; 1ST YEAR; CHILDREN; SYMPTOMS; ADOLESCENT; LEUKEMIA AB Objective: Health-related quality of life (HRQoL) has become an increasingly important measure of research and treatment outcomes across all medical specialties. However, to date, there has not been an in-depth review of research relevant specifically to HRQoL in the populations of children and adolescents with cancer. In this review, the authors examine the effects of cancer on HRQoL from diagnosis to remission/survivorship and the end of life. Design: A literature search was conducted using Medline and PsycINFO for articles published from 2002 to 2011. Studies included patients from diagnosis to remission and also the terminally ill. Twenty-nine studies specifically addressing HRQoL were selected after reaching consensus and study quality check. Results: Children who are newly diagnosed with cancer and are undergoing treatment or are terminally ill have impaired HRQoL. Survivors of childhood cancer have high HRQoL (with the exception of those who experienced medical comorbidity or PTSD). The authors found that demographic differences, cancer types, and treatment regimens, all significantly influence the negative impact of cancer on patients' HRQoL. Conclusions: There are specific and identifiable impacts of childhood cancer on patients' HRQoL that are significant and complex across the span of the illness. There is a need for continued research in many areas related to this population, especially related to those with terminal illness in order to improve patient care. C1 [Fakhry, Hala] Cairo Univ, Fac Med, Dept Psychiat, Cairo, Egypt. [Goldenberg, Matthew] Banner Good Samaritan Med Ctr, Dept Psychiat, Phoenix, AZ USA. [Sayer, Gregory; Gowrinathan, Shanthi; Ishak, William Waguih] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90095 USA. [San Aye, San; Vo Ngoctram; Gowrinathan, Shanthi; Ishak, William Waguih] Cedars Sinai Med Ctr, Dept Psychiat, Los Angeles, CA 90048 USA. [Bagot, Kara] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Pi, Sarah] Univ Calif Los Angeles, Los Angeles, CA USA. [Ghazzaoui, Rassil] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Ghazzaoui, Rassil] Amer Univ Beirut, Beirut, Lebanon. [Vo Ngoctram] Univ Calif Irvine, Dept Psychiat, Irvine, CA 92717 USA. [Bolton, Michael] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Ishak, WW (reprint author), Cedars Sinai Med Ctr, Dept Psychiat, 8730 Alden Dr,Thalians W-157, Los Angeles, CA 90048 USA. EM Waguih.IsHak@cshs.org RI IsHak, Waguih/C-1336-2011 OI IsHak, Waguih/0000-0003-1970-4756 FU NIMH NIH HHS [R25 MH077823] NR 51 TC 9 Z9 9 U1 4 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-206X EI 1536-7312 J9 J DEV BEHAV PEDIATR JI J. Dev. Behav. Pediatr. PD JUL-AUG PY 2013 VL 34 IS 6 BP 419 EP 436 DI 10.1097/DBP.0b013e31828c5fa6 PG 18 WC Behavioral Sciences; Psychology, Developmental; Pediatrics SC Behavioral Sciences; Psychology; Pediatrics GA 298XU UT WOS:000330358800056 PM 23838588 ER PT J AU Mohamed, BA Yang, W Litt, H Rosas, SE AF Mohamed, Bonita A. Yang, Wei Litt, Harold Rosas, Sylvia E. TI Valvular Calcification, Inflammation, and Mortality in Dialysis Patients SO JOURNAL OF HEART VALVE DISEASE LA English DT Article ID CARDIAC-VALVE CALCIFICATION; CHRONIC KIDNEY-DISEASE; ALL-CAUSE MORTALITY; HEMODIALYSIS-PATIENTS; CARDIOVASCULAR MORTALITY; PLASMA INTERLEUKIN-6; FETUIN-A; CALCIUM; ASSOCIATION; ATHEROSCLEROSIS AB Background and aim of the study: The study aim was to determine the correlates of valvular calcification (VC), including clinical and physiologic parameters, in individuals new to dialysis. In addition, the association of VC with coronary artery calcification (CAC) progression and mortality was investigated. Methods: A total of 101 incident dialysis individuals underwent electrocardiogram-triggered multislice computed tomography (CT) to monitor the presence and quantification of calcification. The average follow up was 2.85 +/- 0.72 years. Results: Twenty-six (25.7%) patients had only one valve calcified, while 10 (9.9%) had calcifications in both valves. Patients with VC were older, more likely to have a history of diabetes and/or cardiovascular disease (CVD), more likely to have CAC, and to be Caucasian; fibrinogen and interleukin-6 (IL-6) levels were also higher in these patients. Multivariable Poisson regression analysis revealed older age, history of CVD, increasing fibrinogen, and presence of CAC were independently associated with the presence of VC. Patients with VC also had a higher median annualized CAC progression compared to those without VC (2.90 versus 105.2, p = 0.004). The mortality rate per 100 years was 2.57 in patients without VC, compared to 4.20 and 13.76, respectively, for those with one or two calcified valves. An increasing number of calcified valves was associated with a higher mortality after adjustment for gender and race [HR 2.2 (1.03-4.69), p = 0.04], but was not statistically significant after adjustment for inflammatory markers such as IL-6 or fibrinogen. Conclusion: Traditional and novel risk factors are associated with the presence of VC, which is a risk marker for CAC progression and mortality in incident dialysis patients. C1 [Mohamed, Bonita A.] Penn Hosp, Dept Med, Philadelphia, PA 19107 USA. [Yang, Wei] Ctr Clin Epidemiol & Biostat, Philadelphia, PA USA. [Litt, Harold] Univ Penn, Perelman Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Rosas, Sylvia E.] Univ Penn, Perelman Sch Med, Dept Med, Renal Electrolyte & Hypertens Div, Philadelphia, PA 19104 USA. [Rosas, Sylvia E.] Philadelphia VA Med Ctr, Dept Med, Philadelphia, PA USA. RP Rosas, SE (reprint author), Univ Penn, Perelman Sch Med, Renal Electrolyte & Hypertens Div, 1 Founders,3400 Spruce St, Philadelphia, PA 19104 USA. EM Sylvia.Rosas@uphs.upenn.edu FU NIH [R21 HL 086971]; Veterans Health Administration; National Center for Research Resources [UL1RR024134]; [R01 DK 080033] FX These studies were supported by NIH grants R21 HL 086971 and an American Recovery and Reinvestment Act supplement. Salary support was also provided by the Veterans Health Administration and R01 DK 080033 (S.E.R.). The project was supported by Grant Number 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 19 TC 4 Z9 5 U1 0 U2 3 PU I C R PUBLISHERS PI NORTHWOOD PA CRISPIN HOUSE, 12/A SOUTH APPROACH, MOOR PARK, NORTHWOOD HA6 2ET, ENGLAND SN 0966-8519 J9 J HEART VALVE DIS JI J. Heart Valve Dis. PD JUL PY 2013 VL 22 IS 4 BP 584 EP 590 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 303OE UT WOS:000330683000021 PM 24224425 ER PT J AU King, BJ Gilmore-Bykovskyi, AL Roiland, RA Polnaszek, BE Bowers, BJ Kind, AJH AF King, Barbara J. Gilmore-Bykovskyi, Andrea L. Roiland, Rachel A. Polnaszek, Brock E. Bowers, Barbara J. Kind, Amy J. H. TI The Consequences of Poor Communication During Transitions from Hospital to Skilled Nursing Facility: A Qualitative Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE care transitions; communication; hospital to skilled nursing facility ID CARE TRANSITIONS; BOUNCING BACK; PHYSICIANS; STROKE AB OBJECTIVES: To examine how skilled nursing facility (SNF) nurses transition the care of individuals admitted from hospitals, the barriers they experience, and the outcomes associated with variation in the quality of transitions. DESIGN: Qualitative study using grounded dimensional analysis, focus groups, and in-depth interviews. SETTING: Five Wisconsin SNFs. PARTICIPANTS: Twenty-seven registered nurses. MEASUREMENTS: Semistructured questions guided the focus group and individual interviews. RESULTS: SNF nurses rely heavily on written hospital discharge communication to transition individuals into the SNF effectively. Nurses cited multiple inadequacies of hospital discharge information, including regular problems with medication orders (including the lack of opioid prescriptions for pain), little psychosocial or functional history, and inaccurate information regarding current health status. These communication inadequacies necessitated repeated telephone clarifications, created care delays (including delays in pain control), increased SNF staff stress, frustrated individuals and family members, contributed directly to negative SNF facility image, and increased risk of rehospitalization. SNF nurses identified a specific list of information and components that they need to facilitate a safe, high-quality transition. CONCLUSION: Nurses note multiple deficiencies in hospital-to-SNF transitions, with poor quality discharge communication being identified as the major barrier to safe and effective transitions. This information should be used to refine and support the dissemination of evidence-based interventions that support transitions of care, including the Interventions to Reduce Acute Care Transfers program. C1 [King, Barbara J.; Gilmore-Bykovskyi, Andrea L.; Roiland, Rachel A.; Bowers, Barbara J.] Univ Wisconsin, Sch Nursing, Madison, WI 53792 USA. [Gilmore-Bykovskyi, Andrea L.; Polnaszek, Brock E.; Kind, Amy J. H.] Univ Wisconsin, Div Geriatr, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Gilmore-Bykovskyi, Andrea L.; Polnaszek, Brock E.; Kind, Amy J. H.] Univ Wisconsin, Hlth Innovat Program, Madison, WI 53792 USA. [Roiland, Rachel A.; Kind, Amy J. H.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. RP King, BJ (reprint author), Univ Wisconsin, Sch Nursing, H6-246 CSC,600 Highland Ave, Madison, WI 53792 USA. EM bjking2@wisc.edu OI King, Barbara/0000-0003-0577-9028; Bowers, Barbara/0000-0002-3226-0718 FU National Institute on Aging [K23AG034551]; American Federation for Aging Research; John A. Hartford Foundation; Atlantic Philanthropies; Starr Foundation; Madison VA Geriatric Research, Education and Clinical Center (GRECC) [2013-05]; John A. Hartford Foundation Building Academic Geriatric Nursing Capacity Program; National Institute of Nursing Research [F31NR013097-01]; University of Wisconsin School of Medicine and Public Health's Health Innovation Program; Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research; National Center for Research Resources, National Institutes of Health [1UL1RR025011] FX This project was supported by the National Institute on Aging Paul B. Beeson Patient-Oriented Research Career Development Award (K23AG034551, PI, Kind), in partnership with the American Federation for Aging Research, the John A. Hartford Foundation, the Atlantic Philanthropies, and the Starr Foundation and the Madison VA Geriatric Research, Education and Clinical Center (GRECC-Manuscript 2013-05). Roiland and Gilmore-Bykovskyi received support from the John A. Hartford Foundation Building Academic Geriatric Nursing Capacity Program. Roiland's contributions were supported by an F31 National Research Service Award from the National Institute of Nursing Research (F31NR013097-01). Additional support was provided by the University of Wisconsin School of Medicine and Public Health's Health Innovation Program; the Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research; and the Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health (1UL1RR025011). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 26 TC 34 Z9 35 U1 4 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2013 VL 61 IS 7 BP 1095 EP 1102 DI 10.1111/jgs.12328 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 297FT UT WOS:000330241800007 PM 23731003 ER PT J AU Li, LDT Mills, WL White, DL Li, A Gutierrez, AM Berger, DH Naik, AD AF Li, Linda T. Mills, Whitney L. White, Donna L. Li, Alexa Gutierrez, Amanda M. Berger, David H. Naik, Aanand D. TI Causes and Prevalence of Unplanned Readmissions After Colorectal Surgery: A Systematic Review and Meta-Analysis SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Review DE epidemiology; geriatric; outcomes; rehospitalization ID HOSPITAL READMISSION; LAPAROSCOPIC COLECTOMY; INTESTINAL SURGERY; CONTROLLED-TRIAL; HEART-FAILURE; CARE; CANCER; QUALITY; TRANSITIONS; OUTCOMES AB A systematic review and meta-analysis of the current literature was conducted to compare the overall and cause-specific readmission rates after colorectal surgery of older adults with those of younger individuals. Potential predictors of unplanned readmission were also identified. Estimated pooled readmission rates were calculated and reported as pooled proportions with associated 95% confidence intervals (CI) in 60,131 total readmissions; 11.0% (95% CI = 10.0-12.0) of all admissions after colorectal surgery resulted in unplanned readmission at 30 days. Older adults had a lower rate of readmission than younger individuals. Bowel obstruction was the most common cause of unplanned readmission, accounting for 33.4% of all unplanned readmissions, followed by surgical site infection (15.7%) and intraabdominal abscess (12.6%). Several age-related predictors of unplanned readmission were identified, such as poor functional capacity, multiple comorbidities, chronic obstructive pulmonary disease, and discharge to a nonhome destination. The findings of this review will help guide the development of future interventions to reduce preventable readmissions after colorectal surgery in older adults. C1 [Li, Linda T.; Berger, David H.] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Li, Linda T.; Mills, Whitney L.; White, Donna L.; Berger, David H.; Naik, Aanand D.] Baylor Coll Med, Houston Vet Affairs Hlth Serv Res & Dev Ctr Excel, Houston, TX 77030 USA. [White, Donna L.] Baylor Coll Med, Sect Gastroenterol & Hepatol, Houston, TX 77030 USA. [Li, Alexa; Gutierrez, Amanda M.] Rice Univ, Houston, TX USA. [Berger, David H.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Naik, Aanand D.] Baylor Coll Med, Dept Internal Med, Houston, TX 77030 USA. [Naik, Aanand D.] Michael E DeBakey VA Med Ctr, Houston, TX USA. RP Li, LDT (reprint author), Baylor Coll Med, Michael E DeBakey Dept Surg, 1 Baylor Plaza,Rm 404D, Houston, TX 77030 USA. EM linday@bcm.edu OI Gutierrez, Amanda/0000-0002-4496-5328 FU Doris Duke Charitable Foundation; Cancer Prevention and Research Institute of Texas; Veterans Integrated Service Network [16]; Veterans Affairs Office of Academic Affiliations; National Institute of Diabetes and Digestive and Kidney Diseases [DK081736-01]; Texas Medical Center Digestive Diseases Center [NIH DK58338] FX This review was supported with resources and the use of facilities at the Houston Veterans Affairs Health Services Research and Development Center of Excellence (HFP90-020) at the Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas. Dr. Naik receives support from a Doris Duke Charitable Foundation Clinical Scientist Development award. Dr. Berger holds a grant from the Cancer Prevention and Research Institute of Texas and a Veterans Engineering Resource Center grant from Veterans Integrated Service Network 16. Dr. Mills is a postdoctoral fellow in health services research supported by the Veterans Affairs Office of Academic Affiliations. Dr. White was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award DK081736-01 and the Texas Medical Center Digestive Diseases Center (NIH DK58338). NR 27 TC 15 Z9 16 U1 4 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2013 VL 61 IS 7 BP 1175 EP 1181 DI 10.1111/jgs.12307 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 297FT UT WOS:000330241800019 PM 23730901 ER PT J AU Bhakta, A Bloom, M Warren, H Shah, N Casas, T Ewing, T Bukur, M Chung, R Ley, E Margulies, D Malinoski, D AF Bhakta, Akash Bloom, Matthew Warren, Heather Shah, Nirvi Casas, Tamara Ewing, Tyler Bukur, Marko Chung, Rex Ley, Eric Margulies, Daniel Malinoski, Darren TI The impact of implementing a 24/7 open trauma bed protocol in the surgical intensive care unit on throughput and outcomes SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article; Proceedings Paper CT 26th Annual Scientific Assembly of the Eastern-Association-for-the-Surgery-of-Trauma CY JAN 15-19, 2013 CL Scottsdale, AZ SP Eastern Assoc Surg Trauma DE Emergency department throughput; emergency department length of stay; ICU triage ID LENGTH-OF-STAY; EMERGENCY-DEPARTMENT; AMBULANCE DIVERSION; ADMITTED PATIENTS; ADMISSION; OCCUPANCY AB BACKGROUND: Increased emergency department (ED) length of stay (LOS) has been associated with increased mortality in trauma patients. In 2010, we implemented a 24/7 open trauma bed protocol in our designated trauma intensive care units (TICUs) to facilitate rapid admission from the ED. This required maintenance of a daily bump list and timely transferring of patients out of the TICU. We hypothesized that ED LOS and mortality would decrease after implementation. METHODS: The following data from patients admitted directly from the ED to any ICU were retrospectively compared before (2009) and after (2011) the implementation of a trauma bed protocol at a Level I trauma center: age, sex, Glasgow Coma Scale (GCS) score, shock on admission (systolic blood pressure G 90 mm Hg), mechanism, injury severity scores (Injury Severity Score [ISS] and Abbreviated Injury Scale [AIS] score), ED LOS, ICU readmission rates, and mortality. RESULTS: Of the patients, 267 (17%) of 1,611 before and 262 (21%) of 1,266 (p < 0.01) after the protocol were admitted directly to the ICU, despite similar characteristics. ED LOS decreased from 4.2 +/- 4.0 hours to 3.1 +/- 2.1 hours (p < 0.01) in all patients as well as patients with an ISS of greater than 24 (3.1 +/- 2.5 vs. 2.2 +/- 1.6, p < 0.05) and a head AIS score of greater than 2 (4.2 +/- 4.9 vs. 3.1 +/- 2.0, p = 0.01). Mortality was unchanged for all patients (9% vs. 8%, p = 0.58) but trends toward improved mortality were found after protocol implementation inpatients with an ISS of greater than 24 (30% vs. 13%, p = 0.07) and in patients with a head AIS score of greater than 2 (12% vs. 6%, p = 0.08). A greater proportion of total patients were admitted to a designated TICU after implementation (83% vs. 93%, p G 0.01). ICU readmissions were unchanged (0.3% vs. 1.5%, p = 0.21). CONCLUSION: The implementation of a 24/7 open trauma bed protocol in the surgery ICU was associated with a decreased ED LOS and increased admissions to designated TICUs in all patients. Improved throughput was achieved without increases in ICU readmissions. (J Trauma Acute Care Surg. 2013; 75: 97-101. Copyright (C) 2013 by Lippincott Williams & Wilkins) C1 [Bhakta, Akash] Midwestern Univ, Glendale, AZ USA. [Bloom, Matthew; Warren, Heather; Casas, Tamara; Bukur, Marko; Chung, Rex; Ley, Eric; Margulies, Daniel] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Shah, Nirvi] Western Univ Hlth Sci, Pomona, CA USA. [Ewing, Tyler] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Malinoski, Darren] Portland VA Med Ctr, Dept Surg, Portland, OR USA. RP Malinoski, D (reprint author), Oregon Hlth & Sci Univ, Portland VA Med Ctr, Sect Surg Crit Care, POB 1034-P3ANES, Portland, OR 97207 USA. EM Darren.malinoski@va.gov NR 25 TC 6 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD JUL PY 2013 VL 75 IS 1 BP 97 EP 101 DI 10.1097/TA.0b013e31829849e5 PG 5 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 300EV UT WOS:000330448100026 PM 23778446 ER PT J AU Yeh, DD AF Yeh, Daniel D. TI The acute care surgery model: Managing traumatic brain injury without an inpatient neurosurgical consultation EDITORIAL CRITIQUE SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Yeh, DD (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD JUL PY 2013 VL 75 IS 1 BP 105 EP 105 PG 1 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 300EV UT WOS:000330448100028 ER PT J AU McNichol, L Lund, C Rosen, T Gray, M AF McNichol, Laurie Lund, Carolyn Rosen, Ted Gray, Mikel TI Medical Adhesives and Patient Safety: State of the Science Consensus Statements for the Assessment, Prevention, and Treatment of Adhesive-Related Skin Injuries SO JOURNAL OF WOUND OSTOMY AND CONTINENCE NURSING LA English DT Article DE Bandages; Dressings; Medical adhesive; Skin integrity; Skin stripping; Skin tear; Surgical tape ID TAPE; INFECTION; OUTBREAK; BACTERIA; ZYGOMYCOSIS AB Skin injury related to medical adhesive usage is a prevalent but underrecognized complication that occurs across all care settings and among all age groups. If proper technique for application and/or removal of adhesive products is not used, tissue trauma can occur, impacting patient safety and quality of life and increasing healthcare costs. Little guidance exists in the literature regarding appropriate selection and proper use of adhesive products to minimize medical adhesive-related skin injury, as well as best practices for skin care preventive strategies, application and removal techniques, and assessment and treatment of such injuries. In an effort to define best practices for prevention of such injury, a consensus panel of 23 recognized key opinion leaders convened to establish consensus statements on the assessment, prevention, and treatment of medical adhesive-related skin injury. The consensus summit was held in December 2012 and was made possible by an unrestricted educational grant from 3M. This document details the consensus definitions and statements and identifies research priorities for development of new adhesive technologies and protocols for skin protection. C1 [McNichol, Laurie] Cone Hlth Syst, Greensboro, NC USA. [Lund, Carolyn] Childrens Hosp, Oakland, CA 94609 USA. [Lund, Carolyn] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. [Rosen, Ted] Baylor Coll Med, Houston, TX 77030 USA. [Rosen, Ted] Houston Vet Affairs Med Ctr, Houston, TX USA. [Gray, Mikel] Univ Virginia, Charlottesville, VA 22908 USA. RP Gray, M (reprint author), Univ Virginia, Dept Urol, POB 800422, Charlottesville, VA 22908 USA. EM MG5K@hscmail.mcc.virginia.edu FU 3M; 3M, St. Paul, Minnesota FX The Medical Adhesives & Patient Safety Consensus Panel thanks the following individuals for their special contributions to the project: Laurie McNichol, Carolyn Lund, and Ted Rosen for their leadership, dedication, and time commitment in making this project a reality; 3M for the educational grant support and Summit venue, without which this project would not have been possible; Magellan Medical Technology Consultants for their role in planning and facilitating the Summit; Mikel Gray for his expertise in moderating the Summit; and Marie Sabo Recine, MS, MT(ASCP), for providing medical writing assistance.; The content of this document is based on the results of a 2-day roundtable discussion held December 10 to 11, 2012, in St. Paul, Minnesota, and was made possible by an unrestricted educational grant from 3M, St. Paul, Minnesota. The information contained herein does not necessarily represent the opinions of all authors and panel members, 3M, or Magellan Medical Technology Consultants. NR 78 TC 17 Z9 19 U1 3 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1071-5754 EI 1528-3976 J9 J WOUND OSTOMY CONT JI J. Wound Ostomy Cont. Nurs. PD JUL-AUG PY 2013 VL 40 IS 4 BP 365 EP 380 DI 10.1097/WON.0b013e3182995516 PG 16 WC Nursing SC Nursing GA 300JZ UT WOS:000330461500006 PM 23759927 ER PT J AU Wallace, ZS Carruthers, MN Khosroshahi, A Carruthers, R Shinagare, S Stemmer-Rachamimov, A Deshpande, V Stone, JH AF Wallace, Zachary S. Carruthers, Mollie N. Khosroshahi, Arezou Carruthers, Robert Shinagare, Shweta Stemmer-Rachamimov, Anat Deshpande, Vikram Stone, John H. TI IgG4-Related Disease and Hypertrophic Pachymeningitis SO MEDICINE LA English DT Article ID MR-IMAGING FINDINGS; OF-THE-LITERATURE; SYSTEMIC-DISEASE; CRANIAL PACHYMENINGITIS; SPINAL PACHYMENINGITIS; SCLEROSING DISEASE; CORD COMPRESSION; GRANULOMATOSIS; HYPOPHYSITIS; PSEUDOTUMOR AB Hypertrophic pachymeningitis (HP) is an inflammatory condition in which the dura mater of the cranium or spine becomes thickened, leading to symptoms that result from mass effect, nerve compression, or vascular compromise. The differential diagnosis of HP includes immune-mediated conditions such as rheumatoid arthritis and vasculitis, malignancies, and infections. Many times, no diagnosis is reached; in such cases, the disease has been described as idiopathic HP. IgG4-related disease (IgG4-RD) is a recently described inflammatory condition known to cause tumefactive lesions at myriad anatomical locations. Both IgG4-RD and idiopathic HP share similar demographics, histopathology, and natural history. We hypothesized that IgG4-RD is a common cause of idiopathic HP. To investigate this hypothesis, we identified all pathology specimens diagnosed as noninfectious HP during 25 years at our institution. Fourteen cases had stained slides and paraffin blocks to permit review of the original hematoxylin and eosin stained slides as well as immunostaining of cell blocks. Recently published consensus guidelines describing characteristic histopathology and the necessary quantity of IgG4+ plasma cell infiltrate were used to diagnose IgG4-RD. Four cases (66.6%) that had been regarded previously as representing idiopathic HP were diagnosed as IgG4-RD; of all the reviewed cases, IgG4-RD represented 29% of cases. Of the remaining cases, 3 cases were associated with granulomatosis with polyangiitis (GPA), 2 with lymphoma, and 1 each with rheumatoid arthritis, giant cell arteritis, and sarcoidosis. Two of the cases could not be diagnosed more precisely and were classified as undifferentiated HP. Clinical history, serologic tests, cerebrospinal fluid studies, and radiology alone could not identify the cause of HP. Rather, biopsy with histopathology and immunostaining was necessary to reach an accurate diagnosis. Significant IgG4+ plasma cell infiltrates were observed in rheumatoid arthritis, granulomatosis with polyangiitis, and lymphoma, underscoring the importance of histopathology in making the diagnosis of IgG4-RD. This case series demonstrates that IgG4-RD may be the most common etiology of noninfectious HP and highlights the necessity of biopsy for accurate diagnosis. C1 [Wallace, Zachary S.; Carruthers, Mollie N.; Khosroshahi, Arezou; Stone, John H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Carruthers, Mollie N.; Khosroshahi, Arezou; Stone, John H.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Rheumatol Unit, Boston, MA 02114 USA. [Carruthers, Robert] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Shinagare, Shweta; Stemmer-Rachamimov, Anat; Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, 55 Fruit St Yawkey 2, Boston, MA 02114 USA. EM jhstone@partners.org FU Genentech; Roche FX Dr. Stone reports financial support for work outside this study from Genentech and Roche (consulting fees in the area of systemic vasculitis) and a grant/grant pending to his institution from Genentech (clinical trial to investigate the role of rituximab in the treatment of IgG4-related disease). The other authors have no funding or conflicts of interest to disclose. NR 50 TC 38 Z9 45 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD JUL PY 2013 VL 92 IS 4 BP 206 EP 216 DI 10.1097/MD.0b013e31829cce35 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 300KH UT WOS:000330462300002 PM 23793110 ER PT J AU Reynolds, KL Higgins, MJ AF Reynolds, Kerry L. Higgins, Michaela J. TI Endocrine therapy for breast cancer: a tough pill to swallow SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID AROMATASE INHIBITORS; TAMOXIFEN THERAPY; HORMONAL-THERAPY; WOMEN; ADHERENCE; DISCONTINUATION; PERSISTENCE; LETROZOLE; TRIALS C1 [Reynolds, Kerry L.; Higgins, Michaela J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Reynolds, KL (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 25 TC 2 Z9 2 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUL PY 2013 VL 20 IS 7 BP 714 EP 716 DI 10.1097/gme.0b013e3182955b77 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 300JT UT WOS:000330460900002 PM 23760435 ER PT J AU Pasquale, LR AF Pasquale, Louis R. TI There is more to the relation between intraocular pressure and metabolic syndrome than meets the eye: a connection to estrogen deficiency SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID OPEN-ANGLE GLAUCOMA; TYPE-2 DIABETES-MELLITUS; BLOOD-PRESSURE; LIFE-STYLE; ROTTERDAM; RISK; WOMEN C1 Harvard Univ, Brigham & Womens Hosp, Mass Eye & Ear Infirm, Channing Div Network Med,Dept Ophthalmol,Med Sch, Boston, MA 02115 USA. RP Pasquale, LR (reprint author), Harvard Univ, Brigham & Womens Hosp, Mass Eye & Ear Infirm, Channing Div Network Med,Dept Ophthalmol,Med Sch, Boston, MA 02115 USA. NR 19 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD JUL PY 2013 VL 20 IS 7 BP 719 EP 720 DI 10.1097/gme.0b013e318294096b PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 300JT UT WOS:000330460900004 PM 23676635 ER PT J AU Hauptman, JS Dadour, A Oh, T Baca, CB Vickrey, BG Vassar, S Sankar, R Salamon, N Vinters, HV Mathern, GW AF Hauptman, Jason S. Dadour, Andrew Oh, Taemin Baca, Christine B. Vickrey, Barbara G. Vassar, Stefanie Sankar, Raman Salamon, Noriko Vinters, Harry V. Mathern, Gary W. TI Time to Pediatric Epilepsy Surgery Is Longer and Developmental Outcomes Lower for Government Compared With Private Insurance SO NEUROSURGERY LA English DT Article DE Craniotomy; Disparities; Health inequity; Hemispherectomy; Socioeconomic ID TEMPORAL-LOBE EPILEPSY; POPULATION-BASED-ANALYSIS; UNITED-STATES; INTERNATIONAL LEAGUE; PUBLIC INSURANCE; INFANTILE SPASMS; UCLA EXPERIENCE; SEIZURE FREEDOM; SPECIALTY CARE; HEALTH-CARE AB BACKGROUND: It is unclear if socioeconomic factors like type of insurance influence time to referral and developmental outcomes for pediatric patients undergoing epilepsy surgery. OBJECTIVE: This study determined whether private compared with state government insurance was associated with shorter intervals of seizure onset to surgery and better developmental quotients for pediatric patients undergoing epilepsy surgery. METHODS: A consecutive cohort (n = 420) of pediatric patients undergoing epilepsy surgery were retrospectively categorized into those with Medicaid (California Children's Services; n = 91) or private (Preferred Provider Organization, Health Maintenance Organization, Indemnity; n = 329) insurance. Intervals from seizure onset to referral and surgery and Vineland developmental assessments were compared by insurance type with the use of log-rank tests. RESULTS: Compared with private insurance, children with Medicaid had longer intervals from seizure onset to referral for evaluation (log-rank test, P = .034), and from seizure onset to surgery (P = .017). In a subset (25%) that had Vineland assessments, children with Medicaid compared with private insurance had lower Vineland scores presurgery (P = .042) and postsurgery (P = .003). Type of insurance was not associated with seizure severity, types of operations, etiology, postsurgical seizure-free outcomes, and complication rate. CONCLUSION: Compared with Medicaid, children with private insurance had shorter intervals from seizure onset to referral and to epilepsy surgery, and this was associated with lower Vineland scores before surgery. These findings may reflect delayed access for uninsured children who eventually obtained state insurance. Reasons for the delay and whether longer intervals before epilepsy surgery affect long-term cognitive and developmental outcomes warrant further prospective investigations. C1 [Hauptman, Jason S.; Dadour, Andrew; Oh, Taemin; Mathern, Gary W.] Univ Calif Los Angeles, David Geffen Sch Med, Mattel Childrens Hosp, Dept Neurosurg, Los Angeles, CA 90095 USA. [Baca, Christine B.; Vickrey, Barbara G.; Vassar, Stefanie; Sankar, Raman; Vinters, Harry V.] Univ Calif Los Angeles, David Geffen Sch Med, Mattel Childrens Hosp, Dept Neurol, Los Angeles, CA 90095 USA. [Baca, Christine B.; Vickrey, Barbara G.; Vassar, Stefanie] VA Greater Los Angeles Hlth Care Syst, Dept Neurol, Los Angeles, CA USA. [Sankar, Raman] Univ Calif Los Angeles, David Geffen Sch Med, Mattel Childrens Hosp, Dept Pediat, Los Angeles, CA 90095 USA. [Sankar, Raman] Univ Calif Los Angeles, David Geffen Sch Med, Mattel Childrens Hosp, Div Pediat Neurol, Los Angeles, CA 90095 USA. [Salamon, Noriko] Univ Calif Los Angeles, David Geffen Sch Med, Mattel Childrens Hosp, Div Neuroradiol, Los Angeles, CA 90095 USA. [Vinters, Harry V.] Univ Calif Los Angeles, David Geffen Sch Med, Mattel Childrens Hosp, Sect Neuropathol, Los Angeles, CA 90095 USA. [Mathern, Gary W.] Univ Calif Los Angeles, David Geffen Sch Med, Mattel Childrens Hosp, Dept Psychiat & Biobehav Med, Los Angeles, CA 90095 USA. RP Mathern, GW (reprint author), 710 Westwood Plaza,Room 2123, Los Angeles, CA 90095 USA. EM gmathern@ucla.edu FU NIH [R01 NS38992]; Epilepsy Foundation Grant [213971]; University of California Pediatric Neuropathology Consortium FX This research was supported in part by NIH R01 NS38992 and Epilepsy Foundation Grant 213971. Dr Vinters was supported in part by the University of California Pediatric Neuropathology Consortium. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. NR 39 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X EI 1524-4040 J9 NEUROSURGERY JI Neurosurgery PD JUL PY 2013 VL 73 IS 1 BP 152 EP 157 DI 10.1227/01.neu.0000429849.99330.6e PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 299FJ UT WOS:000330380900044 PM 23615092 ER PT J AU Barroilhet, L Van Hanegem, L Bernstein, M Feldman, S AF Barroilhet, Lisa Van Hanegem, Lennie Bernstein, Marilyn Feldman, Sarah TI Potential Effects of Updated Pap Test Screening Guidelines and Adenocarcinoma In Situ of the Cervix EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Barroilhet, Lisa] Univ Wisconsin, Madison, WI 53715 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. RP Barroilhet, L (reprint author), Univ Wisconsin, Madison, WI 53715 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUL PY 2013 VL 68 IS 7 BP 518 EP 519 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 301DH UT WOS:000330512500012 ER PT J AU Stamatiou, GA Stankovic, KM AF Stamatiou, Georgios A. Stankovic, Konstantina M. TI A Comprehensive Network and Pathway Analysis of Human Deafness Genes SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Deafness genes; ERK 1/2; GPCR; HNF4A; MAPK1; Molecular pathways analysis; TGFB1 ID SENSORINEURAL HEARING-LOSS; NUCLEAR FACTOR 4-ALPHA; GROWTH-FACTOR-BETA; ANGIOTENSIN-ALDOSTERONE SYSTEM; SYNDROMIC RECESSIVE DEAFNESS; DOWN-REGULATION; ANALGESIC USE; MAP KINASE; RECEPTOR; ACTIVATION AB Objective: To perform comprehensive network and pathway analyses of the genes known to cause genetic hearing loss. Study Design: In silico analysis of deafness genes using ingenuity pathway analysis (IPA). Methods: Genes relevant for hearing and deafness were identified through PubMed literature searches and the Hereditary Hearing Loss Homepage. The genes were assembled into 3 groups: 63 genes that cause nonsyndromic deafness, 107 genes that cause nonsyndromic or syndromic sensorineural deafness, and 112 genes associated with otic capsule development and malformations. Each group of genes was analyzed using IPA to discover the most interconnected, that is, "nodal" molecules, within the most statistically significant networks (p < 10(-45)). Results: The number of networks that met our criterion for significance was 1 for Group 1 and 2 for Groups 2 and 3. Nodal molecules of these networks were as follows: transforming growth factor beta1 (TGFB1) for Group 1, MAPK3/MAPK1 MAP kinase (ERK 1/2) and the G protein coupled receptors (GPCR) for Group 2, and TGFB1 and hepatocyte nuclear factor 4 alpha (HNF4A) for Group 3. The nodal molecules included not only those known to be associated with deafness (GPCR), or with predisposition to otosclerosis (TGFB1), but also novel genes that have not been described in the cochlea (HNF4A) and signaling kinases (ERK 1/2). Conclusion: A number of molecules that are likely to be key mediators of genetic hearing loss were identified through three different network and pathway analyses. The molecules included new candidate genes for deafness. Therapies targeting these molecules may be useful to treat deafness. C1 [Stamatiou, Georgios A.] Univ Athens, Hippokrat Gen Hosp, Dept Otolaryngol, Athens, Greece. [Stankovic, Konstantina M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Stankovic, KM (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM konstantina_stankovic@meei.harvard.edu FU NIDCD [K08 DC010419]; Bertarelli Foundation FX Source of Funding: NIDCD K08 DC010419 (K.M.S.) and the Bertarelli Foundation (K.M.S.). NR 72 TC 6 Z9 6 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD JUL PY 2013 VL 34 IS 5 BP 961 EP 970 PG 10 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 299CB UT WOS:000330371400032 PM 23770690 ER PT J AU Tan, G Teo, I Srivastava, D Smith, D Smith, SL Williams, W Jensen, MP AF Tan, Gabriel Teo, Irene Srivastava, Devika Smith, Donna Smith, Shirley L. Williams, Wright Jensen, Mark P. TI Improving Access to Care for Women Veterans Suffering from Chronic Pain and Depression Associated with Trauma SO PAIN MEDICINE LA English DT Article DE Rural; Women Veterans; Chronic Pain; Depression; Trauma; Biofeedback ID HEART-RATE-VARIABILITY; POSTTRAUMATIC-STRESS-DISORDER; MEMORY-CONCENTRATION TEST; HEALTH-CARE; PSYCHOMETRIC PROPERTIES; IRAQI FREEDOM; BIOFEEDBACK; VALIDATION; PTSD; SYMPTOMS AB Objective. Access to care has become a priority for the Veterans Administration (VA) health care system as a significant number of veterans enrolled in the VA health care system reside in rural areas. The feasibility and effects of a novel clinical intervention that combined group therapy and biofeedback training was evaluated on women veterans living in rural areas. Methods. The study was conducted at selected community-based outpatient clinics (CBOCs) in Texas. Thirty four women veterans with chronic pain and comorbid depression and/or posttraumatic stress disorder (PTSD) were recruited. Five sessions of education/therapy were delivered via telemedicine in combination with daily home practice of a portable biofeedback device (Stress Eraser (R), Helicor, New York, NY, USA). Participants responded to self-report questionnaires at baseline, at posttreatment, and at 6-week follow-up. Daily practice logs were also maintained by participants. Results. The clinical protocol was acceptable, easy to administer, and associated with statistically significant decreases in self-reported pain unpleasantness, pain interference, depressive symptoms, PTSD symptoms, and sleep disturbance at posttreatment. Improvements were maintained at 6-week follow-up. Qualitative analyses indicated that many participants 1) wished to continue to meet as a support group in their respective CBOCs and 2) felt less isolated and more empowered to cope with their problems of daily living as a result of the treatment. Conclusions. It is feasible to provide treatment to women veterans living in rural areas by utilizing video-teleconferencing technology between larger VA medical centers and facilities at CBOCs in more rural settings. A controlled trial of the intervention is warranted. C1 [Tan, Gabriel] Natl Univ Singapore, Singapore 119077, Singapore. [Teo, Irene] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Srivastava, Devika] Fordham Univ, New York, NY 10023 USA. [Smith, Donna; Smith, Shirley L.; Williams, Wright] Michael E DeBakey Vet Affair Med Ctr, Houston, TX USA. [Williams, Wright] Baylor Coll Med, Houston, TX 77030 USA. [Jensen, Mark P.] Univ Washington, Seattle, WA 98195 USA. RP Tan, G (reprint author), Natl Univ Singapore, Clin Psychol Program, 21 Lower Kent Ridge Rd, Singapore 119077, Singapore. EM psygt@nus.edu.sg FU Alergan; Covidien; Depomed; Endo Pharmaceuticals; Merck; Pfizer; RTI Health Solutions; ZARS Pharma; Zogeniz FX In the past 12 months, Dr. Jensen has received grant or research support, or fees for consulting services, from Alergan, Covidien, Depomed, Endo Pharmaceuticals, Merck, Pfizer, RTI Health Solutions, ZARS Pharma, and Zogeniz. NR 48 TC 2 Z9 2 U1 4 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD JUL PY 2013 VL 14 IS 7 BP 1010 EP 1020 DI 10.1111/pme.12131 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 297GY UT WOS:000330245100015 PM 23659470 ER PT J AU Chen, YL Liebsch, N Kobayashi, W Goldberg, S Kirsch, D Calkins, G Childs, S Schwab, J Hornicek, F DeLaney, T AF Chen, Yen-Lin Liebsch, Norbert Kobayashi, Wendy Goldberg, Saveli Kirsch, David Calkins, Geoffrey Childs, Stephanie Schwab, Joseph Hornicek, Francis DeLaney, Thomas TI Definitive High-Dose Photon/Proton Radiotherapy for Unresected Mobile Spine and Sacral Chordomas SO SPINE LA English DT Article DE chordoma; nonoperation; radiotherapy ID CARBON ION RADIOTHERAPY; SACROCOCCYGEAL CHORDOMA; SURGICAL-MANAGEMENT; IRRADIATION; EXPERIENCE; SURGERY; SACRECTOMY AB Study Design. A retrospective review. Objective. The purpose of this study is to report the results of highdose proton based definitive radiotherapy for unresected spinal chordomas. Summary of Background Data. Spine chordoma is treated primarily by surgical resection. However, local recurrence rate is high. Adjuvant radiotherapy improves local control. In certain locations, such as high sacrum, resection may result in significant neurological dysfunction. Methods. We retrospectively reviewed 24 patients with newly diagnosed, previously untreated spinal chordomas (core biopsy only; no prior incision or resection) treated with high-dose definitive radiotherapy alone using protons and photons at our center from 1988 to 2009. Results. Reasons for radiotherapy alone included medical inoperability (3) and concern for neurological dysfunction based on spine level (21). Median age was 69.5 years. Tumor locations included cervical (2), thoracic (1), lumbar (2), S1-S2 (17), and S3 or below (2). Median maximal tumor diameter was 6.6 cm (1.4-25.5), and median tumor volume was 198.3 cm(3) (4.65-2061). Median total dose was 77.4 GyRBE (proton dose unit, gray relative biological effectiveness). Analysis at median follow-up of 56 months showed overall survival of 91.7% and 78.1%, chordoma specific survival of 95.7% and 81.5%, local progression free survival of 90.4% and 79.8% and metastases free survival of 86.5% and 76.3%, at 3 and 5 years respectively. Tumor volume more than 500 cm 3 was correlated with worse overall survival. Long-term side effects included 8 sacral insufficiency fractures (none required surgical stabilization), 1 secondary malignancy, 1 foot drop, 1 erectile dysfunction, 1 perineal numbness, 2 worsening urinary/fecal incontinence, and 4 grade-2 rectal bleeding. None required new colostomy. All surviving patients remained ambulatory. Conclusion. These results support the use of high-dose definitive radiotherapy for patients with medically inoperable or otherwise unresected, mobile spine or sacrococcygeal chordomas. C1 [Chen, Yen-Lin; Liebsch, Norbert; Kobayashi, Wendy; Goldberg, Saveli; Calkins, Geoffrey; Childs, Stephanie; DeLaney, Thomas] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Schwab, Joseph; Hornicek, Francis] Massachusetts Gen Hosp, Dept Orthoped Oncol, Boston, MA 02114 USA. [Kirsch, David] Duke Univ, Med Ctr, Div Radiat Oncol, Durham, NC 27710 USA. [Kirsch, David] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. [Chen, Yen-Lin; Liebsch, Norbert; Goldberg, Saveli; Schwab, Joseph; Hornicek, Francis; DeLaney, Thomas] Harvard Univ, Sch Med, Boston, MA USA. RP Chen, YL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, 50 Fruit St, Boston, MA 02114 USA. EM ychen9@partners.org FU Kenneth Stanton Fund; Jennifer Hunter Yates Sarcoma Foundation; NIH/NCI Proton Federal Share Grant FX Kenneth Stanton Fund, the Jennifer Hunter Yates Sarcoma Foundation, and NIH/NCI Proton Federal Share Grant funds were received to support this work. NR 29 TC 30 Z9 31 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD JUL 1 PY 2013 VL 38 IS 15 BP E930 EP E936 DI 10.1097/BRS.0b013e318296e7d7 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 298XR UT WOS:000330358500004 PM 23609202 ER PT J AU Igoe, A Scofield, RH AF Igoe, Ann Scofield, R. Hal TI Autoimmunity and infection in Sjogren's syndrome SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE autoimmunity; infection; Sjogren's syndrome; virus ID HEPATITIS-C-VIRUS; ARYL-HYDROCARBON RECEPTOR; EPSTEIN-BARR-VIRUS; PARVOVIRUS B19 INFECTION; SALIVARY-GLANDS; MURINE CYTOMEGALOVIRUS; SICCA SYNDROME; ALPHA-FODRIN; IN-VIVO; B-CELLS AB Purpose of review To summarize the recent developments concerning the potential viral pathomechanisms and involvement of viruses in Sjogren's syndrome, and to highlight the areas for future research and therapies. Recent findings Activated IFN-1 pathway plays an important part in the autoimmune disease process of Sjogren's syndrome; therefore, several therapies aiming to reduce or inhibit the IFN-1 production and its effects may be a target for future treatment plans. Activated aryl hydrocarbon receptor may interact with latent Epstein-Barr virus (EBV) infection, which in turn may predispose to the development of Sjogren's syndrome. It is estimated that the population is 95% positive for EBV serology. Microbial factors may incite autoimmune disease. Although this hypothesis is proven in a few illnesses such as rheumatic fever, there is no definitive evidence of an infectious environmental trigger in Sjogren's syndrome. However, there are circumstantial data with regard to viruses and several potential mechanisms of disease. These include antigen mimicry, polyclonal lymphocyte activation, and infection-mediated innate end-organ inflammation. In addition, hepatitis C virus infection clearly causes a Sjogren's-syndrome-like illness. Summary Data continue to implicate viral infection in the cause of Sjogren's syndrome, but there are no definitive studies incriminating a particular virus. C1 [Igoe, Ann; Scofield, R. Hal] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Program, Oklahoma City, OK 73104 USA. [Igoe, Ann; Scofield, R. Hal] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Igoe, Ann; Scofield, R. Hal] US Dept Vet Affairs, Oklahoma City, OK USA. RP Scofield, RH (reprint author), Oklahoma Med Res Fdn, Arthrit & Immunol Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM hal-scofield@omrf.ouhsc.edu FU NIH [1 P50 AR060804] FX The authors acknowledge the support provided by the NIH grants to RHS 1 P50 AR060804. NR 95 TC 18 Z9 19 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 EI 1531-6963 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD JUL PY 2013 VL 25 IS 4 BP 480 EP 487 DI 10.1097/BOR.0b013e32836200d2 PG 8 WC Rheumatology SC Rheumatology GA 298YF UT WOS:000330359900011 PM 23719365 ER PT J AU Byeon, HK Duvvuri, U Kim, WS Park, YM Hong, HJ Koh, YW Choi, EC AF Byeon, Hyung Kwon Duvvuri, Umamaheswar Kim, Won Shik Park, Young Min Hong, Hyun Jun Koh, Yoon Woo Choi, Eun Chang TI Transoral Robotic Retropharyngeal Lymph Node Dissection With or Without Lateral Oropharyngectomy SO JOURNAL OF CRANIOFACIAL SURGERY LA English DT Article DE Transoral robotic surgery; retropharyngeal lymph node dissection; minimally invasive surgery; oropharyngeal and hypopharyngeal carcinoma ID SQUAMOUS-CELL CARCINOMA; MODIFIED FACELIFT; NECK DISSECTION; THYROID-CANCER; METASTASIS; SURGERY; HEAD; HYPOPHARYNX; IMPACT; SPACE AB Retropharyngeal lymph node (RPLN) metastases can occur from advanced head and neck malignancies. Surgical access to RPLNs can be challenging. Considering the more aggressive conventional approach methods, there is an increasing need for minimally invasive techniques. Applying transoral robotic surgery (TORS) to access the RPLN has never been reported in the literature. The purpose of this study was to describe our experience with transoral robotic RPLN dissection for oropharyngeal and hypopharyngeal squamous cell carcinomas. We conducted a retrospective review of TORS cases performed at Severance Hospital, a tertiary care medical center from December 2011 to July 2012. Demographic, clinicopathologic, and treatment characteristics were abstracted from the medical record as well as complications and were analyzed descriptively. A total of 5 TORS procedures with transoral robotic RPLN dissection have been performed at Severance Hospital. Of these, 4 patients were treated for oropharyngeal squamous cell carcinoma and 1 for hypopharyngeal squamous cell carcinoma. The mean operation time for TORS including the robotic RPLN dissection was 84 +/- 18.5 minutes. The operation time included time for docking of the robotic arms (4.8 +/- 1.3 minutes), console working time for primary tumor removal (50 +/- 8.9 minutes), and console working time for RPLN dissection (29.2 +/- 9.4 minutes). No patients experienced complications related to the transoral robotic RPLN dissection. Transoral robotic RPLN dissection is a feasible approach for accessing retropharyngeal lymph nodes. This particular operative technique can serve as a minimal invasive surgery in removing pathologic RPLNs. C1 [Byeon, Hyung Kwon; Kim, Won Shik; Park, Young Min; Hong, Hyun Jun; Koh, Yoon Woo; Choi, Eun Chang] Yonsei Univ, Coll Med, Dept Otorhinolaryngol, Seoul, South Korea. [Duvvuri, Umamaheswar] Vet Affairs Pittsburgh Hlth Syst, Pittsburgh, PA USA. [Duvvuri, Umamaheswar] Univ Pittsburgh, Med Ctr, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USA. RP Koh, YW (reprint author), Yonsei Univ Hlth Syst, Severance Hosp, Yonsei Univ, Dept Otorhinolaryngol,Coll Med, 50 Yonsei Ro, Seoul 120752, South Korea. EM ywkohent@yuhs.ac NR 23 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1049-2275 EI 1536-3732 J9 J CRANIOFAC SURG JI J. Craniofac. Surg. PD JUL PY 2013 VL 24 IS 4 BP 1156 EP 1161 DI 10.1097/SCS.0b013e318293f860 PG 6 WC Surgery SC Surgery GA 295PW UT WOS:000330129000075 PM 23851761 ER PT J AU Lorenzo, L AF Lorenzo, Lenora TI Partnering with patients to promote holistic diabetes management: Changing paradigms SO JOURNAL OF THE AMERICAN ASSOCIATION OF NURSE PRACTITIONERS LA English DT Review DE Nurse practitioners; diabetes; behavioral health; coaching; empowerment; health promotion; Motivational Interviewing ID CHRONIC CARE MODEL; SELF-MANAGEMENT; GROUP VISITS; BEHAVIOR-CHANGE; INTERVENTIONS; HEALTH; CHALLENGES; STRATEGIES; ADHERENCE; DISPARITIES AB Purpose: To provide a review of best practice for clinical management of diabetes mellitus (DM) for nurse practitioners (NPs) and accelerate incorporation of key findings into current practice. Data source: A search was conducted in Pub Med, Ovid, CINAHL, and Cochrane's Database of Systematic Reviews. Conclusions: There are many challenges for DM care identified in the current health system. There is a great need to change care paradigms to engage patients in partnership for enhanced management and self-management in DM. A review of the best practice evidence revealed numerous models of care, strategies, and tools available to enhance diabetes care and promote health and well-being. The primary focus of this article is to engage NP clinicians to incorporate new strategies to augment management and improve clinical outcomes. Implications for practice: Incorporation of best practice for DM management may accelerate the paradigm shift tomore patient-focused care. Engaged, informed, and activated patients along with clinicians working in partnerships may enhance clinical outcomes. C1 [Lorenzo, Lenora] US Dept Vet Affairs, Pacific Isl Hlth Care Syst, Spark Matsunaga Ctr, Honolulu, HI 96783 USA. [Lorenzo, Lenora] Univ Hawaii Manoa, Sch Nursing & Dent Hyg, Honolulu, HI 96822 USA. RP Lorenzo, L (reprint author), US Dept Vet Affairs, Pacific Isl Hlth Care Syst, Spark Matsunaga Ctr, 459 Patterson Rd, Honolulu, HI 96783 USA. EM lenora.lorenzo@va.gov NR 62 TC 4 Z9 4 U1 5 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2327-6886 EI 2327-6924 J9 J AM ASSOC NURSE PRA JI J. Am. Assoc. Nurs. Pract. PD JUL PY 2013 VL 25 IS 7 BP 351 EP 361 DI 10.1111/1745-7599.12004 PG 11 WC Health Care Sciences & Services; Nursing SC Health Care Sciences & Services; Nursing GA 296GU UT WOS:000330174000003 PM 24170618 ER PT J AU Whitten, SK Stanik-Hutt, J AF Whitten, Stacey K. Stanik-Hutt, Julie TI Group cognitive behavioral therapy to improve the quality of care to opioid-treated patients with chronic noncancer pain: A practice improvement project SO JOURNAL OF THE AMERICAN ASSOCIATION OF NURSE PRACTITIONERS LA English DT Article DE Quality improvement; primary care; pain management; cognitive behavioral therapy (CBT); outpatient ID BECK DEPRESSION INVENTORY; MANAGEMENT; OUTCOMES; MULTIDISCIPLINARY; INTERVENTIONS; METAANALYSIS; GUIDELINES; TRIALS; LIFE AB Purpose: To enhance outcomes of patients with chronic noncancer pain (CNCP) treated with opioids in a primary care setting by implementing an evidence-based quality improvement project. Data sources: The project consisted of the implementation of a 6-week cognitive behavioral therapy (CBT) program. Twenty-two patients with CNCP completed the program. Impact of the project was evaluated by comparing pre-and postintervention participant self-reports of mood on the Beck Depression Inventory and functional status on the Brief Pain Inventory and Short Form-36. Patient perception of treatment benefit was also measured using the Patient Global Impression of Change. Qualitative provider perceptions of the program were also collected. Paired t-test statistics were used to analyze the data. Conclusions: Mood (including negative attitude, performance difficulty, and physical complaints), and patient impression of treatment benefit improved significantly after CBT was added. Primary care providers reported that the CBT supported their overall management of these complex patients. Implications for practice: The addition of a CBT program improved selected outcomes in this self-selected sample of patients with CNCP treated with opioids. C1 [Whitten, Stacey K.] US Dept Vet Affairs, Community Based Outreach Clin, Bennington, VT 05201 USA. [Stanik-Hutt, Julie] Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. [Stanik-Hutt, Julie] Johns Hopkins Univ Hosp, Dept Acute & Chron Care, Baltimore, MD 21287 USA. RP Whitten, SK (reprint author), US Dept Vet Affairs, Community Based Outreach Clin, Bennington, VT 05201 USA. EM stacey.whitten@va.gov OI Stanik - Hutt, Julie/0000-0003-0728-7297 NR 28 TC 0 Z9 0 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2327-6886 EI 2327-6924 J9 J AM ASSOC NURSE PRA JI J. Am. Assoc. Nurs. Pract. PD JUL PY 2013 VL 25 IS 7 BP 368 EP 376 DI 10.1111/j.1745-7599.2012.00800.x PG 9 WC Health Care Sciences & Services; Nursing SC Health Care Sciences & Services; Nursing GA 296GU UT WOS:000330174000005 PM 24170620 ER PT J AU Mochel, MC Arakaki, RY Wang, GL Kroshinsky, D Hoang, MP AF Mochel, Mark C. Arakaki, Ryan Y. Wang, Guilin Kroshinsky, Daniela Hoang, Mai P. TI Cutaneous Calciphylaxis: A Retrospective Histopathologic Evaluation SO AMERICAN JOURNAL OF DERMATOPATHOLOGY LA English DT Article DE calciphylaxis; von Kossa; Alizarin red; vascular calcification; perieccrine calcification ID CALCIFIC UREMIC ARTERIOLOPATHY; CHRONIC-RENAL-FAILURE; VASCULAR CALCIFICATION; SODIUM THIOSULFATE; PATIENT; HEMODIALYSIS; PATHOGENESIS; NECROSIS; RISK; PREVALENCE AB Calciphylaxis is a rare and life-threatening disease characterized by cutaneous necrosis and vascular calcification. Often, skin biopsy specimens are not diagnostic because of the limited depth of the specimen, biopsy site, and clinical stage. To better understand the utility of various histologic features in rendering the diagnosis of calciphylaxis and to compare von Kossa versus Alizarin red stains in the detection of calcium deposits, we retrospectively analyzed the histologic features and histochemical stain findings of 56 skin biopsies from 27 consecutive patients seen at Massachusetts General Hospital from October 2002 to April 2012, with confirmed diagnosis of calciphylaxis and compared with that of 19 skin biopsies from 17 patients with other disease processes. All forms of vascular calcification and vascular thrombosis were significantly associated with cutaneous calciphylaxis. Perieccrine calcium deposition, highly specific to calciphylaxis, was the only form of calcium deposition noted in 4 (7%) skin biopsies from patients with calciphylaxis. Although the staining appears to be comparable, the deposits seen on Alizarin red appeared larger and were birefringent. Although subtle, perieccrine calcification may aid in the diagnosis of calciphylaxis in settings where typical vascular and extravascular calcification are not identified. Performing both von Kossa and Alizarin red stains might increase the detection of calcium deposit. C1 [Mochel, Mark C.; Wang, Guilin; Hoang, Mai P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Arakaki, Ryan Y.; Kroshinsky, Daniela] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Arakaki, Ryan Y.; Kroshinsky, Daniela] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hoang, MP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 820, Boston, MA 02114 USA. EM mhoang@partners.org NR 37 TC 17 Z9 18 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0193-1091 EI 1533-0311 J9 AM J DERMATOPATH JI Am. J. Dermatopathol. PD JUL PY 2013 VL 35 IS 5 BP 582 EP 586 DI 10.1097/DAD.0b013e31827c7f5d PG 5 WC Dermatology SC Dermatology GA 292UH UT WOS:000329927500008 PM 23328789 ER PT J AU Post, MJD Thurnher, MM Clifford, DB Nath, A Gonzalez, RG Gupta, RK Post, KK AF Post, M. J. D. Thurnher, M. M. Clifford, D. B. Nath, A. Gonzalez, R. G. Gupta, R. K. Post, K. K. TI CNS-Immune Reconstitution Inflammatory Syndrome in the Setting of HIV Infection, Part 1: Overview and Discussion of Progressive Multifocal Leukoencephalopathy-Immune Reconstitution Inflammatory Syndrome and Cryptococcal-Immune Reconstitution Inflammatory Syndrome SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Review ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS-INFECTION; CENTRAL-NERVOUS-SYSTEM; OF-THE-LITERATURE; RISK-FACTORS; AIDS PATIENTS; CLINICAL-MANIFESTATIONS; MULTIPLE-SCLEROSIS; PROLONGED SURVIVAL; FOLLOW-UP AB While uncommon, CNS-IRIS developing after the initiation of HAART in the setting of HIV-related severe immunosuppression is characterized by an intense inflammatory reaction to dead or latent organisms or to self-antigens due to a heightened but dysregulated immune response. While this reaction can range from mild to fulminating, encompassing a very wide clinical spectrum, it is important to recognize because changes in medical management may be necessary to prevent neurologic decline and even death. Once contained, however, this inflammatory response can be associated with improved patient outcome as immune function is restored. Among the infectious organisms that are most commonly associated with CNS-IRIS are the JC virus and Cryptococcus organisms, which will be the subject of this review. CD8 cell infiltration in the leptomeninges, perivascular spaces, blood vessels, and even parenchyma seems to be the pathologic hallmark of CNS-IRIS. While recognition of CNS-IRIS may be difficult, the onset of new or progressive clinical symptoms, despite medical therapy and despite improved laboratory data, and the appearance on neuroimaging studies of contrast enhancement, interstitial edema, mass effect, and restricted diffusion in infections not typically characterized by these findings in the untreated HIV-infected patient should raise the strong suspicion for CNS-IRIS. While CNS-IRIS is a diagnosis of exclusion, the neuroradiologist can play a critical role in alerting the clinician to the possibility of this syndrome. C1 [Post, M. J. D.] Univ Miami, Miller Sch Med, Jackson Mem Med Ctr, Sect Neuroradiol,Dept Radiol, Miami, FL 33136 USA. [Thurnher, M. M.] Univ Vienna, Dept Radiol, Univ Hosp Vienna, Vienna, Austria. [Clifford, D. B.] Washington Univ, Dept Neurol, St Louis, MO USA. [Nath, A.] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Gonzalez, R. G.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Gonzalez, R. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gupta, R. K.] Sanjay Gandhi Postgrad Inst Med Sci, Dept Radiol, Lucknow, Uttar Pradesh, India. [Post, K. K.] UMass Mem Med Ctr, Dept Internal Med, Worcester, MA USA. RP Post, MJD (reprint author), Univ Miami, Miller Sch Med, Jackson Mem Med Ctr, Sect Neuroradiol,Dept Radiol, West Wing 279,1611 NW 12th Ave, Miami, FL 33136 USA. EM jpost@med.miami.edu FU Millennium; Genentech FX Majda Thurnher-UNRELATED: Royalties: Amirsys. David Clifford-UNRELATED: Consultancy: All <$10,000 annually: Biogen Idec, Genentech, Millennium, Genzyme, Bristol Myers Squibb, Pfizer, Janssen, Expert Testimony: Biogen Idec, Comments: European Medicines Agency (EMA) discussion of natalizumab, Payment for Development of Educational Presentations: Millennium, payment for teaching video on exam for PML; Genentech, payment for teaching video on PML diagnosis, Other: Millennium, Independent Adjudication Committee, Genzyme, Data Monitoring Committee, Chair; Genentech, Panel of Experts, Translational Immunology Consultant; Pfizer, Data Safety Monitoring Committee (DSMB). NR 99 TC 12 Z9 12 U1 0 U2 3 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUL PY 2013 VL 34 IS 7 BP 1297 EP 1307 DI 10.3174/ajnr.A3183 PG 11 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 290DZ UT WOS:000329734800007 PM 22790246 ER PT J AU Post, MJD Thurnher, MM Clifford, DB Nath, A Gonzalez, RG Gupta, RK Post, KK AF Post, M. J. D. Thurnher, M. M. Clifford, D. B. Nath, A. Gonzalez, R. G. Gupta, R. K. Post, K. K. TI CNS-Immune Reconstitution Inflammatory Syndrome in the Setting of HIV Infection, Part 2: Discussion of Neuro-Immune Reconstitution Inflammatory Syndrome with and without Other Pathogens SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Review ID ACTIVE ANTIRETROVIRAL THERAPY; CENTRAL-NERVOUS-SYSTEM; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; OF-THE-LITERATURE; RISK-FACTORS; VIRUS-INFECTION; CYTOMEGALOVIRUS ENCEPHALITIS; CLINICAL-MANIFESTATIONS; IMAGING FINDINGS; HAART ERA AB While the previous review of CNS-IRIS in the HIV-infected patient on highly active antiretroviral therapy (Part 1) dealt with an overview of the biology, pathology, and neurologic presentation of this condition and a discussion of the atypical imaging findings in PML-IRIS and cryptococcal meningitis-IRIS due to the robust inflammatory response, the current review (Part 2) discusses the imaging findings in other commonly encountered organisms seen in association with CNS-IRIS, namely, VZV, CMV, HIV, Candida organisms, Mycobacterium tuberculosis, and Toxoplasma gondii. Also described is the imaging appearance of CNS-IRIS when not associated with a particular organism. Recognition of these imaging findings will give credence to the diagnosis of CNS-IRIS and will allow the clinician to institute changes in medical management, if necessary, so that immune reconstitution and improved patient outcome can occur with time. C1 [Post, M. J. D.] Univ Miami, Miller Sch Med, Jackson Mem Med Ctr, Sect Neuroradiol,Dept Radiol, Miami, FL 33136 USA. [Thurnher, M. M.] Univ Vienna, Univ Hosp Vienna, Dept Radiol, Vienna, Austria. [Clifford, D. B.] Washington Univ, Dept Neurol, St Louis, MO USA. [Nath, A.] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Gonzalez, R. G.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Gonzalez, R. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gupta, R. K.] Sanjay Gandhi Postgrad Inst Med Sci, Dept Radiol, Lucknow, Uttar Pradesh, India. [Post, K. K.] UMass Mem Med Ctr, Dept Internal Med, Worcester, MA USA. RP Post, MJD (reprint author), Univ Miami, Miller Sch Med, Jackson Mem Med Ctr, Sect Neuroradiol,Dept Radiol, West Wing 279,1611 NW 12th Ave, Miami, FL 33136 USA. EM jpost@med.miami.edu FU Millennium; Genentech FX Majda Thurnher-UNRELATED: Royalties: Amirsys. David Clifford-UNRELATED: Consultancy: All <$10,000 annually: Biogen Idec, Genentech, Millennium, Genzyme, Bristol Myers Squibb, Pfizer, Janssen, Expert Testimony: Biogen Idec, Comments: European Medicines Agency (EMA) discussion of natalizumab, Payment for Development of Educational Presentations: Millennium, payment for the teaching video on the examination for PML; Genentech, payment for the teaching video on PML diagnosis, Other: Millennium, Independent Adjudication Committee, Genzyme, Data Monitoring Committee, Chair; Genentech, Panel of Experts, Translational Immunology Consultant; Pfizer, Data Safety Monitoring Committee (DSMB). NR 79 TC 5 Z9 6 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUL PY 2013 VL 34 IS 7 BP 1308 EP 1318 DI 10.3174/ajnr.A3184 PG 11 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 290DZ UT WOS:000329734800008 PM 22790252 ER PT J AU Phelan, E Kamani, D Shin, J Randolph, GW AF Phelan, Eimear Kamani, Dipti Shin, Jennifer Randolph, Gregory W. TI Neural Monitored Revision Thyroid Cancer Surgery: Surgical Safety and Thyroglobulin Response SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE revision thyroid surgery; IONM; neural monitoring; hypocalcemia; recurrent laryngeal nerve injury; hypoparathyroidism; complications of revision surgery; thyroid cancer recurrence; papillary thyroid carcinoma; thyroglobulin Tg response ID CENTRAL COMPARTMENT DISSECTION; ETHANOL INJECTION TREATMENT; NODE DISSECTION; CARCINOMA; RECURRENT; HYPOCALCEMIA; REOPERATION; ABLATION; EFFICACY AB Objective To evaluate the postoperative complications and to evaluate and stratify thyroglobulin (Tg) response associated with revision surgery for thyroid malignancy. Study Design Case series with chart review. Settings Academic, tertiary care center. Subjects and Methods All patients with regionally recurrent thyroid carcinoma and who underwent revision thyroid surgery by the senior author (GWR) during a 5-year period were identified. All patients had pre- and postoperative laryngeal examination and underwent surgery with standardized neural monitoring. Postoperative complications and thyroglobulin (Tg) response were recorded. Results One hundred seventeen cases meeting the criteria for revision surgery for recurrent thyroid cancer were identified. Among this group, 30% presented for their third or higher revision procedure. Preoperative permanent vocal cord palsy was present in 14% (n = 16), and 19% (n = 22) had preoperative permanent hypocalcaemia. There were no new cases of either temporary or permanent vocal cord palsy in our study group. Approximately 5% developed temporary and 3% permanent hypocalcaemia requiring medical treatment. The mean basal Tg following revision surgery was 5.6 ng/ml (range, 0.2-32.7), which represented a mean postoperative significant decline in Tg of approximately 90%. In nearly 40%, basal Tg was undetectable postoperatively. Tg response was stratified based on the number of revision surgeries, Tg decline was observed in 90% of all cases, 92% after first revision surgery, 85% after second, 34% after third, and 70% after fifth revision surgeries. Conclusion Revision thyroid cancer surgery can be performed with low rates of complications and significant impact on Tg levels even after multiple revision surgeries. C1 [Phelan, Eimear; Kamani, Dipti; Shin, Jennifer; Randolph, Gregory W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Thyroid & Parathyroid Surg,Dept Otol & Laryng, Boston, MA USA. [Randolph, Gregory W.] Massachusetts Gen Hosp, Dept Surg, Endocrine Surg Serv, Div Surg Oncol, Boston, MA 02114 USA. RP Randolph, GW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Div Thyroid & Parathyroid Surg, 243 Charles St, Boston, MA 02114 USA. EM gregory_randolph@meei.harvard.edu RI Shin, Jennifer/A-3169-2016 NR 24 TC 5 Z9 5 U1 1 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD JUL PY 2013 VL 149 IS 1 BP 47 EP 52 DI 10.1177/0194599813489662 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 285XD UT WOS:000329427400006 PM 23695590 ER PT J AU Liachko, NF McMillan, PJ Guthrie, CR Bird, TD Leverenz, JB Kraemer, BC AF Liachko, Nicole F. McMillan, Pamela J. Guthrie, Chris R. Bird, Thomas D. Leverenz, James B. Kraemer, Brian C. TI CDC7 Inhibition Blocks Pathological TDP-43 Phosphorylation and Neurodegeneration SO ANNALS OF NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; TAU-INDUCED NEUROTOXICITY; CAENORHABDITIS-ELEGANS; DNA-REPLICATION; KINASE INHIBITORS; C-ELEGANS; S PHASE; HEXANUCLEOTIDE REPEAT; CHROMATIN BINDING AB ObjectiveKinase hyperactivity occurs in both neurodegenerative disease and cancer. Lesions containing hyperphosphorylated aggregated TDP-43 characterize amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 inclusions. Dual phosphorylation of TDP-43 at serines 409/410 (S409/410) drives neurotoxicity in disease models; therefore, TDP-43-specific kinases are candidate targets for intervention. MethodsTo find therapeutic targets for the prevention of TDP-43 phosphorylation, we assembled and screened a comprehensive RNA interference library targeting kinases in TDP-43 transgenic Caenorhabditis elegans. ResultsWe show CDC7 robustly phosphorylates TDP-43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture. In frontotemporal lobar degeneration (FTLD)-TDP cases, CDC7 immunostaining overlaps with the phospho-TDP-43 pathology found in frontal cortex. Furthermore, PHA767491, a small molecule inhibitor of CDC7, reduces TDP-43 phosphorylation and prevents TDP-43-dependent neurodegeneration in TDP-43-transgenic animals. InterpretationTaken together, these data support CDC7 as a novel therapeutic target for TDP-43 proteinopathies, including FTLD-TDP and amyotrophic lateral sclerosis. Ann Neurol 2013;74:39-52 C1 [Liachko, Nicole F.; Guthrie, Chris R.; Bird, Thomas D.; Kraemer, Brian C.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Liachko, Nicole F.; Bird, Thomas D.; Kraemer, Brian C.] Univ Washington, Dept Med, Seattle, WA USA. [McMillan, Pamela J.; Leverenz, James B.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. [McMillan, Pamela J.; Leverenz, James B.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Bird, Thomas D.; Leverenz, James B.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Leverenz, James B.] Vet Affairs Puget Sound Hlth Care Syst, Parkinsons Dis Res Educ & Clin Ctr, Seattle, WA 98108 USA. RP Kraemer, BC (reprint author), Vet Affairs Puget Sound Hlth Care Syst, S182,1660 South Columbian Way, Seattle, WA 98108 USA. EM kraemerb@u.washington.edu FU Department of Veterans Affairs [1147891]; Career Development Award [CDA1]; National Institute on Aging [AG 000057-31]; NIH [NINDS R01NS064131]; NIA [P50AG005136-27]; NINDS [P50NS2062684-02]; Muscular Dystrophy Association, ALS Division [218523] FX This work was supported by grants from the Department of Veterans Affairs (Merit Review Grant #1147891, B.C.K.; Career Development Award [CDA1], N.F.L.), a National Institute on Aging training grant (AG 000057-31, N.F.L.), the NIH (NINDS R01NS064131, B.C.K.; NIA P50AG005136-27 and NINDS P50NS2062684-02, J.B.L.), and the Muscular Dystrophy Association (218523), ALS Division (B.C.K.). NR 61 TC 22 Z9 22 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2013 VL 74 IS 1 BP 39 EP 52 DI 10.1002/ana.23870 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 282UH UT WOS:000329198600007 PM 23424178 ER PT J AU Mannix, R Meehan, WP Mandeville, J Grant, PE Gray, T Berglass, J Zhang, J Bryant, J Rezaie, S Chung, JY Peters, NV Lee, C Tien, LW Kaplan, DL Feany, M Whalen, M AF Mannix, Rebekah Meehan, William P. Mandeville, Joseph Grant, Patricia E. Gray, Tory Berglass, Jacqueline Zhang, Jimmy Bryant, John Rezaie, Shervin Chung, Joon Yong Peters, Nicholas V. Lee, Christopher Tien, Lee W. Kaplan, David L. Feany, Mel Whalen, Michael TI Clinical Correlates in an Experimental Model of Repetitive Mild Brain Injury SO ANNALS OF NEUROLOGY LA English DT Article ID ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; MOUSE MODEL; COGNITIVE PERFORMANCE; HEAD-INJURY; A-BETA; TRANSGENIC MICE; EARLY ADULTHOOD; DEFICITS; MEMORY AB ObjectiveAlthough there is growing awareness of the long-term cognitive effects of repetitive mild traumatic brain injury (rmTBI; eg, sports concussions), whether repeated concussions cause long-term cognitive deficits remains controversial. Moreover, whether cognitive deficits depend on increased amyloid deposition and tau phosphorylation or are worsened by the apolipoprotein E4 allele remains unknown. Here, we use an experimental model of rmTBI to address these clinical controversies. MethodsA weight drop rmTBI model was used that results in cognitive deficits without loss of consciousness, seizures, or gross or microscopic evidence of brain damage. Cognitive function was assessed using a Morris water maze (MWM) paradigm. Immunostaining and enzyme-linked immunosorbent assay (ELISA) were used to assess amyloid deposition and tau hyperphosphorylation. Brain volume and white matter integrity were assessed by magnetic resonance imaging (MRI). ResultsMice subjected to rmTBI daily or weekly but not biweekly or monthly had persistent cognitive deficits as long as 1 year after injuries. Long-term cognitive deficits were associated with increased astrocytosis but not tau phosphorylation or amyloid (by ELISA); plaques or tangles (by immunohistochemistry); or brain volume loss or changes in white matter integrity (by MRI). APOE4 was not associated with worse MWM performance after rmTBI. InterpretationWithin the vulnerable time period between injuries, rmTBI produces long-term cognitive deficits independent of increased amyloid or tau phosphorylation. In this model, cognitive outcome is not influenced by APOE4 status. The data have implications for the long-term mental health of athletes who suffer multiple concussions. Ann Neurol 2013;74:65-75 C1 [Mannix, Rebekah; Meehan, William P.; Berglass, Jacqueline; Zhang, Jimmy] Boston Childrens Hosp, Div Emergency Med, Boston, MA USA. [Mannix, Rebekah; Meehan, William P.; Mandeville, Joseph; Grant, Patricia E.; Feany, Mel; Whalen, Michael] Harvard Univ, Sch Med, Boston, MA USA. [Meehan, William P.] Sports Concuss Clin, Div Sports Med, Boston, MA USA. [Meehan, William P.] Micheli Ctr Sports Injury Prevent, Boston, MA USA. [Mandeville, Joseph; Grant, Patricia E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Grant, Patricia E.] Childrens Hosp Boston, Dept Radiol, Boston, MA 02115 USA. [Gray, Tory; Bryant, John; Rezaie, Shervin; Chung, Joon Yong; Peters, Nicholas V.; Lee, Christopher; Whalen, Michael] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Gray, Tory; Bryant, John; Rezaie, Shervin; Chung, Joon Yong; Peters, Nicholas V.; Lee, Christopher; Whalen, Michael] Massachusetts Gen Hosp, Neurosci Ctr, Charlestown, MA 02129 USA. [Tien, Lee W.; Kaplan, David L.] Tufts Univ, Dept Biomed Engn, Boston, MA 02111 USA. [Feany, Mel] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Mannix, R (reprint author), Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM Rebekah.Mannix@childrens.harvard.edu; MWhalen@Partners.org FU NFL; NICHD [T32HD040128-06]; Charles Hood Foundation; NIH National Institute of Neurological Disorders and Stroke [R21NS075226] FX This study was supported by the NFL Charities Medical Grant (R. M., W. P. M., M. W.), NICHD T32HD040128-06 (W. P. M.), Charles Hood Foundation (R. M.), and NIH National Institute of Neurological Disorders and Stroke R21NS075226 (M. W.). NR 46 TC 38 Z9 38 U1 5 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2013 VL 74 IS 1 BP 65 EP 75 DI 10.1002/ana.23858 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 282UH UT WOS:000329198600009 PM 23922306 ER PT J AU Thomas, D Blay, JY Chawla, S Choy, E Grimer, R Ferrari, S Reichardt, P Rutkowski, P Qian, Y Jacobs, I AF Thomas, D. Blay, J. -Y. Chawla, S. Choy, E. Grimer, R. Ferrari, S. Reichardt, P. Rutkowski, P. Qian, Y. Jacobs, I. TI EFFICACY AND SAFETY OF DENOSUMAB IN GIANT CELL TUMOUR OF BONE (GCTB): UPDATED RESULTS WITH INDEPENDENT RADIOGRAPHIC ASSESSMENT OF RESPONSE SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Thomas, D.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Blay, J. -Y.] Ctr Leon Berard, F-69373 Lyon, France. [Chawla, S.] Sarcoma Oncol Ctr, Los Angeles, CA USA. [Choy, E.] Massachusetts Gen Hosp, Dana Farber Harvard Canc Ctr, Boston, MA 02114 USA. [Grimer, R.] Royal Orthopaed Hosp, Birmingham B31 2AP, W Midlands, England. [Ferrari, S.] Ist Ortoped Rizzoli, Bologna, Italy. [Reichardt, P.] HELIOS Klin Bad Saarow, Bad Saarow Pieskow, Germany. [Rutkowski, P.] Inst Marii Sklodowskiej Curie, Ctr Onkol, Warsaw, Poland. [Qian, Y.; Jacobs, I.] Amgen Inc, Thousand Oaks, CA 91320 USA. RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD JUL PY 2013 VL 9 SU 2 SI SI BP 46 EP 46 PG 1 WC Oncology SC Oncology GA 286IT UT WOS:000329462300012 ER PT J AU Chan, A Goss, P Barrios, C Finkelstein, DM Iwata, H Martin, M Coleman, R Braun, A Zhou, Y Maniar, T AF Chan, A. Goss, P. Barrios, C. Finkelstein, D. M. Iwata, H. Martin, M. Coleman, R. Braun, A. Zhou, Y. Maniar, T. TI DENOSUMAB VERSUS PLACEBO AS ADJUVANT TREATMENT FOR WOMEN WITH EARLY-STAGE BREAST CANCER AT HIGH RISK OF DISEASE RECURRENCE (D-CARE) SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Chan, A.] Curtin Univ, Perth, WA 6845, Australia. [Goss, P.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Barrios, C.] PUCRS Sch Med, Porto Alegre, RS, Brazil. [Finkelstein, D. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Iwata, H.] Aichi Canc Ctr Hosp, Nagoya, Aichi 464, Japan. [Martin, M.] Hosp Gregorio Maranon, Madrid, Spain. [Coleman, R.] Univ Sheffield, Sheffield, S Yorkshire, England. [Braun, A.; Zhou, Y.; Maniar, T.] Amgen Inc, Thousand Oaks, CA 91320 USA. RI Barrios, Carlos/G-8525-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD JUL PY 2013 VL 9 SU 2 SI SI BP 53 EP 53 PG 1 WC Oncology SC Oncology GA 286IT UT WOS:000329462300022 ER PT J AU Yoong, J Park, ER Greer, JA Jackson, VA Gallagher, ER Pirl, WF Back, AL Temel, JS AF Yoong, J. Park, E. R. Greer, J. A. Jackson, V. A. Gallagher, E. R. Pirl, W. F. Back, A. L. Temel, J. S. TI EARLY PALLIATIVE CARE IN ADVANCED LUNG CANCER: A QUALITATIVE STUDY SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Yoong, J.; Park, E. R.; Greer, J. A.; Jackson, V. A.; Gallagher, E. R.; Pirl, W. F.; Temel, J. S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yoong, J.] Northern Hosp, Melbourne, Vic, Australia. [Yoong, J.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Back, A. L.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD JUL PY 2013 VL 9 SU 2 SI SI BP 64 EP 64 PG 1 WC Oncology SC Oncology GA 286IT UT WOS:000329462300054 ER PT J AU Bartusik, D Aebisher, D Ghogare, A Ghosh, G Abramova, I Hasan, T Greer, A AF Bartusik, Dorota Aebisher, David Ghogare, Ashwini Ghosh, Goutam Abramova, Inna Hasan, Tayyaba Greer, Alexander TI A Fiberoptic (Photodynamic Therapy Type) Device with a Photosensitizer and Singlet Oxygen Delivery Probe Tip for Ovarian Cancer Cell Killing SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID GENERATION; RELEASE; COMPLEX; SAFE; HEAD; NECK AB A portable fiber optic-based sensitizer delivery (FOSD) device has been developed and studied. Before there might be success in photodynamic therapy (PDT) and antibacterial ambitions, an understanding of basic factors on device performance was needed. Thus, the device was examined for the localized delivery of sensitizer molecules in ovarian cancer cells and production of high concentrations of singlet oxygen for their eradication in vitro. The device tip releases stored pheophorbide by attack of singlet oxygen from sensitized oxygen gas delivered through the hollow fiber using 669nm laser light. The performance of the device was enhanced when configured with a fluorosilane tip by virtue of its Teflon-like property compared with a conventional glass tip (greater sensitizer quantities were photoreleased and laterally diffused, and greater amounts of ovarian OVCAR-5 cancer cells were killed). No cell damage was observed at 2.2N of force applied by the probe tip itself, an amount used for many of the experiments described here. C1 [Bartusik, Dorota; Aebisher, David; Ghogare, Ashwini; Ghosh, Goutam; Abramova, Inna; Greer, Alexander] CUNY Brooklyn Coll, Dept Chem, Grad Ctr, Brooklyn, NY 11210 USA. [Hasan, Tayyaba] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hasan, Tayyaba] Harvard Univ, Sch Med, Boston, MA USA. RP Hasan, T (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM thasan@mgh.harvard.edu; agreer@brooklyn.cuny.edu FU NIH-National Institute of General Medical Sciences [NIH SC1GM093830]; NIH-National Cancer Institute [5R01CA160998] FX D.B., D.A., A.G., G.G., I.A. and A.G. acknowledge support from the NIH-National Institute of General Medical Sciences (NIH SC1GM093830). Grant support to T.H. was provided by the NIH-National Cancer Institute (5R01CA160998). We thank Mihaela Minnis for grinding and shaping of glass caps, Stanley Kimani for culturing cells and suggestions and Leda Lee for the graphic arts work. We are also thankful Zhong Wang (Hunter College Bio-Imaging Facility) and Mim Nakarmi (Brooklyn College Physics Department) for use of requisite equipment. NR 33 TC 13 Z9 14 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-8655 EI 1751-1097 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL PY 2013 VL 89 IS 4 SI SI BP 936 EP 941 DI 10.1111/php.12072 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 284GN UT WOS:000329304200026 PM 23495787 ER PT J AU Rizvi, I Anbil, S Alagic, N Celli, JP Zheng, LZ Palanisami, A Glidden, MD Pogue, BW Hasan, T AF Rizvi, Imran Anbil, Sriram Alagic, Nermina Celli, Jonathan P. Zheng, Lei Zak Palanisami, Akilan Glidden, Michael D. Pogue, Brian W. Hasan, Tayyaba TI PDT Dose Parameters Impact Tumoricidal Durability and Cell Death Pathways in a 3D Ovarian Cancer Model SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID INTRAPERITONEAL PHOTODYNAMIC THERAPY; DERIVATIVE MONOACID RING; SINGLET OXYGEN LUMINESCENCE; MULTICELL TUMOR SPHEROIDS; INDUCED PROTOPORPHYRIN-IX; ENDOTHELIAL GROWTH-FACTOR; PHASE-II TRIAL; IN-VIVO; FLUENCE RATE; 5-AMINOLEVULINIC ACID AB The successful implementation of photodynamic therapy (PDT)-based regimens depends on an improved understanding of the dosimetric and biological factors that govern therapeutic variability. Here, the kinetics of tumor destruction and regrowth are characterized by systematically varying benzoporphyrin derivative (BPD)-light combinations to achieve fixed PDT doses (MxJcm(-2)). Three endpoints were used to evaluate treatment response: (1) Viability evaluated every 24h for 5days post-PDT; (2) Photobleaching assessed immediately post-PDT; and (3) Caspase-3 activation determined 24h post-PDT. The specific BPD-light parameters used to construct a given PDT dose significantly impact not only acute cytotoxic efficacy, but also treatment durability. For each dose, PDT with 0.25M BPD produces the most significant and sustained reduction in normalized viability compared to 1 and 10M BPD. Percent photobleaching correlates with normalized viability for a range of PDT doses achieved within BPD concentrations. To produce a cytotoxic response with 10M BPD that is comparable to 0.25 and 1M BPD a reduction in irradiance from 150 to 0.5mWcm(-2) is required. Activated caspase-3 does not correlate with normalized viability. The parameter-dependent durability of outcomes within fixed PDT doses provides opportunities for treatment customization and improved therapeutic planning. C1 [Rizvi, Imran; Anbil, Sriram; Alagic, Nermina; Celli, Jonathan P.; Zheng, Lei Zak; Palanisami, Akilan; Glidden, Michael D.; Hasan, Tayyaba] Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Celli, Jonathan P.; Glidden, Michael D.] Univ Massachusetts, Dept Phys, Boston, MA 02125 USA. [Pogue, Brian W.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. RP Hasan, T (reprint author), Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM thasan@mgh.harvard.edu OI Rizvi, Imran/0000-0001-9673-4700 FU National Cancer Institute at the National Institutes of Health [R01CA158415, R01CA160998, K99CA155045]; Eleanor and Miles Shore Fellowship Program for Scholars in Medicine FX Dr. Hasan and Dr. Celli wish to acknowledge support from the following grants from the National Cancer Institute at the National Institutes of Health: R01CA158415, R01CA160998 (TH) and K99CA155045 (JPC). Dr. Celli also acknowledges support from the Eleanor and Miles Shore Fellowship Program for Scholars in Medicine. NR 135 TC 24 Z9 25 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-8655 EI 1751-1097 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL PY 2013 VL 89 IS 4 SI SI BP 942 EP 952 DI 10.1111/php.12065 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 284GN UT WOS:000329304200027 PM 23442192 ER PT J AU Romanova, M Liang, LJ Deng, ML Li, ZP Heber, D AF Romanova, Maria Liang, Li-Jung Deng, Max L. Li, Zhaoping Heber, David TI Effectiveness of the MOVE! Multidisciplinary Weight Loss Program for Veterans in Los Angeles SO PREVENTING CHRONIC DISEASE LA English DT Article ID LIFE-STYLE INTERVENTION; OBESE ADULTS; OLDER-ADULTS; POUNDS LOST; TRIAL; PREVALENCE; MANAGEMENT; ADHERENCE; DESIGN; BURDEN AB Introduction The purpose of this study was to evaluate the effectiveness of the MOVE! Weight Management Program for Veterans (MOVE!) in achieving weight loss in veterans who attended the multidisciplinary weight management program in the VA Greater Los Angeles Healthcare System. Methods From April 1, 2006, to December 31, 2009, 382 veterans enrolled in the MOVE! program; 377 veterans attended at least 3 group sessions and were included in this study. All veterans were encouraged to complete 8 weekly group sessions on nutrition, lifestyle changes, and behavior modification in a group setting led by a multidisciplinary team. After completing the session, veterans had the option of continuing with a support group that meets monthly. The change in weight from 1 year pre-enrollment in MOVE! to 1, 2, and 3 years postenrollment was analyzed. Results Veterans gained 1.4 kg per year (standard error [SE] = 0.47, P = .003) before enrolling in MOVE!. One year after the enrollment participants lost on average 2.2 kg (SE = 0.42; P < .001). The pre-enrollment slope for weight change was significantly different from the postenrollment slope. Conclusion Findings from this study support the need for a long-term weight management program such as MOVE! in primary care settings to assist overweight and obese VA patients in achieving and maintaining weight loss to reduce the risk and progression of age-related chronic diseases such as diabetes and heart disease. C1 [Romanova, Maria; Deng, Max L.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Liang, Li-Jung; Heber, David] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Li, Zhaoping] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. [Li, Zhaoping] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Human Nutr, Los Angeles, CA 90095 USA. RP Li, ZP (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Med, W111A, Los Angeles, CA 90073 USA. EM zhaoping.li@va.gov NR 28 TC 8 Z9 8 U1 3 U2 7 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2013 VL 10 AR UNSP 120325 DI 10.5888/pcd10.120325 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 285KF UT WOS:000329392200004 ER PT J AU Zhao, J Mialki, RK Wei, JX Coon, TA Zou, CB Chen, BB Mallampalli, RK Zhao, YT AF Zhao, Jing Mialki, Rachel K. Wei, Jianxin Coon, Tiffany A. Zou, Chunbin Chen, Bill B. Mallampalli, Rama K. Zhao, Yutong TI SCF E3 ligase F-box protein complex SCFFBXL19 regulates cell migration by mediating Rac1 ubiquitination and degradation SO FASEB JOURNAL LA English DT Article DE small GTPase protein; protein stability; phosphorylation; cell motility ID I-KAPPA-B; SIGNAL-INDUCED UBIQUITINATION; BRONCHIAL EPITHELIAL-CELLS; DEPENDENT PROTEOLYSIS; C-MYC; PHOSPHORYLATION; KINASE; UBIQUITYLATION; ACETYLATION; RECEPTOR AB Rac1, a member of the Rho family of GTPases, regulates diverse cellular functions, including cytoskeleton reorganization and cell migration. F-box proteins are major subunits within the Skp1-Cul1-F-box (SCF) E3 ubiquitin ligases that recognize specific substrates for ubiquitination. The role of F-box proteins in regulating Rac1 stability has not been studied. Mouse lung epithelial (MLE12) cells were used to investigate Rac1 stability and cell migration. Screening of an F-box protein library and in vitro ubiquitination assays identified FBXL19, a relatively new member of the F-box protein family that targets Rac1 for its polyubiquitination and proteasomal degradation. Overexpression of FBXL19 decreased both Rac1 active and inactive forms and significantly reduced cellular migration. Protein kinase AKT-mediated phosphorylation of Rac1 at serine(71) was essential for FBXL19-mediated Rac1 ubiquitination and depletion. Lysine(166) within Rac1 was identified as a polyubiquitination acceptor site. Rac1(S71A) and Rac1(K166R) mutant proteins were resistant to FBXL19-mediated ubiquitination and degradation. Further, ectopically expressed FBXL19 reduced cell migration in Rac1-overexpressing cells (P<0.01, Rac1 cells vs. FBXL19+Rac1 cells), but not in Rac1 lysine(166) mutant-overexpressing cells. FBXL19 diminished formation of the migratory leading edge. Thus, SCFFBXL19 targets Rac1 for its disposal, a process regulated by AKT. These findings provide the first evidence of an F-box protein targeting a small G protein for ubiquitination and degradation to modulate cell migration.Zhao, J., Mialki, R. K., Wei, J., Coon, T. A., Zou, C., Chen, B. B., Mallampalli, R. K., Zhao, Y. SCF E3 ligase F-box protein complex SCFFBXL19 regulates cell migration by mediating Rac1 ubiquitination and degradation. C1 [Zhao, Jing; Mialki, Rachel K.; Wei, Jianxin; Coon, Tiffany A.; Zou, Chunbin; Chen, Bill B.; Mallampalli, Rama K.; Zhao, Yutong] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Zhao, Jing; Mialki, Rachel K.; Wei, Jianxin; Coon, Tiffany A.; Zou, Chunbin; Chen, Bill B.; Mallampalli, Rama K.; Zhao, Yutong] Univ Pittsburgh, Sch Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. RP Zhao, YT (reprint author), Univ Pittsburgh, Sch Med, Dept Med, 3459 5th Ave,NW 628 MUH, Pittsburgh, PA 15213 USA. EM zhaoy3@upmc.edu RI Wei, Jianxin/P-5431-2016 FU U.S. National Institutes of Health [RO1 HL01916, HL112791, HL097376, HL098174, HL116472]; American Heart Association [12SDG9050005, 12SDG12040330]; Merit Review Award from the United States FX This study was supported by U.S. National Institutes of Health grants RO1 HL01916 and HL112791 (to Y.Z.), HL097376 and HL098174 (to R. K. M.), and HL116472 (to B. B. C.); American Heart Association awards 12SDG9050005 (to J.Z.) and 12SDG12040330 (to C.Z.); and a Merit Review Award from the United States (to R. K. M.). The authors declare no conflicts of interest. NR 45 TC 12 Z9 13 U1 2 U2 8 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JUL PY 2013 VL 27 IS 7 BP 2611 EP 2619 DI 10.1096/fj.12-223099 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 277TA UT WOS:000328841000010 PM 23512198 ER PT J AU Crowder, SW Horton, LW Lee, SH McClain, CM Hawkins, OE Palmer, AM Bae, H Richmond, A Sung, HJ AF Crowder, Spencer W. Horton, Linda W. Lee, Sue Hyun McClain, Colt M. Hawkins, Oriana E. Palmer, Amanda M. Bae, Hojae Richmond, Ann Sung, Hak-Joon TI Passage-dependent cancerous transformation of human mesenchymal stem cells under carcinogenic hypoxia SO FASEB JOURNAL LA English DT Article DE aging; reactive oxygen species; p53; experimental models ID BONE-MARROW; MATRIX METALLOPROTEINASES; REPLICATIVE SENESCENCE; DOWN-REGULATION; TUMOR INVASION; DIFFERENTIATION; P53; CULTURE; PROLIFERATION; MECHANISMS AB Bone marrow-derived human mesenchymal stem cells (hMSCs) either promote or inhibit cancer progression, depending on factors that heretofore have been undefined. Here we have utilized extreme hypoxia (0.5% O-2) and concurrent treatment with metal carcinogen (nickel) to evaluate the passage-dependent response of hMSCs toward cancerous transformation. Effects of hypoxia and nickel treatment on hMSC proliferation, apoptosis, gene and protein expression, replicative senescence, reactive oxygen species (ROS), redox mechanisms, and in vivo tumor growth were analyzed. The behavior of late passage hMSCs in a carcinogenic hypoxia environment follows a profile similar to that of transformed cancer cells (i.e., increased expression of oncogenic proteins, decreased expression of tumor suppressor protein, increased proliferation, decreased apoptosis, and aberrant redox mechanisms), but this effect was not observed in earlier passage control cells. These events resulted in accumulated intracellular ROS in vitro and excessive proliferation in vivo. We suggest a mechanism by which carcinogenic hypoxia modulates the activity of three critical transcription factors (c-MYC, p53, and HIF1), resulting in accumulated ROS and causing hMSCs to undergo cancer-like behavioral changes. This is the first study to utilize carcinogenic hypoxia as an environmentally relevant experimental model for studying the age-dependent cancerous transformation of hMSCs.Crowder, S. W., Horton, L. W., Lee, H. H., McClain, C. M., Hawkins, O. E., Palmer, A. M. Bae, H., Richmond, A., Sung, H.-J. Passage-dependent cancerous transformation of human mesenchymal stem cells under carcinogenic hypoxia. C1 [Crowder, Spencer W.; Lee, Sue Hyun; Palmer, Amanda M.; Sung, Hak-Joon] Vanderbilt Univ, Med Ctr, Dept Biomed Engn, Nashville, TN 37235 USA. [Crowder, Spencer W.; Sung, Hak-Joon] Vanderbilt Univ, Med Ctr, Ctr Stem Cell Biol, Nashville, TN 37235 USA. [Horton, Linda W.; Hawkins, Oriana E.; Richmond, Ann] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN 37235 USA. [McClain, Colt M.] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37235 USA. [Horton, Linda W.; Hawkins, Oriana E.; Richmond, Ann] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN USA. [Bae, Hojae; Sung, Hak-Joon] Kyung Hee Univ, Sch Dent, Dept Maxillofacial Biomed Engn, Seoul, South Korea. RP Sung, HJ (reprint author), Vanderbilt Univ, Dept Biomed Engn, VU Stn B, Box 351631, Nashville, TN 37235 USA. EM hak-joon.sung@vanderbilt.edu RI Richmond, Ann/A-3048-2014 FU Vanderbilt Start-Up; U.S. National Institutes of Health [HL091465]; National Cancer Institute [CA34590-30]; U.S. Department of Veterans Affairs FX The authors are grateful for technical help from Dae Kwang Jung. This research is supported by Vanderbilt Start-Up, the U.S. National Institutes of Health (HL091465), the National Cancer Institute (CA34590-30; A.R.), and a Senior Research Career Scientist Award from the U.S. Department of Veterans Affairs (A.R.). NR 46 TC 11 Z9 12 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD JUL PY 2013 VL 27 IS 7 BP 2788 EP 2798 DI 10.1096/fj.13-228288 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 277TA UT WOS:000328841000027 PM 23568779 ER PT J AU Gross, AH Cromwell, J Fonteyn, M Matulonis, UA Hayman, LL AF Gross, Anne H. Cromwell, Jerry Fonteyn, Marsha Matulonis, Ursula A. Hayman, Laura L. TI Hopelessness and Complementary Therapy Use in Patients With Ovarian Cancer SO CANCER NURSING LA English DT Article DE CAM; Hope; Hopelessness; Massage; Ovarian cancer; Quality of life; Spirituality ID QUALITY-OF-LIFE; ALTERNATIVE MEDICINE USE; QUESTIONNAIRE MODULE; MASSAGE THERAPY; CLINICAL-TRIALS; HOPE; SPIRITUALITY; DEPRESSION; DISTRESS; ILLNESS AB Background: Hopelessness negatively affects ovarian cancer patients' quality of life (QOL). Research validating the effects of complementary and alternative medicine (CAM) use on QOL and hope is scarce, even though QOL and hope are reasons that patients cite for using CAM therapy. Clinicians need effective, evidence-based interventions to improve QOL and reduce hopelessness. Objective: The objectives of this study were to examine factors influencing hopelessness in patients with newly diagnosed disease, long-term survivors, and patients experiencing ovarian cancer recurrence and to examine the effects of CAM on hopelessness in the same population. Methods: Surveys of ovarian cancer patients (N = 219) undergoing treatment at a comprehensive cancer center in the United States were analyzed. Descriptive, correlation, and multivariate analyses described variables and demonstrated the effects of sociodemographics, disease state, psychological distress, QOL, CAM use, and faith on hopelessness. Results: Patients ages 65 years or older (-0.95, P = .03), with strong faith (-0.28, P = .00), and good QOL (0.11, P = .00) directly reduced hopelessness scores (mean, 3.37). Massage therapy substantially reduced hopelessness scores (-1.07, P = .02); holding age constant, employed patients were twice as likely to use massage (odds ratio, 2.09; P = .04). Patients who had newly diagnosed and recurrent ovarian cancer were more hopeless because of greater distress from symptoms and adverse effects of treatment. Conclusion: Patients who used massage therapy were significantly less hopeless, as were those with strong faith and well-controlled disease symptoms and treatment for adverse effects. Implications for Practice: Support of spiritual needs and symptom management are important interventions to prevent and/or reduce hopelessness, especially for patients with newly diagnosed and recurrent ovarian cancer. Further research testing the positive effect of massage interventions on hopelessness is needed. C1 [Gross, Anne H.; Fonteyn, Marsha] Dana Farber Canc Inst, Dept Nursing & Patient Care Serv, Boston, MA 02215 USA. [Matulonis, Ursula A.] Dana Farber Canc Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. [Cromwell, Jerry; Hayman, Laura L.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. RP Gross, AH (reprint author), Dana Farber Canc Inst, Dept Nursing & Patient Care Serv, 450 Brookline Ave, Boston, MA 02215 USA. EM anne_gross@dfci.harvard.edu NR 48 TC 8 Z9 9 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X EI 1538-9804 J9 CANCER NURS JI Cancer Nurs. PD JUL-AUG PY 2013 VL 36 IS 4 BP 256 EP 264 DI 10.1097/NCC.0b013e31826f3bc4 PG 9 WC Oncology; Nursing SC Oncology; Nursing GA 276IN UT WOS:000328743800010 PM 23086133 ER PT J AU Jeudin, P Liveright, E del Carmen, MG Perkins, RB AF Jeudin, Patricia Liveright, Elizabeth del Carmen, Marcela G. Perkins, Rebecca B. TI Race, ethnicity and income as factors for HPV vaccine acceptance and use SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Article; Proceedings Paper CT 23rd National Immunisation Conference for Health Care Workers (NIC) CY DEC 07, 2012 CL Manchester, ENGLAND DE HPV vaccine; vaccine uptake; racial disparities; vaccine acceptance; review; income; pediatrics; policy; vaccinology ID HUMAN-PAPILLOMAVIRUS VACCINATION; CLINICAL PREVENTIVE SERVICES; CONTINUING MEDICAL-EDUCATION; CERVICAL-CANCER; UNITED-STATES; ADOLESCENT FEMALES; HESITANT PARENTS; PRIMARY-CARE; SOCIOECONOMIC-STATUS; SERIES INITIATION AB If distributed equitably, Human Papillomavirus (HPV) vaccines have the potential to reduce racial disparities in HPV-related diseases and cervical cancers. However, current trends in the US indicate low uptake among all adolescents, with persistent disparities among minority and low-income adolescents despite largely positive views of vaccination among their parents. As Black, Hispanic, and Asian populations continue to grow in the US over the next 40 y, it is imperative that we not only improve HPV vaccination rates overall, but focus on high-risk populations to prevent an increase in cervical cancer disparities. This review discusses initiation and completion rates of the three-dose HPV vaccine series among adolescents in high-risk groups and describes cultural similarities and differences in motivation and barriers to vaccination. The goal of this review is to highlight factors leading to vaccination in different adolescent racial groups and to help guide the development of strategies to increase rates of vaccine initiation and completion among groups at the highest risk for developing cervical cancer. C1 [Jeudin, Patricia; Liveright, Elizabeth; Perkins, Rebecca B.] Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. [del Carmen, Marcela G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol, Boston, MA USA. RP Perkins, RB (reprint author), Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. EM Rebecca.Perkins@bmc.org FU American Cancer Society [MRSG-09-151-01] FX American Cancer Society Mentored Research Scholar Grant (MRSG-09-151-01). NR 116 TC 4 Z9 4 U1 3 U2 15 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD JUL 1 PY 2013 VL 9 IS 7 BP 1413 EP 1420 DI 10.4161/hv.24422 PG 8 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 273YR UT WOS:000328572700012 PM 23571170 ER PT J AU Palmer, JA Meterko, M Zhao, SB Berlowitz, D Mobley, E Hartmann, CW AF Palmer, Jennifer A. Meterko, Mark Zhao, Shibei Berlowitz, Dan Mobley, Esther Hartmann, Christine W. TI Nursing Home Employee Perceptions of Culture Change SO RESEARCH IN GERONTOLOGICAL NURSING LA English DT Article ID LONG-TERM-CARE; PATIENT SAFETY CLIMATE; HIGH-RELIABILITY ORGANIZATIONS; CREATING HIGH-RELIABILITY; HEALTH-CARE; STRUCTURAL EMPOWERMENT; INDIVIDUALIZED CARE; RESIDENT OUTCOMES; CHANGE MODELS; HOSPITALS AB This study examined nursing home staff members' comfort levels with specific culture change scenarios and observed whether there were differences by occupation. We conducted a cross-sectional survey of 218 staff members in all occupational categories at four Veterans Health Administration Community Living Centers (i.e., nursing homes). Staff indicated their comfort level using a 9-point scale (1 = not at all comfortable to 9 = extremely comfortable). The culture change scenarios were divided into three subscales: Resident Safety (5 items), Resident Experience (5 items), and Staff Experience (2 items). Overall, respondents were slightly uncomfortable with the scenarios (overall mean = 4.57). Staff reported least comfort with the Resident Safety subscale (mean = 3.63) and most comfort with the Resident Experience subscale (mean = 5.65), with significant differences within these two subscales by occupational category. Existent power differentials among staff may influence comfort levels with culture change. Assessing staff comfort with culture change may help guide implementation efforts in a strategic manner. C1 [Palmer, Jennifer A.; Zhao, Shibei; Berlowitz, Dan; Mobley, Esther; Hartmann, Christine W.] Edith Nourse Rogers Mem Vet Adm Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA 01730 USA. [Meterko, Mark] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. RP Palmer, JA (reprint author), Edith Nourse Rogers Mem Vet Adm Hosp, 200 Springs Rd, Bedford, MA 01730 USA. EM Jennifer.Palmer1@va.gov FU U.S. Department of Veterans Affairs, Veterans Health Administration, Health Services Research & Development Service Career Development Award [CDA08-008-2] FX The authors have disclosed no potential conflicts of interest, financial or otherwise. This work was supported by a U.S. Department of Veterans Affairs, Veterans Health Administration, Health Services Research & Development Service Career Development Award (CDA08-008-2 to C.W.H.). The supporting source had no role in study design; in collection, analysis, or interpretation of data; in writing the report; or in the decision to submit the report for publication. The opinions expressed in this article do not necessarily represent the official views of the U.S. Department of Veterans Affairs. NR 46 TC 1 Z9 1 U1 1 U2 10 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1940-4921 EI 1938-2464 J9 RES GERONTOL NURS JI Res. Gerontol. Nurs. PD JUL PY 2013 VL 6 IS 3 BP 152 EP 160 DI 10.3928/19404921-20130610-01 PG 9 WC Nursing SC Nursing GA 268WR UT WOS:000328201900002 PM 23777296 ER PT J AU Borsook, D Becerra, L Fava, M AF Borsook, D. Becerra, L. Fava, M. TI Use of functional imaging across clinical phases in CNS drug development SO TRANSLATIONAL PSYCHIATRY LA English DT Review ID DISEASE-MODIFYING THERAPIES; MILD COGNITIVE IMPAIRMENT; MEDIAL PREFRONTAL CORTEX; SURROGATE END-POINTS; ALZHEIMERS-DISEASE; PLACEBO-RESPONSE; HEALTHY-VOLUNTEERS; MAJOR DEPRESSION; DOUBLE-BLIND; NEUROPATHIC PAIN AB The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I-IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase Ill trials and provide insights into disease modification in phase IV trials. C1 [Borsook, D.; Becerra, L.] Harvard Univ, Childrens Hosp, Sch Med, Ctr Pain & Brain,MGH, Boston, MA 02115 USA. [Borsook, D.; Becerra, L.] Harvard Univ, Sch Med, McLean Hosp, Ctr Pain & Brain,MGH, Boston, MA USA. [Borsook, D.; Becerra, L.] Massachusetts Gen Hosp, Dept Psychiat, Clin Trials & Network Inst CTNI, Boston, MA 02114 USA. [Borsook, D.; Becerra, L.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Anesthesia & Crit Care,PAIN Grp,MGH, Waltham, MA 02453 USA. [Borsook, D.; Becerra, L.; Fava, M.] Harvard Univ, Sch Med, Dept Psychiat, MGH, Boston, MA 02115 USA. [Borsook, D.; Becerra, L.] Harvard Univ, Sch Med, Dept Radiol, MGH, Boston, MA 02115 USA. RP Borsook, D (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Anesthesia & Crit Care,PAIN Grp,MGH, 9 Hope Ave, Waltham, MA 02453 USA. EM david.borsook@childrens.harvard.edu FU Herland's Fund for Pain Research FX This study was supported by the Herland's Fund for Pain Research. NR 126 TC 11 Z9 12 U1 4 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD JUL PY 2013 VL 3 AR e282 DI 10.1038/tp.2013.43 PG 19 WC Psychiatry SC Psychiatry GA 258OA UT WOS:000327467400007 PM 23860483 ER PT J AU Katz, IR Kemp, JE Blow, FC McCarthy, JF Bossarte, RM AF Katz, Ira R. Kemp, Janet E. Blow, Frederic C. McCarthy, John F. Bossarte, Robert M. TI Changes in Suicide Rates and in Mental Health Staffing in the Veterans Health Administration, 2005-2009 SO PSYCHIATRIC SERVICES LA English DT Article ID SYSTEM; RISK; MORTALITY AB Objective: Between 2005 and 2009, the Veterans Health Administration (VHA) enhanced its mental health programs and increased outpatient mental health staffing by 52.8%. However, suicide rates among VHA patients remained the same. This study evaluated this finding by examining variability in staffing increases between VHA's 21 regional networks (Veterans Integrated Service Networks) (VISNs) and associations with suicide rates. Methods: Suicide rates among VHA patients were derived from the National Death Index and VHA clinical and administrative records for 2005 and 2009. Comparisons across VISNs used measures of proportional change in mental health staffing (overall and in inpatient, residential, intensive case management, and outpatient programs) and comparable measures of mental health staffing per 1,000 mental health patients. Results: Significant correlations were found between proportional changes from 2005 to 2009 in suicide rates and outpatient mental health staffing (r=-.453, p=.039) and outpatient mental health staffing per 1,000 patients (r=-.533, p=.013). The ten VISNs above the median in proportional changes in mental health staffing had average decreases in suicide rates of 12.6% while those below had increases of 11.6% (p=.005). For proportional changes in mental health staffing per 1,000 patients, those above the median had decreases of 11.2% and those below had increases of 13.8%(p=.014). For the average VISN, it would have required a 27.5%-36.8% increase in outpatient staff over 2005 levels to decrease suicide rates by 10%. Conclusions: Mental health enhancements in VHA were associated with decreases in suicide rates in VISNs where the increases in mental health outpatient staffing were greatest. C1 [Katz, Ira R.] US Dept Vet Affairs VA, Off Mental Hlth Operat, Philadelphia, PA USA. [Katz, Ira R.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Kemp, Janet E.] VA Cent Off, Off Suicide Prevent, Off Mental Hlth Serv, Washington, DC USA. [Blow, Frederic C.; McCarthy, John F.] VA Med Ctr, Serious Mental Illness Treatment Resource & Evalu, Ann Arbor, MI USA. [Blow, Frederic C.; McCarthy, John F.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Bossarte, Robert M.] VA Med Ctr, Ctr Excellence, Canandaigua, NY USA. [Bossarte, Robert M.] Univ Rochester, Dept Psychiat, Rochester, NY USA. RP Katz, IR (reprint author), Philadelphia VA Med Ctr, Univ & Woodland Ave, Philadelphia, PA 19104 USA. EM ira.katz2@va.gov FU Office of Mental Health Operations; Office of Suicide Prevention of the VHA FX Support was provided by the Office of Mental Health Operations and the Office of Suicide Prevention of the VHA. Data for this report were acquired and analyses were conducted by the VHA for evaluation of its mental health and suicide prevention programs. NR 18 TC 5 Z9 6 U1 3 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JUL PY 2013 VL 64 IS 7 BP 620 EP 625 DI 10.1176/appi.ps.201200253 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 255XW UT WOS:000327274400005 PM 23494171 ER PT J AU Weiss, A Schechter, M Chang, G AF Weiss, Anthony Schechter, Mark Chang, Grace TI Case Management for Frequent Emergency Department Users SO PSYCHIATRIC SERVICES LA English DT Letter C1 [Weiss, Anthony] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Weiss, Anthony; Chang, Grace] Partners Psychiat & Mental Hlth, Boston, MA USA. [Schechter, Mark] North Shore Med Ctr, Salem, MA USA. [Schechter, Mark] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Chang, Grace] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. RP Weiss, A (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. FU NIAAA NIH HHS [K24 AA00289] NR 5 TC 3 Z9 3 U1 1 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JUL PY 2013 VL 64 IS 7 BP 715 EP 716 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 255XW UT WOS:000327274400023 PM 23821178 ER PT J AU Snow, JW Hale, AE Isaacs, SK Baggish, AL Chan, SY AF Snow, Jonathan W. Hale, Andrew E. Isaacs, Stephanie K. Baggish, Aaron L. Chan, Stephen Y. TI Ineffective delivery of diet-derived microRNAs to recipient animal organisms SO RNA BIOLOGY LA English DT Article ID ENDOTHELIAL-CELL MIGRATION; SYSTEMIC RNA-INTERFERENCE; CROSS-KINGDOM REGULATION; GENE-EXPRESSION; INGESTION; EXOSOMES; MIRNAS; TISSUE; COMMUNICATION; MECHANISMS C1 [Snow, Jonathan W.] Columbia Univ Barnard Coll, Dept Biol, New York, NY 10027 USA. [Hale, Andrew E.; Chan, Stephen Y.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Isaacs, Stephanie K.; Baggish, Aaron L.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Chan, SY (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. EM sychan@partners.org FU National Institutes of Health [K08HL096834]; Lerner Foundation; Harris Foundation; Radovsky-McArthur Foundation; Watkins Foundation; Gilead Sciences (Gilead Research Scholars Fund); Pulmonary Hypertension Association FX We thank Dr SK Chan (critical advice and reading of manuscript) and S. Tribuna (administrative assistance). This work was supported by the National Institutes of Health (K08HL096834 to SYC); the Lerner, Harris, Radovsky-McArthur and Watkins Foundations (S.Y.C.); Gilead Sciences (Gilead Research Scholars Fund to SYC) and the Pulmonary Hypertension Association (SYC). NR 66 TC 59 Z9 61 U1 3 U2 22 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD JUL 1 PY 2013 VL 10 IS 7 BP 1107 EP 1116 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 260CJ UT WOS:000327572300009 PM 23669076 ER PT J AU Lebreton, F van Schaik, W McGuire, AM Godfrey, P Griggs, A Mazumdar, V Corander, J Cheng, L Saif, S Young, S Zeng, QD Wortman, J Birren, B Willems, RJL Earl, AM Gilmore, MS AF Lebreton, Francois van Schaik, Willem McGuire, Abigail Manson Godfrey, Paul Griggs, Allison Mazumdar, Varun Corander, Jukka Cheng, Lu Saif, Sakina Young, Sarah Zeng, Qiandong Wortman, Jennifer Birren, Bruce Willems, Rob J. L. Earl, Ashlee M. Gilmore, Michael S. TI Emergence of Epidemic Multidrug-Resistant Enterococcus faecium from Animal and Commensal Strains SO MBIO LA English DT Article ID STAPHYLOCOCCUS-AUREUS; ANTIMICROBIAL RESISTANCE; MUTATION FREQUENCIES; NOSOCOMIAL PATHOGEN; GENOME SEQUENCE; GLOBAL SPREAD; AVOPARCIN; RECOMBINATION; POPULATION; IDENTIFICATION AB Enterococcus faecium, natively a gut commensal organism, emerged as a leading cause of multidrug-resistant hospital-acquired infection in the 1980s. As the living record of its adaptation to changes in habitat, we sequenced the genomes of 51 strains, isolated from various ecological environments, to understand how E. faecium emerged as a leading hospital pathogen. Because of the scale and diversity of the sampled strains, we were able to resolve the lineage responsible for epidemic, multidrug-resistant human infection from other strains and to measure the evolutionary distances between groups. We found that the epidemic hospital-adapted lineage is rapidly evolving and emerged approximately 75 years ago, concomitant with the introduction of antibiotics, from a population that included the majority of animal strains, and not from human commensal lines. We further found that the lineage that included most strains of animal origin diverged from the main human commensal line approximately 3,000 years ago, a time that corresponds to increasing urbanization of humans, development of hygienic practices, and domestication of animals, which we speculate contributed to their ecological separation. Each bifurcation was accompanied by the acquisition of new metabolic capabilities and colonization traits on mobile elements and the loss of function and genome remodeling associated with mobile element insertion and movement. As a result, diversity within the species, in terms of sequence divergence as well as gene content, spans a range usually associated with speciation. IMPORTANCE Enterococci, in particular vancomycin-resistant Enterococcus faecium, recently emerged as a leading cause of hospital-acquired infection worldwide. In this study, we examined genome sequence data to understand the bacterial adaptations that accompanied this transformation from microbes that existed for eons as members of host microbiota. We observed changes in the genomes that paralleled changes in human behavior. An initial bifurcation within the species appears to have occurred at a time that corresponds to the urbanization of humans and domestication of animals, and a more recent bifurcation parallels the introduction of antibiotics in medicine and agriculture. In response to the opportunity to fill niches associated with changes in human activity, a rapidly evolving lineage emerged, a lineage responsible for the vast majority of multidrug-resistant E. faecium infections. C1 [Lebreton, Francois; van Schaik, Willem; Gilmore, Michael S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. [Lebreton, Francois; van Schaik, Willem; Gilmore, Michael S.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Lebreton, Francois; van Schaik, Willem; McGuire, Abigail Manson; Godfrey, Paul; Griggs, Allison; Mazumdar, Varun; Saif, Sakina; Young, Sarah; Zeng, Qiandong; Wortman, Jennifer; Birren, Bruce; Earl, Ashlee M.; Gilmore, Michael S.] Broad Inst, Cambridge, MA USA. [van Schaik, Willem; Willems, Rob J. L.] Univ Med Ctr Utrecht, Dept Med Microbiol, Utrecht, Netherlands. [Corander, Jukka; Cheng, Lu] Univ Helsinki, Dept Math & Stat, Helsinki, Finland. RP Gilmore, MS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. EM michael_gilmore@meei.harvard.edu RI Manson, Abigail/B-7132-2016; Willems, Rob/E-3681-2010; OI Manson, Abigail/0000-0002-3800-0714; Wortman, Jennifer/0000-0002-8713-1227 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900018C]; NIH/NIAID [AI083214, AI072360]; European Union [282004] FX This project was funded in part by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract HHSN272200900018C. Portions of this work were also supported by NIH/NIAID grants AI083214 (Harvardwide Program on Antibiotic Resistance), and AI072360. W. V. S. and R.J.L.W. were supported by the European Union Seventh Framework Programme (FP7-HEALTH-2011-single-stage) "Evolution and Transfer of Antibiotic Resistance" (EvoTAR) under grant agreement number 282004. NR 61 TC 52 Z9 52 U1 4 U2 24 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2013 VL 4 IS 4 AR e00534-13 DI 10.1128/mBio.00534-13 PG 10 WC Microbiology SC Microbiology GA 250UK UT WOS:000326881100054 ER PT J AU Mirzakhani, H Nozari, A Ehrenfeld, JM Peterfreund, R Szabo, M Walsh, JL Jiang, YD Sandberg, W Rosow, C Wang, J AF Mirzakhani, Hooman Nozari, Ala Ehrenfeld, Jesse M. Peterfreund, Robert Szabo, Michele Walsh, John L. Jiang, Yandong Sandberg, Warren Rosow, Carl Wang, Jingping TI Profound Hypotension After Anesthetic Induction with Propofol in Patients Treated with Rifampin SO ANESTHESIA AND ANALGESIA LA English DT Article ID BLOOD; INFECTIONS; MECHANISMS; SURGERY; SHOCK AB Rifampin is commonly used for the treatment of tuberculosis and staphylococcal infections, as well as for prevention of infection in cardiac valve and bone surgeries. We report a case of profound hypotension after anesthesia induction with propofol in a patient who was treated with two 600 mg doses of rifampin for prophylaxis of infection before surgery. In a retrospective case-control study of 75 patients, we confirmed this potentially serious drug-drug interaction. After rifampin, there was a significant and prolonged arterial blood pressure reduction when patients received propofol, but not thiopental. (Anesth Analg 2013;117:61-4) C1 [Mirzakhani, Hooman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Broad Inst MIT & Harvard,Dept Anesthesia & Crit C, Boston, MA USA. [Nozari, Ala; Peterfreund, Robert; Szabo, Michele; Walsh, John L.; Jiang, Yandong; Rosow, Carl; Wang, Jingping] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. [Ehrenfeld, Jesse M.; Sandberg, Warren] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37212 USA. RP Nozari, A (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, GRJ-4-416,55 Fruit St, Boston, MA 02114 USA. EM anozari@partners.org OI Ehrenfeld, Jesse/0000-0003-3427-0140; Mirzakhani, Hooman/0000-0002-2290-4436; Sandberg, Warren/0000-0002-9246-777X NR 21 TC 0 Z9 0 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD JUL PY 2013 VL 117 IS 1 BP 61 EP 64 DI 10.1213/ANE.0b013e318292cbd0 PG 4 WC Anesthesiology SC Anesthesiology GA 246BV UT WOS:000326512300010 PM 23687230 ER PT J AU Felsenfeld, A Rodriguez, M Levine, B AF Felsenfeld, Arnold Rodriguez, Mariano Levine, Burton TI New insights in regulation of calcium homeostasis SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE calcium; calcium sensing receptor; hypercalcemia; hypocalcemia; parathyroid hormone ID SENSING RECEPTOR GENE; PARATHYROID-HORMONE; AZOTEMIC RATS; PHOSPHATE; DISEASE; KIDNEY; GROWTH; PTH; HYPERPARATHYROIDISM; PHOSPHORUS AB Purpose of reviewRegulation of calcium homeostasis during a lifetime is a complex process reflecting a balance among intestinal calcium absorption, bone calcium influx and efflux, and renal calcium excretion. Perturbations can result in hypocalcemia or hypercalcemia and adaptations in calcium handling must occur during growth and aging.Recent findingsStudy of the calcium sensing receptor in the thick ascending limb of Henle and TRPV5 in the distal tubule continues to provide insights into regulation of renal calcium excretion. Hypercalcemia-induced secretion of calcitonin via activation of the calcium-sensing receptor may protect against the development of hypercalcemia. A calcilytic was shown to increase serum calcium by decreasing renal calcium excretion. Ezrin, a cross-linking protein important for renal phosphate handling, is also involved in the regulation of intestinal calcium absorption. Increased 1,25-hydroxyvitamin D (1,25D) values were shown to protect against the development of hypocalcemia by increasing calcium efflux and decreasing calcium influx in bone. Finally, fibroblast growth factor 23 stimulation, which should result in suppression of 1,25D, was shown to be prevented in a model of vitamin D deficiency in which maintenance of 1,25D is important in minimizing hypocalcemia.SummaryRecent information has provided new insights on how intestinal, bone and renal mechanisms are regulated to maintain calcium homeostasis. C1 [Felsenfeld, Arnold; Levine, Burton] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Felsenfeld, Arnold; Levine, Burton] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rodriguez, Mariano] Hosp Univ Reina Sofia, IMIBIC, REDINREN, Serv Nefrol, Cordoba 14004, Spain. RP Rodriguez, M (reprint author), Hosp Univ Reina Sofia, Lab Unidad Invest Imib, Avd Menendez Pidal S-N, Cordoba 14004, Spain. EM marianorodriguezportillo@gmail.com FU Syskid grant; Government grant [SAS111221, CTS-5205, CVI/7925, PI11/02055] FX Part of the work was sponsored by Syskid and Government grants (SAS111221; CTS-5205; CVI/7925 and PI11/02055). NR 32 TC 11 Z9 11 U1 3 U2 42 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2013 VL 22 IS 4 BP 371 EP 376 DI 10.1097/MNH.0b013e328362141e PG 6 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 247BJ UT WOS:000326588200002 PM 23736839 ER PT J AU Bhan, I Tamez, H Thadhani, R AF Bhan, Ishir Tamez, Hector Thadhani, Ravi TI Impact of new vitamin D data on future studies and treatment SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE cardiovascular disease; chronic kidney disease; immunity; vitamin D ID CHRONIC KIDNEY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; HIGH-DOSE CHOLECALCIFEROL; PLACEBO-CONTROLLED TRIAL; HEMODIALYSIS-PATIENTS; ORAL CALCITRIOL; MORTALITY; SURVIVAL; SUPPLEMENTATION; PARICALCITOL AB Purpose of reviewThis review evaluates recently published data on clinical effects of vitamin D supplementation, focusing on randomized, placebo-controlled trials and nontraditional actions on the cardiovascular and immune systems.Recent findingsSeveral randomized trials evaluating vitamin D therapy have recently emerged, in both the general population and in individuals with chronic kidney disease (CKD). In the former, measurable effects on cardiovascular risk factors have not been detected, with the possible exception of a modest reduction in blood pressure. Studies aimed at boosting immunity have demonstrated efficacy only in specific, high-risk populations. In CKD, the benefits of nutritional vitamin D appear largely limited to earlier stages of disease. Benefits of active vitamin D agents, outside of their known effects on mineral metabolism, have also thus far eluded detection. One possible exception that has accumulated supportive evidence is the link between active vitamin D analogs and decreased proteinuria. Large-scale clinical trials, now underway, will be critical to understanding of the potential benefits and hazards of vitamin D treatment.SummaryNew trials evaluating the effects of vitamin D supplementation have failed to reveal any robust clinical benefits beyond its known actions on mineral and bone disease. C1 [Bhan, Ishir; Tamez, Hector; Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Bhan, I (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM ibhan@partners.org FU Abbott Laboratories FX R.I.T. has a research grant from Abbott Laboratories and is a consultant to Fresenius Medical Care North America and Diasorin. I.B. and H.T. have no conflicts of interest. NR 32 TC 2 Z9 2 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2013 VL 22 IS 4 BP 377 EP 382 DI 10.1097/MNH.0b013e3283621408 PG 6 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 247BJ UT WOS:000326588200003 PM 23666416 ER PT J AU Le, H Wong, S Iftikar, T Keenan, H King, GL Hsu, WC AF Le, Hung Wong, Sophia Iftikar, Tracy Keenan, Hillary King, George L. Hsu, William C. TI Characterization of Factors Affecting Attainment of Glycemic Control in Asian Americans With Diabetes in a Culturally Specific Program SO DIABETES EDUCATOR LA English DT Article ID ETHNIC-DIFFERENCES; PACIFIC ISLANDERS; NATIVE HAWAIIANS; CARE; KNOWLEDGE; BARRIERS AB Purpose The purpose of this study is to examine the effectiveness of a culturally specific pilot clinic for Asian Americans (AA) in reaching glycemic target and to characterize factors affecting the attainment of glycemic control in comparison with white counterparts. Methods This electronic health record review included all new AA patients with type 2 diabetes (n = 109) in a culturally specific program and a randomly selected sample of new white patients with type 2 diabetes (n = 218) in the adult clinic within the same time period and diabetes center. Results AA and whites had a comparable proportion of patients with A1C 7% (32.1%, 34.9%; P = .621) at baseline and after 12 months of care (48.6%, 56.0%; P = .210), with a similar A1C decline (-0.9% 1.6%, -0.8% +/- 1.7%, P = .710) by 12 months. Factors associated with the lack of success in reaching target in AA but not in whites included older age, lower educational attainment, less likelihood of having health insurance, and a need for more educational visits. The percentage of AA reaching A1C 7%, as compared to whites, worsened among those with highest initial A1C when stratified by ascending quartiles (96.7% vs 85.2%, P = .101; 61.9% vs 58.9%, P = .813; 24.0% vs 37.7%, P = .230; 15.2% vs 35.4%, P = .044). Conclusion While a culturally specific diabetes program in a specialty setting achieved a similar glycemic outcome for AA compared with whites, reasons for not reaching glycemic target differed. The findings suggest that the elimination of diabetes disparities requires not only culturally and linguistically specific programs, but must also identify and address the socio-environmental differences unique to each population. C1 [Le, Hung; Wong, Sophia; Iftikar, Tracy; King, George L.; Hsu, William C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Asian Amer Diabet Initiat, Boston, MA 02115 USA. [Keenan, Hillary; King, George L.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dianne Nunnally Hoppes Lab Diabet Complicat, Boston, MA 02115 USA. RP Hsu, WC (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM William.Hsu@joslin.harvard.edu FU NIDDK NIH HHS [P30 DK036836] NR 31 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 EI 1554-6063 J9 DIABETES EDUCATOR JI Diabetes Educ. PD JUL PY 2013 VL 39 IS 4 BP 452 EP 461 DI 10.1177/0145721713492217 PG 10 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA 245EE UT WOS:000326442300005 PM 23771841 ER PT J AU Beverly, EA Fitzgerald, SM Brooks, KM Hultgren, BA Ganda, OP Munshi, M Weinger, K AF Beverly, Elizabeth A. Fitzgerald, Shane M. Brooks, Kelly M. Hultgren, Brittney A. Ganda, Om P. Munshi, Medha Weinger, Katie TI Impact of Reinforcement of Diabetes Self-Care on Poorly Controlled Diabetes A Randomized Controlled Trial SO DIABETES EDUCATOR LA English DT Article ID QUALITY-OF-LIFE; GLYCEMIC CONTROL; COMPLICATIONS TRIAL; INTENSIVE TREATMENT; PROBLEM AREAS; ADULTS; INTERVENTIONS; IMPLEMENTATION; QUESTIONNAIRE; METAANALYSIS AB Purpose The purpose of the study was to assess the value of reinforcing diabetes self-management for improving glycemia and self-care among adults with type 2 diabetes who had at least 3 hours of prior diabetes education. Methods In this randomized controlled trial, 134 participants (75% white, 51% female, 59 9 years old, 13 8 years with diabetes, A1C = 8.4% +/- 1.2%) were randomized to either a group map-based program (intervention) or group education on cholesterol and blood pressure (control). Participants were assessed for A1C levels, diabetes self-care behaviors (3-day pedometer readings, 6-minute walk test, blood glucose checks, frequency of self-care), and psychosocial factors (distress, frustration, quality of life) at baseline, 3, 6, and 12 months post intervention and health literacy at baseline. Results Groups did not differ on baseline characteristics including A1C levels, health literacy, or self-care; however, the intervention group had more years of education than controls. Intervention arm participants modestly improved A1C levels at 3 months post intervention but did not maintain that improvement at 6 and 12 months while control patients did not improve A1C levels at any time during follow-up. Importantly, frequency of self-reported self-care, diabetes quality of life, diabetes-related distress, and frustration with diabetes self-care improved in both groups over time. Conclusions Reinforcing self-care with diabetes education for patients who have not met glycemic targets helps improve A1C and could be considered a necessary component of ongoing diabetes care. The best method to accomplish reinforcement needs to be established. C1 [Beverly, Elizabeth A.; Fitzgerald, Shane M.; Brooks, Kelly M.; Hultgren, Brittney A.; Ganda, Om P.; Munshi, Medha; Weinger, Katie] Joslin Diabet Ctr, Boston, MA 02215 USA. [Beverly, Elizabeth A.; Ganda, Om P.; Munshi, Medha; Weinger, Katie] Harvard Univ, Sch Med, Boston, MA USA. RP Weinger, K (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM Katie.Weinger@joslin.harvard.edu FU American Diabetes Association (ADA) [7-08-CR-62]; Diabetes and Endocrinology Research Core NIH [P30 DK36836]; NIH [T32 DK007260] FX This work was supported by the American Diabetes Association (ADA) grant 7-08-CR-62, the Diabetes and Endocrinology Research Core NIH P30 DK36836, and the NIH Training Grant No. T32 DK007260. Bayer HealthCare LLC (Tarrytown, New York) contributed glucose meters and test strips. ADA and these companies had no role in the conduct of the study or preparation of this manuscript.. NR 40 TC 9 Z9 9 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 EI 1554-6063 J9 DIABETES EDUCATOR JI Diabetes Educ. PD JUL PY 2013 VL 39 IS 4 BP 504 EP 514 DI 10.1177/0145721713486837 PG 11 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA 245EE UT WOS:000326442300008 PM 23640303 ER PT J AU Broyles, LM Kraemer, KL Kengor, C Gordon, AJ AF Broyles, Lauren M. Kraemer, Kevin L. Kengor, Caroline Gordon, Adam J. TI A Tailored Curriculum of Alcohol Screening, Brief Intervention, and Referral to Treatment (SBIRT) for Nurses in Inpatient Settings SO JOURNAL OF ADDICTIONS NURSING LA English DT Article DE alcohol consumption; continuing education; counseling; curricula; inpatients; nurses; screening; training ID EMERGENCY-DEPARTMENT; SUBSTANCE USE; IMPLEMENTATION; CARE; DRINKERS; DRINKING; PROGRAM AB A package of clinical strategies known as alcohol screening, brief intervention, and referral to treatment (SBIRT) is increasingly recommended for reducing unhealthy alcohol use, the spectrum of alcohol consumption from at-risk drinking (defined as consumption above recommended guidelines) to alcohol abuse and alcohol dependence. The United States' Joint Commission issued new SBIRT-related hospital accreditation measures for alcohol. Ongoing initiatives aim to promote, support, and sustain SBIRT implementation in hospital settings. In hospital settings, nurse-delivered SBIRT may be a particularly viable and efficient model for SBIRT implementation. However, like physicians, most nurses have not been trained in how to perform SBIRT, and few authors have described alcohol-related curricula specifically for nurses. In addition, historical differences in nurse and physician professional scopes of practice, role perceptions, and patterns of care delivery suggest the need for effective SBIRT initial and continuing education and training that are tailored to the nursing profession and inpatient environments. In this article, we provide an in-depth description of the registered nurse SBIRT curriculum and describe its development and contents as well as various nurse-and setting-specific adaptations. In addition, we describe how we engaged nursing stakeholders in the development and implementation of the curriculum and discuss potential implications for future SBIRT training and delivery by nurses. SBIRT continuing education and training for nurses represents one of the first steps in expanded SBIRT implementation. Comprehensive workforce and organizational development of inpatient and nurse-delivered SBIRT may provide the means to address the entire spectrum of unhealthy alcohol use across healthcare settings. C1 [Broyles, Lauren M.; Gordon, Adam J.] Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Broyles, Lauren M.; Gordon, Adam J.] Univ Pittsburgh, Vet Integrated Serv, Network Mental Illness 4, Res Educ & Clin Ctr,VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Broyles, Lauren M.; Kraemer, Kevin L.; Gordon, Adam J.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Broyles, Lauren M.; Kraemer, Kevin L.; Gordon, Adam J.] Univ Pittsburgh, Ctr Res Hlth Care, Pittsburgh, PA USA. [Kengor, Caroline] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. RP Broyles, LM (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr,Bldg 2,Rm 4020W 151C H, Pittsburgh, PA 15206 USA. EM lauren.broyles@va.gov FU VA Quality Enhancement Research Initiative Program [RRP 09-064]; Health Services Research & Development service of the U.S. Department of Veterans Affairs [CDA 10-014] FX We acknowledge the staff nurses and nursing administrators from the five West patient care units and the nursing leadership at the VA Pittsburgh Healthcare System (VAPHS) for their support and participation in the study. We also extend acknowledgment to Mr. Scott Guido, audio visual production specialist, and the medical media department at VAPHS for their assistance in the development of audiovisual materials for this curriculum. Funding for this study was provided by VA Quality Enhancement Research Initiative Program (RRP 09-064, Principal Investigator, L. M. Broyles). The funding body played no role in the design; data collection, analysis, and interpretation of the data; the writing of the manuscript; nor the decision to submit the manuscript for publication. Dr. Broyles is currently supported by a Career Development Award (CDA 10-014) from the Health Services Research & Development service of the U.S. Department of Veterans Affairs. The material is the result of work supported with resources and the use of facilities at the VAPHS, Pittsburgh, PA. 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. NR 68 TC 3 Z9 3 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1088-4602 EI 1548-7148 J9 J ADDICT NURS JI J. Addict. Nurs. PD JUL-SEP PY 2013 VL 24 IS 3 BP 130 EP 141 DI 10.1097/JAN.0b013e3182a4cb0b PG 12 WC Substance Abuse; Nursing SC Substance Abuse; Nursing GA 245YE UT WOS:000326500000002 PM 24621542 ER PT J AU Strobbe, S Perhats, C Broyles, LM AF Strobbe, Stephen Perhats, Cydne Broyles, Lauren M. TI Expanded Roles and Responsibilities for Nurses in Screening, Brief Intervention, and Referral to Treatment (SBIRT) for Alcohol Use SO JOURNAL OF ADDICTIONS NURSING LA English DT Editorial Material DE alcohol; brief intervention; nurses; referral to treatment; SBIRT; screening AB It is the position of the International Nurses Society on Addictions and the Emergency Nurses Association that nurses in all practice settings be prepared to deliver screening, brief intervention, and referral to treatment, or SBIRT, to identify and effectively respond to alcohol use and related disorders across the lifespan. C1 [Strobbe, Stephen] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. [Strobbe, Stephen] Int Nurses Soc Addict, Lenexa, KS USA. [Perhats, Cydne] Emergency Nurses Assoc, Inst Emergency Nursing Res, Des Plaines, IL USA. [Broyles, Lauren M.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Broyles, Lauren M.] Univ Pittsburgh, Pittsburgh, PA USA. RP Strobbe, S (reprint author), Univ Michigan, Sch Nursing, 400 North Ingalls St, Ann Arbor, MI 48109 USA. EM strobbe@umich.edu NR 10 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1088-4602 EI 1548-7148 J9 J ADDICT NURS JI J. Addict. Nurs. PD JUL-SEP PY 2013 VL 24 IS 3 BP 203 EP 204 DI 10.1097/JAN.0b013e3182a6914f PG 2 WC Substance Abuse; Nursing SC Substance Abuse; Nursing GA 245YE UT WOS:000326500000014 PM 24621553 ER PT J AU Ho, JE Larson, MG Ghorbani, A Cheng, S Vasan, RS Wang, TJ Januzzi, JL AF Ho, Jennifer E. Larson, Martin G. Ghorbani, Anahita Cheng, Susan Vasan, Ramachandran S. Wang, Thomas J. Januzzi, James L., Jr. TI Soluble ST2 predicts elevated SBP in the community SO JOURNAL OF HYPERTENSION LA English DT Article DE biological markers; blood pressure; epidemiology; hypertension; immune system; risk factors ID FAMILY-MEMBER ST2; DECOMPENSATED HEART-FAILURE; MYOCARDIAL-INFARCTION; ENDOTHELIAL-CELLS; NATRIURETIC PEPTIDE; CARDIAC STRUCTURE; ACUTE DYSPNEA; SERUM-LEVELS; T-CELLS; IL-33 AB Background:Soluble ST2 (sST2) is an emerging prognostic biomarker in patients with existing cardiovascular disease. ST2 and its ligand, interleukin-33 (IL-33), are expressed in endothelial cells, and may play an important role in the development of early atherosclerosis and vascular biology. We sought to investigate the association of sST2 and progression of blood pressure (BP), as well as the development of hypertension.Methods:Circulating sST2 concentrations were measured in 1834 participants (mean age 56 years, 57% women) of the community-based Framingham Offspring study. Participants were free of hypertension at baseline. Multivariable linear and logistic regression models were used to evaluate the association of sST2 concentrations and subsequent BP outcomes.Results:Higher sST2 concentrations were associated with incident hypertension over 3 years of follow-up [multivariable-adjusted odds ratio per 1 standard deviation increase in sST2 1.22, 95% confidence interval 1.05-1.42, P=0.01]. Individuals in the upper sST2 quartile had a 2.6mmHg greater increase in SBP compared with those in the lowest quartile (P for trend across quartiles 0.002) and a 1.8mmHg greater increase in pulse pressure (P for trend 0.005). In contrast, sST2 concentrations were not associated with changes in DBP (P=0.27).Conclusion:These findings suggest that sST2 concentrations predict changes in BP physiology typically seen with aging and progressive arterial stiffness. Further studies are needed to elucidate underlying mechanisms by which the ST2/IL-33 pathway may contribute to BP physiology. C1 [Ho, Jennifer E.; Larson, Martin G.; Cheng, Susan; Vasan, Ramachandran S.; Wang, Thomas J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Ho, Jennifer E.; Larson, Martin G.; Cheng, Susan; Vasan, Ramachandran S.; Wang, Thomas J.] Boston Univ, Sch Med, Framingham, MA USA. [Ho, Jennifer E.] Boston Univ, Dept Med, Cardiovasc Med Sect, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Ghorbani, Anahita; Wang, Thomas J.; Januzzi, James L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. [Cheng, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Cardiol, Boston, MA USA. [Vasan, Ramachandran S.; Januzzi, James L., Jr.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovascu Res Ctr,Dept Med, Boston, MA 02115 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5984,32 Fruit St, Boston, MA 02114 USA. EM jjanuzzi@partners.org OI Larson, Martin/0000-0002-9631-1254; Ho, Jennifer/0000-0002-7987-4768; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Heart Association; Ellison Foundation FX This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195). J.E.H. is supported by an American Heart Association Clinical Research Program award. S.C. is supported by an award from the Ellison Foundation. NR 40 TC 10 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD JUL PY 2013 VL 31 IS 7 BP 1431 EP 1436 DI 10.1097/HJH.0b013e3283611bdf PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 247DR UT WOS:000326595500013 PM 23615326 ER PT J AU Walker, WA Iyengar, R AF Walker, W. Allan Iyengar, Rajashri TI Stop Considering Atopic Dermatitis as an Allergic Disease Reply SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Letter ID MUTATIONS; FOOD C1 [Walker, W. Allan; Iyengar, Rajashri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Walker, WA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 EI 1536-4801 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD JUL PY 2013 VL 57 IS 1 DI 10.1097/MPG.0b013e3182923787 PG 2 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 248ZD UT WOS:000326744500011 PM 23961548 ER PT J AU Iverson, KM Dick, A McLaughlin, KA Smith, BN Bell, ME Gerber, MR Cook, N Mitchell, KS AF Iverson, Katherine M. Dick, Alexandra McLaughlin, Katie A. Smith, Brian N. Bell, Margret E. Gerber, Megan R. Cook, Natasha Mitchell, Karen S. TI Exposure to Interpersonal Violence and Its Associations With Psychiatric Morbidity in a US National Sample: A Gender Comparison SO PSYCHOLOGY OF VIOLENCE LA English DT Article DE crime victims; child abuse; parental violence; intimate partner violence; rape; prevalence; moderation; gender ID POSTTRAUMATIC-STRESS-DISORDER; COMORBIDITY SURVEY-REPLICATION; INTIMATE PARTNER VIOLENCE; COGNITIVE-PROCESSING THERAPY; MENTAL-HEALTH OUTCOMES; CHILDHOOD SEXUAL-ABUSE; DOMESTIC VIOLENCE; PHYSICAL HEALTH; PROLONGED EXPOSURE; NCS-R AB Objectives: We examine gender differences in population rates of various types of interpersonal violence in a U.S. national sample and investigate gender as a moderator of the associations between interpersonal violence and lifetime mental disorders and suicide attempts. Methods: Data were drawn from the National Comorbidity Survey-Replication study; 5,692 women and men completed interviews assessing lifetime exposure to nine types of interpersonal violence, Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) mental health diagnoses, and suicide attempts. Results: Approximately 46% of women and 42% of men reported one or more types of interpersonal violence. Women were more likely to experience kidnapping, physical assault by an intimate partner, rape, sexual assault, and stalking, whereas men were more likely to experience mugging or physical assault by someone other than parents or an intimate partner. Interpersonal violence was associated with risk for many mental disorders and attempted suicide. Although women were at higher risk for several forms of interpersonal violence, the impact of interpersonal violence on mental health outcomes did not vary by gender. Conclusions: It is clearly important to identify and provide mental health treatment to women after interpersonal violence exposure. Findings also underscore the need for prevention and intervention efforts for women and men, including routine screening for interpersonal violence by health care providers and appropriate treatment to address mental health conditions. C1 [Iverson, Katherine M.; Dick, Alexandra; Smith, Brian N.; Bell, Margret E.; Cook, Natasha; Mitchell, Karen S.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. [Iverson, Katherine M.] Boston Univ, Sch Med, Dept Psychol, Boston, MA 02215 USA. [McLaughlin, Katie A.] Boston Childrens Hosp, Dept Psychiat, Div Gen Pediat, Boston, MA USA. [McLaughlin, Katie A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Smith, Brian N.; Bell, Margret E.; Mitchell, Karen S.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Gerber, Megan R.] VA Boston Healthcare Syst, Womens Hlth, Boston, MA 02130 USA. [Gerber, Megan R.] Boston Univ, Sch Med, Dept Gen Internal Med, Boston, MA 02215 USA. RP Iverson, KM (reprint author), VA Boston Healthcare Syst, 150 South Huntington Ave 116B-3, Boston, MA 02130 USA. EM katherine.iverson@va.gov OI Gerber, Megan/0000-0002-8444-5554; McLaughlin, Katie/0000-0002-1362-2410 FU NIMH NIH HHS [K01 MH093750, K01 MH092526] NR 58 TC 17 Z9 17 U1 2 U2 19 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 2152-0828 EI 2152-081X J9 PSYCHOL VIOLENCE JI Psychol. Violence PD JUL PY 2013 VL 3 IS 3 BP 273 EP 287 DI 10.1037/a0030956 PG 15 WC Psychology, Clinical; Criminology & Penology; Family Studies SC Psychology; Criminology & Penology; Family Studies GA 246TU UT WOS:000326562800008 PM 25232484 ER PT J AU Horowitz, PM Chiocca, EA AF Horowitz, Peleg M. Chiocca, E. Antonio TI Nanotechnology-Based Strategies for the Diagnosis and Treatment of Intracranial Neoplasms SO WORLD NEUROSURGERY LA English DT Editorial Material DE CD20; Cell targeting; Nanomedicine; PCNSL; Theranostic ID BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; DRUG-DELIVERY; NANOPARTICLES; CELLS; MODEL C1 [Horowitz, Peleg M.; Chiocca, E. Antonio] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Horowitz, Peleg M.; Chiocca, E. Antonio] Brigham & Womens Faulkner Hosp, Inst Neurosci, Boston, MA USA. [Horowitz, Peleg M.; Chiocca, E. Antonio] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Horowitz, Peleg M.] Broad Inst MIT & Harvard, Boston, MA USA. RP Chiocca, EA (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM EAChiocca@partners.org OI Horowitz, Peleg/0000-0002-5177-1783 NR 18 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL-AUG PY 2013 VL 80 IS 1-2 BP 53 EP 55 DI 10.1016/j.wneu.2013.02.039 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 247VQ UT WOS:000326651100014 PM 23416779 ER PT J AU Maiwald, S Zwetsloot, PP Sivapalaratnam, S Dallinga-Thie, GM AF Maiwald, Stephanie Zwetsloot, Peter-Paul Sivapalaratnam, Suthesh Dallinga-Thie, Geesje M. TI Monocyte gene expression and coronary artery disease SO CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE LA English DT Review DE atherosclerosis; coronary artery disease; gene expression; monocytes ID DENSITY-LIPOPROTEIN CHOLESTEROL; PREDICT CARDIOVASCULAR EVENTS; ISCHEMIC-HEART-DISEASE; PERIPHERAL-BLOOD; PPAR-GAMMA; HYPERTENSIVE PATIENTS; OXIDATIVE STRESS; STATIN TREATMENT; FOS EXPRESSION; OXIDIZED LDL AB Purpose of reviewDespite current therapy, coronary artery disease (CAD) remains the major cause of morbidity and mortality worldwide. CAD is the consequence of a complex array of deranged metabolic processes including the immune system. In this context, monocytes and macrophages are indisputable players. Thus, monocyte gene expression analysis could be a powerful tool to provide new insights in the pathophysiology of CAD and improve identification of individuals at risk. We discuss current literature assessing monocyte gene expression and its association with CAD.Recent findingsMonocyte surface markers CD14(++) and CD16(+) have been established as biomarkers for increased cardiovascular disease risk in a large number of studies. More in-depth gene expression analysis identified several interesting genes, such as ABCA1, CD36 and MSR1 with an increased expression in circulating monocytes from patients with CAD. The results for CD36 were replicated in one other study. For ABCA1 and MSR1 conflicting data are published.SummaryRecent findings indicate that genetic differences exist in circulating monocytes of patients suffering from CAD, giving us more insights into the underlying mechanisms. However, larger studies are required to prove that monocytes' expression signature could serve as a marker for diagnostic purposes in the future. C1 [Maiwald, Stephanie; Sivapalaratnam, Suthesh; Dallinga-Thie, Geesje M.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Zwetsloot, Peter-Paul] Univ Med Ctr Utrecht, Dept Cardiol, Utrecht, Netherlands. [Zwetsloot, Peter-Paul] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Sivapalaratnam, Suthesh] Massachusetts Gen Hosp, Ctr Human Genom Res, Boston, MA 02114 USA. RP Sivapalaratnam, S (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM s.sivapalaratnam@amc.uva.nl FU NETSIM; ATHEROS FX S.M. is supported by a grant from NETSIM. S. S. is supported by a grant from ATHEROS. NR 63 TC 4 Z9 4 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1363-1950 EI 1473-6519 J9 CURR OPIN CLIN NUTR JI Curr. Opin. Clin. Nutr. Metab. Care PD JUL PY 2013 VL 16 IS 4 BP 411 EP 417 DI 10.1097/MCO.0b013e32836236f9 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 247AZ UT WOS:000326586600007 PM 23739627 ER PT J AU Wong, JC Hazrati, LN AF Wong, Janice C. Hazrati, Lili-Naz TI Parkinson's disease, parkinsonism, and traumatic brain injury SO CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES LA English DT Review DE Chronic traumatic encephalopathy; dementia pugilistica; movement disorder; neurodegeneration; neuropathology ID PERSISTENT VEGETATIVE STATE; LONG-TERM CONSEQUENCES; HEAD-INJURY; ALPHA-SYNUCLEIN; RISK-FACTORS; POSTTRAUMATIC PARKINSONISM; SUBSTANTIA-NIGRA; ENCEPHALOPATHY; VULNERABILITY; EPIDEMIOLOGY AB We review the relationship between traumatic brain injury (TBI) and the development of idiopathic Parkinson's disease (PD) or secondary parkinsonism. Limited by methodological issues such as recall bias and confounding risk factors, epidemiological studies on the association between TBI and idiopathic PD have so far yielded mixed results. While clinical reports describe parkinsonism - often with lesions in the substantia nigra - secondary to traumatic brain injury, these do not represent cases of idiopathic PD. In laboratory studies, animal models of traumatic brain injury demonstrate neuronal loss in the substantia nigra, altered dopaminergic metabolism, or altered synuclein pathology. While parkinsonism does occur secondary to TBI, the relationship between TBI and subsequent idiopathic PD remains controversial. C1 [Wong, Janice C.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Wong, Janice C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Wong, Janice C.] Harvard Univ, Sch Med, Boston, MA USA. [Hazrati, Lili-Naz] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 3H2, Canada. [Hazrati, Lili-Naz] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada. RP Hazrati, LN (reprint author), Univ Toronto, Tanz Ctr Res, Tanz Ctr Res Neurodegenerat Dis, 6 Queens Pk Crescent West, Toronto, ON M5S 3H2, Canada. EM lilinaz.hazrati@utoronto.ca NR 39 TC 7 Z9 7 U1 0 U2 25 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-8363 EI 1549-781X J9 CRIT REV CL LAB SCI JI Crit. Rev. Clin. Lab. Sci. PD JUL-OCT PY 2013 VL 50 IS 4-5 BP 103 EP 106 DI 10.3109/10408363.2013.844678 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 242LQ UT WOS:000326243800002 PM 24156652 ER PT J AU Feeney, MP Hunter, LL Kei, J Lilly, DJ Margolis, RH Nakajima, HH Neely, ST Prieve, BA Rosowski, JJ Sanford, CA Schairer, KS Shahnaz, N Stenfelt, S Voss, SE AF Feeney, M. Patrick Hunter, Lisa L. Kei, Joseph Lilly, David J. Margolis, Robert H. Nakajima, Hideko Heidi Neely, Stephen T. Prieve, Beth A. Rosowski, John J. Sanford, Chris A. Schairer, Kim S. Shahnaz, Navid Stenfelt, Stefan Voss, Susan E. TI Consensus Statement: Eriksholm Workshop on Wideband Absorbance Measures of the Middle Ear SO EAR AND HEARING LA English DT Article C1 [Feeney, M. Patrick; Lilly, David J.] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR 97239 USA. [Feeney, M. Patrick] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Hunter, Lisa L.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Kei, Joseph] Univ Queensland, Sch Hlth & Rehabil Sci, Hearing Res Unit Children, Brisbane, Qld 4072, Australia. Univ Minnesota, Dept Otolaryngol, Minneapolis, MN USA. [Margolis, Robert H.] Audiology Inc, Arden Hills, MN USA. [Nakajima, Hideko Heidi; Rosowski, John J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Nakajima, Hideko Heidi] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Neely, Stephen T.] Boys Town Natl Res Hosp, Omaha, NE 68131 USA. [Prieve, Beth A.] Syracuse Univ, Dept Commun Sci & Disorders, Syracuse, NY USA. [Sanford, Chris A.] Idaho State Univ, Dept Commun Sci & Disorders, Pocatello, ID 83209 USA. [Schairer, Kim S.] James H Quillen Vet Affairs Med Ctr, Audiol & Speech Language Pathol Serv, Mountain Home, TN USA. [Shahnaz, Navid] Univ British Columbia, Sch Audiol & Speech Sci, Vancouver, BC V5Z 1M9, Canada. [Stenfelt, Stefan] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Voss, Susan E.] Smith Coll, Picker Engn Program, Northampton, MA 01063 USA. RP Feeney, MP (reprint author), Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM patrick.feeney@va.gov OI Neely, Stephen/0000-0002-1349-5386; Stenfelt, Stefan/0000-0003-3350-8997 FU Oticon Foundation FX This article was based on discussions held at the Eriksholm Workshop on Wideband Absorbance Measures of the Middle Ear, for which support was provided by the Oticon Foundation. The content of this article does not represent the views of the Department of Veterans Affairs or of the U. S. Government. NR 2 TC 11 Z9 11 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JUL PY 2013 VL 34 SU 1 BP S78 EP S79 DI 10.1097/AUD.0b013e31829c726b PG 2 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 242XC UT WOS:000326278100014 PM 23900186 ER PT J AU Feeney, MP AF Feeney, M. Patrick TI Eriksholm Workshop on Wideband Absorbance Measures of the Middle Ear SO EAR AND HEARING LA English DT Editorial Material C1 [Feeney, M. Patrick] Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, Portland, OR 97239 USA. [Feeney, M. Patrick] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. RP Feeney, MP (reprint author), Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, NCRAR, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM patrick.feeney@va.gov NR 0 TC 0 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JUL PY 2013 VL 34 SU 1 BP S1 EP S2 DI 10.1097/AUD.0b013e31829c70f0 PG 2 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 242XC UT WOS:000326278100001 PM 23900175 ER PT J AU Lilly, DJ Margolis, RH AF Lilly, David J. Margolis, Robert H. TI Wideband Acoustic Immittance Measurements of the Middle Ear: Introduction and Some Historical Antecedents SO EAR AND HEARING LA English DT Article ID TYMPANOMETRY; IMPEDANCE; FREQUENCY; EFFUSION; INFANTS C1 [Lilly, David J.] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR USA. [Margolis, Robert H.] Audiology Inc, Arden Hills, MN USA. RP Lilly, DJ (reprint author), Vet Adm Med Ctr, 3710 SW VA Hosp Rd, Portland, OR 97207 USA. EM lillyd@ohsu.edu NR 25 TC 0 Z9 2 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JUL PY 2013 VL 34 SU 1 BP S4 EP S8 DI 10.1097/AUD.0b013e31829db80f PG 5 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 242XC UT WOS:000326278100003 PM 23900181 ER PT J AU Nakajima, HH Rosowski, JJ Shahnaz, N Voss, SE AF Nakajima, Hideko Heidi Rosowski, John J. Shahnaz, Navid Voss, Susan E. TI Assessment of Ear Disorders Using Power Reflectance SO EAR AND HEARING LA English DT Article ID TYMPANIC-MEMBRANE PERFORATIONS; HUMAN MIDDLE-EAR; CONDUCTIVE HEARING-LOSS; ENERGY REFLECTANCE; CANAL REFLECTANCE; SOUND-TRANSMISSION; OTOSCLEROTIC EARS; UMBO VELOCITY; TYMPANOMETRY; MECHANISMS C1 [Nakajima, Hideko Heidi; Rosowski, John J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Nakajima, Hideko Heidi; Rosowski, John J.] Massachusetts Eye & Ear Infirm, EPL, Boston, MA 02114 USA. [Shahnaz, Navid] Univ British Columbia, Sch Audiol & Speech Sci, Vancouver, BC V5Z 1M9, Canada. [Voss, Susan E.] Smith Coll, Picker Engn Program, Northampton, MA 01063 USA. RP Nakajima, HH (reprint author), Massachusetts Eye & Ear Infirm, EPL, 243 Charles St, Boston, MA 02114 USA. EM heidi_nakajima@meei.harvard.edu FU NIDCD NIH HHS [R01 DC004798, R03 DC011158] NR 19 TC 5 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JUL PY 2013 VL 34 SU 1 BP S48 EP S53 DI 10.1097/AUD.0b013e31829c964d PG 6 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 242XC UT WOS:000326278100009 PM 23900180 ER PT J AU Rosowski, JJ Stenfelt, S Lilly, D AF Rosowski, John J. Stenfelt, Stefan Lilly, David TI An Overview of Wideband Immittance Measurements Techniques and Terminology: You Say Absorbance, I Say Reflectance SO EAR AND HEARING LA English DT Article ID MIDDLE-EAR FUNCTION; ENERGY REFLECTANCE; IMPEDANCE; EARDRUM; COEFFICIENT; CATS C1 [Rosowski, John J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Rosowski, John J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Stenfelt, Stefan] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Lilly, David] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR USA. RP Rosowski, JJ (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM john_rosowski@meei.harvard.edu OI Stenfelt, Stefan/0000-0003-3350-8997 FU NIDCD NIH HHS [R01 DC004798] NR 35 TC 12 Z9 13 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JUL PY 2013 VL 34 SU 1 BP S9 EP S16 DI 10.1097/AUD.0b013e31829d5a14 PG 8 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 242XC UT WOS:000326278100004 PM 23900187 ER PT J AU Sanford, CA Hunter, LL Feeney, MP Nakajima, HH AF Sanford, Chris A. Hunter, Lisa L. Feeney, M. Patrick Nakajima, Hideko Heidi TI Wideband Acoustic Immittance: Tympanometric Measures SO EAR AND HEARING LA English DT Article ID CONDUCTIVE HEARING-LOSS; MIDDLE-EAR PRESSURE; OTOACOUSTIC EMISSIONS; REFLECTANCE TYMPANOMETRY; HUMAN INFANTS; ADULTS; CHILDREN; MATURATION; IMPEDANCE C1 [Sanford, Chris A.] Idaho State Univ, Dept Commun Sci & Disorders, Pocatello, ID 83209 USA. [Hunter, Lisa L.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Feeney, M. Patrick] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR USA. [Feeney, M. Patrick] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Nakajima, Hideko Heidi] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Nakajima, Hideko Heidi] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Sanford, CA (reprint author), Idaho State Univ, 921 S 8th Ave,Mail Stop 8116, Pocatello, ID 83209 USA. EM sanfchri@isu.edu NR 21 TC 1 Z9 2 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JUL PY 2013 VL 34 SU 1 BP S65 EP S71 DI 10.1097/AUD.0b013e31829c7250 PG 7 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 242XC UT WOS:000326278100012 PM 23900184 ER PT J AU Schairer, KS Feeney, MP Sanford, CA AF Schairer, Kim S. Feeney, M. Patrick Sanford, Chris A. TI Acoustic Reflex Measurement SO EAR AND HEARING LA English DT Article ID MIDDLE-EAR; REFLECTANCE; THRESHOLDS; ADMITTANCE; IMPEDANCE; CHILDREN; HEARING; INFANTS C1 [Schairer, Kim S.] James H Quillen Vet Affairs Med Ctr, Audiol & Speech Language Pathol Serv, Mountain Home, TN 37684 USA. [Feeney, M. Patrick] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR USA. [Feeney, M. Patrick] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Sanford, Chris A.] Idaho State Univ, Dept Commun Sci & Disorders, Pocatello, ID 83209 USA. RP Schairer, KS (reprint author), James H Quillen Vet Affairs Med Ctr, Box 4000, Mountain Home, TN 37684 USA. EM kim.schairer@va.gov FU Department of Veterans Affairs Rehabilitation Research and Development Service Research Enhancement Award Program FX This work was supported by Department of Veterans Affairs Rehabilitation Research and Development Service Research Enhancement Award Program. NR 23 TC 3 Z9 3 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JUL PY 2013 VL 34 SU 1 BP S43 EP S47 DI 10.1097/AUD.0b013e31829c70d9 PG 5 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 242XC UT WOS:000326278100008 PM 23900179 ER PT J AU Voss, SE Stenfelt, S Neely, ST Rosowski, JJ AF Voss, Susan E. Stenfelt, Stefan Neely, Stephen T. Rosowski, John J. TI Factors That Introduce Intrasubject Variability Into Ear-Canal Absorbance Measurements SO EAR AND HEARING LA English DT Article ID REFLECTION COEFFICIENT; IMPEDANCE; INFANTS; ADULTS C1 [Voss, Susan E.] Smith Coll, Northampton, MA 01063 USA. [Stenfelt, Stefan] Linkoping Univ, Linkoping, Sweden. [Neely, Stephen T.] Boys Town Natl Res Hosp, Omaha, NE 68131 USA. [Rosowski, John J.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Voss, SE (reprint author), Smith Coll, 51 Coll Lane, Northampton, MA 01063 USA. EM svoss@smith.edu OI Neely, Stephen/0000-0002-1349-5386; Stenfelt, Stefan/0000-0003-3350-8997 FU NIDCD NIH HHS [R15 DC007615] NR 15 TC 3 Z9 4 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 EI 1538-4667 J9 EAR HEARING JI Ear Hear. PD JUL PY 2013 VL 34 SU 1 BP S60 EP S64 DI 10.1097/AUD.0b013e31829cfd64 PG 5 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 242XC UT WOS:000326278100011 PM 23900183 ER PT J AU Spur, EM Decelle, EA Cheng, LL AF Spur, Eva-Margarete Decelle, Emily A. Cheng, Leo L. TI Metabolomic imaging of prostate cancer with magnetic resonance spectroscopy and mass spectrometry SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Review DE Prostate cancer; Metabolomics; Metabolomic imaging; Magnetic resonance spectroscopy; Mass spectrometry ID MR SPECTROSCOPY; PROTON NMR; PATHOLOGICAL ANALYSIS; DEPRIVATION THERAPY; TISSUE; RESOLUTION; ANTIGEN; LOCALIZATION; PROFILES; GROWTH AB Metabolomic imaging of prostate cancer (PCa) aims to improve in vivo imaging capability so that PCa tumors can be localized noninvasively to guide biopsy and evaluated for aggressiveness prior to prostatectomy, as well as to assess and monitor PCa growth in patients with asymptomatic PCa newly diagnosed by biopsy. Metabolomics studies global variations of metabolites with which malignancy conditions can be evaluated by profiling the entire measurable metabolome, instead of focusing only on certain metabolites or isolated metabolic pathways. At present, PCa metabolomics is mainly studied by magnetic resonance spectroscopy (MRS) and mass spectrometry (MS). With MRS imaging, the anatomic image, obtained from magnetic resonance imaging, is mapped with values of disease condition-specific metabolomic profiles calculated from MRS of each location. For example, imaging of removed whole prostates has demonstrated the ability of metabolomic profiles to differentiate cancerous foci from histologically benign regions. Additionally, MS metabolomic imaging of prostate biopsies has uncovered metabolomic expression patterns that could discriminate between PCa and benign tissue. Metabolomic imaging offers the potential to identify cancer lesions to guide prostate biopsy and evaluate PCa aggressiveness noninvasively in vivo, or ex vivo to increase the power of pathology analysis. Potentially, this imaging ability could be applied not only to PCa, but also to different tissues and organs to evaluate other human malignancies and metabolic diseases. C1 [Spur, Eva-Margarete; Decelle, Emily A.; Cheng, Leo L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA. [Spur, Eva-Margarete; Decelle, Emily A.; Cheng, Leo L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02129 USA. [Spur, Eva-Margarete] Charite, D-13353 Berlin, Germany. RP Cheng, LL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, CNY 6,149 13th St, Boston, MA 02129 USA. EM cheng@nmr.mgh.harvard.edu FU PHS/NIH [CA115746, CA162959, CA141139]; MGH A.A. Martinos Center for Biomedical Imaging FX This work was supported by PHS/NIH grants CA115746, CA162959, and CA141139 (LLC), and the MGH A.A. Martinos Center for Biomedical Imaging. NR 67 TC 6 Z9 6 U1 5 U2 28 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD JUL PY 2013 VL 40 SU 1 BP S60 EP S71 DI 10.1007/s00259-013-2379-x PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 237CU UT WOS:000325846600009 PM 23549758 ER PT J AU Sachs, MC Zhou, XH AF Sachs, Michael C. Zhou, Xiao-Hua TI Partial summary measures of the predictiveness curve SO BIOMETRICAL JOURNAL LA English DT Article DE Biomarker; Classification; Prediction; Summary statistic ID LOGISTIC-REGRESSION; ALZHEIMERS-DISEASE; MARKER; RISK; STATISTICS; MODELS AB In the evaluation of a biomarker for risk prediction, one can assess the performance of the biomarker in the population of interest by displaying the predictiveness curve. In conjunction with an assessment of the classification accuracy of a biomarker, the predictiveness curve is an important tool for assessing the usefulness of a risk prediction model. Inference for a single biomarker or for multiple biomarkers can be performed using summary measures of the predictiveness curve. We propose two partial summary measures, the partial total gain and the partial proportion of explained variation, that summarize the predictiveness curve over a restricted range of risk. The methods we describe can be used to compare two biomarkers when there are existing thresholds for risk stratification. We describe inferential tools for one and two samples that are shown to have adequate power in a simulation study. The methods are illustrated by assessing the accuracy of a risk score for predicting the onset of Alzheimer's disease. C1 [Sachs, Michael C.] Univ Washington, Kidney Res Inst, Seattle, WA 98104 USA. [Sachs, Michael C.] Univ Washington, Div Nephrol, Seattle, WA 98104 USA. [Zhou, Xiao-Hua] Univ Washington, HSRD Ctr Excellence, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98108 USA. RP Sachs, MC (reprint author), Univ Washington, Kidney Res Inst, Seattle, WA 98104 USA. EM sachsmc@u.washington.edu FU NIA [U01 AG016976]; NIMH [T32 MH073521] FX The authors are grateful to Margaret Pepe and Carolyn Rutter in addition to an associate editor and the reviewers for their helpful comments and suggestions. This work was supported, in part, by NIA grant U01 AG016976 and NIMH grant T32 MH073521. NR 18 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0323-3847 EI 1521-4036 J9 BIOMETRICAL J JI Biom. J. PD JUL PY 2013 VL 55 IS 4 BP 589 EP 602 DI 10.1002/bimj.201200146 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 237RA UT WOS:000325887000009 PM 23508801 ER PT J AU Wiener, L Pao, M Battles, H Zadeh, S Patenaude, AF Madan-Swain, A Friebert, S Elkin, D Kupst, MJ AF Wiener, Lori Pao, Maryland Battles, Haven Zadeh, Sima Patenaude, Andrea Farkas Madan-Swain, Avi Friebert, Sarah Elkin, David Kupst, Mary Jo CA Lone-Parent Study Grp TI Socio-Environmental Factors Associated With Lone Parenting Chronically Ill Children SO CHILDRENS HEALTH CARE LA English DT Article ID NEWLY-DIAGNOSED CANCER; DISTRESS THERMOMETER; CHILDHOOD-CANCER; CHRONIC ILLNESS; HEALTH-PROBLEMS; MOTHERS; DEPRESSION; SUPPORT; SINGLE; CAREGIVERS AB This article reports findings from 2 studies assessing the relation between parental perception of "lone" parenting and socioeconomic factors, including low income, perception of child health, and parental emotional distress among parents of chronically ill children. In both studies, parents who considered themselves a lone parent when caring for their ill child had significantly lower incomes and greater distress (i.e., were more likely to score at or above clinical or "case" cutoffs on the Brief Symptom Inventory) than those who considered themselves to be married or partnered. Longitudinal research is needed to determine the impact of lone parenting and low income on parental and child health outcomes over time. C1 [Wiener, Lori] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pao, Maryland] NIMH, NIH, Bethesda, MD 20892 USA. [Battles, Haven; Zadeh, Sima] NCI, NIH, Bethesda, MD 20892 USA. [Patenaude, Andrea Farkas] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Madan-Swain, Avi] Univ Alabama Birmingham, Div Hematol Oncol, Birmingham, AL 35294 USA. [Friebert, Sarah] Akron Childrens Hosp, Div Pediat Palliat Care, Akron, OH USA. [Elkin, David] Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, Jackson, MS 39216 USA. [Kupst, Mary Jo] Med Coll Wisconsin, Milwaukee, WI 53226 USA. RP Wiener, L (reprint author), NCI, Behav Sci Core, Psychosocial Support & Res Program, Pediat Oncol Branch,Ctr Canc Res, 10 Ctr Dr, Bethesda, MD 20892 USA. EM wienerl@mail.nih.gov OI Kearney, Julia/0000-0003-1113-9617 NR 37 TC 2 Z9 2 U1 0 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0273-9615 EI 1532-6888 J9 CHILD HEALTH CARE JI Child. Health Care PD JUL 1 PY 2013 VL 42 IS 3 SI SI BP 264 EP 280 DI 10.1080/02739615.2013.816612 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 218UN UT WOS:000324458100007 ER PT J AU Gadikota, HR Kikuta, S Qi, W Nolan, D Gill, TJ Li, G AF Gadikota, Hemanth R. Kikuta, Shinsuke Qi, Wei Nolan, David Gill, Thomas J. Li, Guoan TI Effect of Increased Iliotibial Band Load on Tibiofemoral Kinematics and Force Distributions: A Direct Measurement in Cadaveric Knees SO JOURNAL OF ORTHOPAEDIC & SPORTS PHYSICAL THERAPY LA English DT Article DE gluteus maximus; joint forces; knee osteoarthritis; robotic testing system; tensor fascia latae ID IN-VIVO; PIVOT-SHIFT; OSTEOARTHRITIS; JOINT; PROGRESSION; GAIT; HIP; MALALIGNMENT; PRESSURES; WALKING AB STUDY DESIGN: Controlled laboratory study using cadaveric knee specimens and a repeated-measures design. OBJECTIVES: To investigate the effect of increased iliotibial band load (assumed to represent increased tensor fascia latae and gluteus maximus strength) on tibiofemoral kinematics and force distribution on the tibiofemoral articulation. BACKGROUND: Owing to the difficulty in measuring in vivo joint loading, there is limited evidence on the direct relationship between increased iliotibial band load and force distribution in the tibiofemoral articulation. METHODS: Eight fresh-frozen cadaveric knee specimens were used in this study. A robotic testing system assessed tibiofemoral kinematics under 3 simulated loading conditions: (1) 300-N quadriceps load, 100-N hamstrings load, O-N iliotibial band load; (2) 300-N quadriceps load, 100-N hamstrings load, 50-N iliotibial band load; and (3) 300-N quadriceps load, 100-N hamstrings load, 100-N iliotibial band load. The load distribution in the medial and lateral tibiofemoral articulation was also measured under these loading conditions by using piezoelectric pressure sensors. Data were collected and analyzed at full extension and at 5 degrees, 10 degrees, 15 degrees, 20 degrees, 25 degrees, and 30 degrees of knee flexion. RESULTS: The loads transmitted through the medial tibiofemoral articulation significantly decreased when the load on the iliotibial band was increased, with a concomitant significant increase in lateral tibiofemoral articulation load. Greater iliotibial band load also increased anterior tibial translation and valgus tibial rotation, and decreased the amount of internal tibial rotation and medial tibial translation. CONCLUSION: The present study demonstrated that an increase in iliotibial band load, when tested in a non weight-bearing condition in a cadaveric model, can significantly decrease the loads transmitted through the medial tibiofemoral articulation. C1 [Gadikota, Hemanth R.; Gill, Thomas J.; Li, Guoan] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Gadikota, Hemanth R.; Gill, Thomas J.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA USA. [Kikuta, Shinsuke] Nihon Univ, Sch Med, Dept Orthopaed Surg, Tokyo, Japan. [Qi, Wei] Chinese Peoples Liberat Army Gen Hosp, Dept Orthopaed Surg, Beijing, Peoples R China. [Nolan, David] Massachusetts Gen Hosp, Sports Phys Therapy Serv, Boston, MA 02114 USA. [Nolan, David] Northeastern Univ, Dept Phys Therapy, Boston, MA 02115 USA. RP Li, G (reprint author), Massachusetts Gen Hosp, Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org NR 33 TC 3 Z9 3 U1 0 U2 5 PU J O S P T, PI ALEXANDRIA PA 1111 NORTH FAIRFAX ST, STE 100, ALEXANDRIA, VA 22314-1436 USA SN 0190-6011 J9 J ORTHOP SPORT PHYS JI J. Orthop. Sports Phys. Ther. PD JUL PY 2013 VL 43 IS 7 BP 478 EP 485 DI 10.2519/jospt.2013.4506 PG 8 WC Orthopedics; Rehabilitation; Sport Sciences SC Orthopedics; Rehabilitation; Sport Sciences GA 236FW UT WOS:000325781900006 PM 23508365 ER PT J AU de Groot, NL Spiegel, BMR van Haalen, HGM de Wit, NJ Siersema, PD van Oijen, MGH AF de Groot, N. L. Spiegel, B. M. R. van Haalen, H. G. M. de Wit, N. J. Siersema, P. D. van Oijen, M. G. H. TI Gastroprotective Strategies in Chronic NSAID Users: A Cost-Effectiveness Analysis Comparing Single-Tablet Formulations with Individual Components SO VALUE IN HEALTH LA English DT Article DE compliance; cost-effectiveness; cost-utility; dyspepsia; gastrointestinal bleeding; nonsteroidal anti-inflammatory drugs; proton pump inhibitors. ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SELECTIVE CYCLO-OXYGENASE-2 INHIBITORS; PROTON PUMP INHIBITORS; RHEUMATOID-ARTHRITIS; PEPTIC-ULCER; GASTROINTESTINAL COMPLICATIONS; TRADITIONAL NSAIDS; COX-2 INHIBITORS; ELDERLY-PATIENTS; CONTROLLED-TRIAL AB Objectives: To evaluate the cost-effectiveness of competing gastroprotective strategies, including single-tablet formulations, in the prevention of gastrointestinal (GI) complications in patients with chronic arthritis taking nonsteroidal anti-inflammatory drugs (NSAIDs). Methods: We performed a cost-utility analysis to compare eight gastroprotective strategies including NSAIDs, cyclooxygenase-2 inhibitors, proton pump inhibitors (PPIs), histamine-2 receptor antagonists, misoprostol, and single-tablet formulations. We derived estimates for outcomes and costs from medical literature. The primary outcome was incremental cost per quality-adjusted life-year gained. We performed sensitivity analyses to assess the effect of GI complications, compliance rates, and drug costs. Results: For average-risk patients, NSAID + PPI cotherapy was most cost-effective. The NSAID/PPI single-tablet formulation became cost-effective only when its price decreased from (sic)0.78 to (sic)0.56 per tablet, or when PPI compliance fell below 51% in the NSAID + PPI strategy. All other strategies were more costly and less effective. The model was highly sensitive to the GI complication risk, costs of PPI and NSAID/PPI single-tablet formulation, and compliance to PPI. In patients with a threefold higher risk of GI complications, both NSAID + PPI cotherapy and single-tablet formulation were cost-effective. Conclusions: NSAID + PPI cotherapy is the most cost-effective strategy in all patients with chronic arthritis irrespective of their risk for GI complications. For patients with increased GI risk, the NSAID/PPI single-tablet formulation is also cost-effective. C1 [de Groot, N. L.; van Haalen, H. G. M.; Siersema, P. D.; van Oijen, M. G. H.] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, NL-3508 GA Utrecht, Netherlands. [Spiegel, B. M. R.] Vet Affairs Greater Los Angeles Hlth Care Syst, Div Gastroenterol & Hepatol, Los Angeles, CA USA. [Spiegel, B. M. R.] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Spiegel, B. M. R.; van Oijen, M. G. H.] Univ Calif Los Angeles, Vet Affairs Ctr Outcomes Res & Educ CORE, Los Angeles, CA USA. [de Wit, N. J.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3508 GA Utrecht, Netherlands. RP de Groot, NL (reprint author), Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, POB 85500,Internal Code F02-618, NL-3508 GA Utrecht, Netherlands. EM n.l.degroot-3@umcutrecht.nl FU AstraZeneca FX This study has been sponsored by an unrestricted educational research grant by AstraZeneca. NR 51 TC 2 Z9 2 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD JUL-AUG PY 2013 VL 16 IS 5 BP 769 EP 777 DI 10.1016/j.jval.2013.05.002 PG 9 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 232CL UT WOS:000325466600010 PM 23947970 ER PT J AU Lin, VW Wong, ES Wright, A Flum, DR Garrison, LP Alfonso-Cristancho, R Sullivan, SD AF Lin, Vincent W. Wong, Edwin S. Wright, Andrew Flum, David R. Garrison, Louis P., Jr. Alfonso-Cristancho, Rafael Sullivan, Sean D. TI Association between Health-Related Quality of Life and Body Mass After Adjustable Gastric Banding: A Nonlinear Approach SO VALUE IN HEALTH LA English DT Article DE EQ-5D; gastric banding; health-related quality of life; health utility; obesity ID BARIATRIC SURGERY; WEIGHT-LOSS; COST-EFFECTIVENESS; MORBID-OBESITY; EQ-5D UTILITY; BYPASS; INDEX; SCORES; STATES; TRIAL AB Objective: To estimate the relationship between health utilities and body mass index (BMI) among a cohort of obese patients who underwent laparoscopic adjustable gastric banding (LAGB). Methods: We used a cross-sectional survey to ascertain demographic, clinical, and health utility data from patients who had undergone LAGB in Washington State from 2004 to 2010. The EuroQol five-dimensional (EQ-5D) questionnaire was used for health utility estimation. We calculated adjusted EQ-5D questionnaire indices across BMI categories by using a two-part model. We also used logistic regression to examine the relationship between BMI and the likelihood of reporting problems on each of the EQ-5D questionnaire dimension. Results: Data were obtained from 790 subjects. The mean adjusted EQ-5D questionnaire indices for all obese BMI categories were significantly lower than those in the normal weight category. The relationship between BMI and EQ-5D questionnaire indices was nonlinear. Respondents classified as morbidly obese II (BMI > 50 kg/m(2)) had the greatest decrement (-0.15, 95% confidence interval -0.28 to -0.01) in EQ-5D questionnaire indices. The association between EQ-5D questionnaire indices and BMI at the time of the survey was weaker after adjusting for weight loss after LAGB. Respondents with higher BMI were more likely to report having problems in the mobility, usual/activity, pain/discomfort, and anxiety/depression dimensions (trend test, P < 0.05), but not for the self-care dimension (trend test, P = 0.08). Conclusions: The EQ-5D questionnaire has a negative and nonlinear relationship with BMI for obese patients who had LAGB. The relationship is confounded by weight loss. Within the EQ-5D questionnaire dimensions, patients are more likely to report having problems in the mobility, usual/activity, pain/discomfort, and anxiety/depression dimensions in higher BMI categories, but not in the self-care dimension. C1 [Lin, Vincent W.; Flum, David R.; Garrison, Louis P., Jr.; Alfonso-Cristancho, Rafael; Sullivan, Sean D.] Univ Washington, Pharmaceut Outcomes Res & Policy Program, Seattle, WA 98195 USA. [Wong, Edwin S.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Wright, Andrew; Flum, David R.; Alfonso-Cristancho, Rafael] Univ Washington, Dept Surg, Seattle, WA 98195 USA. RP Sullivan, SD (reprint author), Univ Washington, Sch Pharm, Pharmaceut Outcomes Res & Policy Program, 1959 Northeast Pacific Ave,H-375Q,Box 357630, Seattle, WA 98195 USA. EM sdsull@u.washington.edu FU Department of Defense Agreement [FA7014-08-0002]; National Institutes of Digestive Disease and Kidney [1R21DK069677] FX The study was supported by Department of Defense Agreement (grant no. FA7014-08-0002) and National Institutes of Digestive Disease and Kidney (grant no. 1R21DK069677). NR 37 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 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD JUL-AUG PY 2013 VL 16 IS 5 BP 823 EP 829 DI 10.1016/j.jval.2013.05.001 PG 7 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 232CL UT WOS:000325466600016 PM 23947976 ER PT J AU Yang, L Neale, BM Liu, L Lee, SH Wray, NR Ji, N Li, HM Qian, QJ Wang, DL Li, J Faraone, SV Wang, YF AF Yang, Li Neale, Benjamin M. Liu, Lu Lee, S. Hong Wray, Naomi R. Ji, Ning Li, Haimei Qian, Qiujin Wang, Dongliang Li, Jun Faraone, Stephen V. Wang, Yufeng CA Psychiat GWAS Consortium ADHD TI Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: Genome-wide association study of both common and rare variants SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; GWAS; pathway; neurodevelopment ID DEFICIT/HYPERACTIVITY DISORDER; BIPOLAR DISORDER; SCHIZOPHRENIA; LINKAGE; GENE; POLYMORPHISM; METAANALYSIS; SCAN; ADHD; DUPLICATIONS AB Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case-control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein-Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P=0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P=0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P=0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology. (c) 2013 Wiley Periodicals, Inc. C1 [Yang, Li; Liu, Lu; Ji, Ning; Li, Haimei; Qian, Qiujin; Wang, Yufeng] Peking Univ Sixth Hosp, Inst Mental Hlth, Beijing 100191, Peoples R China. [Yang, Li; Liu, Lu; Ji, Ning; Li, Haimei; Qian, Qiujin; Wang, Yufeng] Minist Hlth, Key Lab Mental Hlth, Beijing, Peoples R China. [Neale, Benjamin M.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lee, S. Hong; Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Wang, Dongliang; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA. [Li, Jun] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. RP Wang, YF (reprint author), Peking Univ Sixth Hosp, Inst Mental Hlth, 51 Huayuan Bei Rd, Beijing 100191, Peoples R China. EM sfaraone@childpsychresearch.org; wangyf@bjmu.edu.cn RI Lesch, Klaus-Peter/J-4906-2013; Romanos, Marcel/D-7695-2017; Sonuga-Barke, Edmund/D-9137-2011; Kuntsi, Jonna/G-9750-2011; Franke, Barbara/D-4836-2009; Renner, Tobias/I-2120-2013; Lee, Sang Hong/A-2569-2011; Medland, Sarah/C-7630-2013; Wray, Naomi/C-8639-2015; OI Lesch, Klaus-Peter/0000-0001-8348-153X; Kent, Lindsey/0000-0002-5315-3399; Franke, Barbara/0000-0003-4375-6572; Lee, Sang Hong/0000-0001-9701-2718; Medland, Sarah/0000-0003-1382-380X; Wray, Naomi/0000-0001-7421-3357; Anney, Richard/0000-0002-6083-407X; Thapar, Anita/0000-0002-3689-737X; Faraone, Stephen/0000-0002-9217-3982; Cormand, Bru/0000-0001-5318-4382 FU National Natural Science Foundation of China [30800302, 81071109]; Chinese Ministry of Health [200802073]; Ministry of Education Program for New Century Excellent Talents in University [NCET-11-0013]; Ministry of Science and Technology [2007BAI17B03]; National Institute of Health [R13MH059126, R01MH62873, U01MH085518, R01MH081803, U01MH085515, K23MH066275-01, R01MH58277]; Australian Research council [FT0991360]; Australian National Health and Medical Research Council [1011506, 1047956]; Children's Hospital of Philadelphia; Affymetrix Power Award; Sidney Sax Public Health Fellowship [443036]; Wellcome Trust, UK; UMC Utrecht Genvlag Grant; Radboud University; Nijmegen Medical Centre; Deutsche Forschungsgemeinschaft [KFO 125, SFB 581, GRK 1156, ME 1923/5-1, ME 1923/5-3, GRK 1389]; BundesministeriumfurBildung und Forschung [BMBF 01GV0605]; Canadian Institutes of Health Research [MOP 64277, 44070, 74699]; [SCHA 542/10-3] FX Grant sponsor: National Natural Science Foundation of China; Grant numbers: 30800302, 81071109; Grant sponsor: Chinese Ministry of Health; Grant number: 200802073; Grant sponsor: Ministry of Education Program for New Century Excellent Talents in University; Grant number: NCET-11-0013; Grant sponsor: Ministry of Science and Technology; Grant number: 2007BAI17B03; Grant sponsor: National Institute of Health Grants; Grant numbers: R13MH059126, R01MH62873, U01MH085518, R01MH081803, U01MH085515, K23MH066275-01, R01MH58277; Grant sponsor: Funding from the Australian Research council; Grant number: FT0991360; Grant sponsor: Australian National Health and Medical Research Council; Grant numbers: 1011506, 1047956; Grant sponsor: Children's Hospital of Philadelphia; Grant sponsor: Affymetrix Power Award; Grant sponsor: Sidney Sax Public Health Fellowship; Grant number: 443036; Grant sponsor: Wellcome Trust, UK; Grant sponsor: UMC Utrecht Genvlag Grant and Internal Grant of Radboud University, Nijmegen Medical Centre; Grant sponsor: Deutsche Forschungsgemeinschaft; Grant numbers: KFO 125, SFB 581, GRK 1156, ME 1923/5-1, ME 1923/5-3, GRK 1389; Grant sponsor: J. Meyer; Grant number: SCHA 542/10-3; Grant sponsor: BundesministeriumfurBildung und Forschung; Grant number: BMBF 01GV0605; Grant sponsor: Canadian Institutes of Health Research; Grant numbers: MOP 64277, 44070, 74699. NR 40 TC 52 Z9 58 U1 3 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUL PY 2013 VL 162B IS 5 BP 419 EP 430 DI 10.1002/ajmg.b.32169 PG 12 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 166IX UT WOS:000320549100001 PM 23728934 ER PT J AU Berg, KC Swanson, SA Stiles-Shields, EC Eddy, KT Peterson, CB Le Grange, D AF Berg, Kelly C. Swanson, Sonja A. Stiles-Shields, E. Colleen Eddy, Kamryn T. Peterson, Carol B. Le Grange, Daniel TI Response patterns on interview and questionnaire versions of the Eating Disorder Examination and their impact on latent structure analyses SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID BULIMIA-NERVOSA; SELF-REPORT; ANOREXIA-NERVOSA; PROFILE ANALYSIS; DSM-IV; PERSONALITY; PHENOTYPES; PSYCHOPATHOLOGY; CLASSIFICATION; SYMPTOMS AB Objective: The purpose of this investigation was to compare the latent structures of the interview (EDE) and questionnaire (EDE-Q) versions of the Eating Disorder Examination. Methods: Participants were 280 children, adolescents, and young adults seeking eating disorder treatment. Two separate latent structure analyses (LSAs) were conducted; one used variables from the EDE as indicators and the other used the corresponding variables from the EDE-Q as indicators. Results: The EDE and EDE-Q models both yielded four-class solutions. Three of the four classes from the EDE-Q model demonstrated moderate to high concordance with their paired class from the EDE model. Using the EDE-Q to detect the EDE, the sensitivity and specificity of measuring certain classes varied from poor (18.6%) to excellent (93.7%). The overall concordance was moderate (kappa=.49). Discussion: These data suggest that LSAs using the EDE and EDE-Q may be directly compared; however, differences between results may represent inconsistencies in response patterns rather than true differences in psychopathology. (C) 2013 Elsevier Inc. All rights reserved. C1 [Berg, Kelly C.; Peterson, Carol B.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55454 USA. [Swanson, Sonja A.; Le Grange, Daniel] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stiles-Shields, E. Colleen] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Eddy, Kamryn T.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Berg, KC (reprint author), Univ Minnesota, Dept Psychiat, 606-24th Ave South,Suite 602, Minneapolis, MN 55454 USA. EM bergx143@umn.edu OI Stiles-Shields, Colleen/0000-0002-6759-8380 FU NIMH NIH HHS [T32 MH082761] NR 67 TC 1 Z9 1 U1 1 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD JUL PY 2013 VL 54 IS 5 BP 506 EP 516 DI 10.1016/j.comppsych.2012.12.006 PG 11 WC Psychiatry SC Psychiatry GA 229YJ UT WOS:000325303500013 PM 23375185 ER PT J AU Hasegawa, K Tsugawa, Y Brown, DFM Mansbach, JM Camargo, CA AF Hasegawa, Kohei Tsugawa, Yusuke Brown, David F. M. Mansbach, Jonathan M. Camargo, Carlos A., Jr. TI Trends in Bronchiolitis Hospitalizations in the United States, 2000-2009 SO PEDIATRICS LA English DT Article DE bronchiolitis; trends; hospitalization; incidence; mortality; hospital charge ID VIRUS-ASSOCIATED HOSPITALIZATIONS; PROSPECTIVE MULTICENTER; EMERGENCY-DEPARTMENT; YOUNG-CHILDREN; VIRAL ETIOLOGY; RISK-FACTORS; US CHILDREN; HEALTH-CARE; INFANTS; BURDEN AB OBJECTIVE: To examine temporal trend in the national incidence of bronchiolitis hospitalizations, use of mechanical ventilation, and hospital charges between 2000 and 2009. METHODS: We performed a serial, cross-sectional analysis of a nationally representative sample of children hospitalized with bronchiolitis. The Kids Inpatient Database was used to identify children <2 years of age with bronchiolitis by International Classification of Diseases, Ninth Revision, Clinical Modification code 466.1. Primary outcome measures were incidence of bronchiolitis hospitalizations, mechanical ventilation (noninvasive or invasive) use, and hospital charges. Temporal trends were evaluated accounting for sampling weights. RESULTS: The 4 separated years (2000, 2003, 2006, and 2009) of national discharge data included 544 828 weighted discharges with bronchiolitis. Between 2000 and 2009, the incidence of bronchiolitis hospitalization decreased from 17.9 to 14.9 per 1000 person-years among all US children aged <2 years (17% decrease; P-trend < .001). By contrast, there was an increase in children with high-risk medical conditions (5.9%-7.9%; 34% increase; P-trend < .001) and use of mechanical ventilation (1.9%-2.3%; 21% increase; P-trend = .008). Nationwide hospital charges increased from $1.34 billion to $1.73 billion (30% increase; P-trend < .001); this increase was driven by a rise in the geometric mean of hospital charges per case from $6380 to $8530 (34% increase; P-trend < .001). CONCLUSIONS: Between 2000 and 2009, we found a significant decline in bronchiolitis hospitalizations among US children. By contrast, use of mechanical ventilation and hospital charges for bronchiolitis significantly increased over this same period. C1 [Hasegawa, Kohei; Brown, David F. M.; Mansbach, Jonathan M.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Hasegawa, Kohei; Tsugawa, Yusuke; Brown, David F. M.; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Tsugawa, Yusuke; Mansbach, Jonathan M.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Tsugawa, Yusuke] St Lukes Life Sci Inst, Ctr Clin Epidemiol, Tokyo, Japan. Boston Childrens Hosp, Boston, MA USA. RP Hasegawa, K (reprint author), Harvard Univ, Sch Med, Dept Emergency Med, Massachusetts Gen Hosp, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM khasegawa1@partners.org FU St Luke's Life Science Institute (Tokyo, Japan); National Institutes of Health (Bethesda, MD) [U01 AI-87881]; National Institutes of Health (NIH) FX Drs Hasegawa and Tsugawa were supported in part by St Luke's Life Science Institute (Tokyo, Japan). Drs Mansbach and Camargo were supported in part by National Institutes of Health grant U01 AI-87881 (Bethesda, MD). The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Funded by the National Institutes of Health (NIH). NR 40 TC 88 Z9 90 U1 0 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP 28 EP 36 DI 10.1542/peds.2012-3877 PG 9 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900042 PM 23733801 ER PT J AU Broder-Fingert, S Shui, A Pulcini, CD Kurowski, D Perrin, JM AF Broder-Fingert, Sarabeth Shui, Amy Pulcini, Christian D. Kurowski, Daniel Perrin, James M. TI Racial and Ethnic Differences in Subspecialty Service Use by Children With Autism SO PEDIATRICS LA English DT Article DE racial disparity; autism; access; diagnosis; specialty care ID HEALTH-CARE; SPECTRUM DISORDERS; PSYCHIATRIC-DISORDERS; DISPARITIES; ACCESS; DIAGNOSIS; DISEASE; COMMUNICATION; IMPACT; ASDS AB OBJECTIVE: To describe racial differences in use of specialty care among children with autism spectrum disorder. METHODS: We identified patients ages 2 to 21 years with an International Classification of Diseases, Ninth Revision code of autism (299.0) seen from 2000 to 2011 at a major academic health center by using a research patient data repository and determined rates of specialty provider visits and procedures by race. We then used logistic regression to determine the associations of rates of subspecialty visits and procedures with race and ethnicity, controlling for gender, age, and payer type. RESULTS: We identified 3615 patients (2935 white, 243 Hispanic, 188 African American, and 249 other). The most striking differences were in use of gastroenterology (GI)/nutrition services. Nonwhite children were less likely to use GI/nutrition specialty providers (African American, odds ratio = 0.32 [95th percentile confidence interval: 0.18-0.55]; Hispanic, 0.32 [0.20-0.51]; other, 0.56 [0.34-0.92]) as well as neurology (African American, 0.52 [0.33-0.83]; Hispanic, 0.40 [0.27-0.59]) and psychiatry/psychology (African American, 0.44 [0.27-0.72]; Hispanic, 0.60 [0.41-0.88]; other, 0.62 [0.38-0.99]). Nonwhite children were less likely to have had GI studies: colonoscopy (African American, 0.23 [0.10-0.53]; Hispanic, 0.26 [0.14-0.50]), endoscopy (African American, 0.31 [0.16-0.58]; Hispanic, 0.27 [0.16-0.46]; other, 0.53 [0.31-0.90]), and stool studies (African American, 0.49 [0.30-0.91]). Hispanic children had lower rates of neurologic and other testing: EEG (Hispanic, 0.53 [0.35-0.78]), brain MRI (African American, 0.37 [0.22-0.63]; Hispanic, 0.62 [0.42-0.90]), sleep study (Hispanic, 0.18 [0.04-0.76]), and neuropsychiatric testing (Hispanic, 0.55 [0.32-0.96]). CONCLUSIONS: We found racial and ethnic differences among children diagnosed with autism in use of care and procedures. Possible explanations for these findings include differences in presentation, referral rates, or referral follow through. C1 [Broder-Fingert, Sarabeth; Shui, Amy; Kurowski, Daniel; Perrin, James M.] Harvard Univ, Sch Med, Dept Pediat, MassGen Hosp Children, Boston, MA 02115 USA. [Broder-Fingert, Sarabeth; Shui, Amy; Kurowski, Daniel; Perrin, James M.] Ctr Child & Adolescent Hlth Res & Policy, Boston, MA 02114 USA. [Pulcini, Christian D.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Broder-Fingert, S (reprint author), Ctr Child & Adolescent Hlth Res & Policy, 100 Cambridge St,Room 1542, Boston, MA 02114 USA. EM sbroder-finger@partners.org OI Broder-Fingert, Sarabeth/0000-0002-0932-4461 FU Nancy Lurie Marks Foundation; Autism Speaks FX Dr Perrin received an unrestricted grant from the Nancy Lurie Marks Foundation to support policy research in ASD, as well as from Autism Speaks for support for work related to autism network. NR 33 TC 10 Z9 10 U1 2 U2 16 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP 94 EP 100 DI 10.1542/peds.2012-3886 PG 7 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900050 PM 23776121 ER PT J AU Winickoff, JP Nabi-Burza, E Chang, YC Finch, S Regan, S Wasserman, R Ossip, D Woo, H Klein, J Dempsey, J Drehmer, J Hipple, B Weiley, V Murphy, S Rigotti, NA AF Winickoff, Jonathan P. Nabi-Burza, Emara Chang, Yuchiao Finch, Stacia Regan, Susan Wasserman, Richard Ossip, Deborah Woo, Heide Klein, Jonathan Dempsey, Janelle Drehmer, Jeremy Hipple, Bethany Weiley, Victoria Murphy, Sybil Rigotti, Nancy A. TI Implementation of a Parental Tobacco Control Intervention in Pediatric Practice SO PEDIATRICS LA English DT Article DE Smoking cessation; tobacco smoke exposure; parental smoking; pediatrics; secondhand smoke ID SMOKE EXPOSURE; HEALTH-PROGRAMS; ADOLESCENT SMOKING; CHILD HEALTH; SUSTAINABILITY; PROTECT; CARE AB OBJECTIVE: To test whether routine pediatric outpatient practice can be transformed to assist parents in quitting smoking. METHODS: Cluster RCT of 20 pediatric practices in 16 states that received either CEASE intervention or usual care. The intervention gave practices training and materials to change their care delivery systems to provide evidence-based assistance to parents who smoke. This assistance included motivational messaging; proactive referral to quitlines; and pharmacologic treatment of tobacco dependence. The primary outcome, assessed at an exit interview after an office visit, was provision of meaningful tobacco control assistance, defined as counseling beyond simple advice (discussing various strategies to quit smoking), prescription of medication, or referral to the state quitline, at that office visit. RESULTS: Among 18 607 parents screened after their child's office visit between June 2009 and March 2011, 3228 were eligible smokers and 1980 enrolled (999 in 10 intervention practices and 981 in 10 control practices). Practices' mean rate of delivering meaningful assistance for parental cigarette smoking was 42.5% (range 34%-66%) in the intervention group and 3.5% (range 0%-8%) in the control group (P<.0001). Rates of enrollment in the quitline (10% vs 0%); provision of smoking cessation medication (12% vs 0%); and counseling for smoking cessation (24% vs 2%) were all higher in the intervention group compared with the control group (P<.0001 for each). CONCLUSIONS: A system-level intervention implemented in 20 outpatient pediatric practices led to 12-fold higher rates of delivering tobacco control assistance to parents in the context of the pediatric office visit. C1 [Winickoff, Jonathan P.; Nabi-Burza, Emara; Chang, Yuchiao; Dempsey, Janelle; Hipple, Bethany; Murphy, Sybil] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Res & Policy, Boston, MA 02114 USA. [Winickoff, Jonathan P.; Klein, Jonathan] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Winickoff, Jonathan P.; Nabi-Burza, Emara; Chang, Yuchiao; Regan, Susan; Hipple, Bethany; Rigotti, Nancy A.] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA. [Chang, Yuchiao; Regan, Susan; Rigotti, Nancy A.] Amer Acad Pediat, MP Richmond Ctr Excellence, Elk Grove Village, IL USA. [Woo, Heide; Drehmer, Jeremy] Amer Acad Pediat, Pediat Res Off Settings, Elk Grove Village, IL USA. [Wasserman, Richard] Univ Vermont, Dept Pediat, Burlington, VT USA. [Ossip, Deborah] Univ Rochester, Med Ctr, Dept Publ Hlth Sci, Rochester, NY 14642 USA. [Woo, Heide] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA USA. RP Winickoff, JP (reprint author), Massachusetts Gen Hosp Children, Ctr Child & Adolescent Hlth Res & Policy, 15th Floor,Suite 1542A,100 Cambridge St, Boston, MA 02114 USA. EM jwinickoff@partners.org OI Drehmer, Jeremy/0000-0002-5022-5836 FU National Institutes of Health National Cancer Institute grant [R01-CA127127]; National Institute on Drug Abuse; Agency for Healthcare Research and Quality; Flight Attendant Medical Research Institute; Pediatric Research in Office Settings Network; Health Resources and Services Administration Maternal and Child Health Bureau [HRSA 5-UA6-10-001]; American Academy of Pediatrics; National Institutes of Health (NIH) FX Supported by the National Institutes of Health National Cancer Institute grant R01-CA127127 (to Dr Winickoff), the National Institute on Drug Abuse, and the Agency for Healthcare Research and Quality. This study was also partially supported by a grant from the Flight Attendant Medical Research Institute to the American Academy of Pediatrics Julius B. Richmond Center, and the Pediatric Research in Office Settings Network, which receives core funding from the Health Resources and Services Administration Maternal and Child Health Bureau (HRSA 5-UA6-10-001) and the American Academy of Pediatrics. The funders had no role in the design or conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review, and approval of the manuscript. Funded by the National Institutes of Health (NIH). NR 44 TC 30 Z9 30 U1 0 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP 109 EP 117 DI 10.1542/peds.2012-3901 PG 9 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900052 PM 23796741 ER PT J AU Shapiro-Mendoza, C Kotelchuck, M Barfield, W Davin, CA Diop, H Silver, M Manning, SE AF Shapiro-Mendoza, Carrie Kotelchuck, Milton Barfield, Wanda Davin, Carol A. Diop, Hafsatou Silver, Michael Manning, Susan E. TI Enrollment in Early Intervention Programs Among Infants Born Late Preterm, Early Term, and Term SO PEDIATRICS LA English DT Article DE late preterm; early intervention; developmental outcomes; developmental disabilities; prematurity; gestational age; postnatal development; follow-up studies ID POSTNATAL GLUCOSE-HOMEOSTASIS; GESTATIONAL-AGE; UNITED-STATES; PREMATURE-INFANTS; BIRTH-WEIGHT; OUTCOMES; MORTALITY; RISK; MORBIDITY; RATES AB OBJECTIVE: To compare the prevalence of and characteristics associated with early intervention (EI) program enrollment among infants born late preterm (34-36 weeks' gestation), early term (37-38 weeks' gestation), and term (39-41 weeks' gestation). METHODS: A Massachusetts cohort of 554 974 singleton infants born during 1998 through 2005 and survived the neonatal period was followed until the third birthday of each infant. Data came from the Pregnancy to Early Life Longitudinal Data System that linked birth certificates, birth hospital discharge reports, death certificates, and EI program enrollment records. We calculated prevalence and adjusted risk ratios to compare differences and understand associations. RESULTS: The prevalence of EI program enrollment increased with each decreasing week of gestation before 41 weeks (late preterm [23.5%], early term [14.9%], and term [11.9%]. In adjusted analyses, the strongest predictors of EI enrollment (adjusted risk ratio >= 1.20) for all gestational age groups were male gender, having a congenital anomaly, and having mothers who were >= 40 years old, nonhigh school graduates, and recipients of public insurance. CONCLUSIONS: Infants born late preterm and early term have higher prevalence of EI program services enrollment than infants born at term, and may benefit from more frequent monitoring for developmental delays or disabilities. C1 [Shapiro-Mendoza, Carrie; Barfield, Wanda] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30341 USA. [Davin, Carol A.; Diop, Hafsatou; Silver, Michael; Manning, Susan E.] Massachusetts Dept Publ Hlth, Boston, MA USA. [Kotelchuck, Milton] Harvard Univ, Sch Med, Boston, MA USA. [Kotelchuck, Milton] MassGen Hosp Children, Boston, MA USA. RP Shapiro-Mendoza, C (reprint author), Ctr Dis Control & Prevent, Div Reprod Hlth, MS K-23,4770 Buford Highway NE, Atlanta, GA 30341 USA. EM ayn9@cdc.gov FU Centers for Disease Control and Prevention [200-2009-31671] FX Supported by the Centers for Disease Control and Prevention contract 200-2009-31671, "Pregnancy to Early Life Longitudinal Data System (PELL)." NR 39 TC 8 Z9 9 U1 0 U2 8 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2013 VL 132 IS 1 BP E61 EP E69 DI 10.1542/peds.2012-3121 PG 9 WC Pediatrics SC Pediatrics GA 197HW UT WOS:000322841900008 PM 23796745 ER PT J AU Spence, MM Shin, PJ Lee, EA Gibbs, NE AF Spence, Michele M. Shin, Patrick J. Lee, Eric A. Gibbs, Nancy E. TI Risk of Injury Associated with Skeletal Muscle Relaxant Use in Older Adults SO ANNALS OF PHARMACOTHERAPY LA English DT Article ID MEDICATION USE; CLAIMS AB BACKGROUND: The use of skeletal muscle relaxants (SMRs) among older adults is associated with sedation and confusion, which may lead to an increased risk of falls and injuries. SMRs continue to be used among older adults, although they are on the Beers list as drugs to avoid in the elderly. OBJECTIVE: To investigate the relationship between SMR use and subsequent risk of injury. METHODS: This was a retrospective case-control study of members aged 65 years or older enrolled in an integrated health care system. Cases were defined as patients with a documented injury resulting in either a hospitalization or an emergency department or urgent care visit from January 2009 through December 2010. Cases were matched to controls in a 1: 4 ratio by age and sex. Patients had to be enrolled and alive on the date of an injury (index date). SMR exposure for all cases and controls was evaluated within 60 days prior to the index date. Conditional logistic regression adjusted for covariates was performed, with risk estimates presented as odds ratios with 95% confidence intervals. RESULTS: From a base population of 322,806 older adults, we identified 27,974 cases of injury and 104,303 matched controls. Among the cases, 365 (1.30%) used an SMR; among the controls, 801 (0.77%) used an SMR in the 60 days prior to the index date. After adjustment for demographic and clinical covariates, risk of injury was significantly increased for patients using an SMR compared to no use (OR 1.32, 95% CI 1.16-1.50; p < 0.001). Carisoprodol was associated with an increased risk of injury (OR 1.73, 95% CI 1.04-2.88; p = 0.036), as were methocarbamol (OR 1.42, 95% CI 1.16-1.75; p = 0.001) and cyclobenzaprine (OR 1.22, 95% CI 1.02-1.45; p = 0.029). CONCLUSIONS: Older adults using SMRs have an increased risk of injury. These findings provide evidence to support current recommendations to avoid the use of SMRs in elderly patients. C1 [Spence, Michele M.] Kaiser Permanente, Pharm Outcomes Res Grp, Downey, CA USA. [Shin, Patrick J.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Lee, Eric A.] Kaiser Permanente, West Los Angeles Med Ctr, Dept Internal Med, Los Angeles, CA USA. [Lee, Eric A.; Gibbs, Nancy E.] Kaiser Permanente Southern Calif Reg, High Risk Drugs Elderly, Oakland, CA USA. [Gibbs, Nancy E.] Kaiser Permanente, Baldwin Pk Med Ctr, Dept Family Practice, Baldwin Pk, CA USA. RP Spence, MM (reprint author), Kaiser Permanente, Pharm Outcomes Res Grp, Downey, CA USA. EM Michele.M.Spence@kp.org NR 21 TC 6 Z9 6 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL-AUG PY 2013 VL 47 IS 7-8 BP 993 EP 998 DI 10.1345/aph.1R735 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 225UP UT WOS:000324989500017 PM 23821610 ER PT J AU Allen, JL Kautz, SA Neptune, RR AF Allen, Jessica L. Kautz, Steven A. Neptune, Richard R. TI The influence of merged muscle excitation modules on post-stroke hemiparetic walking performance SO CLINICAL BIOMECHANICS LA English DT Article DE Forward dynamics simulation; Muscle synergies; Gait; Biomechanics ID MOTOR CONTROL; COORDINATION; PATTERNS; STROKE; PROGRESSION; LOCOMOTION; GAIT AB Background: Post-stroke subjects with hemiparesis typically utilize a reduced number of modules or co-excited muscles compared to non-impaired controls, with at least one module resembling the merging of two or more non-impaired modules. In non-impaired walking, each module has distinct contributions to important biomechanical functions, and thus different merged module combinations post-stroke may result in different functional consequences. Methods: Three-dimensional forward dynamics simulations were developed for non-impaired controls and two groups of post-stroke hemiparetic subjects with different merged module combinations to analyze how paretic leg muscle contributions to body support, forward propulsion, mediolateral control and leg swing are altered. Findings: The potential of the plantarflexors to generate propulsion was impaired in both hemiparetic groups while the remaining functional consequences differed depending on which modules were merged. Paretic leg swing was impaired during pre-swing when Modules 1 (hip abductors and knee extensors during early stance), and 2 (plantarflexors during late stance) were merged and during late swing when Modules 1 and 4 (hamstrings during late swing into early stance) were merged. When Modules 1 and 4 were merged, body support during early stance was also impaired. Interpretation: These results suggest that improving plantarflexor ability to generate propulsion is critical during rehabilitation regardless of module composition. If Modules 1 and 2 are merged, then rehabilitation should also focus on improving paretic leg pre-swing whereas if Modules 1 and 4 are merged, then rehabilitation should also focus on improving early stance body support and late paretic leg swing. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Allen, Jessica L.; Neptune, Richard R.] Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA. [Kautz, Steven A.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Kautz, Steven A.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Neptune, RR (reprint author), Univ Texas Austin, Dept Mech Engn, 204 E Dean Keeton St,Stop C2200, Austin, TX 78712 USA. EM rneptune@mail.utexas.edu OI Kautz, Steven/0000-0003-3151-8235 FU NIH [R01 HD46820]; National Science Foundation FX This work was supported by NIH Grant R01 HD46820 and the National Science Foundation Graduate Research Fellowship Program. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NICHD or NSF. NR 27 TC 18 Z9 19 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 J9 CLIN BIOMECH JI Clin. Biomech. PD JUL PY 2013 VL 28 IS 6 BP 697 EP 704 DI 10.1016/j.clinbiomech.2013.06.003 PG 8 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 225PT UT WOS:000324975500015 PM 23830138 ER PT J AU Wang, YJ Zhang, YL Hennig, K Gale, JP Hong, YJ Cha, AN Riley, M Wagner, F Haggarty, SJ Holson, E Hooker, J AF Wang, Yajie Zhang, Yan-Ling Hennig, Krista Gale, Jennifer P. Hong, Yijia Cha, Anna Riley, Misha Wagner, Florence Haggarty, Stephen J. Holson, Edward Hooker, Jacob TI Class I HDAC imaging using [H-3] CI-994 autoradiography SO EPIGENETICS LA English DT Article DE CI-994; HDAC; autradiography; benzamide; class I; density; inhibitor ID HISTONE DEACETYLASE INHIBITORS; SCHWANN-CELL MYELINATION; THERAPEUTIC AGENTS; RAT-BRAIN; PHASE-I; COMBINATION; DISEASE; CANCER; ACID; VIVO AB [H-3]CI-994, a radioactive isotopologue of the benzamide CI-994, a class I histone deacetylase inhibitor (HDACi), was evaluated as an autoradiography probe for ex vivo labeling and localizing of class I HDAC (isoforms 1-3) in the rodent brain. After protocol optimization, up to 80% of total binding was attributed to specific binding. Notably, like other benzamide HDACi, [H-3]CI-994 exhibits slow binding kinetics when measured in vitro with isolated enzymes and ex vivo when used for autoradiographic mapping of HDAC1-3 density. The regional distribution and density of HDAC1-3 was determined through a series of saturation and kinetics experiments. The binding properties of [H-3]CI-994 to HDAC1-3 were characterized and the data were used to determine the regional B-max of the target proteins. K-d values, determined from slice autoradiography, were between 9.17 and 15.6 nM. The HDAC1-3 density (B-max), averaged over whole brain sections, was of 12.9 picomol mg(-1) protein. The highest HDAC1-3 density was found in the cerebellum, followed by hippocampus and cortex. Moderate to low receptor density was found in striatum, hypothalamus and thalamus. These data were correlated with semi-quantitative measures of each HDAC isoform using western blot analysis and it was determined that autoradiographic images most likely represent the sum of HDAC1, HDAC2, and HDAC3 protein density. In competition experiments, [H-3]CI-994 binding can be dose-dependently blocked with other HDAC inhibitors, including suberoylanilide hydroxamic acid (SAHA). In summary, we have developed the first known autoradiography tool for imaging class I HDAC enzymes. Although validated in the CNS, [H-3]CI-994 will be applicable and beneficial to other target tissues and can be used to evaluate HDAC inhibition in tissues for novel therapies being developed. [H-3]CI-994 is now an enabling imaging tool to study the relationship between diseases and epigenetic regulation. C1 [Wang, Yajie; Hong, Yijia; Cha, Anna; Riley, Misha; Hooker, Jacob] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr,Dept Radiol, Charlestown, MA USA. [Zhang, Yan-Ling; Gale, Jennifer P.; Wagner, Florence; Holson, Edward] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Hennig, Krista; Haggarty, Stephen J.] Harvard Univ, Sch Med, Dept Neurol, Ctr Human Genet Res,Simches Res Ctr,CPZN 5242, Boston, MA 02115 USA. [Hennig, Krista; Haggarty, Stephen J.] Harvard Univ, Sch Med, Dept Psychiat, Ctr Human Genet Res,Simches Res Ctr,CPZN 5242, Boston, MA 02115 USA. RP Hooker, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr,Dept Radiol, Charlestown, MA USA. EM hooker@nmr.mgh.harvard.edu OI Hong, Helena/0000-0002-2232-6402; Hooker, Jacob/0000-0002-9394-7708; Haggarty, Stephen J./0000-0002-7872-168X FU NIH [5R01DA030321, P30DA028800, R01DA028301] FX The authors would like to thank Drs Jinsheng Yang and Wei Zhao for technical support in analysis of the autoradiography data, Dr Chao Wei's lab for mouse brain tissue, Drs Changning Wang and Frederick 'Al' Schroeder for scientific discussion and the NIH for financial support (5R01DA030321, P30DA028800, and R01DA028301). NR 45 TC 16 Z9 16 U1 0 U2 8 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 J9 EPIGENETICS-US JI Epigenetics PD JUL 1 PY 2013 VL 8 IS 7 BP 756 EP 764 DI 10.4161/epi.25202 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 222OU UT WOS:000324741500011 PM 23803584 ER PT J AU Roper, K Cooley, ME McDermott, K Fawcett, J AF Roper, Kristin Cooley, Mary E. McDermott, Kathleen Fawcett, Jacqueline TI Health-Related Quality of Life After Treatment of Hodgkin Lymphoma in Young Adults SO ONCOLOGY NURSING FORUM LA English DT Article ID LONG-TERM SURVIVORS; POSTTREATMENT CANCER SURVIVORS; SUPPORTIVE CARE SERVICES; DISEASE SURVIVORS; PSYCHOLOGICAL DISTRESS; PSYCHOSOCIAL INTERVENTIONS; DEPRESSIVE SYMPTOMS; GENERAL-POPULATION; BREAST-CANCER; ADAPTATION AB Purpose/Objectives: To describe changes in health-related quality of life (HRQOL) and to identify supportive care services used after treatment for Hodgkin lymphoma (HL) in young adults. Design: A longitudinal, repeated-measures study design was used to test the feasibility of data collection at the conclusion of treatment for HL and at one, three, and six months post-treatment. Setting: Participants were identified from two large comprehensive cancer centers in New England. Sample: 40 young adults with newly diagnosed, HL were enrolled in the study prior to the completion of chemotherapy or radiation. Methods: Data were collected by interviews, standardized questionnaires, and medical record reviews. Main Research Variables: HRQOL variables defined as symptom distress, functional status, emotional distress, and intimate relationships; use of specific supportive care services; and baseline demographic and disease-related information. Findings: Results indicate that symptom distress improved at one month post-treatment and remained low at three and six months. Similarly, functional status improved at one month post-treatment. Only 13% of the sample had significant emotional distress at baseline, and this decreased to 8% over time. Patients placed high value on their intimate relationships (i.e., family and friends or sexual partners). A variety of supportive care services were used after treatment, the most common of which were related to economic issues. However, by six months post-treatment, services shifted toward enhancing nutrition and fitness. Conclusions: The results from this study suggest that HRQOL in young adults with HL improved one-month post-treatment and that interest in using supportive care services was high. Implications for Nursing: Facilitating the use of supportive care services at the end of cancer treatment appears to be an important part of helping young adults transition to survivorship. Knowledge Translation: Supportive care services appear to be a vital component of the transition to survivorship and often change over time from an emphasis on economic issues to enhancing wellness through nutrition and fitness programs. C1 [Roper, Kristin; Cooley, Mary E.] Dana Farber Canc Inst, Phyllis F Cantor Ctr, Boston, MA 02115 USA. [Cooley, Mary E.; Fawcett, Jacqueline] Univ Massachusetts, Coll Nursing & Exercise Sci, Boston, MA 02125 USA. [McDermott, Kathleen] Dana Farber Canc Inst, Lymphoma Res Program, Boston, MA 02115 USA. RP Roper, K (reprint author), Dana Farber Canc Inst, Phyllis F Cantor Ctr, Boston, MA 02115 USA. EM kroper@partners.org FU ONS Foundation; Dana-Farber Cancer Institute; National Cancer Institute [1 U56 CA11863502] FX Kristin Roper, RN, MS, is a clinical inquiry specialist at the Phyllis F. Cantor Center, Dana-Farber Cancer Institute; Mary E. Cooley, PhD, RN, FAAN, is a nurse scientist at the Phyllis F. Cantor Center, Dana-Farber Cancer Institute, and an assistant professor in the College of Nursing and Exercise Science at the University of Massachusetts; Kathleen McDermott, RN, BSN, OCN (R), is an RN in the lymphoma research program at Dana-Farber Cancer Institute; and Jacqueline Fawcett, PhD, FAAN, is a professor in the College of Nursing and Exercise Science at the University of Massachusetts, all in Boston. The authors take full responsibility for the content of this article. This article was supported in part by an ONS Foundation 2004 Novice Researcher Mentorship Grant, the Dana-Farber Cancer Institute 2004 Friends Grant, and a grant from the National Cancer Institute (#1 U56 CA11863502). Roper can be reached at kropergpartners.org, with copy to editor at ONFEditorgons.org. (Submitted April 2012. Accepted for publication October 12, 2012.) NR 77 TC 4 Z9 4 U1 0 U2 7 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD JUL PY 2013 VL 40 IS 4 BP 349 EP 360 DI 10.1188/13.ONF.349-360 PG 12 WC Oncology; Nursing SC Oncology; Nursing GA 220EO UT WOS:000324565200008 PM 23803268 ER PT J AU Patel, M Vavvas, DG AF Patel, Mrinali Vavvas, Demetrios G. TI Fundus Autofluorescence in Ampiginous Choroiditis SO OPHTHALMIC SURGERY LASERS & IMAGING LA English DT Article AB Fundus autofluorescence (FAF) is being increasingly employed in the evaluation of retinal diseases. We report the first description of FAF findings during the natural history of ampiginous choroiditis and correlate these findings to fundus photography, infrared imaging, and cross-sectional optical coherence tomography. In a patient with a 12-month recurring, relapsing course of ampiginous choroiditis, there was a predictable pattern of FAF findings. At the time of presentation with a whitish-yellow, creamy clinical lesion, FAF reveals a diffuse, subtle hyperautofluorescence at the site of activity. As the clinical lesion fades, the FAF takes on a more intense, discrete, coalesced hyperautofluorescence, which decreases and becomes stippled over time, eventually giving way to a patch of hypoautofluorescence at the site of inactivity. Examination over the patient's long course suggests that FAF evolves predictably during exacerbations and remissions, and the FAF findings reveal activity well after the clinical lesion resolves. FAF is a simple, noninvasive, and effective modality for following the evolution of ampiginous choroiditis. C1 [Patel, Mrinali; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, Boston, MA USA. RP Vavvas, DG (reprint author), Mass Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM demetrios_vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 NR 7 TC 0 Z9 0 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1542-8877 J9 OPHTHAL SURG LAS IM JI Ophthalmic Surg. Lasers Imaging PD JUL-AUG PY 2013 VL 44 IS 4 BP 393 EP 397 DI 10.3928/23258160-20130715-10 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 219UB UT WOS:000324534900014 PM 23883534 ER PT J AU Metti, AL Cauley, JA Ayonayon, HN Harris, TB Rosano, C Williamson, JD Yaffe, K AF Metti, Andrea L. Cauley, Jane A. Ayonayon, Hilsa N. Harris, Tamara B. Rosano, Caterina Williamson, Jeff D. Yaffe, Kristine CA Hlth Aging & Body Composition Stud TI The Demographic and Medical Correlates of Plasma A beta 40 and A beta 42 SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE plasma amyloid beta; dementia; cognitive decline; biomarker; epidemiology ID MILD COGNITIVE IMPAIRMENT; INSULIN-DEGRADING ENZYME; ALZHEIMERS-DISEASE; CEREBROSPINAL-FLUID; BODY-COMPOSITION; INFLAMMATORY MARKERS; AFRICAN-AMERICAN; APOLIPOPROTEIN-E; AMYLOID-BETA; RISK AB Plasma amyloid -42 (A42) and A42/A40 are increasingly recognized as biomarkers for dementia, with low levels indicating increased risk. Little is known about the demographic and medical correlates of plasma A40 or A42. In 997 community-dwelling, nondemented older adults from the Health, Aging, and Body Composition Study, we determined the cross-sectional association between a wide range of demographic and medical variables with A40 and A42. In multivariate stepwise linear regression models, A40 was significantly associated with race (=-14.70, F=22.01, P<0.0001), age (=1.34, F=6.39, P=0.01), creatinine (=52.91, F=151.77, P<0.0001), and the serum brain-derived neurotrophic factor (=-0.0004, F=7.34, P=0.007); A42 was significantly associated with race (=-3.72, F=30.83, P<0.0001), sex (=1.39, F=4.32, P=0.04), education (=1.50, F=4.78, P=0.03), apolipoprotein E e4 genotype (=-2.82, F=16.57, P<0.0001), and creatinine (=9.32, F=120.09, P<0.0001). These correlates should be considered as potential confounders in future studies investigating plasma A as a biomarker of dementia. Understanding fully how these correlates mediate or modify the association between plasma A and dementia will be a fundamental step in determining the biological pathways through which plasma A40 and A42 are associated with dementia, and in determining their full potential as biomarkers. C1 [Metti, Andrea L.; Cauley, Jane A.; Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Ayonayon, Hilsa N.; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Harris, Tamara B.] NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Williamson, Jeff D.] Wake Forest Univ, Med Ctr, Dept Geriatr & Gerontol, Winston Salem, NC USA. RP Metti, AL (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, Dept Epidemiol, 130 N Bellefield,4th Floor,Room 456, Pittsburgh, PA 15213 USA. EM alw111@pitt.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, K24 AG031155]; NINR [R01-NR012459]; NIH, National Institute on Aging; National Institutes of Health [2T32AG000181] FX The Health, Aging and Body Composition Study is supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A. L. M. is supported by the National Institutes of Health Training Grant (2T32AG000181). K.Y. is supported in part by NIA Grant K24 AG031155. The remaining authors declare no conflicts of interest. NR 34 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2013 VL 27 IS 3 BP 244 EP 249 DI 10.1097/WAD.0b013e318260a8cb PG 6 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 210FM UT WOS:000323814700008 PM 22732677 ER PT J AU Kato, S Zhang, RG Roberts, JD AF Kato, Shin Zhang, Ruiguang Roberts, Jesse D., Jr. TI Proprotein convertases play an important role in regulating PKGI endoproteolytic cleavage and nuclear transport SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE guanosine 3 ',5 '-cyclic monophosphate-dependent protein kinase I; proprotein convertase; nitric oxide and guanosine 3 ',5 '-cyclic monophosphate signaling ID DEPENDENT PROTEIN-KINASE; SMOOTH-MUSCLE-CELLS; KEX2-LIKE PROCESSING ENDOPROTEASE; NITRIC-OXIDE; CYCLIC-GMP; GENE-EXPRESSION; IN-VITRO; MATRIX-METALLOPROTEINASE; PROHORMONE CONVERTASES; SECRETORY PATHWAY AB Nitric oxide and cGMP modulate vascular smooth muscle cell (SMC) phenotype by regulating cell differentiation and proliferation. Recent studies suggest that cGMP-dependent protein kinase I (PKGI) cleavage and the nuclear translocation of a constitutively active kinase fragment, PKGI gamma, are required for nuclear cGMP signaling in SMC. However, the mechanisms that control PKGI proteolysis are unknown. Inspection of the amino acid sequence of a PKGI cleavage site that yields PKGI gamma and a protease database revealed a putative minimum consensus sequence for proprotein convertases (PCs). Therefore we investigated the role of PCs in regulating PKGI proteolysis. We observed that overexpression of PCs, furin and PC5, but not PC7, which are all expressed in SMC, increase PKGI cleavage in a dose-dependent manner in human embryonic kidney (HEK) 293 cells. Moreover, furin-induced proteolysis of mutant PKGI, in which alanines were substituted into the putative PC consensus sequence, was decreased in these cells. In addition, overexpression of furin increased PKGI proteolysis in LoVo cells, which is an adenocarcinoma cell line expressing defective furin without PC activity. Also, expression of alpha(1)-PDX, an engineered serpin-like PC inhibitor, reduced PC activity and decreased PKGI proteolysis in HEK293 cells. Last, treatment of low-passage rat aortic SMC with membrane-permeable PC inhibitor peptides decreased cGMP-stimulated nuclear PKGI gamma translocation. These data indicate for the first time that PCs have a role in regulating PKGI proteolysis and the nuclear localization of its active cleavage product, which are important for cGMP-mediated SMC phenotype. C1 [Kato, Shin; Zhang, Ruiguang; Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Gen Med Serv, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Pain Med & Crit Care, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Pediat, Div Newborn Med, Boston, MA 02114 USA. [Kato, Shin; Zhang, Ruiguang; Roberts, Jesse D., Jr.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Roberts, JD (reprint author), Massachusetts Gen Hosp East, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM roberts@cvrc.mgh.harvard.edu FU National Heart, Lung, and Blood Institute [HL-094608]; MGH Executive Committee for Research; Department of Anesthesia, Critical Care, and Pain Medicine FX This work was supported by National Heart, Lung, and Blood Institute Grant HL-094608, the MGH Executive Committee for Research, and Department of Anesthesia, Critical Care, and Pain Medicine. NR 95 TC 3 Z9 3 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD JUL PY 2013 VL 305 IS 2 BP L130 EP L140 DI 10.1152/ajplung.00391.2012 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 183MC UT WOS:000321818300004 PM 23686857 ER PT J AU Routson, RL Clark, DJ Bowden, MG Kautz, SA Neptune, RR AF Routson, Rebecca L. Clark, David J. Bowden, Mark G. Kautz, Steven A. Neptune, Richard R. TI The influence of locomotor rehabilitation on module quality and post-stroke hemiparetic walking performance SO GAIT & POSTURE LA English DT Article DE Hemiparesis; Biomechanics; Therapy; Muscle synergies ID MUSCLE CONTRIBUTIONS; BODY SUPPORT; PROPULSION; STROKE; GAIT; SPEED AB Recent studies have suggested the biomechanical subtasks of walking can be produced by a reduced set of co-excited muscles or modules. Individuals post-stroke often exhibit poor inter-muscular coordination characterized by poor timing and merging of modules that are normally independent in healthy individuals. However, whether locomotor therapy can influence module composition and timing and whether these improvements lead to improved walking performance is unclear. The goal of this study was to examine the influence of a locomotor rehabilitation therapy on module composition and timing and post-stroke hemiparetic walking performance. Twenty-seven post-stroke hemiparetic subjects participated in a 12-week locomotor intervention incorporating treadmill training with body weight support and manual trainers accompanied by training overground walking. Electromyography (EMG), kinematic and ground reaction force data were collected from subjects both pre- and post-therapy and from 19 age-matched healthy controls walking on an instrumented treadmill at their self-selected speed. Non-negative matrix factorization was used to identify the module composition and timing from the EMG data. Module timing and composition, and various measures of walking performance were compared pre- and post-therapy. In subjects with four modules pre- and post-therapy, locomotor training resulted in improved timing of the ankle plantarflexor module and a more extended paretic leg angle that allowed the subjects to walk faster and with more symmetrical propulsion. In addition, subjects with three modules pre-therapy increased their number of modules and improved walking performance post-therapy. Thus, locomotor training has the potential to influence module composition and timing, which can lead to improvements walking performance. (C) 2013 Elsevier B.V. All rights reserved. C1 [Routson, Rebecca L.; Neptune, Richard R.] Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA. [Clark, David J.] Malcom Randall VA Med Ctr, Brain Rehabil Res Ctr, Gainesville, FL USA. [Clark, David J.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Bowden, Mark G.; Kautz, Steven A.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Bowden, Mark G.; Kautz, Steven A.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. RP Neptune, RR (reprint author), Univ Texas Austin, Dept Mech Engn, 204 E Dean Keeton St,Stop C2200, Austin, TX 78712 USA. EM rneptune@mail.utexas.edu OI Kautz, Steven/0000-0003-3151-8235 FU NIH [R01 HD46820]; Department of Veterans Affairs RRD Merit Review [B3983-R]; NSF GRFP FX This work was supported by NIH Grant R01 HD46820, Department of Veterans Affairs RR&D Merit Review B3983-R, and the NSF GRFP. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NICHD, NSF, the Department of Veterans Affairs or the United States Government. NR 24 TC 31 Z9 32 U1 3 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0966-6362 J9 GAIT POSTURE JI Gait Posture PD JUL PY 2013 VL 38 IS 3 BP 511 EP 517 DI 10.1016/j.gaitpost.2013.01.020 PG 7 WC Neurosciences; Orthopedics; Sport Sciences SC Neurosciences & Neurology; Orthopedics; Sport Sciences GA 216KZ UT WOS:000324283600026 PM 23489952 ER PT J AU Sowers, MR Zheng, HY Greendale, GA Neer, RM Cauley, JA Ellis, J Johnson, S Finkelstein, JS AF Sowers, MaryFran R. Zheng, Huiyong Greendale, Gail A. Neer, Robert M. Cauley, Jane A. Ellis, Jayne Johnson, Sarah Finkelstein, Joel S. TI Changes in Bone Resorption Across the Menopause Transition: Effects of Reproductive Hormones, Body Size, and Ethnicity SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID EARLY PERIMENOPAUSAL WOMEN; FINAL MENSTRUAL PERIOD; LINKED N-TELOPEPTIDES; LIFE-STYLE FACTORS; MINERAL DENSITY; POSTMENOPAUSAL WOMEN; ENDOGENOUS HORMONES; OLDER WOMEN; INACCURACIES INHERENT; BIOCHEMICAL MARKERS AB Objective: Our objective was to characterize changes in bone resorption in relation to the final menstrual period (FMP), reproductive hormones, body mass index (BMI), and ethnicity. Methods: Urinary type I collagen N-telopeptide (NTX), estradiol, and FSH levels were measured annually for up to 8 years spanning the menopause transition in 918 African American, Chinese, Japanese, or Caucasian women. Results: Urinary NTX began to increase sharply about 2 years before the FMP, reaching its peak level about 1 to 1.5 years after the FMP. NTX levels declined modestly from 2 to 6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began increasing rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI <25 kg/m(2) and smallest in women with BMI >30 kg/m(2). Increases in NTX were greatest in Japanese women and smallest in African Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI. Summary: During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss. C1 [Sowers, MaryFran R.; Zheng, Huiyong] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Greendale, Gail A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Neer, Robert M.; Finkelstein, Joel S.] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ellis, Jayne] Alere Int, Cranfield, Beds, England. [Johnson, Sarah] SPD Dev Co Ltd, Bedford, England. RP Finkelstein, JS (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Thier 1051,50 Blossom St, Boston, MA 02114 USA. EM jfinkelstein@partners.org OI Cauley, Jane A/0000-0003-0752-4408 FU National Institutes of Health (NIH), U.S. Department of Health and Human Services, through the National Institute of Aging (NIA); National Institute of Nursing Research (NINR); NIH Office of Research on Women's Health (ORWH) [U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495] FX The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), U.S. Department of Health and Human Services, through the National Institute of Aging (NIA), the National Institute of Nursing Research (NINR), and the NIH Office of Research on Women's Health (ORWH) (Grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH, or the NIH. NR 51 TC 20 Z9 21 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP 2854 EP 2863 DI 10.1210/jc.2012-4113 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600049 PM 23666961 ER PT J AU Misra, M Katzman, DK Clarke, H Snelgrove, D Brigham, K Miller, KK Klibanski, A AF Misra, Madhusmita Katzman, Debra K. Clarke, Hannah Snelgrove, Deirdre Brigham, Kathryn Miller, Karen K. Klibanski, Anne TI Hip Structural Analysis in Adolescent Boys With Anorexia Nervosa and Controls SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TRABECULAR STRUCTURE-ANALYSIS; PANEL VOLUME CT; BONE MASS; OSTEOPOROTIC FRACTURES; POSTMENOPAUSAL WOMEN; FINITE-ELEMENT; DISTAL RADIUS; DENSITY; GIRLS; GEOMETRY AB Context: We have reported lower hip bone mineral density (BMD) in adolescent boys with anorexia nervosa (AN) compared with controls. Although studies have described bone structure in girls with AN, these data are not available for boys. Hip structural analysis (HSA) using dual-energy x-ray absorptiometry is a validated technique to assess hip geometry and strength while avoiding radiation associated with quantitative computed tomography. Objective: We hypothesized that boys with AN would have impaired hip structure/strength (assessed by HSA) compared with controls. Design and Setting: We conducted a cross-sectional study at a clinical research center. Subjects and Intervention: We used HSA techniques on hip dual-energy x-ray absorptiometry scans in 31 previously enrolled boys, 15 with AN and 16 normal-weight controls, 12 to 19 years old. Results: AN boys had lower body mass index SD score (P < .0001), testosterone (P = .0005), and estradiol (P = .006) than controls. A larger proportion of AN boys had BMD Z-scores <-1 at the femoral neck (60% vs 12.5%, P = 0008). Using HSA, at the narrow neck and trochanter region, boys with AN had lower cross-sectional area (P = .03, 0.02) and cortical thickness (P = .02, 0.03). Buckling ratio at the trochanter region was higher in AN (P = .008). After controlling for age and height, subperiosteal width at the femoral shaft, cross-sectional moment of inertia (narrow neck and femoral shaft), and section modulus (all sites) were lower in AN. The strongest associations of HSA measures were observed with lean mass, testosterone, and estradiol. On multivariate analysis, lean mass remained associated with most HSA measures. Conclusions: Boys with AN have impaired hip geometric parameters, associated with lower lean mass. C1 [Misra, Madhusmita; Clarke, Hannah; Miller, Karen K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Pediat Endocrine, Boston, MA 02114 USA. [Brigham, Kathryn] Massachusetts Gen Hosp, Div Adolescent & Young Adult Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Katzman, Debra K.; Snelgrove, Deirdre] Hosp Sick Children, Div Adolescent Med, Toronto, ON M5G 2L3, Canada. [Katzman, Debra K.; Snelgrove, Deirdre] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 2L3, Canada. Univ Toronto, Toronto, ON M5G 2L3, Canada. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457,55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org FU National Institutes of Health [1 UL1 RR025758-01, 2 RO1 DK062249, 1 K24 HD071843-01A1] FX This work was supported by National Institutes of Health Grants 1 UL1 RR025758-01, 2 RO1 DK062249, and 1 K24 HD071843-01A1. NR 28 TC 12 Z9 12 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2013 VL 98 IS 7 BP 2952 EP 2958 DI 10.1210/jc.2013-1457 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 196MV UT WOS:000322780600061 PM 23653430 ER PT J AU Keliher, EJ Reiner, T Earley, S Klubnick, J Tassa, C Lee, AJ Ramaswamy, S Bardeesy, N Hanahan, D DePinho, RA Castro, CM Weissleder, R AF Keliher, Edmund J. Reiner, Thomas Earley, Sarah Klubnick, Jenna Tassa, Carlos Lee, Andrew J. Ramaswamy, Sridhar Bardeesy, Nabeel Hanahan, Douglas DePinho, Ronald A. Castro, Cesar M. Weissleder, Ralph TI Targeting Cathepsin E in Pancreatic Cancer by a Small Molecule Allows In Vivo Detection SO NEOPLASIA LA English DT Article ID EPITHELIAL-CELLS; EXPRESS MARKERS; TUMORS; PROTEASE; ADENOCARCINOMAS; DIAGNOSIS; MODEL AB When resectable, invasive pancreatic ductal adenocarcinoma (PDAC) is most commonly treated with surgery and radiochemotherapy. Given the intricate local anatomy and locoregional mode of dissemination, achieving clean surgical margins can be a significant challenge. On the basis of observations that cathepsin E (CTSE) is overexpressed in PDAC and that an United States Food and Drug Administration (FDA)-approved protease inhibitor has high affinity for CTSE, we have developed a CTSE optical imaging agent [ritonavir tetramethyl-BODIPY (RIT-TMB)] for potential intraoperative use. We show nanomolar affinity [half maximal inhibitory concentration (IC50) of 39.9 +/- 1.2 nM] against CTSE of the RIT-TMB in biochemical assays and intracellular accumulation and target-to-background ratios that allow specific delineation of individual cancer cells. This approach should be useful for more refined surgical staging, planning, and resection with curative intent. C1 [Keliher, Edmund J.; Reiner, Thomas; Earley, Sarah; Klubnick, Jenna; Tassa, Carlos; Castro, Cesar M.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Reiner, Thomas] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Lee, Andrew J.; Ramaswamy, Sridhar; Bardeesy, Nabeel; Castro, Cesar M.; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Hanahan, Douglas] Swiss Inst Expt Canc Res, Lausanne, Switzerland. [DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu FU Lustgarten Foundation for Pancreatic Cancer Research; National Institute of Health [2P01CA117969, 2P50CA086355, PO1-AI54904] FX This work was supported in part by a grant from the Lustgarten Foundation for Pancreatic Cancer Research and by grants from the National Institute of Health (2P01CA117969, 2P50CA086355, and PO1-AI54904). NR 26 TC 11 Z9 11 U1 2 U2 21 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD JUL PY 2013 VL 15 IS 7 BP 684 EP + DI 10.1593/neo.13276 PG 13 WC Oncology SC Oncology GA 219DY UT WOS:000324487100001 PM 23814481 ER PT J AU Majumdar, S Gong, EM Di Vizio, D Dreyfuss, J DeGraff, DJ Hager, MH Park, PJ Bellmunt, J Matusik, RJ Rosenberg, JE Adam, RM AF Majumdar, Shyama Gong, Edward M. Di Vizio, Dolores Dreyfuss, Jonathan DeGraff, David J. Hager, Martin H. Park, Peter J. Bellmunt, Joaquim Matusik, Robert J. Rosenberg, Jonathan E. Adam, Rosalyn M. TI Loss of Sh3gl2/Endophilin A1 Is a Common Event in Urothelial Carcinoma that Promotes Malignant Behavior SO NEOPLASIA LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; INVASIVE BLADDER-CANCER; TUMOR-SUPPRESSOR LOCI; PHASE-II TRIAL; SMOOTH-MUSCLE; GROWTH-FACTOR; TRACT CARCINOMA; DOWN-REGULATION; STEM-CELLS; GENE AB Urothelial carcinoma (UC) causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1) as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR) and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1) enhanced proliferation and colony formation in vitro, 2) inhibited EGF-induced EGFR internalization and increased EGFR activation, 3) stimulated phosphorylation of Src family kinases and STAT3, and 4) promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression. C1 [Majumdar, Shyama; Gong, Edward M.; Di Vizio, Dolores; Hager, Martin H.; Adam, Rosalyn M.] Harvard Univ, Sch Med, Boston Childrens Hosp, Urol Dis Res Ctr, Boston, MA USA. [Majumdar, Shyama; Gong, Edward M.; Di Vizio, Dolores; Hager, Martin H.; Adam, Rosalyn M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Di Vizio, Dolores] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Canc Biol Program, Los Angeles, CA 90048 USA. [Dreyfuss, Jonathan] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [DeGraff, David J.; Matusik, Robert J.] Vanderbilt Univ, Med Ctr, Dept Urol Surg, Nashville, TN USA. [DeGraff, David J.; Matusik, Robert J.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA. [Bellmunt, Joaquim] Univ Hosp Del Mar IMIM, Med Oncol Serv, Barcelona, Spain. [Rosenberg, Jonathan E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rosenberg, Jonathan E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Adam, RM (reprint author), Boston Childrens Hosp, John F Enders Res Labs, Urol Dis Res Ctr, Rm 1061-1,300 Longwood Ave, Boston, MA 02115 USA. EM rosalyn.adam@childrens.harvard.edu OI Dreyfuss, Jonathan/0000-0001-7242-3991 FU Children's Urological Foundation; American Cancer Society Great Lakes Division-Michigan Cancer Research Fund Postdoctoral Fellowship FX The authors acknowledge the financial support from the Children's Urological Foundation. D.J.D. was supported by the American Cancer Society Great Lakes Division-Michigan Cancer Research Fund Postdoctoral Fellowship. NR 49 TC 11 Z9 12 U1 0 U2 2 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD JUL PY 2013 VL 15 IS 7 BP 749 EP + DI 10.1593/neo.121956 PG 13 WC Oncology SC Oncology GA 219DY UT WOS:000324487100007 PM 23814487 ER PT J AU Prasad, R Katiyar, SK AF Prasad, Ram Katiyar, Santosh K. TI Prostaglandin E-2 Promotes UV Radiation-Induced Immune Suppression through DNA Hypermethylation SO NEOPLASIA LA English DT Article ID GREEN TEA POLYPHENOLS; INDUCED SYSTEMIC IMMUNOSUPPRESSION; NONMELANOMA SKIN-CANCER; ULTRAVIOLET-RADIATION; MOUSE SKIN; MICE; RECEPTOR; GENES; METHYLATION; IRRADIATION AB Exposure of mice to UV radiation results in suppression of the contact hypersensitivity (CHS) response. Here, we report that the UV-induced suppression of CHS is associated with increases in the levels of cyclooxygenase-2 (COX-2), prostaglandin E-2 (PGE(2)), and PGE2 receptors in the exposed skin. UV radiation-induced suppression of CHS was inhibited by topical treatment of the skin with celecoxib or indomethacin (inhibitors of COX-2) or AH6809 (an EP2 antagonist). Moreover, mice deficient in COX-2 were found to be resistant to UV-induced suppression of CHS. The exposure of wild-typemice to UVB radiation resulted in DNA hypermethylation, increased DNA methyltransferase (Dnmt) activity, and elevated levels of Dnmt1, Dnmt3a, and Dnmt3b proteins in the skin, and these responses were downregulated on topical treatment of the site of exposure after irradiation with indomethacin or EP2 antagonist. Topical treatment of UVB-exposed COX-2-deficient mice with PGE(2) enhanced the UVB-induced suppression of CHS as well as global DNA methylation and elevated the levels of Dnmt activity and Dnmt proteins in the skin. Intraperitoneal injection of 5-aza-2'-deoxycytidine (5-Aza-dc), a DNA demethylating agent, restored the CHS response to 2,4-dinitrofluorobenzene in UVB-exposed skin and this was associated with the reduction in global DNA methylation and Dnmt activity and reduced levels of Dnmt proteins. Furthermore, treatment with 5-Aza-dc reversed the effect of PGE(2) on UV-induced suppression of CHS in COX-2-deficient mice. These findings reveal a previously unrecognized role for PGE(2) in the promotion of UVB-induced immunosuppression and indicate that it is mediated through PGE(2) regulation of DNA methylation. C1 [Prasad, Ram; Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Skin Dis Res Ctr, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 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 National Institutes of Health/National Center for Complementary and Alternative Medicine/National Cancer Institute [CA140197, AT002536]; Veterans Administration Merit Review Award [1I01BX001410-01] FX This research was financially supported by the National Institutes of Health/National Center for Complementary and Alternative Medicine/National Cancer Institute (CA140197 and AT002536 to S. K. K.) and the Veterans Administration Merit Review Award (1I01BX001410-01 to S. K. K.). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 7 Z9 7 U1 0 U2 6 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD JUL PY 2013 VL 15 IS 7 BP 795 EP 804 DI 10.1593/neo.13424 PG 10 WC Oncology SC Oncology GA 219DY UT WOS:000324487100011 PM 23814491 ER PT J AU Timpone, VM Hirsch, JA Gilligan, CJ Chandra, RV AF Timpone, Vincent M. Hirsch, Joshua A. Gilligan, Christopher J. Chandra, Ronil V. TI Computed Tomography Guidance for Spinal Intervention: Basics of Technique, Pearls, and Avoiding Pitfalls SO PAIN PHYSICIAN LA English DT Review DE Computed tomography; fluoroscopy; analgesia; epidural injection; spinal injection; back pain; safety ID EPIDURAL STEROID INJECTIONS; CT FLUOROSCOPY; RADIATION; EXPOSURE; PAIN; POSITION; PATIENT AB The utilization of spinal interventional pain techniques has grown rapidly over the last decade. However, practitioners use widely different techniques in these procedures, particularly in the use of image guidance. The importance of image guidance was highlighted by the fact that in recent systematic reviews on therapeutic effectiveness of epidural steroid injections and facet joint interventions, only studies that used image guidance were included. The choice of image guidance remains a matter of physician preference with conventional fluoroscopic or Computed Tomography (CT) guidance most common. There are many advantages to CT guidance for certain spinal interventional pain procedures, mainly due to increased needle tip positioning accuracy. CT guidance provides greater anatomical detail that facilitates accurate needle trajectory planning, monitoring and final placement. Unlike conventional fluoroscopy that may be hindered by tissue overlap and lack of surrounding anatomical detail CT guidance offers direct visualization of the entire needle trajectory and the surrounding soft tissue and bone structures. Large osteophytes and adjacent vascular structures can be identified and safely avoided. The goals of this narrative review are to provide a basic overview of CT techniques available for spinal interventional pain procedures, to discuss the potential advantages and disadvantages of CT guidance, to provide a simple step-by-step approach to use of CT guidance, to share technical pearls, and to discuss methods to avoid potential pitfalls. This review will provide interventional pain physicians with knowledge of relevant CT image acquisition techniques and appropriate radiation dose reduction strategies. This will contribute to increased technical success rates while reducing radiation dose to the patient and staff. C1 [Timpone, Vincent M.; Hirsch, Joshua A.] Harvard Univ, Sch Med, Dept Radiol, Div Diagnost Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Dept Radiol, Div Intervent Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Gilligan, Christopher J.] Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Ctr Pain Med,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Chandra, Ronil V.] Monash Hlth, Monash Med Ctr, Dept Diagnost Imaging, Intervent Neuroradiol Unit, Melbourne, Vic, Australia. RP Timpone, VM (reprint author), Harvard Univ, Sch Med, Dept Radiol, Div Diagnost Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM vtimpone@partners.org RI chen, zhu/K-5923-2013 NR 24 TC 3 Z9 3 U1 0 U2 2 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2013 VL 16 IS 4 BP 369 EP 377 PG 9 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 213EI UT WOS:000324037000025 PM 23877453 ER PT J AU Manchikanti, L Pampati, V Falco, FJE Hirsch, JA AF Manchikanti, Laxmaiah Pampati, Vidyasagar Falco, Frank J. E. Hirsch, Joshua A. TI Assessment of the Growth of Epidural Injections in the Medicare Population from 2000 to 2011 SO PAIN PHYSICIAN LA English DT Review DE Spinal pain; interventional pain management; epidural injections; caudal epidural; lumbar epidural; cervical epidural; cervical transforaminal; lumbar transforaminal ID LOW-BACK-PAIN; ACTIVE-CONTROL TRIAL; RANDOMIZED CONTROLLED-TRIAL; CENTRAL SPINAL STENOSIS; LUMBAR DISC HERNIATION; COST-UTILITY ANALYSIS; MANAGING CHRONIC PAIN; DOUBLE-BLIND TRIAL; 2-YEAR FOLLOW-UP; SURGERY SYNDROME AB Background: Among the many diagnostic and therapeutic interventions available for the management of chronic pain, epidural steroid injections are one of the most commonly used modalities. The explosive growth of this technique is relevant in light of the high cost of health care in the United States and abroad, the previous literature assessing the effectiveness of epidural injections has been sparse with highly variable outcomes based on technique, outcome measures, patient selection, and methodology. However, the recent assessment of fluoroscopically directed epidural injections has shown improved evidence with proper inclusion criteria, methodology, and outcome measures. The exponential growth of epidural injections is illustrated in multiple reports. The present report is an update of the analysis of the growth of epidural injections in the Medicare population from 2000 to 2011 in the United States. Study Design: Analysis of utilization patterns of epidural procedures in the Medicare population in the United States from 2000 to 2011. Objectives: The primary purpose of this assessment was to evaluate the use of all types of epidural injections (i.e., caudal, interlaminar, and transforaminal in the lumbar, cervical, and thoracic regions) with an assessment of specialty and regional characteristics. Methods: This assessment was performed utilizing the Centers for Medicare and Medicaid Services (CMS) Physician/Supplier Procedure Summary (PSPS) Master data from 2000 to 2011. Results: Epidural injections in Medicare beneficiaries increased significantly from 2000 to 2011. Overall, epidural injections increased 130% per 100,000 Medicare beneficiaries with an annual increase of 7.5%. The increases per 100,000 Medicare recipients were 123% for cervical/thoracic interlaminar epidural injections; 25% for lumbar/sacral interlaminar, or caudal epidural injections; 142% for cervical/thoracic transforaminal epidural injections; and 665% for lumbar/sacral transforaminal epidural injections. The use of epidurals increased 224% in the radiologic specialties (interventional radiology and diagnostic radiology) and 145% in psychiatric settings, whereas and physical medicine and rehabilitation physicians' use of epidurals increased 520%. Limitations: Study limitations include lack of inclusion of Medicare Advantage patients. In addition, the statewide data is based on claims which may include the contiguous or other states. Conclusions: Epidural injections in Medicare recipients increased significantly. The growth was significant for some specialties (radiology, physical medicine and rehabilitation, and psychiatry) and for certain procedures (lumbosacral transforaminal epidural injections). C1 [Manchikanti, Laxmaiah; Pampati, Vidyasagar] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys, Newark, DE USA. [Falco, Frank J. E.] Temple Univ Hosp & Med Sch, Pain Med Fellowship Program, Philadelphia, PA 19140 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Endovasc Neurosurg & Neuroendovasc Program, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 91 TC 47 Z9 50 U1 0 U2 2 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2013 VL 16 IS 4 BP E349 EP E363 PG 15 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 213EI UT WOS:000324037000002 PM 23877459 ER PT J AU Saxena, AP Hirsch, AE Yoo, AJ Gilligan, C Hirsch, JA AF Saxena, Akriti P. Hirsch, Ariel E. Yoo, Albert J. Gilligan, Christopher Hirsch, Joshua A. TI The Use of Advanced Imaging and Representation of Workers Compensation in Vertebral Augmentation: A Single-Center Comparison with the INVEST Trial SO PAIN PHYSICIAN LA English DT Review DE Spinal fractures/therapy; vertebroplasty/methods; kyphoplasty; evidence-based medicine; pain management; treatment outcome ID OSTEOPOROTIC COMPRESSION FRACTURES; PERCUTANEOUS VERTEBROPLASTY; CONSERVATIVE THERAPY; CLINICAL-OUTCOMES; RANDOMIZED-TRIAL; RESEARCH DESIGN; FOLLOW-UP; PAIN; PREDICTORS AB Background: Vertebral augmentation (VA) techniques have changed the paradigm of treatment during the past decade and involve injection of polymethylmethacrylate (PMMA) cement directly into a compressed vertebral body. During the summer of 2009, the INVEST trial was one of 2 randomized controlled studies that reported equivalence between vertebroplasty and a control procedure. Objective: In this analysis, we sought to compare the subset of patients studied in the INVEST trial to a tertiary academic institution with respect to 2 variables: Workers compensation status and presence of advanced imaging prior to the procedure. Study Design: Retrospective review of 634 procedures. Methods: We performed a retrospective review of 634 vertebral augmentation procedures at our institution between June 2004 and August 2008, overlapping with the dataset of the INVEST trial. The primary comparison was whether patients received Workers compensation and/or advanced imaging prior to the procedure. The study was IRB approved, and in accordance with HIPAA guidelines. Results: There were 409 patients who underwent 634 procedures between June 2004 and August 2008. Among 634 procedures, only 3 included Workers compensation. Therefore, the majority of patients (> 99%) did not receive Workers compensation compared to the INVEST trial (11 - 13%). Similarly, in 629 out of 634 procedures (99.2%), patients underwent advanced imaging comprised of magnetic resonance imaging (MRI), computed tomography (CT) or bone scan. Limitations: We simply looked at 2 elements of the patient demographic in a time-matched fashion and compared it to the U. S. based INVEST trial. It is possible that despite our diligent efforts to review the data set, we have inadvertently excluded some patients, the incorporation of whom might have changed the statistics. Conclusion: We reviewed our time-matched database in terms of 2 variables we thought curious in the INVEST trial. In comparison to our practice, where advanced imaging is essentially required and Workers compensation largely not seen, these aspects of the INVEST trial's population stood out. C1 [Saxena, Akriti P.] Tufts Med Ctr, Dept Internal Med, Boston, MA USA. [Hirsch, Ariel E.] Boston Univ, Med Ctr, Dept Radiat Oncol, Boston, MA USA. [Yoo, Albert J.; Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Gilligan, Christopher] Massachusetts Gen Hosp, Ctr Pain Med, Boston, MA 02114 USA. RP Hirsch, JA (reprint author), Massachusetts Gen Hosp, Dept NeuroIntervent Radiol, 55 Fruit St,GRB 289, Boston, MA 02114 USA. EM JAHIRSCH@partners.org NR 35 TC 0 Z9 0 U1 0 U2 0 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2013 VL 16 IS 4 BP E391 EP E396 PG 6 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 213EI UT WOS:000324037000005 PM 23877462 ER PT J AU Patel, JN Fuchs, CS Owzar, K Chen, ZH McLeod, HL AF Patel, Jai N. Fuchs, Charles S. Owzar, Kouros Chen, Zihua McLeod, Howard L. TI Gastric cancer pharmacogenetics: progress or old tripe? SO PHARMACOGENOMICS LA English DT Review DE association; cancer; gastric; genetic; germline; mutation; pharmacogenetics; variation ID GLUTATHIONE-S-TRANSFERASE; ADVANCED ESOPHAGOGASTRIC CANCER; DIHYDROPYRIMIDINE DEHYDROGENASE GENE; THYMIDYLATE SYNTHASE GENE; PHASE-II TRIAL; SEVERE 5-FLUOROURACIL-ASSOCIATED TOXICITY; PLUS INFUSIONAL 5-FLUOROURACIL; ADVANCED COLORECTAL-CANCER; ADJUVANT CHEMOTHERAPY; 1ST-LINE TREATMENT AB Gastric cancer remains the second most frequent cause of cancer-related mortality. While surgery is traditionally the initial treatment for early-stage disease, the addition of chemotherapy has been shown to significantly increase overall survival and progression-free survival in advanced and metastatic stages of disease. However, despite the incorporation of newer chemotherapies and regimens into gastric cancer clinical trials, the response rate and median overall survival for treated patients has not significantly improved throughout the years; therefore, newer therapeutic approaches to improve upon the medication selection process are warranted. Treatment and dose selection based on patient factors, such as genetic variation, may provide a more rational and potentially more powerful means of personalizing chemotherapy. This review provides an update on the current status of pharmacogenetic studies regarding germline DNA mutations that may alter response to chemotherapeutic agents used to treat gastric cancer, including perspectives on clinical translation and future work. C1 [Patel, Jai N.; McLeod, Howard L.] Univ N Carolina, UNC Inst Pharmacogenom & Individualized Therapy, Chapel Hill, NC 27599 USA. [Patel, Jai N.; McLeod, Howard L.] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Owzar, Kouros] Duke Dept Biostat & Bioinformat, Durham, NC USA. [Chen, Zihua] Xiang Ya Hosp, Changsha, Hunan, Peoples R China. RP McLeod, HL (reprint author), Univ N Carolina, UNC Inst Pharmacogenom & Individualized Therapy, 120 Mason Farm Rd,CB 7361,Room 1010, Chapel Hill, NC 27599 USA. EM hmcleod@unc.edu NR 112 TC 5 Z9 5 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD JUL PY 2013 VL 14 IS 9 BP 1053 EP 1064 DI 10.2217/PGS.13.88 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 211RI UT WOS:000323927200013 PM 23837480 ER PT J AU Ruddy, JM Jones, JA Ikonomidis, JS AF Ruddy, Jean Marie Jones, Jeffery A. Ikonomidis, John S. TI Pathophysiology of Thoracic Aortic Aneurysm (TAA): Is It Not One Uniform Aorta? Role of Embryologic Origin SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Thoracic Aortic Aneurysm; Matrix metalloproteinases; Transforming growth factor-beta; Extracellular matrix remodeling ID SMOOTH-MUSCLE-CELLS; TGF-BETA ACTIVATION; PROTEIN-KINASE-C; SYNDROME TYPE-IV; MARFAN-SYNDROME; ANGIOTENSIN-II; MOUSE MODEL; GROWTH; RECEPTOR; MUTATIONS AB Thoracic aortic aneurysm (TAA) is a clinically silent and potentially fatal disease whose pathophysiology is poorly understood. Application of data derived from animal models and human tissue analysis of abdominal aortic aneurysms may prove misleading given current evidence of structural and biochemical aortic heterogeneity above and below the diaphragm. Genetic predisposition is more common in TAA and includes multi-faceted syndromes such as Marfan, Loeys-Dietz, and type IV Ehlers-Danlos as well as autosomal-dominant familial patterns of inheritance. Investigation into the consequences of these known mutations has provided insight into the cell signaling cascades leading to degenerative remodeling of the aortic medial extracellular matrix (ECM) with TGF-beta playing a major role. Targeted research into modifying the upstream regulation or downstream effects of the TGF-beta 1 pathway may provide opportunities for intervention to attenuate TAA progression. (C) 2013 Elsevier Inc. All rights reserved. C1 [Ruddy, Jean Marie; Jones, Jeffery A.; Ikonomidis, John S.] Med Univ S Carolina, Div Cardiothorac Surg, Dept Surg, Charleston, SC 29425 USA. [Ruddy, Jean Marie; Jones, Jeffery A.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. RP Ikonomidis, JS (reprint author), Med Univ S Carolina, Div Cardiothorac Surg, 25 Courtenay Dr,Suite 7030, Charleston, SC 29425 USA. EM ikonomij@musc.edu FU NIH/NIA [AG036954]; NIH/NHLBI [HL102121]; Veterans Affairs Merit Award [1 I01 BX000904-01] FX This study was supported by the following grants: NIH/NIA AG036954, NIH/NHLBI HL102121 and Veterans Affairs Merit Award 1 I01 BX000904-01. NR 57 TC 16 Z9 17 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD JUL-AUG PY 2013 VL 56 IS 1 BP 68 EP 73 DI 10.1016/j.pcad.2013.04.002 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 214RJ UT WOS:000324153000009 PM 23993239 ER PT J AU Chahine, LM Qiang, J Ashbridge, E Minger, J Yearout, D Horn, S Colcher, A Hurtig, HI Lee, VMY Van Deerlin, VM Leverenz, JB Siderowf, AD Trojanowski, JQ Zabetian, CP Chen-Plotkin, A AF Chahine, Lama M. Qiang, Judy Ashbridge, Emily Minger, James Yearout, Dora Horn, Stacy Colcher, Amy Hurtig, Howard I. Lee, Virginia M-Y. Van Deerlin, Vivianna M. Leverenz, James B. Siderowf, Andrew D. Trojanowski, John Q. Zabetian, Cyrus P. Chen-Plotkin, Alice TI Clinical and Biochemical Differences in Patients Having Parkinson Disease With vs Without GBA Mutations SO JAMA NEUROLOGY LA English DT Article ID GLUCOCEREBROSIDASE GENE-MUTATIONS; LEWY BODY DISORDERS; GAUCHER-DISEASE; RISK-FACTOR; ONSET; NEUROINFLAMMATION; SUSCEPTIBILITY; CARRIERS; TYPE-2; MODEL AB IMPORTANCE Biochemical abnormalities present in GBA (mut/wt) carriers may offer new pathogenetic insights to and potential therapeutic targets in Parkinson disease (PD). OBJECTIVE To determine whether patients having PD with vs without GBA mutations differ in clinical phenotype or plasma protein expression. DESIGN AND SETTING Case-control study of patients having PD with vs without GBA mutations. Clinical characteristics were compared between groups, and biochemical profiling of 40 plasma proteins was performed to identify proteins that differed in expression between groups. PARTICIPANTS The discovery cohort included 20 patients having PD with GBA mutations. Clinical characteristics of GBA-associated PD cases were compared with those of 242 patients having PD in whom GBA mutations were excluded by full gene sequencing. MAIN OUTCOME MEASURES Biochemical profiling was available for all 20 GBA-associated PD cases, as well as a subset (87 of 242) of the GBA-negative PD cases. The replication cohort included 19 patients having PD with GBA mutations and 41 patients having PD without GBA mutations. RESULTS Compared with patients having PD without GBA mutations, patients having PD with GBA mutations were younger at disease onset (P = .04) and were more likely to demonstrate cognitive dysfunction (P = .001). In a multiple regression model that included age, sex, and assay batch as covariates, GBA mutation status was significantly associated with plasma levels of interleukin 8 (P = .001), monocyte chemotactic protein 1 (P = .008), and macrophage inflammatory protein 1 alpha (P = .005). The association between interleukin 8 and GBA mutation status was replicated (P = .03) in a separate cohort of patients having PD with vs without GBA mutations. CONCLUSIONS AND RELEVANCE Patients having PD with GBA mutations have earlier age at disease onset and are more likely to demonstrate cognitive dysfunction. Monocyte-associated inflammatory mediators may be elevated in patients having PD with GBA mutations. C1 [Chahine, Lama M.; Qiang, Judy; Ashbridge, Emily; Minger, James; Horn, Stacy; Colcher, Amy; Hurtig, Howard I.; Chen-Plotkin, Alice] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lee, Virginia M-Y.; Van Deerlin, Vivianna M.; Trojanowski, John Q.] Univ Penn, Ctr Neurodegenerat Dis Res, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Horn, Stacy; Colcher, Amy; Hurtig, Howard I.; Lee, Virginia M-Y.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Chen-Plotkin, Alice] Univ Penn, Morris K Udall Ctr Excellence Parkinsons Dis Res, Perelman Sch Med, Philadelphia, PA 19104 USA. [Lee, Virginia M-Y.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Chen-Plotkin, Alice] Univ Penn, Inst Aging, Perelman Sch Med, Philadelphia, PA 19104 USA. [Siderowf, Andrew D.] Avid Radiopharmaceut, Philadelphia, PA USA. [Yearout, Dora; Leverenz, James B.; Zabetian, Cyrus P.] Univ Washington, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Yearout, Dora; Leverenz, James B.; Zabetian, Cyrus P.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Leverenz, James B.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Chen-Plotkin, A (reprint author), Univ Penn, Dept Neurol, Perelman Sch Med, 3400 Spruce St, Philadelphia, PA 19104 USA. EM chenplot@mail.med.upenn.edu OI Zabetian, Cyrus/0000-0002-7739-4306 FU University of Pennsylvania; Pfizer (Penn Pfizer Alliance); Morris K. Udall Center of Excellence for Parkinson's Disease Research from the National Institute of Neurological Disorders and Stroke [NS-053488, P50 NS062684]; National Institutes of Health [R01 NS065070, AG-033101]; Department of Veterans Affairs [1I01BX000531]; Burroughs Wellcome Fund Career Award for Medical Scientists; Doris Duke Clinician Scientist Development Award; Benaroya Fund FX The biomarker data in this project were obtained through a partnership grant between the University of Pennsylvania and Pfizer (Penn Pfizer Alliance). The clinical data in this project were collected through the support of Morris K. Udall Center of Excellence for Parkinson's Disease Research grants NS-053488 and P50 NS062684 from the National Institute of Neurological Disorders and Stroke. Dr Zabetian is supported by grant R01 NS065070 from the National Institutes of Health and by Merit Award 1I01BX000531 from the Department of Veterans Affairs. Dr Chen-Plotkin is supported by grant AG-033101 from the National Institutes of Health and by a Burroughs Wellcome Fund Career Award for Medical Scientists, a Doris Duke Clinician Scientist Development Award, and the Benaroya Fund. NR 33 TC 29 Z9 31 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6149 J9 JAMA NEUROL JI JAMA Neurol. PD JUL PY 2013 VL 70 IS 7 BP 852 EP 858 DI 10.1001/jamaneurol.2013.1274 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 206YN UT WOS:000323563000007 PM 23699752 ER PT J AU Friedman, SD Baker, LD Borson, S Jensen, JE Barsness, SM Craft, S Merriam, GR Otto, RK Novotny, EJ Vitiello, MV AF Friedman, Seth D. Baker, Laura D. Borson, Soo Jensen, J. Eric Barsness, Suzanne M. Craft, Suzanne Merriam, George R. Otto, Randolph K. Novotny, Edward J. Vitiello, Michael V. TI Growth Hormone-Releasing Hormone Effects on Brain gamma-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy Aging SO JAMA NEUROLOGY LA English DT Article ID AGE-RELATED DECLINE; ALZHEIMERS-DISEASE; GABA CONCENTRATION; OLDER-ADULTS; N-ACETYLASPARTYLGLUTAMATE; INDIVIDUAL-DIFFERENCES; BODY-COMPOSITION; CONTROLLED-TRIAL; H-1 MRS; CORTEX AB IMPORTANCE Growth hormone-releasing hormone (GHRH) has been previously shown to have cognition-enhancing effects. The role of neurotransmitter changes, measured by proton magnetic resonance spectroscopy, may inform the mechanisms for this response. OBJECTIVE To examine the neurochemical effects of GHRH in a subset of participants from the parent trial. DESIGN Randomized, double-blind, placebo-controlled substudy of a larger trial. SETTING Clinical research unit at the University of Washington School of Medicine. PARTICIPANTS Thirty adults (17 with mild cognitive impairment [MCI]), ranging in age from 55 to 87 years, were enrolled and successfully completed the study. INTERVENTIONS Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analogue of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline and weeks 10 and 20, participants underwent brain magnetic resonance imaging and spectroscopy protocols and cognitive testing and provided blood samples after fasting. Participants also underwent glucose tolerance tests before and after intervention. MAIN OUTCOMES AND MEASURES Brain levels of glutamate, inhibitory transmitters.-aminobutyric acid (GABA) and N-acetylaspartylglutamate (NAAG), and myo-inositol (MI), an osmolyte linked to Alzheimer disease in humans, were measured in three 2 x 2 x 2-cm(3) left-sided brain regions (dorsolateral frontal, posterior cingulate, and posterior parietal). Glutamate, GABA, and MI levels were expressed as ratios to creatine plus phosphocreatine, and NAAG was expressed as a ratio to N-acetylaspartate. RESULTS After 20 weeks of GHRH administration, GABA levels were increased in all brain regions (P < .04), NAAG levels were increased (P = .03) in the dorsolateral frontal cortex, and MI levels were decreased in the posterior cingulate (P = .002). These effects were similar in adults with MCI and older adults with normal cognitive function. No changes in the brain levels of glutamate were observed. In the posterior cingulate, treatment-related changes in serum insulin-like growth factor 1 were positively correlated with changes in GABA (r = 0.47; P = .001) and tended to be negatively correlated with MI (r = -0.34; P = .06). Consistent with the results of the parent trial, a favorable treatment effect on cognition was observed in substudy participants (P = .03). No significant associations were observed between treatment-related changes in neurochemical and cognitive outcomes. Glucose homeostasis in the periphery was not reliably affected by GHRH administration and did not account for treatment neurochemical effects. CONCLUSIONS Twenty weeks of GHRH administration increased GABA levels in all 3 brain regions, increased NAAG levels in the frontal cortex, and decreased MI levels in the posterior cingulate. To our knowledge, this is the first evidence that 20 weeks of somatotropic supplementation modulates inhibitory neurotransmitter and brain metabolite levels in a clinical trial, and it provides preliminary support for one possible mechanism to explain favorable GHRH effects on cognition in adults with MCI and in healthy older adults. C1 [Friedman, Seth D.; Otto, Randolph K.] Seattle Childrens Hosp, Dept Radiol, Seattle, WA 98105 USA. [Novotny, Edward J.] Seattle Childrens Hosp, Dept Neurol, Seattle, WA 98105 USA. [Baker, Laura D.; Borson, Soo; Barsness, Suzanne M.; Craft, Suzanne; Vitiello, Michael V.] Univ Washington, Dept Psychiat, Sch Med, Seattle, WA 98195 USA. [Baker, Laura D.; Borson, Soo; Barsness, Suzanne M.; Craft, Suzanne; Vitiello, Michael V.] Univ Washington, Sch Med, Dept Behav Sci, Seattle, WA USA. [Merriam, George R.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Baker, Laura D.; Craft, Suzanne] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Merriam, George R.] Vet Affairs Puget Sound Hlth Care Syst, Res & Dev, Seattle, WA USA. [Jensen, J. Eric] Harvard Univ, McLean Hosp, Belmont, MA 02178 USA. RP Friedman, SD (reprint author), Seattle Childrens Hosp, Dept Radiol, 4800 Sandpoint Way,Room R4488, Seattle, WA 98105 USA. EM seth.friedman@seattlechildrens.org OI Vitiello, Michael/0000-0002-9776-0473 FU National Institute on Aging, National Institutes of Health [R01 AG030484-01, AG025515]; National Center for Research Resources, National Institutes of Health [ULRR025014] FX This project was supported by the National Institute on Aging, National Institutes of Health (grants R01 AG030484-01 [principal investigator, Dr Friedman] and AG025515 [principal investigator, Dr Vitiello]). A portion of this work was conducted through the Clinical Research Center Facility at the University of Washington Medical Center, which is supported by the National Center for Research Resources, National Institutes of Health (grant ULRR025014). NR 50 TC 11 Z9 12 U1 2 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6149 J9 JAMA NEUROL JI JAMA Neurol. PD JUL PY 2013 VL 70 IS 7 BP 883 EP 890 DI 10.1001/jamaneurol.2013.1425 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 206YN UT WOS:000323563000011 PM 23689947 ER PT J AU Ducharme, S Guiot, MC Nikelski, J Chertkow, H AF Ducharme, Simon Guiot, Marie-Christine Nikelski, James Chertkow, Howard TI Does a Positive Pittsburgh Compound B Scan in a Patient With Dementia Equal Alzheimer Disease? SO JAMA NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; COGNITIVE IMPAIRMENT; NATIONAL INSTITUTE; RECOMMENDATIONS; HEMORRHAGE; BURDEN; BRAIN AB IMPORTANCE The clinical role of amyloid brain positron emission tomographic imaging in the diagnosis of Alzheimer disease is currently being formulated. The specificity of a positive amyloid scan is a matter of contention. OBSERVATIONS An 83-year-old Canadian man presented with a 5-year history of predominantly short-term memory loss and functional impairment. Clinical evaluation revealed significant, gradually progressive short-term memory loss in the absence of any history of strokes or other neuropsychiatric symptoms. The patient met clinical criteria for probable Alzheimer disease but had a higher than expected burden of white matter disease on magnetic resonance imaging. A positron emission tomographic Pittsburgh Compound B scan was highly positive in typical Alzheimer disease distribution. The patient died of an intracerebral hemorrhage 6 months after the assessment. Autopsy revealed cerebral amyloid angiopathy in the complete absence of amyloid plaques or neurofibrillary tangles. CONCLUSIONS AND RELEVANCE This patient demonstrates that a positive Pittsburgh Compound B scan in a patient with clinical dementia meeting criteria for probable Alzheimer disease is not proof of an Alzheimer disease pathophysiological process. A positive Pittsburgh Compound B scan in typical Alzheimer disease distribution in a patient with dementia can be secondary to cerebral amyloid angiopathy alone. C1 [Ducharme, Simon] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Ducharme, Simon] Harvard Univ, McLean Hosp, Boston, MA 02115 USA. [Ducharme, Simon] McGill Univ, Dept Psychiat, Montreal, PQ H3T 1E2, Canada. [Guiot, Marie-Christine; Chertkow, Howard] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3T 1E2, Canada. [Nikelski, James; Chertkow, Howard] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. RP Chertkow, H (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, 3755 Cote Ste Catherine Rd, Montreal, PQ H3T 1E2, Canada. EM howard.chertkow@mcgill.ca FU Canadian Institutes for Health Research; Fonds de la recherche en sante du Quebec FX Dr Chertkow is supported by operating grants from the Canadian Institutes for Health Research and the Fonds de la recherche en sante du Quebec. NR 16 TC 9 Z9 9 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6149 J9 JAMA NEUROL JI JAMA Neurol. PD JUL PY 2013 VL 70 IS 7 BP 912 EP 914 DI 10.1001/jamaneurol.2013.420 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 206YN UT WOS:000323563000014 PM 23689280 ER PT J AU Papakonstantinou, NA Stamou, MI Baikoussis, NG Goudevenos, J Apostolakis, E AF Papakonstantinou, Nikolaos A. Stamou, Maria I. Baikoussis, Nikolaos G. Goudevenos, John Apostolakis, Efstratios TI Sex differentiation with regard to coronary artery disease SO JOURNAL OF CARDIOLOGY LA English DT Review DE Coronary artery disease; Coronary heart disease; Myocardial infarction; Pathophysiology; Myocardial infarction; Treatment; Myocardium ID ACUTE MYOCARDIAL-INFARCTION; IN-HOSPITAL MORTALITY; SHORT-TERM MORTALITY; GENDER-DIFFERENCES; BYPASS-SURGERY; PREHOSPITAL DELAY; CARDIAC-SURGERY; UNSTABLE ANGINA; HEART-DISEASE; WOMEN AB Coronary artery disease was considered a male disease for many years. However, nowadays, coronary artery disease constitutes the leading cause of death in women, although there are a lot of gender-related differences regarding the presentation of acute myocardial infarction, its diagnosis, its treatment, short- and long-term mortality rates, and post-acute myocardial infarction complications. Generally, women have smaller and stiffer hearts and cardiac vessels, suffering a greater extent of atherosclerosis and endothelial and smooth muscle dysfunction. They are usually older than men and they have more comorbidities such as hypertension, renal impairment, and diabetes mellitus. Moreover, female coronary artery disease, the diagnosis of which is more complicated due to more false negative results of some diagnostic method S in women, is more often presented with atypical symptoms and women's symptoms of typical or atypical angina are more severe. Furthermore, women delay significantly more in seeking care and they are more frequently undertreated. Finally, women are associated with generally poorer in-hospital and long-term prognosis having almost two-fold higher early mortality and they are more prone to complications such as bleeding complications, shock, and heart failure, as well as to post-myocardial infarction depression and poorer physical function and mental health. In this review, we discuss these sex-related differences according to current literature. (C) 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. C1 [Papakonstantinou, Nikolaos A.] Univ Hosp Ioannina, Sch Med, Dept Gen Surg, Ioannina 45500, Greece. [Stamou, Maria I.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Reprod Endocrine Unit,Harvard Reprod Endocrine Sc, Boston, MA 02114 USA. [Baikoussis, Nikolaos G.] Inst Mutualiste Montsuris, Dept Cardiac Surg, F-75014 Paris 14, France. [Goudevenos, John] Univ Hosp Ioannina, Sch Med, Dept Cardiol, Ioannina 45500, Greece. [Apostolakis, Efstratios] Univ Hosp Ioannina, Sch Med, Dept Cardiothorac Surg, Ioannina 45500, Greece. RP Papakonstantinou, NA (reprint author), Stratigou Makrigianni 5B, Ioannina 45445, Greece. EM nikppk@yahoo.gr NR 59 TC 13 Z9 14 U1 1 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0914-5087 J9 J CARDIOL JI J. Cardiol. PD JUL-AUG PY 2013 VL 62 IS 1-2 BP 4 EP 11 DI 10.1016/j.jjcc.2013.03.001 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 211AB UT WOS:000323875400002 PM 23642501 ER PT J AU Gurkar, AU Chu, K Raj, L Bouley, R Lee, SH Kim, YB Dunn, SE Mandinova, A Lee, SW AF Gurkar, Aditi U. Chu, Kiki Raj, Lakshmi Bouley, Richard Lee, Seung-Hwan Kim, Young-Bum Dunn, Sandra E. Mandinova, Anna Lee, Sam W. TI Identification of ROCK1 kinase as a critical regulator of Beclin1-mediated autophagy during metabolic stress SO NATURE COMMUNICATIONS LA English DT Article ID BINDING PROTEIN RHO; BCL-X-L; CELL-DEATH; MICROSATELLITE INSTABILITY; GLUCOSE-HOMEOSTASIS; CANCER-CELLS; DAP-KINASE; BH3 DOMAIN; BECLIN 1; SURVIVAL AB The Ser/Thr Rho kinase 1 (ROCK1) is known to have major roles in a wide range of cellular activities, including those involved in tumour metastasis and apoptosis. Here we identify an indispensable function of ROCK1 in metabolic stress-induced autophagy. Applying a proteomics approach, we characterize Beclin1, a proximal component of the phosphoinositide 3-kinase class III lipid-kinase complex that induces autophagy, as an interacting partner of ROCK1. Upon nutrient deprivation, activated ROCK1 promotes autophagy by binding and phosphorylating Beclin1 at Thr119. This results in the specific dissociation of the Beclin1-Bcl-2 complex without affecting the Beclin1-UVRAG interaction. Conversely, inhibition of ROCK1 activity increases Beclin1-Bcl-2 association, thus reducing nutritional stress-mediated autophagy. Genetic knockout of ROCK1 function in mice also leads to impaired autophagy as evidenced by reduced autophagosome formation. These results show that ROCK1 acts as a prominent upstream regulator of Beclin1-mediated autophagy and maintains a homeostatic balance between apoptosis and autophagy. C1 [Gurkar, Aditi U.; Chu, Kiki; Raj, Lakshmi; Mandinova, Anna; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Gurkar, Aditi U.; Chu, Kiki; Raj, Lakshmi; Mandinova, Anna; Lee, Sam W.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Bouley, Richard] Massachusetts Gen Hosp, Simches Res Ctr, Div Nephrol, Boston, MA 02129 USA. [Lee, Seung-Hwan; Kim, Young-Bum] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Lee, Seung-Hwan; Kim, Young-Bum] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Dunn, Sandra E.] Univ British Columbia, Dept Paediat, Vancouver, BC V5Z 4H4, Canada. [Mandinova, Anna; Lee, Sam W.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Mandinova, Anna; Lee, Sam W.] MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA. RP Lee, SW (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149 13th St, Charlestown, MA 02129 USA. EM swlee@partners.org OI Lee, Seung-Hwan/0000-0002-3964-3877 FU Inflammatory Bowel Disease Grant [DK43351]; Boston Area Diabetes and Endocrinology Research Center (BADERC) [DK57521]; NIH [CA127247, CA149477, CA140615, DK083567]; Canadian Institute for Health Research grant FX Electron microscopy was performed by M. McKee and FRET was performed in the Microscopy Core of Center for Systems Biology/Program in Membrane Biology, which is partially supported by an Inflammatory Bowel Disease Grant DK43351 and a Boston Area Diabetes and Endocrinology Research Center (BADERC) Award DK57521. We thank E. White for cell lines, N. Mizushima for GFP-LC3. This work is supported by NIH grants CA127247 and CA149477 to S. W. L., CA140615 to A. M. and DK083567 to Y.-B.K. A Canadian Institute for Health Research grant supported S.E.D. NR 60 TC 35 Z9 37 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2013 VL 4 AR 2189 DI 10.1038/ncomms3189 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 208XT UT WOS:000323716600025 PM 23877263 ER PT J AU Zhou, F Lu, Y Ficarro, SB Adelmant, G Jiang, WY Luckey, CJ Marto, JA AF Zhou, Feng Lu, Yu Ficarro, Scott B. Adelmant, Guillaume Jiang, Wenyu Luckey, C. John Marto, Jarrod A. TI Genome-scale proteome quantification by DEEP SEQ mass spectrometry SO NATURE COMMUNICATIONS LA English DT Article ID EMBRYONIC STEM-CELLS; SELF-RENEWAL; INTERACTION NETWORK; QUANTITATIVE PROTEOMICS; IONIZATION EFFICIENCY; IN-VIVO; CHROMATOGRAPHY; ONLINE; DIFFERENTIATION; PLURIPOTENCY AB Advances in chemistry and massively parallel detection underlie DNA-sequencing platforms that are poised for application in personalized medicine. In stark contrast, systematic generation of protein-level data lags well behind genomics in virtually every aspect: depth of coverage, throughput, ease of sample preparation and experimental time. Here, to bridge this gap, we develop an approach based on simple detergent lysis and single-enzyme digest, extreme, orthogonal separation of peptides and true nanoflow liquid chromatography-tandem mass spectrometry that provides high peak capacity and ionization efficiency. This automated, deep efficient peptide sequencing and quantification mass spectrometry platform provides genome-scale proteome coverage equivalent to RNA-seq ribosomal profiling and accurate quantification for multiplexed isotope labels. In a model of the embryonic to epiblast transition in murine stem cells, we unambiguously quantify 11,352 gene products that span 70% of Swiss-Prot and capture protein regulation across the full detectable range of high-throughput gene expression and protein translation. C1 [Zhou, Feng; Lu, Yu; Ficarro, Scott B.; Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Zhou, Feng; Lu, Yu; Ficarro, Scott B.; Adelmant, Guillaume; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ficarro, Scott B.; Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Jiang, Wenyu; Luckey, C. John] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Marto, JA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM jarrod_marto@dfci.harvard.edu FU National Institutes of Health [T32HL66987-11]; National Blood Foundation; Department of Pathology at the Brigham and Women's Hospital FX Generous support for this work was provided (to J.A.M) by the Dana-Farber Cancer Institute and the National Institutes of Health (NINDS, P01NS047572). Y.L. acknowledges support from a National Institutes of Health training grant in transfusion medicine (T32HL66987-11). C.J.L. acknowledges support from the National Blood Foundation and the Department of Pathology at the Brigham and Women's Hospital. We thank Dr Stuart Orkin (Dana-Farber Cancer Institute and Children's Hospital, Boston, MA) for kindly providing the gel-adapted J1 murine embryonic stem cells used in this study. We also thank Dr Nicholas Ingolia (Carnegie Institution for Science, Baltimore, MD) for helpful discussions related to mESC ribosomal profiling data. In addition, we thank Christie Hunter and Sean Seymour of AB Sciex for support and technical assistance with the 5600 Triple TOF mass spectrometer and Protein Pilot search software. NR 60 TC 24 Z9 29 U1 2 U2 54 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2013 VL 4 AR 2171 DI 10.1038/ncomms3171 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 208XT UT WOS:000323716600007 PM 23863870 ER PT J AU Mananga, ES AF Mananga, Eugene Stephane TI Progress in spin dynamics solid-state nuclear magnetic resonance with the application of Floquet-Magnus expansion to chemical shift anisotropy SO SOLID STATE NUCLEAR MAGNETIC RESONANCE LA English DT Article DE Solid-state NMR; Average Hamiltonian theory; Floquet theory; Floquet-Magnus expansion; BABA pulse sequence; CSA ID ROTATING SOLIDS; CROSS-POLARIZATION; AVERAGING METHODS; NMR-SPECTROSCOPY; LOCK SEQUENCES; 2-SPIN SYSTEMS; ANGLE; SPECTRA; ROTOR; EXCITATION AB The purpose of this article is to present an historical overview of theoretical approaches used for describing spin dynamics under static or rotating experiments in solid state nuclear magnetic resonance. The article gives a brief historical overview for major theories in nuclear magnetic resonance and the promising theories. We present the first application of Floquet-Magnus expansion to chemical shift anisotropy when irradiated by BABA pulse sequence. (C) 2013 Elsevier Inc. All rights reserved. C1 [Mananga, Eugene Stephane] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mananga, Eugene Stephane] Massachusetts Gen Hosp, Ctr Adv Radiol Sci, Div Nucl Med & Mol Imaging Phys, Dept Radiol, Boston, MA 02114 USA. RP Mananga, ES (reprint author), Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM emananga@pet.mgh.harvard.edu FU NIH [R01-HL110241, T32-EB013180] FX The author acknowledges assistance from Harvard University, Harvard Medical School, Massachusetts General Hospital, and the United States National Institute of Health. Research supported by NIH (R01-HL110241 and T32-EB013180). NR 60 TC 4 Z9 4 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 0926-2040 J9 SOLID STATE NUCL MAG JI Solid State Nucl. Magn. Reson. PD JUL-SEP PY 2013 VL 54 BP 1 EP 7 DI 10.1016/j.ssnmr.2013.04.001 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical; Physics, Condensed Matter; Spectroscopy SC Chemistry; Physics; Spectroscopy GA 212MG UT WOS:000323986900001 PM 23711337 ER PT J AU Kim, S Li, L Maliga, Z Yin, Q Wu, H Mitchison, TJ AF Kim, Sujeong Li, Lingyin Maliga, Zoltan Yin, Qian Wu, Hao Mitchison, Timothy J. TI Anticancer Flavonoids Are Mouse-Selective STING Agonists SO ACS CHEMICAL BIOLOGY LA English DT Article ID CYCLIC DI-GMP; AGENT 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID; ACETIC-ACID; CYTOSOLIC DNA; KAPPA-B; DMXAA; RECOGNITION; ANALOGS; REVEALS; SIGNALS AB The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor-specific vascular damage and other antitumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the antitumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy. C1 [Kim, Sujeong; Li, Lingyin; Maliga, Zoltan; Mitchison, Timothy J.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Yin, Qian; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. RP Mitchison, TJ (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. EM timothy_mitchison@hms.harvard.edu FU National Cancer Institute [CA139980]; Novartis Institutes for Biomedical Research; Jane Coffin Childs Fund FX We thank Y. Feng and J. Tallarico at Novartis Institutes for Biomedical Research for providing the flavonoids and helpful discussion. We thank M. Loose for help with protein production, T. Yuan for help with the ITC experiments, and P. Choi for helpful discussions on the manuscript. We thank the Harvard Medical School ICCB screening facility for help with the fluorescence polarization assays. This research was supported by the National Cancer Institute (CA139980) and Novartis Institutes for Biomedical Research. L. Li thanks the Jane Coffin Childs Fund for her postdoctoral fellowship. NR 32 TC 19 Z9 21 U1 1 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUL PY 2013 VL 8 IS 7 BP 1396 EP 1401 DI 10.1021/cb400264n PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 188RA UT WOS:000322210100005 PM 23683494 ER PT J AU Liu, FY Zhang, X Weisberg, E Chen, S Hur, W Wu, H Zhao, Z Wang, WC Mao, M Cai, CM Simon, NI Sanda, T Wang, JH Look, AT Griffin, JD Balk, SP Liu, QS Gray, NS AF Liu, Feiyang Zhang, Xin Weisberg, Ellen Chen, Sen Hur, Wooyoung Wu, Hong Zhao, Zheng Wang, Wenchao Mao, Mao Cai, Changmeng Simon, Nicholas I. Sanda, Takaomi Wang, Jinhua Look, A. Thomas Griffin, James D. Balk, Steven P. Liu, Qingsong Gray, Nathanael S. TI Discovery of a Selective Irreversible BMX Inhibitor for Prostate Cancer SO ACS CHEMICAL BIOLOGY LA English DT Article ID TYROSINE KINASE ETK/BMX; ACTIVATION; PCI-32765; RECEPTOR; GROWTH; CELLS AB BMX is a member of the TEC family of nonreceptor tyrosine kinases. We have used structure-based drug design in conjunction with kinome profiling to develop a potent, selective, and irreversible BMX kinase inhibitor, BMX-IN-1, which covalently modifies Cys496. BMX-IN-1 inhibits the proliferation of Tel-BMX-transformed Ba/F3 cells at two digit nanomolar concentrations but requires single digit micromolar concentrations to inhibit the proliferation of prostate cancer cell lines. Using a combinatorial kinase inhibitor screening strategy, we discovered that the allosteric Akt inhibitor, MK2206, is able to potentiate BMX inhibitors antiproliferation efficacy against prostate cancer cells. C1 [Liu, Feiyang; Zhang, Xin; Wu, Hong; Zhao, Zheng; Wang, Wenchao; Mao, Mao; Liu, Qingsong] Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China. [Liu, Feiyang; Zhang, Xin; Hur, Wooyoung; Wu, Hong; Wang, Wenchao; Wang, Jinhua; Liu, Qingsong] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Dept Canc Biol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Weisberg, Ellen; Griffin, James D.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Chen, Sen; Cai, Changmeng; Simon, Nicholas I.; Balk, Steven P.] Beth Israel Deaconess Med Ctr, Dept Med, Hematol Oncol Div, Boston, MA 02215 USA. [Chen, Sen; Cai, Changmeng; Simon, Nicholas I.; Balk, Steven P.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Sanda, Takaomi; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. RP Balk, SP (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Hematol Oncol Div, Boston, MA 02215 USA. EM sbalk@bidmc.harvard.edu; Qsliu97@hmfl.ac.cn; nathanael_gray@dfci.harvard.edu OI liu, qing song/0000-0002-7829-2547; Cai, Changmeng/0000-0002-8701-2586 FU Chinese Academy of Sciences; Mazzone Foundation FX We thank Chinese Academy of Sciences training grant for support of F.L. and W.H. We also want to thank Mazzone Foundation for support of the BMX project (Balk and Gray). NR 16 TC 11 Z9 11 U1 3 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD JUL PY 2013 VL 8 IS 7 BP 1423 EP 1428 DI 10.1021/cb4000629 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 188RA UT WOS:000322210100010 PM 23594111 ER PT J AU Naboush, A Hamdy, O AF Naboush, Ali Hamdy, Osama TI MEASURING VISCERAL AND HEPATIC FAT IN CLINICAL PRACTICE AND CLINICAL RESEARCH SO ENDOCRINE PRACTICE LA English DT Article ID MULTIFREQUENCY BIOELECTRICAL-IMPEDANCE; MAGNETIC-RESONANCE-SPECTROSCOPY; SUBCUTANEOUS ADIPOSE-TISSUE; BODY-MASS INDEX; WAIST CIRCUMFERENCE; ABDOMINAL FAT; RISK-FACTORS; LIVER FAT; COMPUTED-TOMOGRAPHY; CARDIOVASCULAR-DISEASE AB Objective: To review how visceral and hepatic fat are measured in clinical practice and clinical research. Methods: We examine different methods employed to assess visceral and hepatic fat in the literature. Results: Fat in the human body is located in 2 main compartments: subcutaneous and visceral, which also includes liver fat. Visceral and liver fats are associated with the metabolic complications of obesity like hypertension, diabetes, and atherosclerosis. Therefore, there is a need to detect those fats early in life before the development of cardiometabolic syndrome (CMS). Many modalities have been proposed to measure visceral and liver fat. Indirect measurements can be done through waist circumference (WC), dual-energy X-ray absorptiometry (DEXA), ultrasound, and bioelectric impedance, whereas direct methods include computed tomography (CT) and magnetic resonance imaging (MRI). An ideal measurement method should be noninvasive, reliable, suitable for all body sizes, widely available, cost and time effective, show low variability, and have no or limited radiation exposure. Conclusion: Measuring visceral and liver fat is not a straightforward procedure in clinical practice or research; several variables may affect measure accuracy and validity. C1 [Naboush, Ali] Staten Isl Univ Hosp, Boston, MA USA. [Hamdy, Osama] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Naboush, A (reprint author), Staten Isl Univ Hosp, Internal Med Off, 475 Seaview Ave, Staten Isl, NY 10305 USA. EM Naboush@hotmail.com OI Naboush, Ali/0000-0002-4072-5888 NR 79 TC 8 Z9 9 U1 1 U2 10 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X J9 ENDOCR PRACT JI Endocr. Pract. PD JUL-AUG PY 2013 VL 19 IS 4 BP 587 EP 595 DI 10.4158/EP12331.OR PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208TV UT WOS:000323703700009 PM 23425646 ER PT J AU Baker, CW Almukhtar, T Bressler, NM Glassman, AR Grover, S Kim, SJ Murtha, TJ Rauser, ME Stockdale, C AF Baker, Carl W. Almukhtar, Talat Bressler, Neil M. Glassman, Adam R. Grover, Sandeep Kim, Stephen J. Murtha, Timothy J. Rauser, Michael E. Stockdale, Cynthia CA Diabetic Retinopathy Clinical Res TI Macular Edema After Cataract Surgery in Eyes Without Preoperative Central-Involved Diabetic Macular Edema SO JAMA OPHTHALMOLOGY LA English DT Article ID RETINOPATHY; PHACOEMULSIFICATION; PROGRESSION; PREVALENCE; EXTRACTION; LENS AB IMPORTANCE The incidence of development or worsening of macular edema (ME) is variable in eyes without diabetic ME (DME) undergoing cataract surgery. OBJECTIVE To estimate the incidence of central-involved ME 16 weeks following cataract surgery in eyes with diabetic retinopathy without definite central-involved DME preoperatively. DESIGN, SETTING, AND PARTICIPANTS In a multicenter, prospective, observational study, 293 participants with diabetic retinopathy without definite central subfield thickening on optical coherence tomography (OCT) underwent cataract surgery. EXPOSURE Cataract extraction surgery performed within 28 days of enrollment of eyes without DME in individuals with diabetes mellitus. MAIN OUTCOMES AND MEASURES Development of central-involved ME defined as the following: (1) OCT central subfield thickness of 250 mu m or greater (time-domain OCT) or 310 mu m or greater (spectral-domain OCT) with at least a 1-step increase in logOCT central subfield thickness preoperatively to the 16-week visit; (2) at least a 2-step increase in logOCT central subfield thickness preoperatively to the 16-week visit; or (3) nontopical treatment for ME received before the 16-week visit with either of the OCT criteria met at the time of treatment. RESULTS The median participant age was 65 years. The median visual acuity letter score was 69 letters (Snellen equivalent 20/40). Forty-four percent of eyes had a history of treatment for DME. Sixteen weeks postoperatively, central-involved ME was noted in 0% (95% CI, 0%-20%) of 17 eyes with no preoperative DME. Of eyes with non-central-involved DME, 10% (95% CI, 5%-18%) of 97 eyes without central-involved DME and 12%(95% CI, 7%-19%) of 147 eyes with possible central-involved DME at baseline progressed to central-involved ME. History of DME treatment was significantly associated with central-involved ME development (P<.001). CONCLUSIONS AND RELEVANCE In eyes with diabetic retinopathy without concurrent central-involved DME, presence of non-central-involved DME immediately prior to cataract surgery or history of DME treatment may increase the risk of developing central-involved ME 16 weeks after cataract extraction. C1 [Baker, Carl W.] Paducah Retinal Ctr, Paducah, KY USA. [Almukhtar, Talat; Glassman, Adam R.; Stockdale, Cynthia] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Bressler, Neil M.] Wilmer Ophthalmol Inst, Baltimore, MD USA. [Grover, Sandeep] Univ Florida, Dept Ophthalmol, Hlth Sci Ctr Jacksonville, Coll Med, Jacksonville, FL USA. [Kim, Stephen J.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Murtha, Timothy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Rauser, Michael E.] Loma Linda Univ Hlth Care, Dept Ophthalmol, Loma Linda, CA USA. RP Almukhtar, T (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Ste 350, Tampa, FL 33647 USA. EM drcrstat6@jaeb.org OI Grover, Sandeep/0000-0002-3771-7510 FU National Eye Institute [EY14231, EY018817]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services FX This work was supported through cooperative agreements EY14231 and EY018817 from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, US Department of Health and Human Services. NR 16 TC 13 Z9 14 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD JUL PY 2013 VL 131 IS 7 BP 870 EP 879 DI 10.1001/jamaophthalmol.2013.2313 PG 10 WC Ophthalmology SC Ophthalmology GA 206VW UT WOS:000323553600008 ER PT J AU Merkow, RP Bilimoria, KY Ko, CY AF Merkow, Ryan P. Bilimoria, Karl Y. Ko, Clifford Y. TI Surgical Quality Measurement An Evolving Science SO JAMA SURGERY LA English DT Editorial Material ID CARE C1 [Merkow, Ryan P.; Bilimoria, Karl Y.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Merkow, Ryan P.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Surg Outcomes & Qual Improvement Ctr, Dept Surg, Chicago, IL 60611 USA. [Merkow, Ryan P.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Northwestern Inst Comparat Effectiveness Res NICE, Chicago, IL 60611 USA. [Merkow, Ryan P.] Univ Chicago, Pritzker Sch Med, Dept Surg, Chicago, IL 60637 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Merkow, RP (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clair St,22nd Fl, Chicago, IL 60611 USA. EM rmerkow@facs.org NR 6 TC 9 Z9 9 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6254 J9 JAMA SURG JI JAMA Surg. PD JUL PY 2013 VL 148 IS 7 BP 586 EP 587 DI 10.1001/jamasurg.2013.128 PG 2 WC Surgery SC Surgery GA 206WP UT WOS:000323556600001 PM 23864242 ER PT J AU Epstein, AJ Groeneveld, PW Harhay, MO Yang, FF Polsky, D AF Epstein, Andrew J. Groeneveld, Peter W. Harhay, Michael O. Yang, Feifei Polsky, Daniel TI Impact of Minimally Invasive Surgery on Medical Spending and Employee Absenteeism SO JAMA SURGERY LA English DT Article ID LAPAROSCOPIC CHOLECYSTECTOMY; MODELS; COSTS AB IMPORTANCE As many surgical procedures have undergone a transition from a standard, open surgical approach to a minimally invasive one in the past 2 decades, the diffusion of minimally invasive surgery may have had sizeable but overlooked effects on medical expenditures and worker productivity. OBJECTIVE To examine the impact of standard vs minimally invasive surgery on health plan spending and workplace absenteeism for 6 types of surgery. DESIGN Cross-sectional regression analysis. SETTING National health insurance claims data and matched workplace absenteeism data from January 1, 2000, to December 31, 2009. PARTICIPANTS A convenience sample of adults with employer-sponsored health insurance who underwent either standard or minimally invasive surgery for coronary revascularization, uterine fibroid resection, prostatectomy, peripheral revascularization, carotid revascularization, or aortic aneurysm repair. MAIN OUTCOMES AND MEASURE Health plan spending and workplace absenteeism from 14 days before through 352 days after the index surgery. RESULTS There were 321 956 patients who underwent surgery; 23 814 were employees with workplace absenteeism data. After multivariable adjustment, mean health plan spending was lower for minimally invasive surgery for coronary revascularization (-$30 850; 95% CI, -$31 629 to -$30 091), uterine fibroid resection (-$1509; 95% CI, -$1754 to -$1280), and peripheral revascularization (-$12 031; 95% CI, -$15 552 to -$8717) and higher for prostatectomy ($1350; 95% CI, $611 to $2212) and carotid revascularization ($4900; 95% CI, $1772 to $8370). Undergoing minimally invasive surgery was associated with missing significantly fewer days of work for coronary revascularization (mean difference, -37.7 days; 95% CI, -41.1 to -34.3), uterine fibroid resection (mean difference, -11.7 days; 95% CI, -14.0 to -9.4), prostatectomy (mean difference, -9.0 days; 95% CI, -14.2 to -3.7), and peripheral revascularization (mean difference, -16.6 days; 95% CI, -28.0 to -5.2). CONCLUSIONS AND RELEVANCE For 3 of 6 types of surgery studied, minimally invasive procedures were associated with significantly lower health plan spending than standard surgery. For 4 types of surgery, minimally invasive procedures were consistently associated with significantly fewer days of absence from work. C1 [Epstein, Andrew J.; Groeneveld, Peter W.] US Dept Vet Affairs, Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Epstein, Andrew J.; Groeneveld, Peter W.; Harhay, Michael O.; Yang, Feifei; Polsky, Daniel] Univ Penn, Perelman Sch Med, Dept Med, Div Gen Internal Med, Philadelphia, PA USA. [Epstein, Andrew J.; Groeneveld, Peter W.; Polsky, Daniel] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Epstein, AJ (reprint author), Univ Penn, Perelman Sch Med, 423 Guardian Dr, Philadelphia, PA 19104 USA. EM eandrew@mail.med.upenn.edu OI Harhay, Michael/0000-0002-0553-674X FU Institute for Health Technology Studies FX This work was supported by a research grant from the Institute for Health Technology Studies. NR 14 TC 21 Z9 21 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6254 J9 JAMA SURG JI JAMA Surg. PD JUL PY 2013 VL 148 IS 7 BP 641 EP 647 DI 10.1001/jamasurg.2013.131 PG 7 WC Surgery SC Surgery GA 206WP UT WOS:000323556600016 PM 23552709 ER PT J AU Hicks, CW Hodin, RA Bordeianou, L AF Hicks, Caitlin W. Hodin, Richard A. Bordeianou, Liliana TI Possible Overuse of 3-Stage Procedures for Active Ulcerative Colitis SO JAMA SURGERY LA English DT Article ID POUCH-ANAL ANASTOMOSIS; POSTOPERATIVE COMPLICATIONS; ADENOMATOUS POLYPOSIS; SEPTIC COMPLICATIONS; INFLIXIMAB; RISK; SURGERY; COLECTOMY; DISEASE; 2-STAGE AB IMPORTANCE There is an assumption that patients treated with 3-stage procedures for active ulcerative colitis are undergoing a safer surgical approach and thus spared the complications associated with a 2-stage procedure. However, there is a paucity of data addressing the validity of this assumption, and the optimal staging approach for patients traditionally considered at high risk for anastomotic leak remains unclear. OBJECTIVES To identify factors associated with 3-vs 2-stage procedures and to determine their impact on surgical outcomes. DESIGN Retrospective analysis of patients who underwent 2-stage or 3-stage ileal pouch-anal anastomosis (IPAA) surgery for active ulcerative colitis due to failure of medical management over a 10.5-year period (September 1, 2000, to March 30, 2011). The mean (SEM) follow-up was 5.15 (0.24) years (range, 0.26-11.09 years). SETTING Single large academic medical center. PATIENTS One hundred forty-four patients treated with 3- or 2-stage IPAA surgery for active ulcerative colitis. Among these patients, 77 were male and 67 were female. The mean (SEM) age was 34.6 (1.0) years (range, 11-67 years). Of the 144 patients, 116 (80.6%) had a 2-stage procedure and 28 (19.4%) had a 3-stage procedure. INTERVENTIONS Two-stage vs 3-stage IPAA procedures for active ulcerative colitis. MAIN OUTCOMES AND MEASURES Factors leading to decision for 3-stage procedure, postoperative outcomes with 3-stage vs 2-stage procedures, and risks for complications in patients undergoing 3-stage vs 2-stage procedures. RESULTS Of 144 patients, only 19.4% had a 3-stage procedure. Decision to perform a 3-stage vs 2-stage procedure was affected by emergent status (P < .001) and hemodynamic instability (P = .04) but not by age, sex, body mass index, use of steroids, or use of anti-tumor necrosis factor agents. For patients with 2-stage procedures, multivariate regression revealed that the number of perioperative complications was affected by surgeon experience (P = .02) but not by emergent status, use of steroids, or use of anti-tumor necrosis factor agents. Two-stage procedures were associated with more perioperative complications on univariate analysis (P = .05), but multivariate regression suggested that this difference was due to surgeon experience (P = .02) rather than to creation of an IPAA at the first operation (P = .55). Importantly, 2-stage procedures did not change the risk of anastomotic leak when all operations were taken into account (odds ratio = 1.09; P = .94). In the long term (mean [SEM], 5.2 [0.2] years), patients who underwent 2-stage surgery had a lower risk of anal stricture (odds ratio = 8.21; P = .01) and no differences in fistula or abscess formation or in pouch failure. CONCLUSIONS AND RELEVANCE In patients with active ulcerative colitis, use of steroids and anti-tumor necrosis factor agents alone do not appear to justify the decision to avoid IPAA creation at the first operation provided that it is performed by a high-volume inflammatory bowel disease surgeon. C1 [Hicks, Caitlin W.] Johns Hopkins Univ Hosp, Dept Surg, Baltimore, MD 21287 USA. [Hicks, Caitlin W.; Hodin, Richard A.; Bordeianou, Liliana] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Hicks, CW (reprint author), Johns Hopkins Univ Hosp, Dept Surg, 600 N Wolfe St,Tower 110, Baltimore, MD 21287 USA. EM caitlin.hicks@gmail.com NR 28 TC 14 Z9 16 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6254 J9 JAMA SURG JI JAMA Surg. PD JUL PY 2013 VL 148 IS 7 BP 658 EP 664 DI 10.1001/2013.jamasurg.325 PG 7 WC Surgery SC Surgery GA 206WP UT WOS:000323556600020 PM 23700124 ER PT J AU Werner, RM Konetzka, RT Kim, M AF Werner, Rachel M. Konetzka, Rita T. Kim, Michelle TI Quality Improvement Under Nursing Home Compare: The Association Between Changes in Process and Outcome Measures SO MEDICAL CARE LA English DT Article DE nursing homes; quality improvement; quality of care ID LONG-TERM-CARE; HOSPITAL QUALITY; OF-CARE; PERFORMANCE; RESIDENTS; MORTALITY; IMPACT; PAIN; ASSESSMENTS; MANAGEMENT AB Background: Changes in resident outcomes may be driven by many factors, including changes in nursing home care processes. Understanding what processes, if any, lead to successful improvements in resident outcomes could create a stronger case for the continued use of these outcome measures in nursing home report cards.Objective: To test the extent to which improvements in outcomes of care are explained by changes in nursing home processes, a setting where, to our knowledge, this link has not been previously studied.Research Design/Measures: We describe facility-level changes in resident processes and outcomes before and after outcomes were publicly reported. We then assess the extent to which the changes in outcomes are associated with changes in nursing home processes of care, using the public release of information on nursing home outcomes as a source of variation in nursing home outcomes to identify the process-outcome relationship.Subjects: All 16,623 US nursing homes included in public reporting from 2000 to 2009 in Online Survey, Certification and Reporting and the nursing home Minimum Data Set.Results: Of the 5 outcome measures examined, only improvements in the percentage of nursing home residents in moderate or severe pain were associated with changes in nursing home processes of care. Furthermore, these changes in the measured process of care explained only a small part of the overall improvement in pain prevalence.Conclusions: A large portion of the improvements in nursing home outcomes were not associated with changes in measured processes of care suggesting that processes of care typically measured in nursing homes do little to improve nursing home performance on outcome measures. Developing quality measures that are related improved patient outcomes would likely benefit quality improvement. Understanding the mechanism behind improvements in nursing home outcomes is key to successfully achieving broad quality improvements across nursing homes. C1 [Werner, Rachel M.] Philadelphia VAMC, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Werner, Rachel M.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Konetzka, Rita T.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Kim, Michelle] Univ Chicago, Dept Hlth Care Syst, Chicago, IL 60637 USA. RP Werner, RM (reprint author), Philadelphia VAMC, Ctr Hlth Equ Res & Promot, Blockley Hall,Room 1230,423 Guardian Dr, Philadelphia, PA 19104 USA. EM rwerner@upenn.edu FU National Institute on Aging [R01 AG034182]; VA HSR&D Career Development Award FX Funded by the National Institute on Aging under Grant number R01 AG034182. R.M.W. was supported in part by a VA HSR&D Career Development Award. NR 30 TC 4 Z9 4 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2013 VL 51 IS 7 BP 582 EP 588 DI 10.1097/MLR.0b013e31828dbae4 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 202ML UT WOS:000323221000005 PM 23756645 ER PT J AU Mull, HJ Chen, Q O'Brien, WJ Shwartz, M Borzecki, AM Hanchate, A Rosen, AK AF Mull, Hillary J. Chen, Qi O'Brien, William J. Shwartz, Michael Borzecki, Ann M. Hanchate, Amresh Rosen, Amy K. TI Comparing 2 Methods of Assessing 30-Day Readmissions What is the Impact on Hospital Profiling in the Veterans Health Administration? SO MEDICAL CARE LA English DT Article DE readmissions; Veterans Affairs (US); quality assessment; public reporting; hospital quality AB Background: The Centers for Medicare and Medicaid Services' (CMS) all-cause readmission measure and the 3M Health Information System Division Potentially Preventable Readmissions (PPR) measure are both used for public reporting. These 2 methods have not been directly compared in terms of how they identify high-performing and low-performing hospitals. Objectives: To examine how consistently the CMS and PPR methods identify performance outliers, and explore how the PPR preventability component impacts hospital readmission rates, public reporting on CMS' Hospital Compare website, and pay-for-performance under CMS' Hospital Readmission Reduction Program for 3 conditions (acute myocardial infarction, heart failure, and pneumonia). Methods: We applied the CMS all-cause model and the PPR software to VA administrative data to calculate 30-day observed FY08-10 VA hospital readmission rates and hospital profiles. We then tested the effect of preventability on hospital readmission rates and outlier identification for reporting and pay-for-performance by replacing the dependent variable in the CMS all-cause model (Yes/No readmission) with the dichotomous PPR outcome (Yes/No preventable readmission). Results: The CMS and PPR methods had moderate correlations in readmission rates for each condition. After controlling for all methodological differences but preventability, correlations increased to >90%. The assessment of preventability yielded different outlier results for public reporting in 7% of hospitals; for 30% of hospitals there would be an impact on Hospital Readmission Reduction Program reimbursement rates. Conclusions: Despite uncertainty over which readmission measure is superior in evaluating hospital performance, we confirmed that there are differences in CMS-generated and PPR-generated hospital profiles for reporting and pay-for-performance, because of methodological differences and the PPR's preventability component. C1 [Mull, Hillary J.; Chen, Qi; O'Brien, William J.; Shwartz, Michael; Hanchate, Amresh; Rosen, Amy K.] VA Boston Healthcare Syst, COLMR, Boston, MA USA. [Mull, Hillary J.; Rosen, Amy K.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Shwartz, Michael] Boston Univ, Sch Management, Boston, MA 02215 USA. [Borzecki, Ann M.; Hanchate, Amresh] Boston Univ, Sch Med, Boston, MA 02118 USA. [Borzecki, Ann M.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Borzecki, Ann M.] Bedford VAMC, CHQOER, Bedford, MA USA. RP Chen, Q (reprint author), 150 S Huntington Ave, Boston, MA 02130 USA. EM qi.chen2@va.gov OI Hanchate, Amresh/0000-0002-7038-4463 FU Department of Veterans Affairs Health Services Research and Development Service [IIR 09-369-2] FX Supported by Department of Veterans Affairs Health Services Research and Development Service Grant Number IIR 09-369-2. NR 16 TC 9 Z9 9 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2013 VL 51 IS 7 BP 589 EP 596 DI 10.1097/MLR.0b013e31829019a4 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 202ML UT WOS:000323221000006 PM 23604016 ER PT J AU Merkow, RP Bentrem, DJ Chung, JW Paruch, JL Ko, CY Bilimoria, KY AF Merkow, Ryan P. Bentrem, David J. Chung, Jeanette W. Paruch, Jennifer L. Ko, Clifford Y. Bilimoria, Karl Y. TI Differences in Patients, Surgical Complexity, and Outcomes After Cancer Surgery at National Cancer Institute-designated Cancer Centers Compared to Other Hospitals SO MEDICAL CARE LA English DT Article DE outcomes; quality; ACS NSQIP; surgery; risk adjustment; oncology; cancer; surgical oncology; American College of Surgeons; National Cancer Institute Cancer Center ID QUALITY IMPROVEMENT INITIATIVES; RISK-ADJUSTMENT; VOLUME; MORTALITY; PROGRAM; CARE; SURVIVAL; SAFETY AB Background: Interest in comparing hospital surgical quality continues to increase, particularly with respect to examining certain hospital designations such as National Cancer Institute-designated Cancer Centers (NCI-CC). Our objectives were to compare patients, surgical complexity, and risk-adjusted 30-day outcomes following major cancer surgery at NCI-CC versus non-NCI centers. Methods: From the American College of Surgeons National Surgical Quality Improvement Program, patients were identified who underwent colorectal, pancreatic, or esophagogastric resection for cancer (2007-2011). Regression methods were used to evaluate characteristics associated with undergoing treatment at NCI-CCs and surgical-complexity-adjusted 30-day morbidity, mortality, and prolonged length-of-stay at NCI-CC versus non-NCI centers. Results: NCI-CCs performed 20.2% of colorectal (10,555/52,265), 53.5% of pancreatic (6335/11,838), and 49.8% of esophagogastric (1596/3208) operations for cancer. NCI-CCs were more likely to treat patients who were younger, white, and with fewer comorbidities, but were more likely to perform more complex procedures including synchronous liver resection (eg, colorectal), adjacent organ resections (rectal cancer), and vascular reconstructions (eg, pancreas) (all P<0.05). NCI-CCs had a lower mortality rate for colorectal surgery only (1.2% vs. 1.9%) and increased rates of superficial surgical site infection (SSI) for colorectal (9.8% vs. 7.1%) and pancreatic (10.7% vs. 8.8%) surgery. No differences existed for the remaining complications by NCI-CC designation status. NCI-CCs were distributed throughout hospital quality rankings for all procedures and complications assessed. Conclusions: NCI-CCs treated younger, healthier patients, but performed more complex procedures. Patients treated at NCI-CCs had a lower risk of mortality for colorectal resection, but morbidity was similar to non-NCI centers. Comparison of cancer surgery hospital quality is feasible and should adjust for differences in patient demographics, comorbidities, and surgical complexity. C1 [Merkow, Ryan P.; Paruch, Jennifer L.; Ko, Clifford Y.; Bilimoria, Karl Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Merkow, Ryan P.; Bentrem, David J.; Chung, Jeanette W.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Surg Outcomes & Qual Improvement Ctr, Dept Surg, Chicago, IL 60611 USA. [Merkow, Ryan P.; Bentrem, David J.; Chung, Jeanette W.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Northwestern Inst Comparat Effectiveness Res NICE, Chicago, IL 60611 USA. [Merkow, Ryan P.; Paruch, Jennifer L.] Univ Chicago, Pritzker Sch Med, Dept Surg, Chicago, IL 60637 USA. [Bentrem, David J.] Jesse Brown VA Med Ctr, Dept Surg, Chicago, IL USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. RP Bilimoria, KY (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 636 St Clair St,22nd Floor, Chicago, IL 60611 USA. EM kbilimoria@facs.org FU NICER FX R.P.M., D.J.B., and K.Y.B. are supported by NICER. NR 34 TC 7 Z9 7 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2013 VL 51 IS 7 BP 606 EP 613 DI 10.1097/MLR.0b013e3182928f44 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 202ML UT WOS:000323221000008 PM 23604012 ER PT J AU Fung, V Price, M Busch, AB Landrum, MB Fireman, B Nierenberg, A Dow, WH Hui, R Frank, R Newhouse, JP Hsu, J AF Fung, Vicki Price, Mary Busch, Alisa B. Landrum, Mary Beth Fireman, Bruce Nierenberg, Andrew Dow, William H. Hui, Rita Frank, Richard Newhouse, Joseph P. Hsu, John TI Adverse Clinical Events Among Medicare Beneficiaries Using Antipsychotic Drugs: Linking Health Insurance Benefits and Clinical Needs SO MEDICAL CARE LA English DT Article DE Medicare; antipsychotics; benefit design ID D COVERAGE GAP; PART-D; PRIOR AUTHORIZATION; BIPOLAR DISORDER; SCHIZOPHRENIA; MEDICATIONS; RISK; COSTS; HOSPITALIZATION; QUETIAPINE AB Objective: Medicare Part D provides formulary protections for antipsychotics but does not exempt these drugs from cost-sharing. We investigated the impact of Part D coverage on antipsychotic drug spending, adherence, and clinical outcomes among beneficiaries with varying indications for use.Methods: We conducted a historical cohort study of Medicare Advantage beneficiaries who received antipsychotic drugs, with diagnoses of schizophrenia or bipolar disorder or with no mental health diagnoses (N=10,190). Half had a coverage gap; half had no gap because of low-income subsidies. Using fixed effects regression models, we examined changes in spending and adherence as beneficiaries experienced cost-sharing increases after reaching the gap. We examined changes in hospitalizations and emergency department visits using proportional hazard models.Results: Across all diagnostic groups, total monthly expenditure on antipsychotic drugs decreased with cost-sharing increases in the gap compared with those with no gap (eg, schizophrenia: -$123 95% confidence interval [-$138, -$108]), and out-of-pocket spending increased (eg, schizophrenia: $104 [$98, $110]). Adherence similarly decreased, with the largest declines among those with schizophrenia (-20.6 percentage points [-22.3, -18.9] in proportion of days covered). Among beneficiaries with schizophrenia and bipolar disorder, hospitalizations and emergency department visit rates increased with cost-sharing increases (eg, schizophrenia: hazard ratio=1.32 [1.06, 1.65] for all hospitalizations), but did not among subjects without mental health diagnoses. Clinical event rates did not change among beneficiaries with low-income subsidies without gaps.Conclusions: There is evidence of interruptions in antipsychotic use attributable to Part D cost-sharing. Adverse events increased among beneficiaries with approved indications for use, but not among beneficiaries without such indications. C1 [Fung, Vicki] Midatlantic Permanente Med Grp, Midatlantic Permanente Res Inst, Rockville, MD USA. [Price, Mary; Fireman, Bruce] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Busch, Alisa B.] McLean Hosp, Belmont, MA 02178 USA. [Busch, Alisa B.; Landrum, Mary Beth; Frank, Richard; Newhouse, Joseph P.; Hsu, John] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Busch, Alisa B.] Partners HealthCare, Partners Psychiat & Mental Hlth, Hlth Serv Res Div, Boston, MA USA. [Nierenberg, Andrew] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Dow, William H.] Univ Calif Berkeley, Sch Publ Hlth, Div Hlth Policy & Management, Berkeley, CA 94720 USA. [Hui, Rita] Kaiser Permanente, Pharm Outcomes Res Grp, Oakland, CA USA. [Newhouse, Joseph P.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, Harvard Kennedy Sch, Boston, MA 02115 USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Hsu, John] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Fung, V (reprint author), Mongan Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM vfung@partners.org OI Dow, William/0000-0002-4080-1668 FU National Institute of Mental Health [5R01MH090284, K01MH071714]; National Institute on Aging [R01AG029316] FX The National Institute of Mental Health (5R01MH090284 and K01MH071714) and the National Institute on Aging (R01AG029316) provided the funding for this study. NR 39 TC 5 Z9 5 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2013 VL 51 IS 7 BP 614 EP 621 DI 10.1097/MLR.0b013e31829019c5 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 202ML UT WOS:000323221000009 PM 23752219 ER PT J AU Fendt, SM Bell, EL Keibler, MA Olenchock, BA Mayers, JR Wasylenko, TM Vokes, NI Guarente, L Vander Heiden, MG Stephanopoulos, G AF Fendt, Sarah-Maria Bell, Eric L. Keibler, Mark A. Olenchock, Benjamin A. Mayers, Jared R. Wasylenko, Thomas M. Vokes, Natalie I. Guarente, Leonard Vander Heiden, Matthew G. Stephanopoulos, Gregory TI Reductive glutamine metabolism is a function of the alpha-ketoglutarate to citrate ratio in cells SO NATURE COMMUNICATIONS LA English DT Article ID PYRUVATE-DEHYDROGENASE; FLUX ANALYSIS; CANCER; HYPOXIA; GROWTH; PROLIFERATION; CARBOXYLATION; DISTRIBUTIONS; ADAPTATION; KINASE AB Reductively metabolized glutamine is a major cellular carbon source for fatty acid synthesis during hypoxia or when mitochondrial respiration is impaired. Yet, a mechanistic understanding of what determines reductive metabolism is missing. Here we identify several cellular conditions where the alpha-ketoglutarate/citrate ratio is changed due to an altered acetyl-CoA to citrate conversion, and demonstrate that reductive glutamine metabolism is initiated in response to perturbations that result in an increase in the alpha-ketoglutarate/citrate ratio. Thus, targeting reductive glutamine conversion for a therapeutic benefit might require distinct modulations of metabolite concentrations rather than targeting the upstream signalling, which only indirectly affects the process. C1 [Fendt, Sarah-Maria; Keibler, Mark A.; Wasylenko, Thomas M.; Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Bell, Eric L.; Mayers, Jared R.; Guarente, Leonard; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Olenchock, Benjamin A.; Mayers, Jared R.; Vokes, Natalie I.; Vander Heiden, Matthew G.] MIT, Koch Inst Canc Res, Cambridge, MA 02139 USA. [Olenchock, Benjamin A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Olenchock, Benjamin A.; Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Stephanopoulos, G (reprint author), MIT, Dept Chem Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM gregstep@mit.edu OI Fendt, Sarah-Maria/0000-0001-6018-9296 FU German Research Foundation (DFG) [FE1185]; NRSA [F32 CA132358]; NIH [5-P30-CA14051-39, 1R01CA160458-01A1]; Damon Runyon Cancer Research Foundation; Burrough's Wellcome Fund; Smith Family FX S.M.F. is supported by the German Research Foundation (DFG), grant FE1185. E.L.B. is supported by NRSA postdoctoral fellowship F32 CA132358. M.G.V.H. acknowledges NIH grant 5-P30-CA14051-39 and support from the Damon Runyon Cancer Research Foundation, the Burrough's Wellcome Fund and the Smith Family. We also acknowledge NIH grant 1R01CA160458-01A1 to G.S. NR 37 TC 74 Z9 74 U1 4 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2013 VL 4 AR 2236 DI 10.1038/ncomms3236 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 208YH UT WOS:000323718300001 PM 23900562 ER PT J AU Pers, TH Dworzynski, P Thomas, CE Lage, K Brunak, S AF Pers, Tune H. Dworzynski, Piotr Thomas, Cecilia Engel Lage, Kasper Brunak, Soren TI MetaRanker 2.0: a web server for prioritization of genetic variation data SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RARE-VARIANT ASSOCIATION; GENOME-WIDE ASSOCIATION; CANDIDATE GENES; COMPLEX TRAITS; DISEASE; NETWORK; DISORDERS; HEIGHT; RISK; LOCI AB MetaRanker 2.0 is a web server for prioritization of common and rare frequency genetic variation data. Based on heterogeneous data sets including genetic association data, protein-protein interactions, large-scale text-mining data, copy number variation data and gene expression experiments, MetaRanker 2.0 prioritizes the protein-coding part of the human genome to shortlist candidate genes for targeted follow-up studies. MetaRanker 2.0 is made freely available at www.cbs.dtu.dk/services/MetaRanker-2.0. C1 [Pers, Tune H.; Dworzynski, Piotr; Thomas, Cecilia Engel; Lage, Kasper; Brunak, Soren] Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Pers, Tune H.] Childrens Hosp Boston, Div Endocrinol, Boston, MA USA. [Pers, Tune H.] Childrens Hosp Boston, Ctr Basic & Translat Obes Res, Boston, MA USA. [Pers, Tune H.; Lage, Kasper] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Lage, Kasper; Brunak, Soren] Univ Copenhagen, Fac Hlth Sci, NNF Ctr Prot Res, Copenhagen, Denmark. [Lage, Kasper] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Lage, Kasper] Harvard Univ, Sch Med, Boston, MA USA. RP Brunak, S (reprint author), Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. EM brunak@cbs.dtu.dk OI Engel Thomas, Cecilia/0000-0001-6201-6380 FU Danish Council for Independent Research Medical Sciences (FSS); Novo Nordisk Foundation; Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark FX Danish Council for Independent Research Medical Sciences (FSS) (to T. H. P.); Novo Nordisk Foundation (to S. B.). Funding for open access charge: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark. NR 26 TC 14 Z9 14 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2013 VL 41 IS W1 BP W104 EP W108 DI 10.1093/nar/gkt387 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 207MC UT WOS:000323603200017 PM 23703204 ER PT J AU Seyhan, M Cakmak, S Donmez, F Gereli, A AF Seyhan, Mustafa Cakmak, Selami Donmez, Ferdi Gereli, Arel TI Blocking Screws for the Treatment of Distal Femur Fractures SO ORTHOPEDICS LA English DT Article ID RETROGRADE INTRAMEDULLARY NAIL; POLLER SCREWS; FEMORAL FRACTURES; FIXATION; TIBIA; PLATE AB Intramedullary nailing is one of the most convenient biological options for treating distal femoral fractures. Because the distal medulla of the femur is wider than the middle diaphysis and intramedullary nails cannot completely fill the intramedullary canal, intramedullary nailing of distal femoral fractures can be difficult when trying to obtain adequate reduction. Some different methods exist for achieving reduction. The purpose of this study was determine whether the use of blocking screws resolves varus or valgus and translation and recurvatum deformities, which can be encountered in antegrade and retrograde intramedullary nailing. Thirty-four patients with distal femoral fractures underwent intramedullary nailing between January 2005 and June 2011. Fifteen patients treated by intramedullary nailing and blocking screws were included in the study. Six patients had distal diaphyseal fractures and 9 had distal diaphyseo-metaphyseal fractures. Antegrade nailing was performed in 7 patients and retrograde nailing was performed in 8. Reduction during surgery and union during follow-up were achieved in all patients with no significant complications. Mean follow-up was 26.6 months. Mean time to union was 12.6 weeks. The main purpose of using blocking screws is to achieve reduction, but they are also useful for maintaining permanent reduction. When inserting blocking screws, the screws must be placed 1 to 3 cm away from the fracture line to avoid from propagation of the fracture. When applied properly and in an adequate way, blocking screws provide an efficient solution for deformities encountered during intramedullary nailing of distal femur fractures. C1 [Cakmak, Selami] GATA Haydarpasa Hosp, Dept Orthopaed & Traumatol, Istanbul, Turkey. [Cakmak, Selami] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. RP Cakmak, S (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, 55 Fruit St, Boston, MA 02114 USA. EM selamicakmak@gmail.com NR 17 TC 3 Z9 3 U1 0 U2 8 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0147-7447 J9 ORTHOPEDICS JI Orthopedics PD JUL PY 2013 VL 36 IS 7 BP E936 EP E941 DI 10.3928/01477447-20130624-26 PG 6 WC Orthopedics SC Orthopedics GA 187KD UT WOS:000322115900015 PM 23823053 ER PT J AU Khanam, F Sheikh, A Sayeed, A Bhuiyan, S Choudhury, FK Salma, U Pervin, S Sultana, T Ahmed, D Goswami, D Hossain, L Mamun, KZ Charles, RC Brooks, WA Calderwood, SB Cravioto, A Ryan, ET Qadri, F AF Khanam, Farhana Sheikh, Alaullah Sayeed, Abu Bhuiyan, Saruar Choudhury, Feroza Kaneez Salma, Umme Pervin, Shahnaz Sultana, Tania Ahmed, Dilruba Goswami, Doli Hossain, Lokman Mamun, K. Z. Charles, Richelle C. Brooks, W. Abdullah Calderwood, Stephen B. Cravioto, Alejandro Ryan, Edward T. Qadri, Firdausi TI Evaluation of a Typhoid/Paratyphoid Diagnostic Assay (TPTest) Detecting Anti-Salmonella IgA in Secretions of Peripheral Blood Lymphocytes in Patients in Dhaka, Bangladesh SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID POLYMERASE-CHAIN-REACTION; BONE-MARROW CULTURES; TYPHOID-FEVER; WIDAL TEST; CLINICAL-FEATURES; ENTERIC FEVER; ENDEMIC AREA; CHILDREN; TESTS; PARATYPHI AB Background: Rapid and reliable diagnostic assays for enteric (typhoid and paratyphoid) fever are urgently needed. We report the characterization of novel approach utilizing lymphocyte secretions, for diagnosing patients with enteric fever by the TPTest procedure. Methodology: TPTest detects Salmonella-specific IgA responses in lymphocyte culture supernatant. We utilized TPTest in patients with suspected enteric fever, patients with other illnesses, and healthy controls. We also evaluated simplified modifications of TPTest for adaptation in laboratories with limited facilities and equipment. Principal Findings: TPTest was positive in 39 (27 typhoid and 12 paratyphoid A) patients confirmed by blood culture and was negative in 74 healthy individuals. Among 32 individuals with other illnesses, 29 were negative by TPTest. Of 204 individuals with suspected enteric fever who were negative by blood culture, 44 were positive by TPTest and the patients were clinically indistinguishable from patients with confirmed bacteremia, except they were more likely to be under 5 years of age. We evaluated simplifications in TPTest, including showing that lymphocytes could be recovered using lysis buffer or buffy coat method as opposed to centrifugation, that incubation of cells at 37 degrees C did not require supplemental CO2, and that results were available for majority of samples within 24 hours. Positive results by TPTest are transient and revert to negative during convalescence, supporting use of the test in endemic areas. The results can also be read using immunodot blot approach as opposed to ELISA. Since no true gold standard currently exists, we used a number of definitions of true positives and negatives. TPTest had sensitivity of 100% compared to blood culture, and specificity that ranged from 78-97% (73-100, 95% CI), depending on definition of true negative. Conclusion: The TPTest is useful for identification of patients with enteric fever in an endemic area, and additional development of simplified TPTest is warranted. C1 [Khanam, Farhana; Sheikh, Alaullah; Sayeed, Abu; Bhuiyan, Saruar; Choudhury, Feroza Kaneez; Salma, Umme; Sultana, Tania; Ahmed, Dilruba; Goswami, Doli; Hossain, Lokman; Brooks, W. Abdullah; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res Icddr B, Dhaka, Bangladesh. [Pervin, Shahnaz; Mamun, K. Z.] DMCH, Dept Microbiol, Dhaka, Bangladesh. [Charles, Richelle C.; Calderwood, Stephen B.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Charles, Richelle C.; Calderwood, Stephen B.; Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Cravioto, Alejandro] Int Vaccine Inst, Seoul, South Korea. RP Khanam, F (reprint author), Int Ctr Diarrhoeal Dis Res Icddr B, Dhaka, Bangladesh. EM fqadri@icddrb.org FU icddr,b; National Institutes of Health; National Institute of Allergy & Infectious Diseases [AI100023, AI077883, AI058935, AI89721]; Fogarty International Center [TW005572]; Swedish International Development Cooperation Agency FX This research was supported by the icddr,b and extramural grants from the National Institutes of Health, including the National Institute of Allergy & Infectious Diseases (AI100023 and AI077883 [ETR FQ], AI058935 [SBC ETR], and AI89721 [RCC]), and the Fogarty International Center, Training Grant in Vaccine Development and Public Health (TW005572 [FK AS SB TS FQ]), as well as by the Swedish International Development Cooperation Agency (FQ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 15 Z9 15 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2013 VL 7 IS 7 AR e2316 DI 10.1371/journal.pntd.0002316 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 190EJ UT WOS:000322321500030 PM 23951368 ER PT J AU Drain, PK Evert, J Gardner, P AF Drain, Paul K. Evert, Jessica Gardner, Pierce TI Bring Global Health and Global Medicine Home Reply SO ACADEMIC MEDICINE LA English DT Letter C1 [Drain, Paul K.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Drain, Paul K.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Drain, Paul K.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Evert, Jessica] Child & Family Hlth Int, San Francisco, CA USA. [Gardner, Pierce] SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. RP Drain, PK (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM pdrain@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JUL PY 2013 VL 88 IS 7 BP 908 EP 909 DI 10.1097/ACM.0b013e31829527aa PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 200AQ UT WOS:000323038400006 PM 23799432 ER PT J AU Tsai, AC Ordonez, AE Reus, VI Mathews, CA AF Tsai, Alexander C. Ordonez, Anna E. Reus, Victor I. Mathews, Carol A. TI Eleven-Year Outcomes From an Integrated Residency Program to Train Research Psychiatrists SO ACADEMIC MEDICINE LA English DT Article ID MENTAL-HEALTH RESEARCHERS; PHYSICIAN-SCIENTISTS; CLINICAL-RESEARCH; FUTURE GENERATIONS; ACADEMIC MEDICINE; CHALLENGES; OBSTACLES; PIPELINE; TRENDS; MODEL AB In 2000, to address the critical shortage of research psychiatrists, faculty in the Residency Training Program in General Adult Psychiatry at the University of California, San Francisco, School of Medicine developed and implemented a research resident training program (RRTP). In this article, the authors describe the program's development process, including its organizational structure, eligibility criteria for residents, and core program elements, and they report 11 years of outcomes data. Notable RRTP components include research and career mentorship, individualized training plans, the integration of clinical and research experiences, protected research time, and research funding. From 2000 to 2011, the RRTP enrolled 48 residents. The authors' primary outcome of interest in determining the success of the program was whether or not each RRTP resident entered a postdoctoral research fellowship after graduation. The authors found that more than 80% of graduates had matriculated to postdoctoral research fellowships, irrespective of their previous doctoral-level training in the basic or social sciences. The authors conclude that this flexible, individualized, and innovative training program for psychiatry residents was successful in facilitating the entry of participants into primary research careers, reasoning that it may serve as a model for other residency programs with similar goals. More widespread adoption of similar educational models may help to address the critical shortage of research psychiatrists. C1 [Tsai, Alexander C.] Harvard Univ, Sch Med, Boston, MA USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Dept Psychiat, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Ordonez, Anna E.; Reus, Victor I.; Mathews, Carol A.] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Ordonez, Anna E.] San Francisco Gen Hosp, Div Infant Child & Adolescent Psychiat, San Francisco, CA 94110 USA. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, Room 1529-E3,100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org RI reus, victor/I-7923-2015; OI reus, victor/0000-0002-8193-5697; Tsai, Alexander/0000-0001-6397-7917 FU National Institutes of Health (NIH) Research Education Grant [R25 MH-060482]; NIH Mentored Patient-Oriented Research Career Development Award [K23 MH-096620] FX The RRTP is funded by National Institutes of Health (NIH) Research Education Grant R25 MH-060482 (PI: Reus VI [2000-2010]; Contact PI: Mathews CA [2010-present]); and through funds committed by Dr. Craig Van Dyke during the program's partial overlap with his tenure as chair (2000-2008), and by Dr. Renee Binder during her tenure as interim chair (2008-2011) of the Department of Psychiatry at the University of California, San Francisco, School of Medicine. Dr. Tsai acknowledges salary support through NIH Mentored Patient-Oriented Research Career Development Award K23 MH-096620. NR 31 TC 6 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JUL PY 2013 VL 88 IS 7 BP 983 EP 988 DI 10.1097/ACM.0b013e318294f95d PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 200AQ UT WOS:000323038400029 PM 23702520 ER PT J AU Hofer, CB Harris, DR Saavedra, MC Haberer, JE Romeiro, J Mussi-Pinhata, MM Stankievich, E Gomes, IM Kreitchmann, R Read, JS AF Hofer, Cristina B. Harris, D. Robert Saavedra, Mariza C. Haberer, Jessica E. Romeiro, Juliana Mussi-Pinhata, Marisa M. Stankievich, Erica Gomes, Ivete M. Kreitchmann, Regis Read, Jennifer S. CA NISDI LILAC Study Team TI Adherence to antiretroviral prophylaxis during early infancy in Latin America SO BRAZILIAN JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID SINGLE-DOSE NEVIRAPINE; TO-CHILD TRANSMISSION; HIV; PREVENTION; REGIMEN C1 [Hofer, Cristina B.] Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira, Rio De Janeiro, RJ, Brazil. [Hofer, Cristina B.] Univ Fed Rio de Janeiro, Dept Prevent Med, Rio De Janeiro, RJ, Brazil. [Harris, D. Robert] Westat Corp, Rockville, MD USA. [Saavedra, Mariza C.] Hosp Fed Servidores Estado, Rio De Janeiro, RJ, Brazil. [Haberer, Jessica E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Romeiro, Juliana] Univ Fed Minas Gerais, Sch Med, Grp Estudos HIV AIDS, Belo Horizonte, MG, Brazil. [Mussi-Pinhata, Marisa M.] Univ Sao Paulo, Dept Pediat, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil. [Stankievich, Erica] Hosp Gen Agudos JM Ramos Mejia, Serv Inmunocomprometidos, Buenos Aires, DF, Argentina. [Gomes, Ivete M.] Hosp Geral Nova Iguacu, Rio De Janeiro, RJ, Brazil. [Kreitchmann, Regis] Irmandade de Santa Casa Misercordia Porto Alegre, Porto Alegre, RS, Brazil. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. RP Hofer, CB (reprint author), Rua Bruno Lobo 50, Rio De Janeiro, RJ, Brazil. EM cbhofer@hucff.ufrj.br RI Melo, Anderson/L-6758-2014; OI Mofenson, Lynne/0000-0002-2818-9808; Melo, Anderson/0000-0002-4606-7791; Harris, Donald/0000-0002-8262-3716; Alarcon, Jorge/0000-0002-0800-2380 FU NICHD NIH HHS [HHSN267200800001C, HHSN275201300003C, N01-HD-3-3345, N01-HD-8-0001]; NIDDK NIH HHS [HHSN267200800001G]; PHS HHS [HHSN267200800001C] NR 5 TC 0 Z9 0 U1 0 U2 1 PU CONTEXTO PI SALVADOR PA RUA ALFREDO MAGALHAES, 04-BARRA, SALVADOR, BAHIA 40140-140, BRAZIL SN 1413-8670 J9 BRAZ J INFECT DIS JI Braz. J. Infect. Dis. PD JUL-AUG PY 2013 VL 17 IS 4 BP 495 EP 496 DI 10.1016/j.bjid.2012.11.006 PG 2 WC Infectious Diseases SC Infectious Diseases GA 204AN UT WOS:000323336800019 PM 23680065 ER PT J AU Mayer, EL Scheulen, ME Beckman, J Richly, H Duarte, A Cotreau, MM Strahs, AL Agarwal, S Steelman, L Winer, EP Dickler, MN AF Mayer, Erica L. Scheulen, M. E. Beckman, J. Richly, H. Duarte, A. Cotreau, M. M. Strahs, A. L. Agarwal, S. Steelman, L. Winer, E. P. Dickler, M. N. TI A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Metastatic breast cancer; Paclitaxel; Tivozanib; VEGFR inhibitor ID ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; NEOADJUVANT CHEMOTHERAPY; TYROSINE KINASES; PLUS BEVACIZUMAB; TRIAL; COMBINATION; HYPERTENSION; ASSOCIATION; BIOMARKERS AB Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease >= 6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging. C1 [Mayer, Erica L.; Winer, E. P.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Scheulen, M. E.; Richly, H.] Univ Duisburg Essen, West German Canc Ctr, Dept Med Oncol, Univ Hosp Essen, Essen, Germany. [Beckman, J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Duarte, A.; Cotreau, M. M.; Strahs, A. L.; Agarwal, S.; Steelman, L.] AVEO Oncol, Cambridge, MA USA. [Dickler, M. N.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Mayer, EL (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM emayer@partners.org OI Beckman, Joshua/0000-0001-8332-8439 FU AVEO Oncology; Astellas FX This work was supported by AVEO Oncology and Astellas. NR 36 TC 12 Z9 13 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2013 VL 140 IS 2 BP 331 EP 339 DI 10.1007/s10549-013-2632-9 PG 9 WC Oncology SC Oncology GA 202UN UT WOS:000323245200013 PM 23868188 ER PT J AU Russo, AL Arvold, ND Niemierko, A Wong, N Wong, JS Bellon, JR Punglia, RS Golshan, M Troyan, SL Brock, JE Harris, JR AF Russo, Andrea L. Arvold, Nils D. Niemierko, Andrzej Wong, Nathan Wong, Julia S. Bellon, Jennifer R. Punglia, Rinaa S. Golshan, Mehra Troyan, Susan L. Brock, Jane E. Harris, Jay R. TI Margin status and the risk of local recurrence in patients with early-stage breast cancer treated with breast-conserving therapy SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Surgical margin; Breast-conserving therapy; Local recurrence ID RADIATION-THERAPY; CONSERVATIVE SURGERY; SURGICAL MARGINS; RE-EXCISION; ESTROGEN-RECEPTOR; SYSTEMIC THERAPY; POSITIVE MARGINS; LUMPECTOMY; CARCINOMA; WOMEN AB We sought to assess whether a close surgical margin (>0 and <2 mm) after breast-conserving therapy (BCT) confers an increased risk of local recurrence (LR) compared with a widely negative margin (>= 2 mm). We studied 906 women with early-stage invasive breast cancer treated with BCT between January 1998 and October 2006; 91 % received adjuvant systemic therapy. Margins were coded as: (1) widely negative (n = 729), (2) close (n = 85), or (3) close (n = 84)/positive (n = 8) but having no additional tissue to remove according to the surgeon. Cumulative incidence of LR and distant failure (DF) were calculated using the Kaplan-Meier method. Gray's competing-risk regression assessed the effect of margin status on LR and Cox proportional hazards regression assessed the effect on DF, controlling for biologic subtype, age, and number of positive lymph nodes (LNs). Three hundred seventy-seven patients (41.6 %) underwent surgical re-excision, of which 63.5 % had no residual disease. With a median follow-up of 87.5 months, the 5-year cumulative incidence of LR was 2.5 %. The 5-year cumulative incidence of LR by margin status was 2.3 % (95 % CI 1.4-3.8 %) for widely negative, 0 % for close, and 6.4 % (95 % CI 2.7-14.6 %) for no additional tissue, p = 0.3. On multivariate analysis, margin status was not associated with LR; however, triple-negative subtype (AHR 3.7; 95 % CI 1.6-8.8; p = 0.003) and increasing number of positive LNs (AHR 1.6; 95 % CI 1.1-2.3; p = 0.025) were associated. In an era of routine adjuvant systemic therapy, close surgical margins and maximally resected close/positive margins were not associated with an increased risk of LR compared to widely negative margins. Additional studies are needed to confirm this finding. C1 [Russo, Andrea L.] Harvard Radiat Oncol Program, Boston, MA USA. [Arvold, Nils D.; Wong, Nathan; Wong, Julia S.; Bellon, Jennifer R.; Punglia, Rinaa S.; Harris, Jay R.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Arvold, Nils D.; Wong, Nathan; Wong, Julia S.; Bellon, Jennifer R.; Punglia, Rinaa S.; Golshan, Mehra; Troyan, Susan L.; Harris, Jay R.] Brigham & Womens Hosp, Boston, MA 02215 USA. [Niemierko, Andrzej] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Golshan, Mehra; Troyan, Susan L.] Dana Farber Canc Inst, Div Surg Oncol, Boston, MA 02215 USA. [Brock, Jane E.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. RP Harris, JR (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. EM jharris@lroc.harvard.edu NR 38 TC 18 Z9 18 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2013 VL 140 IS 2 BP 353 EP 361 DI 10.1007/s10549-013-2627-6 PG 9 WC Oncology SC Oncology GA 202UN UT WOS:000323245200015 PM 23836011 ER PT J AU Sulz, MC Siebert, U Arvandi, M Gothe, RM Wurm, J von Kanel, R Vavricka, SR Meyenberger, C Sagmeister, M AF Sulz, Michael C. Siebert, Uwe Arvandi, Marjan Gothe, Raffaella M. Wurm, Johannes von Kaenel, Roland Vavricka, Stephan R. Meyenberger, Christa Sagmeister, Markus CA Swiss IBD Cohort Study Grp TI Predictors for hospitalization and outpatient visits in patients with inflammatory bowel disease: results from the Swiss Inflammatory Bowel Disease Cohort Study SO EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Article DE decision-making; inflammatory bowel disease; predictors; resource consumption AB Objectives Patients with inflammatory bowel disease (IBD) have a high resource consumption, with considerable costs for the healthcare system. In a system with sparse resources, treatment is influenced not only by clinical judgement but also by resource consumption. We aimed to determine the resource consumption of IBD patients and to identify its significant predictors.Materials and methods Data from the prospective Swiss Inflammatory Bowel Disease Cohort Study were analysed for the resource consumption endpoints hospitalization and outpatient consultations at enrolment [1187 patients; 41.1% ulcerative colitis (UC), 58.9% Crohn's disease (CD)] and at 1-year follow-up (794 patients). Predictors of interest were chosen through an expert panel and a review of the relevant literature. Logistic regressions were used for binary endpoints, and negative binomial regressions and zero-inflated Poisson regressions were used for count data.Results For CD, fistula, use of biologics and disease activity were significant predictors for hospitalization days (all P-values <0.001); age, sex, steroid therapy and biologics were significant predictors for the number of outpatient visits (P=0.0368, 0.023, 0.0002, 0.0003, respectively). For UC, biologics, C-reactive protein, smoke quitters, age and sex were significantly predictive for hospitalization days (P=0.0167, 0.0003, 0.0003, 0.0076 and 0.0175 respectively); disease activity and immunosuppressive therapy predicted the number of outpatient visits (P=0.0009 and 0.0017, respectively). The results of multivariate regressions are shown in detail.Conclusion Several highly significant clinical predictors for resource consumption in IBD were identified that might be considered in medical decision-making. In terms of resource consumption and its predictors, CD and UC show a different behaviour. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Sulz, Michael C.; Meyenberger, Christa; Sagmeister, Markus] Kantonsspital St Gallen, Dept Gastroenterol & Hepatol, CH-9007 St Gallen, Switzerland. [von Kaenel, Roland] Univ Hosp Bern, Inselspital, Div Psychosomat Med, CH-3010 Bern, Switzerland. [Vavricka, Stephan R.] Univ Zurich Hosp, Dept Gastroenterol, CH-8091 Zurich, Switzerland. [Siebert, Uwe; Arvandi, Marjan; Gothe, Raffaella M.; Wurm, Johannes] UMIT Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth & Hlth Technol Assessment, Hall In Trol, Austria. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Inst Technol Assessment,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Sagmeister, M (reprint author), Kantonsspital St Gallen, Dept Gastroenterol & Hepatol, Rorschacherstr 95, CH-9007 St Gallen, Switzerland. EM sagmeister@hin.ch RI Rogler, Gerhard/O-5308-2015; OI Rogler, Gerhard/0000-0002-1733-9188; Tutuian, Radu/0000-0001-9182-2517; Mueller, Christoph/0000-0002-3921-8678 FU Swiss National Science Foundation (SNF) [33CSCO_134274]; ABBOTT Switzerland FX The Swiss Inflammatory Bowel Disease Cohort Study group received (a) a grant from the Swiss National Science Foundation (SNF) [Grant No. 33CSCO_134274] and (b) an unrestricted educational grant from ABBOTT Switzerland. NR 19 TC 8 Z9 8 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-691X J9 EUR J GASTROEN HEPAT JI Eur. J. Gastroenterol. Hepatol. PD JUL PY 2013 VL 25 IS 7 BP 790 EP 797 DI 10.1097/MEG.0b013e32836019b9 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 202LA UT WOS:000323216000006 PM 23571609 ER PT J AU Tyson, GL Richardson, PA White, DL Kuzniarek, J Ramsey, DJ Tavakoli-Tabasi, S El-Serag, HB AF Tyson, Gia L. Richardson, Peter A. White, Donna L. Kuzniarek, Jill Ramsey, David J. Tavakoli-Tabasi, Shahriar El-Serag, Hashem B. TI Dietary Fructose Intake and Severity of Liver Disease in Hepatitis C Virus-infected Patients SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE sugar; viral hepatitis; epidemiology; nutrition ID BIOCHEMICAL MARKERS; COMBINATION THERAPY; INSULIN-RESISTANCE; CORN SYRUP; FIBROSIS; STEATOSIS; CONSUMPTION; VALIDATION; PEGINTERFERON AB Background and Goals: Dietary fructose intake in the United States has been increasing, and fructose intake has been associated with the metabolic syndrome and hepatic steatosis. This study aimed to determine whether dietary fructose intake is associated with advanced hepatic fibrosis and inflammation in an hepatitis C virus (HCV)-infected male population. Study: We conducted a cross-sectional study of HCV-infected male veterans. The main exposure variable was daily dietary fructose calculated from the National Cancer Institute Diet History Questionnaire and the main outcome variables were FibroSURE-ActiTest determined hepatic fibrosis (F0-F3=mild vs. F3/F4-F4=advanced) and inflammation (A0-A2=mild vs. A2/A3-A3=advanced). We examined this association in logistic regression adjusting for demographic, clinical, and other dietary variables. Results: Among 313 HCV+ males, 103 (33%) had advanced fibrosis and 89 (28%) had advanced inflammation. Median daily fructose intake was 46.8 g (interquartile range, 30.4 to 81.0). Dietary fructose intake across quartiles among males with advanced versus mild fibrosis was 21.4% versus 25.2%, 32.0% versus 24.8%, 24.3% versus 25.2%, and 22.3% versus 24.8%, respectively, and among males with advanced versus mild inflammation was 20.2% versus 25.5%, 41.6% versus 21.4%, 22.5% versus 25.9%, and 15.7% versus 27.2%, respectively. In multivariate analysis, there were no significant associations between daily fructose intake and advanced fibrosis. There was a significant association only between the second quartile of daily fructose intake (30 to 48 g) and advanced inflammation. Conclusions: There were no significant associations between dietary fructose intake and hepatic fibrosis risk, as assessed by FibroSURE, in HCV-infected males. Additional research is needed to clarify the potential role of fructose intake and HCV-related hepatic inflammation. C1 [Tyson, Gia L.; Richardson, Peter A.; White, Donna L.; Kuzniarek, Jill; Ramsey, David J.; El-Serag, Hashem B.] Michael E DeBakey VA Med Ctr, Houston VA Hlth Serv Res & Dev Ctr Excellence, Houston, TX USA. [Tavakoli-Tabasi, Shahriar] Baylor Coll Med, Infect Dis Sect, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Tyson, Gia L.; White, Donna L.; El-Serag, Hashem B.] Baylor Coll Med, Gastroenterol Sect, Houston, TX 77030 USA. [Tyson, Gia L.; White, Donna L.; El-Serag, Hashem B.] Baylor Coll Med, Sect Hepatol, Houston, TX 77030 USA. [Tyson, Gia L.; Richardson, Peter A.; White, Donna L.; Kuzniarek, Jill; Ramsey, David J.; El-Serag, Hashem B.] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Tyson, GL (reprint author), 2450 Holcombe Blvd,Suite 01Y, Houston, TX 77021 USA. EM giatyson@hotmail.com FU VA Clinical Research and Development Merit Review Award [H-22934, T32 DK083266-01A1]; National Institute of Diabetes Digestive and Kidney Diseases [DK081736-01, DK078154-03]; Houston Veterans Affairs Health Services Research and Development Center of Excellence [HFP90-020] FX Supported partly by VA Clinical Research and Development Merit Review Award H-22934, T32 DK083266-01A1, the National Institute of Diabetes Digestive and Kidney Diseases DK081736-01 and DK078154-03, and the Houston Veterans Affairs Health Services Research and Development Center of Excellence HFP90-020. NR 26 TC 1 Z9 1 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD JUL PY 2013 VL 47 IS 6 BP 545 EP 552 DI 10.1097/MCG.0b013e31827244d9 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 202LM UT WOS:000323217700016 PM 23426443 ER PT J AU Jacoby, SD Smith, A AF Jacoby, Susan D. Smith, Amy TI Increasing Certified Nurse-Midwives' Confidence in Managing the Obstetric Care of Women with Female Genital Mutilation/Cutting SO JOURNAL OF MIDWIFERY & WOMENS HEALTH LA English DT Article DE female genital mutilation; cutting; female circumcision; midwives; simulated learning; cultural; infibulation; deinfibulation ID SOMALI WOMEN; EXPERIENCES; GUIDELINES AB Introduction: In response to an increase in the number of women who immigrate to the United States from countries that practice female genital mutilation/cutting (FGM/C; infibulation), US clinicians can expand their knowledge and increase confidence in caring for women who have experienced infibulation. This article describes a comprehensive education program on FGM/C and the results of a pilot study that examined its effect on midwives' confidence in caring for women with infibulation. Methods: An education program was developed that included didactic information, case studies, a cultural roundtable, and a hands-on skills laboratory of deinfibulation and repair. Eleven certified nurse-midwives (CNMs) participated in this pilot study. Participants completed ameasureof- confidence survey tool before and after the education intervention. Results: Participants reported increased confidence in their ability to provide culturally competent care to immigrant women with infibulation when comparisons of preeducation and posteducation survey confidence logs were completed. Discussion: Following the education programand the knowledge gained fromit, thesemidwivesweremore confident about their ability to perform anterior episiotomy and to deliver necessary care to women with FGM/C in a culturally competent context. This education program should be expanded as more women who have experienced infibulation immigrate to the United States. C1 [Jacoby, Susan D.] Mt Royal Univ, Calgary, AB T3E 6K6, Canada. [Smith, Amy] Boston Coll, Connell Sch Nursing, Chestnut Hill, MA 02167 USA. [Smith, Amy] Massachusetts Gen Hosp, Vincent OB Midwifery Serv, Boston, MA 02114 USA. RP Jacoby, SD (reprint author), Mt Royal Univ, 4825 Mt Royal Gate SW, Calgary, AB T3E 6K6, Canada. EM sjacoby@mtroyal.ca NR 23 TC 9 Z9 9 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-9523 J9 J MIDWIFERY WOM HEAL JI J. Midwifery Women Health PD JUL PY 2013 VL 58 IS 4 BP 451 EP 456 DI 10.1111/j.1542-2011.2012.00262.x PG 6 WC Nursing SC Nursing GA 202FZ UT WOS:000323200700013 PM 23931662 ER EF